Cindy Farley

Tracheoesophageal Fistula Formation in Patients With Lung Cancer Treated With Chemoradiation and Bevacizumab

PURPOSE Tracheoesophageal fistulae are rare complications of thoracic cancers and their treatments. Novel antiangiogenic agents in cancer treatment such as bevacizumab potentially impact wound healing and may contribute to tracheoesophageal fistula development. PATIENTS AND METHODS We conducted two independent phase II clinical trials in small-cell lung cancer and non-small-cell lung cancer using bevacizumab in combination with chemotherapy and radiation. Both trials were intended to assess preliminary efficacy and safety outcomes. Results For the limited-stage small-cell lung cancer trial, 29 patients were enrolled beginning April 2006, and closed early due to toxicity in March 2007 (14-month median follow-up). The locally advanced, non-small-cell lung cancer trial opened with enrollment limited to five patients in February 2007, and closed early due to safety in December 2007. In each trial, we observed tracheoesophageal fistulae development and related morbidity and mortality, prompting early trial closures, US Food and Drug Administration warnings, and a change in bevacizumab labeling. CONCLUSION The current data from the final reports from these two trials suggest bevacizumab and chemoradiotherapy are associated with a relatively high incidence of tracheoesophageal fistulae formation in both small-cell lung cancer and non-small-cell lung cancer settings. Strategies to safely incorporate novel antiangiogenic agents into combined-modality therapy in lung cancer are needed.

Phase II trial of bevacizumab and erlotinib in carcinomas of unknown primary site: the Minnie Pearl Cancer Research Network.

PURPOSE Treatment remains poor for many patients with carcinoma of unknown primary site (CUP), and no effective second-line treatment has been identified. Combination inhibition of vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) with bevacizumab and erlotinib has proved efficacious and well tolerated in other solid tumors. We therefore have evaluated the efficacy and toxicity of this combination in patients with CUP. PATIENTS AND METHODS Patients with CUP who either had received previous chemotherapy or were previously untreated with poor-prognosis clinical features were eligible for this study. All patients received bevacizumab 10 mg/kg IV every 2 weeks, along with erlotinib 150 mg orally daily. Patients were re-evaluated after 8 weeks of treatment; those with objective response or stable disease continued treatment until disease progression. RESULTS Forty-seven (92%) of 51 patients received at least 8 weeks of treatment. Five patients (10%) had partial responses, and 29 patients (61%) had stable disease as the best response. The median survival for the entire group was 7.4 months, with 33% of patients alive at 1 year. This regimen was well tolerated by most patients. CONCLUSION The combination of bevacizumab and erlotinib has substantial activity in the treatment of patients with CUP. The median survival is superior to survival previously reported with second-line chemotherapy, and is similar to the results of many first-line chemotherapy trials in this setting. This regimen merits further evaluation in patients with CUP.

Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network.

The aim of this study was to compare the efficacy of single‐agent weekly docetaxel with the combination of docetaxel and gemcitabine in elderly and/or poor performance status patients with advanced nonsmall cell lung cancer (NSCLC).

Phase II Trial of Irinotecan, Carboplatin, and Bevacizumab in the Treatment of Patients with Extensive-Stage Small-Cell Lung Cancer

Introduction: Bevacizumabs role in the treatment of small cell lung cancer (SCLC) is unknown. A multicenter phase II trial with bevacizumab plus chemotherapy was conducted in patients with untreated extensive-stage SCLC. Methods: Eligibility: no prior SCLC chemotherapy, no active brain metastases, no hemoptysis, and Eastern Cooperative Oncology Group performance status 0–1. Treatment consisted of irinotecan (60 mg/m2) administered intravenously (IV) on days 1, 8, 15; carboplatin area under the concentration-time curve = 4, IV, on day 1; bevacizumab (10 mg/kg, IV) on days 1 and 15 every 28 days for up to six cycles. Restaging was performed every two cycles (8 weeks). Patients with no progression received maintenance bevacizumab. Primary end point is 40% improvement in historical median time to progression (TTP) of 6 months. Results: Fifty-one patients were enrolled from February 2006 to March 2007 (22-month median follow-up). Baseline features: median age 66 years (range 46–81 years); male 57%; and Eastern Cooperative Oncology Group performance status 0–1 33/67%. Objective response rate 84% (95% CI 71–93%): 1 complete and 42 partial responses. Two patients (4%) had stable disease, and two patients had progressive disease. Four patients were unassessable because of treatment-related toxicity. Median TTP was 9.13 months (95% CI 7.36–9.46 months). Median overall survival was 12.1 months (95% CI 9.6–13.5 months); 1- and 2-year overall survivals were 51 and 14%, respectively. Grade 3/4 toxicity (≥10%): neutropenia (39%), thrombocytopenia (22%), dehydration (10%), diarrhea (31%), fatigue (20%), and pulmonary symptoms (10%). No significant bleeding occurred. Conclusions: In this phase II trial, irinotecan, carboplatin, and bevacizumab achieved response, TTP, and survival outcomes that compare favorably with larger randomized trials using chemotherapy alone. Randomized trials can best assess bevacizumabs impact in the first-line treatment of extensive-stage SCLC.

Treatment of Advanced Renal Cell Carcinoma with the Combination Bevacizumab/Erlotinib/Imatinib: A Phase I/II Trial

PURPOSE The aim of this study was to evaluate the efficacy and toxicity of imatinib, a platelet-derived growth factor-beta receptor antagonist, when added to the combination bevacizumab/erlotinib in the treatment of patients with advanced clear cell renal carcinoma. PATIENTS AND METHODS Ninety-four patients with metastatic clear cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks, erlotinib 150 mg orally daily, and imatinib 400 mg orally daily. Patients were reevaluated after 8 weeks of treatment; patients with objective response or stable disease (SD) continued to receive treatment until they experienced tumor progression. RESULTS Fifteen of 88 evaluable patients (17%; 95% confidence interval, 10%-26%) had partial responses, whereas an additional 54 patients (61%) had SD. The median progression-free and overall survival for all patients was 8.9 months and 17.2 months, respectively. The addition of imatinib markedly increased toxicity compared with the bevacizumab/erlotinib regimen; the most common grade 3/4 toxicities were diarrhea, rash, and fatigue. CONCLUSION Bevacizumab/erlotinib/imatinib was unacceptably toxic in this group of patients. Inhibition of the PDGF receptor (PDGFR) with imatinib did not appear to improve efficacy compared retrospectively with the results of treatment with bevacizumab/erlotinib. The importance of PDGFR inhibition in the treatment of advanced clear cell renal carcinoma remains unclear. Further development of this particular combination is not planned or recommended.

Phase I/II Trial of Preoperative Oxaliplatin, Docetaxel, and Capecitabine With Concurrent Radiation Therapy in Localized Carcinoma of the Esophagus or Gastroesophageal Junction

PURPOSE Preoperative chemoradiotherapy is a primary treatment option for patients with resectable esophageal cancer. Combination regimens using newer agents may improve patient outcomes. This multicenter community-based phase I/II trial examined a modern triplet regimen comprised of oxaliplatin, docetaxel, and capecitabine (ODC) combined with radiation therapy (RT). PATIENTS AND METHODS The primary end point was the pathologic complete response (pCR) rate. Eligibility criteria included resectable stage I to III cancer of the mid-/distal-esophagus or gastroesophageal junction, measurable disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Treatment included oxaliplatin 40 mg/m(2), docetaxel 20 mg/m(2) (intravenous, weekly x 5); capecitabine 1,000 mg/m(2) orally twice daily on days 1 to 7, 15 to 21, and 29 to 35; and concurrent RT (45 Gy). Resection was performed during weeks 9 to 12. ODC and RT safety was determined in a phase I portion (n = 10) preceding phase II. RESULTS Fifty-nine patients were enrolled (September 2005 to February 2008; phase I/cohort 1, 10 patients; phase I/cohort 2/phase II, 49 patients). Baseline characteristics included median age of 63 years; 84% male; ECOG PS 0 and 1, 51% and 49%, respectively; adenocarcinoma and squamous cell, 69% and 18%, respectively; stage I, II, and III, 12%, 41%, and 45%, respectively. Phase I revealed no dose-limiting toxicity. Responses: pCR rate, 49%; objective response rate, 61% (24 complete and six partial responses); stable disease, 6%; and progressive disease, 2%. Sixty-nine percent of patients underwent surgery. Survival: median follow-up, 116 weeks; median disease-free survival (DFS) and overall survival (OS) were 16.3 and 24.1 months, respectively. Two-year DFS and OS were 45.1% and 52.2%, respectively. Most common (>or= 5%) grade 3 to 4 nonhematologic toxicities were anorexia (20%), dehydration (16%), diarrhea (8%), dysphagia (10%), esophagitis (20%), fatigue (12%), hyperglycemia (6%), nausea (16%), pulmonary symptoms (14%), sepsis (6%), and vomiting (16%). All other grade 3 to 4 hematologic and nonhematologic toxicities were uncommon (< 5%). CONCLUSION Preoperative ODC plus RT is active and relatively safe in patients with locoregional esophageal cancer. Importantly, this therapy can be administered within 8 weeks. This regimen warrants additional study in this setting and in combination with newer biologic agents.

Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial.

Purpose:To compare the results of empiric first-line therapy with paclitaxel/carboplatin/etoposide (PCE) versus gemcitabine/irinotecan, both followed by single-agent gefitinib, in patients with carcinoma of unknown primary site. Patients and Methods:Patients with previously untreated carcinoma of unknown primary site were randomized to receive either PCE or gemcitabine/irinotecan. Responding and stable patients continued treatment for 4 to 6 cycles. Patients with no evidence of tumor progression at that time received single-agent gefitinib until tumor progression. The trial was designed to detect an improvement in the 2-year survival rate from 20% to 30%. Results:Between September 2003 and July 2008, 198 patients entered this multicenter, community-based trial. Because of slow accrual, the trial was stopped short of its target accrual of 320 patients. Clinical characteristics were comparable for patients receiving PCE (N = 93) and gemcitabine/irinotecan (N = 105). PCE and gemcitabine/irinotecan produced similar 2-year survival (15% vs. 18%), median survival (7.4 months vs. 8.5 months), median progression-free survival (3.3 months vs. 5.3 months), and response rate (18% vs. 18%). Grade 3/4 neutropenia, thrombocytopenia, anemia, febrile neutropenia, and red blood cells transfusions were more common with PCE; diarrhea was more common with gemcitabine/irinotecan. The median duration of gefitinib maintenance was 3 months, suggesting no role as a maintenance therapy in this setting. Discussion:The PCE and gemcitabine/irinotecan regimens have comparable efficacy in the first-line treatment of patients with carcinoma of unknown primary site. Gemcitabine/irinotecan is the preferable regimen, due to its favorable toxicity profile. However, the moderate efficacy of both regimens underscores the need for novel treatment approaches in this patient population.

Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network.

The purpose of the current study was to evaluate the efficacy and toxicity of weekly bortezomib in the treatment of patients with recurrent/refractory multiple myeloma.

Phase II Trial of Weekly Docetaxel, Vinorelbine, and Trastuzumab in the First-Line Treatment of Patients with HER2-Positive Metastatic Breast Cancer

BACKGROUND The combinations of trastuzumab/docetaxel and trastuzumab/vinorelbine are highly active in the treatment of patients with HER2-positive metastatic breast cancer (MBC). We investigated the feasibility and safety of a 3-drug combination of trastuzumab, docetaxel, and vinorelbine as first-line therapy in this patient group. PATIENTS AND METHODS Sixty patients with previously untreated, measurable HER2-positive MBC (immunohistochemistry 3+ and/or fluorescence in situ hybridization positive) were treated with docetaxel 30 mg/m2 intravenously (I.V.) and vinorelbine 25 mg/m2 I.V. on days 1 and 8 of each 3-week cycle. Trastuzumab was given weekly (4-mg/kg loading dose followed by 2 mg/kg/week). Patients were evaluated after 6 weeks; responders/stable patients continued treatment until progression. RESULTS Patients received a median of 11 treatment cycles (range, 1-22 cycles). Forty-one of 60 patients (68%) had major responses (16 complete responses [27%], 25 partial responses [42%]). An additional 13 patients (22%) had stable disease for > or = 6 months. After a median follow-up of 58 months, median progression-free survival was 12 months (95% CI, 9.1-16.3 months), and the median overall survival was 40.8 months (95% CI, 25-not reached). Neutropenia (72% grade 4) was the most common hematologic toxicity; 8 patients were hospitalized for febrile neutropenia. A total of 67% of patients required dose modifications for neutropenia during cycles 1 or 2. Other grade 3/4 toxicities included fatigue (12%), hyperglycemia (7%), and myalgias (7%). There were no treatment-related deaths. CONCLUSION The combination of trastuzumab, docetaxel, and vinorelbine is highly active as first-line treatment for patients with HER2-positive MBC. However, this regimen offers no obvious advantages over other less myelosuppressive trastuzumab-containing regimens, and its routine use is not supported by the study.

Oxaliplatin and Capecitabine in the Treatment of Patients With Recurrent or Refractory Carcinoma of Unknown Primary Site: A Phase 2 Trial of the Sarah Cannon Oncology Research Consortium

Despite the widespread use of oxaliplatin‐based regimens for colorectal and other gastrointestinal cancers, there is surprisingly little information regarding their empiric use for the treatment of carcinoma of unknown primary site (CUP). In the current study, the combination of oxaliplatin and capecitabine in patients with recurrent and refractory CUP was examined.