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Annals of Oncology
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Annals of Oncology 23: 2919–2924, 2012 doi:10.1093/annonc/mds123 Published online 10 July 2012
Prophylactic cranial irradiation in small-cell lung cancer: Findings from a North Central Cancer Treatment Group Pooled Analysis S. E. Schild1*, N. R. Foster2, J. P. Meyers2, H. J. Ross3, P. J. Stella4, Y. I. Garces5, K. R. Olivier5, J. R. Molina6, L. R. Past7 & A. A. Adjei5 on behalf of North Central Cancer Treatment Group 1 Department of Radiation Oncology, Mayo Clinic, Scottsdale; 2Section of Biomedical Statistics and Informatics, Mayo Clinic, Rochester; 3Division of Medical Oncology, Mayo Clinic; 4Michigan Cancer Research Consortium, Ann Arbor; 5Department of Radiation Oncology, Mayo Clinic, Rochester; 6Department of Medical Oncology, Mayo Clinic, Rochester; 7Department of Radiation Oncology, Luther Hospital Eau Claire; 8Department of Medicine, Roswell Park Cancer Institute, Buffalo, USA
Received 20 January 2012; revised 12 March 2012; accepted 14 March 2012
Background: This pooled analysis evaluated the outcomes of prophylactic cranial irradiation (PCI) in 739 small-cell lung cancer (SCLC patients with stable disease (SD) or better following chemotherapy ± thoracic radiation therapy (TRT) to examine the potential advantage of PCI in a wider spectrum of patients than generally participate in PCI trials. Patients and methods: Three hundred eighteen patients with extensive SCLC (ESCLC) and 421 patients with limited SCLC (LSCLC) participated in four phase II or III trials. Four hundred fifty-nine patients received PCI (30 Gy/15 or 25 Gy/10) and 280 did not. Survival and adverse events (AEs) were compared. Results: PCI patients survived significantly longer than non-PCI patients {hazard ratio [HR] = 0.61 [95% confidence interval (CI): 0.52–0.72]; P < 0.0001}. The 1- and 3-year survival rates were 56% and 18% for PCI patients versus 32% and 5% for non-PCI patients. PCI was still significant after adjusting for age, performance status, gender, stage, complete response, and number of metastatic sites (HR = 0.82, P = 0.04). PCI patients had significantly more grade 3+ AEs (64%) compared with non-PCI patients (50%) (P = 0.0004). AEs associated with PCI included alopecia and lethargy. Dose fractionation could be compared only for LSCLC patients and 25 Gy/10 was associated with significantly better survival compared with 30 Gy/15 (HR = 0.67, P = 0.018). Conclusions: PCI was associated with a significant survival benefit for both ESCLC and LSCLC patients who had SD or a better response to chemotherapy ± TRT. Dose fractionation appears important. PCI was associated with an increase in overall and specific grade 3+ AE rates. Key words: PCI, prophylactic cranial irradiation, radiotherapy, small-cell lung cancer, survival *Corresponding author: Dr S. E. Schild, Department of Radiation Oncology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85255, USA. Tel: +1-480-301-8133; Fax: +1-480-301-7687; E-mail:
[email protected]
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
[email protected].
original articles
Annals of Oncology
introduction Prophylactic cranial irradiation (PCI) was introduced into clinical practice in the 1960s for patients with acute lymphoblastic leukemia who had a high risk of failure in the central nervous system [1]. It was first tested for patients with small-cell lung cancer (SCLC) in the 1970s following the recognition that the blood brain barrier appeared to restrict the penetration of most chemotherapeutic agents into the brain leaving it as a sanctuary site for relapse. The first PCI trials demonstrated substantial reductions in brain metastases [2]. Unfortunately, soon thereafter, a number of long-term survivors of SCLC were noted to have various neurologic abnormalities including dementia [3–5]. Magnetic resonance imaging (MRI) findings were described as ‘leukoencephalopathy’ due to changes within the white matter consistent with demyelization. These findings were especially frequent when PCI was delivered with large daily doses (such as 3.6 Gy daily fractions × 10 for a total of 36 Gy) or concurrently with chemotherapy [6]. These reports of leukoencephalopathy contributed to a subsequent lack of enthusiasm for PCI. In spite of these hesitations, careful prospective studies revealed that PCI improved survival for both extensive SCLC (ESCLC) and limited SCLC (LSCLC) and
was reasonably safe when administered sequentially after chemotherapy using less toxic dose fractionation regimens. However, the adoption of PCI has not been universal due to concerns about toxicity and efficacy.
patients and methods This pooled analysis included 739 patients with SCLC who participated in four phase II or III North Central Cancer Treatment Group trials (Table 1). Patients with stable disease (SD) or better following chemotherapy ± thoracic radiation therapy (TRT) were included to examine the potential advantage of PCI in a broader spectrum of patients than generally participate in randomized PCI trials. Responses were based on history and physical examination, chest radiographs (86-20-51 and 89-20-51), and computed tomography (CT) scans (89-20-52 and 95-2052). Of these, 318 patients had ESCLC and 421 patients had LSCLC. Four hundred fifty-nine patients received PCI (30 Gy/15 or 25 Gy/10) and 280 did not. All patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) ranging from zero to two. Study guidelines varied as to which patients were to receive PCI. In 86-20-51, ESCLC patients were to receive TRT and PCI (30 Gy/15) if they had a complete response (CR) outside of the chest. All patients with LSCLC were to receive TRT and PCI (30 Gy/15) if they had SD or a better response to the initial therapy (chemotherapy). Trial 89-20-51 included only ESCLC patients who were to
Table 1. Study characteristics Protocol
86-20-51
89-20-51
89-20-52
95-20-53
N (stable or better included in landmark analysis) Stage
394
131
149
65
LSCLC: 207 (53%) ESCLC: 187 (47%) CR: 163 (42%) PR: 92 (23%) SD: 20 (5%) REGR: 119 (30%) 11.1 mos. (10.5–12)
ESCLC
LSCLC
LSCLC
CR: 42 (32%) PR: 27 (21%) SD: 8 (6%) REGR: 54 (41%) 8 mos. (7.4–8.7)
CR: 118 (79%) PR: 13 (9%) SD: 2 (1%) REGR: 16 (11%) 15.3 mos. (12–17.7)
CR: 16 (25%) PR: 15 (23%) SD: 3 (5%) REGR: 31 (48%) 20.3 mos. (16.6–27)
280 (71%)
32 (24%)
88 (59%)
59 (91%)
30 Gy/15 300 (76%)
30 Gy/15 55 (42%)
30 Gy/15 126 (85%)
25 Gy/10 24 (37%)
March 1987 August 1990 III 0–2 A:B:C:D: etoposide + cisplatin + CAV + TRT + PCI (if CR outside of chest for ESCLC; if stable or better response for LSCLC) + recombinant gamma interferon or observation (for CR pts only)
August 1990 July 1993 III 0–2 A: etoposide + cisplatin + Megace + TRT + PCI (for CR pts only)
September 1990 November 1996 III 0–2 A: etoposide + cisplatin + standard TRT + etoposide + cisplatin + PCI (for CR pts only) B: etoposide + cisplatin + AHSCTRT + etoposide + cisplatin + PCI (for CR pts only)
October 1996 March 1999 II 0–2 A: etoposide + cisplatin + PCI (if regression or better on chest X-ray) + AHSCTRT + etoposide + cisplatin
Best response
Median subsequent survival (95% confidence interval) Frequency (%) that received PCI PCI dose Frequency (%) that received TRT Date opened Date closed Phase Performance status (PS) Agentsa
B: etoposide + cisplatin + placebo + TRT + PCI (for CR pts only)
a
Patients with central nervous system only progression, typically allowed whole brain radiation therapy across all studies. CAV = cyclophosphamide, doxorubicin, vincristine; AHSCTRT, accelerated hyperfractionated split-course thoracic radiotherapy; CR, complete response; ESCLC, extensive small-cell lung cancer; LSCLC, limited small-cell lung cancer; Megace, megestrol acetate; mos, months; PCI, prophylactic cranial irradiation; PR, partial response; pts, patients; SD, stable disease; TRT, thoracic radiation therapy.
| Schild et al.
Volume 23 | No. 11 | November 2012
original articles
Annals of Oncology achieve a CR after initial therapy to receive PCI (30 Gy/15). Trial 89-20-52 included only LSCLC patients who were to achieve a CR to receive PCI (30 Gy/15). Trial 95-20-53 included only LSCLC patients who were to achieve any response to initial therapy to receive PCI. Only 95-20-53 utilized the most common current PCI regimen, 25 Gy in 10 fractions, which was administered after initial chemotherapy but before TRT. Institutional Review Boards at the study sites had approved these trials and all participants provided written informed consent. See Table 1 for a detailed listing of the individual trial characteristics. Baseline characteristics were compared between the PCI and no-PCI groups using the chi-square test for categorical data and the Wilcoxon rank sum test for continuous data. Survival and adverse events (AEs) were compared using a landmark analysis that included patients who had SD or better. AEs were compared between the PCI and no-PCI groups via the chi-square test. Overall survival (OS) from the landmark time was assessed for patients who received PCI versus no PCI, where the landmark time was the time at which the patients could have started the PCI treatment per protocol. Survival from the landmark time is reported in this study. The Kaplan–Meier method [7] was used to compare the survival distributions for each group assessed. The Cox proportional hazards model was used for both the univariate and the multivariate analyses [8]. Score and likelihood ratio P values were reported for the univariate and multivariate models, respectively, after stratifying by study. The Wald test was used to test the significance of each individual category for variables with more than two categories. Hazard ratios (HRs) and the associated 95% confidence intervals (CI) were reported for the univariate and multivariate results. The likelihood ratio test (stratified by study) was used to test for the interaction effect between PCI and the best response categories of CR, partial response (PR), regression (REGR, a response less than PR), and SD. All tests were two sided, with P values
