Value of prophylactic cranial irradiation given at complete remission in small cell lung carcinoma. Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomised trial. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC) Comparative study of prophylactic cranial irradiation in patients with small cell lung cancer achieving a complete response: a long-term follow-up result. Controlled clinical trial of prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission.
The optimal use of "prophylactic" cranial irradiation (PCI) in patients with small cell lung cancer remains undetermined. This study reviews the impact of PCI, given at complete remission (CR), on neurologic relapse in 172 consecutive patients with small cell lung cancer treated in three sequential chemotherapy protocols at the University of Maryland Cancer Center. In the first study of 38 patients, none received PCI. In the second study of 109 patients, the first 28 achieving CR were randomized to 3000 rad of PCI in ten fractions (PCI+) or to observation (PCI-). Thereafter, based on interim analysis, all patients achieving CR received PCI. In the third study, to date, 25 patients achieving CR have received PCI. Overall, 169 patients were evaluable for neurologic relapse, and 30 of 90 patients achieving CR received PCI. Among all patients with CR, with adjustment for disease extent, there was a significant delay to any neurologic relapse (P = 0.01) and cerebral metastases (P = 0.02) for PCI+ compared to PCI- patients. Among PCI- patients with CR, cerebral metastases alone occurred in 28% as the sole site and in 33% as the initial site, whereas cerebral relapse occurred prior to systemic relapse in only one PCI+ patient with CR. Patient survival however, was not significantly altered by PCI. PCI at CR confers effective and worthwhile local control in the CNS, especially during periods of systemic response, and a small percentage of patients may benefit. Systemic drug resistance still determines overall survival. Prophylactic cranial irradiation (PCI) reduces the risk of cranial metastasis in small cell lung cancer (SCLC), but the magnitude and value of this reduction, the risks of radiation morbidity and whether PCI influences survival are unclear. We conducted a randomised trial in patients with limited-stage SCLC who had had a complete response to induction therapy. Initially, patients were randomised equally to (1) PCI 36 Gy in 18 daily fractions, (2) PCI 24 Gy in 12 fractions and (3) no PCI; subsequently, to increase the rate of accrual, randomisation was to clinicians' choice of PCI regimen versus no PCI (at a 3:2 ratio). The endpoints were appearance of brain metastases, survival, cognitive function, and quality of life (QoL). Three hundred and fourteen patients (194 PCI, 120 No PCI) were randomised. In the revised design, the most commonly used PCI regimens were 30 Gy in 10 fractions and 8 Gy in a single dose. With PCI, there was a large and highly significant reduction in brain metastases (HR = 0.44, 95% CI 0.29-0.67), a significant advantage in brain-metastasis-free survival (HR = 0.75, 95% CI 0.58-0.96) and a non-significant overall survival advantage (HR = 0.86, 95% CI 0.66-1.12). In both groups, there was impairment of cognitive function and QoL before PCI and additional impairment at 6 months and 1 year, but no consistent difference between the two groups and thus no evidence over 1 year of major impairment attributable to PCI. PCI can safely reduce the risk of brain metastases. Further research is needed to define optimal dose and fractionation and to clarify the effect on survival. Patients with SCLC achieving a complete response to induction therapy should be offered PCI. Between 1981 and 1986, a total of 46 patients with small cell lung cancer (SCLC) achieving a complete response by chemotherapy with or without chest irradiation were randomized either to receive prophylactic cranial irradiation (PCI) or not. With a median follow-up time of 8.5 years for both groups, only five of 23 patients (22%) in the PCI group developed brain relapse, while 12 out of 23 (52%) in the no PCI group did so (P < 0.05). The frequency of patients developing a sole brain relapse during their whole clinical course was 4% for the PCI group and 17% for the no PCI group, however, the difference was not statistically significant. Patient survival was better for the PCI group (median survival time of 21 months, and 5-year survival rate of 22%) as compared with the no PCI group (median survival time of 15 months, and 5-year survival rate of 13%), showing a marginal significance (P = 0.097). Late neurologic toxicity was infrequent; only one developed a mild deterioration among seven long-term disease-free survivors in the PCI group. These results appear to warrant further clinical trials to clarify the utility of PCI in patients with SCLC achieving a complete response. We conducted a randomised clinical trial on 211 patients with small-cell lung cancer in complete remission (CR). The aim of this trial was to evaluate the effect of prophylactic cranial irradiation (PCI) on overall survival. Eligible patients were randomly assigned to receive either PCI (100 patients) or no PCI (111 patients). Each centre was allowed to use its own PCI protocol as long as the total dose was within the range of 24-30 Gy and delivered in less than 3 weeks with fractions of 3 Gy or less. The mean follow-up is 5 years. The survival curves do not differ significantly (P = 0.25) between the two groups. The 4-year overall survival rate (95% confidence interval) is 22% [15-32%] in the PCI group versus 16% [10-25%] in the control group. The relative risk of death in the PCI group compared to the control group is 0.84 (95% CI = [0.62-1.13]). The incidence of brain metastasis is lower in the PCI group, but the difference is not statistically significant (P = 0.14). The 4-year cumulative rate of brain metastasis is 44% [32-57%] in the PCI group compared to 51% [38-63%] in the control group. In conclusion, in this study, which had to be closed prematurely, no significant difference was found in terms of the incidence of brain metastases nor in survival. Prophylactic cranial irradiation in patients with small-cell lung cancer decreases the overall rate of brain metastases without an effect on overall survival. It has been suggested that this treatment may increase neuropsychological syndromes and brain abnormalities indicated by computed tomography scans. However, other retrospective data suggested a beneficial effect on overall survival for patients in complete remission.
                Our purpose was to evaluate the effects of prophylactic cranial irradiation on brain metastasis, overall survival, and late-occurring toxic effects in patients with small-cell lung cancer in complete remission.
                We conducted a prospective study of 300 patients who had small-cell lung cancer that was in complete remission. The patients were randomly assigned to receive either prophylactic cranial irradiation delivering 24 Gy in eight fractions during 12 days (treatment group) or no prophylactic cranial irradiation (control group). A neuropsychological examination and a computed tomography scan of the brain were performed at the time of random assignment and repeatedly assessed at 6, 18, 30, and 48 months. Patterns of failure were analyzed according to total event rates and also according to an isolated first site of relapse, using a competing-risk approach.
                Two hundred ninety-four patients who did not have brain metastases at the time of random assignment were analyzed. The 2-year cumulative rate of brain metastasis as an isolated first site of relapse was 45% in the control group and 19% in the treatment group (P < 10(-6)). The total 2-year rate of brain metastasis was 67% and 40%, respectively (relative risk = 0.35; P < 10(-13)). The 2-year overall survival rate was 21.5% in the control group and 29% in the treatment group (relative risk = 0.83; P = .14). There were no significant differences between the two groups in terms of neuropsychological function or abnormalities indicated by computed tomography brain scans.
                Prophylactic cranial irradiation given to patients with small-cell lung cancer in complete remission decreases the risk of brain metastasis threefold without a significant increase in complications. A possible beneficial effect on overall survival should be tested with a higher statistical power.
                The results of the trial favor, at present, the indication of prophylactic cranial irradiation for patients who are in complete remission. A longer follow-up and confirmatory trials are needed to fully assess late-occurring toxic effects. The possible effect on overall survival needs to be evaluated with a larger number of patients in complete remission, and a meta-analysis of similar trials is recommended.
Prophylactic cranial irradiation significantly improves survival and disease-free survival for patients with small cell lung cancer in complete remission. Further clinical trials are needed to confirm the potential greater benefit on brain metastasis rate suggested when cranial irradiation is given earlier or at higher doses.