Joanna M. Brell

Gemcitabine Alone Versus Gemcitabine Plus Radiotherapy in Patients With Locally Advanced Pancreatic Cancer: An Eastern Cooperative Oncology Group Trial

PURPOSE The purpose of this trial was to evaluate the role of radiation therapy with concurrent gemcitabine (GEM) compared with GEM alone in patients with localized unresectable pancreatic cancer. PATIENTS AND METHODS Patients with localized unresectable adenocarcinoma of the pancreas were randomly assigned to receive GEM alone (at 1,000 mg/m(2)/wk for weeks 1 to 6, followed by 1 week rest, then for 3 of 4 weeks) or GEM (600 mg/m(2)/wk for weeks 1 to 5, then 4 weeks later 1,000 mg/m(2) for 3 of 4 weeks) plus radiotherapy (starting on day 1, 1.8 Gy/Fx for total of 50.4 Gy). Measurement of quality of life using the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire was also performed. RESULTS Of 74 patients entered on trial and randomly assigned to receive GEM alone (arm A; n = 37) or GEM plus radiation (arm B; n = 34), patients in arm B had greater incidence of grades 4 and 5 toxicities (41% v 9%), but grades 3 and 4 toxicities combined were similar (77% in A v 79% in B). No statistical differences were seen in quality of life measurements at 6, 15 to 16, and 36 weeks. The primary end point was survival, which was 9.2 months (95% CI, 7.9 to 11.4 months) and 11.1 months (95% CI, 7.6 to 15.5 months) for arms A and B, respectively (one-sided P = .017 by stratified log-rank test). CONCLUSION This trial demonstrates improved overall survival with the addition of radiation therapy to GEM in patients with localized unresectable pancreatic cancer, with acceptable toxicity.

Phase II Study of Docetaxel and Gefitinib as Second-Line Therapy in Gemcitabine Pretreated Patients with Advanced Pancreatic Cancer

Background: There is no standard second-line therapy for advanced pancreatic cancer (APC). We evaluated the epidermal growth factor receptor (EGFR) inhibitor gefitinib and docetaxel in a phase II study following gemcitabine failure. Methods: EGFR overexpression was not required. The initial docetaxel dose was 75 mg/m2 on day 1 every 21 days. Due to febrile neutropenia in 8 of the first 18 patients, the dose was reduced to 60 mg/m2. Gefitinib, 250 mg/day orally, was given continuously. Results: Forty-one patients received treatment and were evaluable. Febrile neutropenia was seen in 11 patients (27%), with most events occurring at the docetaxel dose of 75 mg/m2 (8 of 18 patients). Common treatment-related grade 3/4 toxicities were: fatigue (7%), nausea (7%), diarrhea (5%) and vomiting (2%). There was 1 partial response and stable disease in 19 patients. Time to progression was 1.8 months and median survival was 4.5 months (95% CI 2.9–5.7). Conclusion: The tolerability and feasibility of second-line therapy for APC was demonstrated. The combination of gefitinib and docetaxel showed evidence of limited efficacy.

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

SummaryPurpose: Pre-clinical models have demonstrated the benefit of metronomic schedules of cytotoxic chemotherapy combined with anti-angiogenic compounds. This trial was undertaken to determine the toxicity of a low dose regimen using docetaxel and thalidomide. Patients and Methods: Patients with advanced solid tumors were enrolled. Thalidomide 100mg twice daily was given with escalating doses of docetaxel from 10 to 30mg/m2/week. One cycle consisted of 12 consecutive weeks of therapy. The maximal tolerated dose (MTD) was defined as the dose of thalidomide along with docetaxel that caused ≤grade 1 non-hematologic or ≤grade 2 hematologic toxicity for cycle one. Results: Twenty-six patients were enrolled. Dose-limiting toxicities (DLTs) were bradycardia, fatigue, fever, hyperbilirubinemia, leukopenia, myocardial infarction, and neutropenia. Prolonged freedom from disease progression was observed in 44.4% of the evaluable patients. Conclusions: This anti-angiogenic regimen was well tolerated and demonstrated clinical benefit. The recommended phase II dosing schedule is thalidomide 100mg twice daily with docetaxel 25mg/m2/week.

Fluoropyrimidine cardiotoxicity: time for a contemporaneous appraisal

Introduction: Fluoropyrimidines (FPDs) are a fundamental component of many chemotherapy regimens. Cardiotoxic adverse events (AEs) such as angina, ischemia, arrhythmias, and cardiomyopathy associated with 5‐fluorouracil (5‐FU) and capecitabine (CAPE) have been sparingly described in studies, primarily through case reports. Data from the 1990s revealed an estimated incidence of 0.5% to 19%, with cardiovascular fatalities occurring in ≤28%. The current use of FPDs includes multiple dosing regimens, oral or intravenous delivery, and administration with additional cardiotoxic therapies. As such, it is imperative to better define the cardiotoxicity risk in the modern treatment era. We comprehensively evaluated the incidence, prevalence, and ascertainment of cardiovascular risk factors and disease within ECOG‐ACRIN (Eastern Cooperative Group Cancer Research Group – American College of Radiology Imaging Network) Cancer Research Group clinical trials incorporating 5‐FU and CAPE. Materials and Methods: Case report forms and clinical study reports from the ECOG‐ACRIN Cancer Research Group database of phase II and III clinical trials incorporating 5‐FU and CAPE were evaluated. A total of 16 trials from 2002 to 2017 were identified that had used bolus 5‐FU (n = 1), continuous infusion 5‐FU (n = 10) or CAPE (n = 5). Results: A history of cardiovascular disease was variably defined and was an exclusion criterion in 13 of the 16 studies (81%). The baseline risk factors and history of cardiac disease were specifically collected in only 3 studies (19%). All studies collected cardiovascular AEs using the Common Terminology Criteria for Adverse Events version available at the time of the study. Fewer than half (7 of 16; 44%) of the study case report forms had also specifically requested information on cardiac ischemia/infarction. In the 12 completed studies with clinical study reports, the following AEs were reported: dyspnea, ≤16%; arrhythmias, ≤6%; and angina, ischemia, and elevated troponin, ≤5%. Some trials only recorded cardiac AEs that were possibly associated with the novel drug being studied and not those attributed to the standard of care in the 5‐FU/CAPE arm, further decreasing the numerical incidence. Conclusion: Inconsistent clinical trial reporting of cardiac AEs precluded accurate and precise delineation of the epidemiology of FPD‐related cardiovascular AEs. Prospective knowledge of the definition and natural history will lead to the development of risk factor stratification and prechemotherapy interventions to reduce or prevent cardiotoxicity. We propose that the prospective collection of baseline cardiac data and prespecified cardiac endpoints are necessary to fully understand the incidence and cardiac risk of FDPs. Micro‐Abstract The fluoropyrimidines, 5‐fluorouracil and capecitabine can cause cardiotoxicity. In a review of 16 Eastern Cooperative Group Cancer Research Group–American College of Radiology Imaging Network fluoropyrimidine‐based treatment studies, exclusion of premorbid cardiovascular disease was common. Less than half of the studies (43%) specifically evaluated cardiac ischemic events. Standardized collection of cardiovascular risk factor and outcome data in oncologic trials is needed.

Phase I pharmacokinetic trial of docetaxel and thalidomide: A regimen based on anti-angiogenic therapeutic principles

3135 Background: Preclinical models suggest that chronic, low-dose administration of anticancer therapy (cytotoxic agent and an angiogenesis inhibitor) may result in prolonged periods of freedom from progression (FFP) and tumor regression. This outcome may derive from continuous drug exposure and more pronounced anti-angiogenic rather than cytotoxic effects. METHODS Patients (pts) with advanced cancer for whom there is no curative or meaningful palliative therapy are eligible and enrolled in cohorts of 3. Pts are treated with a weekly dose of docetaxel (IV) with thalidomide (PO) given every 12 hours for 84 days (12 weeks) of continuous therapy. Since we sought to pilot a metronomic schedule over 12 weeks dose-limiting toxicity (DLT) was defined as ≥ grade 2 non-hematologic or ≥ grade 3 hematologic. Plasma concentrations of both drugs were determined by HPLC / MS-MS and pts were observed for response. RESULTS Sixteen pts have been enrolled; 5 are not evaluable [docetaxel hypersensitivity not considered DLT (3 pts) and 2 pts withdrew before 12 weeks]. All pts received thalidomide 100 mg bid. Docetaxel was escalated from 10, 20, 25, and 30 mg/m2 in 3, 3, 3, and 2 pts respectively. A total of 17 cycles have been completed. A single DLT (grade 3 fatigue) occurred at 30 mg/m2. There has been no myelosuppression. There has been 1 PR (SCLC), and 4 pts with FFP of >115 (prostate), 182 (papillary thyroid), >230 (prostate), and 321 days (melanoma). Measured trough plasma thalidomide concentrations of 466 ng/ml (range 344-682) have been achieved. Docetaxel plasma concentrations are consistent with previous reports of weekly schedules. CONCLUSIONS The 12-week metronomic schedule of this regimen is feasible with a very acceptable safety profile. Clinical activity and prolonged FFP have been observed in a highly refractory population early in this study. (This trial is supported in part by the NIH grant MO1 RR00080, Aventis Oncology and Celgene.) No significant financial relationships to disclose.