small cell lung cancer frequently develop brain metastases (go
here) since chemotherapy penetrates
poorly into the brain (the blood-brain-barrier creates a 'sanctuary site'.)
Using low dose prophylactic irradiation to the brain (called PCI) will
significantly lower the risk of developing brain metastases (in the study below from 59%
to 33%) but high doses can cause problems (with memory or dementia.) Even
patients with extensive stage small cell will benefit from PCI if they
respond to chemotherapy (go here).
If patients are in a complete remission and off chemotherapy, we generally recommend they consider brain radiation based on the data below and the current NCCN guidelines. The usual doses are 200cGy X 15 - 18 or 250cGy X 10. (See dose trial RTOG 0212 and see NCCN radiation dose guidelines and review article.) With these low doses the risk of brain damage is quite low (go here).
Prophylactic Cranial Irradiation for Patients with Small-Cell Lung Cancer in Complete Remission
Anne Auperin, for the Prophylactic Cranial Irradiation Overview Collaborative Group
Prophylactic cranial irradiation reduces the incidence of brain metastasis in patients with small-cell lung cancer. Whether this treatment, when given to patients in complete remission, improves survival is not known. We performed a meta-analysis to determine whether prophylactic cranial irradiation prolongs survival. We analyzed individual data on 987 patients with small-cell lung cancer in complete remission who took part in seven trials that compared prophylactic cranial irradiation with no prophylactic cranial irradiation. The main end point was survival.
relative risk of death in the treatment group as compared with the control group was 0.84
, which corresponds to a 5.4 percent increase in the rate of survival at three years (15.3
percent in the control group vs. 20.7 percent in the treatment group).
Prophylactic cranial irradiation also increased the rate of disease-free survival
(relative risk of recurrence or death, 0.75)
Conclusions. Prophylactic cranial irradiation improves both overall survival and disease-free survival among patients with small-cell lung cancer in complete remission. (N Engl J Med 1999;341:476-84.)
|Radiation Dose||Relative Risk of Brain Metastases|
Small-cell lung cancer, the type of lung cancer most strongly associated with tobacco exposure, accounts for 20 to 25 percent of all cases of lung cancer (approximately 45,000 new cases per year in the United States). The majority of patients are treated with combination chemotherapy (etoposide and cisplatin) for four to six months, with or without concurrent thoracic irradiation. The median survival for patients who are not treated is only 6 to 12 weeks, whereas for patients treated with combination chemotherapy, the median survival is 10 to 12 months. For patients with extensive disease (disease extending beyond one hemithorax or beyond regional lymph nodes) who are treated with combination chemotherapy, the median survival is only seven to nine months.
Limited disease (disease confined to the lung) accounts for 30 to 40 percent of all newly diagnosed cases of small-cell lung cancer. It is now treated with combination chemotherapy and thoracic irradiation of the site of the primary tumor. With this approach, the median survival is 18 months, and up to 25 percent of patients survive for more than 2 years. The use of combination chemotherapy and concurrent thoracic irradiation of the site of the primary tumor in these patients is based on the results of meta-analyses that revealed that chemotherapy plus thoracic irradiation improved the overall two- or three-year rate of survival by 5.4 percent, as compared with chemotherapy alone. More recent studies aimed at defining the best method of combining chemotherapy with thoracic irradiation have indicated that twice-daily thoracic irradiation given concurrently with chemotherapy results in two- and five-year survival rates of 44 percent and 22 percent, respectively. These results confirm the importance of both thoracic irradiation and chemotherapy in the treatment of patients with limited small-cell lung cancer.
A major cause of morbidity and mortality in patients with small-cell lung cancer is brain metastasis, which in most patients results in multiple tumors. At the time of initial diagnosis, brain metastases can be detected in up to 10 percent of patients, and 1 to 2 percent of these patients have metastases only in the brain. However, among patients who complete chemotherapy, an additional 30 to 70 percent subsequently have clinically apparent brain metastases, and even more have such metastases at autopsy. (Moreover, among patients who have a complete remission with chemotherapy, approximately 15 percent have brain metastases as the initial or sole manifestation of recurrence. As the length of survival after diagnosis increases, the risk of metastases to the brain increases. Thus, as chemotherapy with concurrent thoracic irradiation becomes more effective for patients with limited small-cell lung cancer, the frequency of brain metastases later in the course of the disease may continue to rise.
For many years, prophylactic cranial irradiation has been used in patients with small-cell lung cancer in the belief that the treatment of microscopic or subclinical metastases would prevent or delay the onset of symptomatic brain metastases, but its efficacy for this purpose has been uncertain. Those who advocate prophylactic cranial irradiation point out that it is a safe way to reduce the overall incidence of brain metastases, even if only a small number of patients benefit.Others argue against routine prophylactic cranial irradiation. They point out that the brain is rarely the sole site of recurrence, that radiation can be neurotoxic, and that radiation therapy does not prolong survival.
In this issue of the Journal, Auperin et al. report the results of a detailed meta-analysis of the efficacy of prophylactic cranial irradiation in 987 patients (847 patients with limited disease and 140 patients with extensive disease) who took part in seven trials and who had complete remission with chemotherapy, with or without thoracic irradiation. Prophylactic cranial irradiation was associated with an absolute decrease of 25.3 percent in the cumulative incidence of brain metastasis at three years, from 58.6 percent in the control group to 33.3 percent in the treatment group. More important, prophylactic cranial irradiation was also associated with an absolute increase in overall survival of 5.4 percent at three years, from 15.3 percent in the control group to 20.7 percent in the treatment group. Prophylactic cranial irradiation was beneficial in patients with either limited or extensive disease. As previously reported in the two largest trials included in the meta-analysis, in which neuropsychological tests were performed on most but not all patients before, during, and after treatment, neurocognitive impairment was often detected at diagnosis, but no deterioration was found after prophylactic cranial irradiation.
Can we now conclude that prophylactic cranial irradiation should become standard treatment for all patients with small-cell lung cancer who are in complete remission? I think so. This study confirms that there is a small absolute survival advantage for patients who receive prophylactic cranial irradiation. Even though this advantage is small, it is important: early studies of thoracic irradiation in patients with limited-stage small-cell lung cancer revealed no significant trend toward improved survival, but when large numbers of patients were studied, the small absolute survival benefit associated with thoracic irradiation was identified. Today, for almost all patients with limited small-cell lung cancer, thoracic irradiation is an integral part of therapy.
We still do not know how best to integrate prophylactic cranial irradiation with chemotherapy in patients with small-cell lung cancer. The optimal dose of radiation, volume of tissue to be irradiated, and duration and timing of prophylactic cranial irradiation have not been determined. Also, questions remain regarding the safety and long-term neuropsychological consequences of prophylactic cranial irradiation. The study found a significant survival benefit, but it should be noted that four of the trials included in the meta-analysis had fewer than 100 patients, which suggests that there may have been some selection bias.
On the basis of the data presented, it is now reasonable to include prophylactic cranial irradiation as part of the treatment of patients with limited small-cell lung cancer who are in complete remission (usually evident after three or four cycles of chemotherapy) and of patients with extensive disease who have isolated metastases and are in complete remission. To minimize the risk of neurologic damage, prophylactic cranial irradiation should not be administered concurrently with chemotherapy or to elderly patients. As treatment of the primary tumor in patients with small-cell lung cancer improves, brain metastases are likely to become an increasingly frequent manifestation of treatment failure. Thus, studies are needed to define the optimal dose and fractionation schedule for prophylactic cranial irradiation and to determine how best to integrate this therapy with chemotherapy and thoracic irradiation.