Lung Cancer

LUNG CANCER: A SERIOUS PROBLEM

Lung cancer kills more men and women than any other form of cancer. It is estimated that by the year 2000, over three hundred thousand people will die from lung cancer in the United States alone. The economic loss is calculated to be over two billion dollars a year.

Most lung cancers begin to grow silently, without any symptoms. Patients with lung cancer often do not develop symptoms until the cancer is in an advanced stage. The actual time from when one cell becomes cancerous until it is large enough to be diagnosed or produce symptoms may take as long as 10 to 40 years. Since the majority of lung cancer is diagnosed at a relatively late stage, only 10% of all lung cancer patients are ultimately cured. If the patient cannot be cured by surgery at the time the cancer is found, there is a 50% chance that death will occur in less than one year.







WHAT ARE CAUSES OF LUNG CANCER?

Smoking: 90% of patients with lung cancer have a smoking history. There is a direct relationship between amount of tobacco exposure and risk for developing lung cancer. Stopping smoking is associated with a gradual decrease in risk, but an appreciable diminution of riskoccurs only after a long period of time(more than 6 months).

Occupational and atmospheric pollution: Exposure to agents such as arsenic, asbestos, beryllium, chloromethylethers, mustard gas and radiation has been linked with development of lung cancer.

Inhalation of combustion byproducts: In Asians, the population of cases attributable to active smoking may not be as high. The rate of deaths from smoking-related lung cancer has been reported to be as low as 6% among Asian women, however, an additional lung cancer risk unrelated to smoking has been observed among Chinese women. Nosmoking risk factors in these patients include inhalation of combustion byproducts from cooking, heating stoves, and oil furnaces.

The risk of lung cancer is greater for those living in urban areas. This risk is approximately 1.2 to 2.3 times that of people living in rural areas. There is also an increased risk of lung cancer in smokers whose close relatives have had lung cancer. Scarring in the lungs from previous infections or injury can be associated with and increased risk of cancer.

WHAT ARE TYPES OF LUNG CANCER?

Lung cancers are broadly classified into small cell or non-small cell. Non-small cell cancers are further divided into adenocarcinomas, bronchoalveolar-alveolar, squamous cell and large cell carcinomas. Approximately, 75-85 percent of lung cancers are non-small cell cancers and 15-25 percent are small cell cancers of the lung.

Non-Small Cell Cancer of the Lung

Adenocarcinoma is the most common non-small cell cancer of the lung. The majority of these cancers develop in the periphery (outer part) of the lung. Since these cancers are in the outer portion of the lung, the patient often does not have any symptoms when the cancer is found on a chest x-ray. Adenocarcinomas tend to metastasize (spread to other parts of the body) to the bone, the central nervous system (the brain and spinal cord), the adrenal glands, the liver, and the opposite lung.

Frequently, there is scarring in adenocarcinomas. Sometimes, the cancer arises in an area of old scarring of the lung. In other cases, the scar appears to arise secondary to the growth of the cancer.




Pulmonary adenocarcinoma, glandular formation. The tumor is growing along the alveoli, without distortion ofthe normal architecture. This latter feature is consistent with bronchioloalveolar carcinoma



Bronchoalveolar carcinoma or alveolar cell carcinoma is a non-small cell carcinoma that can be found throughout the respiratory tract. When it is discovered as a single mass on a patient's x-ray, this type of lung cancer has an excellent prognosis. Five year survival after surgery is in the 75-90 percent range. If, however, it is found in its diffuse form (meaning it has spread beyond a single mass), the prognosis is quite poor.

Squamous cell carcinomas comprise 30-40 percent of non-small cell carcinomas of the lung. This type of cancer tends to be located in the more central portion of the lung. Often, this is in a bronchus (a large airway of the lung). Since these cancers are located near or in these airways, they can cause symptoms earlier in their growth. Coughing and production of phlegm (sputum) that is bloody are common symptoms. The cancer can block airways which can lead to shortness of breath orpneumonia.

Squamous cell carcinoma. The cells have dense cytoplasm and form whorls, with a dense center called keratin pearls. Intercellular bridges and spindle formation can be seen


Large cell carcinomas represent about 10 percent of non-small cell cancers of the lung. This form of lung cancer has fewer structural characteristics when viewed under a microscope. It is sometimes difficult to distinguish this form of lung cancer from cancers which have spread to the lung from another place in the body.

Small Cell Cancer of the Lung

Small cell cancer is the most aggressive type of lung cancer and has the worst prognosis. These cancers tend to grow rapidly and metastasize to other parts of the body early.

Small cell cancer of the lung is usually seen as a mass located in the central portion of the chest on chest x-ray. The primary cancer spreads to lymph nodes of the chest and also enters the blood stream which carries it to other organs such as the liver, bone, brain and spinal cord, kidneys, pancreas, and adrenal glands.

It is rare that small cell cancer of the lung can be cured with surgery because either the primary cancer is too large to be removed or it has already spread to other parts of the body. However, small cell cancer of the lung is generally quite responsive to radiation therapy and chemotherapy.


Typical histology of small-cell lung cancer. The cells grow in sheets, with no specific architecture. They are small and display scant cytoplasm. Mitoses are numerous, and necrosis is present. The nuclei can be ovoid or elongated and resemble oat cells


WHAT ARE SYMPTOMS OF LUNG CANCER?
Lung cancers such as squamous cell and small cell cancers can cause symptoms such as cough, shortness of breath, bloody sputum, chest pain, wheezing or pneumonia. Adenocarcinomas are generally more common in the outer portion of the lung and can cause chest pain with breathing, coughing or shortness of breath. Most commonly patients have no symptoms when the disease is first detected on a chest x-ray.

Small cell cancers and adenocarcinomas of the lung are also first seen with symptoms of metastatic disease. In other words, the problems and symptoms are those involving the organs or structures to which the cancer has spread and not necessarily the lungs.

Symptoms that may indicate the cancer has spread include hoarsenessof the voice (due to spread of the cancer to nerves which control the vocal cords), difficulty in swallowing, and swelling of the face, arms and neck. Metastatic spread of the cancer outside the lung and chest can occur with any of the lung cancer types, but most commonly with small cell cancers and adenocarcinomas. Headaches, weakness, numbness or paralysis may indicate spread of the cancer to the brain or spinal cord. This requires urgent treatment. Bone pain or pain in the abdomen can be symptoms of cancer spread to these areas.

HOW TO DETECT LUNG CANCER?
Lung cancer can be diagnosed once it is suspected in one of four ways:

Examination of the sputum can show cancer cells. The sputum is generally collected over a three day period to increase the likelihood of making a correct diagnosis as compared to a single sputum collection.
Fiberoptic bronchoscopy utilizes a small flexible lighted tube which is passed into the nasal canal and then into the appropriate bronchus (airway) to the cancer, which is then biopsied. A biopsy (a small piece of tissue) is obtained by either brushing the surface of the lesion or inserting a needle into the lesion and withdrawing a small sample of tissue.
FIBEROPTIC BRONCHOSCOPE


Percutaneous needle biopsy involves inserting a thin needle into the mass through the skin and chest wall. This is useful for lesions that are close to the surface of the lung. This approach is often aided by the use of a CAT scan to guide the needle into the mass. In a small number of cases, a slight collapse of the lung (pneumothorax) occurs. This is usually self-limiting and only in about five percent of cases is it necessary to insert a tube into the chest to re-expand the lung.
Excision or surgical removal of the suspected mass can lead to the diagnosis. This can be performed through a small incision into the chest (thoracotomy), or more recently with thoracoscopy. This procedure involves inserting a small thin video camera into the chest and removing a small wedge of lung tissue using either a mechanical stapling device or laser.






HOW TO DETECT METASTASIS OF LUNG CANCER?
Metastasis of lung cancer is present in over 50 percent of patients at the time of the diagnosis of the lung cancer.

Mediastinoscopy, or looking into the central portion of the chest through a small incision made just below the collar line, is used to sample the lymph nodes in the central portion of the chest (mediastinum). This helps evaluate the extent of the tumor. If the cancer has spread to these lymph nodes, the chance of surgically curing the lung cancer is eliminated.

Bone metastasis is suggested by bone pain or abnormal blood tests (elevated serum calcium, or elevated alkaline phosphatase). X-rays or bone scans are used to evaluate the areas suspected of being cancerous.

Liver metastasis may result in pain in the upper right portion of the abdomen, swelling of the abdomen, or abnormal blood tests of the liver. The diagnosis can be made by liver ultrasound and CT scan.

Brain and spinal cord metastasis can occur with or without neurological symptoms. CA and MRI scans of the brain and spinal cord will usually reveal these metastastic tumor sites.




Mediastinal lymph nodes and adjacent structures. Ao = aorta; PA = pulmonary artery; Inf. pulm. ligt. = inferior pulmonary ligament.
Aortopulmonary window lymph node region and adjacent structures. Ao = aorta; PA = pulmonary artery; Inf. pulm. ligt. = inferior pulmonary ligament


HOW TO TREAT LUNG CANCER?
Treatment choices and chances of long term survival in lung cancer depend on the type of cancer, its location and size, lymph node involvement, and whether there is evidence of cancer spread to other parts of the body outside of the lungs.

TRADITIONAL THERAPIES

Surgery is the only treatment which may offer a definitive or complete cure. Unfortunately, only one-half of patients with lung cancer are surgical candidates. If the spread of cancer to the lymph nodes is found at the time of removal of the lung cancer, the chances of the cancer recurring is quite high.

Preoperative evaluation is extremely important, not only to exclude non-resectable cancers (i.e. those cancers which technically cannot be surgically removed), but to exclude patients with severe heart or lung problems who might not survive the operation. Palliative surgical resection of the tumor is sometimes performed, whereby the cancer is removed knowing that this will not cure the patient, but will likely improve the quality of life remaining for the patient

Mortality rate for surgery is 5-10 percent. Of all lung cancer patients, 25-40 percent undergo surgery. 20 to 33 percent undergo an attempted curative resection. 5 to 8 percent of cancers cannot be removed because they are too widespread. Another 5 percent receive palliative resections.

Surgical resection for lung cancer generally involves removing the cancer along with a portion of normal lung tissue and adjacent lymph nodes (lobectomy). In some cases the surgery requires removal of the entire lung on one side of the chest (pneumonectomy).


Adenocarcinoma. A large gray tumor is present in the apex of the upper lobe of this surgical specimen. The peripheral location is typical of adenocarcinomas This lobectomy specimen contains a bronchogenic tumor with prominent peribronchial growth Squamous cell carcinoma. This endobronchial tumor arises from and fills the right mainstem bronchus


Radiation therapy is the local treatment of cancer using various types of radioactive x-ray beams. These treatments prolong life in some patients, and improve the quality of life while relieving pain in others. It rarely cures patients of lung cancer. The major role of radiation therapy is to relieve symptoms.


Three-dimensional conformal radiation treatment plan for a right-sided T4 lung cancer. The color-wash display demonstrates that the high-dose region (red) conforms to the hatched target volume. Blue areas receive very low doses. Areas of underdosing and overdosing can be readily identified and appropriate action taken. These displays are invaluable (especially in conjunction with dose-volume histograms) and are available in axial, sagittal, and coronal planes Composite treatment plans for postoperative radiotherapy for a right lung T2N2 squamous cell carcinoma treated surgically by right upper lobectomy and mediastinal lymph node dissection. The computed tomographic scan is taken through the upper ediastinum, and the target volume is the purple oval shape

Chemotherapy is the use of medications and drugs which are known to kill cancer cells. Chemotherapy is widely accepted as the primary treatment for small cell cancers. In early small cell cancers of the lung, there is a higher success rate with chemotherapy, especially if the cancer is only in the chest.

In cases of non-small cell cancers of the lung, chemotherapy can be used alone or in combination with radiation therapy.

Non-small cell lung cancer (NSCLC)

Early-stage disease (stage Ⅰ,Ⅱ)
Surgical resection is the treatment of choice,provided patients are medically fit for the operation.Lobectomy is the operation of choice in patients with adequate pulmonary reserves.
For patients who are medically unfit for operation, radiation therapy is the therapy of choice.
Based on current data, adjuvant chemotherapy is not associated with a statistically significant survival advantage.
StageⅢA disease (T3N1 or T1-3 N2M0)
Surgical resection is the therapy of choice, but requires an experienced and skilled thoracic surgeon.
Neoadjuvant chemotherapy has the theoretic advantage of diminishing nodal involvement, thus making surgical intervention more easy, more likely to have an impact on survival, and more likely to provide immediate systemic therapy in patients at high risk for distal relapse. However, local treatment is delayed, and the tumor volume, if it does not respond adequately to the chemotherapy, may become unresectable.
StageⅢB disease (in absence of malignant pleuraleffusion)
Traditionally radiation therapy alone is the standard therapy,but is associated with 5-year failure rates within the ipsilateral chest and systemically of 90% and 50% to 70%,respectively.
Chemotherapy is added in an attempt to overcome these high relapse rates and poor outcomes with radiation alone.
Cisplatin based chemotherapy shows a significant overall benefit, with a 10% reduction in the risk of death, or an absolute benefit of 3% at 2 years and 2% at 5 years.
Figure 1 Anatiomic Staging　For Lung Cancer

Advanced disease (StageⅢB disease with malignant pleuraleffusion, and stage Ⅳ)
The survival of patients with advanced stage NSCLC) is extremely poor. The therapeutic approach includes consideration of systemic chemotherapy or supportive therapy alone if the patient’s general condition is not suitable for systemic chemotherapy.
The cisplatin-based regimen show a benefit with an absolute improvement in survival of 10% at 1 year,or an increase in median survival of 1.5 months.
Agents in phase Ⅲ trials in patients with advanced NSCLC include the taxanes (paclitaxel and docetaxel), vinca alkaloid (vinorelbine), antimetabolite (gemcitabine), and camptothecin (irinotecan).These agents have shown promise ,both as single agents and in combination with a platinum agent, with one-year survival rates of up to 40%.
Suggested therapeutic chemotherapy regimens

Paclitaxel +Carboplatin

Premedication

Dexamethasone, 20mg p.o.,for two doses,12 and 6 hours before starting paclitaxel on day1.
Diphenhydramine,50 mg,i.v., andranitidine,50mg i.v.,0.5 hour before starting paclitaxel on day 1.
Chemotherapy

Paclitaxel,225 mg/m2 i.v. over 3 hours on day 1(total dose/cycle = 225 mg/m2);
Carboplatin,i.v.,over 60 minutes on day 1,after paclitaxel; dosage is calculated bythe Calvert formula to achieve a target area under the curve(AUC) of 6 mg/ml/min.
Treatment cycle repeats every 21 days.Treatment duration is a total of 6 cycles.

Calvert formula: Total dose (mg)=(target AUC[mg/ml/min]) ′ (GFR[ml/min]+25)

Vinorelbine + Cisplatin

Vinorelbine,25 mg/m2/dose i.v. infusion over 30 minutes for four doses,day 1,8,15,and 22 (total dose/cycle100mg/m2);
Cisplatin,100 mg/m2 i.v.,day 1(total dose100mg/m2)
Treatment cycle repeats every 28 days.Treatment duration is a total of 6 cycles.

Gemcitabine +Cisplatin

Gemcitabine,1 000mg/m2 per dose i.v. infusion over 30 minutes for 4 doses,day 1,8 and 15 (total dose/cycle,3 000mg/m2);
Cisplatin,100 mg/m2 i.v.,day 1(total dose/cycle,100 mg/m2)
Treatment cycle repeats every 28 days.Treatment duration is a total of 6 cycles.

(图1120) (图1121)






Small cell lung cancer (SCLC)

Limited-stage disease
Combined chemotherapy with concurrent thoracic radiation is recommended.

Chemotherapy:Combination chemotherapy is the standard approach in initial treatment,with 80% to 90% response rates,50% to 60% complete response rates,and 2-year survival rates of 15% to 40%.The most used regimen is:

Etoposide,100 mg/m2 i.v. days 1-3;cisplatin 25mg/m2 i.v. days 1-3;Etoposide 80mg/m2 i.v. days 1-3;cisplatin 80mg/m2 i.v. day 1.Cycles repeates every 3 weeks,for 4 cycles.

Radiotherapy:Total dose is 40 to 50 Gy.Administration either concurrent or interdigitating with chemotherapy is favored over sequential regimen. Prophylactic cranial radiation may be considered in patients with complete response, because the risk of developing brain metastases in 2-year survivors approaches 50% to 60%.

Extensive-stage disease
Combination chemotherapy without thoracic radiation is the cornerstone of therapy. Combination chemotherapies identical to those used in limited-stage disease are used with overall response rates of 60% to 80%, complete response rates of 15% to 20%, and median survival of 7 to 11 months. For patients with the poor performance status, single-agent chemotherapy with oral VP-16 may be used.

Recurrent disease or disease progressing on initial therapy
Traditional options are limited, with a median survival of 2 to 3 months. Thoracic radiation should be considered in those patients whose recurrence is confined to the thorax and who have not previously received radiation. Patients who have not received a platinum-containing regimen may benefit from combinations containing cisplatin. Taxol and topotecan as single agents have also shown to have some effects.

NOVAL THERAPIES

Photodynamic therapy(PDT): PDT is a non-thermal light chemical reaction and need oxygen, photosensitive substance (photosensitizer) and laser simultaneously to participate in. Photosensitizer is absorbed by neoplasm tissue and accumulates in the cells for a long time. Photosensitizer is activated with the appropriate wavelength of light and reacts with oxygen to generate reactive single state oxygen and photochemical substance that are toxic to cells leads to apoptosis and necrosis of cancer; PDT can result in local vascular lesion of tumor; PDT can make tumor tissue ischemic necrosis and initiate immune reaction of antitumor. Photosensitizer is exposed to laser light and subsequently reacts with oxygen, and gives rise to single state oxygen and toxic photochemical substance.

1996 USformally Approved PDT for treatment lung cancer
Microinvasive non-small cell lung cancer, unable to be given surgery and radiotherapy
Obstructingnon-small cell lung cancer
PDT efficacy is as fellow:

For lung cancer with bronchial obtruction, PDT induce improvement of air-way obstruction
Treatment of lung cancer with PDT was approved by FDA,USA
For early bronchial cancer, PDT has the cure rate of 90%;for
obstructive cancer, the improvement rate of 85 percent

Our experience proved that combination therapy of photodynamic therapy and percutaneous cryoablation with argon-heliun system is effective for obstructive non-small cell lung carcinoma, as below in a published paper:

Aim: To investigate the therapeutic efficacy of combined photodynamic therapy and percutaneous cryoablation with argon-helium system for unresectable, obstructive non-small cell lung carcinoma.

Method: Forty-one patients with obstructive non-small cell lung carcinoma, whose tumors were considered nonresectable because of local aggression of tumor (stage Ⅲb on TNM) or poor lung function of patients (severe obstructive lung disease), were given the combination therapy. At first, photodynamic therapy was performed. Patients received with photosensitizer (Photofrin 2mg/kg or Hematoporphyrin 5mg/kg), intravenous infusion, and 48 and 72 hours later, 630nm red laser illumination through bronchoscopy. Then, percutaneous cryoablation with argon-helium system under guidance of B-mode sonography or CT was given. The therapeutic efficacy was estimated according to changes of symptoms tumor size and survival.

Results: Among 41 patients received the combination therapy, 90.2 percenthad some improvement of subjective symptoms, significant decrease of symptom score, especially marked relief of dyspnoea. Bronchoscopy showed that endobronchial tumor was ablated on different degrees in all patients, with complete resolution in 41.5 % of patients. CT showed that lung tumor had CR of 34.1% and PR of 41.4%.According to the radiographic evidence, collapse of lung resolved completely in 29.6% of patients with previous collapse, and diminished in 70.4% of patients. The 6- and 12-month survival were 44% and 71% respectively. There were no severe complications in photodynamic therapy or percutaneous cryoablation with argon-helium system.

Conclusion: Combinationof photodynamic therapy and percutaneous cryoablation with argon-helium system can eliminate endo- and extra-bronchial tumor masses,respectively, and is complementary to each other,therefore,raise the therapeutic efficacy for unresectable obstructive non-small cell lung carcinoma.

Endobronchial implants: This therapy is used for palliating endobronchial obstruction due to tumor. The stent with radioactive iodine-125 seeds may as a brachytherapy.

Cryoablation: Under CT guidance, percutaneous cryoablation may be used for unresectable lung cancer. It’s advantages are as fellows:

Cryoablation employs extremely low temperature to destroy cancerous tissue. It has been shown to be as effective as surgical resection for treatment of cancer some parenchymal organs.
Because cryoablation is a focal treatment, it has the advantage over surgical resection of being able to destroy only the necessary amount of targeting tissue while sparing more noninvolved tissue of organ.
Because of the warming effect of flowing blood, arge blood vessels, such as the aorta, superior or inferior vena cava and portal vein, are impervious to the effect of freezing., the Hence tumors close to these venous systems can be treated with cryoablation, whereas resection of tumors close to major vascular structures is not possible.
In contrast with ethanol injection or radiofrequency ablation, which are eligible only for small tumors, cryoablation is possible for treatment of larger or small tumors. Using various caliber of probes or simultaneous placement of more probes, cryoablation can treat the tumor as large as more than 10 cm in size.
The treatment can be safely repeated and may be used along with standard treatments such as surgery, chemotherapy, and radiation.



Percutaneous microwave coagulation(PMCT): A trial showed that CT-guided percutaneous puncture was performed using a needle mono-pole microwave antenna with 65W, 2 450 MHz microwave delivered in 60 seconds to 20 peripheral lung cancer patients, including 8 suffering from primary lung cancer and 12 metastatic lung cancer (totally 28 lesions). Sixteen patients were alive after having been followed-up for 3 approximately 24 months. All patients showed nodules decreased in size. Diminution of over 50% was observed in 13 nodules and 3, completely disappeared. The overall response rate was 57.1%. Ellipsoid shadow 3.5 cm x 2.5 cm across was observed by CT in lesions immediately after coagulation. Gasification within the coagulated area was observed in a week with a high density in the peripheral region. Consolidation was observed in 3 months and the lesion disappeared 1 year later. Complete tumor necrosis was proved by biopsy. No side-effects or complications were observed. The data showthat PMCT is a new safe treatment for lung cancer, giving marked effect but minimum trauma.


Monoclonal antibodies to tumor factor receptors

There are following agents used for treatment of lung cancer

GENERIC NAME: gefitinib

BRAND NAME: Iressa
DRUG CLASS AND MECHANISM: Gefitinib is a drug that is used to treat several types of lung cancer. It works by preventing lung cancer cells from growing and multiplying.

Many cells, including cancer cells, have receptors on their surfaces for epidermal growth factor (EGF), a protein that is normally produced by the body and that promotes the growth and multiplication of cells. When EGF attaches to epidermal growth factor receptors (EGFRs), it causes an enzyme called tyrosine kinase to become active within the cells. Tyrosine kinase triggers chemical processes that cause the cells, including cancer cells, to grow, multiply, and spread. Gefitinib attaches to EGFRs and thereby blocks the attachment of EGF and the activation of tyrosine kinase. This mechanism for stopping cancer cells from growing and multiplying is very different from the mechanisms of chemotherapy and hormonal therapy. Gefitinib was approved by the FDA in May of 2003.

PREPARATIONS: Clear capsules of 50 mg.

STORAGE: Capsules should be stored at room temperature.

PRESCRIBED FOR: Gefitinib is used alone (monotherapy) for the treatment of patients with a certain type of lung cancer (non-small cell lung cancer or NSCLC) that has not responded to chemotherapy.

DOSING: Gefitinib is taken by mouth. The dose is 250 mg once daily. The dose is the same for men or women of any age or weight, and gefitinib can be taken with or without food

DRUG INTERACTIONS: Gefitinib may increase the blood-thinning effects of warfarin (Coumadin) and increase the risk of bleeding. Therefore, patients receiving gefitinib and warfarin at the same time should have more frequent testing of the "thinness" of their blood. Patients who receive drugs that increase an enzyme in the liver called CYP 3A4 that destroys gefitinib (e.g., rifampin or phenytoin (Dilantin) may need a higher dose of gefitinib to maintain the effectiveness of gefitinib. Similarly, patients who receive drugs that reduce CYP 3A4, e.g., ketoconazole (Nizoral), itraconazole (Sporanox), fluconazole (Diflucan), erythromycin, clarithromycin (Biaxin), ritonavir (Norvir), nelfinavir (Viracept), indinavir (Crixivan), nefazodone (Serzone), as well as grapefruit juice, may need a lower dose of gefitinib to prevent side effects from increased levels of gefitinib.

SIDE EFFECTS: About one in one hundred persons receiving gefitinib develop a potentially serious lung condition called interstitial lung disease that causes inflammation within the lung. Therefore, patients taking gefitinib who develop new or worsening cough, fever, or difficulty in breathing should contact their physician immediately. Eye irritation has been observed in patients receiving gefitinib, and patients who develop the onset of new eye symptoms should contact their physician. All patients taking gefitinib should seek medical advice promptly if they develop severe or persistent diarrhea, nausea, loss of appetite, or vomiting. Gefitinib should not be used by pregnant women. It is not known whether gefitinib is secreted in human milk. Since there is a possibility of toxicity in nursing infants, it is recommended that breast feeding be stopped if the mother is treated with gefitinib.

GENERIC NAME: erlotinib
BRAND NAME: Tarceva
DRUG CLASS AND MECHANISM:Erlotinib is a synthetic or man-made drug that is used for treating cancer. It is approved for treatment of non-small cell lung cancer (NSCLC) by the FDA in November of 2004.

Many cells, including cancer cells, have receptors on their surfaces for epidermal growth factor (EGF), a protein that is normally produced by the body and that promotes the growth and multiplication of cells. When EGF attaches to epidermal growth factor receptors (EGFRs), it causes an enzyme called tyrosine kinase to become active within the cells. Tyrosine kinase triggers chemical processes that cause the cells, including cancer cells, to grow, multiply, and spread. Erlotinib attaches to EGFRs and thereby blocks the attachment of EGF and the activation of tyrosine kinase. This mechanism for stopping cancer cells from growing and multiplying is very different from the mechanisms of chemotherapy and hormonal therapy.

PREPARATIONS: Erlotinib is available as 25, 100, and 150 mg white, round tablets.

STORAGE: Erlotinib should be stored at room temperature. PRESCRIBED FOR: Erlotinib is used for patients with metastatic or locally advanced non-small cell lung cancer (NSCLC) who have failed at least one previous round of chemotherapy.

Patients who received erlotinib had an average survival of 6.7 months compared to 4.7 months in patients who received placebo. In addition, 31% of patients receiving erlotinib in the study were alive at one year compared to 22% of patients receiving placebo.

It is expected that erlotinib will be approved for the treatment of pancreatic cancer in 2005. Erlotinib also is being studied as a treatment for other cancers including ovarian and head and neck cancers.

DOSING: The usual dose of erlotinib is 150 mg taken at least one hour before or two hours after eating to avoid an interaction with food that may reduce absorption of erlotinib.

DRUG INTERACTIONS: CYP3A4 is an enzyme in the liver that breaks-down and helps to eliminate erlotinib from the body. Drugs that inhibit CYP3A4 can result in high levels of erlotinib in the body, and the high levels can result in toxicity from erlotinib. Such drugs include atazanavir (Reyataz), clarithromycin (Biaxin), indinavir (Crixivan), itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone), nelfinavir (Viracept), ritonavir (Norvir), saquinavir (Invirase; Fortovase), telithromycin (Ketek), and voriconazole (VFEND). In patients receiving these drugs, a lower dose of erlotinib may be needed to prevent toxicity.

Some drugs increase the activity of the enzyme CYP3A4 and the elimination of erlotinib may reduce the levels of erlotinib in the body and the drug ineffective. Drugs that do this include rifampicin (Rifadin), rifabutin (Mycobutin), rifapentine (Priftin), phenytoin (Dilantin), carbamazepine (Tegretol), phenobarbital and St. John's Wort. These drugs should be avoided in patients taking erlotinib, if possible. If alternative drugs are not an option, higher doses of erlotinib may be required.

SIDE EFFECTS: The most common side effects due to erlotinib are
rash, diarrhea, loss of appetite, and fatigue. Any of these can occur
in about half of all patients who receive the medicine, but these
effects are usually mild. There have been rare reports of serious
lung disease, including deaths, in patients receiving erlotinib for
treatment of NSCLC or other tumors.