Priya Kumar

Phase III Randomized Trial of Induction Chemotherapy in Patients With N2 or N3 Locally Advanced Head and Neck Cancer

PURPOSE Induction chemotherapy (IC) before radiotherapy lowers distant failure (DF) rates in locally advanced squamous cell carcinoma of the head and neck (SCCHN). The goal of this phase III trial was to determine whether IC before chemoradiotherapy (CRT) further improves survival compared with CRT alone in patients with N2 or N3 disease. PATIENTS AND METHODS Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were randomly assigned to CRT alone (CRT arm; docetaxel, fluorouracil, and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week) versus two 21-day cycles of IC (docetaxel 75 mg/m(2) on day 1, cisplatin 75 mg/m(2) on day 1, and fluorouracil 750 mg/m(2) on days 1 to 5) followed by the same CRT regimen (IC + CRT arm). The primary end point was overall survival (OS). Secondary end points included DF-free survival, failure pattern, and recurrence-free survival (RFS). RESULTS A total of 285 patients were randomly assigned. The most common grade 3 to 4 toxicities during IC were febrile neutropenia (11%) and mucositis (9%); during CRT (both arms combined), they were mucositis (49%), dermatitis (21%), and leukopenia (18%). Serious adverse events were more common in the IC arm (47% v 28%; P = .002). With a minimum follow-up of 30 months, there were no statistically significant differences in OS (hazard ratio, 0.91; 95% CI, 0.59 to 1.41), RFS, or DF-free survival. CONCLUSION IC did not translate into improved OS compared with CRT alone. However, the study was underpowered because it did not meet the planned accrual target, and OS was higher than predicted in both arms. IC cannot be recommended routinely in patients with N2 or N3 locally advanced SCCHN.

Allogeneic Hematopoietic Stem Cell Transplantation in Adult Acute Lymphocytic Leukemia: Impact of Donor Source on Survival

We studied the relative impact of donor source on outcomes following myeloablative hematopoietic stem cell transplantation (HSCT) for adult patients with acute lymphocytic leukemia (ALL). In this single center study, 138 patients aged 18-61 (median 31) years underwent myeloablative conditioning followed by allogeneic HSCT. Stem cell source was an HLA matched related donor (MRD) in 90, HLA matched unrelated donor (URD:M) in 15, HLA mismatched unrelated donor (URD:MM) in 14, and HLA 0-2 (A, B, DRB1) mismatched umbilical cord blood (UCB) in 19 patients. At the time of HSCT, 70 patients were in first clinical remission (CR1), 57 in CR2, and 11 in > or =CR3. Twenty-one patients had T-lineage disease; 43 patients (31%) had high-risk cytogenetics of either t(9;22) (n = 33), t(4;11) or t(1,19) abnormalities, with the remainder (69%) having normal cytogenetics. White blood cell count (WBC) > or =30 x 10(9)/L at diagnosis was documented in 33%. Demographics and disease characteristics were similar in all 4 groups except all UCB recipients were treated since 1996 and received growth factors. Overall survival (OS) at 3 years for the UCB group was 66% (95% confidence interval [CI] 44%-89%) compared to 27% (95% CI 17%-36%) in the MRD group, and only 13% (95% CI 0%-31%) and 14% (95% CI 0%-33%) in the URD:M and URD:MM groups, respectively. Similarly leukemia free survival (LFS) at 3 years was better in the UCB group at 61% (95% CI 38%-84%) than 27% (95% CI 18%-36%) in the MRD and only 13% (95% CI 0%-31%) in the URD:M group and 14% (95%CI 0%-33%) in URD:MM group. Relapse rates at 3 years were 5% (95% CI 0%-15%) in the UCB group compared to 26% (95% CI 16%-35%) in the MRD, 20% (95% CI 1%-39%) in the URD:M groups, and 0% in the URD:MM groups. Transplant-related mortality (TRM) at 3 years was the lowest in the UCB group at 34% and higher in the other donor groups: MRD 47%, URD:M 67%, and URD:MM 86%. In multiple regression analysis, 5 independent risk factors were significantly associated with poorer OS and LFS: use of URD:MM (relative risk [RR] 2.5, 95% CI, 1.2-5.1, P = .01), > or =CR3 at HSCT (RR 3.5, 95% CI, 1.2-9.6, P = .02), WBC > or =30 x 10(9)/l (RR 1.9, 95% CI, 1.2-3.0, P = .01) at diagnosis, recipient and donor (R/D) cytomegalovirus (CMV) seropositive (RR 3.8, 95% CI, 2.0-7.4, P < .01), and > or =2 induction regimens to achieve initial CR (RR 3.5, 95% CI, 1.2-9.6, P = .02). Graft-versus-host disease (GVHD) was associated with improved LFS (RR 0.4, 95% CI, 0.2-0.6, P < .01). When compared with URD:M, OS with UCB was better (RR 0.3, 95% CI, 0.1-0.7, P = .01), supporting the use of UCB as an alternative stem cell source for adults with ALL.

Phase I study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor

Bortezomib inhibits nuclear factor-κB (NF-κB). Cetuximab is a chimeric mouse–human antibody targeted against epidermal growth factor receptor (EGFR). We hypothesised that concomitant blockade of NF-κB and EGFR signalling would overcome EGFR-mediated resistance to single-agent bortezomib and induce apoptosis through two molecular pathways. The aim of this phase I trial was to establish the maximum tolerated dose (MTD) for bortezomib plus cetuximab in patients with EGFR-expressing epithelial tumours. The 21-day treatment cycle consisted of bortezomib administered on days 1 and 8 through dose escalation (1.3–2 mg m−2). Cetuximab was delivered at a dose of 250 mg m−2 on days 1, 8 and 15 (400 mg m−2 day 1 cycle 1). A total of 37 patients were enroled and given a total 91 cycles. No grade ⩾3 haematological toxicity was noted. Non-hematological grade ⩾3 toxicities included fatigue (22% of patients), dyspnoea (16%) and infection (11%). The MTD was not reached at the highest tested bortezomib dose (2.0 mg m−2). Efficacy outcomes included disease progression in 21 patients (56.7%) and stable disease (SD) at 6 weeks in 16 patients (43.3%). Five of the six patients with SD at 12 weeks were diagnosed with cancers of the lungs or head and neck. This combination therapy was moderately effective in extensively pretreated patients with non-small cell lung or head and neck cancers and warrants further investigation.

Safety and effectiveness of bevacizumab-containing treatment for non-small-cell lung cancer: final results of the ARIES observational cohort study.

Introduction: Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor, was approved by the US Food and Drug Administration for the treatment of advanced non–small-cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel. ARIES (Avastin Regimens: Investigation of Effectiveness and Safety), a prospective observational cohort study, evaluated outcomes in a large, community-based population of patients with first-line NSCLC. Methods: From 2006 to 2009, ARIES enrolled patients with locally advanced or metastatic NSCLC who were eligible for bevacizumab, excluding those with predominantly squamous histology. Patients were required to provide informed consent and to have initiated bevacizumab with chemotherapy within 4 months before enrollment. There were no protocol-defined treatments or assessments. The dosing of bevacizumab and chemotherapy, and the choice of chemotherapy regimen, was at the discretion of the treating physician. Results: ARIES enrolled 1967 patients with first-line NSCLC. At study closure, median follow-up was 12.5 months (range, 0.2–65.5). Median age was 65 years (range, 31–93), and 252 patients (12.8%) identified as never smokers. Median progression-free survival was 6.6 months (95% confidence interval, 6.3–6.9), and median overall survival was 13.0 months (95% confidence interval, 12.2–13.8) with first-line bevacizumab plus chemotherapy. Incidences of bevacizumab-associated adverse events (19.7% overall) were consistent with those in randomized controlled trials of bevacizumab in NSCLC. Conclusion: Results from ARIES demonstrate similar outcomes to randomized controlled trials of bevacizumab when added to standard chemotherapy in a real-world patient population with advanced NSCLC.

Phase II study of biweekly carboplatin, gemcitabine, and bevacizumab as first-line treatment in patients with stage IIIB/IV NSCLC.

Background:This study was initiated to assess the safety and efficacy of biweekly carboplatin and gemcitabine with bevacizumab in treatment-naive patients with advanced and metastatic non–small cell lung cancer (NSCLC). Patients and Methods:An open-label, nonrandomized phase II clinical trial was conducted. Treatment consisted of a biweekly cycle of gemcitabine, carboplatin, and bevacizumab for a maximum of 6 cycles. If no disease progression or intolerable side effects were observed, maintenance therapy with bevacizumab was continued until disease progressed. Progression-free survival, overall survival (OS), objective response rate, and the safety and tolerability of the therapy were assessed. Results:Treatment was administered to 35 patients with stage IIIB/IV NSCLC. Median age of the patients was 64.5 years, with 58% being male. Median number of cycles of treatment was 6 (range, 4 to 28 cycles); median number of days of treatment was 117 days (range, 43 to 451 d). Sixty-six percent of patients experienced grade ≥3 toxicities. Hypertension (19%) was the most common adverse event. Pulmonary hemorrhage (3%) and pulmonary abscess (3%) were the causes of treatment-related deaths. There were 48% patients with partial response, 23% with stable disease, and 29% with progressive disease. Median progression-free survival was 2.6 months [95% confidence interval (CI), 1.6-3.4], and median OS was 13.4 months (95% CI, 8.4-24). The 2-year OS rate was 30% (95% CI, 12%-51%). Conclusions:Biweekly therapy with combination of carboplatin, gemcitabine, and bevacizumab in advanced inoperable NSCLC provided limited benefit and was associated with excessive toxicity. Further testing of this regimen is not recommended. ClinicalTrials.gov Identifier:NCT00400803

Dose escalating study of biweekly gemcitabine and carboplatin in patients with advanced cancer.

Combination chemotherapy with gemcitabine and carboplatin administered on a 3-week cycle is used commonly in the treatment of cancer. The purpose of our study was to establish a safe dose of combined gemcitabine and carboplatin when administered on a biweekly schedule to patients with advanced solid tumors. Gemcitabine was given intravenously over 30 minutes followed by carboplatin also given intravenously over 30 minutes once every 2 weeks (one cycle). Five dose levels were examined, ranging from gemcitabine at 1250 mg/m2 to 2000 mg/m2 and carboplatin at an area under the curve of 2.5 to 3.0. Twenty-six patients were studied (18 male and 8 female) with a median age of 57 years (range, 41–83 years); ECOG performance status was 0 or 1 in 22 patients (85%); median number of prior chemotherapy regimens was 2 (range, 0–4); median number of cycles administered per patient was 3 (range, 1–9) with a total of 89 cycles. Two dose-limiting toxicities were observed. Delay in treatment was seen in a total of 8 cycles with 6 of the delays due to myelosuppression. Grade 3 or 4 hematologic toxicity rates were as follows: anemia in one cycle (1%), neutropenia in 13 cycles (15%), and thrombocytopenia in one cycle of chemotherapy (1%). There were no hospitalizations for neutropenic fever. Mild fatigue was the most common nonhematologic toxicity. The median time to progression was 40 days (mean, 49 days; range, 4–133 days). Of the 21 evaluable patients, partial response or stable disease was observed in 11 (42%). The maximum tested dose of gemcitabine at 2000 mg/m2 and carboplatin at area under the curve of 3.0 was well tolerated on a biweekly schedule. Our findings indicate that further investigation of this biweekly regimen is warranted in patients with advanced cancer.

Preliminary Treatment Patterns and Safety Outcomes for Non—Small-Cell Lung Cancer from ARIES, a Bevacizumab Treatment Observational Cohort Study

Abstract Background Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, provides benefit in advanced non—smallcell lung cancer (NSCLC), prolonging progression-free and overall survival. Observational cohort studies such as ARIES (“Avastin® Regimens: Investigation of Treatment Effects and Safety”) provide valuable safety and effectiveness data for a broader patient population than controlled trials, such as Eastern Cooperative Oncology Group (ECOG) 4599, which have strict eligibility criteria required for study participation. The ARIES study objective is to further delineate clinical outcomes associated with bevacizumab use in a real-world setting in patients with advanced NSCLC. Patients and Methods Patients with locally advanced/metastatic nonsquamous NSCLC, whose first therapy includes bevacizumab, may enroll. There are no protocol-specified treatments or assessments. Data are collected at baseline, then quarterly, including targeted safety events, until death, consent withdrawal, loss to follow-up, or study closure. ARIES is conducted at 276 US sites. Planned NSCLC accrual is 2000 patients. Results As of February 14, 2008, 996 evaluable patients with NSCLC have been enrolled. Median follow-up is 6.1 months; 84% of patients have ≥ 1 quarterly update. Key demographics are shown in Table 1. Targeted serious adverse events (SAEs) to date include venous thromboembolic events and other events, 2%; grade 3/4 bleeding and arterial thromboembolic events, 1% each; gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome, pulmonary hemorrhage, hypertension, and wound complications, Conclusion Low rates of targeted SAEs were preliminarily observed despite the inclusion of patients underrepresented in E4599, including those with ECOG performance status ≥ 2, brain metastasis, therapeutic anticoagulation at baseline, and older age. Updated safety data, treatment patterns (with bevacizumab dose and duration), and demographics will be provided at the meeting, based on > 1300 patients.