Phase III Study of the Eastern Cooperative Oncology Group (ECOG 2597): Induction Chemotherapy Followed by Either Standard Thoracic Radiotherapy or Hyperfractionated Accelerated Radiotherapy for Patients With Unresectable Stage IIIA and B Non–Small-Cell Lung Cancer

University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 06/2005; 23(16):3760-7. DOI: 10.1200/JCO.2005.09.108
Source: PubMed


To compare once-daily radiation therapy (qdRT) with hyperfractionated accelerated radiation therapy (HART) after two cycles of induction chemotherapy.
Eligible patients were treatment naive, and had stage IIIA and B unresectable non-small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0/1, and normal organ function. Induction chemotherapy consisted of two cycles of carboplatin area under time-concentration curve 6 mg/mL . min plus paclitaxel 225 mg/m2 on day 1. RT consisted of arm 1 (qdRT), 64 Gy (2 Gy/d), versus arm 2 (HART), 57.6 Gy (1.5 Gy tid for 2.5 weeks). A total of 388 patients were needed to detect a 50% increase in median survival from 14 months of qdRT to 21 months of HART; accrual was not achieved and the study closed prematurely.
Of 141 patients enrolled, 83% were randomly assigned after chemotherapy to qdRT (n = 59) or HART (n = 60). Median survival was 20.3 and 14.9 months for HART and qdRT, respectively (P = .28). Overall response was 25% and 22% for HART and qdRT, respectively (P = .69). Two- and 3-year survival was 44% and 34% for HART, and 24% and 14% for qdRT, respectively. Grade > or = 3 toxicities included esophagitis in 14 v nine patients, and pneumonitis in 0 v 6 patients for HART and qdRT, respectively. Any subsequent trials of the HART regimen must address the issues that led to early closure, including slow accrual, logistics of HART, mucosal toxicity, and the fact that concurrent chemoradiotherapy now seems more effective than sequential treatment.
After two cycles of induction chemotherapy with carboplatin-paclitaxel, HART is feasible with an acceptable toxicity profile. Although statistical significance was not achieved and the study closed early, there was a positive statistical trend suggesting a survival advantage with the HART regimen.

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    • "Interestingly we note that the only randomised trial which compared sequential with concurrent chemotherapy using an accelerated radiotherapy scheme, found no difference in survival between the arms [25]. Furthermore, the best results reported in a phase III study of chemoradiation in locally advanced NSCLC have come from the combination of 2 cycles of carboplatin-paclitaxel followed by hyperfractionated accelerated radiation therapy (HART) [26]. We think that this approach warrants further investigation. "
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    ABSTRACT: We conducted a phase II study combining induction chemotherapy with continuous hyperfractionated accelerated radiotherapy (CHART) in locally advanced non-small-cell lung cancer (NSCLC). A total of 40 patients with stage III NSCLC were enrolled. All patients received 3 cycles of chemotherapy followed by CHART (56 Gy in 36 fractions over 12 days). The primary outcome measure was radiation toxicity. Secondary endpoints were response rate, overall survival, disease-free survival and loco-regional progression-free survival. Acute radiation toxicity was minimal and there were no significant late toxicities. The response rate after completion of chemoradiation was 65%. The median and 2-year overall survival, progression-free survival and loco-regional progression-free survivals were 15.7 months, 28%; 12.1 months, 23%; and 26.4 months, 51%, respectively. Induction chemotherapy can be safely combined with CHART. The survival results are consistent with previous studies of chemotherapy followed by accelerated radiotherapy. This approach should be compared with synchronous chemoradiation to determine if it represents a less toxic alternative.
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    • "In prospective trials this was shown to be equivalent to conventional fractionation for patients with squamous cell head and neck cancer and superior to conventional fractionation for both local control and overall survival for patients with NSCLC. A subsequent trial conducted in the US compared a modification of CHART called HART, which eliminated the weekend treatments and increased total dose to 57.6 Gy in 36 fractions over 2.5 weeks, to conventional fractionation in patients with Stage III NSCLC following two cycles of induction carboplatin and paclitaxel and found an improvement in median survival of 14.9 to 20.3 months and three-year survival from 14% to 34% [51]. These differences unfortunately did not reach statistical significance because the trial was closed prematurely with only half of its planned accrual. "
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    • "In the CHART-study reduction of the OTT from 6 weeks to 12 days resulted in improved outcome with radiotherapy alone, indicating an influence of repopulation [44]. Several other studies report about improved results while shortening the OTT, for radiotherapy alone or for chemo-radiation [18,45-47]. Assuming that accelerated repopulation begins 28 days after start of treatment and that each day of prolongation hereafter should be compensated by 0.5 Gy, 66 Gy administered in 32 days could be equivalent to a BED10 of 93 Gy [Dische 02, Hermann 04, Fowler 04]. "
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