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.
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