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Journal of Clinical Oncology, Vol 25, No 31 (November 1), 2007: pp. 4987-4992 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.5468
Prophylactic Cranial Irradiation in Operable Stage IIIA Non–Small-Cell Lung Cancer Treated With Neoadjuvant Chemoradiotherapy: Results From a German Multicenter Randomized Trial
From the Departments of Radiotherapy, Internal Medicine (Cancer Research), Neurology, and Diagnostic and Interventional Radiology; Institute for Biomathematics and Statistics, University of Duisburg-Essen; Department of Internal Medicine/Hematology/Oncology, Kliniken Essen-Mitte; Departments of Pulmonology and Thoracic Surgery, Ruhrlandklinik, Essen; Department of Pulmonology, Asklepios Klinik, Gauting; Department of Thoracic Surgery, University of Freiburg, Freiburg; Department of Internal Medicine (Med Klinik III), Technical University, Munich; and the Department of Radiotherapy, Charité Campus-Mitte, Berlin, Germany Address reprint requests to: Christoph Pöttgen, MD, Department of Radiotherapy, University of Duisburg-Essen, Germany Hufelandstrasse 55, D-45122 Essen, Germany; e-mail: christoph.poettgen{at}uk-essen.de
Purpose To investigate the role of prophylactic cranial irradiation (PCI) within a trimodality protocol (chemotherapy, chemoradiotherapy, surgery) for patients with operable stage IIIA non–small-cell lung cancer (NSCLC). Patients and Methods After mediastinoscopic staging, patients with operable stage IIIA NSCLC were enrolled to a German multicenter trial and randomly assigned to receive either primary resection followed by adjuvant thoracic radiation therapy (50 to 60 Gy; arm A) or preoperative chemotherapy (cisplatin/etoposide [PE]; three cycles) followed by concurrent chemoradiotherapy (PE plus 45 Gy; 1.5 Gy twice per day) and definitive surgery (arm B), respectively. Patients in arm B were scheduled to receive PCI (30 Gy; 2 Gy daily fractions). Results One hundred twelve patients were randomly assigned between November 1994 and July 2001. One hundred six patients were eligible (arm A: 51, arm B: 55), 90 males and 16 females, 50 with squamous cell, 16 with large cell, five with adenosquamous, and 35 with adenocarcenoma (median age, 57 years; range, 37 to 71 years). Forty-three patients received PCI as scheduled in arm B. Eleven long-term survivors (arm A: four; arm B: seven) underwent a comprehensive neuropsychological examination. PCI significantly reduced the probability of brain metastases as first site of failure (7.8% at 5 years v 34.7%; P = .02), the overall brain relapse rate was reduced comparably (9.1% at 5 years v 27.2%; P = .04). A slightly reduced neurocognitive performance in comparison with the age-matched normal population was found for patients in both treatment groups. No significant difference between patients who were treated with or without PCI could be noted. Conclusion PCI is effective in preventing brain metastases following this aggressive trimodality approach. Neurocognitive late effects are not significantly different between patients treated with or without PCI.
One third of all patients with non–small-cell lung cancer (NSCLC) are found to have locally advanced tumors (ie, stages IIIA and IIIB) at the time of initial diagnosis. Only 30% of these present with operable tumors characterized by stage IIIA with involvement of only one lymph node station.1,2 Several reports have demonstrated the brain as a frequent site of first treatment failure in stage IIIA and IIIB NSCLC and have focused interest toward strategies for prevention of brain relapse. After curative treatment approaches—either those including surgery or those based on combined chemotherapy and radiation protocols—the observed incidence rates for brain metastases as the first site of failure range from 10% to 30%, and the brain can be identified as a major site of overall failure.3-8 The actuarial risk of brain relapse is even higher when concurrent risks are more rigorously controlled within trimodality protocols including surgery after induction therapy.9,10 Neoadjuvant treatment using either preoperative chemotherapy or combined chemoradiotherapy followed by resection results in cure rates of 20% to 30% at 5 years and has been shown to improve survival over treatment with surgery alone.11-14 Our group started a prospective randomized protocol for primarily resectable stage IIIA NSCLC in 1994 comparing surgery and postoperative thoracic radiation therapy with neoadjuvant therapy (chemotherapy and thoracic radiation therapy and prophylactic cranial irradiation [PCI]) followed by surgery (trimodality). At that time, the standard treatment for patients with operable stage IIIA at most European centers was surgery followed by radiation therapy. It was the aim of this study to control all concurrent risks (ie, cerebral, distant extracerebral, and locoregional in the trimodality arm). In the other arm, postoperative radiation therapy was added in order to reduce the risk of locoregional recurrences in these stage IIIA patients.15 This trial recruited patients from November 1994 to July 2001, but was closed at a planned interim analysis due to slow accrual. By July 2001, randomized studies of adjuvant chemotherapy after resection demonstrated a significant benefit for patients in terms of overall survival, and resection followed by chemotherapy became part of the standard treatment algorithm of completely resected NSCLC.16 The primary end point of the trial was survival at 2 years. We have analyzed brain relapses as a secondary end point both in the trimodality arm as well as in the bimodality arm with local treatment only to investigate the administration of PCI within this setting.
Patients with primarily resectable, locally advanced NSCLC (operable stage IIIA according to the International Union Against Cancer classification from 1987) were included in this prospectively randomized German multicenter trial. This trial was approved by the local ethics committee and was sponsored by Deutsche Krebshilfe. All patients provided written informed consent.
Histologic diagnosis was obtained via bronchoscopy and/or mediastinoscopy. Further staging procedures included computed tomography of the thorax and brain, computed tomography and ultrasound of the abdomen, bone scintigraphy, clinical examination, laboratory investigations, and pulmonary function tests. Eligible patients were randomly assigned between two study arms (Table 1) . Treatment in the standard arm (arm A) was primary curative resection (lobectomy, pneumonectomy, combined with ipsilateral mediastinal lymph node dissection) followed by postoperative thoracic radiation therapy (50 Gy, in daily fractions of 2 Gy, 5 times per week; 60 Gy in case of R1 resection). Patients in arm B were treated preoperatively: induction therapy started with three cycles of chemotherapy consisting of cisplatin (60 mg/m2, days 1 and 7, every 21 days) with etoposide (150 mg/m2, days 3 to 5). Three weeks after administration of the third chemotherapy cycle, concurrent chemoradiotherapy was started. In order to keep the time interval from the start of preoperative chemoradiotherapy until surgery as short as possible, irradiation was hyperfractionated and accelerated with 1.5 Gy twice daily (
After completion of the fourth chemotherapy cycle (at least 4 hours after the last drug application), patients in arm B routinely received PCI. The clinical target volume encompassed the whole brain and meninges above the foramen magnum. For the planning target volume, an additional margin of 5 to 10 mm was added. Irradiation of cranial segments of the cervical spine or orbital contents, respectively, was not planned. Irradiation was performed with parallel opposed fields with an anterior 5° gantry angle for better sparing of the eyes. If necessary, individual lead blocks were used. Gamma rays of a cobalt-60 unit (source-axis distance 80 cm) or 3 to 8 MV photons of a linear accelerator (source-axis distance 100 cm) were permitted. A total dose of 30 Gy, given in 2 Gy fractions (5 times per week), was prescribed at the isocenter. After completion of chemotherapy and radiation therapy, patients were referred to thoracic surgery aiming at resection with curative intent. Patients were examined during follow-up at a regular schedule with clinical visits every 2 months followed by longer intervals (3, 6, and 12 months) after 1, 2, and 5 years. All long-term survivors were invited to a visit with a comprehensive neuropsychological test battery (attention, memory, associative learning, information processing) including the Trail-Making Test (version A and B), the Wechsler Memory Scale, Digit Span, Benton Test, subtests 3, 6, and 9 of the Achievement Measure System (Leistungsprüfsystem nach Horn), Corsi block tapping, and the Attention Test Battery (Testbatterie zur Aufmerksamkeitsprüfung [TAP]) for divided attention (TAPdiv) and selective attention (TAPsel) between February 2004 and March 2005 (Table 2). 17-19 Minimum patient follow-up in that period was 4 years.
On the day of the neuropsychological examination, T2- and T1-weighted magnetic resonance imaging (MRI) studies without and with contrast agent (Magnevist; Schering, Berlin, Germany) were performed using a 1.5 Tesla MRI scanner (Espree; Siemens, Erlangen, Germany) with a standard head coil. Further MRI studies were not routinely planned during follow-up. White matter abnormalities in the T2-weighted images were graded as follows: grade 0, no periventricular hyperintensity; grade 1, discontinuous, periventricular, hyperintensity-rounded, hyperintense foci seen at the angles of the frontal horns bilaterally, with caps of hyperintensity surrounding the occipital horns medially and laterally or streaks of hyperintensity extending along the atria of the lateral ventricles; grade 2, continuous periventricular hyperintensity, with a pencil-thin continuous line of hyperintensity surrounding the ventricles; grade 3, periventricular halo, (ie, a band of hyperintensity of variable thickness with smooth lateral margins surrounding the ventricles); grade 4, diffuse white matter hyperintensity extending from the ventricular lining to the corticomedullary junction.20
Data Analysis Neuropsychological test results were analyzed using the SPSS software package, version 11.0 (SPSS Inc). Different patient groups (arm A v arm B, PCI v no PCI) were compared using the Mann-Whitney U test.
Between November 1994 and July 2001, 112 patients were randomly assigned onto this prospective multicenter trial. Due to slow accrual, mainly attributed to the strict selection criteria of this patient group and with the upcoming results of the benefit of adjuvant chemotherapy in international studies,16,23,24 this study was terminated at a planned interim analysis after 112 enrolled patients. One hundred six patients were eligible: 51 in arm A and 55 in arm B, 90 male and 16 female patients, with a median age of 57 years (range, 37 to 71 years). Squamous cell histologies were found in 50 patients, adenocarcinoma histologies were found in 35 patients, adenosquamous histologies were found in five patients, and large cell histologies were found in 16 patients.
At a median follow-up of 116 months (range, 66 to 148 months), 15 patients were still alive (arm A: eight; arm B: seven; date of last analysis: March 15, 2007). Five-year overall survival rates account for 18% in arm A versus 16% in arm B (P = .15, Wilcoxon test). The 5-year event-free survival was 20% (arm A) versus 24% (arm B; P = .12). Thirteen patients developed brain metastases: nine patients in arm A and four patients in arm B. Intercurrent or toxic deaths and extracerebral relapses either alone or together were equally distributed between both treatment arms. During the first 36 months after treatment, extracerebral relapses occurred in 28 patients in arm A. The same number was observed in arm B. Intercurrent deaths were observed in two patients from arm A versus seven patients from arm B (P
Brain Relapses
Tumor-Dependent Prognostic Factors In an exploratory analysis of prognostic parameters using a Cox proportional hazards model in the patients of arm A, neither histology (squamous cell histology v all others) nor T stage (T1/2 v T3/4) nor lymph node status (N0 and N1 v N2) revealed a statistically significant difference between the probability of brain metastasis at 2 years at first site of relapse.
Neurocognitive Late Effects One patient from arm A developed a single brain metastasis 3 months after thoracic surgery. After extirpation of the brain metastasis, he received adjuvant whole-brain radiotherapy (40 Gy in daily fractions of 2 Gy). For evaluation of neurocognitive effects, he was evaluated as prophylactically irradiated. Results by treatment (PCI v no PCI) are presented in Table 3. In all subtests, no significant difference between patients treated with or without PCI could be observed. Test results were given as percentage ranks in comparison to an age-matched normal population for the respective tests as indicated in Table 3. A percentage rank of lower than 50 represents a worse than median achievement in comparison with the age-matched normal population. In seven subtests, the mean percentage rank of the PCI group was slightly better than the non-PCI group. Patients without PCI achieved better results in four subtests (Table 3).
MRI Scans In 10 patients (five patients treated with and without PCI) MRIs were performed. A leukencephalopathy grade 1 was found in one patient (20%) from arm A, while three patients (60%) in arm B showed equivalent signs of mild leukencephopathy (P = .2,  2 test). Higher degrees of white matter changes were found in none of the patients.
Recent trials have documented that increasing efficacy of treatment by adding curative surgery to induction chemoradiotherapy leads to locoregional recurrence rates of 17% to 48%.4,6,11,13,25,26 These rates seem to be lower in comparison with nonoperative approaches resulting in improved disease-free survival.11 However, brain metastases occur in up to 40% to 50% of instances and represent the most common site of failure in resected patients.6,9,27,28 Even in the selected populations of patients with early stage NSCLC, the risk of cerebral metastases is high. Since the use of adjuvant chemotherapy after resection of early-stage lung cancer within the large international trials only affected the reduction of extracerebral disease recurrences and did not reduce the incidence of cerebral relapses,16,23,29 the value of PCI in this patient population has become a new and important issue of discussion.30 PCI as administered in our randomized trial—although not the primary end point and aim of this investigation—clearly demonstrated efficacy in significantly reducing the probability of brain metastases at first site of relapse. Furthermore, PCI reduced the incidence of brain metastases during follow-up. This is in line with the results of earlier randomized and recent nonrandomized trials of trimodality therapy, but is shown herein for the operable subgroup of stage IIIA patients.5,10,31-35 Several factors have been associated with an increased risk of brain metastasis after resection including histology (squamous v nonsquamous), age (younger than 50 years v older patients), nodal status at resection (pN0 v residual nodal disease), and induction chemotherapy protocol (use of a taxane-platinum combination v other platinum-based regimens).3,9,28 In this study, none of these parameters gained statistical significance, probably due to the limited number of patients. Some concern has been raised regarding neurocognitive toxicity mainly based on the results of PCI in small-cell lung cancer.36,37 However, the results of this study do not add evidence for increased late cognitive deficits. One disadvantage of our trial is the missing of neurocognitive testing at baseline. Nevertheless, no significant differences in the patient cohort receiving PCI in comparison with those without PCI could be detected despite a detailed neuropsychological investigation in long-term survivors more than 4 years after therapy. Nevertheless, the knowledge about neurocognitive impairments attributed to PCI may reduce patients' acceptance of PCI within clinical trials. Newer radiation techniques are underway allowing the reduction of the radiation dose to neurocognitive specifically sensitive structures (eg, lymbic and thalamic system38), such as thalamic avoidance with helical tomotherapy or other intensity-modulated radiotherapy techniques.39,40 Stereotactic radiosurgery or surgery with or without whole-brain radiotherapy has been shown to improve therapeutic efficacy in the treatment of manifest brain metastases as well as functional independence of all patients in comparison to whole-brain radiotherapy alone. However, increased survival after stereotactic radiation therapy or surgery in combination with whole-brain radiotherapy has only been observed for patients with a single brain metastasis and the surviving fraction of these patients after 3 years is approximately 13%.41 Nevertheless, a majority of patients (70% in this study) develop multiple brain metastases at first recurrence and this risk can be reduced by more than 50% with PCI. At the moment, the hypothesis that the reduction of the incidence of brain metastases in patients with locally advanced NSCLC leads to improved survival remains unproven.42 The Radiation Therapy Oncology Group phase III trial addressing this question is currently underway, and by June 2007, had accrued 328 patients. To establish the value of PCI for survival, 1,058 patients are required and patients should be strongly encouraged to take part in this trial.43 With an underlying actuarial risk of brain metastases found in this study similar to that of N2/N3 patients in other studies, PCI seems an attractive option also in a palliative sense to avoid symptomatic brain metastases during their lifetimes. In summary, all efforts must be undertaken to improve the treatment efficacy against systemic metastases in this patient cohort. The brain is one important aspect of the problem of the spread of systemic disease; PCI may add to the improvement of treatment results with regard to overall survival and should be further investigated as a part of multimodality treatment concepts for locally advanced NSCLC.
The author(s) indicated no potential conflicts of interest.
Conception and design: Christoph Pöttgen, Wilfried Eberhardt, Georgios Stamatis, Herbert Hirche, Hans-Jochen Wilke, Martin Stuschke Administrative support: Wilfried Eberhardt, Martin Stuschke Provision of study materials or patients: Christoph Pöttgen, Wilfried Eberhardt, Andreas Grannass, Soenke Korfee, Georg Stüben, Helmut Teschler, Georgios Stamatis, Horst Wagner, Bernward Passlick, Volker Petersen, Volker Budach, Hans Wilhelm, Isabel Wanke, Hans-Jochen Wilke, Martin Stuschke Collection and assembly of data: Christoph Pöttgen, Wilfried Eberhardt, Andreas Grannass, Soenke Korfee, Georg Stüben, Helmut Teschler, Georgios Stamatis, Horst Wagner, Bernward Passlick, Volker Petersen, Volker Budach, Hans Wilhelm, Isabel Wanke, Herbert Hirche, Hans-Jochen Wilke, Martin Stuschke Data analysis and interpretation: Christoph Pöttgen, Wilfried Eberhardt, Andreas Grannass, Soenke Korfee, Hans Wilhelm, Herbert Hirche, Martin Stuschke Manuscript writing: Christoph Pöttgen, Wilfried Eberhardt, Martin Stuschke Final approval of manuscript: Christoph Pöttgen, Wilfried Eberhardt, Andreas Grannass, Soenke Korfee, Georg Stüben, Helmut Teschler, Georgios Stamatis, Horst Wagner, Bernward Passlick, Volker Petersen, Volker Budach, Hans Wilhelm, Isabel Wanke, Herbert Hirche, Hans-Jochen Wilke, Martin Stuschke
Supported by a grant from Deutsche Krebshilfe (project No. 70-2141). Presented in part at the 23rd Annual Meeting of the European Society for Therapeutic Radiology and Oncology (ESTRO 23), Amsterdam, the Netherlands, October 25-28, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
6 hours, interfraction interval, 5 times per week) up to a total dose of 45 Gy. 
