Effect of the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal Cancer: The NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial.

IMPORTANCE: The role of epidermal growth factor receptor (EGFR) inhibition in chemoradiation strategies in the nonoperative treatment of patients with esophageal cancer remains uncertain. OBJECTIVE: To evaluate the benefit of cetuximab added to concurrent chemoradiation therapy for patients undergoing nonoperative treatment of esophageal carcinoma. DESIGN, SETTING, AND PARTICIPANTS: A National Cancer Institute (NCI) sponsored, multicenter, phase 3, randomized clinical trial open to patients with biopsy-proven carcinoma of the esophagus. The study accrued 344 patients from 2008 to 2013. INTERVENTIONS: Patients were randomized to weekly concurrent cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation of 50.4 Gy/1.8 Gy fractions with or without weekly cetuximab (400 mg/m2 on day 1 then 250 mg/m2 weekly). MAIN OUTCOMES AND MEASURES: Overall survival (OS) was the primary endpoint, with a study designed to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided α = .025. RESULTS: Between June 30, 2008, and February 8, 2013, 344 patients were enrolled. This analysis used all data received at NRG Oncology through April 12, 2015. Sixteen patients were ineligible, resulting in 328 evaluable patients, 159 in the experimental arm and 169 in the control arm. Patients were well matched between the treatment arms for patient and tumor characteristics: 263 (80%) with T3 or T4 disease, 215 (66%) N1, and 62 (19%) with celiac nodal involvement. Incidence of grade 3, 4, or 5 treatment-related adverse events at any time was 71 (46%), 35 (23%), or 6 (4%) in the experimental arm and 83 (50%), 28 (17%), or 2 (1%) in the control arm, respectively. A clinical complete response (cCR) rate of 81 (56%) was observed in the experimental arm vs 92 (58%) in the control arm (Fisher exact test, P = .66). No differences were seen in cCR between treatment arms for either histology (adenocarcinoma or squamous cell). Median follow-up for all patients was 18.6 months. The 24- and 36-month local failure for the experimental arm was 47% (95% CI, 38%-57%) and 49% (95% CI, 40%-59%) vs 49% (95% CI, 41%-58%) and 49% (95% CI, 41%-58%) for the control arm (HR, 0.92; 95% CI, 0.66-1.28; P = .65). The 24- and 36-month OS rates for the experimental arm were 45% (95% CI, 37%-53%) and 34% (95% CI, 26%-41%) vs 44% (95% CI, 36%-51%) and 28% (95% CI, 21%-35%) for the control arm (HR, 0.90; 95% CI, 0.70-1.16; P = .47). CONCLUSIONS AND RELEVANCE: The addition of cetuximab to concurrent chemoradiation did not improve OS. These phase 3 trial results point to little benefit to current EGFR-targeted agents in an unselected patient population, and highlight the need for predictive biomarkers in the treatment of esophageal cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00655876.

A final report of a phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy (LDFWAR) in patients with advanced solid malignancies and peritoneal carcinomatosis with a dose escalation in ovarian and fallopian tube cancers.

BACKGROUND: The combination of low-dose radiation therapy with PARP inhibition enhances anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with ABT-888 in patients with peritoneal carcinomatosis with a dose escalation in ovarian and fallopian cancer patients (OV). METHODS: Patients were treated with veliparib, 40-400mg orally BID on days 1-21 of 3 28-day cycles on 6 dose levels. Dose levels 5 and 6 included only OV patients. LDFWAR consisted of 21.6Gy in 36 fractions, 0.6Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor material and quality of life were serially assessed. RESULTS: 32pts were treated. Median follow-up was 45months (10-50). The most common treatment-related grade 3 and 4 toxicities were lymphopenia (59%), anemia (9%), thrombocytopenia (12%), neutropenia (6%), leukopenia (6%), nausea (6%), diarrhea (6%), anorexia (6%), vomiting (6%) and fatigue (6%). The maximum tolerated dose was determined to be 250mg PO BID. Median PFS was 3.6months and median OS was 9.1months. In OV patients, OS was longer for platinum-sensitive patients (10.9mo) compared to platinum-resistant patients (5.8mo). QoL decreased for all groups during treatment. Germline BRCA status was known for 14/18 patients with OV cancers, 5 of whom were BRCA mutation carriers. One objective response (3%) was observed. CONCLUSION: ABT-888 plus LDFWAR is tolerable with gastrointestinal symptoms, fatigue and myelosuppression as the most common toxicities. The single observed objective response was in a germline BRCA mutated, platinum-sensitive patient.

Primary Gross Tumor Volume is an Important Prognostic Factor in Locally Advanced Esophageal Cancer Patients Treated with Trimodality Therapy.

PURPOSE: This study investigated the relationship between tumor volume and outcomes in patients receiving trimodality therapy for locally advanced esophageal cancer. METHODS: Between 2001 and 2012, 67 patients treated for esophageal cancer with chemoradiotherapy followed by esophagectomy who had available gross tumor volume (GTV) information were analyzed (35 node-negative, 32 node-positive patients with primary and nodal GTV contoured as separate regions of interest). All gross tumor volumes (GTVs) were contoured at the time of radiotherapy treatment planning. GTV optimal cutoff values were determined with receiver operating characteristic analysis and deemed significant when χ (2) analysis demonstrated differences in examined prognostic variables. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Cox proportional hazards model. RESULTS: GTVprimary (P = 0.034) and N stage were significant multivariate predictors for improved local control; GTVprimary was the only multivariate predictor of PFS (P = 0.0299) and OS (P = 0.001228) at 5 years. Univariate predictors of 5-year PFS and OS included GTVprimary, node number, and metastatic lymph node ratio. GTVprimary >85 cc was the best predictor for local failure (33.3 %; 8.7 % if ≤85 cc). GTVprimary >46 cc correlated with an increased risk of 5-year distant failure (37.1 %; 6.7 % if ≤46 cc). CONCLUSIONS: GTVprimary was a significant multivariate predictor for improved local control, PFS, and OS. GTVprimary is a more powerful predictor of patient outcomes than traditional TNM staging and should be part of the decision-making process when determining optimal local and systemic options for patients with locally advanced esophageal cancer.

A Phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy in patients with advanced solid malignancies and peritoneal carcinomatosis.

PURPOSE: The combination of low-dose radiotherapy with PARP inhibition has been shown to enhance antitumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with escalating doses of veliparib (ABT-888), a small-molecule PARP inhibitor, in patients with peritoneal carcinomatosis from advanced solid tumor malignancies. EXPERIMENTAL DESIGN: Patients were treated with veliparib (80-320 mg daily) for a total of 3 cycles. LDFWAR consisted of 21.6 Gy in 36 fractions, 0.6 Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor cells (CTC) were collected and evaluated for γ-H2AX. Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. RESULTS: Twenty-two patients were treated. Treatment-related grade 3 and 4 toxicities included lymphopenia (68%), anemia (9%), thrombocytopenia (14%), neutropenia (4%), leukopenia (9%), ascites (4%), vomiting (4%), and dyspnea (4%). No objective responses were observed. Disease stabilization (≥24 weeks) was observed in 7 patients (33%). Median progression-free survival (mPFS) was 4.47 months and median overall survival (mOS) was 13.04 months. In the subset of 8 ovarian and fallopian cancers, mPFS was 6.77 months and mOS was 17.54 months compared with mPFS 2.71 months and mOS 13.01 months in others. Patients with ovarian and fallopian cancers had better QoL over time than those with other cancers. An increased percentage of γ-H2AX-positive CTCs was observed in a subset of patients (3/6 with >2 CTCs at baseline). CONCLUSIONS: Combined veliparib and LDFWAR is a well-tolerated regimen that resulted in prolonged disease stability for some patients with advanced solid tumors and carcinomatosis, particularly in the ovarian and fallopian cancer subpopulation.

Neoadjuvant paclitaxel poliglumex, cisplatin, and radiation for esophageal cancer: a phase 2 trial.

PURPOSE: To evaluate the pathologic complete response (CR) rate and safety of paclitaxel poliglumex (PPX), cisplatin, and concurrent radiation for patients with esophageal cancer. PATIENTS AND METHODS: Patients with adenocarcinoma or squamous cell carcinoma of the esophagus or gastroesophageal junction with no evidence of distant metastasis received PPX (50 mg/m(2)/wk) and cisplatin (25 mg/m(2)/wk) for 6 weeks with 50.4 Gy concurrent radiation. Six to eight weeks after completion of chemoradiotherapy, patients underwent surgical resection. RESULTS: Forty patients were enrolled, 37 patients with adenocarcinoma and 3 patients with squamous cell cancer. The treatment-related grade 3 nonhematologic toxicities included esophagitis (7%), nausea (7%), and fatigue (5%). Three patients with clinical endoscopic CR (2 with squamous cell cancer) refused surgery. Twelve of the remaining 37 patients (32%) had a pathologic CR. The 12 patients with pathologic CR all had adenocarcinoma. CONCLUSION: PPX, cisplatin, and concurrent radiation are well tolerated, easily administered regimen for esophageal cancer with a low incidence of significant esophagitis and a high pathologic CR rate consistent with the preclinical data of PPX and radiation.

Outcomes after trimodality therapy for esophageal cancer: the impact of histology on failure patterns.

OBJECTIVES: This retrospective analysis of patients undergoing neoadjuvant chemoradiation followed by surgical resection was performed to determine if histology or pathologic response affected local-regional control (LRC), survival outcomes or patterns of failure. METHODS: We performed a review of 164 patients who underwent neoadjuvant chemoradiation followed by surgical resection from 1992 to 2006 for esophageal cancer. Information on patient characteristics, pathologic response, failure patterns, and survival was collected. Survival was estimated by the Kaplan-Meier method, and Cox multivariable Regression model was used to analyze trends. RESULTS: The median follow-up was 18 months and 27 months in surviving patients. The 3-year overall survival (OS) and LRC was 46% and 79%. The overall response for the entire cohort included a pathologic complete response (pCR) rate of 41.4%, 21.3% with microscopic residual disease (mRD) and 36.3% with gross residual disease (gRD). The 3-year OS of patients who achieved a pCR versus mRD versus gRD was 58%, 53%, and 29%. OS was significantly improved in patients with a pCR and mRD compared with gRD (P = 0.001). On multivariate analysis both pCR and mRD correlated with an improved OS. Squamous cell cancers (SCC) had a higher rate of pCR than adenocarcinomas (AC), 54% versus 34.8% (P = 0.01). The 3 year LRC for patients with SCC and AC was 100% and 71% (P = 0.03). Among SCC with recurrence, there were no local failures and all failed distantly (P = 0.001). CONCLUSIONS: Patients with microscopic residual disease following trimodality therapy had similar outcomes to patients achieving a pCR. Patients with SCC were more likely to achieve a pCR, and had a higher propensity to fail distantly when compared with patients with AC. This data should be considered in the design of future clinical trials.