Esophageal Cancer

WHAT IS ESOPHAGUS?

The esophagus is a muscular tube that extends from the neck to the abdomen and connects the mouth to the stomach.

The esophagus or gullet is a muscular canal, about 23 to 25 cm. long, extending from the pharynx to the stomach. It begins in the neck at the lower border of the cricoid cartilage, ends at the cardiac orifice of the stomach. The general direction of the esophagus is vertical; but it presents two slight curves in its course. The esophagus also presents antero-posterior flexures corresponding to the curvatures of the cervical and thoracic portions of the vertebral column. It is the narrowest part of the digestive tube, and is most contracted at its commencement, and at the point where it passes through the diaphragm.

WHAT IS ESOPHAGEAL CANCER?
The lining of the esophagus is the most common region for cancers of the esophagus to begin. Most of the length of the esophageal is lined with squamous cells, which, if they degenerate into a malignant tumor, give rise to squamous cell cancer. The very bottom portion of the esophagus and the region where the esophagus and stomach join are lined with columnar cells that can give rise to malignant tumors called adenocarcinomas. Other rare forms of esophageal cancer include sarcoma and small cell cancer.

HOW COMMON IS ESOPHAGEAL CANCER?
Esophageal cancer constitutes 1.5% of all malignancies and 10% to 15% of all gastrointestinal malignancies.
Esophageal cancer is more common in eastern countries than western countries. Esophageal cancer is the first or second most common cancer in China.
90% of esophageal cancer are squamous cell carcinoma, but during the past decades, the incidence of adenocarcinomas has increased dramatically, for example, in United States, it accounts for about 50% of new cases, a rate of acceleration greater than that of any other cancer.
Esophageal cancer is not nearly as common as cancers of the breast, lung, prostate, or colon in the U.S. and it is estimated that an annual incidence of esophageal cancer of between 12,000 and 18,000 new cases.

WHAT CAUSES ESOPHAGEAL CANCER?
The causes for esophageal cancer differ depending in what type of cancer is being considered. The risk factors for squamous cell cancer include smoking tobacco and heavy use of alcohol. People who are infected with human papilloma virus are also at increased risk. Those who suffer from achalasia (a benign esophageal disease), chronic scarring of the esophagus due to prior injury, or tylosis (a rare genetic disorder) are also at increased risk.

The risk factors for adenocarcinoma are less well understood. People who have Barrett's esophagus, an abnormal lining of the bottom part of the esophagus that is related to acid reflux problems, are at increased risk, as are people who have longstanding acid reflux problems alone.

WHO GETS ESOPHAGEAL CANCER?
Most people who develop esophageal cancer are in their 50's to 70's. The median age at diagnosis is 67 years, rarely occurring in people younger than 25 year. Male / female patient ratio is 2 to 4/1.

Adenocarcinomas are more common among men than women and are much more likely to occur in Caucasions.

WHAT ARE THE SYMPTOMS OF ESOPHAGEAL CANCER?
The most common symptom of esophageal cancer is difficulty swallowing, or the sticking of food before it gets into the stomach. This is usually a progressive problem which begins initially when large pieces of poorly chewed food are swallowed, but can worsen to the point that thin liquids won't go down easily. Esophageal cancer may also cause weight loss, pain with swallowing, regurgitation of undigested food, and bleeding manifested by vomiting blood or passing old blood with bowel movements.

HOW TO FIND ESOPHAGEAL CANCER?
The main symptoms of esophageal cancer, including difficulty swallowing and weight loss, should prompt a visit to your physician. There is no simple way to determine whether you have esophageal cancer.

In someone who is suspected of having esophageal cancer, several tests are appropriate. An endoscopy is usually the first step in evaluation. This is an outpatient test performed under sedation in which a flexible telescope is passed through your mouth and down your esophagus into your stomach. The telescope permits the physician performing the test to look at the lining of the esophagus and take a small bite of tissue, or biopsy, of any areas that look suspicious. The tissue is looked at under a microscope to determine whether there is cancer present.

Other common tests include an x-ray of the esophagus and stomach performed while swallowing a liquid that shows up on x-rays, giving your physician a picture of the lining of your esophagus. Most patients will also undergo computed tomography, or a CT scan, of the chest and abdomen to get a picture of the lungs, liver, and other organs surrounding the esophagus.

Carcinoma of mid esophagus. Esophageal contrast radiograph (barium swallow) shows a region of mucosal irregularity and marked narrowing of the mid esophagus. Biopsy demonstrated squamous cell carcinoma


HOW IS STAGING OF ESOPHAGEAL CANCER PERFORMED?

If an esophageal cancer is diagnosed, staging is the process that physicians use to determine how advanced the cancer is and whether the cancer has spread. Depending on the type of cancer, specific staging tests are performed aimed at investigating the most common areas for that cancer to spread. For esophageal cancer, the common areas of spread are the lymph glands (or lymph nodes), lungs, liver, adrenal glands, kidneys, bones, and lining of the chest and abdomen.



Squamous cell carcinoma of esophagus, moderately differentiated. This invasive carcinoma has focally prominent keratinization and occasional squamous pearls

The CT scan of the chest and abdomen is useful to evaluate the lungs, liver, and adrenal glands for spread from an esophageal cancer, but is not much good for looking at lymph nodes for potential cancer spread. The main tumor and adjacent lymph nodes are sometimes evaluated using endoscopic ultrasonography, or EUS. This is an endoscopic test that utilizes a special telescope which emits ultrasound waves that can produce a picture of the tumor and surrounding lymph nodes. A bone scan is sometimes performed to determine whether the cancer has spread to the bones. An experimental staging test is PET scanning, which currently is being assessed for its usefulness in evaluating esophageal cancer.





HOW IS ESOPHAGEAL CANCER TREATED?

The treatment of any cancer depends in part on the stage of cancer at the time it is diagnosed. Other considerations include the overall condition of the patient and specific symptoms the patient is having. Most cancers of the esophagus are diagnosed at a relatively late stage because symptoms of swallowing difficulty don't begin until many months after the cancer begins to grow.

Primary treatment modalities include surgery alone or chemotherapy with radiation therapy. Combined modality therapy (chemotherapy plus surgery, or chemotherapy and radiation therapy plus surgery) is under clinical evaluation. Effective palliation may be obtained in individual cases with various combinations of surgery, chemotherapy, radiation therapy, stents, photodynamic therapy, and endoscopic therapy with Nd: YAG laser.

TRADITIONAL TREATMENT
Surgery,including transthoracic esophaectomy, endothoracic endoesofageal resection, remains the mainstay of esophageal cancer. The overall 5-year survival in cases amenable to surgery ranges from 5% to 20%.
Radiation therapy includes(1)Radiation alone, is for unresectable cancer, at least 50 to 60 Gy at 1.8 to 2.0 Gy per fraction, with 5-year survival ranges from 0 to 10%,and median survival is typically about 12 months. (2)Preoperative radiation may increase respectability, decrease tumor seeding at the time of surgery, and increase radiosensitivity due to oxygenated cells. Radiation dose is 20 to 40 Gy in 10 to 20 fractions (1-4 weeks).The time interval between the completion of radiation and surgery ranged between 1 and 4 weeks. (3) Postoperative radiation, is frequently given if the surgical resection is incomplete or the surgical margins are positive to prevent morbidity from locoregional relapse. The total dose is 45 to 50 Gy.
Chemotherapy is very important because that even for patients with clinical localized carcinoma of the esophagus, the occult metastases are present at the diagnosis. Cisplatin has been considered one of the more active agent, with a single-agent response rate consistently in the range of about 20%.Others include 5-fluorouracil (5-FU), motomycin, bleomycin, paclitaxel, vinorelbine, and gemcitabine.
Commonest used formula is

Cisplatin,100mg/m2i.v.,day 1(total dose/cycle, 100mg/m2; 5-FU,100mg/m2 per day by continuous i.v. infusion for 5 days, days 1-5(total dose/cycle,5000mg/m2).

Treatment cycle duration is 28 days;
Three complete cyclesmay be given before surgery;
Chemotherapy may be repeated for two postoperative cycles if patient achieves a response or stable disease.
· Combined preoperative chemotherapy and radiotherapy: current data do not support the routine use of this combination, but the approach is being addressed further in future.The formula is

Cisplatin, 20 mg/m2 per day, by continuous i.v. infusion for 10 days, days 1-5 and 17-21 (total dose/cycle,200mg/m2);
Vinblastine,1mg/m2 per day i.v. bolus for 8 days,day 1-4 and 17-21(total dose/cycle,8mg/m2);
Radiotion therapy,1.5 Gy twice daily,day 1-5,8-12,and 15-19;
Surgery on day 21.


NOVAL THERAPIES

·Photodynamic therapy, as a cold photochemical therapy, may bring radical result with curable rate of about 90% for superficial Tis or T1 stage cancer of the esophagus, and give palliation result for advanced cancer of the esophagus, with the improvement rate of dysphagia of more than 90%.The methos is



Porfimer sodium (Photofrin or Photosan), 2mg/kg body weight by slow i.v. injection over 3-5 minutes, 40-50h later, following by
Laser light (630nm wavelength) with a fiberoptic probe through endoscope. The laser light dose is 300 jouls/cm of tumor approved by FDA, USA.
This therapy may be repeated typically within 96 to 120 hours after porfimer sodium injection.
This therapy may be used with other therapies simultaneously.
·Endoluminal tumor destruction, may use laser, e lectrocoagulation or radiofrequency.

·Radioactive stent implincation using a special esophageal stent to that 125iodine seeds adhere. Number of seeds and implantation locations are determined according to plan system. The therapy has dual effects of palliative dilation and endoluminal brachytherapy.

·Luminal dilatation using dilate-able stent.

·For metastatic disease in liver and lungs, the transarterial chemoembolization and cryoablation with “Argon-Helium knife” may be used. Palliative chemotherapy is only used in patients with a good performance status.

WHAT IS THE PROGNOSIS FOR ESOPHAGEAL CANCER?
The likelihood of being cured of cancer depends in large part on the stage of the cancer at the time it is diagnosed. From 80% to 90% of patients with the earliest stage of esophageal cancer can expect to be alive and cancer free 5 years after treatment. However, since the typical esophageal cancer is discovered at a relatively advanced stage, the overall success rate in curing esophageal cancer is disappointing.















Infiltrating ductal carcinomas:




Infiltrating ductal carcinoma and ductal carcinoma in situ. Mammogram shows a round mass with ill-defined margins and malignant-appearing calcifications Infiltrating ductal carcinoma. Mammogram shows two irregular masses with spiculated margins Infiltrating ductal carcinoma, grade 3 (poorly differentiated). Note the prominent cellular pleomorphism, mitotic figures, and absence of tubule formation. This is a Papanicolaou-stained direct smear Fine needle aspiration of infiltrating ductal carcinoma, cytologically high grade. Note large cells with prominent pleomorphism and overlapping/crowding without apparent tubule formation. This is a Papanicolaou-stained direct smear

Infiltrating lobular carcinomas:

Infiltrating lobular carcinoma. The neoplastic cells and their nuclei are uniformly small and round. Note the single file pattern of infiltration and the desmoplastic stroma

Breast biopsy specimens must be evaluated carefully, particularly now that breast-conserving surgery is selected increasingly as an alternative to mastectomy. Specimens should be processed so that their margins can be identified when visualized under the microscope. Coating specimens with India ink is a technique commonly used for identifying margins. Pathologists should record the dimensions of excised specimens, the size of the tumor, and its gross and microscopical relationships to the specific margins. Such other factors as the amount of associated ductal carcinoma in situ, lymphatic invasion, tumor grade, and histologic type (ductal, lobular, tubular, mucinous, medullary, inflammatory, etc.) may be important in assessing prognosis and selecting treatment.


An ultrasound-guided needle biopsy. Arrows point to needle Fine needle aspiration of infiltrating ductal carcinoma, cytologically low grade. Note the intermediate-size cells with focal tubule formation. Many single cells are also present, typical of invasive carcinoma Fine needle aspiration of infiltrating ductal carcinoma, cytologically high grade. Note large cells with prominent pleomorphism and overlapping/crowding without apparent tubule formation. This is a Papanicolaou-stained direct smear Fine needle aspiration of lobular carcinoma. The Papanicolaoustained direct smear contains many dyshesive cells (cells appear singly rather than in glands or sheets). The cells are small and some have a “signet ring” morphology (intracytoplasmic mucin droplets that push the nucleus to the periphery of the cell)






The two types of carcinoma in situ—lobular and ductal—differ in a number of ways. In both types, malignant-appearing cells are seen under the microscope, but the cells are not invading outside of the lobular or ductal lumen.

Lobular Carcinoma In Situ

Lobular carcinoma in situ (LCIS) never forms a palpable mass, rarely is the cause of an abnormality on a mammogram, and usually is found accidentally on biopsy of some other lesion. LCIS occurs diffusely throughout both breasts and is associated with approximately a 10% to 15% risk of invasive cancer in each breast. The risk of invasive cancer for the breast contralateral to that undergoing biopsy is the same as for the breast with biopsy-proved LCIS. LCIS is viewed as a risk factor for subsequent breast cancer and is related more closely to atypical hyperplasia than to ductal carcinoma in situ (DCIS). Patients with LCIS are given one of two options: observation with careful follow-up or bilateral mastectomies. Most women select observation.

Lobular carcinoma in situ. The lobule is filled and expanded by a uniform population of small cells

Ductal Carcinoma In Situ

DCIS differs from LCIS in that it may form a mass, although most often today it is diagnosed by biopsy for microcalcifications seen on mammography. Usually, DCIS is unilateral and frequently is found in only one quadrant of one breast. The risk for subsequent cancer is primarily in the quadrant that has undergone biopsy if the DCIS is not eradicated adequately. The natural history of DCIS is not well understood, and it remains unclear how often such lesions progress to invasive cancers. On the basis of nuclear differentiation and the presence or absence of necrosis, several different systems have been devised to divide DCIS into three groups: high-, intermediate-, and low-grade. These systems recognize that different DCIS lesions behave with different potential for microinvasion and for development of microvessel density and have different proliferative rates. Ultimately, a comprehensive system that includes both molecular markers of biological behavior and histologic features likely will provide a meaningful basis for diagnosis and treatment. At the present time, no single system is recognized universally, but the risk for recurrence is considerably lower with low-grade lesions than with high-grade lesions, regardless of whether postoperative irradiation is used.


Ductal carcinoma in situ. Mammogram demonstrates extensive fine calcification, malignant in appearance Ductal carcinoma in situ. Specimen radiograph shows wire in place and comedo-type calcifications. The arrow indicates calcification at margin of specimen Ductal carcinoma in situ, cribriform type. This duct is replaced by a uniform population of neoplastic cells, forming round back-to-back glands. Some of the glands contain dark blue microcalcifications

In the majority of cases, the diagnosis of DCIS can be established readily. Problems arise, however, in differentiating DCIS from lesions at both ends of the spectrum. On the benign end, distinguishing DCIS from atypical ductal hyperplasia can be difficult; on the opposite

end, distinguishing some cases of DCIS from DCIS with focal stromal invasion can be difficult. In some instances, DCIS can resemble LCIS.

Mastectomy, long considered the standard treatment for DCIS, is associated with local tumor control and survival rates approaching 100% but is likely to represent overtreatment for many patients. DCIS appears to be a disease of one ductal system. Frequently, it is multifocal within a small area close to the indexlesion and rarely is multicentric or present in different parts of the breast distinct and at a distant from the indexfocus. In most cases, the disease was confined to one quadrant. These observations provided a rationale for breast-conserving treatment. Eight-year results from a randomized National Surgical Adjuvant Breast and Bowel Project trial (NSABBP-17) showed that local recurrences had been reduced by 55% and that invasive cancers have been reduced by 71% for patients receiving radiotherapy and wide excision as compared with wide excision alone.

A reasonable assumption is that low-grade DCIS identified by small areas of microcalcifications and excised with widely negative margins should be treated adequately without radiotherapy. However, selection criteria still are evolving. High-quality mammograms and careful margin assessment are essential to achieve low recurrence rates, regardless of whether the treatment includes radiotherapy. Axillary node dissection is not a standard of care at this time. For patients with extensive high-grade DCIS in which the risk of microinvasion or frank invasion is high, lower axillary dissection may be recommended. Typically, axillary dissection is not recommended for patients with limited DCIS treated with a breast-conserving approach because of the extremely low probability of nodal metastases.

A large randomized trial (NSABBP-24) demonstrated that the addition of tamoxifen to lumpectomy or lumpectomy and radiotherapy further reduced the risk of invasive and noninvasive local recurrences and of the incidence of contralateral breast cancers.

TRADITIONAL TREATMENTS

Early-stage breast cancer

Surgery: Breast preservation with lumpectomy with radiation is the preferred treatment.
Radiation: As a part of the breast-coserving treatment (lumpectomy), breast radiation is performed with 4 500 to 5 000 cGy boost to tumor-excision site.
Systemic chemotherapy: Combination chemotherapy can reduce the annual risk of death by 20%, and in 10 years produces an absolute improvement in survival of 7% to 11% in women younger than 50 years.
Hormone therapy: Tamoxifen is a selective estrogen-receptor modulator (SERM), can decrease the risk of recurrence by 42% and the absolute risk of death by 22% in patients with ER-positive tumors. Combination of tamoxifen with chemotherapy can cause a 25%-30% reduction in recurrence, compared with chemotherapy alone.
Locally advanced breast cancer
Initial surgery is only used to biopsy to confirm the diagnosis and to identify the receptor status.
Resection operation is done after the best response to preoperative chemotherapy.
Neoadjuvant (primary) chemotherapy produces the tumor shrinks by 50% and allows surgical resection with clear margins in more than 65% of the women treated.
Radiation to chest wall and supraclavicular area is done after surgery.
Metastatic breast cancer
Surgery and /or radiation may be used for local control.
Hormone agents may be used as the first-line therapy in patient with positive hormone receptor.Hormone agents used are:
1. SERM with combined estrogen agonist and estrogen antagonist activity

2. Tamoxifen (Nolvadex), 20 mg/day, p.o.

3. Toremifene (Fareston), 60mg/day p.o.

4. Progestins
5. Megestrol acetate (Megace), 40 mg/dose p.o. 4 times daily

6.Aromatase inhibitors
Anastrozole(Arimidex), 1mg/day p.o.

Letrozole(femara), 2.5mg/day p.o.

Aminoglutethimide, 250 mg/dose p.o. 4 times daily;

hydrocortisone replacement to offset cortisol suppression associated with aminoglutethimide.

7.LHRH agonist analogue in premenopausal women
Leuprolide (Lupron Depot), 7.5mg/dose,i.m. monthly,OR

Leuprolide (Lupron Depot), 22.5mg/dose i.m. every 3 months, OR Leuprolide (Lupron Depot), 30mg/dose i.m. every 4 months

8.GnRH agonist analogue
Goserelin (Zoladex), 3.6mg/dose,s.c. implant into the abdomen wall every 28 days OR

Goserelin (Zoladex), 10.8mg/dose,s.c. implant into the abdomen wall every 12 weeksUsed in patients who have tumors that express either ER or PR receptors or both receptors

Chemotherapy may be used as the initial treatment in hormone receptor-negative patients.

Commonly used chemotherapy regimens are

AC: Dororubicin, 60mg/m2 i.v. on day 1 (total dose/cycle, 60mg/m2);

Cyclophosphamide,600mg/m2 i.v., on day 1 (total

dose/cycle, 600mg/m2);

Treatment cycles are repeated every 21-28 days depending on hematology recovery.

CMF: Cyclophosphamide, 100mg/m2 per day p.o. for 14 days, day 1-14(total dose/cycle,1 400mg/m2);

Methotrexate (MTX), 40mg/m2 per dose i.v. for two doses, day 1 and 8(total dose/cycle,20mg/m2)

5-FU, 600mg/m2 per dose i.v. for 2 doses,day1 and 8 (total dose/cycle 1,200mg/m2)

Treatment cycles are repeated every 28 days.

AC-P: Dororubicin, 60mg/m2 i.v. on day 1 (total dose/cycle, 60mg/m2);

Cyclophosphamide, 600mg/m2 i.v.,on day 1′4 cycles (total dose/cycle, 60mg/m2)

Followed by

Paclitaxel 175mg/m2 per dose i.v. over 3 hours every 3 weeks′4 cycles (total dose/cycle,175mg/m2);

Treatment cycles are repeated every 21 days.

Recurrent breast cancer

For local recurrence surgical excision and radiation are choice.
Chemotherapy and hormone therapy are as for metastatic breast cancer.
NOVAL THERAPIES
Photodynamic therapy, as a cold photochemical therapy, may bring radical result with curable rate of about 90% for superficial Tis or T1 stage cancer of the esophagus, and give palliation result for advanced cancer of the esophagus, with the improvement rate of dysphagia of more than 90%.The methos is

Porfimer sodium (Photofrin or Photosan), 2mg/kg body weight by slow i.v. injection over 3-5 minutes, 40-50h later, following by
Laser light (630nm wavelength) with a fiberoptic probe through endoscope. The laser light dose is 300 jouls/cm of tumor approved by FDA, USA.
This therapy may be repeated typically within 96 to 120 hours after porfimer sodium injection.
This therapy may be used with other therapies simultaneously.
·Endoluminal tumor destruction, may use laser, e lectrocoagulation or radiofrequency.

·Radioactive stent implincation using a special esophageal stent to that 125iodine seeds adhere. Number of seeds and implantation locations are determined according to plan system. The therapy has dual effects of palliative dilation and endoluminal brachytherapy.

·Luminal dilatation using dilate-able stent.

·For metastatic disease in liver and lungs, the transarterial chemoembolization and cryoablation with “Argon-Helium knife” may be used. Palliative chemotherapy is only used in patients with a good performance status.

WHAT IS THE PROGNOSIS FOR ESOPHAGEAL CANCER?
The likelihood of being cured of cancer depends in large part on the stage of the cancer at the time it is diagnosed. From 80% to 90% of patients with the earliest stage of esophageal cancer can expect to be alive and cancer free 5 years after treatment. However, since the typical esophageal cancer is discovered at a relatively advanced stage, the overall success rate in curing esophageal cancer is disappointing.