Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group. Cranial irradiation in cancer of the lung of all cell types. Controlled clinical trial of prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Value of prophylactic cranial irradiation given at complete remission in small cell lung carcinoma.
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. Beginning in February 1984, 187 evaluable patients with adenocarcinoma or large cell carcinoma of the lung clinically confined to the chest were randomized to receive either conventionally fractionated thoracic irradiation alone or thoracic irradiation with concurrent, prophylactic cranial irradiation. The study population included 161 patients treated for medically or surgically inoperable primary cancers, and 26 patients undergoing adjuvant postoperative mediastinal irradiation following attempted curative resection of primary cancers found to have metastasized to hilar or mediastinal lymph nodes. Elective brain irradiation was not effective in preventing the clinical appearance of brain metastases, although the time to develop brain metastases appears to have been delayed. Eighteen of 94 patients (19%) randomized to chest irradiation alone have developed brain metastases as opposed to 8/93 patients (9%) randomized to receive prophylactic cranial irradiation (p = .10). No survival difference was observed between the treatment arms. Among the 26 patients undergoing prior resection of all gross intrathoracic disease, brain metastases were observed in 3/12 patients (25%) receiving adjuvant chest irradiation alone, compared to none of 14 receiving prophylactic cranial irradiation (p = .06). In the absence of fully reliable therapy for the primary disease, and without effective systemic therapy preventing dissemination to other, extrathoracic sites, prophylactic cranial irradiation for inoperable non-small cell lung cancer cannot be justified in routine clinical practice. Further investigation in the adjuvant, postoperative setting may be warranted. The Veterans Administration Lung Group conducted a prospective study of irradiation for subclinical brain metastases in patients with inoperable carcinoma of the lung between 1975 and 1978. Patients were randomized to receive whole-brain irradiation (2,000 rads in two weeks) or no brain treatment, and to receive one of two regimens of thoracic irradiation. Three hundred twenty-three patients with normal radionuclide brain scans were able to be evaluated. The rate of clinical brain metastasis was 26% for patients with small cell carcinoma vs 10% for the "non-small-cell" group. A statistically insignificant decrease in the rate of brain metastasis was found among irradiated patients with small cell carcinoma. The frequency of brain metastasis in the non-small-cell patients was reduced from 13% to 6% by irradiation. Prophylactic cranial irradiation can decrease morbidity from non-small-cell carcinoma of the lung. 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. 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 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.