This is the second of two parts in the Reference Library by Dr. Gadgeel on small cell lung cancer.

Patients with Limited Stage Small Cell Lung Cancer

As stated in the prior chapter from the reference library on basic principles and workup of small cell lung cancer (SCLC), in patients with limited disease (LD)-SCLC, the cancer is only detected in the lung, or the lung and the lymph nodes. But even if it is only detected in these sites it is known, based on prior studies, we remain concerned that the cancer has spread to other parts of the body but that it has not yet grown in these other sites for it to be seen on the scans.

It is for this reason chemotherapy is always included in the treatment of LD-SCLC . Chemotherapy goes throughout the body and therefore will not only attack the cancer visible in the primary lung tumor and the lymph nodes, but also the SCLC cells in the other parts of the body that may exist but remain invisible on the scans.

Chemotherapy by itself can eradicate SCLC in areas where it is not big enough to be seen on the scans. As far as the SCLC that is big enough to be seen, chemotherapy can shrink the cancer but cannot be expected to eradicate it completely. Therefore for the SCLC in the lungs and lymph nodes, radiation therapy is utilized, combined with chemotherapy. Thus limited SCLC is routinely treated with both chemotherapy and radiation therapy directed to disease in the chest. This chemotherapy and radiation is generally given concurrently, since the chemotherapy makes the radiation therapy stronger against the cancer than what it would be by itself (called radiosensitization). There is also evidence that giving the radiation earlier rather than later is most beneficial.

Specifics of Treatment for LD-SCLC

Cisplatin or Carboplatin, with Etoposide

The chemotherapy typically consists of 2 drugs -- cisplatin or carboplatin -- combined with etoposide. This combination is given most commonly over three days with cisplatin or carboplatin given on the first day with etoposide, and then etoposide alone given on 2^nd and 3^rd days. All drugs are given intravenously. The chemotherapy is repeated every 3 weeks for a total of 4 or sometimes 6 cycles.

Radiation therapy is targeted to the small cell lung cancer in the chest that can be seen on the scans. Radiation therapy generally is given daily Monday-Friday for about 6-7 weeks.

Some doctors also give radiation therapy twice daily Monday-Friday, based on a clinical trial that demonstrated particularly favorable survival with this approach. If given twice daily, the duration of radiation is for 3 weeks. There has to be a minimum of 6 hours between the two sessions if given on the same day.

Common side-effects of this treatment

Nausea/Vomiting - Usually can be well controlled with appropriate anti-nausea medications

Fatigue - A general sense of tiredness is experienced by many patients about 1 or 2 days after the chemotherapy. The extent of the tiredness varies from patient to patient. This symptom generally lasts for 2-4 days with the intensity of the tiredness reducing with every passing day. It is possible that the extent of the tiredness may be worse with each subsequent round of chemotherapy

Lowering of blood counts, particularly whiteblood cell count - The lowering of white blood count is usually for only few days, which is less worrisome than a situation in which the white blood cell count is very low for a week or longer, as is typical in treating leukemia or some other cancers. However during this typically brief time of low blood cell counts, the patient is at higher risk for getting an infection. If a patient during this period gets an infection, then the infection could spread in the body very rapidly, since the number of white blood cells is not adequate to fight it, so intravenous antibiotics are needed. It is therefore very important that a patient on chemotherapy go to the emergency room right away if they get a fever of 101°F or more at anytime during the treatment period. The probability of this happening is very low, less than 5%.

Esophagitis (inflammation and swelling of the esophagus) - The esophagus connects the mouth to the stomach. It runs at the back of the middle of the chest. Even though radiation doctors have become very good at targeting the radiation only to the cancer, there is some extension of the radiation treatment to the surrounding structures, including the esophagus. This can cause inflammation and swelling in the esophagus, which makes swallowing food painful. Usually this starts about 2-3 weeks into treatment. In most patients this can be managed readily with proper instructions on food intake, hydration with fluids and medications. However, in < 10% of the patients, it may be severe enough that the patient has a difficult time swallowing food or water and may need to be admitted to the hospital for intravenous fluids and other support.

Pneumonitis (inflammation and swelling of the lung) - Some patients may develop inflammation in the lungs, usually in the area of radiation. This can cause coughing, shortness of breath, and fever. This usually happens about 2-6 months after radiation and is felt to be a reaction in the lung to the treatment. In about 10% of the patients, it could be severe enough to require admission to the hospital. Though it can resolve on its own with time, it is severe enough, treatment with steroids may be needed, with oxygen support also sometimes added as well. Most patients recover from this condition significantly or even completely.

Since this side effect may occur even several months after completion of treatment, it is important for the patient to inform their doctors if they develop new cough or shortness of breath and not assume it is an unrelated minor issue such as a cold.

Prophylactic Cranial Radiation (PCI) - Almost 50% of SCLC patients can develop brain metastases. Chemotherapy can go to all different parts of the body but one area it does not reach in sufficient amount is the brain. This is because the brain is covered by something known as the blood-brain barrier that limits the amount of chemotherapy that can get through.

Thus, if any SCLC cells have travelled to the brain, they likely would not be adequately treated with chemotherapy alone. Therefore patients with limited stage SCLC who have completed chemotherapy are treated with radiation to the brain. This radiation is given from Monday-Friday for about 3 weeks.

There is a small chance that this radiation treatment may affect the cognitive function of the brain in the future, but this risk is felt to be quite low compared with the benefits of markedly reducing the risk of brain metastases in patients otherwise highly likely to develop them.

Outcome of Chemotherapy+Radiation Therapy in LD-SCLC Patients

Data to date suggest that with chemotherapy and radiation, about 20% of the patients with LD-SCLC can have their cancer eradicated and therefore cured.

Unfortunately, this also means that 80% of the patients are not cured. In these patients, the cancer may shrink and may even become small enough that it cannot be seen on the scans, but it has not been completely eliminated. The cancer in these patients will eventually recur, generally within the first 2-3 years, though patients can have late (after the first 3 years) recurrences. Even in patients in whom the cancer is not cured, the treatment rendered does provide benefit, since survival is far longe rwith treatment than without; quality of life is also significantly improved with treatment.

PCI improves the survival by 5%. Thus, the cure rate is improved from about 20% with chemotherapy and radiation therapy to about 25% with the addition of PCI.

It isn't possible to predict which patients can be cured before starting therapy. Instead, only gradual follow-up after treatment will the greatest beneficiaries of treatment be clarified.

Generally, physical exam and scans are done every 3-6 months for the first 2-3 years and yearly scans thereafter. There are no data that shows that these scans help find the recurrence of cancer sooner than if scans are done only at the time of patient developing symptoms. However, it is generally accepted practice to obtain the scans on the schedule described above.

Treatment of Extensive Stage Small Cell Lung Cancer Patients

The primary treatment of SCLC with extensive disease (ED-SCLC) is chemotherapy. The chemotherapy used in ED-SCLC patients is generally the same as discussed for patients with LD-SCLC.

Cisplatin or Carboplatin, with Etoposide

The treatment is repeated every 3 weeks, with cisplatin or carboplatin given on the first day and etoposide typically given over about 3 days.

Scans to assess the response of the cancer to this treatment are done after every 2-3 rounds (or about 6-9 weeks). This chemotherapy is able to shrink the cancer or stabilize the cancer in about 60-70% of patients with ED-SCLC. In addition, relief of cancer-related symptoms can be fairly quick with this chemotherapy. Assuming that the cancer is shrinking or stable and the patient is tolerating the treatment without significant side-effects, the treatment is extended for 4 or perhaps up to 6 cycles. There are no data to suggest that extending treatment with this chemotherapy beyond this point has any benefit.

After this fixed duration of treatment, patients are monitored with physical examination and scans to assess if the cancer is remaining stable. This assessment is usually done every 6-8 weeks. Unfortunately, it is expected in ED-SCLC that the cancer will show evidence of growth again, at which point the next chemotherapy treatment is started or consideration of a focus exclusively on symptom management.

Adverse Effects of this Treatment

Nausea and vomiting, fatigue, and reduced blood cell counts are all seen as described in the section on LD-SCLC above. However, both esophagitis and pneumonitis described in the treatment of LD-SCLC are rarely seen in the absence of chest radiation.

Cisplatin or Carboplatin, with Irinotecan

In a trial conducted in Japan, the combination of cisplatin and irinotecan was found to be better than cisplatin and etoposide. Two separate trials were conducted in the United States to confirm the results of this trial. Both the trials failed to show that the combination of cisplatin and irinotecan is better than cisplatin and etoposide. The results with the two treatments were very similar. The reasons for the disparity in results between the Japanese and US trials are unclear, but it is thought that genetic differences in how different chemotherapy agents are metabolized by different racial groups may be a major factor. In Japan, the combination of cisplatin and irinotecan is used for the treatment of patients with ED-SCLC. In the US, however, this is not as commonly used as a combination of a platinum agent with etoposide.

If cisplatin and irinotecan is given, the treatment is most commonly administered as follows-

Cisplatin is given once every 3 or 4 weeks. Irinotecan is given on a weekly basis for 2 weeks out of 3, or 3 weeks out of 4. The schedule of the 2 drugs is repeated every 3 or 4 weeks. This treatment is also given for 4 cycles.

Adverse Effects of this Treatment

Nausea and vomiting, fatigue, and reduced blood cell counts are all seen as described above.

Diarrhea - Irinotecan is known to cause diarrhea, which can be severe. The diarrhea usually starts about 1 or 2 days after treatment. It is very important for the patient to start taking an anti-diarrheal medication immediately with the onset of diarrhea to control it effectively. In a small percentage of patients, the diarrhea can be severe despite taking an anti-diarrheal and may even require hospitalization for management that includes intravenous fluid support.

Management of Brain Metastases

Small cell lung cancer patients with evidence of brain metastases require whole brain radiation to treat the brain metastases. Because brain metastases in SCLC are so commonly a multifocal process, stereotactic brain radiation is not an accepted alternative in this setting.

The timing of the brain radiation could vary. If the patient has evidence of brain metastases on the scans but has no symptoms from the brain metastases, chemotherapy can be initiated first with close monitoring of the brain metastases on the scans, and the brain radiation can be done following the completion of some initial chemotherapy. However, if the patient has any symptoms that are related to the brain metastases, these patients should be first treated with whole brain radiation and then treated with chemotherapy. Depending upon the patient's condition the doctors may decide to start with chemotherapy and the whole brain radiation together.

Prophylactic Cranial Radiation-

Because the potential for spread to the brain in small cell lung cancer patients is very high, as noted above, PCI has also been evaluated for patients with ED-SCLC. A recent European study demonstrated that patients with ED-SCLC, no evidence of brain metastases, and who have responded to first line chemotherapy benefit from receiving brain radiation following the completion of front line chemotherapy. The benefit is in the form of extending survival and markedly reducing the chance of the patient developing subsequent brain metastases.

Based on these results small cell lung cancer patients are considered for brain radiation following the completion of chemotherapy. However it is important to mention that due to certain reservations regarding this trial, the strategy of brain radiation following chemotherapy is not applied to all patients.

Second Line Treatment

As mentioned above, it is expected that cancer will eventually progress in a patient with ED-SCLC at some time point following the completion of first line therapy, usually in the range of months. At the time of progression, patients are most commonly treated with a drug called topotecan (Hycamtin). This drug is FDA approved for the treatment of patients with ED-SCLC whose cancer has progressed following treatment with prior chemotherapy and has been shown to improve qualify of life and also survival in this setting.

Topotecan is usually administered over 5 days every 3 weeks. Because this schedule typically leads to a very significant drop in blood counts and is also inconvenient for many patients who may be symptomatic from their relapsed cancer, some doctors also treat patients with weekly administration of topotecan. Topoecan can be administered intravenously or orally.

As in the first line setting, scans are usually done after 2 rounds (about 6 weeks) of chemotherapy to assess the status of the cancer. When treating recurrent SCLC patients, the treatment with topotecan is usually continued until there is evidence that the treatment is not working or the patient does not tolerate the side-effects from the treatment.

Topotecan is able to keep the cancer controlled on an average for about 3 months. Again the duration for which the cancer is controlled varies from patient to patient. The probability of topotecan working is higher in a patient whose cancer was controlled for longer than 3 months after completing the first chemotherapy.

Adverse effects of Topotecan

Lowering of blood counts, particularly white blood cell count and platelets - The probability of the white blood cell count dropping significantly is high enough for some doctors to consider giving an injection called neulasta, which can reduce the extent and duration of the drop in white blood cells ,even with the very first round of topotecan.

Nausea/Vomiting - Not very common with this chemotherapy but could occur.

Diarrhea- May occur, though not common

Fatigue- Also possible but not very common.

Retreatment with Cisplatin (or Carboplatin) and Etoposide

In a small proportion of patients with ED-SCLC, the cancer may remain controlled for longer than 6 months after the initial treatment. In these patients, re-treatment with the original treatment is often considered, and the cancer could be controlled with the same chemotherapy again. Usually the control of the cancer with re-treatment does not last as long as the first time, and in some patients re-treatment with the same chemotherapy may not work at all.

Subsequent Chemotherapy

If topotecan does not control or shrink the cancer or does so for a period of time before the cancer starts growing again, it is feasible to treat with other chemotherapy drugs, but we don't have good evidence to support the use of other chemotherapy drugs following the use of a platinum agent with etoposide in first line therapy followed by topotecan as second line therapy. The lack of data does not mean there is no benefit from such therapy, but rather that we don't know if doing more chemotherapy is valuable or not.

If the general condition of the patient is relatively good, many oncologist may consider offering these patients other chemotherapy drugs such as Taxol (paclitaxel) or Gemzar (gemcitabine). It is important to remember that these patients could be considered for clinical trials evaluating investigational drugs. However, many patients in this setting are struggling with increasing cancer-related side effects and cumulative toxicity issues with chemotherapy. For such patients, supportive care rather than further anti-cancer treatment may be most advisablee.

The GRACE Lung Cancer Reference Library is made possible by an unrestricted educational grant from Pfizer Oncology.