Treatment was deemed a success if the patient remained alive for at least 12 months

Treatment was deemed a success if the patient remained alive for at least 12 months. majority experienced PS 2. The overall response rate Clonixin was 67% and the disease control rate was 93%. Treatment was well tolerated. The median PFS and OS were 11 and 17 months, respectively. The overall 12-month OS was 57%, which narrowly missed the pre-specified target for significance. Conclusions Patients with poor risk stage III NSCLC experienced better than expected outcomes with a regimen of induction carboplatin/nab-paclitaxel followed by TRT and erlotinib. However, as per the statistical design, the 12-month OS was not sufficiently high to warrant further studies. INTRODUCTION Patients with locally advanced non-small cell lung malignancy (NSCLC) treated with concurrent chemotherapy and thoracic radiotherapy (TRT) have a 20% to 25% probability of long-term disease-free survival (1). However, patients with adverse prognostic features, such as poor performance status (PS) and/or significant excess weight loss (WL), which represent a sizable percentage of patients, have a worse prognosis and do not seem to benefit from the standard approach (2). No specific treatment guidelines exist for this subset and management options in clinical practice range from palliative radiotherapy to sequential treatment or an attenuated concurrent approach. Building around the pre-clinical rationale that inhibitors of the epidermal growth factor receptor (EGFR) are strong radiation sensitizers (3), the Malignancy and Leukemia Group B (CALGB 30106) published a trial in which a subset of 21 patients with locally advanced disease and poor PS were treated with induction chemotherapy followed by gefitinib, an EGFR tyrosine kinase inhibitor (TKI), administered concomitantly with TRT (4). The median survival was an unprecedented 19 months, which could not be accounted for by the few patients with EGFR mutated tumors. Based on this experience, we designed a phase II trial of two cycles of induction chemotherapy with carboplatin and nab-paclitaxel followed by TRT and concurrent erlotinib for patients with stage IIIA/B NSCLC and poor risk features. Molecular evaluation for EGFR mutations was performed in available tumor specimens. The trial was conducted by the former CALGB, now Alliance for Clinical Trials in Oncology, and the former Radiation Therapy Oncology Group (RTOG), now NRG Oncology. PATIENTS AND METHODS Patients with histologically or cytologically documented NSCLC, with unresectable stage IIIA or IIIB by the AJCC version 6 staging system (T1-3 N2; T4 N0-2; and N3 patients except for contralateral hilar or supraclavicular involvement), were eligible if they experienced either PS 2 or PS 0-1 and 10% excess weight loss within 3 months prior to enrollment. A formal variation between a PS 2 on the basis of cancer-related impairment versus pre-existing co-morbidities was not made but the ECOG level, which was utilized for eligibility purposes, implies the latter. Prior chemotherapy, radiotherapy, or targeted therapy was not permitted. Measurable disease was required, as was normal renal, liver, and bone marrow function. A PET scan was motivated but not mandated. Evaluation by a medical and a radiation oncologist prior to study enrollment was required. Participation in the correlative molecular component had to be offered but patients could opt out. Patients received two cycles of induction chemotherapy with carboplatin and nab-paclitaxel. The first 17 patients were treated, respectively, with an AUC of 6 and 100 mg/m2 on days 1, 8, and 15 every 28 days. A preliminary toxicity analysis showed high rates of grade 3 (29%) and grade 4 (18%) neutropenia, which led to several day 15 omissions, and prompted a protocol modification to carboplatin to an AUC of 5 and the nab-paclitaxel to be administered on days 1 and 8 every 21 days (same doses). Erlotinib at a dose of 150 mg daily was administered from day 1 of TRT until its completion. Radiation started on week 7, assuming no evidence of progressive disease and recovery from chemotherapy-induced toxicities. Radiation was delivered at 2Gy/day 5 days/week for 33 fractions and a total dose of 66Gy. Radiation planning was based on post-induction scans but originally involved lymph node regions were included in the treatment volume. There was no elective nodal irradiation. All patients were treated with 3-dimensional conformal radiotherapy; IMRT was not allowed. The use of systems to control or compensate for respiratory motion was permitted. Quality assurance was performed by the Quality Assurance Review Center (QARC), and the Chair of the Alliance RT committee. Response was evaluated after induction therapy (8 weeks), after concurrent therapy (16 weeks), and then every 3 months for 1 year and every 6.Participation in Clonixin the correlative molecular component had to be offered but patients could opt out. Patients received two cycles of induction chemotherapy with carboplatin and nab-paclitaxel. The median age was 68 (range, 39 to 88) and 32% were 75 years of age. Patients were evenly distributed between stage IIIA and IIIB and the majority experienced PS 2. The overall response rate was 67% and the disease control rate was 93%. Treatment was well tolerated. The median PFS and OS were 11 and 17 months, respectively. The overall 12-month Rabbit Polyclonal to MAP9 OS was 57%, which narrowly missed the pre-specified target for significance. Conclusions Patients with poor risk stage III NSCLC experienced better than expected outcomes with a regimen of induction carboplatin/nab-paclitaxel followed by TRT and erlotinib. However, as per the statistical design, the 12-month OS was not sufficiently high to warrant further studies. INTRODUCTION Patients with locally advanced non-small cell lung malignancy (NSCLC) treated with concurrent chemotherapy and thoracic radiotherapy (TRT) have a 20% to 25% probability of long-term disease-free survival (1). However, patients with adverse prognostic features, such as poor performance status (PS) and/or significant excess weight loss (WL), which represent a sizable percentage of patients, have a worse prognosis and do not seem to benefit from the standard approach (2). No specific treatment guidelines exist for this subset and management options in clinical practice range from palliative radiotherapy to sequential treatment or an attenuated concurrent approach. Building on the pre-clinical rationale that inhibitors of the epidermal growth factor receptor (EGFR) are strong radiation sensitizers (3), the Cancer and Leukemia Group B (CALGB 30106) published a trial in which a subset of 21 patients with locally advanced disease and poor PS were treated with induction chemotherapy followed by gefitinib, an EGFR tyrosine kinase inhibitor (TKI), administered concomitantly with TRT (4). The median survival was an unprecedented 19 months, which could not be accounted for by the few patients with EGFR mutated tumors. Based on this experience, we designed a phase II trial of two cycles of induction chemotherapy with carboplatin and Clonixin nab-paclitaxel followed by TRT and concurrent erlotinib for patients with stage IIIA/B NSCLC and poor risk features. Molecular evaluation for EGFR mutations was performed in available tumor specimens. The trial was conducted by the former CALGB, now Alliance for Clinical Trials in Oncology, and the former Radiation Therapy Oncology Group (RTOG), now NRG Oncology. PATIENTS AND METHODS Patients with histologically or cytologically documented NSCLC, with unresectable stage IIIA or IIIB by the AJCC version 6 staging system (T1-3 N2; T4 N0-2; and N3 patients except for contralateral hilar or supraclavicular involvement), were eligible if they had either PS 2 or PS 0-1 and 10% weight loss within 3 months prior to enrollment. A formal distinction between a PS 2 on the basis of cancer-related impairment versus pre-existing co-morbidities was not made but the ECOG scale, which was used for eligibility purposes, implies the latter. Prior chemotherapy, radiotherapy, or targeted therapy was not permitted. Measurable disease was required, as was normal renal, liver, and bone marrow function. A PET scan was encouraged but not mandated. Evaluation by a medical and a radiation oncologist prior to study enrollment was required. Participation in the correlative molecular component had to be offered but patients could opt out. Patients received two cycles of induction chemotherapy with carboplatin and nab-paclitaxel. The first 17 patients were treated, respectively, with an AUC of 6 and 100 mg/m2 on days 1, 8, and 15 every 28 days. A preliminary toxicity analysis showed high rates of grade 3 (29%) and grade 4 (18%) neutropenia, which led to several day 15 omissions, and prompted a protocol modification to carboplatin to an AUC of 5 and the nab-paclitaxel to be administered on days 1 and 8 every 21 days (same doses). Erlotinib at a dose of 150 mg daily was administered from day 1 of TRT until its completion. Radiation started on week 7, assuming no evidence of progressive disease and recovery from chemotherapy-induced toxicities. Radiation was delivered at 2Gy/day 5 days/week for 33 fractions and a total dose of 66Gy. Radiation planning was based on post-induction scans but originally involved lymph node regions were included in the treatment volume. There was no elective nodal irradiation. All patients were treated with 3-dimensional conformal radiotherapy; IMRT was not allowed. The use of systems to control or compensate for respiratory motion was permitted. Quality assurance was performed by the Quality Assurance Review Center (QARC), and the Chair of the Alliance RT committee. Response was evaluated after induction.