WHAT IS SKIN CANCER?
Skin cancer is a disease in which malignant (cancer) cells form in the tissues of the skin.
The skin is the body’s largest organ. It protects against heat, sunlight, injury, and infection. Skin also helps control body temperature and stores water, fat, and vitamin D. The skin has several layers, but the two main layers are the epidermis (upper or outer layer) and the dermis (lower or inner layer). Skin cancer begins in the epidermis, which is made up of 3 kinds of cells:
Squamous cells: Thin, flat cells that form the top layer of the epidermis.
Basal cells: Round cells under the squamous cells.
Melanocytes: Found in the lower part of the epidermis, these cells make melanin, the pigment that gives skin its natural color. When skin is exposed to the sun, melanocytes make more pigment, causing the skin to tan, or darken.
Skin cancer can occur anywhere on the body, but it is most common in skin that has been exposed to sunlight, such as the face, neck, hands, and arms. There are several types of cancer that start in the skin. The most common types are basal cell carcinoma and squamous cell carcinoma, which are nonmelanoma skin cancers. Actinic keratosis is a skin condition that sometimes develops into squamous cell carcinoma.
WHAT ARE THE RISK FACTORS OF SKIN CANCER?
Skin color and exposure to sunlight can affect the risk of developing nonmelanoma skin cancer and actinic keratosis.
Risk factors for basal cell carcinoma and squamous cell carcinoma include the following:
Being exposed to a lot of natural or artificial sunlight.
Having a fair complexion (blond or red hair, fair skin, green or blue eyes, history of freckling).
Having scars or burns on the skin.
Being exposed to arsenic.
Having chronic skin inflammation or skin ulcers.
Being treated with radiation.
Taking immunosuppressive drugs (for example, after an organ transplant).
Having actinic keratosis.
Risk factors for actinic keratosis include the following:
Being exposed to a lot of sunlight.
Having a fair complexion (blond or red hair, fair skin, green or blue eyes, history of freckling).
HOW TO DETECT SKIN CANCER?
Nonmelanoma skin cancer and actinic keratosis often appear as a change in the skin.
Not all changes in the skin are a sign of nonmelanoma skin cancer or actinic keratosis, but a doctor should be consulted if changes in the skin are seen.
Possible signs of nonmelanoma skin cancer include the following:
A sore that does not heal.
Areas of the skin that are:
Small, raised, smooth, shiny, and waxy.
Small, raised, and red or reddish-brown.
Flat, rough, red or brown, and scaly.
Scaly, bleeding, or crusty.
Similar to a scar and firm.
Possible signs of actinic keratosis include the following:
A rough, red, pink, or brown, raised, scaly patch on the skin.
Cracking or peeling of the lower lip that is not helped by lip balm or petroleum jelly.
Tests or procedures that examine the skin are used to detect (find) and diagnose nonmelanoma skin cancer and actinic keratosis.
The following procedures may be used:
Skin examination: A doctor or nurse checks the skin for bumps or spots that look abnormal in color, size, shape, or texture.
Biopsy: All or part of the abnormal-looking growth is cut from the skin and viewed under a microscope to see if cancer cells are present. There are 3 main types of skin biopsies:
Shave biopsy: A sterile razor blade is used to “shave-off” the abnormal-looking growth.
Punch biopsy: A special instrument called a punch or a trephine is used to remove a circle of tissue from the abnormal-looking growth.
Excisional biopsy: A scalpel is used to remove the entire growth.
Stages of Skin Cancer
The following stages are used for nonmelanoma skin cancer:
Stage 0 (Carcinoma in Situ)
In stage 0, cancer is found only in the epidermis (topmost layer of the skin), in the layer of cells in which the cancer began. Stage 0 cancer is also called carcinoma in situ.
Stage I: the tumor is 2 centimeters or smaller.
Stage II: the tumor is larger than 2 centimeters.
Stage III: cancer has spread below the skin to cartilage, muscle, or bone and/or to nearby lymph nodes, but not to other parts of the body.
Stage IV: cancer has spread to other places in the body.
HOW TO TREAT SKIN CANCER?
Treatment choices are based on the type of nonmelanoma skin cancer or precancerous skin condition diagnosed:
Basal cell carcinoma
Basal cell carcinoma is the most common type of skin cancer. It usually occurs on areas of the skin that have been in the sun, most often on the nose. Often this cancer appears as a small raised bump that has a smooth, pearly appearance. Another type looks like a scar and is flat and firm to the touch. Basal cell carcinoma may spread to tissues around the cancer, but it usually does not spread to other parts of the body.
Squamous cell carcinoma
Squamous cell carcinoma occurs on areas of the skin that have been in the sun, such as the ears, lower lip, and the back of the hands. Squamous cell carcinoma may also appear on areas of the skin that have been burned or exposed to chemicals or radiation. Often this cancer appears as a firm red bump. Sometimes the tumor may feel scaly or bleed or develop a crust. Squamous cell tumors may spread to nearby lymph nodes.
Actinic keratosis
Actinic keratosis is a skin condition that is not cancer, but sometimes changes into squamous cell carcinoma. It usually occurs in areas that have been exposed to the sun, such as the face, the back of the hands, and the lower lip. It appears as rough, red, pink, or brown, raised, scaly patches on the skin, or cracking or peeling of the lower lip that is not helped by lip balm or petroleum jelly.
Four types of standard treatment are used
Surgery
One or more of the following surgical procedures may be used to treat nonmelanoma skin cancer or actinic keratosis:
Mohs micrographic surgery: The tumor is cut from the skin in thin layers. During surgery, the edges of the tumor and each layer of tumor removed are viewed through a microscope to check for cancer cells. Layers continue to be removed until no more cancer cells are seen. This type of surgery removes as little normal tissue as possible and is often used to remove skin cancer on the face.
Simple excision: The tumor is cut from the skin along with some of the normal skin around it.
Shave excision: The abnormal area is shaved off the surface of the skin with a small blade.
Electrodesiccation and curettage: The tumor is cut from the skin with a curette (a sharp, spoon-shaped tool). A needle-shaped electrode is then used to treat the area with an electric current that stops the bleeding and destroys cancer cells that remain around the edge of the wound. The process may be repeated one to three times during the surgery to remove all of the cancer.
Cryosurgery: A treatment that uses an instrument to freeze and destroy abnormaltissue, such as carcinoma in situ. This type of treatment is also called cryotherapy.
Laser surgery: A surgical procedure that uses a laser beam (a narrow beam of intense light) as a knife to make bloodless cuts in tissue or to remove a surface lesion such as a tumor.
Dermabrasion: Removal of the top layer of skin using a rotating wheel or small particles to rub away skin cells.
Radiation therapy
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.
Chemotherapy
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Chemotherapy for nonmelanoma skin cancer and actinic keratosis is usually topical (applied to the skin in a cream or lotion). The way the chemotherapy is given depends on the condition being treated.
Retinoids (drugs related to vitamin A) are sometimes used to treat or prevent nonmelanoma skin cancer. The retinoids may be taken by mouth or applied to the skin. The use of retinoids is being studied in clinical trials for treatment and prevention of actinic keratosis.
Photodynamic therapy
Photodynamic therapy (PDT) is a cancer treatment that uses a drug and a certain type of laser light to kill cancer cells. A drug that is not active until it is exposed to light is injected into a vein. The drug collects more in cancer cells than in normal cells. Fiberoptic tubes are then used to deliver the laser light to the cancer cells, where the drug becomes active and kills the cells. Photodynamic therapy causes little damage to healthy tissue. It is used mainly to treat tumors on or just under the skin or in the lining of internal organs, such as the lungs and the esophagus.
Biologic therapy
Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against disease. This type of cancer treatment is also called biotherapy or immunotherapy, which is also used to lessen side effects that may be caused by some cancer treatments.
HOW TO DETECT PROGNOSIS SKIN CANCER?
Certain factors affect prognosis (chance of recovery) and treatment options.
The prognosis (chance of recovery) depends mostly on the stage of the cancer and the type of treatment used to remove the cancer.
Treatment options depend on the following:
The stage of the cancer (whether it has spread deeper into the skin or to other places in the body).
The type of cancer.
The size and location of the tumor.
The patient’s general health.
2009年1月10日星期六
RENAL CELL CARCINOMA
WHAT IS RENAL CELL CARCINOMA?
Renal cell cancer is a disease in which malignant (cancer) cells form in tubules of the kidney.
Renal cell cancer (also called kidney cancer or renal adenocarcinoma) is a disease in which malignant (cancer) cells are found in the lining of tubules (very small tubes) in the kidney. There are 2 kidneys, one on each side of the backbone, above the waist. The tiny tubules in the kidneys filter and clean the blood, taking out waste products and making urine. The urine passes from each kidney into the bladder through a long tube called a ureter. The bladder stores the urine until it is passed from the body.
The incidence of renal cell carcinoma is 31,200 cases per year, representing 2–3% of new cancers. Men are affected approximately twice as often as are women, and the mean age at diagnosis is approximately 60 years. Some 4,500 patients died of renal cancer in 1998.
WHAT ARE ETIOLOGIC FACTORS OF RENAL CANCER?
Little is known about the causes of renal cancer. Risk factors that have been proved or implicated include:
Smoking, obesity, analgesic abuse, and occupational exposure to cadmium or aromatic hydrocarbons.
Approximately 1% of renal cancers cluster in families, most of whose members have abnormalities on the short arm of chromosome 3 and on the p53 gene on chromosome 17. Features suggestive of familial renal cell cancer include a history of two or more first-degree relatives with the same cancer, multicentric cancer, bilateral cancer, and early-onset cancer.
Patients with acquired renal cystic disease are nearly 100 times more likely to develop renal cell carcinoma than is the general population, and the risk is particularly high in men who have large kidneys and are receiving hemodialysis.
More than 80% of patients with von Hippel-Lindau (VHL) disease have an inactivated VHL gene (chromosome 3p25), and renal cancer is the most common cause of death.
HOW TO DETECT RENAL CANCER?
Early Detection
Screening may be useful in high-risk patients, such as those with VHL disease, dialysis-dependent acquired renal cystic disease, autosomal dominant polycystic kidney disease, tuberous sclerosis, familial renal cell cancer, and symptoms suggestive of cancer. Genetic counseling also is indicated for many of the individuals in these groups.
Possible signs of renal cell cancer include blood in the urine and a lump in the abdomen.
These and other symptoms may be caused by renal cell cancer or by other conditions. There may be no symptoms in the early stages. Symptoms may appear as the tumor grows. A doctor should be consulted if any of the following problems occur:
Blood in the urine.
A lump in the abdomen.
A pain in the side that doesn't go away.
Loss of appetite.
Weight loss for no known reason.
Anemia.
Tests that examine the abdomen and kidneys are used to detect (find) and diagnose renal cell cancer.
The following tests and procedures may be used:
Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that produces it.
Urinalysis: A test to check the color of urine and its contents, such as sugar, protein, blood, and bacteria.
Liver function test: A procedure in which a sample of blood is checked to measure the amounts of enzymes released into it by the liver. An abnormal amount of an enzyme can be a sign that cancer has spread to the liver. Certain conditions that are not cancer may also increase liver enzyme levels.
Intravenous pyelogram (IVP): A series of x-rays of the kidneys, ureters, and bladder to find out if cancer is present in these organs. A contrast dye is injected into a vein. As the contrast dye moves through the kidneys, ureters, and bladder, x-rays are taken to see if there are any blockages.
Case 1. Small left renal cell carcinoma is subtle on this intravenous urographic image Case 1. Small renal cell carcinoma. Tomogram
Case 1. Small renal cell carcinoma. Contrast-enhanced CT scan
Ultrasound: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.
Case 2. Large renal cell carcinoma. Delayed tomogram Case 2. Large renal cell carcinoma. Sonogram
Case 2. Large renal cell carcinoma. Contrast-enhanced CT scan
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
Renal cell carcinoma. Computed tomography demonstrates a large infiltrating mass in the right kidney, extending into the right renal vein
MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
Case 3. Left renal cell carcinoma in patient who underwent prior right nephrectomy for renal cell carcinoma. T1-weighted axial MRI Case 3. Left renal cell carcinoma in patient with prior right nephrectomy for renal cell carcinoma. T2-weighted axial MRI with renal vein invasion and extension of tumor into the inferior vena cava
Case 3. Left renal cell carcinoma in patient with prior right nephrectomy for renal cell carcinoma. Tumor extends into the intrahepatic inferior vena cava
Biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer. A thin needle is inserted into the tumor and a sample of tissue is withdrawn. A pathologist then views the tissue under a microscope to check for cancer cells.
The histologic classification was based chiefly on light-microscopical tumor appearance but is consistent with the prevailing genetic understanding of tumors.
Conventional (clear-cell) renal carcinoma is the most common cancer of the renal cortex, accounting for approximately 70% of cases.
Papillary renal cell carcinoma accounts for approximately 15% of renal cell cancers.
Papillary renal cell carcinoma. The well-differentiated neoplastic cells cover delicate stalks of benign fibrovascular tissue
Chromophobe renal carcinoma accounts for 5% or so of cases of renal cell carcinoma.
Collecting-duct carcinoma is a rare renal cell carcinoma, representing fewer than 1% of cases.
Staging
The staging system for renal cell cancer is based on the degree of tumor spread beyond the kidney. Involvement of blood vessels may not be a poor prognostic sign if the tumor is otherwise confined to the substance of the kidney. Abnormal liver function test results may be due to a paraneoplastic syndrome that is reversible with tumor removal and do not necessarily represent metastatic disease. Except when computed tomography (CT) examination is equivocal or when iodinated contrast material is contraindicated, CT scanning is as good as or better than magnetic resonance imaging (MRI) for detecting renal masses.
The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.
HOW TO TREAT RENAL CELL CANCER?
TRADITIONAL TREATMENT
Surgery
Surgery is the preferred treatment for resectable renal cancer .Radical nephrectomy consists of removal of the kidney, perinephric fat, Gerota’s capsule, and lymph nodes and is useful for localized cancer and for palliation of intractable bleeding and pain. Most surgeons prefer an open approach to nephrectomy, but several investigators have advocated laparoscopic nephrectomy for cancers measuring less than 6 cm in diameter. Partial nephrectomy, also known as nephron-sparing surgery, is increasingly popular, owing to improved surgical methods and outcome. Partial nephrectomy is adequate treatment for small localized cancer and also offers some value for bilateral synchronous cancer, cancer in a functionally or anatomically solitary kidney, cancer in a patient with compromised renal function, and cancer in a patient with VHL disease. Bench surgery is a variation of partial nephrectomy and consists of removal of the kidney, resection of the tumor or tumors, and autotransplantation of the residual kidney.
Cancer-specific survival after nephrectomy varies by stage and grade. Five-year survival rates are 60–80%, 50–80%, 15–35%, and less than 15% for stages I, II, III, and IV, respectively. Solitary metastases also are cured occasionally by resection, especially in such soft tissues as the lung. Venous invasion can be treated successfully with surgery in some cases; five-year cancerspecific survival rates were 50–60% and 3–50% for renal vein and vena caval involvement, respectively.
Embolectomy may be useful for management of disease in some patients, despite massive pulmonary involvement.
Chemotherapy
Adjuvant chemotherapy or radiation have not been shown to prevent or decrease relapse rates. A review of 155 trials including 80 single agents showed a median response rate of only 4%.The overall response rates for vinblastine, and 5-FU or FUDR were 6% to 9%,and 5% to 8%,respectively. A trial combining gemcitabine with infusional 5-FU reported a 17% response rate.
Radiotherapy
The propensity for irradiation nephritis precludes routine use of radiotherapy for primary treatment of renal cancer. Sometimes, postoperative irradiation is used and may be useful for patients with residual local cancer, extension of cancer into perinephric fat, regional lymph node involvement, renal vein invasion, and cancer spillage or transection during surgery. It is used also after surgical excision of metastases. Palliative radiotherapy for metastatic renal cancer is particularly effective for bone pain, with a response rate of up to 86%
NOVAL THERAPIES
Immunotherapy
Biological therapy or immunotherapy that exploits the host immune system has generated considerable interest in recent years, owing to preliminary favorable results with cytokines for patients with metastatic renal cancer. The results with interferon-α now are considered generally modest, and this agent as monotherapy has little long-term efficacy for treatment of metastases. Interleukin-2 augments natural killer cell function, and monotherapy has resulted in complete or partial responses in up to 70% of patients; however, severe renal, cardiopulmonary, and other toxicities are limiting.
Combination therapy consisting of interleukin-2 and tumor-infiltrating lymphocytes or interferon-α has provided promising results, and trials continue to optimize this therapy. Autolymphocyte therapy, consisting of reinfusing autologous lymphocytes after activation in culture and irradiation to inactivate suppressor T lymphocytes, has shown definitive responses in previously refractory disease .
The future of immunotherapy rests on cancer vaccines, gene therapy, and adoptive immunotherapy. Approaches under investigation include combinations of cytokine therapy, use of new cytokines, combinations of cytokine modulation and autologous cancer vaccination, and use of genetically engineered cancer cells to augment endogenous immune system responses. Activation of cytotoxic T lymphocytes may be the common mechanism of action of many of these disparate treatments, including gene therapy. Adoptive immunotherapy that exploits dendritic cells as effectors is actively being investigated.
Interleukin-2(IL-2)therapy
High-dose regimen: High-dose IL-2 is only agent approved by FDA, U.S. for treatment of metastatic RCC. A group of patients treated with high-dose IL-2 showed durable response, being CR of 7%,PR of 8%,with a median response duration of 54 months for all responses. The schedule is
IL-2 600 000 to 720 000 U/kg i.v. infused over 15 minutes every 8 hours until toxicity or 14 doses for 5 days. Repeat the cycle once after a 7-to 10-day rest, with one or two additional courses repeated every 6 to 12 weeks if there is evidence of tumor stabilization or regression.
Low dose(i.v.) regimen:72 000 U/kg i.v. bolus every 8 hours to a maximum of 15 doses every 7 to 10 days for two cycles(one course),with an additional course if there is evidence of tumor stabilization or regression. One or two additional courses may be given if further regression is observed.
Low dose(SQ) regimen: First 5-day cycle:18 million U/day s.c., for 5 days(week 1).Subsequent 5-day cycles:9 million U/day s.c., for 2 days, and then 18 million U/day s.c.,3 days/week(weeks 2 through 6).
Interferon-atherapy
Interferon-a(IFN-a)can produce response rates of 12% to 15% for RCC patients; complete response (2% to 5%) are generally observed in patients with lung metastases .Usual regimen is 5 million to 10 million U/m2 s.c., three to five times per week, or daily.
Interleukin-2 (IL-2) plus Interferon-atherapy
Some trials reported response rates and overall survival of combination similar or superior to that of high dose IL-2 alone.
IL-2 20 million U/m2 s.c., days 3 to 5,weeks 1 and 4;5 million U/m2 s.c., days 1,3,and 5,weeks 2,3,5,and 6.
IFN-a:6 million U/m2 s.c., day 1,weeks 1 and 4;6 million U/m2 s.c., days 1,3,and 5,weeks 2,3,5 and 6.Repeat cycle every 8 weeks.
Hormonal Therapy
Progesterone has been used for treatment of metastatic cancer. However, its efficacy has not been proved.
Percutaneous mini-invasional ablation
Cryoablation and radiofrequency ablation may be used for unresectable cancer of kidneys and matastatic masses in other organs such as liver and lungs.
Renal cell cancer is a disease in which malignant (cancer) cells form in tubules of the kidney.
Renal cell cancer (also called kidney cancer or renal adenocarcinoma) is a disease in which malignant (cancer) cells are found in the lining of tubules (very small tubes) in the kidney. There are 2 kidneys, one on each side of the backbone, above the waist. The tiny tubules in the kidneys filter and clean the blood, taking out waste products and making urine. The urine passes from each kidney into the bladder through a long tube called a ureter. The bladder stores the urine until it is passed from the body.
The incidence of renal cell carcinoma is 31,200 cases per year, representing 2–3% of new cancers. Men are affected approximately twice as often as are women, and the mean age at diagnosis is approximately 60 years. Some 4,500 patients died of renal cancer in 1998.
WHAT ARE ETIOLOGIC FACTORS OF RENAL CANCER?
Little is known about the causes of renal cancer. Risk factors that have been proved or implicated include:
Smoking, obesity, analgesic abuse, and occupational exposure to cadmium or aromatic hydrocarbons.
Approximately 1% of renal cancers cluster in families, most of whose members have abnormalities on the short arm of chromosome 3 and on the p53 gene on chromosome 17. Features suggestive of familial renal cell cancer include a history of two or more first-degree relatives with the same cancer, multicentric cancer, bilateral cancer, and early-onset cancer.
Patients with acquired renal cystic disease are nearly 100 times more likely to develop renal cell carcinoma than is the general population, and the risk is particularly high in men who have large kidneys and are receiving hemodialysis.
More than 80% of patients with von Hippel-Lindau (VHL) disease have an inactivated VHL gene (chromosome 3p25), and renal cancer is the most common cause of death.
HOW TO DETECT RENAL CANCER?
Early Detection
Screening may be useful in high-risk patients, such as those with VHL disease, dialysis-dependent acquired renal cystic disease, autosomal dominant polycystic kidney disease, tuberous sclerosis, familial renal cell cancer, and symptoms suggestive of cancer. Genetic counseling also is indicated for many of the individuals in these groups.
Possible signs of renal cell cancer include blood in the urine and a lump in the abdomen.
These and other symptoms may be caused by renal cell cancer or by other conditions. There may be no symptoms in the early stages. Symptoms may appear as the tumor grows. A doctor should be consulted if any of the following problems occur:
Blood in the urine.
A lump in the abdomen.
A pain in the side that doesn't go away.
Loss of appetite.
Weight loss for no known reason.
Anemia.
Tests that examine the abdomen and kidneys are used to detect (find) and diagnose renal cell cancer.
The following tests and procedures may be used:
Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that produces it.
Urinalysis: A test to check the color of urine and its contents, such as sugar, protein, blood, and bacteria.
Liver function test: A procedure in which a sample of blood is checked to measure the amounts of enzymes released into it by the liver. An abnormal amount of an enzyme can be a sign that cancer has spread to the liver. Certain conditions that are not cancer may also increase liver enzyme levels.
Intravenous pyelogram (IVP): A series of x-rays of the kidneys, ureters, and bladder to find out if cancer is present in these organs. A contrast dye is injected into a vein. As the contrast dye moves through the kidneys, ureters, and bladder, x-rays are taken to see if there are any blockages.
Case 1. Small left renal cell carcinoma is subtle on this intravenous urographic image Case 1. Small renal cell carcinoma. Tomogram
Case 1. Small renal cell carcinoma. Contrast-enhanced CT scan
Ultrasound: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.
Case 2. Large renal cell carcinoma. Delayed tomogram Case 2. Large renal cell carcinoma. Sonogram
Case 2. Large renal cell carcinoma. Contrast-enhanced CT scan
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
Renal cell carcinoma. Computed tomography demonstrates a large infiltrating mass in the right kidney, extending into the right renal vein
MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
Case 3. Left renal cell carcinoma in patient who underwent prior right nephrectomy for renal cell carcinoma. T1-weighted axial MRI Case 3. Left renal cell carcinoma in patient with prior right nephrectomy for renal cell carcinoma. T2-weighted axial MRI with renal vein invasion and extension of tumor into the inferior vena cava
Case 3. Left renal cell carcinoma in patient with prior right nephrectomy for renal cell carcinoma. Tumor extends into the intrahepatic inferior vena cava
Biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer. A thin needle is inserted into the tumor and a sample of tissue is withdrawn. A pathologist then views the tissue under a microscope to check for cancer cells.
The histologic classification was based chiefly on light-microscopical tumor appearance but is consistent with the prevailing genetic understanding of tumors.
Conventional (clear-cell) renal carcinoma is the most common cancer of the renal cortex, accounting for approximately 70% of cases.
Papillary renal cell carcinoma accounts for approximately 15% of renal cell cancers.
Papillary renal cell carcinoma. The well-differentiated neoplastic cells cover delicate stalks of benign fibrovascular tissue
Chromophobe renal carcinoma accounts for 5% or so of cases of renal cell carcinoma.
Collecting-duct carcinoma is a rare renal cell carcinoma, representing fewer than 1% of cases.
Staging
The staging system for renal cell cancer is based on the degree of tumor spread beyond the kidney. Involvement of blood vessels may not be a poor prognostic sign if the tumor is otherwise confined to the substance of the kidney. Abnormal liver function test results may be due to a paraneoplastic syndrome that is reversible with tumor removal and do not necessarily represent metastatic disease. Except when computed tomography (CT) examination is equivocal or when iodinated contrast material is contraindicated, CT scanning is as good as or better than magnetic resonance imaging (MRI) for detecting renal masses.
The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.
HOW TO TREAT RENAL CELL CANCER?
TRADITIONAL TREATMENT
Surgery
Surgery is the preferred treatment for resectable renal cancer .Radical nephrectomy consists of removal of the kidney, perinephric fat, Gerota’s capsule, and lymph nodes and is useful for localized cancer and for palliation of intractable bleeding and pain. Most surgeons prefer an open approach to nephrectomy, but several investigators have advocated laparoscopic nephrectomy for cancers measuring less than 6 cm in diameter. Partial nephrectomy, also known as nephron-sparing surgery, is increasingly popular, owing to improved surgical methods and outcome. Partial nephrectomy is adequate treatment for small localized cancer and also offers some value for bilateral synchronous cancer, cancer in a functionally or anatomically solitary kidney, cancer in a patient with compromised renal function, and cancer in a patient with VHL disease. Bench surgery is a variation of partial nephrectomy and consists of removal of the kidney, resection of the tumor or tumors, and autotransplantation of the residual kidney.
Cancer-specific survival after nephrectomy varies by stage and grade. Five-year survival rates are 60–80%, 50–80%, 15–35%, and less than 15% for stages I, II, III, and IV, respectively. Solitary metastases also are cured occasionally by resection, especially in such soft tissues as the lung. Venous invasion can be treated successfully with surgery in some cases; five-year cancerspecific survival rates were 50–60% and 3–50% for renal vein and vena caval involvement, respectively.
Embolectomy may be useful for management of disease in some patients, despite massive pulmonary involvement.
Chemotherapy
Adjuvant chemotherapy or radiation have not been shown to prevent or decrease relapse rates. A review of 155 trials including 80 single agents showed a median response rate of only 4%.The overall response rates for vinblastine, and 5-FU or FUDR were 6% to 9%,and 5% to 8%,respectively. A trial combining gemcitabine with infusional 5-FU reported a 17% response rate.
Radiotherapy
The propensity for irradiation nephritis precludes routine use of radiotherapy for primary treatment of renal cancer. Sometimes, postoperative irradiation is used and may be useful for patients with residual local cancer, extension of cancer into perinephric fat, regional lymph node involvement, renal vein invasion, and cancer spillage or transection during surgery. It is used also after surgical excision of metastases. Palliative radiotherapy for metastatic renal cancer is particularly effective for bone pain, with a response rate of up to 86%
NOVAL THERAPIES
Immunotherapy
Biological therapy or immunotherapy that exploits the host immune system has generated considerable interest in recent years, owing to preliminary favorable results with cytokines for patients with metastatic renal cancer. The results with interferon-α now are considered generally modest, and this agent as monotherapy has little long-term efficacy for treatment of metastases. Interleukin-2 augments natural killer cell function, and monotherapy has resulted in complete or partial responses in up to 70% of patients; however, severe renal, cardiopulmonary, and other toxicities are limiting.
Combination therapy consisting of interleukin-2 and tumor-infiltrating lymphocytes or interferon-α has provided promising results, and trials continue to optimize this therapy. Autolymphocyte therapy, consisting of reinfusing autologous lymphocytes after activation in culture and irradiation to inactivate suppressor T lymphocytes, has shown definitive responses in previously refractory disease .
The future of immunotherapy rests on cancer vaccines, gene therapy, and adoptive immunotherapy. Approaches under investigation include combinations of cytokine therapy, use of new cytokines, combinations of cytokine modulation and autologous cancer vaccination, and use of genetically engineered cancer cells to augment endogenous immune system responses. Activation of cytotoxic T lymphocytes may be the common mechanism of action of many of these disparate treatments, including gene therapy. Adoptive immunotherapy that exploits dendritic cells as effectors is actively being investigated.
Interleukin-2(IL-2)therapy
High-dose regimen: High-dose IL-2 is only agent approved by FDA, U.S. for treatment of metastatic RCC. A group of patients treated with high-dose IL-2 showed durable response, being CR of 7%,PR of 8%,with a median response duration of 54 months for all responses. The schedule is
IL-2 600 000 to 720 000 U/kg i.v. infused over 15 minutes every 8 hours until toxicity or 14 doses for 5 days. Repeat the cycle once after a 7-to 10-day rest, with one or two additional courses repeated every 6 to 12 weeks if there is evidence of tumor stabilization or regression.
Low dose(i.v.) regimen:72 000 U/kg i.v. bolus every 8 hours to a maximum of 15 doses every 7 to 10 days for two cycles(one course),with an additional course if there is evidence of tumor stabilization or regression. One or two additional courses may be given if further regression is observed.
Low dose(SQ) regimen: First 5-day cycle:18 million U/day s.c., for 5 days(week 1).Subsequent 5-day cycles:9 million U/day s.c., for 2 days, and then 18 million U/day s.c.,3 days/week(weeks 2 through 6).
Interferon-atherapy
Interferon-a(IFN-a)can produce response rates of 12% to 15% for RCC patients; complete response (2% to 5%) are generally observed in patients with lung metastases .Usual regimen is 5 million to 10 million U/m2 s.c., three to five times per week, or daily.
Interleukin-2 (IL-2) plus Interferon-atherapy
Some trials reported response rates and overall survival of combination similar or superior to that of high dose IL-2 alone.
IL-2 20 million U/m2 s.c., days 3 to 5,weeks 1 and 4;5 million U/m2 s.c., days 1,3,and 5,weeks 2,3,5,and 6.
IFN-a:6 million U/m2 s.c., day 1,weeks 1 and 4;6 million U/m2 s.c., days 1,3,and 5,weeks 2,3,5 and 6.Repeat cycle every 8 weeks.
Hormonal Therapy
Progesterone has been used for treatment of metastatic cancer. However, its efficacy has not been proved.
Percutaneous mini-invasional ablation
Cryoablation and radiofrequency ablation may be used for unresectable cancer of kidneys and matastatic masses in other organs such as liver and lungs.
Rectal Cancer
Cancer of the rectum is a highly treatable and often curable disease when localized. Surgery is the primary treatment and results in cure in approximately 45% of all patients. The prognosis of rectal cancer is clearly related to the degree of penetration of the tumor through the bowel wall and the presence or absence of nodal involvement.
Following treatment of rectal cancer is listed based on stages.
HOW TO TREAT RECTAL CANCER?
Stage I Rectal Cancer
Because of its localized nature, stage I has a high cure rate.
Standard treatment options:
Wide surgical resection and anastomosis when an adequate low anterior resection (LAR) can be performed, with sufficient distal rectum to allow a conventional anastomosis or colo-anal anastomosis.
Wide surgical resection with abdominoperineal resection (APR) for lesions too distal to permit low anterior resection (LAR).
Local transanal or other resection with or without perioperative external-beam irradiation plus fluorouracil (5-FU). There are no randomized trials comparing local excision with or without postoperative chemoradiation treatments to wide surgical resection (LAR and APR). One prospective multicenter phase II study and several larger retrospective series suggest that well-staged patients with small (<4 centimeters) tumors with good histologic prognostic features (well- to moderately-differentiated adenocarcinomas), mobile, and no lymphatic, venous, or perineural invasion, treated with full-thickness local excision that results in negative margins may have outcomes equivalent to APR or LAR with the selective post-operative use chemoradiation therapy. Endoscopic ultrasound studies have been helpful in defining these patients. Patients with tumors that are pathologically T1 may not need postoperative therapy. Patients with tumors that are T2 or greater have lymph node involvement of 20% or more and require additional therapy, such as radiation and chemotherapy, or more standard surgical resection. Patients with poor histologic features should consider LAR or APR and postoperative treatment as dictated by full surgical staging. The selection of patients for local excision may also be improved by newer imaging techniques, such as endorectal magnetic resonance imaging and endorectal ultrasound.
Endocavitary, with or without external-beam, radiation in selected patients with tumors less than 3 centimeters in size, with well-differentiated tumors, and without deep ulceration, tumor fixation or palpable lymph nodes. Special equipment and experience are required to achieve results equivalent to surgery.
Stage II Rectal Cancer
The uterus, vagina, parametria, ovaries, or prostate are sometimes involved. Studies employing preoperative or postoperative radiation therapy alone have demonstrated decreased locoregional failure rates. Significant improvement in overall survival has not been demonstrated with radiation therapy alone except in a single trial of preoperative radiation therapy.
A randomized trial by the Gastrointestinal Tumor Study Group demonstrated an increase in both disease-free interval and overall survival when radiation therapy is combined with chemotherapy following surgical resection in patients whose rectal cancer has penetrated through the bowel wall into the perirectal fat (stage II) or has metastasized to regional lymph nodes (stage III). A disease-free survival advantage has been observed in patients with stage II and III rectal cancer treated with chemotherapy and radiation therapy compared to those treated with radiation therapy alone. An Intergroup trial has demonstrated a 10% improved survival with the use of continuous-infusion fluorouracil (5-FU) throughout the course of radiation therapy when compared with bolus 5-FU. This method of 5-FU administration should be considered standard. The final results of Intergroup trial 0114 showed no survival benefit with the addition of leucovorin, levamisole, or both, to 5-FU administered postoperatively at a median follow-up of 7.4 years. Clinical trials further addressing 5-FU modulation are underway, including the use of oral 5-FU prodrugs. The radiation should be delivered to high-dose levels (45-55 Gy) either preoperatively or postoperatively, with meticulous attention to technique. An analysis of patients treated with postoperative chemotherapy and radiation therapy suggests that these patients may have more chronic bowel dysfunction compared to those who undergo surgical resection alone. Improved radiation planning and techniques can be used to minimize treatment-related complications. These techniques include the use of multiple pelvic fields, prone positioning, customized bowel immobilization molds (belly boards), bladder distention, visualization of the small bowel through oral contrast, and the incorporation of three-dimensional or comparative treatment planning.
Standard treatment options:
Wide surgical resection and low anterior resection with colorectal or colo-anal reanastomosis when feasible, followed by chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.
Wide surgical resection with abdominoperineal resection with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.
Partial or total pelvic exenteration in the uncommon situation where bladder, uterus, vagina, or prostate are invaded, with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.
Preoperative radiation therapy with or without chemotherapy followed by surgery with an attempt to preserve sphincter function with subsequent adjuvant chemotherapy, preferably through participation in a clinical trial.
Intraoperative electron beam radiation therapy (IORT) to the sites of residual microscopic or gross residual disease following surgical extirpation can be considered at institutions where the appropriate equipment is available. When combined with external-beam radiation therapy and chemotherapy in highly selected patients, IORT with or without 5-FU has resulted in improved local control in single institution experiences.
Stage III Rectal Cancer
Stage III rectal cancer denotes disease with lymph node involvement. The number of positive lymph nodes affects prognosis: patients with 1 to 3 involved nodes have superior survival to those with 4 or more involved nodes. Studies employing preoperative or postoperative radiation therapy alone have demonstrated decreased locoregional failure rates. Significant improvement in overall survival has not been demonstrated with pre- or postoperative radiation therapy alone except in a single trial.
Standard treatment options:
Wide surgical resection and low anterior resection with colorectal or coloanal reanastomosis when feasible, followed by chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.
Wide surgical resection with abdominoperineal resection with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.
Partial or total pelvic exenteration in the uncommon situation where bladder, uterus, vagina, or prostate are invaded, with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.
Preoperative radiation therapy with or without chemotherapy followed by surgery with an attempt to preserve sphincter function with subsequent adjuvant chemotherapy, preferably through participation in a clinical trial.
Intraoperative electron beam radiation therapy (IORT) to the sites of residual microscopic or gross residual disease following surgical extirpation can be considered at institutions where the appropriate equipment is available. When combined with external-beam radiation therapy and chemotherapy in highly selected patients, IORT has resulted in improved local control in a single institution experience.
Palliative chemoradiation.
Stage IV Rectal Cancer
Stage IV rectal cancer denotes distant metastatic disease. Local regional approaches to treating liver metastases include hepatic resection and/or intraarterial administration of chemotherapy with implantable infusion ports or pumps. For patients with limited (3 or less) hepatic metastases, resection may be considered with 5-year survival rates of 20% to 40%. Other local ablative techniques that have been used to manage liver metastases include cryosurgery, embolization, and interstitial radiation therapy. For those patients with hepatic metastases deemed unresectable (due to such factors as location, distribution, and excess number), cryosurgical ablation has been associated with long term tumor control.
Standard treatment options:
Surgical resection/anastomosis or bypass of obstructing lesions in selected cases or resection for palliation.
Surgical resection of isolated metastases (liver, lung, ovaries).
Chemoradiation for local palliation.
Chemotherapy alone for distant disease after resection of local disease.
Clinical trials evaluating new drugs and biologic therapy.
Recurrent Rectal Cancer
Locally recurrent rectal cancer may be resectable, particularly if an inadequate prior operation was performed. For patients with local recurrence alone following initial attempted curative resection, aggressive local therapy with repeat low anterior resection and coloanal anastomosis, abdominoperineal resection, or posterior or total pelvic exenteration can lead to long-term disease-free survival. The use of induction chemoradiation for previously non-irradiated patients with locally advanced (pelvic side-wall, sacral, and/or adjacent organ involvement) pelvic recurrence may increase resectability and allow for sphincter preservation. Intraoperative radiation therapy in patients who received previous external beam radiation may improve local control in patients with locally recurrent disease with acceptable morbidity. The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent. Patients with limited pulmonary metastases and patients with both pulmonary and hepatic metastases, may also be considered for surgical resection, with 5-year survival possible in highly selected patients.
Standard treatment options:
Resection of locally recurrent rectal cancer may be palliative or curative in selected patients.
Resection of liver metastases in selected patients (5-year cure rate with resection of solitary metastases exceeds 20%).
Resection of isolated pulmonary or ovarian metastases.
Palliative radiation therapy.
Palliative chemotherapy.
Palliative chemoradiation.
Palliative endoscopic-placed stents to relieve obstruction.
HOW TO ESTIMATE PROGNOSIS OF RECTAL CANCER?
The prognosis of rectal cancer is clearly related to the degree of penetration of the tumor through the bowel wall and the presence or absence of nodal involvement. These 2 characteristics form the basis for all staging systems developed for this disease. Preoperative staging procedures include digital rectal examination, computed tomographic scan or magnetic resonance imaging scan of the abdomen and pelvis, endoscopic evaluation with biopsy, and endoscopic ultrasound (EUS).
EUS is an accurate method of evaluating tumor stage (up to 95% accuracy) and the status of the perirectal nodes (up to 74% accuracy). Accurate staging can influence therapy by helping to determine which patients may be candidates for local excision rather than more extensive surgery and which patients may be candidates for preoperative chemotherapy and radiation therapy to maximize the likelihood of resection with clear margins.
Many other prognostic markers have been evaluated retrospectively in the prognosis of patients with rectal cancer, although most, including allelic loss of chromosome 18q or thymidylate synthase expression, have not been prospectively validated.
Microsatellite instability, also associated with hereditary nonpolyposis rectal cancer, has been shown to be associated with improved survival independent of tumor stage in a population-based series of 607 patients less than 50 years of age with colorectal cancer.
Racial differences in overall survival after adjuvant therapy have been observed, without differences in disease-free survival, suggesting that comorbid conditions play a role in survival outcome in different patient populations.
A major limitation of surgery is the inability to obtain wide radial margins because of the presence of the bony pelvis. In those patients with disease penetration through the bowel wall and/or spread into lymph nodes at the time of diagnosis, local recurrence following surgery is a major problem and often ultimately results in death. The radial margin of resection of rectal primaries may also predict for local recurrence.
Following treatment of rectal cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease.
To date, there have been no large-scale randomized trials documenting the efficacy of a standard, postoperative monitoring program.Carcinoembryonic antigen (CEA) is a serum glycoprotein frequently used in the management of patients with rectal cancer. A review of the use of this tumor marker suggests: that CEA is not useful as a screening test; that postoperative CEA testing be restricted to patients who would be candidates for resection of liver or lung metastases; and that routine use of CEA alone for monitoring response to treatment not be recommended. However, the optimal regimen and frequency of follow-up examinations are not well defined, since the impact on patient survival is not clear and the quality of data is poor. New surveillance methods including CEA immunoscintigraphy and positron tomography are under clinical evaluation.
Although a large number of studies have evaluated various clinical, pathological, and molecular parameters with prognosis, as yet, none have had a major impact on prognosis or therapy. Clinical stage remains the most important prognostic indicator.
Following treatment of rectal cancer is listed based on stages.
HOW TO TREAT RECTAL CANCER?
Stage I Rectal Cancer
Because of its localized nature, stage I has a high cure rate.
Standard treatment options:
Wide surgical resection and anastomosis when an adequate low anterior resection (LAR) can be performed, with sufficient distal rectum to allow a conventional anastomosis or colo-anal anastomosis.
Wide surgical resection with abdominoperineal resection (APR) for lesions too distal to permit low anterior resection (LAR).
Local transanal or other resection with or without perioperative external-beam irradiation plus fluorouracil (5-FU). There are no randomized trials comparing local excision with or without postoperative chemoradiation treatments to wide surgical resection (LAR and APR). One prospective multicenter phase II study and several larger retrospective series suggest that well-staged patients with small (<4 centimeters) tumors with good histologic prognostic features (well- to moderately-differentiated adenocarcinomas), mobile, and no lymphatic, venous, or perineural invasion, treated with full-thickness local excision that results in negative margins may have outcomes equivalent to APR or LAR with the selective post-operative use chemoradiation therapy. Endoscopic ultrasound studies have been helpful in defining these patients. Patients with tumors that are pathologically T1 may not need postoperative therapy. Patients with tumors that are T2 or greater have lymph node involvement of 20% or more and require additional therapy, such as radiation and chemotherapy, or more standard surgical resection. Patients with poor histologic features should consider LAR or APR and postoperative treatment as dictated by full surgical staging. The selection of patients for local excision may also be improved by newer imaging techniques, such as endorectal magnetic resonance imaging and endorectal ultrasound.
Endocavitary, with or without external-beam, radiation in selected patients with tumors less than 3 centimeters in size, with well-differentiated tumors, and without deep ulceration, tumor fixation or palpable lymph nodes. Special equipment and experience are required to achieve results equivalent to surgery.
Stage II Rectal Cancer
The uterus, vagina, parametria, ovaries, or prostate are sometimes involved. Studies employing preoperative or postoperative radiation therapy alone have demonstrated decreased locoregional failure rates. Significant improvement in overall survival has not been demonstrated with radiation therapy alone except in a single trial of preoperative radiation therapy.
A randomized trial by the Gastrointestinal Tumor Study Group demonstrated an increase in both disease-free interval and overall survival when radiation therapy is combined with chemotherapy following surgical resection in patients whose rectal cancer has penetrated through the bowel wall into the perirectal fat (stage II) or has metastasized to regional lymph nodes (stage III). A disease-free survival advantage has been observed in patients with stage II and III rectal cancer treated with chemotherapy and radiation therapy compared to those treated with radiation therapy alone. An Intergroup trial has demonstrated a 10% improved survival with the use of continuous-infusion fluorouracil (5-FU) throughout the course of radiation therapy when compared with bolus 5-FU. This method of 5-FU administration should be considered standard. The final results of Intergroup trial 0114 showed no survival benefit with the addition of leucovorin, levamisole, or both, to 5-FU administered postoperatively at a median follow-up of 7.4 years. Clinical trials further addressing 5-FU modulation are underway, including the use of oral 5-FU prodrugs. The radiation should be delivered to high-dose levels (45-55 Gy) either preoperatively or postoperatively, with meticulous attention to technique. An analysis of patients treated with postoperative chemotherapy and radiation therapy suggests that these patients may have more chronic bowel dysfunction compared to those who undergo surgical resection alone. Improved radiation planning and techniques can be used to minimize treatment-related complications. These techniques include the use of multiple pelvic fields, prone positioning, customized bowel immobilization molds (belly boards), bladder distention, visualization of the small bowel through oral contrast, and the incorporation of three-dimensional or comparative treatment planning.
Standard treatment options:
Wide surgical resection and low anterior resection with colorectal or colo-anal reanastomosis when feasible, followed by chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.
Wide surgical resection with abdominoperineal resection with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.
Partial or total pelvic exenteration in the uncommon situation where bladder, uterus, vagina, or prostate are invaded, with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.
Preoperative radiation therapy with or without chemotherapy followed by surgery with an attempt to preserve sphincter function with subsequent adjuvant chemotherapy, preferably through participation in a clinical trial.
Intraoperative electron beam radiation therapy (IORT) to the sites of residual microscopic or gross residual disease following surgical extirpation can be considered at institutions where the appropriate equipment is available. When combined with external-beam radiation therapy and chemotherapy in highly selected patients, IORT with or without 5-FU has resulted in improved local control in single institution experiences.
Stage III Rectal Cancer
Stage III rectal cancer denotes disease with lymph node involvement. The number of positive lymph nodes affects prognosis: patients with 1 to 3 involved nodes have superior survival to those with 4 or more involved nodes. Studies employing preoperative or postoperative radiation therapy alone have demonstrated decreased locoregional failure rates. Significant improvement in overall survival has not been demonstrated with pre- or postoperative radiation therapy alone except in a single trial.
Standard treatment options:
Wide surgical resection and low anterior resection with colorectal or coloanal reanastomosis when feasible, followed by chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.
Wide surgical resection with abdominoperineal resection with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.
Partial or total pelvic exenteration in the uncommon situation where bladder, uterus, vagina, or prostate are invaded, with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.
Preoperative radiation therapy with or without chemotherapy followed by surgery with an attempt to preserve sphincter function with subsequent adjuvant chemotherapy, preferably through participation in a clinical trial.
Intraoperative electron beam radiation therapy (IORT) to the sites of residual microscopic or gross residual disease following surgical extirpation can be considered at institutions where the appropriate equipment is available. When combined with external-beam radiation therapy and chemotherapy in highly selected patients, IORT has resulted in improved local control in a single institution experience.
Palliative chemoradiation.
Stage IV Rectal Cancer
Stage IV rectal cancer denotes distant metastatic disease. Local regional approaches to treating liver metastases include hepatic resection and/or intraarterial administration of chemotherapy with implantable infusion ports or pumps. For patients with limited (3 or less) hepatic metastases, resection may be considered with 5-year survival rates of 20% to 40%. Other local ablative techniques that have been used to manage liver metastases include cryosurgery, embolization, and interstitial radiation therapy. For those patients with hepatic metastases deemed unresectable (due to such factors as location, distribution, and excess number), cryosurgical ablation has been associated with long term tumor control.
Standard treatment options:
Surgical resection/anastomosis or bypass of obstructing lesions in selected cases or resection for palliation.
Surgical resection of isolated metastases (liver, lung, ovaries).
Chemoradiation for local palliation.
Chemotherapy alone for distant disease after resection of local disease.
Clinical trials evaluating new drugs and biologic therapy.
Recurrent Rectal Cancer
Locally recurrent rectal cancer may be resectable, particularly if an inadequate prior operation was performed. For patients with local recurrence alone following initial attempted curative resection, aggressive local therapy with repeat low anterior resection and coloanal anastomosis, abdominoperineal resection, or posterior or total pelvic exenteration can lead to long-term disease-free survival. The use of induction chemoradiation for previously non-irradiated patients with locally advanced (pelvic side-wall, sacral, and/or adjacent organ involvement) pelvic recurrence may increase resectability and allow for sphincter preservation. Intraoperative radiation therapy in patients who received previous external beam radiation may improve local control in patients with locally recurrent disease with acceptable morbidity. The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent. Patients with limited pulmonary metastases and patients with both pulmonary and hepatic metastases, may also be considered for surgical resection, with 5-year survival possible in highly selected patients.
Standard treatment options:
Resection of locally recurrent rectal cancer may be palliative or curative in selected patients.
Resection of liver metastases in selected patients (5-year cure rate with resection of solitary metastases exceeds 20%).
Resection of isolated pulmonary or ovarian metastases.
Palliative radiation therapy.
Palliative chemotherapy.
Palliative chemoradiation.
Palliative endoscopic-placed stents to relieve obstruction.
HOW TO ESTIMATE PROGNOSIS OF RECTAL CANCER?
The prognosis of rectal cancer is clearly related to the degree of penetration of the tumor through the bowel wall and the presence or absence of nodal involvement. These 2 characteristics form the basis for all staging systems developed for this disease. Preoperative staging procedures include digital rectal examination, computed tomographic scan or magnetic resonance imaging scan of the abdomen and pelvis, endoscopic evaluation with biopsy, and endoscopic ultrasound (EUS).
EUS is an accurate method of evaluating tumor stage (up to 95% accuracy) and the status of the perirectal nodes (up to 74% accuracy). Accurate staging can influence therapy by helping to determine which patients may be candidates for local excision rather than more extensive surgery and which patients may be candidates for preoperative chemotherapy and radiation therapy to maximize the likelihood of resection with clear margins.
Many other prognostic markers have been evaluated retrospectively in the prognosis of patients with rectal cancer, although most, including allelic loss of chromosome 18q or thymidylate synthase expression, have not been prospectively validated.
Microsatellite instability, also associated with hereditary nonpolyposis rectal cancer, has been shown to be associated with improved survival independent of tumor stage in a population-based series of 607 patients less than 50 years of age with colorectal cancer.
Racial differences in overall survival after adjuvant therapy have been observed, without differences in disease-free survival, suggesting that comorbid conditions play a role in survival outcome in different patient populations.
A major limitation of surgery is the inability to obtain wide radial margins because of the presence of the bony pelvis. In those patients with disease penetration through the bowel wall and/or spread into lymph nodes at the time of diagnosis, local recurrence following surgery is a major problem and often ultimately results in death. The radial margin of resection of rectal primaries may also predict for local recurrence.
Following treatment of rectal cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease.
To date, there have been no large-scale randomized trials documenting the efficacy of a standard, postoperative monitoring program.Carcinoembryonic antigen (CEA) is a serum glycoprotein frequently used in the management of patients with rectal cancer. A review of the use of this tumor marker suggests: that CEA is not useful as a screening test; that postoperative CEA testing be restricted to patients who would be candidates for resection of liver or lung metastases; and that routine use of CEA alone for monitoring response to treatment not be recommended. However, the optimal regimen and frequency of follow-up examinations are not well defined, since the impact on patient survival is not clear and the quality of data is poor. New surveillance methods including CEA immunoscintigraphy and positron tomography are under clinical evaluation.
Although a large number of studies have evaluated various clinical, pathological, and molecular parameters with prognosis, as yet, none have had a major impact on prognosis or therapy. Clinical stage remains the most important prognostic indicator.
Prostate Cancer
WHAT IS THE PROSTATE CANCER?
Prostate cancer is a disease in which malignant (cancer) cells form in the tissues of the prostate.
The prostate is a gland in the male reproductive system located just below the bladder (the organ that collects and empties urine) and in front of the rectum (the lower part of the intestine). It is about the size of a walnut and surrounds part of the urethra (the tube that empties urine from the bladder). The prostate gland produces fluid that makes up part of the semen.
Carcinoma of the prostate is predominantly a tumor of older men, which frequently responds to treatment when widespread and may be cured when localized. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone. Because the median age at diagnosis is 72 years, many patients—especially those with localized tumors—may die of other illnesses without ever having suffered significant disability from their cancer. The approach to treatment is influenced by age and coexisting medical problems. Side effects of various forms of treatment should be considered in selecting appropriate management.
HOW TO DETECT PROSTATE CANCER?
Possible signs of prostate cancer include a weak flow of urine or frequent urination.
Prostate cancer should be suspected if any of the following problems occur:
Weak or interrupted flow of urine.
Frequent urination (especially at night).
Difficulty urinating.
Pain or burning during urination.
Blood in the urine or semen.
Nagging pain in the back, hips, or pelvis.
Painful ejaculation.
Tests listed as below are used to detect prostate cancer.
Digital rectal exam (DRE): An exam of the rectum may detect the prostate through the rectal wall for lumps or abnormal areas.
Prostate-specific antigen (PSA) test: PSA is a substance made by the prostate that may be found in an increased amount in the blood of men who have prostate cancer. PSA levels in the blood may also be high in men who have an infection or inflammation of the prostate or BPH (an enlarged, but noncancerous, prostate).
Transrectal ultrasound: Transrectal ultrasound may shows abnormal echo of cancer in prostate and may be used to take a biopsy.
Biopsy: The biopsy may be performed through transrectal or transperineal routes for pathological diagnosis of prostate cancer.The Gleason score ranges from 2-10 and describes how likely it is that a tumor will spread. The lower the number, the less likely the tumor is to spread.
HOW TO TREAT PROSTATE CANCER?
State-of-the-art treatment in prostate cancer provides prolonged disease-free survival for many patients with localized disease but is rarely curative in patients with locally extensive tumor. Even when the cancer appears clinically localized to the prostate gland, a substantial fraction of patients will develop disseminated tumor after local therapy with surgery or irradiation.
Stage I Prostate Cancer
Stage I prostate cancer is defined by American Joint Committee on Cancer (AJCC) TNM classification: T1a, N0, M0, G1 (Gleason 2-4).
The frequency of clinically silent, nonmetastatic prostate cancer that can be found at autopsy greatly increases with age and may be as high as 50% to 60% in men aged 90 years and older. Many stage I cancers are well-differentiated and only focally involve the gland (T1a, N0, M0); most require no treatment other than careful follow-up.
In younger patients (aged 50-60 years) whose expected survival is long, treatment should be considered. Less-differentiated cancers that involve more than a few pieces of resected tissue (T1b, N0, M0) are biologically more aggressive.
Standard treatment options:
Careful observation without further immediate treatment in selected patients.
External-beam radiation therapy. Definitive radiation therapy should be delayed 4 to 6 weeks after transurethral resection to reduce incidence of stricture.
Radical prostatectomy, usually with pelvic lymphadenectomy. Radical prostatectomy may be difficult after a transurethral resection of the prostate. Consideration may be given to postoperative radiation therapy for patients who are found to have capsular penetration or seminal vesicle invasion by tumor at the time of prostatectomy or who have a detectable level of prostate-specific antigen more than 3 weeks after surgery.
Interstitial implantation of radioisotopes (i.e., I-125, palladium, iridium) done through a transperineal technique with either ultrasound or computed tomography (CT) guidance is being done in carefully selected patients with T1 or T2A tumors. Short-term results in these patients are similar to those for radical prostatectomy or external-beam radiation therapy. One advantage is that the implant is performed as outpatient surgery. The rate of maintenance of sexual potency with interstitial implants has been reported to be 86% to 92%, which compares with rates of 10% to 40% with radical prostatectomy and 40% to 60% with external-beam radiation therapy; however, urinary tract frequency, urgency, and less commonly, urinary retention are seen in most patients but subside with time. Rectal ulceration may also be seen. This risk decreased with increased operator experience and modification of implant technique.
Stage II Prostate Cancer
Stage II prostate cancer is defined by American Joint Committee on Cancer (AJCC) TNM classifications:
T1a, N0, M0, G2 (Gleason 3-4).
T1b, N0, M0, any G.
T1c, N0, M0, any G.
T1 (not further specified), N0, M0, any G.
T2, N0, M0, any G.
Standard treatment options:
Radical prostatectomy, usually with pelvic lymphadenectomy. If allowed by the extent of tumor, anatomical dissection that preserves nerves necessary for erection avoids impotence postoperatively in some patients. Consideration may be given to postoperative radiation therapy for patients who are found to have capsular penetration or seminal vesicle invasion by tumor at the time of prostatectomy or a detectable level of prostate-specific antigen more than 3 weeks after surgery. Postoperative radiation therapy does reduce local recurrence.
External-beam irradiation. Prophylactic irradiation of clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve overall survival or prostate cancer-specific survival. Definitive radiation therapy should be delayed 4 to 6 weeks after transurethral resection to reduce incidence of stricture. For patients with bulky T2b tumors, adjuvant hormonal therapy should be considered.
Careful observation without further immediate treatment (in selected patients).
Interstitial implantation of radioisotopes (i.e., I-125, palladium, iridium) done through a transperineal technique with either ultrasound or computed tomography guidance is being done in carefully selected patients with T1 or T2A tumors.
External-beam radiation therapy designed to decrease exposure of normal tissues using methods such as CT-based 3-D conformal treatment planning is under clinical evaluation.
Ultrasound-guided percutaneous cryosurgery is alternative modality. Other clinical trials, including trials of neoadjuvant hormonal therapy followed by radical prostatectomy.
Stage III Prostate Cancer
Stage III prostate cancer is defined by American Joint Committee on Cancer TNM classification: T3, N0, M0, any G.
Standard treatment options
External-beam radiation. Hormonal therapy should be considered in addition to external-beam radiation. Moreover, although Radiation Therapy Oncology Group Trial 9413 showed an increased progression-free survival at 4 years for patients with a 15% estimated risk of lymph node involvement receiving whole-pelvic irradiation as compared with prostate-only irradiation, overall survival and PSA failure rates were not significantly different. Definitive radiation therapy should be delayed until 4 to 6 weeks after transurethral resection to reduce incidence of stricture. Radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography-based 3-D conformal treatment planning is under clinical evaluation.
Hormonal manipulations (orchiectomy or LHRH agonist).
Radical prostatectomy, usually with pelvic lymphadenectomy (in highly selected patients). Consideration may be given to postoperative radiation therapy for patients who are found to have capsular penetration or seminal vesicle invasion by tumor at the time of prostatectomy or a detectable level of prostate-specific antigen more than 3 weeks after surgery. The role of preoperative (neoadjuvant) hormonal therapy is not established at the present time.
Careful observation without further immediate treatment.
Symptomatic treatment
Since many stage III patients have urinary symptoms, control of symptoms is an important consideration in treatment. This may often be accomplished by radiation therapy, radical surgery, transurethral resection of the prostate, or hormonal manipulation.
1.Radiation therapy: External-beam radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography-based 3-D conformal treatment planning is under clinical evaluation.
2.Hormonal manipulations: effectively used as initial therapy for prostate cancer:
Orchiectomy.
Leuprolide or other LHRH agonists (Zoladex) in daily or depot preparations .
Estrogen (diethylstilbestrol [DES] is no longer available).
Nonsteroidal antiandrogen (e.g., flutamide, nilutamide, bicalutamide) or steroidal antiandrogen (cyproterone acetate).
A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or IV prostate cancer (predominantly stage IV) came to the following conclusions:
Overall survival at 2 years using any of the LHRH agonists is similar to treatment with orchiectomy or 3 mg per day of DES (HR=1.26, 95% CI=0.92-1.39).
Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared to orchiectomy (HR=1.22, 95% CI=0.99-1.50).
Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LHRH agonists (0%-4%) than with nonsteroidal antiandrogens (4%-10%).
3.Palliative surgery: (transurethral resection).
4.Interstitial implantation combined with external-beam radiation therapy is being used in selected T3 patients.
5.Mixed-beam (neutron/photon) radiation therapy: A
randomized trial reported improved local control and survival with mixed-beam (neutron/photon) radiation therapy, compared to standard photon radiation therapy. A subsequent randomized study from the same group compared fast-neutron radiation therapy to standard photon radiation therapy. Local-regional control was improved with neutron treatment. Proton-beam radiation therapy is also under investigation.
6.Ultrasound-guided percutaneous cryosurgery: is an
alternative modality which involves destruction of prostate cancer cells by intermittent freezing of the prostate tissue with cryoprobes, followed by thawing.
Stage IV Prostate Cancer
Stage IV prostate cancer is defined by American Joint Committee on Cancer (AJCC) TNM classifications:
T4, N0, M0, any G.
Any T, N1, M0, any G.
Any T, any N, M1, any G.
Hormonal treatment is the mainstay of therapy for distant metastatic (stage D2) prostate cancer. Cure is rarely, if ever, possible, but striking subjective or objective responses to treatment occur in most patients.
In some series, pretreatment levels of prostate-specific antigen (PSA) are inversely correlated with progression-free duration in patients with metastatic prostate cancer who receive hormonal therapy. After hormonal therapy is instituted, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status. Orchiectomy and estrogens yield similar results, and selection of 1 or the other depends on patient preference and the morbidity of expected side effects. Estrogens are associated with the development or exacerbation of cardiovascular disease, especially in high doses. Diethylstilbestrol (DES) in a dose of 1 mg per day is not associated with as frequent cardiovascular complications as higher doses are; however, the use of DES has decreased because of cardiovascular toxic effects, and DES is no longer commercially available in the United States. The psychologic implications of orchiectomy are objectionable to many patients, and many will choose alternative therapy if effective. Combined orchiectomy and estrogens are not indicated to be superior to either treatment administered alone.
Approaches using LHRH agonists and/or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to standard hormonal treatments. The LHRH analog leuprolide (1 mg subcutaneously every day) was found to be as effective as DES (3 mg orally every day) in any T, any N, M1 patients, but caused less gynecomastia, nausea/vomiting, and thromboembolisms. The depot LHRH analog goserelin (Zoladex) was found to be as effective as orchiectomy or DES at a dose of 3 mg per day. A depot preparation of leuprolide (Depo Lupron), which is therapeutically equivalent to leuprolide, is available as a monthly or 3-monthly depot. Castration has been shown to be superior to monotherapy with bicalutamide. A comparison of 1 mg of DES orally 3 times per day to 250 mg of flutamide 3 times per day in patients with metastatic prostate cancer showed similar response rates with both regimens but superior survival with DES. More cardiovascular and/or thromboembolic toxic effects of borderline statistical significance were associated with the DES treatment.
On the basis that the adrenal glands continue to produce androgens after surgical or medical castration, case series studies were performed in which antiandrogen therapy was added to castration. Promising results from such case series led to widespread use of the strategy, known as “maximal androgen blockage” (MAB) or “complete androgen blockade.” However, subsequent randomized controlled trials cast doubt on the efficacy of adding an antiandrogen to castration.
When trials of androgen suppression versus androgen suppression plus either nilutamide or flutamide were examined in a subset analysis, the absolute survival rate at 5 years was better for the combined therapy group (2.9% better, 95% CI=0.3%-5.5%); however, when trials of androgen suppression versus androgen suppression plus cyproterone acetate were examined, the absolute survival trend at 5 years was worse for the combined therapy group (2.8% worse, 95% CI= -7.6% to +2.0%).
Clinical trial evidence of single hormonal therapies and combined androgen blockade was performed in men with stage III or IV prostate cancer (predominantly stage IV) and came to the following conclusions:
Overall survival at 2 years using any of the LHRH agonists is similar to treatment with orchiectomy or 3 mg per day of DES (HR=1.26, 95% CI=0.92-1.39).
Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared to orchiectomy (HR=1.22, 95% CI=0.99-1.50).
Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LHRH agonists (0%-4%) than with nonsteroidal antiandrogens (4%-10%).
Combined androgen blockade was of no greater benefit than single hormonal therapy, with less patient tolerance.
After tumor progression on 1 form of hormonal manipulation develops, an objective tumor response to any other form is uncommon. However, some studies suggest that withdrawal of flutamide (with or without aminoglutethimide administration) is associated with a decline in PSA values and that one may need to monitor for this response before initiating new therapy. To date, no evidence indicates that chemotherapy prolongs survival. Low-dose prednisone may palliate symptoms in about one third of cases.
PC-SPES is an herbal combination stated to contain 8 herbs: chrysanthemum, isatis, licorice, lucid ganoderma, pseudo-ginseng, rubescens, saw palmetto, and scute. Although it was marketed as a dietary supplement for “prostate health,” it was frequently used with therapeutic intent by prostate cancer patients. (“PC” stood for “prostate cancer;” “SPES” is Latin for “hope”). Several uncontrolled case series showed some clinical activity as manifested by reduction in PSA, as well as loss of libido and sexual potency, gynecomastia, and thromboembolism. This led to the hypothesis that its clinical activity could be due to natural or synthetic compounds with estrogenic activity.
Standard treatment options:
Hormonal manipulations effectively used as initial therapy for prostate cancer:
Orchiectomy alone or with an androgen blocker.
LHRH agonists such as leuprolide in daily or depot preparations. (These agents may be associated with tumor flare when used alone; therefore, the initial concomitant use of antiandrogens should be considered in the presence of liver pain, ureteral obstruction, or impending spinal cord compression.)
Leuprolide plus flutamide; however, the addition of an antiandrogen to leuprolide has not been shown to improve survival in a meta-analysis.
Estrogens (DES, chlorotrianisene, ethinyl estradiol, conjugated estrogens U.S.P., DES-diphosphate). (DES is no longer commercially available in the United States.)
External-beam irradiation.
Palliative radiation therapy.
Palliative surgery (transurethral resection).
Recurrent Prostate Cancer
In prostate cancer, the selection of further treatment depends on many factors, including previous treatment, site of recurrence, coexistent illnesses, and individual patient considerations. Definitive radiation therapy can be given to patients who fail only locally following prostatectomy. An occasional patient can be salvaged with prostatectomy after a local recurrence following definitive radiation therapy; however, only about 10% of patients treated initially with radiation will have local relapse only. In these patients, prolonged disease control is often possible with hormonal therapy, with median cancer-specific survival of 6 years after local failure. Cryosurgical ablation of recurrence following radiation is associated frequently with elevated prostate-specific antigen (PSA) and a high complication rate. This technique is still undergoing clinical evaluation. Most relapsing patients who initially received locoregional therapy with surgery or irradiation will fail with disseminated disease and are managed with hormonal therapy. The management of these patients with stage IV disease is discussed in the preceding section. Palliative radiation therapy for bone pain can be very useful. Because of the poor prognosis in prostate cancer patients with relapsing or progressive disease after hormonal therapy, clinical trials are appropriate. These include phase I and II trials of new chemotherapeutic or biologic agents.
Even among patients with metastatic “hormone-refractory prostate cancer,” there is some heterogeneity in prognosis and in retained hormone sensitivity. In such patients who have symptomatic bone disease, several factors are associated with worsened prognosis: poor performance status, elevated alkaline phosphatase, abnormal serum creatinine, and short (<1 year) previous response to hormone therapy. The absolute level of PSA at the initiation of therapy in relapsed or hormone-refractory patients has not been shown to be of prognostic significance. Some patients whose disease has progressed on combined androgen blockade can respond to a variety of second-line hormonal therapies. Aminoglutethimide, hydrocortisone, flutamide withdrawal, progesterone, ketoconazole, and combinations of these therapies have produced PSA responses in 14% to 60% of patients treated and have also produced clinical responses of 0% to 25% when assessed. The duration of these PSA responses has been in the range of 2 to 4 months. Survival rates are similar whether ketoconazole plus hydrocortisone is initiated at the same time as anti-androgen (e.g., flutamide, bicalutamide, or nilutamide) withdrawal or when PSA has risen after an initial trial of anti-androgen withdrawal. Data on whether PSA changes while on chemotherapy are predictive of survival are conflicting.
Patients treated with either luteinizing hormone agonists or estrogens as primary therapy are generally maintained with castrate levels of testosterone.
Painful bone metastases can be a major problem in prostate cancer. Many strategies have been studied for palliation, including pain medication, radiation, corticosteroids, bone-seeking radionuclides, gallium nitrate, and bisphosphonates. External-beam radiation therapy for palliation of bone pain can be very useful. Also, the use of radioisotopes such as strontium-89 has been shown to be effective as palliative treatment of some patients with osteoblastic metastases. When this isotope is given alone, it has been reported to decrease bone pain in 80% of patients treated and is similar to responses with local or hemibody radiation. When used as an adjunct to external-beam radiation therapy, strontium-89 was shown to slow disease progression and to reduce analgesic requirements, compared to external-beam radiation therapy alone.
A multicenter randomized trial of a single intravenous dose of Strontium89 chloride (150 MBq: 4 mCi) versus palliative external-beam radiation in men with painful bone metastases from prostate cancer despite hormone treatment showed similar subjective pain response rates: 34.7% versus 33.3%, respectively. Overall survival was better in the external-beam radiation group than in the Strontium89 chloride group (P=0.046; median survival 11.0 vs. 7.2 months). No statistically significant differences in time-to-subjective progression or in progression-free survival were seen.
Chemotherapy has been reported to provide palliative benefit to some men with hormone-refractory disease. Low-dose prednisone may palliate symptoms in some patients. In a randomized comparison of prednisone (5 mg 4 times per day) with flutamide (250 mg 3 times per day) in patients with disease progression after androgen ablative therapy (castration or luteinizing hormone-releasing hormone [LHRH] agonist), prednisone and flutamide produced similar survival, symptomatic response, PSA response, and time to progression; however, there were statistically significant differences in pain, nausea and vomiting, and diarrhea in patients who received prednisone. A randomized trial showed improved pain control in hormone-resistant patients treated with mitoxantrone plus prednisone compared with those treated with prednisone alone. Differences in overall survival or measured global quality of life between the 2 treatments were not statistically significant.
Currently, no chemotherapy regimen can be considered as standard.
HOW TO DETECT THE PROGNOSIS OF PROSTATE CANCER?
Certain factors affect prognosis (chance of recovery) and treatment options.
The prognosis (chance of recovery) depends on the following:
The stage of the cancer (whether it affects part of the prostate, involves the whole prostate, or has spread to other places in the body).
The patient’s age and health.
Whether the cancer has just been diagnosed or has recurred (come back).
Survival of the patient with prostatic carcinoma is related to the extent of the tumor. When the cancer is confined to the prostate gland, median survival in excess of 5 years can be anticipated. Patients with locally advanced cancer are not usually curable, and a substantial fraction will eventually die of their tumor, although median survival may be as long as 5 years. If prostate cancer has spread to distant organs, current therapy will not cure it. Median survival is usually 1 to 3 years, and most such patients will die of prostate cancer. Even in this group of patients, however, indolent clinical courses lasting for many years may be observed.
Other factors affecting the prognosis of patients with prostate cancer that may be useful in making therapeutic decisions include histologic grade of the tumor, patient’s age, other medical illnesses, and level of PSA. Poorly differentiated tumors are more likely to have already metastasized by the time of diagnosis and are associated with a poorer prognosis. For patients treated with radiation therapy, the combination of clinical tumor (T) stage, Gleason score, and pretreatment PSA level can be used to more accurately estimate the risk of relapse. In most studies, flow cytometry has shown that nuclear DNA ploidy is an independent prognostic indicator for progression and for cause-specific survival in patients with pathologic stages C and D1. Diploid tumors have a more favorable outcome than either tetraploid or aneuploid tumors. The use of flow cytometry techniques and histogram analysis to determine prognosis will require standardization.
Several nomograms have been developed to predict outcomes either prior to or after radical prostatectomy with intent to cure. Preoperative nomograms are based on clinical stage, PSA, and Gleason score. Postoperative nomograms add pathologic findings, such as capsular invasion, surgical margins, seminal vesicle invasion, and lymph node involvement. The nomograms, however, were developed at academic centers and may not be as accurate when generalized to nonacademic hospitals, where the majority of patients are treated. In addition, the nomograms use nonhealth (intermediate) outcomes such as PSA rise or pathologic surgical findings, and subjective endpoints such as the physician's perceived need for additional therapy. In addition, the nomograms may be affected by changing methods of diagnosis or neoadjuvant therapy over time.
Definitive treatment is usually considered for younger men with prostate cancer and no major comorbid medical illnesses because younger men are more likely to die of prostate cancer than older men or men with major comorbid medical illness. Elevations of serum acid phosphatase are associated with poor prognosis in both localized and disseminated disease. PSA, an organ-specific marker with greater sensitivity and high specificity for prostate tissue, is often used as a tumor marker. After radical prostatectomy, detectable PSA levels identify patients at elevated risk of local treatment failure or metastatic disease; however, a substantial proportion of patients with elevated or rising PSA levels after surgery may remain clinically free of symptoms for extended periods of time. Therefore, biochemical evidence of failure on the basis of elevated or slowly rising PSA alone may not be sufficient to alter treatment. For example, in a retrospective analysis of nearly 2,000 men who had undergone radical prostatectomy with curative intent and who were followed for a mean of 5.3 years, 315 men (15%) demonstrated an abnormal PSA ≥0.2 ng/mL, felt to be evidence of “biochemical recurrence.” Of these 315 men, 103 men (34%) developed clinical evidence of recurrence. The median time to development of clinical metastasis after biochemical recurrence was 8 years. After the men developed metastatic disease, the median time to death was an additional 5 years.
After radiation therapy with curative intent, persistently elevated or rising PSA may be a prognostic factor for clinical disease recurrence; however, reported case series have used a variety of definitions of “PSA failure.” It is difficult to base decisions about instituting additional therapy on biochemical failure. The implication of the various definitions of “PSA failure” for overall survival is not known, and as in the surgical series, many biochemical relapses (rising PSA alone) may not be clinically manifested in patients treated with radiation.
Preliminary data from a retrospective cohort of patients with clinically localized prostate cancer treated with either radical prostatectomy or radiation therapy suggested that short posttreatment PSA doubling time (<3 months in this study) is a useful surrogate endpoint for all-cause mortality and prostate cancer mortality after surgery or radiation. This observation should be independently confirmed in a prospective study design and may not apply to patients treated with hormonal therapy.
After hormonal therapy, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status; however, decreases in PSA of less than 80% may not be very predictive. Yet, because PSA expression itself is under hormonal control, androgen deprivation therapy can decrease the serum level of PSA independent of tumor response. Therefore, clinicians cannot rely solely on the serum PSA level to monitor a patient’s response to hormone therapy; they must also follow clinical criteria.
Prostate cancer is a disease in which malignant (cancer) cells form in the tissues of the prostate.
The prostate is a gland in the male reproductive system located just below the bladder (the organ that collects and empties urine) and in front of the rectum (the lower part of the intestine). It is about the size of a walnut and surrounds part of the urethra (the tube that empties urine from the bladder). The prostate gland produces fluid that makes up part of the semen.
Carcinoma of the prostate is predominantly a tumor of older men, which frequently responds to treatment when widespread and may be cured when localized. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone. Because the median age at diagnosis is 72 years, many patients—especially those with localized tumors—may die of other illnesses without ever having suffered significant disability from their cancer. The approach to treatment is influenced by age and coexisting medical problems. Side effects of various forms of treatment should be considered in selecting appropriate management.
HOW TO DETECT PROSTATE CANCER?
Possible signs of prostate cancer include a weak flow of urine or frequent urination.
Prostate cancer should be suspected if any of the following problems occur:
Weak or interrupted flow of urine.
Frequent urination (especially at night).
Difficulty urinating.
Pain or burning during urination.
Blood in the urine or semen.
Nagging pain in the back, hips, or pelvis.
Painful ejaculation.
Tests listed as below are used to detect prostate cancer.
Digital rectal exam (DRE): An exam of the rectum may detect the prostate through the rectal wall for lumps or abnormal areas.
Prostate-specific antigen (PSA) test: PSA is a substance made by the prostate that may be found in an increased amount in the blood of men who have prostate cancer. PSA levels in the blood may also be high in men who have an infection or inflammation of the prostate or BPH (an enlarged, but noncancerous, prostate).
Transrectal ultrasound: Transrectal ultrasound may shows abnormal echo of cancer in prostate and may be used to take a biopsy.
Biopsy: The biopsy may be performed through transrectal or transperineal routes for pathological diagnosis of prostate cancer.The Gleason score ranges from 2-10 and describes how likely it is that a tumor will spread. The lower the number, the less likely the tumor is to spread.
HOW TO TREAT PROSTATE CANCER?
State-of-the-art treatment in prostate cancer provides prolonged disease-free survival for many patients with localized disease but is rarely curative in patients with locally extensive tumor. Even when the cancer appears clinically localized to the prostate gland, a substantial fraction of patients will develop disseminated tumor after local therapy with surgery or irradiation.
Stage I Prostate Cancer
Stage I prostate cancer is defined by American Joint Committee on Cancer (AJCC) TNM classification: T1a, N0, M0, G1 (Gleason 2-4).
The frequency of clinically silent, nonmetastatic prostate cancer that can be found at autopsy greatly increases with age and may be as high as 50% to 60% in men aged 90 years and older. Many stage I cancers are well-differentiated and only focally involve the gland (T1a, N0, M0); most require no treatment other than careful follow-up.
In younger patients (aged 50-60 years) whose expected survival is long, treatment should be considered. Less-differentiated cancers that involve more than a few pieces of resected tissue (T1b, N0, M0) are biologically more aggressive.
Standard treatment options:
Careful observation without further immediate treatment in selected patients.
External-beam radiation therapy. Definitive radiation therapy should be delayed 4 to 6 weeks after transurethral resection to reduce incidence of stricture.
Radical prostatectomy, usually with pelvic lymphadenectomy. Radical prostatectomy may be difficult after a transurethral resection of the prostate. Consideration may be given to postoperative radiation therapy for patients who are found to have capsular penetration or seminal vesicle invasion by tumor at the time of prostatectomy or who have a detectable level of prostate-specific antigen more than 3 weeks after surgery.
Interstitial implantation of radioisotopes (i.e., I-125, palladium, iridium) done through a transperineal technique with either ultrasound or computed tomography (CT) guidance is being done in carefully selected patients with T1 or T2A tumors. Short-term results in these patients are similar to those for radical prostatectomy or external-beam radiation therapy. One advantage is that the implant is performed as outpatient surgery. The rate of maintenance of sexual potency with interstitial implants has been reported to be 86% to 92%, which compares with rates of 10% to 40% with radical prostatectomy and 40% to 60% with external-beam radiation therapy; however, urinary tract frequency, urgency, and less commonly, urinary retention are seen in most patients but subside with time. Rectal ulceration may also be seen. This risk decreased with increased operator experience and modification of implant technique.
Stage II Prostate Cancer
Stage II prostate cancer is defined by American Joint Committee on Cancer (AJCC) TNM classifications:
T1a, N0, M0, G2 (Gleason 3-4).
T1b, N0, M0, any G.
T1c, N0, M0, any G.
T1 (not further specified), N0, M0, any G.
T2, N0, M0, any G.
Standard treatment options:
Radical prostatectomy, usually with pelvic lymphadenectomy. If allowed by the extent of tumor, anatomical dissection that preserves nerves necessary for erection avoids impotence postoperatively in some patients. Consideration may be given to postoperative radiation therapy for patients who are found to have capsular penetration or seminal vesicle invasion by tumor at the time of prostatectomy or a detectable level of prostate-specific antigen more than 3 weeks after surgery. Postoperative radiation therapy does reduce local recurrence.
External-beam irradiation. Prophylactic irradiation of clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve overall survival or prostate cancer-specific survival. Definitive radiation therapy should be delayed 4 to 6 weeks after transurethral resection to reduce incidence of stricture. For patients with bulky T2b tumors, adjuvant hormonal therapy should be considered.
Careful observation without further immediate treatment (in selected patients).
Interstitial implantation of radioisotopes (i.e., I-125, palladium, iridium) done through a transperineal technique with either ultrasound or computed tomography guidance is being done in carefully selected patients with T1 or T2A tumors.
External-beam radiation therapy designed to decrease exposure of normal tissues using methods such as CT-based 3-D conformal treatment planning is under clinical evaluation.
Ultrasound-guided percutaneous cryosurgery is alternative modality. Other clinical trials, including trials of neoadjuvant hormonal therapy followed by radical prostatectomy.
Stage III Prostate Cancer
Stage III prostate cancer is defined by American Joint Committee on Cancer TNM classification: T3, N0, M0, any G.
Standard treatment options
External-beam radiation. Hormonal therapy should be considered in addition to external-beam radiation. Moreover, although Radiation Therapy Oncology Group Trial 9413 showed an increased progression-free survival at 4 years for patients with a 15% estimated risk of lymph node involvement receiving whole-pelvic irradiation as compared with prostate-only irradiation, overall survival and PSA failure rates were not significantly different. Definitive radiation therapy should be delayed until 4 to 6 weeks after transurethral resection to reduce incidence of stricture. Radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography-based 3-D conformal treatment planning is under clinical evaluation.
Hormonal manipulations (orchiectomy or LHRH agonist).
Radical prostatectomy, usually with pelvic lymphadenectomy (in highly selected patients). Consideration may be given to postoperative radiation therapy for patients who are found to have capsular penetration or seminal vesicle invasion by tumor at the time of prostatectomy or a detectable level of prostate-specific antigen more than 3 weeks after surgery. The role of preoperative (neoadjuvant) hormonal therapy is not established at the present time.
Careful observation without further immediate treatment.
Symptomatic treatment
Since many stage III patients have urinary symptoms, control of symptoms is an important consideration in treatment. This may often be accomplished by radiation therapy, radical surgery, transurethral resection of the prostate, or hormonal manipulation.
1.Radiation therapy: External-beam radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography-based 3-D conformal treatment planning is under clinical evaluation.
2.Hormonal manipulations: effectively used as initial therapy for prostate cancer:
Orchiectomy.
Leuprolide or other LHRH agonists (Zoladex) in daily or depot preparations .
Estrogen (diethylstilbestrol [DES] is no longer available).
Nonsteroidal antiandrogen (e.g., flutamide, nilutamide, bicalutamide) or steroidal antiandrogen (cyproterone acetate).
A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or IV prostate cancer (predominantly stage IV) came to the following conclusions:
Overall survival at 2 years using any of the LHRH agonists is similar to treatment with orchiectomy or 3 mg per day of DES (HR=1.26, 95% CI=0.92-1.39).
Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared to orchiectomy (HR=1.22, 95% CI=0.99-1.50).
Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LHRH agonists (0%-4%) than with nonsteroidal antiandrogens (4%-10%).
3.Palliative surgery: (transurethral resection).
4.Interstitial implantation combined with external-beam radiation therapy is being used in selected T3 patients.
5.Mixed-beam (neutron/photon) radiation therapy: A
randomized trial reported improved local control and survival with mixed-beam (neutron/photon) radiation therapy, compared to standard photon radiation therapy. A subsequent randomized study from the same group compared fast-neutron radiation therapy to standard photon radiation therapy. Local-regional control was improved with neutron treatment. Proton-beam radiation therapy is also under investigation.
6.Ultrasound-guided percutaneous cryosurgery: is an
alternative modality which involves destruction of prostate cancer cells by intermittent freezing of the prostate tissue with cryoprobes, followed by thawing.
Stage IV Prostate Cancer
Stage IV prostate cancer is defined by American Joint Committee on Cancer (AJCC) TNM classifications:
T4, N0, M0, any G.
Any T, N1, M0, any G.
Any T, any N, M1, any G.
Hormonal treatment is the mainstay of therapy for distant metastatic (stage D2) prostate cancer. Cure is rarely, if ever, possible, but striking subjective or objective responses to treatment occur in most patients.
In some series, pretreatment levels of prostate-specific antigen (PSA) are inversely correlated with progression-free duration in patients with metastatic prostate cancer who receive hormonal therapy. After hormonal therapy is instituted, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status. Orchiectomy and estrogens yield similar results, and selection of 1 or the other depends on patient preference and the morbidity of expected side effects. Estrogens are associated with the development or exacerbation of cardiovascular disease, especially in high doses. Diethylstilbestrol (DES) in a dose of 1 mg per day is not associated with as frequent cardiovascular complications as higher doses are; however, the use of DES has decreased because of cardiovascular toxic effects, and DES is no longer commercially available in the United States. The psychologic implications of orchiectomy are objectionable to many patients, and many will choose alternative therapy if effective. Combined orchiectomy and estrogens are not indicated to be superior to either treatment administered alone.
Approaches using LHRH agonists and/or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to standard hormonal treatments. The LHRH analog leuprolide (1 mg subcutaneously every day) was found to be as effective as DES (3 mg orally every day) in any T, any N, M1 patients, but caused less gynecomastia, nausea/vomiting, and thromboembolisms. The depot LHRH analog goserelin (Zoladex) was found to be as effective as orchiectomy or DES at a dose of 3 mg per day. A depot preparation of leuprolide (Depo Lupron), which is therapeutically equivalent to leuprolide, is available as a monthly or 3-monthly depot. Castration has been shown to be superior to monotherapy with bicalutamide. A comparison of 1 mg of DES orally 3 times per day to 250 mg of flutamide 3 times per day in patients with metastatic prostate cancer showed similar response rates with both regimens but superior survival with DES. More cardiovascular and/or thromboembolic toxic effects of borderline statistical significance were associated with the DES treatment.
On the basis that the adrenal glands continue to produce androgens after surgical or medical castration, case series studies were performed in which antiandrogen therapy was added to castration. Promising results from such case series led to widespread use of the strategy, known as “maximal androgen blockage” (MAB) or “complete androgen blockade.” However, subsequent randomized controlled trials cast doubt on the efficacy of adding an antiandrogen to castration.
When trials of androgen suppression versus androgen suppression plus either nilutamide or flutamide were examined in a subset analysis, the absolute survival rate at 5 years was better for the combined therapy group (2.9% better, 95% CI=0.3%-5.5%); however, when trials of androgen suppression versus androgen suppression plus cyproterone acetate were examined, the absolute survival trend at 5 years was worse for the combined therapy group (2.8% worse, 95% CI= -7.6% to +2.0%).
Clinical trial evidence of single hormonal therapies and combined androgen blockade was performed in men with stage III or IV prostate cancer (predominantly stage IV) and came to the following conclusions:
Overall survival at 2 years using any of the LHRH agonists is similar to treatment with orchiectomy or 3 mg per day of DES (HR=1.26, 95% CI=0.92-1.39).
Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared to orchiectomy (HR=1.22, 95% CI=0.99-1.50).
Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LHRH agonists (0%-4%) than with nonsteroidal antiandrogens (4%-10%).
Combined androgen blockade was of no greater benefit than single hormonal therapy, with less patient tolerance.
After tumor progression on 1 form of hormonal manipulation develops, an objective tumor response to any other form is uncommon. However, some studies suggest that withdrawal of flutamide (with or without aminoglutethimide administration) is associated with a decline in PSA values and that one may need to monitor for this response before initiating new therapy. To date, no evidence indicates that chemotherapy prolongs survival. Low-dose prednisone may palliate symptoms in about one third of cases.
PC-SPES is an herbal combination stated to contain 8 herbs: chrysanthemum, isatis, licorice, lucid ganoderma, pseudo-ginseng, rubescens, saw palmetto, and scute. Although it was marketed as a dietary supplement for “prostate health,” it was frequently used with therapeutic intent by prostate cancer patients. (“PC” stood for “prostate cancer;” “SPES” is Latin for “hope”). Several uncontrolled case series showed some clinical activity as manifested by reduction in PSA, as well as loss of libido and sexual potency, gynecomastia, and thromboembolism. This led to the hypothesis that its clinical activity could be due to natural or synthetic compounds with estrogenic activity.
Standard treatment options:
Hormonal manipulations effectively used as initial therapy for prostate cancer:
Orchiectomy alone or with an androgen blocker.
LHRH agonists such as leuprolide in daily or depot preparations. (These agents may be associated with tumor flare when used alone; therefore, the initial concomitant use of antiandrogens should be considered in the presence of liver pain, ureteral obstruction, or impending spinal cord compression.)
Leuprolide plus flutamide; however, the addition of an antiandrogen to leuprolide has not been shown to improve survival in a meta-analysis.
Estrogens (DES, chlorotrianisene, ethinyl estradiol, conjugated estrogens U.S.P., DES-diphosphate). (DES is no longer commercially available in the United States.)
External-beam irradiation.
Palliative radiation therapy.
Palliative surgery (transurethral resection).
Recurrent Prostate Cancer
In prostate cancer, the selection of further treatment depends on many factors, including previous treatment, site of recurrence, coexistent illnesses, and individual patient considerations. Definitive radiation therapy can be given to patients who fail only locally following prostatectomy. An occasional patient can be salvaged with prostatectomy after a local recurrence following definitive radiation therapy; however, only about 10% of patients treated initially with radiation will have local relapse only. In these patients, prolonged disease control is often possible with hormonal therapy, with median cancer-specific survival of 6 years after local failure. Cryosurgical ablation of recurrence following radiation is associated frequently with elevated prostate-specific antigen (PSA) and a high complication rate. This technique is still undergoing clinical evaluation. Most relapsing patients who initially received locoregional therapy with surgery or irradiation will fail with disseminated disease and are managed with hormonal therapy. The management of these patients with stage IV disease is discussed in the preceding section. Palliative radiation therapy for bone pain can be very useful. Because of the poor prognosis in prostate cancer patients with relapsing or progressive disease after hormonal therapy, clinical trials are appropriate. These include phase I and II trials of new chemotherapeutic or biologic agents.
Even among patients with metastatic “hormone-refractory prostate cancer,” there is some heterogeneity in prognosis and in retained hormone sensitivity. In such patients who have symptomatic bone disease, several factors are associated with worsened prognosis: poor performance status, elevated alkaline phosphatase, abnormal serum creatinine, and short (<1 year) previous response to hormone therapy. The absolute level of PSA at the initiation of therapy in relapsed or hormone-refractory patients has not been shown to be of prognostic significance. Some patients whose disease has progressed on combined androgen blockade can respond to a variety of second-line hormonal therapies. Aminoglutethimide, hydrocortisone, flutamide withdrawal, progesterone, ketoconazole, and combinations of these therapies have produced PSA responses in 14% to 60% of patients treated and have also produced clinical responses of 0% to 25% when assessed. The duration of these PSA responses has been in the range of 2 to 4 months. Survival rates are similar whether ketoconazole plus hydrocortisone is initiated at the same time as anti-androgen (e.g., flutamide, bicalutamide, or nilutamide) withdrawal or when PSA has risen after an initial trial of anti-androgen withdrawal. Data on whether PSA changes while on chemotherapy are predictive of survival are conflicting.
Patients treated with either luteinizing hormone agonists or estrogens as primary therapy are generally maintained with castrate levels of testosterone.
Painful bone metastases can be a major problem in prostate cancer. Many strategies have been studied for palliation, including pain medication, radiation, corticosteroids, bone-seeking radionuclides, gallium nitrate, and bisphosphonates. External-beam radiation therapy for palliation of bone pain can be very useful. Also, the use of radioisotopes such as strontium-89 has been shown to be effective as palliative treatment of some patients with osteoblastic metastases. When this isotope is given alone, it has been reported to decrease bone pain in 80% of patients treated and is similar to responses with local or hemibody radiation. When used as an adjunct to external-beam radiation therapy, strontium-89 was shown to slow disease progression and to reduce analgesic requirements, compared to external-beam radiation therapy alone.
A multicenter randomized trial of a single intravenous dose of Strontium89 chloride (150 MBq: 4 mCi) versus palliative external-beam radiation in men with painful bone metastases from prostate cancer despite hormone treatment showed similar subjective pain response rates: 34.7% versus 33.3%, respectively. Overall survival was better in the external-beam radiation group than in the Strontium89 chloride group (P=0.046; median survival 11.0 vs. 7.2 months). No statistically significant differences in time-to-subjective progression or in progression-free survival were seen.
Chemotherapy has been reported to provide palliative benefit to some men with hormone-refractory disease. Low-dose prednisone may palliate symptoms in some patients. In a randomized comparison of prednisone (5 mg 4 times per day) with flutamide (250 mg 3 times per day) in patients with disease progression after androgen ablative therapy (castration or luteinizing hormone-releasing hormone [LHRH] agonist), prednisone and flutamide produced similar survival, symptomatic response, PSA response, and time to progression; however, there were statistically significant differences in pain, nausea and vomiting, and diarrhea in patients who received prednisone. A randomized trial showed improved pain control in hormone-resistant patients treated with mitoxantrone plus prednisone compared with those treated with prednisone alone. Differences in overall survival or measured global quality of life between the 2 treatments were not statistically significant.
Currently, no chemotherapy regimen can be considered as standard.
HOW TO DETECT THE PROGNOSIS OF PROSTATE CANCER?
Certain factors affect prognosis (chance of recovery) and treatment options.
The prognosis (chance of recovery) depends on the following:
The stage of the cancer (whether it affects part of the prostate, involves the whole prostate, or has spread to other places in the body).
The patient’s age and health.
Whether the cancer has just been diagnosed or has recurred (come back).
Survival of the patient with prostatic carcinoma is related to the extent of the tumor. When the cancer is confined to the prostate gland, median survival in excess of 5 years can be anticipated. Patients with locally advanced cancer are not usually curable, and a substantial fraction will eventually die of their tumor, although median survival may be as long as 5 years. If prostate cancer has spread to distant organs, current therapy will not cure it. Median survival is usually 1 to 3 years, and most such patients will die of prostate cancer. Even in this group of patients, however, indolent clinical courses lasting for many years may be observed.
Other factors affecting the prognosis of patients with prostate cancer that may be useful in making therapeutic decisions include histologic grade of the tumor, patient’s age, other medical illnesses, and level of PSA. Poorly differentiated tumors are more likely to have already metastasized by the time of diagnosis and are associated with a poorer prognosis. For patients treated with radiation therapy, the combination of clinical tumor (T) stage, Gleason score, and pretreatment PSA level can be used to more accurately estimate the risk of relapse. In most studies, flow cytometry has shown that nuclear DNA ploidy is an independent prognostic indicator for progression and for cause-specific survival in patients with pathologic stages C and D1. Diploid tumors have a more favorable outcome than either tetraploid or aneuploid tumors. The use of flow cytometry techniques and histogram analysis to determine prognosis will require standardization.
Several nomograms have been developed to predict outcomes either prior to or after radical prostatectomy with intent to cure. Preoperative nomograms are based on clinical stage, PSA, and Gleason score. Postoperative nomograms add pathologic findings, such as capsular invasion, surgical margins, seminal vesicle invasion, and lymph node involvement. The nomograms, however, were developed at academic centers and may not be as accurate when generalized to nonacademic hospitals, where the majority of patients are treated. In addition, the nomograms use nonhealth (intermediate) outcomes such as PSA rise or pathologic surgical findings, and subjective endpoints such as the physician's perceived need for additional therapy. In addition, the nomograms may be affected by changing methods of diagnosis or neoadjuvant therapy over time.
Definitive treatment is usually considered for younger men with prostate cancer and no major comorbid medical illnesses because younger men are more likely to die of prostate cancer than older men or men with major comorbid medical illness. Elevations of serum acid phosphatase are associated with poor prognosis in both localized and disseminated disease. PSA, an organ-specific marker with greater sensitivity and high specificity for prostate tissue, is often used as a tumor marker. After radical prostatectomy, detectable PSA levels identify patients at elevated risk of local treatment failure or metastatic disease; however, a substantial proportion of patients with elevated or rising PSA levels after surgery may remain clinically free of symptoms for extended periods of time. Therefore, biochemical evidence of failure on the basis of elevated or slowly rising PSA alone may not be sufficient to alter treatment. For example, in a retrospective analysis of nearly 2,000 men who had undergone radical prostatectomy with curative intent and who were followed for a mean of 5.3 years, 315 men (15%) demonstrated an abnormal PSA ≥0.2 ng/mL, felt to be evidence of “biochemical recurrence.” Of these 315 men, 103 men (34%) developed clinical evidence of recurrence. The median time to development of clinical metastasis after biochemical recurrence was 8 years. After the men developed metastatic disease, the median time to death was an additional 5 years.
After radiation therapy with curative intent, persistently elevated or rising PSA may be a prognostic factor for clinical disease recurrence; however, reported case series have used a variety of definitions of “PSA failure.” It is difficult to base decisions about instituting additional therapy on biochemical failure. The implication of the various definitions of “PSA failure” for overall survival is not known, and as in the surgical series, many biochemical relapses (rising PSA alone) may not be clinically manifested in patients treated with radiation.
Preliminary data from a retrospective cohort of patients with clinically localized prostate cancer treated with either radical prostatectomy or radiation therapy suggested that short posttreatment PSA doubling time (<3 months in this study) is a useful surrogate endpoint for all-cause mortality and prostate cancer mortality after surgery or radiation. This observation should be independently confirmed in a prospective study design and may not apply to patients treated with hormonal therapy.
After hormonal therapy, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status; however, decreases in PSA of less than 80% may not be very predictive. Yet, because PSA expression itself is under hormonal control, androgen deprivation therapy can decrease the serum level of PSA independent of tumor response. Therefore, clinicians cannot rely solely on the serum PSA level to monitor a patient’s response to hormone therapy; they must also follow clinical criteria.
Pancreatic Cancer
WHAT IS PANCREATIC CANCER?
Pancreatic cancer is a disease in which malignant (cancer) cells form in the tissues of the pancreas.
The pancreas is a gland about 6 inches long that is shaped like a thin pear lying on its side. The wider end of the pancreas is called the head, the middle section is called the body, and the narrow end is called the tail. The pancreas lies behind the stomach and in front of the spine.
The pancreas has two main jobs in the body:
To produce juices that help digest (break down) food.
To produce hormones, such as insulin and glucagon, that help control blood sugar levels. Both of these hormones help the body use and store the energy it gets from food.
The digestive juices are produced by exocrine pancreas cells and the hormones are produced by endocrine pancreas cells. About 95% of pancreatic cancers begin in exocrine cells.
Pancreatic adenocarcinoma. Neoplastic glands of variable size and shape are surrounded by desmoplastic stroma
Pancreatic adenocarcinoma. Perineural invasion is present Gastrinoma. Cells with uniformly small, round nuclei are arranged in nests
WHAT ARE RISK FACTORS OF PANCREATIC CANCER?
Smoking and health history can affect the risk of developing pancreatic cancer.
The following are possible risk factors for pancreatic cancer:
Smoking.
Long-standing diabetes.
Chronic pancreatitis.
Certain hereditary conditions, such as hereditary pancreatitis, multiple endocrine neoplasia type 1 syndrome, hereditary nonpolyposis colon cancer (HNPCC; Lynch syndrome), von Hippel-Lindau syndrome, ataxia-telangiectasia, and the familial atypical multiple mole melanoma syndrome (FAMMM).
HOW TO DETECT PANCREATIC CANCER?
Possible signs of pancreatic cancer include jaundice, pain, and weight loss.
These symptoms can be caused by pancreatic cancer or other conditions. A doctor should be consulted if any of the following problems occur:
Jaundice (yellowing of the skin and whites of the eyes).
Pain in the upper or middle abdomen and back.
Unexplained weight loss.
Loss of appetite.
Fatigue.
Pancreatic cancer is difficult to detect (find) and diagnose early.
Pancreatic cancer is difficult to detect and diagnose for the following reasons:
There aren’t any noticeable signs or symptoms in the early stages of pancreatic cancer.
The signs of pancreatic cancer, when present, are like the signs of many other illnesses.
The pancreas is hidden behind other organs such as the stomach, small intestine, liver, gallbladder, spleen, and bile ducts.
Tests that examine the pancreas are used to detect (find), diagnose, and stage pancreatic cancer.
Pancreatic cancer is usually diagnosed with tests and procedures that produce pictures of the pancreas and the area around it. The process used to find out if cancer cells have spread within and around the pancreas is called staging. Tests and procedures to detect, diagnose, and stage pancreatic cancer are usually done at the same time. In order to plan treatment, it is important to know the stage of the disease and whether or not the pancreatic cancer can be removed by surgery. The following tests and procedures may be used:
Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. A spiral or helical CT scan makes a series of very detailed pictures of areas inside the body using an x-ray machine that scans the body in a spiral path.
MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radionuclide glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells.
Endoscopic ultrasound (EUS): A procedure in which an endoscope (a thin, lighted tube) is inserted into the body. The endoscope is used to bounce high-energy sound waves (ultrasound) off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. This procedure is also called endosonography.
Laparoscopy: A surgical procedure to look at the organs inside the abdomen to check for signs of disease. Small incisions (cuts) are made in the wall of the abdomen and a laparoscope (a thin, lighted tube) is inserted into one of the incisions. Other instruments may be inserted through the same or other incisions to perform procedures such as removing organs or taking tissue samples for biopsy.
Endoscopic retrograde cholangiopancreatography (ERCP): A procedure used to x-ray the ducts (tubes) that carry bile from the liver to the gallbladder and from the gallbladder to the small intestine. Sometimes pancreatic cancer causes these ducts to narrow and block or slow the flow of bile, causing jaundice. An endoscope (a thin, lighted tube) is passed through the mouth, esophagus, and stomach into the first part of the small intestine. A catheter (a smaller tube) is then inserted through the endoscope into the pancreatic ducts. A dye is injected through the catheter into the ducts and an x-ray is taken. If the ducts are blocked by a tumor, a fine tube may be inserted into the duct to unblock it. This tube (or stent) may be left in place to keep the duct open. Tissue samples may also be taken.
Percutaneous transhepatic cholangiography (PTC): A procedure used to x-ray the liver and bile ducts. A thin needle is inserted through the skin below the ribs and into the liver. Dye is injected into the liver or bile ducts and an x-ray is taken. If a blockage is found, a thin, flexible tube called a stent is sometimes left in the liver to drain bile into the small intestine or a collection bag outside the body. This test is done only if ERCP cannot be done.
Biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer. There are several ways to do a biopsy for pancreatic cancer. A fine needle may be inserted into the pancreas during an x-ray or ultrasound to remove cells. Tissue may also be removed during a laparoscopy (a surgical incision made in the wall of the abdomen).
Gastrinoma. A transabdominal fine needle aspirate (FNA) shows similar features. The FNA sample was centrifuged, and the cell pellet was embedded in paraffin. Sections were stained with hematoxylin and eosin Gastrinoma. Immunohistochemistry of the cell pellet sections using anti-gastrin antibody demonstrates intracytoplasmic gastrin. Brown chromogen marks cells that contain gastrin Gastrinoma. Negative control (no antibody) for
immunohistochemical assay
HOW TO DETECT STAGE OF PANCREATIC CANCER?
Tests and procedures to stage pancreatic cancer are usually done at the same time as diagnosis.
The following stages are used for pancreatic cancer:
Stage I
In stage I, cancer is found in the pancreas only. Stage I is divided into stage IA and stage IB, based on the size of the tumor.
Stage IA: The tumor is 2 centimeters or smaller.
Stage IB: The tumor is larger than 2 centimeters.
Stage II
In stage II, cancer may have spread to nearby tissue and organs, and may have spread to lymph nodes near the pancreas. Stage II is divided into stage IIA and stage IIB, based on where the cancer has spread.
Stage IIA: Cancer has spread to nearby tissue and organs but has not spread to nearby lymph nodes.
Stage IIB: Cancer has spread to nearby lymph nodes and may have spread to nearby tissue and organs.
Stage III
In stage III, cancer has spread to the major blood vessels near the pancreas and may have spread to nearby lymph nodes.
Stage IV
In stage IV, cancer may be of any size and has spread to distant organs, such as the liver, lung, and peritoneal cavity. It may have also spread to organs and tissues near the pancreas or to lymph nodes.
Recurrent Pancreatic Cancer
Recurrent pancreatic cancer is cancer that has recurred (come back) after it has been treated. The cancer may come back in the pancreas or in other parts of the body.
HOW TO TREAT PANCREATIC CANCER?
There are different types of treatment for patients with pancreatic cancer.
Different types of treatment are available for patients with pancreatic cancer. Some treatments are standard (the currently used treatment), and some are being tested.
Three types of standard treatment are used:
Surgery
One of the following types of surgery may be used to take out the tumor:
Whipple procedure: A surgical procedure in which the head of the pancreas, the gallbladder, part of the stomach, part of the small intestine, and the bile duct are removed. Enough of the pancreas is left to produce digestive juices and insulin.
Ampullary carcinoma. The darker tissue at the top of the photograph is an opened segment of duodenum. The tumor is light tan and the orange-tan tissue is the pancreatic head
Total pancreatectomy: This operation removes the whole pancreas, part of the stomach, part of the small intestine, the common bile duct, the gallbladder, the spleen, and nearby lymph nodes.
Distal pancreatectomy: The body and the tail of the pancreas and usually the spleen are removed.
If the cancer has spread and cannot be removed, the following types of palliative surgery may be done to relieve symptoms:
Surgical biliary bypass
Endoscopic stent placement
Gastric bypass
Radiation therapy
There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer.
Chemotherapy
Even after surgical resection, there are at least 70% risk of locoregional recurrence. Therefore, adjuvant chemotherapy and radiation therapy should be given. The followingregimen showed a significantly prolonged median survival of 20 months versus 11 months for controls with 43% 2-year actual survival(versus 18% for controls).are recommended.
5-FU,500mg/m2/dayby i.v. bolus for the first 3 days of each 200-cGy segment of radiotherapy(total dose/3 day course of 5-FU,1 500mg/m2),followed by
5-FU, 500mg/m2/week by i.v. bolus injection,weekly for up to 2 years.
Commonly recommended regimens are as below as well:
4 500 to 5 400 cGy in divided doses with 5-FU,500mg/m2 /day daily on the first and last 3 days of radiation. Median survival is about 10 months with this treatment.
Gemcitabine,1 000 mg/m2/week i.v. weekly for 3 weeks(day 1,8 and 15) followed by 1 week without gemcitabine(total dose/cycle,
3 000mg/m2).Treatment cycles are repeated every 28 days.
Other types of treatment are being tested in clinical trials. These include the following:
Biologic therapy
Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy. Dendritic cell vaccine may be choice.
There are treatments for pain caused by pancreatic cancer.
Pain can occur when the tumor presses on nerves or other organs near the pancreas. When pain medicine is not enough, there are treatments that act on nerves in the abdomen to relieve the pain. The doctor may inject medicine into the area around affected nerves or may cut the nerves to block the feeling of pain. Radiation therapy with or without chemotherapy can also help relieve pain by shrinking the tumor.
Patients with pancreatic cancer have special nutritional needs.
Surgery to remove the pancreas may interfere with the production of pancreatic enzymes that help to digest food. As a result, patients may have problems digesting food and absorbing nutrients into the body. To prevent malnutrition, the doctor may prescribe medicines that replace these enzymes.
Treatment Options by Stage
Stage I Pancreatic Cancer
Treatment of stage I pancreatic cancer may include the following:
Surgery alone.
Surgery with chemotherapy and radiation therapy.
A clinical trial of surgery followed by radiation therapy with chemotherapy. Chemotherapy is given before, during, and after the radiation therapy.
A clinical trial of surgery followed by chemotherapy.
Stage IIA Pancreatic Cancer
Treatment of stage IIA pancreatic cancer may include the following:
Surgery with or without chemotherapy and radiation therapy.
Radiation therapy with chemotherapy.
Palliative surgery to bypass blocked areas in ducts or the small intestine.
A clinical trial of surgery followed by radiation therapy with chemotherapy. Chemotherapy is given before, during, and after the radiation therapy.
A clinical trial of surgery followed by chemotherapy.
A clinical trial of biologic therapy with radiation therapy and/or chemotherapy.
A clinical trial of radiation therapy combined with chemotherapy and/or radiosensitizers (drugs that make cancer cells more sensitive to radiation so more tumor cells are killed), followed by surgery.
A clinical trial of radiation therapy given during surgery or internal radiation therapy.
Stage IIB Pancreatic Cancer
Treatment of stage IIB pancreatic cancer may include the following:
Surgery with or without chemotherapy and radiation therapy.
Radiation therapy with chemotherapy.
Palliative surgery to bypass blocked areas in ducts or the small intestine.
A clinical trial of surgery followed by radiation therapy with chemotherapy. Chemotherapy is given before, during, and after the radiation therapy.
A clinical trial of surgery followed by chemotherapy.
A clinical trial of biologic therapy with radiation therapy and/or chemotherapy.
A clinical trial of radiation therapy combined with chemotherapy and/or radiosensitizers, followed by surgery.
A clinical trial of radiation therapy given during surgery or internal radiation therapy.
Stage III Pancreatic Cancer
Treatment of stage III pancreatic cancer may include the following:
Surgery with or without chemotherapy and radiation therapy.
Radiation therapy with chemotherapy.
Palliative surgery or stent placement to bypass blocked areas in ducts or the small intestine.
A clinical trial of surgery followed by radiation therapy with chemotherapy. Chemotherapy is given before, during, and after the radiation therapy.
A clinical trial of surgery followed by chemotherapy.
A clinical trial of biologic therapy with radiation therapy and/or chemotherapy.
A clinical trial of radiation therapy combined with chemotherapy and/or radiosensitizers, which may be followed by surgery.
A clinical trial of radiation therapy given during surgery or internal radiation therapy.
Stage IV Pancreatic Cancer
Treatment of stage IV pancreatic cancer may include the following:
Chemotherapy.
Palliative treatments for pain, such as nerve blocks, and other supportive care.
Palliative surgery or stent placement to bypass blocked areas in ducts or the small intestine.
Clinical trials of chemotherapy or biologic therapy.
Treatment Options for Recurrent Pancreatic Cancer
Treatment of recurrent pancreatic cancer may include the following:
Chemotherapy.
Palliative surgery or stent placement to bypass blocked areas in ducts or the small intestine.
Palliative radiation therapy.
Other palliative medical care to reduce symptoms, such as nerve blocks to relieve pain.
Clinical trials of chemotherapy or biologic therapy.
NOVAL THERAPIES
Cryosurgery: Experimental cryodestruction of the pancreas performed in 40 dogs served as a basis for selecting the temperature regimen, exposure time and extent of treatment to be subsequently used in man. Cryodestruction and combined cryoradiotherapy were employed in 30 patients with locally advanced pancreatic cancer. The procedure proved effective as it assured alleviation of pain, improvement in performance status and an increase in survival. CA-19-9 level and T-lymphocyte count, which may be used to predict progression of pancreatic cancer. were followed.
125Iodine seeds implantation: Radioactive Iodine-125 seeds were implanted intraoperatively into the tumor to deliver a minimum peripheral dose of 12,000 cGy over one year. This was followed by external beam radiation (50-55 Gy) and systemic chemotherapy (5-FU, Mitomycin-C +/- CCNU). Incidence of peri-operative mortality was 5% (4/81). Early morbidity was observed in 34% of patients and late complications in 32%. A median survival of 12 months and 2- and 5-year survival rates of 21% and 7% were observed. The determinate 2- and 5-year survival rates were 28% and 13%, respectively. The overall 2- and 5-year survival rates with Stage II disease were 27% and 8% and for Stage III disease, 13% and 3%, respectively (p less than 0.05). The determinate 2- and 5-year survival rates were 34% and 19% for Stage II and 19% and 5% for Stage III disease, respectively (p = 0.08). Local control of disease was achieved in 71% of patients. This combined modality approach appears to have achieved satisfactory local control of primary cancer and long term survival of selected patients.
Ultrasonically guided percutaneous implantation of 125I seeds were performed in 19 patients with cancer of the pancreas in our hospital. Satisfactory seed placement and delivery of the planned radiation dose and clinical improvement was seen in most cases. No difference in survival or palliation was observed between patients treated with seeds alone compared with patients treated with seeds and external radiation. Survival after seed implantation was median 140 days, range 7-401 days. It is considered that ultrasonically guided percutaneous implantation of 125I seeds can be recommended in the treatment of unresectable carcinoma of the pancreas.
Photodynamic therapy:Photodynamic therapy produces local necrosis of tissue with light after prior administration of a photosensitising agent, and in experimental studies can be tolerated by the pancreas and surrounding normal tissue. Patients were photosensitised with 0.15 mg/kg meso-tetrahydroxyphenyl chlorin intravenously. Three days later, light was delivered to the cancer percutaneously using fibres positioned under computerised tomographic guidance. Sixteen patients with inoperable adenocarcinomas (2.5-6 cm in diameter) localised to the region of the head of the pancreas were studied. All presented with obstructive jaundice which was relieved by biliary stenting prior to further treatment. All patients had substantial tumour necrosis on scans after treatment. Eleven had a Karnofsky performance status of 100 prior to treatment. In 10 it returned to 100 at one month. There was no treatment related mortality. The median survival time after photodynamic therapy was 9.5 months (range 4-30). Seven of 16 patients (44%) were alive one year after photodynamic therapy. Therefore, photodynamic therapy can produce necrosis in pancreatic cancers, is a available therapy for pancreatic carcinoma.
HOW TO ESTIMATE PROGNOSIS?
Certain factors affect prognosis (chance of recovery) and treatment options.
The prognosis (chance of recovery) and treatment options depend on the following:
Whether or not the tumor can be removed by surgery.
The stage of the cancer (the size of the tumor and whether the cancer has spread outside the pancreas to nearby tissues or lymph nodes or to other places in the body).
The patient’s general health.
Whether the cancer has just been diagnosed or has recurred (come back).
Pancreatic cancer can be controlled only if it is found before it has spread, when it can be removed by surgery. If the cancer has spread, palliative treatment can improve the patient's quality of life by controlling the symptoms and complications of this disease.
Pancreatic cancer is a disease in which malignant (cancer) cells form in the tissues of the pancreas.
The pancreas is a gland about 6 inches long that is shaped like a thin pear lying on its side. The wider end of the pancreas is called the head, the middle section is called the body, and the narrow end is called the tail. The pancreas lies behind the stomach and in front of the spine.
The pancreas has two main jobs in the body:
To produce juices that help digest (break down) food.
To produce hormones, such as insulin and glucagon, that help control blood sugar levels. Both of these hormones help the body use and store the energy it gets from food.
The digestive juices are produced by exocrine pancreas cells and the hormones are produced by endocrine pancreas cells. About 95% of pancreatic cancers begin in exocrine cells.
Pancreatic adenocarcinoma. Neoplastic glands of variable size and shape are surrounded by desmoplastic stroma
Pancreatic adenocarcinoma. Perineural invasion is present Gastrinoma. Cells with uniformly small, round nuclei are arranged in nests
WHAT ARE RISK FACTORS OF PANCREATIC CANCER?
Smoking and health history can affect the risk of developing pancreatic cancer.
The following are possible risk factors for pancreatic cancer:
Smoking.
Long-standing diabetes.
Chronic pancreatitis.
Certain hereditary conditions, such as hereditary pancreatitis, multiple endocrine neoplasia type 1 syndrome, hereditary nonpolyposis colon cancer (HNPCC; Lynch syndrome), von Hippel-Lindau syndrome, ataxia-telangiectasia, and the familial atypical multiple mole melanoma syndrome (FAMMM).
HOW TO DETECT PANCREATIC CANCER?
Possible signs of pancreatic cancer include jaundice, pain, and weight loss.
These symptoms can be caused by pancreatic cancer or other conditions. A doctor should be consulted if any of the following problems occur:
Jaundice (yellowing of the skin and whites of the eyes).
Pain in the upper or middle abdomen and back.
Unexplained weight loss.
Loss of appetite.
Fatigue.
Pancreatic cancer is difficult to detect (find) and diagnose early.
Pancreatic cancer is difficult to detect and diagnose for the following reasons:
There aren’t any noticeable signs or symptoms in the early stages of pancreatic cancer.
The signs of pancreatic cancer, when present, are like the signs of many other illnesses.
The pancreas is hidden behind other organs such as the stomach, small intestine, liver, gallbladder, spleen, and bile ducts.
Tests that examine the pancreas are used to detect (find), diagnose, and stage pancreatic cancer.
Pancreatic cancer is usually diagnosed with tests and procedures that produce pictures of the pancreas and the area around it. The process used to find out if cancer cells have spread within and around the pancreas is called staging. Tests and procedures to detect, diagnose, and stage pancreatic cancer are usually done at the same time. In order to plan treatment, it is important to know the stage of the disease and whether or not the pancreatic cancer can be removed by surgery. The following tests and procedures may be used:
Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. A spiral or helical CT scan makes a series of very detailed pictures of areas inside the body using an x-ray machine that scans the body in a spiral path.
MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radionuclide glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells.
Endoscopic ultrasound (EUS): A procedure in which an endoscope (a thin, lighted tube) is inserted into the body. The endoscope is used to bounce high-energy sound waves (ultrasound) off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. This procedure is also called endosonography.
Laparoscopy: A surgical procedure to look at the organs inside the abdomen to check for signs of disease. Small incisions (cuts) are made in the wall of the abdomen and a laparoscope (a thin, lighted tube) is inserted into one of the incisions. Other instruments may be inserted through the same or other incisions to perform procedures such as removing organs or taking tissue samples for biopsy.
Endoscopic retrograde cholangiopancreatography (ERCP): A procedure used to x-ray the ducts (tubes) that carry bile from the liver to the gallbladder and from the gallbladder to the small intestine. Sometimes pancreatic cancer causes these ducts to narrow and block or slow the flow of bile, causing jaundice. An endoscope (a thin, lighted tube) is passed through the mouth, esophagus, and stomach into the first part of the small intestine. A catheter (a smaller tube) is then inserted through the endoscope into the pancreatic ducts. A dye is injected through the catheter into the ducts and an x-ray is taken. If the ducts are blocked by a tumor, a fine tube may be inserted into the duct to unblock it. This tube (or stent) may be left in place to keep the duct open. Tissue samples may also be taken.
Percutaneous transhepatic cholangiography (PTC): A procedure used to x-ray the liver and bile ducts. A thin needle is inserted through the skin below the ribs and into the liver. Dye is injected into the liver or bile ducts and an x-ray is taken. If a blockage is found, a thin, flexible tube called a stent is sometimes left in the liver to drain bile into the small intestine or a collection bag outside the body. This test is done only if ERCP cannot be done.
Biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer. There are several ways to do a biopsy for pancreatic cancer. A fine needle may be inserted into the pancreas during an x-ray or ultrasound to remove cells. Tissue may also be removed during a laparoscopy (a surgical incision made in the wall of the abdomen).
Gastrinoma. A transabdominal fine needle aspirate (FNA) shows similar features. The FNA sample was centrifuged, and the cell pellet was embedded in paraffin. Sections were stained with hematoxylin and eosin Gastrinoma. Immunohistochemistry of the cell pellet sections using anti-gastrin antibody demonstrates intracytoplasmic gastrin. Brown chromogen marks cells that contain gastrin Gastrinoma. Negative control (no antibody) for
immunohistochemical assay
HOW TO DETECT STAGE OF PANCREATIC CANCER?
Tests and procedures to stage pancreatic cancer are usually done at the same time as diagnosis.
The following stages are used for pancreatic cancer:
Stage I
In stage I, cancer is found in the pancreas only. Stage I is divided into stage IA and stage IB, based on the size of the tumor.
Stage IA: The tumor is 2 centimeters or smaller.
Stage IB: The tumor is larger than 2 centimeters.
Stage II
In stage II, cancer may have spread to nearby tissue and organs, and may have spread to lymph nodes near the pancreas. Stage II is divided into stage IIA and stage IIB, based on where the cancer has spread.
Stage IIA: Cancer has spread to nearby tissue and organs but has not spread to nearby lymph nodes.
Stage IIB: Cancer has spread to nearby lymph nodes and may have spread to nearby tissue and organs.
Stage III
In stage III, cancer has spread to the major blood vessels near the pancreas and may have spread to nearby lymph nodes.
Stage IV
In stage IV, cancer may be of any size and has spread to distant organs, such as the liver, lung, and peritoneal cavity. It may have also spread to organs and tissues near the pancreas or to lymph nodes.
Recurrent Pancreatic Cancer
Recurrent pancreatic cancer is cancer that has recurred (come back) after it has been treated. The cancer may come back in the pancreas or in other parts of the body.
HOW TO TREAT PANCREATIC CANCER?
There are different types of treatment for patients with pancreatic cancer.
Different types of treatment are available for patients with pancreatic cancer. Some treatments are standard (the currently used treatment), and some are being tested.
Three types of standard treatment are used:
Surgery
One of the following types of surgery may be used to take out the tumor:
Whipple procedure: A surgical procedure in which the head of the pancreas, the gallbladder, part of the stomach, part of the small intestine, and the bile duct are removed. Enough of the pancreas is left to produce digestive juices and insulin.
Ampullary carcinoma. The darker tissue at the top of the photograph is an opened segment of duodenum. The tumor is light tan and the orange-tan tissue is the pancreatic head
Total pancreatectomy: This operation removes the whole pancreas, part of the stomach, part of the small intestine, the common bile duct, the gallbladder, the spleen, and nearby lymph nodes.
Distal pancreatectomy: The body and the tail of the pancreas and usually the spleen are removed.
If the cancer has spread and cannot be removed, the following types of palliative surgery may be done to relieve symptoms:
Surgical biliary bypass
Endoscopic stent placement
Gastric bypass
Radiation therapy
There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer.
Chemotherapy
Even after surgical resection, there are at least 70% risk of locoregional recurrence. Therefore, adjuvant chemotherapy and radiation therapy should be given. The followingregimen showed a significantly prolonged median survival of 20 months versus 11 months for controls with 43% 2-year actual survival(versus 18% for controls).are recommended.
5-FU,500mg/m2/dayby i.v. bolus for the first 3 days of each 200-cGy segment of radiotherapy(total dose/3 day course of 5-FU,1 500mg/m2),followed by
5-FU, 500mg/m2/week by i.v. bolus injection,weekly for up to 2 years.
Commonly recommended regimens are as below as well:
4 500 to 5 400 cGy in divided doses with 5-FU,500mg/m2 /day daily on the first and last 3 days of radiation. Median survival is about 10 months with this treatment.
Gemcitabine,1 000 mg/m2/week i.v. weekly for 3 weeks(day 1,8 and 15) followed by 1 week without gemcitabine(total dose/cycle,
3 000mg/m2).Treatment cycles are repeated every 28 days.
Other types of treatment are being tested in clinical trials. These include the following:
Biologic therapy
Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy. Dendritic cell vaccine may be choice.
There are treatments for pain caused by pancreatic cancer.
Pain can occur when the tumor presses on nerves or other organs near the pancreas. When pain medicine is not enough, there are treatments that act on nerves in the abdomen to relieve the pain. The doctor may inject medicine into the area around affected nerves or may cut the nerves to block the feeling of pain. Radiation therapy with or without chemotherapy can also help relieve pain by shrinking the tumor.
Patients with pancreatic cancer have special nutritional needs.
Surgery to remove the pancreas may interfere with the production of pancreatic enzymes that help to digest food. As a result, patients may have problems digesting food and absorbing nutrients into the body. To prevent malnutrition, the doctor may prescribe medicines that replace these enzymes.
Treatment Options by Stage
Stage I Pancreatic Cancer
Treatment of stage I pancreatic cancer may include the following:
Surgery alone.
Surgery with chemotherapy and radiation therapy.
A clinical trial of surgery followed by radiation therapy with chemotherapy. Chemotherapy is given before, during, and after the radiation therapy.
A clinical trial of surgery followed by chemotherapy.
Stage IIA Pancreatic Cancer
Treatment of stage IIA pancreatic cancer may include the following:
Surgery with or without chemotherapy and radiation therapy.
Radiation therapy with chemotherapy.
Palliative surgery to bypass blocked areas in ducts or the small intestine.
A clinical trial of surgery followed by radiation therapy with chemotherapy. Chemotherapy is given before, during, and after the radiation therapy.
A clinical trial of surgery followed by chemotherapy.
A clinical trial of biologic therapy with radiation therapy and/or chemotherapy.
A clinical trial of radiation therapy combined with chemotherapy and/or radiosensitizers (drugs that make cancer cells more sensitive to radiation so more tumor cells are killed), followed by surgery.
A clinical trial of radiation therapy given during surgery or internal radiation therapy.
Stage IIB Pancreatic Cancer
Treatment of stage IIB pancreatic cancer may include the following:
Surgery with or without chemotherapy and radiation therapy.
Radiation therapy with chemotherapy.
Palliative surgery to bypass blocked areas in ducts or the small intestine.
A clinical trial of surgery followed by radiation therapy with chemotherapy. Chemotherapy is given before, during, and after the radiation therapy.
A clinical trial of surgery followed by chemotherapy.
A clinical trial of biologic therapy with radiation therapy and/or chemotherapy.
A clinical trial of radiation therapy combined with chemotherapy and/or radiosensitizers, followed by surgery.
A clinical trial of radiation therapy given during surgery or internal radiation therapy.
Stage III Pancreatic Cancer
Treatment of stage III pancreatic cancer may include the following:
Surgery with or without chemotherapy and radiation therapy.
Radiation therapy with chemotherapy.
Palliative surgery or stent placement to bypass blocked areas in ducts or the small intestine.
A clinical trial of surgery followed by radiation therapy with chemotherapy. Chemotherapy is given before, during, and after the radiation therapy.
A clinical trial of surgery followed by chemotherapy.
A clinical trial of biologic therapy with radiation therapy and/or chemotherapy.
A clinical trial of radiation therapy combined with chemotherapy and/or radiosensitizers, which may be followed by surgery.
A clinical trial of radiation therapy given during surgery or internal radiation therapy.
Stage IV Pancreatic Cancer
Treatment of stage IV pancreatic cancer may include the following:
Chemotherapy.
Palliative treatments for pain, such as nerve blocks, and other supportive care.
Palliative surgery or stent placement to bypass blocked areas in ducts or the small intestine.
Clinical trials of chemotherapy or biologic therapy.
Treatment Options for Recurrent Pancreatic Cancer
Treatment of recurrent pancreatic cancer may include the following:
Chemotherapy.
Palliative surgery or stent placement to bypass blocked areas in ducts or the small intestine.
Palliative radiation therapy.
Other palliative medical care to reduce symptoms, such as nerve blocks to relieve pain.
Clinical trials of chemotherapy or biologic therapy.
NOVAL THERAPIES
Cryosurgery: Experimental cryodestruction of the pancreas performed in 40 dogs served as a basis for selecting the temperature regimen, exposure time and extent of treatment to be subsequently used in man. Cryodestruction and combined cryoradiotherapy were employed in 30 patients with locally advanced pancreatic cancer. The procedure proved effective as it assured alleviation of pain, improvement in performance status and an increase in survival. CA-19-9 level and T-lymphocyte count, which may be used to predict progression of pancreatic cancer. were followed.
125Iodine seeds implantation: Radioactive Iodine-125 seeds were implanted intraoperatively into the tumor to deliver a minimum peripheral dose of 12,000 cGy over one year. This was followed by external beam radiation (50-55 Gy) and systemic chemotherapy (5-FU, Mitomycin-C +/- CCNU). Incidence of peri-operative mortality was 5% (4/81). Early morbidity was observed in 34% of patients and late complications in 32%. A median survival of 12 months and 2- and 5-year survival rates of 21% and 7% were observed. The determinate 2- and 5-year survival rates were 28% and 13%, respectively. The overall 2- and 5-year survival rates with Stage II disease were 27% and 8% and for Stage III disease, 13% and 3%, respectively (p less than 0.05). The determinate 2- and 5-year survival rates were 34% and 19% for Stage II and 19% and 5% for Stage III disease, respectively (p = 0.08). Local control of disease was achieved in 71% of patients. This combined modality approach appears to have achieved satisfactory local control of primary cancer and long term survival of selected patients.
Ultrasonically guided percutaneous implantation of 125I seeds were performed in 19 patients with cancer of the pancreas in our hospital. Satisfactory seed placement and delivery of the planned radiation dose and clinical improvement was seen in most cases. No difference in survival or palliation was observed between patients treated with seeds alone compared with patients treated with seeds and external radiation. Survival after seed implantation was median 140 days, range 7-401 days. It is considered that ultrasonically guided percutaneous implantation of 125I seeds can be recommended in the treatment of unresectable carcinoma of the pancreas.
Photodynamic therapy:Photodynamic therapy produces local necrosis of tissue with light after prior administration of a photosensitising agent, and in experimental studies can be tolerated by the pancreas and surrounding normal tissue. Patients were photosensitised with 0.15 mg/kg meso-tetrahydroxyphenyl chlorin intravenously. Three days later, light was delivered to the cancer percutaneously using fibres positioned under computerised tomographic guidance. Sixteen patients with inoperable adenocarcinomas (2.5-6 cm in diameter) localised to the region of the head of the pancreas were studied. All presented with obstructive jaundice which was relieved by biliary stenting prior to further treatment. All patients had substantial tumour necrosis on scans after treatment. Eleven had a Karnofsky performance status of 100 prior to treatment. In 10 it returned to 100 at one month. There was no treatment related mortality. The median survival time after photodynamic therapy was 9.5 months (range 4-30). Seven of 16 patients (44%) were alive one year after photodynamic therapy. Therefore, photodynamic therapy can produce necrosis in pancreatic cancers, is a available therapy for pancreatic carcinoma.
HOW TO ESTIMATE PROGNOSIS?
Certain factors affect prognosis (chance of recovery) and treatment options.
The prognosis (chance of recovery) and treatment options depend on the following:
Whether or not the tumor can be removed by surgery.
The stage of the cancer (the size of the tumor and whether the cancer has spread outside the pancreas to nearby tissues or lymph nodes or to other places in the body).
The patient’s general health.
Whether the cancer has just been diagnosed or has recurred (come back).
Pancreatic cancer can be controlled only if it is found before it has spread, when it can be removed by surgery. If the cancer has spread, palliative treatment can improve the patient's quality of life by controlling the symptoms and complications of this disease.
Ovarian Cancer
WHAT IS OVARIAN CANCER?
Ovarian epithelial cancer is a disease in which malignant (cancer) cells form in the tissue covering the ovary.
The ovaries are a pair of organs in the female reproductive system. They are located in the pelvis, one on each side of the uterus (the hollow, pear-shaped organ where a fetus grows). Each ovary is about the size and shape of an almond. The ovaries produce eggs and female hormones (chemicals that control the way certain cells or organs function).
Several malignancies arise from the ovary. Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies and the fifth most frequent cause of cancer death in women, with half of all cases occurring in women over age 65.
WHAT ARE RISK FACTORS OF OVARIAN CANCER?
Women who have a family history of ovarian cancer are at an increased risk of developing ovarian cancer.
The most important risk factor for ovarian cancer is a family history of a first-degree relative (mother, daughter, or sister) with the disease. The highest risk appears in women with 2 or more first-degree relatives with ovarian cancer. The risk is somewhat less for women with one first-degree and one second-degree relative (grandmother or aunt) with ovarian cancer.
In most families affected with the breast and ovarian cancer syndrome or site-specific ovarian cancer, genetic linkage has been found to the BRCA1 locus on chromosome 17q21. BRCA2, also responsible for some instances of inherited ovarian and breast cancer, has been mapped by genetic linkage to chromosome 13q12. The lifetime risk for developing ovarian cancer in patients harboring germline mutations in BRCA1 is substantially increased over the general population. Two retrospective studies of patients with germline mutations in BRCA1 suggest that these women have improved survival compared to BRCA1 negative women. When interpreting these data, it must be considered that the majority of women with a BRCA1 mutation probably have family members with a history of ovarian and/or breast cancer.
Some ovarian cancers are caused by inherited gene mutations (changes).
The genes in cells carry the hereditary information that is received from a person’s parents. Hereditary ovarian cancer makes up approximately 5% to 10% of all cases of ovarian cancer. Three hereditary patterns have been identified: ovarian cancer alone, ovarian and breast cancers, and ovarian and colon cancers.
Women with an increased risk of ovarian cancer may consider surgery to prevent it.
Some women who have an increased risk of ovarian cancer may choose to have a prophylactic oophorectomy (the removal of healthy ovaries so that cancer cannot grow in them). It is not known if this procedure prevents ovarian cancer.
HOW TO DETECT OVARIAN CANCER?
Ovarian cancer is hard to detect (find) early because usually there are no symptoms.
Some women who have early stage ovarian cancer may have symptoms such as vague gastrointestinal (GI) discomfort, pressure in the pelvis, pain, swelling of the abdomen, and shortness of breath. Most of the time, there are no symptoms or they are very mild. By the time symptoms do appear, the cancer is usually advanced.
Tests that examine the ovaries, pelvic area, blood, and ovarian tissue are used to detect (find) and diagnose ovarian cancer.
The following tests and procedures may be used:
Pelvic exam: An exam of the vagina, cervix, uterus, fallopian tubes, ovaries, and rectum. The doctor or nurse inserts one or two lubricated, gloved fingers of one hand into the vagina and the other hand is placed over the lower abdomen to feel the size, shape, and position of the uterus and ovaries. A speculum is also inserted into the vagina and the doctor or nurse looks at the vagina and cervix for signs of disease. A Pap test or Pap smear of the cervix is usually done. The doctor or nurse also inserts a lubricated, gloved finger into the rectum to feel for lumps or abnormal areas.
Ultrasound: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.
CA 125 assay: A test that measures the level of CA 125 in the blood. CA 125 is a substance released by cells into the bloodstream. An increased CA 125 level is sometimes a sign of cancer or other condition.
Barium enema(lower GI series): A series of x-rays of the lower gastrointestinal tract. A liquid that contains barium (a silver-white metallic compound) is put into the rectum. The barium coats the lower gastrointestinal tract and x-rays are taken. This procedure is also called a lower GI series.
Intravenous pyelogram (IVP): A series of x-rays of the kidneys, ureters, and bladder to find out if cancer is present in these organs. A contrast dye is injected into a vein. As the contrast dye moves through the kidneys, ureters, and bladder, x-rays are taken to see if there are any blockages.
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
Biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer. The tissue is removed in a procedure called a laparotomy (a surgical incision made in the wall of the abdomen).
WHAT IS STAGE OF OVARIAL CANCER?
The Federation Internationale de Gynecologie et d’Obstetrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging. The stage of classifications is helpful for making therapy and determing prognosis.
Stage I
Stage I ovarian cancer is limited to the ovaries.
Stage IA: Tumor limited to 1 ovary; capsule intact, no tumor on ovarian surface. No malignant cells in ascites or peritoneal washings.
Stage IB: Tumor limited to both ovaries; capsules intact, no tumor on ovarian surface. No malignant cells in ascites or peritoneal washings.*
Stage IC: Tumor limited to 1 or both ovaries with any of the following: capsule ruptured, tumor on ovarian surface, malignant cells in ascites or peritoneal washings.
Stage II
Stage II ovarian cancer is tumor involving 1 or both ovaries with pelvic extension and/or implants.
Stage IIA: Extension and/or implants on the uterus and/or fallopian tubes. No malignant cells in ascites or peritoneal washings.
Stage IIB: Extension to and/or implants on other pelvic tissues. No malignant cells in ascites or peritoneal washings.
Stage IIC: Pelvic extension and/or implants (stage IIA or IIB) with malignant cells in ascites or peritoneal washings.
Stage III
Stage III ovarian cancer is tumor involving 1 or both ovaries with microscopically confirmed peritoneal implants outside the pelvis. Superficial liver metastasis equals stage III. Tumor is limited to the true pelvis but with histologically verified malignant extension to small bowel or omentum.
Stage IIIA: Microscopic peritoneal metastasis beyond pelvis (no macroscopic tumor).
Stage IIIB: Macroscopic peritoneal metastasis beyond pelvis 2 cm or less in greatest dimension.
Stage IIIC: Peritoneal metastasis beyond pelvis more than 2 cm in greatest dimension and/or regional lymph node metastasis.
Stage IV
Stage IV ovarian cancer is tumor involving 1 or both ovaries with distant metastasis. If pleural effusion is present, there must be positive cytologic test results to designate a case to stage IV. Parenchymal liver metastasis equals stage IV.
HOW TO TREAT OVARIAL CANCER?
Stage I Ovarian Epithelial Cancer
Standard treatment options
If the tumor is well or moderately well differentiated, total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy is adequate for patients with stage IA and IB disease.
If the tumor is grade III, densely adherent, or stage IC, the chance of relapse and subsequent death from ovarian cancer is substantial (up to 20%), although the importance of tumor rupture if it is the only adverse characteristic is not clear. Several treatment approaches that have been taken in such patients are listed below.
Intraperitoneal P-32 or radiation therapy.
Systemic chemotherapy.
Total abdominal and pelvic radiation therapy.
Careful observation without immediate treatment in selected patients (watchful waiting).
As yet, no randomized trial has demonstrated a survival advantage for one of these approaches over another, nor has immediate treatment been shown to prolong life relative to treatment at relapse.
Stage II Ovarian Epithelial Cancer
Standard treatment options
Surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy and tumor debulking to remove all or most of the tumor. If there is no clinically apparent disease outside of the pelvis and systemic therapy is contemplated, additional staging procedures, while possibly influencing choice of therapy, may not influence survival. The options for further treatment include:
If minimal postsurgical residual disease (<1 cm) remains, systemic chemotherapy:
TP: paclitaxel (Taxol) + cisplatin or carboplatin.
CP: cyclophosphamide + cisplatin.
CC: cyclophosphamide + carboplatin.
Total abdominal and pelvic radiation therapy (only if there is no macroscopic upper abdominal disease, and minimal residual pelvic disease is <0.5 cm).
Intraperitoneal P-32 radiation therapy is less frequently used (only if residual tumor is <1 mm). This option is associated with a significant number of late bowel complications.
If macroscopic postsurgical residual disease (>2 cm) remains in the pelvis, combination chemotherapy should be used. The following regimens are commonly used:
TP.
CP
CC.
Stage III and IV Ovarian Epithelial Cancer
The same observations concerning surgery and chemotherapy pertain to patients with stage III or IV disease; however, the outcome of patients with stage IV disease is somewhat less favorable. The role of surgery for patients with stage IV disease is unclear, but in most instances, the bulk of the disease is intra-abdominal and similar surgical procedures are applied as in the management of stage III patients. Also, the options for intraperitoneal (IP) regimens are less likely to apply both practically (as far as inserting an IP catheter at the outset) and theoretically (aimed towards destroying microscopic disease in the peritoneal cavity).
Standard treatment options
Surgery
Surgery has been used as a therapeutic modality and also to adequately stage the disease. Surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy and debulking of as much gross tumor as can safely be performed.
Surgery has a role in reassessment to determine the extent of residual disease, if any, following the initial (induction) chemotherapy.
Approximately one third of patients found to have macroscopic tumor at second-look surgery achieve complete cytoreduction resulting in microscopic residual disease, approximately one third achieve partial debulking resulting in optimal residual disease, and the remainders are left with bulky tumors. Some have reported improved survival in patients who achieve optimal secondary debulking, while others report survival benefit for those left with microscopic disease only. Whether the survival benefit of complete secondary cytoreduction is a function of the surgical debulking or a reflection of the characteristics of the tumor that permits complete cytoreduction is not known. Since there are no controlled clinical trials that demonstrate a survival advantage for the second-look operation, it is often performed either as part of a clinical trial or when a prescribed second-line therapy is being tested. Finally, reassessment surgery has been linked to the introduction of IP catheters, in order to test the pharmacologically derived concept of IP consolidation with drugs delivered directly into the peritoneal cavity. A number of IP regimens have been tested, and phase III trials have provided support for the validity of this concept.
Intraperitoneal regimens
A pharmacologic advantage for this route possibly resulting in an improved outcome pertains only to the minimal or no residual disease setting. Therefore, the extent of residual disease after the initial surgery or at reassessment has been used to guide the development of these treatment strategies. Early reports suggested a role for IP chemotherapy by demonstrating surgically defined complete response rates and prolonged survival in approximately 25% to 35% of patients with small-volume residual persistent disease after a variety of IP regimens. Outcome was particularly favorable in patients defined as platinum-sensitive, a feature indicative of a greater overall responsiveness to other treatments as well.
The use of IP cisplatin as part of the initial up-front approach in stage III optimally-debulked ovarian cancer is supported by the results of 3 randomized clinical trials. These studies tested the role of IP drugs (IP cisplatin in all 3 studies, and IP paclitaxel in the last study) versus the standard IV regimen. In all 3 studies superior progression-free survival was documented favoring the IP arm, and in the 2 fully reported to date, the overall survival was also significantly better in the IP arm.
Chemotherapy options
First-line chemotherapy has been built on 2 premises supported by retrospective analyses and consecutive clinical trials by cooperative groups:
Platinum compounds, up to an “optimal dose-intensity,” represent the core of the treatment (e.g., platinum-based chemotherapy). Clinical trials escalating the drug to 100 mg/m2 every 3 weeks did not support an advantage over 50 mg/m2 every 3 weeks, and adopted 75 mg/m2 as the standard. Similarly for carboplatin, a large retrospective study suggested improved outcome up to a target area under the curve (AUC) of 5, and then a plateau in effectiveness in spite of increasing drug exposure.
Cisplatin and carboplatin yield equivalent results. Several clinical trials supporting the introduction of carboplatin into the clinic demonstrated it yielded similar results in ovarian cancer as cisplatin.
Specifically, treatments that have been advocated and tested fall within the following categories:
Lengthening the number of cycles of the induction platinum-based chemotherapy (however, a single-institution randomized trial of 5 versus 10 cycles was negative). Continuing paclitaxel once a complete clinical response to induction chemotherapy has been achieved. Monthly paclitaxel after a clinical complete response, given for 12 months, has demonstrated a statistically significant advantage in progression-free survival (median 28 months) for these patients over those receiving paclitaxel for only 3 months (median progression-free survival = 21 months). This study of 206 patients was terminated early and is unlikely to be informative with respect to overall survival. Whether to provide maintenance treatment, as given in this study, or to treat upon progression is still uncertain. Moreover, maintenance paclitaxel is associated with increased neuropathy (>25%).
Integrating other active drugs.
Consolidation with high-dose chemotherapy, whether in complete remission or after positive reassessment. Encouraging results from high-dose chemotherapy series and bone-marrow and stem cell autotransplants have been reported. However, the reported benefit appeared confined to patients with platinum-sensitive and small-volume tumors – a situation associated with median survivals that exceed 3 years, often with standard measures alone.
Treatment options under clinical evaluation:
Chemotherapy. Trials are ongoing integrating active drugs in induction, consolidation, or maintenance regimens, added to or following initial carboplatin-based or cisplatin-based treatments.
Other treatments. IP radioimmunoconjugates, vaccines, and targeted drugs are under clinical evaluation, primarily as consolidation therapy
Recurrent Ovarian Epithelial Cancer
It is important to determine the interval between the completion of therapy with cisplatin or carboplatin and the development of recurrent disease. Patients who have had a significant response to cisplatin or carboplatin may respond to treatment with one of these agents; the likelihood that a patient will respond increases as the length of time since the patient was last treated increases. Other platinum agents, such as oxaliplatin, have activity and could be considered. Intraperitoneal (IP) therapy is usually not given beyond consolidation, but could be considered for those patients with low-volume disease and no single nodule greater than 1 cm.
For patients whose disease is platinum-refractory (i.e., with disease that has progressed while on a platinum regimen or that has recurred shortly after completion of a platinum-containing regimen), treatment with paclitaxel (Taxol) historically provided the first agent with consistent activity in these patients and should be considered. Responses have been observed in patients whose disease is platinum-sensitive and those whose disease is platinum-refractory. The primary toxic effect is reversible neutropenia; other rare toxic effects include anaphylactoid reactions (thought to be due to the Cremophor vehicle and/or rapid intravenous administration), cardiac arrhythmias, and peripheral neuropathy. The overall response rate is higher in patients with recurrent ovarian cancer treated with paclitaxel and carboplatin or cisplatin.
Several randomized trials have addressed whether the use of combination therapy is superior to single agents, and the outcome of one of these studies has been published. Overall, in comparison to nonpaclitaxel-containing platinum-based treatment (carboplatin alone in 71%), the use of a platinum-containing regimen with paclitaxel (carboplatin + paclitaxel in 80%) resulted in a prolonged progression-free survival (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.66-0.89, P=.0004; difference at 1 year 10% [50% versus 40%] CI 4% to 15%). Survival was also improved on the carboplatin plus paclitaxel-containing arm (HR 0.82; 95% CI 0.69-0.97; P=.023; difference at 2 years 7% [57% versus 50%] CI 1% to 12%).
Standard treatment options
For patients with platinum-sensitive disease (i.e., a minimum of 5-12 months between completion of a platinum-based regimen and the development of recurrent disease), re-treatment with cisplatin or carboplatin should be considered.
For patients with platinum-refractory disease (i.e., disease that has progressed while on a platinum-based regimen or has recurred shortly after completion of a platinum-based regimen), treatment with paclitaxel should be considered. In a salvage setting, 3-hour infusions are safe, less myelotoxic, and equally effective.
No studies have clearly demonstrated that secondary cytoreduction confers a survival advantage, and its role remains controversial. However, 100 patients with recurrent or progressive disease after standard cytoreduction and platinum-based chemotherapy were re-explored. The 61 patients who had successful cytoreduction (greatest residual tumor diameter <2 cm) had a statistically significant prolongation of survival. Multivariate analyses revealed the cytoreduction to be the most important variable influencing survival. Whether the success of cytoreduction is related to the biologic nature of the tumor is not known.
When disease-related symptoms can be abrogated, surgical intervention may improve the quality of life, such as the reversal of small or large bowel obstruction. However, palliation is rarely achieved when there are multiple areas of partial or complete obstruction, when the transit time is prolonged due to diffuse peritoneal carcinomatosis, or when anatomy requires a bypass that results in the short bowel syndrome.
Other salvage chemotherapy, including several single agents that have been shown to have activity in refractory ovarian cancer, should be considered:
Liposomal doxorubicin: A phase II study of encapsulated doxorubicin given intravenously once every 21 to 28 days demonstrated 1 complete response and 8 partial responses in 35 patients with platinum-refractory or paclitaxel-refractory disease (relative risk = 25.7%). In general, liposomal doxorubicin is well tolerated. The most frequent toxic effects, which are more pronounced following higher doses or when liposomal doxorubicin is given every 3 weeks, include neutropenia, stomatitis, and hand-foot syndrome. Oral and cutaneous toxic effects completely resolve within 5 weeks of drug administration. Nausea is minimal and alopecia rarely occurs.
Topotecan: A topoisomerase I inhibitor, topotecan has been extensively evaluated as a single agent in patients with recurrent epithelial ovarian cancer. In phase II studies of topotecan administered intravenously on days 1 to 5 of a 21-day cycle, objective response rates ranging from 13% to 16.3% have been reported. Objective responses are reported in patients with platinum-refractory disease. Substantial myelosuppression follows administration. Other toxic effects include nausea, vomiting, alopecia, and, rarely, asthenia.
Liposomal doxorubicin and topotecan have been compared in a randomized trial of 474 patients with recurrent ovarian cancer. Response rates (19.7% versus 17.0%, P=.390), progression-free survival (16.1 weeks versus 17.0 weeks; P=.095), and overall survival (60 weeks versus 56.7 weeks, P=.341) did not differ significantly between the liposomal doxorubicin and topotecan arms, respectively.
Gemcitabine: A pyrimidine antimetabolite with similarities to cytosine arabinoside, gemcitabine has shown activity in patients with recurrent ovarian cancer. The response rate ranges from 13% to 19% in evaluable patients. Responses have been observed in patients who are platinum-refractory and/or paclitaxel-refractory as well as in patients with bulky disease.
Fluorouracil and leucovorin: In platinum-resistant recurrent disease, an objective response rate of 10% to 17% has been reported.
Tamoxifen: Some patients (18%) will respond to tamoxifen (20 mg twice daily). A response is more likely in patients with detectable levels of cytoplasmic estrogen receptor on their tumors.
Etoposide: Oral low doses have generated response rates from 6% to 26%.
Ifosfamide: Modest activity has been demonstrated in patients with epithelial ovarian cancer, including disease that is platinum-refractory.
Hexamethylmelamine (HMM): There have been several encouraging reports of orally-administered HMM as salvage chemotherapy after failure of cisplatin-based combination regimens. Response rates in platinum-resistant patients are 12% to 14%.
Some reports suggest a potential role for IP chemotherapy to treat patients with advanced ovarian cancer. Surgically defined complete response occurs in about 30% of patients who have low-volume disease at initiation of therapy (no nodule >0.5 cm). This surgical complete response may have a favorable impact on survival.
NOVAL THERAPIES
High-dose chemotherapy with stem cell transplant
There is evidence that high-dose chemotherapy with stem cell(or bone marrow) transplantation is superior to conventional chemotherapy in relapsed ovarian cancer.
Cryoablation:Percutaneous cryoablation may be used for unresectable ovarial cancer due to patient performance or disease factor.This is a mini-invational therapy and less damage to patient.
Dendritic cell vaccine: Immunomodality is helpful to control ovarial cancer.One such approach uses bone marrow-derived dendritic cells (DCs), phenotypically distinct and very potent antigen-presenting cells, to present tumour-associated antigens (TAAgs) and, thereby, generate tumour-specific immunity. Many observations have led to clinical trials designed to investigate the immunological and clinical effects of Ag-pulsed DCs administered as a therapeutic vaccine to patients with cancer. Although current DC-based vaccination methods are cumbersome and complex, promising preliminary results from clinical trials in patients with ovarial cancer,malignant lymphoma, melanoma, and prostate cancer suggest that immuno-therapeutic strategies, that take advantage of the unique properties of DCs, may ultimately prove both efficacious and widely applicable treatment in patients with cancer.
HOW IS PROGNOSIS OF OVARIAL CANCER?
Ovarian cancer usually spreads via local shedding into the peritoneal cavity followed by implantation on the peritoneum, and via local invasion of bowel and bladder. The incidence of positive nodes at primary surgery has been reported as high as 24% in patients with stage I disease, 50% in patients with stage II disease, 74% in patients with stage III disease, and 73% in patients with stage IV disease.
Prognosis in ovarian cancer is influenced by several factors, but multivariate analyses suggest that the most important favorable factors include:
Younger age.
Good performance status.
Cell type other than mucinous and clear cell.
Lower stage.
Well-differentiated tumor.
Smaller disease volume prior to any surgical debulking.
Absence of ascites.
Smaller residual tumor following primary cytoreductive surgery.
For patients with stage I disease, the most important prognostic factor is grade, followed by dense adherence and large-volume ascites. DNA flow cytometric analysis of stage I and stage IIA patients may identify a group of high-risk patients. Patients with clear cell histology appear to have a worse prognosis. Patients with a significant component of transitional cell carcinoma appear to have a better prognosis..
Although the ovarian cancer-associated antigen, CA 125, has no prognostic significance when measured at the time of diagnosis, it has a high correlation with survival when measured 1 month after the third course of chemotherapy for patients with stage III or stage IV disease. For patients whose elevated CA 125 normalizes with chemotherapy, more than 1 subsequent elevated CA 125 measurement is highly predictive of active disease, but this does not mandate immediate therapy.
Ovarian epithelial cancer is a disease in which malignant (cancer) cells form in the tissue covering the ovary.
The ovaries are a pair of organs in the female reproductive system. They are located in the pelvis, one on each side of the uterus (the hollow, pear-shaped organ where a fetus grows). Each ovary is about the size and shape of an almond. The ovaries produce eggs and female hormones (chemicals that control the way certain cells or organs function).
Several malignancies arise from the ovary. Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies and the fifth most frequent cause of cancer death in women, with half of all cases occurring in women over age 65.
WHAT ARE RISK FACTORS OF OVARIAN CANCER?
Women who have a family history of ovarian cancer are at an increased risk of developing ovarian cancer.
The most important risk factor for ovarian cancer is a family history of a first-degree relative (mother, daughter, or sister) with the disease. The highest risk appears in women with 2 or more first-degree relatives with ovarian cancer. The risk is somewhat less for women with one first-degree and one second-degree relative (grandmother or aunt) with ovarian cancer.
In most families affected with the breast and ovarian cancer syndrome or site-specific ovarian cancer, genetic linkage has been found to the BRCA1 locus on chromosome 17q21. BRCA2, also responsible for some instances of inherited ovarian and breast cancer, has been mapped by genetic linkage to chromosome 13q12. The lifetime risk for developing ovarian cancer in patients harboring germline mutations in BRCA1 is substantially increased over the general population. Two retrospective studies of patients with germline mutations in BRCA1 suggest that these women have improved survival compared to BRCA1 negative women. When interpreting these data, it must be considered that the majority of women with a BRCA1 mutation probably have family members with a history of ovarian and/or breast cancer.
Some ovarian cancers are caused by inherited gene mutations (changes).
The genes in cells carry the hereditary information that is received from a person’s parents. Hereditary ovarian cancer makes up approximately 5% to 10% of all cases of ovarian cancer. Three hereditary patterns have been identified: ovarian cancer alone, ovarian and breast cancers, and ovarian and colon cancers.
Women with an increased risk of ovarian cancer may consider surgery to prevent it.
Some women who have an increased risk of ovarian cancer may choose to have a prophylactic oophorectomy (the removal of healthy ovaries so that cancer cannot grow in them). It is not known if this procedure prevents ovarian cancer.
HOW TO DETECT OVARIAN CANCER?
Ovarian cancer is hard to detect (find) early because usually there are no symptoms.
Some women who have early stage ovarian cancer may have symptoms such as vague gastrointestinal (GI) discomfort, pressure in the pelvis, pain, swelling of the abdomen, and shortness of breath. Most of the time, there are no symptoms or they are very mild. By the time symptoms do appear, the cancer is usually advanced.
Tests that examine the ovaries, pelvic area, blood, and ovarian tissue are used to detect (find) and diagnose ovarian cancer.
The following tests and procedures may be used:
Pelvic exam: An exam of the vagina, cervix, uterus, fallopian tubes, ovaries, and rectum. The doctor or nurse inserts one or two lubricated, gloved fingers of one hand into the vagina and the other hand is placed over the lower abdomen to feel the size, shape, and position of the uterus and ovaries. A speculum is also inserted into the vagina and the doctor or nurse looks at the vagina and cervix for signs of disease. A Pap test or Pap smear of the cervix is usually done. The doctor or nurse also inserts a lubricated, gloved finger into the rectum to feel for lumps or abnormal areas.
Ultrasound: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.
CA 125 assay: A test that measures the level of CA 125 in the blood. CA 125 is a substance released by cells into the bloodstream. An increased CA 125 level is sometimes a sign of cancer or other condition.
Barium enema(lower GI series): A series of x-rays of the lower gastrointestinal tract. A liquid that contains barium (a silver-white metallic compound) is put into the rectum. The barium coats the lower gastrointestinal tract and x-rays are taken. This procedure is also called a lower GI series.
Intravenous pyelogram (IVP): A series of x-rays of the kidneys, ureters, and bladder to find out if cancer is present in these organs. A contrast dye is injected into a vein. As the contrast dye moves through the kidneys, ureters, and bladder, x-rays are taken to see if there are any blockages.
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
Biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer. The tissue is removed in a procedure called a laparotomy (a surgical incision made in the wall of the abdomen).
WHAT IS STAGE OF OVARIAL CANCER?
The Federation Internationale de Gynecologie et d’Obstetrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging. The stage of classifications is helpful for making therapy and determing prognosis.
Stage I
Stage I ovarian cancer is limited to the ovaries.
Stage IA: Tumor limited to 1 ovary; capsule intact, no tumor on ovarian surface. No malignant cells in ascites or peritoneal washings.
Stage IB: Tumor limited to both ovaries; capsules intact, no tumor on ovarian surface. No malignant cells in ascites or peritoneal washings.*
Stage IC: Tumor limited to 1 or both ovaries with any of the following: capsule ruptured, tumor on ovarian surface, malignant cells in ascites or peritoneal washings.
Stage II
Stage II ovarian cancer is tumor involving 1 or both ovaries with pelvic extension and/or implants.
Stage IIA: Extension and/or implants on the uterus and/or fallopian tubes. No malignant cells in ascites or peritoneal washings.
Stage IIB: Extension to and/or implants on other pelvic tissues. No malignant cells in ascites or peritoneal washings.
Stage IIC: Pelvic extension and/or implants (stage IIA or IIB) with malignant cells in ascites or peritoneal washings.
Stage III
Stage III ovarian cancer is tumor involving 1 or both ovaries with microscopically confirmed peritoneal implants outside the pelvis. Superficial liver metastasis equals stage III. Tumor is limited to the true pelvis but with histologically verified malignant extension to small bowel or omentum.
Stage IIIA: Microscopic peritoneal metastasis beyond pelvis (no macroscopic tumor).
Stage IIIB: Macroscopic peritoneal metastasis beyond pelvis 2 cm or less in greatest dimension.
Stage IIIC: Peritoneal metastasis beyond pelvis more than 2 cm in greatest dimension and/or regional lymph node metastasis.
Stage IV
Stage IV ovarian cancer is tumor involving 1 or both ovaries with distant metastasis. If pleural effusion is present, there must be positive cytologic test results to designate a case to stage IV. Parenchymal liver metastasis equals stage IV.
HOW TO TREAT OVARIAL CANCER?
Stage I Ovarian Epithelial Cancer
Standard treatment options
If the tumor is well or moderately well differentiated, total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy is adequate for patients with stage IA and IB disease.
If the tumor is grade III, densely adherent, or stage IC, the chance of relapse and subsequent death from ovarian cancer is substantial (up to 20%), although the importance of tumor rupture if it is the only adverse characteristic is not clear. Several treatment approaches that have been taken in such patients are listed below.
Intraperitoneal P-32 or radiation therapy.
Systemic chemotherapy.
Total abdominal and pelvic radiation therapy.
Careful observation without immediate treatment in selected patients (watchful waiting).
As yet, no randomized trial has demonstrated a survival advantage for one of these approaches over another, nor has immediate treatment been shown to prolong life relative to treatment at relapse.
Stage II Ovarian Epithelial Cancer
Standard treatment options
Surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy and tumor debulking to remove all or most of the tumor. If there is no clinically apparent disease outside of the pelvis and systemic therapy is contemplated, additional staging procedures, while possibly influencing choice of therapy, may not influence survival. The options for further treatment include:
If minimal postsurgical residual disease (<1 cm) remains, systemic chemotherapy:
TP: paclitaxel (Taxol) + cisplatin or carboplatin.
CP: cyclophosphamide + cisplatin.
CC: cyclophosphamide + carboplatin.
Total abdominal and pelvic radiation therapy (only if there is no macroscopic upper abdominal disease, and minimal residual pelvic disease is <0.5 cm).
Intraperitoneal P-32 radiation therapy is less frequently used (only if residual tumor is <1 mm). This option is associated with a significant number of late bowel complications.
If macroscopic postsurgical residual disease (>2 cm) remains in the pelvis, combination chemotherapy should be used. The following regimens are commonly used:
TP.
CP
CC.
Stage III and IV Ovarian Epithelial Cancer
The same observations concerning surgery and chemotherapy pertain to patients with stage III or IV disease; however, the outcome of patients with stage IV disease is somewhat less favorable. The role of surgery for patients with stage IV disease is unclear, but in most instances, the bulk of the disease is intra-abdominal and similar surgical procedures are applied as in the management of stage III patients. Also, the options for intraperitoneal (IP) regimens are less likely to apply both practically (as far as inserting an IP catheter at the outset) and theoretically (aimed towards destroying microscopic disease in the peritoneal cavity).
Standard treatment options
Surgery
Surgery has been used as a therapeutic modality and also to adequately stage the disease. Surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy and debulking of as much gross tumor as can safely be performed.
Surgery has a role in reassessment to determine the extent of residual disease, if any, following the initial (induction) chemotherapy.
Approximately one third of patients found to have macroscopic tumor at second-look surgery achieve complete cytoreduction resulting in microscopic residual disease, approximately one third achieve partial debulking resulting in optimal residual disease, and the remainders are left with bulky tumors. Some have reported improved survival in patients who achieve optimal secondary debulking, while others report survival benefit for those left with microscopic disease only. Whether the survival benefit of complete secondary cytoreduction is a function of the surgical debulking or a reflection of the characteristics of the tumor that permits complete cytoreduction is not known. Since there are no controlled clinical trials that demonstrate a survival advantage for the second-look operation, it is often performed either as part of a clinical trial or when a prescribed second-line therapy is being tested. Finally, reassessment surgery has been linked to the introduction of IP catheters, in order to test the pharmacologically derived concept of IP consolidation with drugs delivered directly into the peritoneal cavity. A number of IP regimens have been tested, and phase III trials have provided support for the validity of this concept.
Intraperitoneal regimens
A pharmacologic advantage for this route possibly resulting in an improved outcome pertains only to the minimal or no residual disease setting. Therefore, the extent of residual disease after the initial surgery or at reassessment has been used to guide the development of these treatment strategies. Early reports suggested a role for IP chemotherapy by demonstrating surgically defined complete response rates and prolonged survival in approximately 25% to 35% of patients with small-volume residual persistent disease after a variety of IP regimens. Outcome was particularly favorable in patients defined as platinum-sensitive, a feature indicative of a greater overall responsiveness to other treatments as well.
The use of IP cisplatin as part of the initial up-front approach in stage III optimally-debulked ovarian cancer is supported by the results of 3 randomized clinical trials. These studies tested the role of IP drugs (IP cisplatin in all 3 studies, and IP paclitaxel in the last study) versus the standard IV regimen. In all 3 studies superior progression-free survival was documented favoring the IP arm, and in the 2 fully reported to date, the overall survival was also significantly better in the IP arm.
Chemotherapy options
First-line chemotherapy has been built on 2 premises supported by retrospective analyses and consecutive clinical trials by cooperative groups:
Platinum compounds, up to an “optimal dose-intensity,” represent the core of the treatment (e.g., platinum-based chemotherapy). Clinical trials escalating the drug to 100 mg/m2 every 3 weeks did not support an advantage over 50 mg/m2 every 3 weeks, and adopted 75 mg/m2 as the standard. Similarly for carboplatin, a large retrospective study suggested improved outcome up to a target area under the curve (AUC) of 5, and then a plateau in effectiveness in spite of increasing drug exposure.
Cisplatin and carboplatin yield equivalent results. Several clinical trials supporting the introduction of carboplatin into the clinic demonstrated it yielded similar results in ovarian cancer as cisplatin.
Specifically, treatments that have been advocated and tested fall within the following categories:
Lengthening the number of cycles of the induction platinum-based chemotherapy (however, a single-institution randomized trial of 5 versus 10 cycles was negative). Continuing paclitaxel once a complete clinical response to induction chemotherapy has been achieved. Monthly paclitaxel after a clinical complete response, given for 12 months, has demonstrated a statistically significant advantage in progression-free survival (median 28 months) for these patients over those receiving paclitaxel for only 3 months (median progression-free survival = 21 months). This study of 206 patients was terminated early and is unlikely to be informative with respect to overall survival. Whether to provide maintenance treatment, as given in this study, or to treat upon progression is still uncertain. Moreover, maintenance paclitaxel is associated with increased neuropathy (>25%).
Integrating other active drugs.
Consolidation with high-dose chemotherapy, whether in complete remission or after positive reassessment. Encouraging results from high-dose chemotherapy series and bone-marrow and stem cell autotransplants have been reported. However, the reported benefit appeared confined to patients with platinum-sensitive and small-volume tumors – a situation associated with median survivals that exceed 3 years, often with standard measures alone.
Treatment options under clinical evaluation:
Chemotherapy. Trials are ongoing integrating active drugs in induction, consolidation, or maintenance regimens, added to or following initial carboplatin-based or cisplatin-based treatments.
Other treatments. IP radioimmunoconjugates, vaccines, and targeted drugs are under clinical evaluation, primarily as consolidation therapy
Recurrent Ovarian Epithelial Cancer
It is important to determine the interval between the completion of therapy with cisplatin or carboplatin and the development of recurrent disease. Patients who have had a significant response to cisplatin or carboplatin may respond to treatment with one of these agents; the likelihood that a patient will respond increases as the length of time since the patient was last treated increases. Other platinum agents, such as oxaliplatin, have activity and could be considered. Intraperitoneal (IP) therapy is usually not given beyond consolidation, but could be considered for those patients with low-volume disease and no single nodule greater than 1 cm.
For patients whose disease is platinum-refractory (i.e., with disease that has progressed while on a platinum regimen or that has recurred shortly after completion of a platinum-containing regimen), treatment with paclitaxel (Taxol) historically provided the first agent with consistent activity in these patients and should be considered. Responses have been observed in patients whose disease is platinum-sensitive and those whose disease is platinum-refractory. The primary toxic effect is reversible neutropenia; other rare toxic effects include anaphylactoid reactions (thought to be due to the Cremophor vehicle and/or rapid intravenous administration), cardiac arrhythmias, and peripheral neuropathy. The overall response rate is higher in patients with recurrent ovarian cancer treated with paclitaxel and carboplatin or cisplatin.
Several randomized trials have addressed whether the use of combination therapy is superior to single agents, and the outcome of one of these studies has been published. Overall, in comparison to nonpaclitaxel-containing platinum-based treatment (carboplatin alone in 71%), the use of a platinum-containing regimen with paclitaxel (carboplatin + paclitaxel in 80%) resulted in a prolonged progression-free survival (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.66-0.89, P=.0004; difference at 1 year 10% [50% versus 40%] CI 4% to 15%). Survival was also improved on the carboplatin plus paclitaxel-containing arm (HR 0.82; 95% CI 0.69-0.97; P=.023; difference at 2 years 7% [57% versus 50%] CI 1% to 12%).
Standard treatment options
For patients with platinum-sensitive disease (i.e., a minimum of 5-12 months between completion of a platinum-based regimen and the development of recurrent disease), re-treatment with cisplatin or carboplatin should be considered.
For patients with platinum-refractory disease (i.e., disease that has progressed while on a platinum-based regimen or has recurred shortly after completion of a platinum-based regimen), treatment with paclitaxel should be considered. In a salvage setting, 3-hour infusions are safe, less myelotoxic, and equally effective.
No studies have clearly demonstrated that secondary cytoreduction confers a survival advantage, and its role remains controversial. However, 100 patients with recurrent or progressive disease after standard cytoreduction and platinum-based chemotherapy were re-explored. The 61 patients who had successful cytoreduction (greatest residual tumor diameter <2 cm) had a statistically significant prolongation of survival. Multivariate analyses revealed the cytoreduction to be the most important variable influencing survival. Whether the success of cytoreduction is related to the biologic nature of the tumor is not known.
When disease-related symptoms can be abrogated, surgical intervention may improve the quality of life, such as the reversal of small or large bowel obstruction. However, palliation is rarely achieved when there are multiple areas of partial or complete obstruction, when the transit time is prolonged due to diffuse peritoneal carcinomatosis, or when anatomy requires a bypass that results in the short bowel syndrome.
Other salvage chemotherapy, including several single agents that have been shown to have activity in refractory ovarian cancer, should be considered:
Liposomal doxorubicin: A phase II study of encapsulated doxorubicin given intravenously once every 21 to 28 days demonstrated 1 complete response and 8 partial responses in 35 patients with platinum-refractory or paclitaxel-refractory disease (relative risk = 25.7%). In general, liposomal doxorubicin is well tolerated. The most frequent toxic effects, which are more pronounced following higher doses or when liposomal doxorubicin is given every 3 weeks, include neutropenia, stomatitis, and hand-foot syndrome. Oral and cutaneous toxic effects completely resolve within 5 weeks of drug administration. Nausea is minimal and alopecia rarely occurs.
Topotecan: A topoisomerase I inhibitor, topotecan has been extensively evaluated as a single agent in patients with recurrent epithelial ovarian cancer. In phase II studies of topotecan administered intravenously on days 1 to 5 of a 21-day cycle, objective response rates ranging from 13% to 16.3% have been reported. Objective responses are reported in patients with platinum-refractory disease. Substantial myelosuppression follows administration. Other toxic effects include nausea, vomiting, alopecia, and, rarely, asthenia.
Liposomal doxorubicin and topotecan have been compared in a randomized trial of 474 patients with recurrent ovarian cancer. Response rates (19.7% versus 17.0%, P=.390), progression-free survival (16.1 weeks versus 17.0 weeks; P=.095), and overall survival (60 weeks versus 56.7 weeks, P=.341) did not differ significantly between the liposomal doxorubicin and topotecan arms, respectively.
Gemcitabine: A pyrimidine antimetabolite with similarities to cytosine arabinoside, gemcitabine has shown activity in patients with recurrent ovarian cancer. The response rate ranges from 13% to 19% in evaluable patients. Responses have been observed in patients who are platinum-refractory and/or paclitaxel-refractory as well as in patients with bulky disease.
Fluorouracil and leucovorin: In platinum-resistant recurrent disease, an objective response rate of 10% to 17% has been reported.
Tamoxifen: Some patients (18%) will respond to tamoxifen (20 mg twice daily). A response is more likely in patients with detectable levels of cytoplasmic estrogen receptor on their tumors.
Etoposide: Oral low doses have generated response rates from 6% to 26%.
Ifosfamide: Modest activity has been demonstrated in patients with epithelial ovarian cancer, including disease that is platinum-refractory.
Hexamethylmelamine (HMM): There have been several encouraging reports of orally-administered HMM as salvage chemotherapy after failure of cisplatin-based combination regimens. Response rates in platinum-resistant patients are 12% to 14%.
Some reports suggest a potential role for IP chemotherapy to treat patients with advanced ovarian cancer. Surgically defined complete response occurs in about 30% of patients who have low-volume disease at initiation of therapy (no nodule >0.5 cm). This surgical complete response may have a favorable impact on survival.
NOVAL THERAPIES
High-dose chemotherapy with stem cell transplant
There is evidence that high-dose chemotherapy with stem cell(or bone marrow) transplantation is superior to conventional chemotherapy in relapsed ovarian cancer.
Cryoablation:Percutaneous cryoablation may be used for unresectable ovarial cancer due to patient performance or disease factor.This is a mini-invational therapy and less damage to patient.
Dendritic cell vaccine: Immunomodality is helpful to control ovarial cancer.One such approach uses bone marrow-derived dendritic cells (DCs), phenotypically distinct and very potent antigen-presenting cells, to present tumour-associated antigens (TAAgs) and, thereby, generate tumour-specific immunity. Many observations have led to clinical trials designed to investigate the immunological and clinical effects of Ag-pulsed DCs administered as a therapeutic vaccine to patients with cancer. Although current DC-based vaccination methods are cumbersome and complex, promising preliminary results from clinical trials in patients with ovarial cancer,malignant lymphoma, melanoma, and prostate cancer suggest that immuno-therapeutic strategies, that take advantage of the unique properties of DCs, may ultimately prove both efficacious and widely applicable treatment in patients with cancer.
HOW IS PROGNOSIS OF OVARIAL CANCER?
Ovarian cancer usually spreads via local shedding into the peritoneal cavity followed by implantation on the peritoneum, and via local invasion of bowel and bladder. The incidence of positive nodes at primary surgery has been reported as high as 24% in patients with stage I disease, 50% in patients with stage II disease, 74% in patients with stage III disease, and 73% in patients with stage IV disease.
Prognosis in ovarian cancer is influenced by several factors, but multivariate analyses suggest that the most important favorable factors include:
Younger age.
Good performance status.
Cell type other than mucinous and clear cell.
Lower stage.
Well-differentiated tumor.
Smaller disease volume prior to any surgical debulking.
Absence of ascites.
Smaller residual tumor following primary cytoreductive surgery.
For patients with stage I disease, the most important prognostic factor is grade, followed by dense adherence and large-volume ascites. DNA flow cytometric analysis of stage I and stage IIA patients may identify a group of high-risk patients. Patients with clear cell histology appear to have a worse prognosis. Patients with a significant component of transitional cell carcinoma appear to have a better prognosis..
Although the ovarian cancer-associated antigen, CA 125, has no prognostic significance when measured at the time of diagnosis, it has a high correlation with survival when measured 1 month after the third course of chemotherapy for patients with stage III or stage IV disease. For patients whose elevated CA 125 normalizes with chemotherapy, more than 1 subsequent elevated CA 125 measurement is highly predictive of active disease, but this does not mandate immediate therapy.
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