Clinical Investigation
Primary Analysis of a Phase II Randomized Trial Radiation Therapy Oncology Group (RTOG) 0212: Impact of Different Total Doses and Schedules of Prophylactic Cranial Irradiation on Chronic Neurotoxicity and Quality of Life for Patients With Limited-Disease Small-Cell Lung Cancer

Presented in part at the Annual Meeting of the American Society for Radiation Oncology, November 1–5, 2009, Chicago, IL.
https://doi.org/10.1016/j.ijrobp.2010.05.013Get rights and content

Purpose

To determine the effect of dose and fractionation schedule of prophylactic cranial irradiation (PCI) on the incidence of chronic neurotoxicity (CNt) and changes in quality of life for selected patients with limited-disease small-cell lung cancer (LD SCLC).

Methods and Materials

Patients with LD SCLC who achieved a complete response after chemotherapy and thoracic irradiation were eligible for randomization to undergo PCI to a total dose of 25 Gy in 10 daily fractions (Arm 1) vs. the experimental cohort of 36 Gy. Those receiving 36 Gy underwent a secondary randomization between daily 18 fractions (Arm 2) and twice-daily 24 fractions (Arm 3). Enrolled patients participated in baseline and follow-up neuropsychological test batteries along with quality-of-life assessments.

Results

A total of 265 patients were accrued, with 131 in Arm 1, 67 in Arm 2, and 66 in Arm 3 being eligible. There are 112 patients (42.2%) alive with 25.3 months of median follow-up. There were no significant baseline differences among groups regarding quality-of-life measures and one of the neuropsychological tests, namely the Hopkins Verbal Learning Test. However, at 12 months after PCI there was a significant increase in the occurrence of CNt in the 36-Gy cohort (p = 0.02). Logistic regression analysis revealed increasing age to be the most significant predictor of CNt (p = 0.005).

Conclusions

Because of the increased risk of developing CNt in study patients with 36 Gy, a total PCI dose of 25 Gy remains the standard of care for patients with LD SCLC attaining a complete response to initial chemoradiation.

Introduction

Small-cell lung cancer (SCLC) comprises approximately 13% of all cases of lung cancer being diagnosed more recently in the United States, of which roughly 30% are found to have limited disease (1). Despite the impact of chemotherapy and chest irradiation for treating the primary disease, brain relapses are still a major concern and may occur in approximately 50% of the time in long-term survivors (2). Although a meta-analysis (3) demonstrated the impact of prophylactic cranial irradiation (PCI) on improving survival in patients with limited-disease SCLC (LD SCLC) who sustained a complete response to chemoradiation, the optimal total dose and fractionation schedule of delivering PCI still remain uncertain.

Recently, the results of an international Phase III trial (PCI 01-EULINT1; ClinicalTrials.gov identifier: NCT 00005062) of more than 700 patients comparing 25 Gy in 10 daily fractions vs. 36 Gy total dose of PCI delivered at institutional choice in either 18 daily fractions or in 24 twice-daily delivered fractions showed no survival benefit in the higher-dose group (4). In fact, this latter study found a lower 2-year overall survival of 37% in the cohort receiving 36 Gy vs. 42% for those receiving 25 Gy (p = 0.05). This multinational PCI trial was already accruing patients at the time of concept development for Radiation Therapy Oncology Group (RTOG) trial 0212.

Therefore, with the support of the National Cancer Institute, RTOG 0212 was designed with two specific goals. First, the study was to contribute patients to the international PCI Phase III trial that evaluated the impact of total dose of PCI on the incidence of brain metastasis at 2 years, overall survival, and disease-free survival. The accrual to the international study was achieved in December 2005; 146 patients were enrolled from RTOG 0212 (4). Second, because there was a two-part randomization scheme not only between 25 Gy vs. 36 Gy total PCI dose but also between daily and twice-daily fractionation with the 36-Gy total PCI dose arms, RTOG 0212 was planned as a Phase II trial to determine the impact of PCI total dose and treatment schedule on incidence of chronic neurotoxicity (CNt) and on quality of life (QoL). This study required a total of 264 evaluable patients, including the first 146 patients coenrolled into the international study, to perform its objectives. Thus, this report is an analysis of the initial results of RTOG 0212.

Section snippets

Patient selection

Histologic or cytologic evidence of SCLC was required. After appropriate staging workup and Zubrod performance status of ≤1 along with RTOG neurological function class of 1 or 2, patients had to have limited disease and achieved a complete response to chemotherapy and consolidative chest radiotherapy that was documented at least on standard chest X-rays within 1 month of study entry. Patients may still have been receiving chest irradiation but must have completed chest irradiation by at least 1

Results

Radiation Therapy Oncology Group Protocol 0212 opened on February 19, 2003 and closed on February 12, 2008. A total of 265 patients were accrued, of whom 264 were eligible for analysis. This evaluation was performed using those eligible patients in RTOG 0212 as of February 23, 2009.

At the time of this analysis, there are 112 patients alive with 25.3 months of median follow-up (range, 0–53.0 months), with 16 patients having less than 12 months of follow-up. There was 1 patient in Arm 2 for whom

Discussion

Since the sentinel meta-analysis published in 1999 regarding 987 patients from seven randomized trials (3), the standard of care for patients with LD SCLC who achieve a complete response after chemoradiation for the primary disease has been to incorporate PCI into their therapeutic regimen. In addition to reducing the risk of brain metastases from 58.6% without PCI to 33.3% at 3 years, PCI was found to result in a 16% reduction in mortality rate that translated into a 5.4% increase in 3-year

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    Supported by Grants RTOG U10 CA21661, CCOP U10 CA37422, and Stat U10 CA32115 from the National Cancer Institute. ClinicalTrials.gov identifier: NCT00057746. This article's contents are the sole responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

    Conflict of interest: none.

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