Predictors of pulmonary toxicity in limited stage small cell lung cancer patients treated with induction chemotherapy followed by concurrent platinum-based chemotherapy and 70 Gy daily radiotherapy: CALGB 30904☆
Introduction
Small cell lung cancer (SCLC) represents 13% of all lung cancers [1]. Patients with limited stage (LS-SCLC) are potentially curable. Standard therapy for LS-SCLC cancer consists of concurrent multiagent chemotherapy and thoracic radiotherapy (TRT) followed by prophylactic cranial radiotherapy for patients with a good response. The median survival for LS-SCLC patients treated in this manner is 18–22 months with 5-year survival of 15–25% [2], [3].
While TRT is integral to the treatment of LS-SCLC, the ideal dose and fractionation is unknown. Intergroup 0096 demonstrated that an accelerated hyperfractionated TRT schedule of 45 Gy in 1.5 Gy twice daily fractions delivered with concurrent and adjuvant cisplatin and etopside improved overall survival compared to 45 Gy in 1.8 Gy daily radiotherapy with the same concurrent and adjuvant chemotherapy [2]. The NCCTG demonstrated no difference in overall survival between split course hyperfractionated and conventionally fractionated radiotherapy with cisplatin etopside [3]. Based on these results and the logistics of twice daily radiotherapy, conventionally fractionated radiotherapy is commonly given [4].
A series of studies investigated dose escalated daily radiotherapy for LS-SCLC. CALGB 8837 investigated the maximal tolerated dose of daily and twice daily radiotherapy delivered with concurrent chemotherapy, demonstrating 70 Gy TRT was tolerable [5]. Subsequently, three studies: CALGB 39808 (NCT00003812) [6] (n = 57), 30002 (NCT00033696) [7] (n = 63), and 30206 (NCT00072527) [8] (n = 78) investigated concurrent carboplatin (AUC = 5), etopside (100 mg/m2) and 70 Gy TRT for LS-SCLC, following two cycles of chemotherapy. These studies formed the basis of one of the experimental arms of CALGB 30610 comparing accelerated hyperfractionated radiotherapy to dose escalated conventionally fractionated radiotherapy and also to accelerated concomitant boost radiotherapy all with concurrent cisplatin and etopside.
Few data exist to predict treatment related cardiopulmonary toxicity in the LS-SCLC population. Usually, the same metrics used to evaluate radiotherapy plans for locoregionally advanced non-small cell lung cancer patients are used to evaluate radiotherapy plans for small cell lung cancer. However, due to differences in the biology of small cell and non-small cell lung cancer, including an increased radiosensitivity of small cell lung cancer, common presentation with substantial mediastinal adenopathy and a distant primary tumor, as well as more rapid progression, this may not be the correct approach. Additionally, current metrics used are based on heterogeneous and often retrospective patient populations. Therefore, we analyzed pooled patient data from CALGB 39808, 30002, and 30206 to assess cardiopulmonary toxicity in a homogeneously treated population of LS-SCLC patients treated with two cycles of induction chemotherapy followed by concurrent carboplatin, etopside and daily radiotherapy to 70 Gy. Additionally, identified patient, tumor, and treatment related factors associated with grade 3 and higher treatment related toxicity with this regimen.
Section snippets
Eligibility
Eligibility criteria for CALGB 39808, 30002, and 30206 have been previously published [6], [7], [8]. Briefly, patients were included with histologically or cytologically confirmed LS-SCLC defined as disease confined to a hemithorax, such that radiotherapy could be given. This included nodal disease limited to the ipsilateral hilum, and bilateral mediastinum, and excluded patients with pleural or pericardial effusions and/or supraclavicular lymphadenopathy. These patients were additionally
Results
Of the 211 patients enrolled on these studies, 100 patients completed all therapy including full dose radiation therapy and had appropriate radiation dose volume information available for review. Patient and tumor characteristics are listed in Table 1a. Included patients were compared to those receiving 4–6 cycles of chemotherapy but without radiation therapy information available to determine if the study sample was representative of the entire cohort. There were no significant demographic,
Post treatment pulmonary toxicity
Three patients experienced grade 3 post-treatment pulmonary toxicity likely related to the treatment; two with grade 3 pneumonitis/pulmonary infiltrates and one with grade 3 singletus. There was no difference in outcome when patients with any attribution of toxicity were included or if the analysis was restricted to patients with toxicity likely related to treatment. No patient experienced grade 4–5 post-treatment pulmonary toxicity. Factors associated with grade 3 or greater post-treatment
Discussion
In this retrospective analysis of 3 completed clinical trials using dose escalated once daily concurrent chemoradiotherapy, we found that traditional dose-volume metrics for non-small cell lung cancer predicted for post-treatment pulmonary toxicity. In particular, patients with larger volumes of lung exposed to 20 Gy and higher mean lung doses were more likely to experience pulmonary toxicity. These data confirm the standard practice of using these dose-volume metrics developed for non-small
Conclusion
In conclusion, a low incidence of grade 3 or higher post-CRT pulmonary toxicity was seen in this population of patients treated with induction chemotherapy followed by concurrent carboplatin, etopside, and 2 Gy daily radiotherapy to 70 Gy. Standard radiation dose-volume metrics including mean lung dose and V20 can predict for higher risk of pulmonary toxicity. Whether the therapeutic index of high dose QD TRT compares favorably with BID TRT is currently under investigation in two phase III
Conflicts of interest
The authors have no conflicts of interest to declare.
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Cited by (8)
Radiation and Systemic Therapy for Limited-Stage Small-Cell Lung Cancer
2022, Journal of Clinical OncologyRadiation toxicities and management
2018, Modern Thoracic OncologyImpact of radiation dose on concurrent chemoradiotherapy for limited-stage small-cell lung cancer
2018, Radiation Oncology Journal
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The research for CALGB 30904 (Alliance) was supported, in part, by grants from the National Cancer Institute (CA31946) to the Alliance for Clinical Trials in Oncology (Monica M. Bertagnolli, M.D., Chair) and to the Alliance Statistics and Data Center (Daniel J. Sargent, Ph.D., CA33601). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. The authors would like to thank the Quality Assurance Review Center (Providence, RI, USA), for their extensive help with data collection for this analysis.
- 1
For the Alliance for Clinical Trials in Oncology.
- 2
Supported by CA47577.
- 3
Supported by CA21060.
- 4
Supported by CA03927.
- 5
Supported by CA41287.