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© 1999 American Society for Clinical Oncology Prophylactic Cranial Irradiation in Locally Advanced Non–Small-Cell Lung Cancer After Multimodality Treatment: Long-Term Follow-Up and Investigations of Late Neuropsychologic EffectsFrom the Departments of Radiotherapy, Internal Medicine (Cancer Research), Radiology, and Neurology, University of Essen Medical School, and Department of Pneumology and Thoracic Surgery, Ruhrlandklinik, Essen-Heidhausen, Germany. Address reprint requests to M. Stuschke, MD, Department of Radiotherapy, University Hospital Charité Berlin, Schumannstr 20/21, 10117 Berlin, Germany.
PURPOSE: Relapse pattern and late toxicities in long-term survivors were analyzed after the introduction of prophylactic cranial irradiation (PCI) into a phase II trial on trimodality treatment of locally advanced (LAD) non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Seventy-five patients with stage IIIA(N2)/IIIB NSCLC were treated with induction chemotherapy, preoperative radiochemotherapy, and surgery. PCI was routinely offered during the second period of study accrual. Patients were given a total radiation dose of 30 Gy (2 Gy per daily fraction) over a 3-week period starting 1 day after the last chemotherapy cycle. RESULTS: Introduction of PCI reduced the rate of brain metastases as first site of relapse from 30% to 8% at 4 years (P = .005) and that of overall brain relapse from 54% to 13% (P < .0001). The effect of PCI was also observed in the good-prognosis subgroup of 47 patients who had a partial response or complete response to induction chemotherapy, with a reduction of brain relapse as first failure from 23% to 0% at 4 years (P = .01). Neuropsychologic testing revealed impairments in attention and visual memory in long-term survivors who received PCI as well as in those who did not receive PCI. T2-weighted magnetic resonance imaging revealed white matter abnormalities of higher grades in patients who received PCI than in those who did not. CONCLUSION: PCI at a moderate dose reduced brain metastases in LAD-NSCLC to a clinically significant extent, comparable to that in limited-disease small-cell lung cancer. Late toxicity to normal brain was acceptable. This study supports the use of PCI within intense protocols for LAD-NSCLC, particularly in patients with favorable prognostic factors.
THE LARGE GROUP OF patients with locally advanced disease stages IIIA and IIIB accounts for approximately one third of all non–small-cell lung cancer (NSCLC) patients and has become a focus for combined-modality trials in recent years.1 Neoadjuvant radiochemotherapy followed by definitive tumor resection has become one of the most active treatment strategies in these NSCLC patients, who have predominantly stage IIIA disease with clinically detectable N2 disease or selected subgroups of stage IIIB disease.2-7 The definitive value of surgery in this clinical setting is still a matter of controversy, and results of large, prospective, randomized trials are eagerly awaited.2 In large trials, locoregional control rates of 50% and higher have been achieved after neoadjuvant chemoradiotherapy and definitive resection.2-4,6 In addition to locoregional recurrences, patients with locally advanced (LAD) NSCLC are exposed to multiple concurrent risks, such as development of extracerebral distant metastases, brain metastases, and second new primary tumors, which most often occur in the respiratory tract. Of these, the brain has turned out to be one of the most frequent sites of initial treatment failure in several trimodality trials and was the site of approximately one third of all relapses observed during long-term follow-up.2-4,6,8 Therefore, treatment strategies to reduce the risk of brain metastases are needed in order to optimize the efficacy of multimodality protocols for LAD-NSCLC. According to the database of the Radiation Therapy Oncology Group, the encountered chemotherapy combinations do not seem to have a reliable influence on the risk of brain metastases.9 Similar findings have long been a matter of discussion in patients with limited-disease small-cell lung cancer (SCLC) in complete clinical remission. Again, the longer patients survive after aggressive initial treatment interventions, the greater the risk of developing later brain relapse.10,11 Prophylactic cranial irradiation (PCI) has been studied extensively in this setting. A survival improvement of approximately 4% at 5 years can be expected from PCI, according to a recent meta-analysis.12 In this analysis, we evaluated the effects of PCI at a moderate total dose of 30 Gy (2 Gy per daily fraction) in our patients with stage IIIA/IIIB NSCLC. They had been treated in a trimodality trial with induction chemotherapy, concurrent radiochemotherapy, and resection.4 Although not investigated in a prospective randomized comparison, PCI was introduced at the middle of the accrual period of this phase II trial and was offered to all consecutive patients starting with concurrent chemoradiotherapy in the second time period. The relapse pattern was determined for all treated patients in this trial. For an overall efficacy/toxicity analysis in these LAD-NSCLC patient subgroups, long-term survivors were compared in both cohorts, using neuropsychologic testing and T2-weighted magnetic resonance imaging (MRI) scans to assess in detail the late effects of the combined treatment on the brain.
Patient Selection Patients with histologically or cytologically proven NSCLC were eligible. They had to have stage IIIA or IIIB disease according to the classification system developed by Mountain.13 Adverse prognostic factors indicated increased relapse risk after surgery alone.4,13,14 Stage IIIA patients had two or more ipsilateral mediastinal lymph node levels involved at mediastinoscopy (39 patients) or a selected subgroup of far-advanced T3 tumors with infiltration of the parietal pericardium or diffuse infiltration less than 2 cm from the carina and no mediastinal lymph node involvement (five patients). Eligible patients with stage IIIB tumors had to have T4 tumors with involvement of the great vessels, vertebral bodies, carina, or recurrent laryngeal nerve or diffuse mediastinal involvement. However, patients with malignant pleural effusion, supraclavicular lymph node involvement, or T4 tumors with esophageal as well as myocardial involvement were excluded from this study. Inclusion criteria included World Health Organization (WHO) performance status of 0 to 2, age between 18 and 70 years, no prior treatment for lung cancer, no other concurrent or previous malignancy, a serum bilirubin level of less than 1.5 mg/dL, a serum creatinine level of less than 1.2 mg/dL, a leukocyte count of more than 4,000/mL, and a platelet count of more than 150,000/mL. Before patients were entered onto the study, the following examinations were performed: mediastinoscopy; bronchoscopy; computed tomography (CT) scans of the chest, upper abdomen, and brain; chest x-rays; radionuclide bone scans; physical examinations; complete blood cell counts; and complete serum chemistry and cardiopulmonary function tests. The whole patient cohort was accrued between March 1991 and December 1994. All patients provided written informed consent before study entry.
Induction Chemotherapy
Preoperative Chemoradiotherapy
PCI
Definitive Surgery
Response Evaluation
Follow-Up
Neuropsychologic Testing and MRI Studies
Mini-mental status test.
Trail-making test.
Wechsler Memory Scale.19
Digit span.
Benton visual retention test.
Divided attention test.
Visual scanning test.
MRI scans.
Data Analysis
Patient Population Patients were entered onto this phase II study from March 1991 to December 1994. Of the 94 patients enrolled, 75 patients went through the whole induction chemotherapy phase and started concurrent radiochemotherapy. All 75 completed this treatment and became eligible for surgery. Thirteen patients did not become candidates for surgical resection, because of previously reported reasons.4 Finally, 62 patients underwent thoracotomy; in 50 patients, the primary tumor could be completely resected, with no evidence of residual disease remaining at the end of the treatment program.
The 75 patients who started with radiochemotherapy were the patient cohort considered for this investigation. The first 28 patients who entered the concurrent chemoradiation phase before December 1992 did not receive PCI, but PCI was offered to all patients in the second accrual period. The characteristics of patients who did and did not receive PCI are listed in Table 1. There was a greater proportion of women in the group of patients who received PCI (P = .04,
Effectiveness of PCI
In addition to univariate analysis, multivariate analysis was used to measure the effect of PCI on the risk of brain relapse as the isolated first failure. The multivariate model included the additional patient- and therapy-related parameters listed in Table 1. PCI, as well as an objective response to induction chemotherapy, became significant in forward selection of prognostic parameters. PCI reduced the relative risk to 0.14 (95% confidence interval [CI], 0.03 to 0.69; P = .01,
The effect of PCI on brain metastases was also studied in subgroups of patients with favorable survival prognoses. Only in these patients with controlled tumor in the chest and a low risk of extracerebral relapse might a significant reduction of brain relapse lead to improved survival. To identify patients with good prognoses, the influence of characteristics listed in Table 1 on survival was analyzed in all 75 patients starting with concurrent chemoradiation. Using these characteristics, response to induction chemotherapy and the application of PCI were significantly associated with favorable survival, whereas lactate dehydrogenase (LDH) activity greater than the upper limit of the normal range (240 U/L) was found to be an adverse prognostic factor. The relative risk of death was reduced to 0.39 (95% CI, 0.21 to 0.723; P = .003) for patients with a partial response (PR) or complete response (CR) to induction chemotherapy. PCI reduced the risk of death in multivariate analysis by a risk ratio of 0.50 (95% CI, 0.26 to 0.94; P = .03). LDH activity greater than 240 U/L at the start of treatment was associated with an increased risk of death by a risk ratio of 3.2 (95% CI, 1.5 to 6.6; P = .002). Survival was 48% ± 6%, 38% ± 6%, 36% ± 6%, and 33% ± 6% at 2, 3, 4, and 5 years, respectively, for all 75 patients. The probabilities of survival at 2 and 4 years were 57% ± 7% and 49% ± 7%, respectively, for the 47 patients who had a PR or CR to induction chemotherapy, 60% ± 7% and 53% ± 8% for the 43 patients with LDH activity
In addition to the brain as the isolated first site of metastasis, we analyzed the times to development of overall brain relapse, irrespective of whether the brain metastases occurred as the first failure or after local or extracerebral distant metastases. The actuarial rates of overall brain relapse were 48% ± 10%, 54% ± 10%, 54% ± 10%, and 61% ± 11% at 2, 3, 4, and 5 years, respectively, without PCI and 8% ± 5%, 13% ± 6%, and 13% ± 6% at 2, 3, and 4 years, respectively, with PCI (P < .0001, log-rank test; Fig 2). A total of 14 of the 28 patients who did not receive PCI developed symptomatic brain metastases, whereas only four of 47 patients did after PCI. PCI reduced the relative risk of overall brain relapse to 0.13 (95% CI, 0.04 to 0.41). In the very-good-prognosis group of patients with PR/CR to induction chemotherapy and an LDH level
Concurrent Risks of Relapse at Other Sites
Neurologic Disorders, Neuropsychologic Functioning, and Imaging Abnormalities in Long-Term Survivors
Tables 2 and 3 also summarize the results of the different neuropsychologic tests. Attention was impaired in both groups of long-term survivors, as shown by the trail-making test. Significant differences between patients treated with or without PCI were not observed. There was no stronger association between the test results and age. Three of five patients who did not receive PCI and seven of nine patients who did achieved percentage ranks below 25%. One patient who did not receive PCI could not perform this test because of an impaired visus caused by senile macula degeneration (patient no. 9). Only 11 patients were given the computer-assisted divided attention test. Three patients refused to continue with this test procedure as the second to last test of the test battery (patients no. 7, 8, and 15), and one patient was unable to perform this task because of his impaired visus. Only two of the five patients who did not receive PCI (patients no. 2 and 4) and one of six patients who did (patient no. 13) performed within the normal range. Verbal memory was tested by the Wechsler Memory Scale and the Wechsler digit span test. The Wechsler Memory Scale did not reveal verbal memory deficits in any of the patients in either group. However, the results of the digit span test were below the normal range in two of five patients who did not receive PCI and in one of nine tested patients who did. Visual memory was tested by the Benton visual retention test, which was rather sensitive and revealed pathologic values in two of the five patients who did not receive PCI and six of nine tested patients who did. No association with age dependency was observed. Perception was tested by the visual scanning test, the results for which were within the normal range in four of five patients who did not receive PCI and three of five patients who did who tried to perform this last task of the test battery. Differences in the frequencies of impairment between the small groups of patients treated with or without PCI did not became significant for any of the above tests. Except for patients no. 10 and 14, the clinical significance of the impairments in the neuropsychologic tests was rather small or absent. Patients treated with PCI had higher grade white matter abnormalities than patients who were not treated with PCI, as detected by T2-weighted MRI (P = .04, Wilcoxon test, Table 2). Grade 4 white matter abnormalities were detected in two of nine patients treated with PCI and zero of four patients not treated with PCI. Patient no. 1 refused the MRI and patient no. 15 had a pacemaker. The two patients with grade 4 white matter abnormalities had the lowest percentage ranks on the most sensitive neuropsychologic tests, the trail-making and Benton tests, so that there was a tendency of impaired neuropsychologic functioning in patients with higher-degree white matter abnormalities. A pathologic cell media or frontal horn index or an increased width of the third ventricle was observed in five of nine patients treated with PCI and one of four patients not treated with PCI.
Although not tested in a randomized comparison, the inclusion of PCI at a moderate dose of 30 Gy (2 Gy per daily fraction) led to a reduction of the risk of brain metastases as isolated first failure from 30% to 8% at 4 years and of the rate of overall brain relapse from 54% to 13% in this investigation. Two other nonrandomized multimodality trials have also given data on PCI in patients with locally advanced NSCLC: The Southwest Oncology Group delivered 36 Gy in 2-Gy daily fractions to all histopathologic subtypes of NSCLC in their phase II trial of neoadjuvant chemoradiation and resection.2 Two of 18 patients treated with PCI and 24 of 108 patients who did not receive PCI developed brain metastases. Although not statistically significant, the overall brain metastasis rate was halved by PCI in that study. The Cancer and Leukemia Group B delivered 30 Gy at 2 Gy per fraction to patients with large-cell or adenocarcinoma in a phase II trial of neoadjuvant chemoradiation and resection for LAD-NSCLC. No brain relapse was observed among the 13 patients who received PCI.5 So far, reports of three randomized trials of PCI in patients with LAD-NSCLC have been published.26-28 All found a trend for a reduced risk of brain metastases after PCI but no impact on survival. The Veterans Administration Lung Group used radiotherapy as the only locoregional treatment to the primary tumor and the mediastinum, which led to a survival rate at 2 years of less than 20%.26 PCI at a low dose of 20 Gy in 2-Gy fractions halved the incidence of brain metastases from five of 70 to two of 60 in squamous cell carcinoma and from five of 19 to zero of 14 in adenocarcinomas.26 The Radiation Therapy Oncology Group randomly assigned 187 patients with inoperable or resected adenocarcinoma and large-cell carcinomas with hilar or mediastinal lymph node metastases to PCI treatment (30 Gy in 3-Gy fractions) or no prophylactic treatment to the brain.27 Inoperable patients were treated with standard radiotherapy to the primary tumor and the mediastinum; patients with resectable tumors received postoperative chest radiotherapy. The incidence of brain metastases was nonsignificantly halved from 18 of 93 to eight of 94 by PCI and the actuarial risks of brain metastases were 30% and 15% at 2 years without and with PCI, respectively.27 In the latter study, 20 patients were at risk for developing brain metastases at the time of 24-month follow-up, approximately the same number as found in our study. In another trial, patients with LAD-NSCLC received cyclophosphamide, doxorubicin, and cisplatin combined with radiation therapy or surgery and postoperative radiation.28 The 30-Gy dose of PCI in 3-Gy fractions reduced the risk of brain metastases from 40% to 8% at 2 years in the whole cohort (P = .002) and from 38% to 0% in patients with squamous cell carcinomas (P = .01). In some of the above studies, PCI was restricted to patients with adenocarcinomas and large-cell carcinomas.5,27 This treatment regimen was based in part on the results of the Radiation Therapy Oncology Group studies of thoracic radiotherapy alone to treat the primary tumor and the mediastinum.9,29 However, the few studies with trimodality treatment for stage IIIA and IIIB NSCLC that reported detailed analyses of brain relapse for different histopathologic subtypes found a high risk of brain metastases for squamous cell carcinomas as well.6,30,31 In the first half of this study, we observed four early brain relapses among 28 patients and two brain failures among 14 patients with squamous cell carcinomas, for a total of six relapses. Because of this high incidence, our group began offering PCI to all patients. According to the above data, subclinical brain metastases that occurred in NSCLC turned out to have radioresponsiveness that was comparable to the brain metastases that occurred in SCLC. Two overviews on dose-response for PCI in patients with SCLC32,33 showed that the risk of brain metastases can be reduced by 65% to 70% by a 30-Gy dose in daily 2-Gy fractions. A similar effect was found in the present study. The primary aim of the use of PCI in NSCLC is to increase the freedom from relapse at any site without inducing severe adverse effects. PCI may improve curative chances only in those patients with locoregional tumor control and no extracerebral distant metastases. In the other patients, PCI nevertheless has a palliative effect and profoundly reduces the high incidence of symptomatic brain metastases from over 50% to less than 20%. The value of PCI has been extensively and controversially discussed for SCLC patients in complete remission for whom concurrent risks turned out to be comparable to those in this study.11,12,34-36 No single randomized trial has demonstrated a survival advantage with PCI in SCLC. However, a recently published meta-analysis sensitive for small differences between treatment arms has revealed a statistically significant survival benefit attributable to PCI of about 4% at 5 years.12 Given the proven high efficacy of PCI in reducing brain relapse, the benefit of PCI to increase survival without quality-of-life impairing side effects depends largely on the toxicity of PCI and, on the other hand, on possibilities of salvage treatment strategies against manifest brain metastases. With respect to the latter point, the actuarial tumor control is less than 20% for manifest brain metastases after whole-brain irradiation with 36 Gy in 3-Gy fractions.37 Surgery and stereotactic radiotherapy with or without whole-brain radiotherapy can lead to control rates markedly greater than 50% at initial sites in the brain in selected patients with fewer than four metastases.37-39 However, generally there was a high probability of progressive metastatic disease at other locations in the CNS after surgery or stereotactic radiotherapy of brain metastases, as well as a high probability of extracerebral progress that may be explained by systemic reseeding from cerebral metastases. Fifty percent or fewer of NSCLC patients have fewer than four metastases at the time of initial brain relapse.40 When the data from the above series are considered together, no more than 20% of all patients with the brain as the only site of relapse might be cured by current therapies for brain metastases. Retrospective studies of neuropsychologic functioning of long-term survivors after PCI for SCLC highlighted treatment-induced impairments.41-46 However, dementia was usually not found.41,43,44,47 Detailed testing in some studies revealed deficits in the areas of attention, visual perception, and memory.43,45,47 Impairments in neuropsychologic functions have been correlated with white matter abnormalities in T2-weighted MRI.41,43 On the basis of results from the present study, we also have to conclude that PCI has some adverse effects on normal brain after long-term follow-up. T2-weighted MRI showed a high sensitivity and revealed abnormalities of higher grade in the group of patients treated with PCI compared with the group treated without PCI. We found impairments in attention and visual memory in both groups of patients. In most patients, these impairments usually did not interfere with daily life functioning and had only limited clinical significance. However, one patient in the group of patients treated with PCI developed dementia. As an additional risk factor, this patient had recurrent strokes caused by extracranial vascular disease. Another patient treated at the age of 64 years needed assistance in daily living because of neuropsychologic impairment. However, because of the limited number of patients, it cannot be concluded from this study alone that age above 60 years is a risk factor for the development of neurotoxicity after whole-brain irradiation at a total dose of 30 Gy in 2-Gy fractions. In addition, the results of the more specific tests, the trail-making test and the Benton test, did not show an age dependence. Overall, the pooled information from the retrospective studies demonstrates some neuropsychologic impairments in long-term lung cancer survivors after treatment that included PCI. Definite conclusions about the effects of PCI on normal brain can be drawn only from prospective studies with repeated longitudinal neuropsychologic testing of patients with the same disease treated either with or without PCI. Recently reported data from such prospective studies have not demonstrated a sustained influence of PCI on neuropsychologic functions.10,11,48,49 Until now, the number of patients who have survived longer than 2 years (long-term survivors) has been rather limited in these trials so that any prospective data have to be regarded as preliminary. The latter studies have uniformly detected a high prevalence of cognitive dysfunction before PCI that may be an indication that disease-related impairments must be considered in order to interpret retrospective analyses. To minimize toxicity, we started PCI at the end of chemotherapy, used daily fractions of 2 Gy, and limited the total dose to 30 Gy.
In conclusion, patients with LAD-NSCLC treated on multimodality protocols who have high locoregional control rates have high risks of brain metastases as the isolated first failure or of overall brain metastases. The respective risks were 42% and 61% in this study. A similarly high risk was also found in the subgroup of patients with favorable prognostic factors, such as response to induction chemotherapy and LDH serum levels
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ABSTRACT
INTRODUCTION
Correct/
2 test). The distributions of all other characteristics were comparable between the two groups. The median follow-up duration of all patients who started with concurrent radiochemotherapy was 56 months (range, 17 to 84 months). The median follow-up duration of the 28 patients who did not receive PCI during the first half of this study was 72 months (range, 17 to 84 months); that of the 47 patients who received PCI was 50 months (range, 24 to 66 months). Only one patient was observed for less than 2 years; he moved and has been lost to follow-up. 
240 U/L and an objective response to induction chemotherapy, and 63% ± 7% and 58% ± 8% for the 24 patients with PCI, LDH activity 
