Cancer Chemother Pharmacol (2013) 72:1247–1254 DOI 10.1007/s00280-013-2308-5
Original Article
A phase III concurrent chemoradiotherapy trial with cisplatin and paclitaxel or docetaxel or gemcitabine in unresectable non‑small cell lung cancer: KASLC 0401 In‑Jae Oh · Kyu‑Sik Kim · Young‑Chul Kim · Hee‑Jung Ban · Yong‑Soo Kwon · Yu‑Il Kim · Sung‑Chul Lim · Woong‑Ki Chung · Taek‑Keun Nam · Joo‑Young Song · Mee‑Sun Yoon · Sung‑Ja Ahn
Received: 15 April 2013 / Accepted: 25 September 2013 / Published online: 5 October 2013 © Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose Concurrent chemoradiotherapy (CCRT) is recommended for the management of patients with unresectable non-small cell lung cancer (NSCLC). This prospective study aimed to compare the efficacy of concurrently delivered cisplatin doublets with paclitaxel, or docetaxel, or gemcitabine. Methods The main eligibility criteria consisted of previously untreated stage IIIB NSCLC. The subjects were randomized into three arms: paclitaxel 45 mg/m2/week (TP), docetaxel 20 mg/m2/week (DP), and gemcitabine 350 mg/ m2/week (GP) in addition to cisplatin 20 mg/m2/week. Three-dimensional conformal radiotherapy was given once daily, weekly 5 fractions and the total prescription dose was 60–66 Gy. The primary endpoint was response rate, and the secondary endpoints were survival and toxicity. Results A total of 101 patients were recruited into this trial of whom 93 (TP: 33, DP: 29, GP: 31) patients were treated with CCRT from March 2005 to July 2007. Similar response rates were observed across arms: TP: 63.6 %, DP: 72.4 %, GP: 61.3 % (p = 0.679). There was no statistically significant difference of median survival (TP: 27.3, DP: I.-J. Oh · K.-S. Kim · Y.-C. Kim · M.-S. Yoon · S.-J. Ahn (*) Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, 322 Seoyang‑ro, Hwasun‑eup, Jeonnam 519‑809, Republic of Korea e-mail:
[email protected] I.-J. Oh · K.-S. Kim · Y.-C. Kim · H.-J. Ban · Y.-S. Kwon · Y.-I. Kim · S.-C. Lim Department of Internal Medicine, Chonnam National University, Gwangju, Republic of Korea W.-K. Chung · T.-K. Nam · J.-Y. Song · M.-S. Yoon · S.-J. Ahn Department of Radiation Oncology, Chonnam National University, Gwangju, Republic of Korea
27.6, GP: 16.5 months, p = 0.771). In subgroup analysis, a survival benefit of consolidation chemotherapy was not seen, but leucopenia (63.2 %) and neutropenia (68.4 %) more than grade 3 were significantly high in DP arm. The grade ≥3 radiation esophagitis was more frequent in the GP arm (22.6 %, p = 0.163). Conclusions Among the three arms, no statistically significant difference in response rate, survival, and toxicity was observed. However, clinically significant radiation toxicity was more frequent in the GP arm. Keywords Non-small cell lung cancer · Concurrent chemoradiotherapy · Paclitaxel · Docetaxel · Gemcitabine
Introduction The standard care for unresectable stage IIIB non-small cell lung cancer (NSCLC) with favorable prognosis has been a combined modality with chemotherapy and radiation since phase III studies showed that concurrent chemoradiotherapy (CCRT) resulted in better survival than did sequential chemoradiotherapy [1–3]. While radiation therapy has become more effective and safe, investigators are still studying which drugs should be combined and how to optimally administer these agents in conjunction with radiation. The Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial to determine whether any of the three arms (cisplatin + gemcitabine, cisplatin + docetaxel, carboplatin + paclitaxel) was superior to cisplatin + paclitaxel and concluded that none of the four combinations offered a significant advantage over the others in the treatment of stage IV NSCLC [4]. Based on these studies, we designed this study to compare the efficacy of regimens, which were effective in chemotherapy alone, of
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the concomitant use with thoracic radiotherapy in locally advanced NSCLC. The improved survival after CCRT is mediated primarily through increased locoregional control of the disease [5]. To decrease distant metastasis, studies on the efficacy of consolidation chemotherapy in addition to CCRT were tried [6–8]. Consolidation chemotherapy with these new agents after CCRT in stage IIIB NSCLC was feasible and resulted in better survival than conventional etoposide + cisplatin combination [8]. Although there were many published results of improved response rates using the CCRT, there was no research comparing these new drug combinations in a prospective trial. So, we designed a prospective randomized study comparing paclitaxel or docetaxel or gemcitabine in combination with cisplatin in a concurrent and consolidation settings.
Methods Study design This was a randomized prospective phase III trial of CCRT for stage IIIB NSCLC patients. The study opened in March 2005 and closed to accrual in July 2007. The protocol was approved by the institutional review board of the hospital and Korean Association for the Study of Lung Cancer. All patients provided written informed consent before enrollment. Patient eligibility Eligible patients were previously untreated, histologically or cytologically documented NSCLC determined to be unresectable or inoperable stage IIIB disease without pleural involvement. Patients were aged between 18 and 75 years and had an ECOG performance score 0–1, weight loss of 8 cm, active uncontrolled
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Cancer Chemother Pharmacol (2013) 72:1247–1254
infection, significant acute gastrointestinal disorders with diarrhea or ileus, known HIV carrier or history of acquired immunodeficiency syndrome, interstitial lung disease or pulmonary fibrosis, inadequate pulmonary function (forced expiratory volume in 1 s ≤0.8 L). Treatment schedules We used a web-based case report form developed by Healthroad Company (Seoul, Korea). Eligible patients were stratified by histology (squamous cell carcinoma vs. adenocarcinoma vs. others) and were then randomly assigned to one of three different combinations of chemotherapeutic agents: paclitaxel 45 mg/m2 + cisplatin 20 mg/m2 (TP), docetaxel 20 mg/m2 + cisplatin 20 mg/m2 (DP), and gemcitabine 350 mg/m2 + cisplatin 20 mg/m2 (GP). Chemotherapy was initiated concurrently with the first date of radiotherapy and repeated weekly for the following 6 weeks. Doses were adjusted if necessary according to hematologic and non-hematologic toxicities. Four weeks after the completion of CCRT with adequate hematological recovery, the patients underwent the 3-week consolidation chemotherapy with the same agent for a maximum of four cycles with paclitaxel 135 mg/m2, docetaxel 75 mg/m2, gemcitabine 1,250 mg/m2, and cisplatin 60 mg/m2. Chemotherapy and radiotherapy began the same day, and radiotherapy was started within 12 h of the injection of chemotherapeutic drugs. CT-simulation-guided 3-dimensional conformal radiotherapy (3D-CRT) plans were used throughout the study period. We did not perform the intensity modulated radiotherapy planning. Radiotherapy was given with photon beams generated by a linear accelerator (Clinac EX, Varian Co., Palo Alto, USA) with an energy of 6 or 10 MV. The gross tumor volume (GTV) was contoured based on the CT or positron emission tomography (PET) imaging. GTV encompassed all detectable primary tumors and positive lymph nodes. Lymph node involvement was defined as enlargement of the diameter (≥1.5 cm of short axis) on CT or [18F]-fluoro-2-deoxy-glucose avidity (standard uptake value >1.5) on PET. Clinical target volume (CTV) was expanded 7–10 mm margin around the GTV, and elective treatment of contralateral hilar lymph node or supraclavicular fossae was not allowed. The median dose of radiation was 60–66 Gy with dose fraction size ranging from 2.0 to 2.4 Gy to GTV. Inhomogeneity correction was performed for the 3D-CRT plan. Tumor response was measured on the basis of response evaluation criteria in solid tumors (RECIST) version 1.0. Imaging studies could be repeated any time if clinically indicated (to confirm radiological progression or pulmonary toxicity, for example). Treatment failure was indicated by the appearance of new lesions or disease progression. Toxicity of chemotherapy was graded according to
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common terminology criteria for adverse events version 3.0. Radiation esophagitis and pneumonitis were graded by toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Follow-up visits were conducted every 3 months for first 1 year after the completion of treatment and after that every 6 months for 2 years. Dose modifications For grade 3–4 mucositis, stomatitis, esophagitis, dermatitis, or other radiotherapy-related toxicity, treatment was delayed until resolution of toxicity to grade 2 or less. For grade 4 hematologic toxicity, the dose of next cycle chemotherapy was reduced by 75 %. Patients were allowed to receive blood transfusions, antibiotics, and antiemetics as deemed appropriate by the physician. The granulocyte colony-stimulating factor could be administrated subcutaneously or intravenously in case of absolute granulocyte count
