Small Cell Lung Cancer: Standard Treatment and New Developments

Introduction
Modern cancer therapy requires a multidisciplinary approach with 3 primary forms of treatment. These treatments include surgery, radiation and chemotherapy. The appropriate treatment options depends on the spread or stage of the disease.

Surgery involves taking out the cancer. For lung cancer, the surgeon may remove an entire lung or just a portion of a lung, depending on the size of the tumor. Radiation therapy uses x-rays to kill cancer cells. The radiation for small cell lung cancer is usually given in the form of a beam (external beam radiation therapy) which can be shaped to conform to the size and shape of the tumor. On occasion, radioactive material may be inserted into the airways in order to deliver a high dose of radiation to a small region; this is done to alleviate an obstruction caused by the cancer. Like surgery, radiation therapy is a local treatment, which means it is used to treat cancer in only one part of the body.

In contrast, chemotherapy is a systemic treatment, which means it is used to treat cancer throughout the entire body. Chemotherapy consists of medications that are given by pill or injection. These medications are delivered throughout the body via the blood.

Since small cell lung cancer spreads to other parts of the body early, the localized forms of treatment (i.e., surgery and radiation therapy) rarely improve survival when used alone. In fact, the role of surgery in most cases is limited to determining what type of cancer the patient has by getting a biopsy (taking a piece of the tumor out so that it can be analyzed under the microscope). The development of effective combinations of chemotherapy has lead to a 4-5-fold improvement in survival time compared with patients who are given no therapy. Furthermore, a small number of patients (about 1 in 10) may live more than 2 years free of the cancer.

Standard Treatment

Limited Stage Disease
In the treatment of limited stage disease, chemotherapy is the cornerstone of treatment because of the high frequency of cancer spread beyond the lungs and the high sensitivity of small cell lung cancer to chemotherapy drugs. Combinations of chemotherapy drugs are given because this leads to better results than those achieved by using one drug alone. Radiation therapy is also given along with the chemotherapy when possible because it improves survival.

The current standard practice is to give combination chemotherapy for 3 to 6 months along with radiation therapy. Studies have shown no benefit in prolonging treatment beyond this period. Combination chemotherapy produces shrinkage of small cell lung cancer in a large proportion (80-90%) of patients. Up to 50-60% of patient experience a complete response which means that the tumors shrink to the point that they become undetectable by standard diagnostic tests. With combination chemotherapy, patients with limited stage small cell lung cancer survive an average of 1 to 2 years. However, according to recent studies using the newest treatments (which includes chemotherapy and radiation therapy), roughly 25% of patients with limited stage disease can live 5 or more years with treatment.

The ideal situation is to combine radiation with chemotherapy because it has been shown to significantly improve survival when compared with chemotherapy alone. However, the combination of treatment modalities does increase the frequency and severity of side effects and complications. Therefore, this combination must be used cautiously or avoided in persons with impaired lung function or poor overall health.
The current standard treatment of patients with limited stage lung cancer should be a combination containing two chemotherapy drugs, most frequently etoposide and cisplatin, plus chest radiation therapy. The total radiation dose is divided into fractions which are usually given once or twice per day. A minority of patients has a small tumor size and may benefit from surgical resection followed by chemotherapy or chemotherapy with chest radiation.

Radiation therapy can also be used to prevent cancer from growing in the brain. Patients who achieve a complete response to chemotherapy with or without chest radiation have about a 60% risk of developing brain metastases within 2-3 years after diagnosis. A large proportion of these patients will have relapse limited to their brain and will die as a result of their brain metastases. Prophylactic radiation treatment of the head has been shown to reduce the risk of developing brain metastases by more than 50% and improve survival by more than 30%. The term prophylactic means that the radiation treatment is given before there is any evidence of cancer in the brain in order to prevent the cancer from developing in the brain in the future.

Extensive Stage Disease
Since in extensive stage small cell lung cancer the disease has spread, chemotherapy is essential since, as mentioned above, it treats cancer throughout the body. The chemotherapy should involve two or more drugs used at moderately high doses in order to produce the best results. There is no obvious improvement in survival when the duration of chemotherapy exceeds 6 months and maintenance chemotherapy (prolonged use of chemotherapy medications usually with lower doses) has not been shown to improve survival.
For patients with extensive stage disease, optimal chemotherapy treatment produces significant shrinkage of the cancer in 60-80% of patients, complete response (see above) rates of 12-20%, and an average survival of 7 to11 months. Because small cell lung cancers are responsive to chemotherapy, a variety of regimens have been studied and many have been shown to be active. The chemotherapy is usually administered every 3 to 4 weeks for a total of 3 to 6 months.

A combination of chemotherapy and chest radiation does not appear to improve survival compared with chemotherapy alone in extensive small cell lung cancer. However, radiation does play an important role in improving control of the disease within the chest and in relief of symptoms. Specifically, radiation is used to provide reduction of primary tumor effects such as blockage of major blood vessels or blockage of the airways (which can cause pneumonia and difficulty breathing). Radiation is also used to help shrink brain, bone, and spine metastases. Preventive radiation treatment of the head may be recommended for people with extensive stage small cell lung cancer who have achieved a complete response with chemotherapy and do not have evidence of brain metastases.

Recurrent Stage
Despite advances in the treatment of small cell lung cancer, the prognosis remains poor. Patients who have relapsed from first line therapy should be candidates for enrollment in clinical trials, which are scientific studies that test new medications and new ways of combining treatments. Based on our experience, patients who did not respond to initial chemotherapy and those who have undergone multiple chemotherapy regimens rarely respond to additional treatment. However, patients who initially responded and relapsed more than 6 months following initial treatment have a better chance of responding to additional chemotherapy, also known as salvage chemotherapy. In other patients, the primary goal should be relief of symptoms using local therapies and pain medication.

Treatment-Related Side Effects
Each type of treatment carries its own set of adverse effects. When selecting a treatment course, physicians must always weigh the potential benefits of the treatment against its potential side effects.

Surgery and other procedures
The side effects of surgery depend upon the surgical approach and extent of resection. The physician performing the procedure must fully explain to the patient the specific potential adverse outcomes associated with the treatment. The risks associated with cutting open the chest and removing the cancer depend upon the location and extent of resection but in general include bleeding, infection and death. Bronchoscopy may result in bleeding, hoarseness, and perforation of the airway. CT guided biopsy may result in bleeding or a collapsed lung.

Radiation Therapy
Side effects associated with radiation therapy, like surgery, depend upon the location of the tumor being treated. Radiation effects are usually divided into acute (occurring during treatment and usually resolving shortly after completion) and late (occurring months or years after completion). Acute effects associated with chest radiation include skin redness, peeling and ulceration, as well as sore throat, difficulty swallowing, cough, fatigue and a decrease in blood counts. These effects are usually managed conservatively but occasionally require temporary stopping of treatment or placement of a feeding tube (a device placed into the stomach through the abdominal wall) for nutrition.
Potentially serious late effects of chest radiation include narrowing of the esophagus (the tube that connects the mouth to the stomach), inflammation of the lung (which can be life-threatening), damage to heart, and damage to the nerves (which may cause pain, discomfort or weakness). These late effects are uncommon, occurring in less than 10-15% of cases. Radiation treatment of the head causes hair loss and can cause headache, nausea, fatigue and inflammation of the ear. Whether or not radiation of the head as currently practiced causes problems with short-term memory or cognitive function remains controversial..

Chemotherapy
Each chemotherapy drug and each drug combination possesses its own set of side effects. In general, patients can experience hair loss, nausea and vomiting, loss of appetite, kidney damage, heart damage, damage to nerves (which causes numbness or pain in the hands and/or feet), and loss of high-pitch hearing. The side effects will depend on which medications the patient receives, the total dose of the medications, and the body’s individual reaction to the medications.

New Developments
Areas of active clinical investigation in small cell lung cancer include evaluation of new chemotherapy drugs, drug combinations and dosing schedules, surgical resection of the primary tumor, the timing of radiation therapy, and changes in the way radiation is delivered.

Dose-Intensive Therapy
It has been hypothesized that the activity of some medications may depend on the schedule of treatment such that more frequent or higher dose (a.k.a. "dose-intensive") therapy may improve the results of treatment. Thus far, 3 scientific studies (in which patients are randomly assigned to one treatment or another) have not yet shown any significant benefit to dose-intensive therapy. Even chemotherapy of an intensity that completely destroys all blood-forming cells and requires bone marrow transplantation has not yet been shown to increase survival in people with small cell lung cancer.

Gene Therapy
Gene therapy was originally conceived as an approach to treatment of genetic disorders. The idea was to transfer a normal copy of a defective gene that would compensate for the damaged original and reverse the disease process. Science has revealed that cancer is a genetic disorder that occurs through a series of changes in a cell’s DNA. Unlike genetic disorders that are inherited, the DNA mutations in cancer are acquired. Nevertheless, gene therapy approaches may potentially be applicable and are under development for virtually all cancers including small cell lung cancer. Their effectiveness and safety remain to be determined and are presently restricted to use in research.

Summary
Treatment of small cell lung cancer generally involves chemotherapy with or without radiation treatment, depending on the location and amount of spread of the cancer. While current therapies are only moderately effective at prolonging survival, new treatments are constantly being developed. Active research will hopefully lead to more effective treatment of this often devastating disease.

Cancer

Reference Material on Cancer

Cancer, in medicine, common term for neoplasms, or tumors, that are malignant. Like benign tumors, malignant tumors do not respond to body mechanisms that limit cell growth. Unlike benign tumors, malignant tumors consist of undifferentiated, or unspecialized, cells that show an atypical cell structure and do not function like the normal cells from the organ from which they derive. Cancer cells, unlike normal cells, lack contact inhibition; cancer cells growing in laboratory tissue culture do not stop growing when they touch each other on a glass or other solid surface but grow in masses several layers deep.

Loss of contact inhibition accounts for two other characteristics of cancer cells: invasiveness of surrounding tissues, and metastasis, or spreading via the lymph system or blood to other tissues and organs. Whereas normal cells have a limited lifespan controlled by the telomere gene, which signals the end of the cell line, cancer cells contain telomerase, an enzyme that alters the telomere gene and allows the cell to continue to divide. Cancer tissue, growing without limits, competes with normal tissue for nutrients, eventually killing normal cells by nutritional deprivation. Cancerous tissue can also cause secondary effects, in which the expanding malignant growth puts pressure on surrounding tissue or organs or the cancer cells metastasize and invade other organs.

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Virtually all organs and tissues are susceptible to cancer. Cancers are usually named for their site of origin. Cancer cells that spread to other organs are similar to those of the original tumor, therefore these secondary (metastatic) cancers are still named for their primary site even though they may have invaded a different organ. For example, lung cancer that has spread to the brain is called metastatic lung cancer, rather than brain cancer. Carcinoma in situ refers to a cancer that has not spread. (See neoplasm for more on cancer nomenclature.)

Cancer is the second leading cause of death in the United States. Lung cancer is the leading cause of cancer death in adults; leukemia is the most common cancer in children. Other common types of cancer include breast cancer (in women), prostate cancer (in men), and colon cancer (see also Hodgkin's disease). The incidence of particular cancers varies around the world and sometimes according to ethnic group. For instance, African Americans have comparatively higher cancer rates and cancer mortality rates. It is unclear whether this is due to differences in exposure or to biological susceptibility. The number of diagnosed cases of cancer rose steadily in the United States for decades, but in 1998 it was announced that the number of new cases had begun to decline.

Causes of Cancer

Cancer results from mutations of certain genes that allow the cells to begin their uncontrolled growth. These mutations are either inherited or acquired. Acquired mutations are caused by repeated insults from triggers (e.g., cigarette smoke or ultraviolet rays) referred to as carcinogens. There is usually a latency period of years or decades between exposure to a carcinogen and the appearance of cancer. This, combined with the individual nature of susceptibility to cancer, makes it very difficult to establish a cause for many cancers.

The most significant avoidable carcinogens are the chemical components of tobacco smoke (see smoking). Dietary components, like excessive consumption of alcohol or of foods high in fat and low in fiber rather than fruits and vegetables that contain antioxidants and necessary micronutrients, have also been linked with various cancers. Some cancers may be triggered by hormone imbalances. For example, some daughters of mothers who had been given DES (diethylstilbestrol) during pregnancy to prevent miscarriage developed vaginal adenocarcinomas as young women. Aflatoxins are natural mold byproducts that can cause cancer of the liver.

Certain carcinogens present occupational hazards. For example, in the asbestos industry, workers have a high probability of developing lung and colon cancer or a particularly virulent cancer of the mesothelium (the lining of the chest and abdomen). Benzene and vinyl chloride are other known industrial carcinogens.

X rays and radioactive elements are also carcinogenic; the high incidence of leukemia and other cancers in Japanese survivors of the atomic bombing of Hiroshima and Nagasaki and the increased incidence of thyroid cancer after the Chernobyl nuclear disaster give evidence of this. Exposure to the ultraviolet radiation of sunlight is the leading cause of skin cancer.

Many other substances have been identified as carcinogenic to a greater or lesser extent, including chemicals in pesticides that leave residues on foods. The Delaney clause, an amendment (1958) to the U.S. Food, Drug, and Cosmetic Act that prohibits even minuscule amounts of carcinogens in the food supply, has provided the impetus for the investigation of many such chemicals but has also been a source of controversy between industry and environmentalists.

In the early 20th cent., the American virologist Peyton Rous showed that certain sarcomas affecting fowl could be transmitted by injection of an agent invisible under the microscope and later indentified as an RNA-containing virus. Other research uncovered oncogenic, or tumor-causing, viruses, first in experimental animals and then in humans. The Epstein-Barr virus, a member of the herpesvirus group, has been linked with a number of human cancers, including the lymphomas that often occur in immunosuppressed people, such as people with AIDS. Several human papillomaviruses (HPV) have also been shown to initiate cancers. For example, some types of HPV cause genital warts known as condylomata acuminata, which can lead to invasive cancer of the cervix, vulva, vagina, or penis, and another human papillomavirus has been associated with some forms of Kaposi's sarcoma. In addition, hepatitis B has been shown to increase the risk of liver cancer. Bacteria have also been associated with cancer. For example, the Helicobacter pylori bacterium that causes many ulcers is also associated with an increased risk of stomach cancer.

Cancer Susceptibility

Risk to humans from carcinogens depends upon the dose and a person's biologic susceptibility. Factors influencing a person's biological susceptibility to cancer include age, sex, immune status, nutritional status, genetics, and ethnicity. Only 5% of all cancers in the United States are thought to be explained by inherited genetic mutations. Known genes associated with hereditary cancer include the aberrant BRCA1 and BRCA2 genes that increase breast cancer risk and the HNPCC gene that is linked with colon cancer. In hereditary forms, it is often the normal gene of the allele that is injured or destroyed, leaving the abnormal inherited gene in control. Nonhereditary cancers sometimes involve the same gene mutations that hereditary forms have.

Tumor Development

Most bodily insults by carcinogens come to nothing because DNA has built-in repair mechanisms, but repeated insults can eventually result in mutations or altered gene expression in key genes called oncogenes and tumor-suppressor genes. Oncogenes produce growth factors, substances that signal a cell to grow and divide into daughter cells; tumor-suppressor genes (such as the p16, p53, and BRCA1 genes) normally produce a negative growth factor that tells a cell when to stop dividing. The abnormally inactivated tumor-suppressor gene or the abnormally activated oncogene is inherited by each of the cell's daughter cells, and a tumor develops. In many cases tumors remain small and in one place (in situ) for years, but some develop their own blood vessels (a process known as angiogenesis) and begin to grow and spread.

Symptoms

The classic symptoms of cancer are rapid weight loss; a change in a wart or mole; a sore that does not heal; difficulty swallowing; chronic hoarseness, blood in phlegm, urine, or stool (a consequence of angiogenesis); chronic abdominal pain; a change in size or shape of the testes; a change in bowel habits; a lump in the breast; and unusual vaginal bleeding. Many of these and other symptoms are often nonspecific, e.g., weakness, loss of appetite, and weight loss, and thus are not obvious in the early stages. Sometimes the side effects of tumor growth are more severe than the actual effects of the malignancy; for example, some tumors secrete materials such as serotonin and histamine that can cause drastic vascular changes. Conversely, cancers that destroy tissue may also have serious effects, e.g., malignant destruction of bone tissue may raise the blood level of calcium.

Prevention and Detection

As more has been learned about cancer, emphasis on prevention and early detection has increased. Cessation of smoking and other tobacco use is the most important controllable means of prevention; smoking causes about 30% of the cancer deaths in the United States. A diet low in fat and high in fiber, including a variety of fruits and vegetables (especially those high in antioxidants), is also recommended. Effective protection against the rays of the sun is recommended to avoid skin cancer. Another preventive approach is vaccination against cancer-causing viruses, such as the hepatitis B virus.

Cancers caught early, before metastasis, have the best cure rates. A number of screening tools are now available to allow early detection and treatment. Among these are monthly breast self-examinations and regular mammography and Pap tests for women, regular self-examination of the testes for young men, and, for older men, regular examination of the prostate gland with blood tests for prostate-specific antigen (PSA) tumor marker (a substance in the body that heralds an increased cancer risk). Sigmoidoscopy plus physical examination and laboratory tests for carcinoembryonic antigen (CEA) are recommended for detection of colon cancer. Self-examination of the skin is important for the early detection of skin cancers. Suspicion of a tumor may be confirmed by X-ray study, endoscopy (see endoscope), blood tests for various tumor markers, and biopsy from which the cells are examined by a pathologist for malignancy.

Treatment

Developments in the treatment of cancer have led to greatly improved survival and quality of life for cancer patients in the past three decades. Traditionally, cancer has been treated by surgery, chemotherapy, and radiation therapy. In recent years immunotherapy has been added to that list. New drugs and techniques are constantly being researched and developed, such as antiangiogenic agents (e.g., angiostatin and endostatin), genetically engineered monoclonal antibodies, retinoid agents, and vaccine agents (stimulating the immune system).

For most kinds of cancer, surgery remains the primary treatment. It is most effective if the cancer is caught while still localized. Some cancers that spread to the lymph system are sometimes treated by extensive surgical removal of tissue, but the trend is toward more conservative procedures (see mastectomy). Cryosurgery, the use of extreme cold, and electrodessication, the use of extreme heat, are also being used to kill cancerous tissue and the surrounding blood supply. If the cancer has metastasized, surgery is often replaced by or followed by radiation therapy (which is a localized therapy) and chemotherapy (which is a system-wide therapy).

For some cancers, radiation therapy—either from an external beam or from implanted radioactive pellets—is the primary treatment. The usual forms are X rays and gamma rays. Use of radioactive elements specific for particular target organs, such as radioactive iodine specific for the thyroid gland, is effective in treating malignancies of those organs.

Cytotoxic chemotherapy is used as a primary treatment for some cancers, such as lymphomas and leukemias or as an addition to surgery or radiation therapy. Cytotoxic drugs (drugs that are toxic to cells) are aimed at rapidly proliferating cells and interfere with nucleic acid and protein synthesis in the cancer cell, but they are often toxic to normal rapidly proliferating cells, such as bone marrow and hair cells. Often a combination of cytotoxic drugs is used. Drugs that reduce side effects may be added to the treatment, such as antinausea agents.

Hormonal chemotherapy is based upon the fact that the growth of some malignant tumors (specifically those of the reproductive organs) is influenced by reproductive hormones. Tamoxifen is a naturally occurring estrogen inhibitor used to prevent breast cancer recurrences. Flutamide is sometimes used in prostate cancer to inhibit androgen uptake. Sex-hormone related drugs such as DES and tamoxifen, which may be carcinogenic under some conditions, have proven to be protective under others.

More specifically targeted drug therapies have begun to be explored as a better understanding of the molecular biology of individual cancers has been developed. Such drugs are designed to kill only cancer cells while having fewer side effects. Gleevec (STI-571), which is used to treat chronic myelogenous leukemia and some other cancers, inhibits certain kinase receptors that become hyperactive in cancer cells, resulting in the cells' rapid reproduction.

Immunotherapy (sometimes called biological therapy) uses substances that help the body mobilize its immune defenses. Some attack the tumor itself, while others bolster the body's ability to withstand conventional chemotherapy treatment. Other new or experimental therapies include drugs that inhibit angiogenesis and photodynamic therapy, in which a patient is given a drug to make the tumor light-sensitive, after which the tumor is exposed to bright laser light. The best choice of treatment will increasingly be influenced by the growing field of molecular pathology, in which characteristics of individual cancers (e.g., virulence or resistance to a particular treatment) can be revealed by analysis of their genetic characteristics rather than by the microscope.

Besides treatment of the cancer itself, progress has been made in the management of the chronic pain that often accompanies cancer and in the education of patients and physicians in such techniques as biofeedback, acupuncture, and meditation and the appropriate use of narcotics and other medications. Because of improvements in early detection and treatment, many more people are now living with cancer. Over half of all people with cancer now survive for five or more years.

Bibliography

See S. S. Lang and R. B. Patt, You Don't Have to Suffer (1994); P. Greenwald et al., Cancer Prevention and Control (1995); M. Dollinger et al., Everyone's Guide to Cancer Therapy (3d ed. 1997); C. N. Coleman, Understanding Cancer (1998). See also publications of the National Cancer Institute and the American Cancer Society.