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Phase I study of accelerated conformal radiotherapy for stage I non-small-cell lung cancer in patients with pulmonary dysfunction: CALGB 39904.

ABSTRACT: The optimal treatment for medically inoperable stage I non-small-cell lung cancer (NSCLC) has not been defined.Cancer and Leukemia Group B trial 39904 prospectively assessed accelerated, once-daily, three-dimensional radiotherapy for early-stage NSCLC. The primary objectives were to define the maximally accelerated course of conformal radiotherapy and to describe the short-term and long-term toxicity of therapy. Entry was limited to patients with clinical stage T1N0 or T2N0 NSCLC (< 4 cm) and pulmonary dysfunction. The nominal total radiotherapy dose remained at 70 Gy, while the number of daily fractions in each successive cohort was reduced.Thirty-nine eligible patients were accrued (eight patients each on cohorts 1 to 4 and seven patients on cohort 5) between January 2001 and July 2005. One grade 3 nonhematologic toxicity was observed in both cohort 3 (dyspnea) and cohort 4 (pain). The major response rate was 77%. After a median follow-up time of 53 months, the actuarial median survival time of all eligible patients was 38.5 months. Local relapse was observed in three patients.Accelerated conformal radiotherapy was well tolerated in a high-risk population with clinical stage I NSCLC. Outcomes are comparable to prospective reports of alternative therapies, including stereotactic body radiation therapy and limited resection, with less apparent severe toxicity. Further investigation of this approach is warranted.

SUBMITTER: Bogart JA

PROVIDER: S-EPMC2815709 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Project description:In this open-label phase I study, the maximum-tolerated dose of cetuximab with concurrent chemoradiotherapy (C-CRT) in stage III non-small-cell lung cancer together with individualized, isotoxic accelerated radiotherapy (RT) was investigated.Patients with stage III non-small-cell lung cancer, World Health Organization performance status 0-1, forced expiratory volume in 1 second more than 50%, carbon monoxide diffusing capacity more than 50%, weight loss less than 10%, and no severe comorbidity were enrolled. Patients without progression after one to two cycles of gemcitabine-carboplatin were included and treated with cetuximab 400 mg/kg d7 and 250 mg/kg weekly together with RT and cisplatin (50 mg/m d1, 8; 40 mg/m d22)-vinorelbine for 5 weeks. Vinorelbine was escalated in three steps; (1) 10 mg/m d1, 8 and 8 mg/m d22, 29; (2) 20 mg/m d1, 8 and 8 mg/m d22, 29; (3) 20 mg/m d1, 8; 15 mg/m d22, 29. An individualized prescribed RT dose based on normal tissue dose constraints was applied (e.g., mean lung dose 19 Gy). The primary endpoint was the maximum-tolerated dose 3 months after the end of C-CRT; secondary endpoints were toxicity and metabolic response as assessed by positron emission tomography.Between September 2007 and October 2010, 25 patients (12 men, 13 women, mean age 59 years) were included. The mean RT dose was 62 ± 6.6 Gy. The vinorelbine dose could be escalated to dose level 3. Twelve of 25 patients experienced greater than or equal to grade 3 toxicity (esophagitis 3, rash 1, diarrhea 1, cough 1, dyspnea 1, vomiting 1, and pulmonary embolism 1). No dose-limiting toxicities were observed. One patient with a complete pathological response in dose level 3 developed a fatal hemoptysis 4 months after RT. Metabolic remissions were observed in 19 of 22 patients.C-CRT with cetuximab and cisplatin-vinorelbine is safe to deliver at full dose. The recommended phase II dose is therefore cetuximab 400 mg/m d7 and 250 mg/m weekly, cisplatin 50 mg/m d1, 8; 40 mg/m d22 and vinorelbine 20 mg/m d1, 8; 15 mg/m d22, 29 for 5 weeks together with RT.

Project description:BackgroundChemoradiotherapy (CRT) is the standard treatment for patients with inoperable stage III non-small cell lung cancer (NSCLC) stage III. With a median OS beyond 30 months, adequate pulmonary function (PF) is essential to ensure acceptable quality of life after treatment. Forced expiratory volume in 1 second (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) are the most widely used parameters to assess lung function. The aim of the current study was to evaluate dose-volume effects of accelerated high-dose radiation on PF.MethodsA total of 72 patients were eligible for the current analysis. After induction chemotherapy, all patients received dose-differentiated accelerated radiotherapy with intensity-modulated radiotherapy (IMRT-DART). PF tests were performed six weeks, three and six months after the end of radiotherapy.ResultsThe median total dose to the tumor was 73.8 Gy (1.8 Gy bid) with a size dependent range between 61.2 and 90 Gy. In the whole cohort, 321 pulmonary function tests were performed. At six months, the median FEV1 relative to baseline was 0.95 (range: 0.56-1.36), and the relative median DLCO decreased to 0.98 (range: 0.64-1.50). The correlation between V20total lung and FEV1 decline was statistically significant (P = 0.023). A total of 13 of 34 (38%) COPD patients had a 4%-21% FEV1 decrease.ConclusionPatients with a V20total lung < 21% are at a low risk for PF decrease after high dose irradiation treatment. Although overall short term FEV1 and DLCO differ only moderately from baseline these changes may be clinically important, especially in patients with COPD.Key pointsSignificant findings: Pulmonary function after high dose irradiation decreases only moderately. FEV1 and DLCO decrease depend on V20total lung . Small differences in lung function may be clinically important for COPD patients. KPS predicts minimal clinically important differences (MCID).What this study addsThis study shows that high-dose irradiation delivered with intensity-modulated techniques does not impair short-term lung function even in patients with compromised respiratory capacity before treatment. This is a pre-requisite for adequate quality of life after thoraco-oncological therapy.

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Phase I study of accelerated conformal radiotherapy for stage I non-small-cell lung cancer in patients with pulmonary dysfunction: CALGB 39904.

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