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0 Original Contribution

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 T.E. PAJAK, PH.D.,~ H.M. SELIM, M.D.,3 J.C. PARADELO, M.D.,4 K. MURRAY, M.D.,5 P. BANSAL, M.D.,6 J.D. COOPER, M.D.,’ S. SILVERMAN,M.D.’ AND J.A. CLEMENT, M.D.*

A.H. RUSSELL, M.D.,’

‘RadiologicalAssociates of Sacramento, Sacramento, CA; ‘RTOG Headquarters, Statistical Unit, Philadelphia, PA; 3LutheranMedical Center, Brooklyn, NY; 4KansasCity CCOP, Kansas City, MO; 5MedicalCollege of Wisconsin, Milwaukee, WI; 6AlleghenyGeneral Hospital, Pittsburgh, PA; ‘New York University, New York, NY; and ‘Geisinger CCOP, Danville, PA 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 tboracic 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 ln 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 8193 patients (9%) randomized to receive prophylactic cranial lrradlatlon @ = .lO). 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 3112 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. Lung neoplasms, Metastasis, Brain, Radiation therapy.

Brain metastasis is a common manifestation of cancer dissemination in patients with primary bronchogenic carcinoma. Overt cerebral metastases may be the source of presenting symptoms at the time of diagnosis of lung cancer in patients with minimal complaints attributable to the primary cancer. Occult brain metastases have been detected at autopsy in 4.5% of patients dying within 30 days following attempted curative resection of lung cancer ostensibly confined to the chest (20). Metastasis to the brain may be the initial, and occasionally solitary, manifestation of recurrence in patients whose primary cancers have been treated by radical radiation or surgical extirpation (4,24). Although the occasional patient may enjoy prolonged survival following neurosurgical removal of a solitary brain metastasis, such treatment is only rarely appropriate for patients with lung cancer, and good outcomes can only be

obtained in carefully selected, prognostically favorable patients (17,28). Patients with brain metastases from bronchogenic carcinoma are most commonly treated with brain irradiation and administration of corticosteroids. Despite a recognized capacity to decrease symptoms and reverse some of the neurological signs, the benefits of such treatment are strictly palliative. Median survival will be 4 months or less ( 1,15), and 50% or more of such patients will die of uncontrolled brain metastases following salvage cranial irradiation (1,13,17,21). The frequency of brain metastases from primary lung cancer is somewhat dependent on histologic type, with small cell anaplastic cancers having a high propensity to disseminate to the brain. prophylactic cranial irradiation (PCI) has achieved some success in decreasing the incidence of subsequent symptomatic brain metastases in pa-

Reprint requests to: Radiation Therapy Oncology Group Headquarters, American College of Radiology, 1101 Market

Street, 14th Floor, Philadelphia, PA 19107. Accepted for publication 22 February 1991.

INTRODUCTION

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I. J. Radiation Oncology 0 Biology 0 Physics

August 1991, Volume 21, Number 3

Table 1. Primary tumor (T) TO

No evidence of primary tumor

TX

Tumor proven by the presence of malignant cells in secretions, but not by roentgenograph or bronchoscopy

Tl

Intrapulmonary, localized; a solitary tumor 3.0 cm or less in greatest diameter, surrounded by lung or visceral pleura and without evidence of invasion proximal to a lobar bronchus at bronchoscopy

T2

Intrapulmonary, extensive; a tumor more than 3.0 cm in greatest diameter or a tumor any size which, with its associated atelectasis or obstructive pneumonitis, extends to the hilar region. At bronchoscopy, the proximal extent of demonstrable tumor must be at least 2.0 cm distal to the carina. Any associated atelectasis or obstructive pneumonitis must involve less than an entire lung; there must be no pleural effusion

T3

Extrapulmonary, intrathoracic localized; this includes T lesions which invade through the visceral pleura into the pleural space or adhere to the parietal pleura; bronchogenic cancers within 2 cm of the carina; no visceral, vascular, neurologic, osseous or cardiac (including pericardial) invasion

T4

Extrapulmonary, intrathoracic extensive; a very extensive T lesion, invading nerves, major vessels, heart, vertebrae and chest wall sites. It is beyond parietal pleura and is into the chest wall, viscera and/or deep mediastinal structures. This does not include patients with extrathoracic visceral metastasis

tients with this histology (7,8,19,23,27), but devastating late neurological injuries have been reported in some long-

term survivors of such treatment (IO,1 1,14,16). The relative importance of radiation alone in causing these injuries (as opposed to the possible additive or synergistic adverse effects of combined radiation and synchronous or metachronous cytotoxic chemotherapy) has been difficult to ascertain. The use of PC1 alone, and in conjunction with adjuvant systemic chemotherapy, has been described for non-small cell lung cancer (3,9,25,29). Reports of efficacy, in the absence of a concurrent randomized control population, have uncertain credibility (9,25). A randomized trial reported as showing a decrease in brain metastases in nonsmall cell lung cancer patients undergoing 30.00 Gy PC1 in combination with systemic chemotherapy has been difficult to interpret because of the heterogeneity of the patient population and the non-uniform treatment delivered for the primary disease (29). A randomized investigation of the Veterans Administration Lung Group studied patients with lung cancer clinically confined to the thorax who were treated with or without 20.00 Gy prophylactic cranial irradiation in addition to therapy directed to the chest (3). Possible benefit was discerned for patients with adenocarcinomas, of whom 29% (5/19 patients) in the control population developed brain metastases, whereas O/14 patients in the electively irradiated population subsequently failed in the brain. Stimulated by that report, the RTOG initiated a prospective randomized trial of elective or prophylactic cranial

irradiation in selected patients with non-small cell carcinoma of the lung. Based on an analysis of lung cancer patients treated with chest irradiation alone in prior RTOG studies, patient entry was restricted to individuals with adenocarcinoma or large cell carcinoma of the lung because of the observation that only 16% of patients with squamous cancers ultimately

developed clinical evidence of brain metastases compared to 30% of patients with adenocarcinomas and large cell carcinomas (24). This observation is consistent with the clinical and autopsy data of Newman and Hansen (22) and Line and Deeley (15), who reported a frequency of brain metastasis in adenocarcinoma and large cell carcinoma approximately twice that observed in squamous cancers. Because of the report of Choi and colleagues (2) that 56% (19/34 patients) of their patients with surgically treated adenocarcinoma AJCC Stages T,_,, N,,,, and T,N, developed brain metastases, postoperative patients with N, or N, disease were included, for whom adjuvant mediastinal irradiation was planned. METHODS AND MATERIALS Patients with inoperable or unresectable adenocarcinoma or large cell carcinoma of the lung confined to the chest, RTOG clinical stages T,,, N,_,, M,,, as well as patients with resected adenocarcinomas and large cell carcinomas of the lung, RTOG surgical stages T,_,, N,,,, MO, were eligible for study entry (Tables 1 and 2) (26). All patients

Prophylactic cranial irradiation for lung cancer ??A. H. RUSSELLef al. Table 2. Regional lymph nodes NO

No demonstrable

spread to lymph nodes

Nl

Spread to lymph nodes in the ipsilateral hilar region

N2

Spread to mediastinal

N3

Supraclavicular or biopsied scalene nodes

or contralateral

hilar lymph nodes

were required to have histologic confirmation of malignancy. Patients were excluded who had prior malignancies, prior radiation or chemotherapy, or significant preexisting neurological deficits on the basis of cerebrovascular disease or primary central nervous system disease. Prior to randomization, all patients were required to furnish signed informed consent documents in compliance with all federal, state, and local institutional requirements protecting the rights of research subjects. All patients were required to undergo routine chest radiography and chest tomography (linear tomography or CT), as well as blood counts and serum chemistries, including a liver profile. Additionally, each patient underwent computerized axial tomography (CT) of the head to exclude the possibility of clinically occult metastases and to establish a baseline series of images with which subsequent scans might be compared. Isotope scans of liver and bone were obtained only if clinical suspicion of metastases existed, or elevation of alkaline phosphatase or liver function tests was detected on initial screening blood work. Following registration and confirmation of eligibility, patients were randomly assigned by RTOG Headquarters to receive chest irradiation alone or chest irradiation with concurrent prophylactic cranial irradiation. The randomization scheme described by Zelen (30) was used to achieve institutional balance and incorporated three patient-related stratifications: prior surgery, pretreatment KPS, and histology. Chest irradiation consisted of a tumor dose of 55.0060.00 Gy in 30 fractions of 1.8-2.0 Gy over 6 weeks in patients without prior surgery, and 50.00 Gy in 25 fractions over 5 weeks to the hilar areas and mediastinum in patients with N, or N, disease following resection of all gross intrathoracic disease. PC1 consisted of 30.00 Gy in 10 fractions of 3.00 Gy over 2 weeks with dose specified at the central axis midplane depth between opposed lateral portals. PC1 commenced concurrently with the sixth fraction of chest irradiation. Chest irradiation was prescribed without corrections for tissue inhomogeneity (lung transmission). The primary tumor and ipsilateral hilum were encompassed with a 2 cm minimum margin. The mediastinal nodes, including subcarinal nodes, were encompassed in all patients with the treatment volume extending down to the diaphragm in patients with primary tumors of the lower lobes. The contralateral hilar nodes were encompassed with a 1 cm

639

margin, and the supraclavicular nodes were required to be treated in all patients with upper lobe primaries. A central review of the radiation therapy delivered for each case was performed by the study chairman. The calibration of every machine on which a patient was treated was verified by the Radiologic Physics Center located at the University of Texas, M.D. Anderson Cancer Center. Individual treatment parameters such as total dose, fractionation, field borders, and elapsed treatment days were reviewed relative to protocol specifications and were scored as follows: per protocol-within 5% of the protocol specifications; minor variation-between 6-15%; major variation acceptable-between 16-20%; major variation unacceptable-in excess of 20%. After each of the individual parameters were scored, a composite evaluation was scored for each case. The possible composite scores were: per protocol, minor variation-acceptable, major variationacceptable, and major variation-unacceptable. Patients could not receive systemic cytotoxic chemotherapy until such time as tumor recurrence or metastasis became clinically apparent. Patients not receiving PC1 who subsequently developed relapse in the brain received 30.00 Gy in 10 fractions at the time of diagnosis of cerebral metastasis. Following completion of treatment, patients were evaluated at intervals of 3 months. Assessments included interval history, general and neurological physical examinations, and chest radiography. Routine isotope scans and serum chemistries were not obtained unless metastases were clinically suspected. An immediate CT scan of the head was required for any patient experiencing new neurologic symptoms, or in whom cerebral metastases were suspected for any reason. A head CT was obtained in all patients surviving 7.5 months from the completion of treatment (approximately 9 months from initiation of irradiation). Statistical method The primary endpoint in the design of this study was time to brain metastases. The target sample size of 180 evaluable randomized patients could detect a reduction in the time adjusted incidence of brain metastases from 25% to 5% at 18 months with 80% statistical power (chance of detecting such a difference if it is true). A decrease from 25% to 10% could be detected with 60% statistical power. The balance between the pretreatment characteristics for each arm was evaluated by the chi-square test (5). Differences in times to brain metastases and survival durations were evaluated by the log rank test (18). All the reported significance levels were based upon a two-sided test. The time events were plotted as step functions using the Kaplan-Meier product-limited method (12). The various survival rates reported at 1 and 2 years were based upon the Kaplan-Meier estimates. With respect to the brain metastases analysis, a patient was considered a failure if that individual developed brain metastasis at any time af-

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1. J. Radiation Oncology 0 Biology 0 Physics

August 1991, Volume 21, Number 3

no

Fig. 1. RTOG 8403 -overall

ter the start of radiation therapy, even if this occurred while the patient was receiving other therapies for progressive disease. With respect to survival analysis, a patient was considered a failure if that individual died regardless of the cause of death. Time to brain metastases and survival were measured from the start of radiation therapy until time of failure or the time of the last follow-up if the patient did not fail. All the analyses were based upon the intention-to-treat principle, which tests the strategy of offering certain treatments to a group of patients irrespective of whether they receive the treatment per protocol or not. This statistical approach represents the most conservative analysis of the results from a randomized clinical trial because it avoids potential biases introduced by excluding otherwise eligible patients. Of 93 evaluable patients randomized to receive PCI, 1 never received PC1 (patient refusal) and 6 additional patients did not complete the protocol specified PC1 treatment, absorbing 6.0 Gy (2 patients), 9.0 Gy, 12.0 Gy, and 15.0 Gy (2 patients).

RESULTS At the time of this analysis, 18 patients remain alive. One hundred sixty-nine patients have been followed until death. No significant difference in duration of survival was detected between the two arms (Fig. 1). Median survival was slightly more than 8 months from study entry in both treatment arms, with 40% and 13% surviving 1 and 2 years

survival time.

in the chest plus PC1 arm and 44% and 21% surviving 1 and 2 years in the chest irradiation alone arm. Eighteen of 94 patients (19%) randomized to receive chest irradiation subsequently developed brain metastases, whereas 8 of 93 (9%) randomized to receive PC1 developed brain metastases @ = 0.10). Although the time adjusted incidence of brain metastases did not significantly differ between the treatment arms, the administration of PC1 did appear to delay the onset of late brain metastasis (Fig. 2). Prior surgical resection of all gross intrathoracic disease was accomplished in 26 patients. Three of the 12 patients (25%) randomized to mediastinal irradiation alone developed brain metastases, whereas none of the 14 patients (0%) randomized to receive PC1 developed brain metastases (p = .06). Among the 16 1 inoperable patients, 15 of 82 (18%) treated only to the chest developed brain metastases compared to S/79 (10%) receiving PC1 @ = .34) (Table 3). In 37 inoperable patients significant deviation from the protocol prescribed treatment plan was observed, mainly because of progressive disease. When the analysis was limited to the inoperable patients whose overall treatment compliance score was judged to be per protocol or with minimal deviation, 15 of the 73 inoperable patients (21%) receiving chest irradiation alone developed brain metastases whereas 5 of 51 (10%) receiving chest irradiation plus PC1 developed brain metastasis (p = .17). Of 169 patients who have died, 124 patients have complete information available concerning the timing of disease recurrence and its locations. Seventy-six patients

Prophylactic cranial irradiation for lung cancer 0

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Table 3. Initial patient characteristics by assigned treatment: evaluable patients

Age

Kamofsky Performance Score Weight loss Histology

T-Stage

N-Stage

Prior surgical resection

Male Female

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.

Beginning in February 1984, 187 evaluable patients with adenocarcinoma or large cell carcinoma of the lung clinically confined to the chest were rando...
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