Joseph Gibbons

The impact of resection margin status and postoperative CA19-9 levels on survival and patterns of recurrence after postoperative high-dose radiotherapy with 5-FU-based concurrent chemotherapy for resectable pancreatic cancer.

Objectives:To analyze the impact of surgical margins and other clinicopathological data on treatment outcomes on 75 patients treated from 1999 to 2006 by initial potentially curative surgery (±intraoperative radiotherapy), followed by high-dose 3-dimensional conformal radiation therapy and concomitant fluoropyrimidine-based chemoradiotherapy. Materials and Methods:All clinical and pathologic data on this patient cohort were analyzed by actuarial Kaplan-Meier survival methodology and by univariate and multivariate Cox proportional hazards methods to measure effects on survival and patterns of failure. Results:With a median follow-up of 28 months, the median, 2-year and 5-year overall survival (OS) rates were 18.1 month, 41% and 23.6%, respectively. Disease-free survival (DFS) rates were of 11.4 months, 35% and 20%, respectively. Only 2 clinicopathological features, positive (≤1 mm) surgical margins (P < 0.05) and a 2-fold (>70 U/mL) elevation of the postoperative serum CA19-9 (P < 0.001) impacted OS and disease-free survival. In patients with negative (>1 mm) surgical margins and a low (≤70 U/mL) postoperative CA19-9, the projected 2- and 5-year OS were 80% and 65%, respectively, compared with 40% and 10% with positive surgical margins and a low CA19-9 and to 10% and 0% with positive or negative surgical margins and a high (>70 U/mL) CA19-9. Positive surgical margins (P < 0.001) and an elevated postoperative CA19-9 (P < 0.001) also predicted early development of distant metastases, whereas isolated loco-regional failure was less common and not affected by these or other clinicopathological features. Conclusions:Using this fluoropyrimidine-based chemoradiotherapy regimen after surgical resection (±intraoperative radiotherapy), positive surgical margins and an elevated (2-fold) postoperative serum CA19-9 level predicted for reduced survival and early development of distant metastatic disease.

Multi-Institutional Phase I Trials of Anticancer Agents

PURPOSE Physicians involved in the conduct of phase I studies of novel anticancer agents have raised concerns about the emergence of multi-institutional phase I trials and about using the optimal biologic dose (OBD) as an alternative to the maximum-tolerated dose (MTD) as the primary end point in early drug development. We sought to determine the factors associated with multi-institutional phase I studies and OBD determination. PATIENTS AND METHODS We reviewed all published phase I trials between January 1998 and June 2006 from two major clinical cancer journals. The following components from each trial were determined: number of participating sites, sponsor, nation where study was conducted, MTD or OBD established, number of patients accrued, mechanism of action of the studied agent, accrual time, and tumor type. RESULTS We identified 463 trials. Fifty-six percent were performed in single institutions. Only 30% reported accrual time. The number of patients enrolled on single institution studies was significantly lower than on multi-institutional studies (P < .05), but there was no difference in accrual time. There was no association between the number of institutions and the sponsor or the mechanism of drug action. National Institutes of Health-sponsored trials enrolled fewer patients per trial than pharmaceutical-sponsored trials (P < .05). Although 99% of trials with cytotoxic agents determined an MTD, only 64% of trials with targeted agents did. CONCLUSION Multi-institutional phase I studies do not decrease the time to study completion and result in an increase in number of patients per trial. One third of trials with targeted agents failed to determine an MTD.

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.

Dramatic response of a gastrointestinal stromal tumor to neadjuvant imatinib therapy

Gastrointestinal stromal tumors (GISTs) are the most common sarcoma of the alimentary tract and are believed to derive from the interstitial Cell of Cajal. Imatinib mesylate (Gleevec®; Novartis, Basel, Switzerland) has revolutionized the treatment of GISTs and is generally used in the metastatic and adjuvant settings. We report the case of a 61-year old man who was treated with neoadjuvant imatinib for a massive gastric GIST with the hope of avoiding a potential multi-visceral resection.

A phase I study of sunitinib malate (S) and gemcitabine (G) in solid tumors.

3046 Background: Continuous daily dosing (CDD) of S with G is a novel regimen that may have broad clinical activity. Methods: Eligible patients had no curative therapy options, adequate organ funct...

Shifting of patient characteristics enrolled on phase I clinical trials

13507 Background: Phase I trials serve an important first step in anticancer drug development. In most studies eligibility includes patients with advanced refractory solid tumors and good performance status (PS) ECOG 0, 1, 2. However, in the past few years a number of new therapies for a variety of solid tumors have been approved. We hypothesized that this has resulted in a changing of the characteristics of those patients enrolled on phase I trials. Methods: We reviewed 191 phase I trials published in the Journal of Clinical Oncology between 1998 and 2006. We reviewed each trial and determined the following patient characteristics: number of patients, gender, median age, race, type of malignancy, and number of prior therapies. Results: Of the trials we reviewed, 136 were in patients with advanced solid tumors. Median age (58 years) of patients did not change over the studied period nor did proportion of female patients (45%). African Americans are significantly underrepresented in phase I trials (8.4% of...