Eric Raefsky

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.

Cyclosporine therapy of aplastic anaemia, congenital and acquired red cell aplasia

Summary. We treated 22 patients with severe aplastic anaemia refractory to antithymocyte globulin (ATG) with cyclosporine, alone or in combination with prednisone. Eight patients showed significant clinical improvement, all but one to transfusion‐independence. Although cyclosporine alone was effective, the addition of prednisone resulted in prompter and fuller haematologic improvement. No patient with an absolute granulocyte count <0·2 × 109/l responded to treatment. Haematologic remissions were sustained beyond the treatment period. Of nine patients with Diamond‐Blackfan syndrome, one showed a complete response to two separate courses of cyclosporine and relapse with withdrawal of therapy, and a second achieved significant reduction in corticosteroid dose without relapse; however, seven cases failed to respond. Two of three adults with acquired pure red cell aplasia recovered. A combination of cyclosporine and corticosteroids may be effective therapy in patients with aplastic anaemia who have failed ATG treatment. Occasional cases of congenital and acquired pure red cell aplasia may also respond to cyclosporine.

Phase II study of neoadjuvant weekly nab-paclitaxel and carboplatin, with bevacizumab and trastuzumab, as treatment for women with locally advanced HER2+ breast cancer.

PURPOSE Neoadjuvant treatment with chemotherapy plus trastuzumab is standard care for women with locally advanced, HER2-positive (HER2(+)) breast cancer. HER2 has been shown to stimulate angiogenesis through vascular endothelial growth factor upregulation. We investigated the feasibility and efficacy of bevacizumab in combination with trastuzumab, nab-paclitaxel, and carboplatin as neoadjuvant therapy for women with locally advanced HER2(+) breast cancer. PATIENTS AND METHODS Twenty-eight women with locally advanced HER2(+) breast cancer received nab-paclitaxel (100 mg/m(2) intravenously [I.V.] days 1,8, and 15) and carboplatin (AUC = 6 I.V. day 1) every 28 days × 6 cycles. Concurrent with chemotherapy, trastuzumab (4 mg/kg loading dose, then 2 mg/kg) and bevacizumab (5 mg/kg I.V.) were administered weekly × 23 weeks. Patients then underwent mastectomy or breast-conserving surgery; pathologic responses were assessed. After surgery, trastuzumab 6 mg/kg and bevacizumab 15 mg/kg were administered every 3 weeks (54 weeks total); locoregional radiotherapy and/or antiestrogen therapy was administered per standard guidelines. RESULTS Twenty-six patients (90%) completed neoadjuvant therapy, with objective responses in 86%. Pathologic complete response (pCR) was confirmed in 14 of the 26 patients (54%) who had surgery. However, bevacizumab-related complications were common postoperatively and during adjuvant trastuzumab/bevacizumab therapy. Ten patients had wound-healing delays or infections (6 patients discontinued therapy); 4 patients had left ventricular ejection fraction (LVEF) decreases (1 patient discontinued therapy). Other severe treatment-related toxicity was uncommon. Only 9 patients (31%) completed all protocol therapy. CONCLUSIONS Neoadjuvant therapy with nab-paclitaxel, carboplatin, trastuzumab, and bevacizumab was feasible in most patients, producing a pCR rate comparable to that in chemotherapy/trastuzumab combinations. In contrast, prolonged bevacizumab/trastuzumab therapy after surgical treatment was not well tolerated, primarily due to bevacizumab-related toxicity. The role of bevacizumab in neoadjuvant therapy remains undefined.

Combination Therapy With Fludarabine and Rituximab Followed by Alemtuzumab in the First-line Treatment of Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma : 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 the combination of fludarabine and rituximab, followed by alemtuzumab, as first‐line treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Combination chemotherapy with gemcitabine and irinotecan in patients with previously treated carcinoma of an unknown primary site: a Minnie Pearl Cancer Research Network Phase II trial.

The current study was performed to evaluate the activity of combination chemotherapy with gemcitabine and irinotecan in patients with previously treated carcinoma of an unknown primary site.

Phase I Study of JM-216 (an Oral Platinum Analogue) in Combination with Paclitaxel in Patients with Advanced Malignancies

This phase I study wasconducted to determine the dose limitingtoxicity, maximum tolerated doses, andrecommended phase II doses of thecombination of JM-216 and paclitaxel. Patients received paclitaxel intravenouslyover one hour on day 1 of each cycle. OralJM-216 was administered on days 1–5starting after the paclitaxel infusion. Cycles were repeated every 21 days. Patients were accrued at nine differentdosing combinations. JM-216 doses rangedfrom 10–80 mg/m2/day and werecombined with paclitaxel doses of 150, 175,or 200 mg/m2. Forty-three patientswere treated with 146 cycles of therapy. Dose-limiting toxicity, consisting offebrile neutropenia and grade 3thrombocytopenia, was encountered in 2patients at the seventh dose level (JM-21680 mg/m2/day + paclitaxel175 mg/m2). Two intermediate doselevels were explored. The first level(JM-216 70 mg/m2/day + paclitaxel175 mg/m2) produced dose-limitingthrombocytopenia in 1 of 6 patients. However, two additional patients alsodemonstrated delayed recovery fromthrombocytopenia following treatment. As aresult, a second intermediate dose level(JM-216 60 mg/m2/day + paclitaxel200 mg/m2) was filled with sixpatients. No dose-limiting toxicities werereported in any patients at this doselevel. The combination of oral JM-216 andpaclitaxel is well-tolerated with minimalnon-hematologic and reversible hematologictoxicity. The recommended dose for phaseII study is JM-216 60 mg/m2/day for 5days and paclitaxel 200 mg/m2 on day 1repeated every 21 days. Higher doses ofJM-216 are associated with more severethrombocytopenia and delayed hematologicrecovery resulting in subsequent dosingdelays.

Rituximab With or Without Bevacizumab for the Treatment of Patients With Relapsed Follicular Lymphoma

INTRODUCTION/BACKGROUND Inhibition of tumor angiogenesis by the interruption of VEGF pathway signaling is of therapeutic value in several solid tumors. Preclinical evidence supports similar importance of the pathway in non-Hodgkin lymphoma. In this randomized phase II trial, we compared the efficacy and toxicity of rituximab with bevacizumab versus single-agent rituximab, in patients with previously-treated follicular lymphoma. PATIENTS AND METHODS Patients (n = 60) were randomized (1:1) to receive rituximab (375 mg/m(2) intravenously [I.V.] weekly for 4 weeks) either as a single agent or with bevacizumab (10 mg/kg I.V. on days 3 and 15). Patients with an objective response or stable disease at week 12 received 4 additional doses of rituximab (at months 3, 5, 7, and 9); patients who received rituximab/bevacizumab also received bevacizumab 10 mg/kg I.V. every 2 weeks for 16 doses. RESULTS After a median follow-up of 34 months, PFS was improved in patients who received rituximab/bevacizumab compared with patients who received rituximab alone (median 20.7 vs. 10.4 months respectively; HR, 0.40 (95% confidence interval [CI], 0.20-0.80); P = .007). Overall survival was also improved numerically (73% vs. 53% at 4 years), but did not reach statistical significance (HR, 0.40 (95% CI, 0.15-1.05); P = .055). The addition of bevacizumab increased the toxicity of therapy, but both regimens were well tolerated (no grade 4 toxicity). CONCLUSION The addition of bevacizumab to rituximab significantly improved PFS. The role of angiogenesis inhibition in the treatment of follicular lymphoma requires further definition in larger clinical trials.

Neutropenia associated with large granular lymphocytes responsive to corticosteroids in vitro and in vivo

We describe a patient with neutropenia associated with increased circulating large granular lymphocytes (LGL). Absolute neutropenia was accompanied by the absence of myeloid precursor cells in the bone marrow. No myeloid progenitor cells (CFU‐C) could be detected by in vitro colony culture. The peripheral blood was also remarkable for the presence of a population of large granular lymphocytes demonstrable by conventional staining. These cells in flow microfluorometry studies expressed antigens Leu 4 (T‐cell antigen receptor), Leu 7 (natural killer cell marker), Leu 2 (suppressor cell marker), and HLA‐DR (activation marker); they lacked Leu 1 (a pan‐T cell antigen), Leu 3 (helper cell marker) and Tac (interleukin 2 receptor). Hematopoietic colony formation in vitro improved with addition of corticosteroids to the culture medium or elimination of the LGL population with complement‐mediated cytotoxicity. Anti‐neutrophil antibodies were present prior to and following therapy. Clinically, administration of prednisone resulted in a normalization of the total white blood cell count and absolute polymorphonuclear cell number, an increase into the normal range of the number of CFU‐C, and elimination of the LGL population. In this case of steroid‐responsive LGL‐associated neutropenia, laboratory studies suggested direct suppression of myelopoiesis by steroid‐responsive LGL.

Paclitaxel and carboplatin adjuvant therapy alone or with radiotherapy for resected nonsmall cell lung carcinoma

The objective of this study was to determine the feasibility and toxicity of paclitaxel and carboplatin given in the adjuvant setting alone for patients with resected Stage IB disease and combined with radiotherapy for patients with resected Stages II and IIIA disease and selected patients with Stage IIIB and IV disease (Revised International System for Staging of Lung Cancer).

A phase I trial of protracted oral fixed‐dose temozolomide

The current Phase I trial was conducted to determine the dose‐limiting toxicity (DLT), maximum tolerated dose, and recommended Phase II dose of oral fixed‐dose temozolomide when administered for 5 of every 7 days on a continuous basis.