Scot C. Remick

Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data.

Although the association between malignancy and thromboembolic disease is well established, the relative risk of developing initial and recurrent deep vein thrombosis (DVT) or pulmonary embolism (PE) among patients with malignancy versus those without malignancy has not been clearly defined. The Medicare Provider Analysis and Review Record (MEDPAR) database was used for this analysis. Patients hospitalized during 1988-1990 with DVT/PE alone, DVT/PE and malignancy, malignancy alone, or 1 of several nonmalignant diseases (other than DVT/PE) were studied. The association of malignancy and nonmalignant disease with an initial episode of DVT/PE, recurrent DVT/PE, and mortality were analyzed. The percentage of patients with DVT/PE at the initial hospitalization was higher for those with malignancy compared with those with nonmalignant disease (0.6% versus 0.57%, p = 0.001). The probability of readmission within 183 days of initial hospitalization with recurrent thromboembolic disease was 0.22 for patients with prior DVT/PE and malignancy compared with 0.065 for patients with prior DVT/PE and no malignancy (p = 0.001). Among those patients with DVT/PE and malignant disease, the probability of death within 183 days of initial hospitalization was 0.94 versus 0.29 among those with DVT/PE and no malignancy (p = 0.001). The relative risk of DVT/PE among patients with specific types of malignancy is described. This study demonstrates that patients with concurrent DVT/PE and malignancy have a more than threefold higher risk of recurrent thromboembolic disease and death (from and cause) than patients with DVT/PE without malignancy. An alternative management strategy may be indicated for such patients.

Phase II trial of docetaxel (Taxotere) in patients with adenocarcinoma of the upper gastrointestinal tract previously untreated with cytotoxic chemotherapy: The Eastern Cooperative Oncology Group (ECOG) results of protocol E1293

The aim of this study was to evaluate the clinical efficacy and safety of docetaxel (Taxotere) in patients with adenocarcinoma of the upper gastrointestinal tract previously untreated with cytotoxic chemotherapy. Docetaxe1100 mg m−2 was administered as a 1 hour intravenous (IV) infusion every 3 weeks to 41 patients. Patients were premedicated prior to each course with dexamethasone, diphenhydramine and cimetidine. Clinical response and toxicity were determined. Objective responses were seen in seven of 41 eligible patients (two complete responses [CRs] and five partial responses [PRs], for an objective response rate of 17% (90% confidence interval [CI], 8% to 30%). The most common toxicity was grade 4 neutropenia, which occurred in 88% of patients; 46% of patients required a dose reduction following an episode of neutropenic fever requiring antibiotic therapy. Additional patients have had reversible grade 3–4 toxicities including nausea, vomiting, stomatitis, diarrhea, fatigue and peripheral neuropathy. Ten patients have had grade 1–3 hypersensitivity reactions. Alopecia has been seen in the majority of patients. Fluid retention grade 1–3 has been observed in patients. Docetaxel administered on this schedule is an active agent in adenocarcinomas of the upper gastrointestinal tract. Further investigation of this drug should be conducted in multi-drug combination programs.

Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma

Rituximab plus intravenous bolus chemotherapy is a standard treatment for immunocompetent patients with B-cell non-Hodgkin lymphoma (NHL). Some studies have suggested that rituximab is associated with excessive toxicity in HIV-associated NHL, and that infusional chemotherapy may be more effective. We performed a randomized phase 2 trial of rituximab (375 mg/m(2)) given either concurrently before each infusional etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH) chemotherapy cycle or sequentially (weekly for 6 weeks) after completion of all chemotherapy in HIV-associated NHL. EPOCH consisted of a 96-hour intravenous infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by intravenous bolus cyclophosphamide given every 21 days for 4 to 6 cycles. In the concurrent arm, 35 of 48 evaluable patients (73%; 95% confidence interval, 58%-85%) had a complete response. In the sequential arm, 29 of 53 evaluable patients (55%; 95% confidence interval, 41%-68%) had a complete response. The primary efficacy endpoint was met for the concurrent arm only. Toxicity was comparable in the 2 arms, although patients with a baseline CD4 count less than 50/microL had a high infectious death rate in the concurrent arm. We conclude that concurrent rituximab plus infusional EPOCH is an effective regimen for HIV-associated lymphoma.

A Phase II Trial of Fosbretabulin in Advanced Anaplastic Thyroid Carcinoma and Correlation of Baseline Serum-Soluble Intracellular Adhesion Molecule-1 with Outcome

BACKGROUND Fosbretabulin is a novel vascular-disrupting agent that has antitumor activity against anaplastic thyroid cancer (ATC) cell lines, xenografts, and demonstrable efficacy in a phase I trial. This phase II study determined the efficacy and safety of fosbretabulin in patients with advanced ATC and whether fosbretabulin altered the natural history of ATC by virtue of doubling the median survival. A secondary aim evaluated the prognostic value of serum soluble intracellular adhesion molecule-1 (sICAM). METHODS Twenty-six patients received fosbretabulin 45 mg/m(2) as a 10-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. sICAM levels were obtained at baseline, over the first two cycles, and end of therapy. Treatment was continued until disease progression. RESULTS Fosbretabulin was well tolerated; grade 3 toxicity was observed in nine patients (35%), and grade 4 toxicity in one (4%). QTc prolongation delayed treatment in four causing one to stop treatment. Median survival was 4.7 months with 34% and 23% alive at 6 and 12 months, respectively. Median duration of stable disease in seven patients was 12.3 months (range, 4.4-37.9 months). Baseline serum sICAM levels were measured in 24 patients with a median 253.5 ng/mL. There was a significant difference in event-free survival among tertiles of baseline sICAM levels (p < 0.009). CONCLUSIONS There were no objective responses seen with single-agent fosbretabulin as administered in this trial, and we did not observe a doubling of survival as our primary endpoint. This is among the largest prospective trials ever conducted for ATC. Fosbretabulin has an acceptable safety profile in patients with advanced ATC, and one-third survived more than 6 months. Despite a small sample size, low baseline sICAM levels were predictive of event-free survival. Further prospective validation of sICAM as a therapeutic biomarker and exploring combination regimens with fosbretabulin are warranted.

Fumagillin analog in the treatment of Kaposi's sarcoma: a phase I AIDS Clinical Trial Group study. AIDS Clinical Trial Group No. 215 Team.

PURPOSE Angiogenesis is a major component of Kaposis sarcoma (KS) and a critical process in tumor growth. The present study was designed primarily to test the toxicity and pharmacokinetics (PK) of the angiogenesis inhibitor TNP-470 and secondarily to evaluate tumor response in patients with early AIDS-related KS. PATIENTS AND METHODS Patients with AIDS-related KS were required to have cutaneous disease with > or = 5 measurable lesions and no evidence of pulmonary, symptomatic gastrointestinal, or acutely life-threatening KS. Thirty-eight patients received TNP-470 by weekly intravenous infusion over 1 hour at one of six dose levels for up to 24 weeks. RESULTS The dose levels tested included 10, 20, 30, 40, 50 and 70 mg/m2. Median CD4 count was 24 cells/microl (range, 0 to 460). Fourteen patients (36%) had > or = 50 cutaneous lesions and 19 (49%) had oral lesions. Adverse events included neutropenia (n = 2), hemorrhage (n = 3), and urticaria (n = 1). PK studies showed wide interpatient and intrapatient variability. Elimination half-life values were short (range, 0.01 to 0.61 hours). Seven patients (18%) achieved a partial response. The median time to partial response was 4 weeks (range, 2 to 25), and the median duration of response was 11 weeks (range, 3 to 26+). CONCLUSION TNP-470, administered as a weekly, 1-hour infusion to patients with early AIDS-KS is well-tolerated at doses up to and including the highest dose tested. Tumor responses were observed in a substantial number of cases and occurred at various dose levels. TNP-470 should be evaluated further in patients with AIDS-KS as a single agent and in combination with other biologic response modifiers in early disease or after initial response to cytotoxic chemotherapy.

Cardiovascular Safety Profile of Combretastatin A4 Phosphate in a Single-Dose Phase I Study in Patients with Advanced Cancer

Purpose: The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P) in a Phase I study in 25 patients with advanced solid tumors. Experimental Design: CA4P was administered in a dose-escalating fashion starting at 18 mg/m2 i.v. every 21 days, and the maximal dosage was 90 mg/m2. Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett’s formula QTc = QT/(R-R interval)1/2, and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and Cmax versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed. Results: After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points [27.2 ms (P < 0.0001) and 30.8 ms (P < 0.0001), respectively] and HR at the 3- and 4-h time points [13.2 beats per minute (bpm; P < 0.01) and 15.1 bpm (P < 0.001), respectively]. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%) of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the first 4 h was correlated to dose (in milligrams) of CA4P (P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve (P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion. Conclusions: CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more experience is gained regarding potential cardiovascular toxicity with this agent.

Anaplastic Thyroid Cancer: A Review of Epidemiology, Pathogenesis, and Treatment

Anaplastic thyroid cancer (ATC) is an uncommon malignancy of the thyroid. Only 1-2% of thyroid cancers are anaplastic, but the disease contributes to 14–50% of the mortality with a median survival of 3 to 5 months. Most patients diagnosed with this disease are 65 years of age or older. The incidence of anaplastic thyroid cancer is decreasing worldwide. Most patients present with a rapidly growing neck mass, dysphagia, or voice change. We performed a comprehensive literature search using PubMed focusing on the treatment of anaplastic thyroid cancer including historical review of treatment and outcomes and investigations of new agents and approaches. A total of sixteen chart review and retrospective studies and eleven prospective studies and/or clinical trials were reviewed. The current standard therapeutic approach is to consider the disease as systemic at time of diagnosis and pursue combined modality therapy incorporating cytoreductive surgical resection where feasible and/or chemoradiation either concurrently or sequentially. Doxorubicin is the most commonly used agent, with a response rate of 22%. Several new agents are currently under investigation. Referral of patients for participation in clinical trials is needed.

Dose-Escalating and Pharmacological Study of Oxaliplatin in Adult Cancer Patients With Impaired Renal Function: A National Cancer Institute Organ Dysfunction Working Group Study

PURPOSE This study was undertaken to determine the toxicities, pharmacokinetics, and maximum tolerated doses of oxaliplatin in patients with renal impairment and to develop formal guidelines for oxaliplatin dosing in this patient population. PATIENTS AND METHODS Thirty-seven adult cancer patients with variable renal function received intravenous oxaliplatin at 60 to 130 mg/m2 every 3 weeks. Patients were stratified by 24-hour creatinine clearance (CrCL) into four cohorts: group A (controls, CrCL > or =60 mL/min), group B (mild dysfunction, CrCL 40 to 59 mL/min), group C (moderate dysfunction, CrCL 20 to 39 mL/min), and group D (severe dysfunction, CrCL <20 mL/min). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations. RESULTS No dose-limiting toxicities were observed in any patient group during the first cycle of therapy. Escalation of oxaliplatin to the maximum dose of 130 mg/m2 was well tolerated in all patient groups with a CrCL > or =20 mL/min (groups A, B, and C). Pharmacokinetic analysis showed that patients with decreased CrCL had a corresponding decrease in the clearance of plasma ultrafiltrable platinum (r2 = 0.765). However, oxaliplatin-induced side effects were not more common or severe in patients with mild to moderate renal dysfunction, despite the decrease in ultrafiltrable platinum clearance. CONCLUSION Oxaliplatin at 130 mg/m2 every 3 weeks is well tolerated by patients with mild to moderate degrees of renal dysfunction. These data strongly support the recommendation that dose reductions of single-agent oxaliplatin are not necessary in patients with a CrCL greater than 20 mL/min.

Primary central nervous system lymphoma in patients with and without the acquired immune deficiency syndrome. A retrospective analysis and review of the literature.

Twenty-two cases of PCL were reviewed, in which 9 patients had AIDS and 13 did not. A review of the literature identified 247 cases of AIDS-related PCL. Differences between patients with AIDS and immunocompetent PCL were noted in our series. AIDS-related PCL when compared to non-AIDS PCL in our series has the following notable clinical features: 1) significantly younger age at presentation, median age 34 versus 59 years; 2) significantly higher incidence of B symptoms, 44% versus 8%; 3) worse median performance status at presentation, 3 versus 1; and, 4) shorter median survival, 3 versus 10 months. Differences in performance status and survival, however, were not significant. AIDS-related PCL is further characterized by frequent (44%) ring-enhancing mass lesions on head CT scan, a finding that makes it clinically difficult to distinguish from toxoplasmosis. Median survival appears to be improved in the absence of opportunistic infection at time of diagnosis of PCL, 6 versus 2 months. The therapeutic approach to patients with PCL, with and without AIDS, is variable. Combined modality therapy may improve the survival in patients with non-AIDS PCL. Therapy for patients with AIDS-related PCL is tailored to the status of the individual and it is, therefore, difficult to make comparisons to non-AIDS PCL patients. AIDS patients are often too ill to tolerate aggressive surgery or systemic treatment and in this instance, radiotherapy alone may be an acceptable alternative. Nonetheless, overall survival for patients with AIDS-related and non-AIDS PCL remains poor.

Phase II Trial of Sorafenib in Patients with Advanced Anaplastic Carcinoma of the Thyroid

BACKGROUND Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy with a median survival of 3-5 months. The BRAF oncogene is mutated to its active form in up to 24% of ATC cases. Sorafenib is a tyrosine kinase inhibitor that acts on the RAF-1 serine/threonine kinase. In preclinical mouse models, sorafenib inhibits the growth of ATC xenografts and improves survival. No study of sorafenib in ATC has been conducted. We conducted a multi-institutional phase II trial of sorafenib in patients with ATC who had failed up to two previous therapies. METHODS The primary endpoint of the trial was the Response Evaluation Criteria In Solid Tumors (RECIST)-defined imaging response rate. Twenty patients with ATC were treated with sorafenib 400 mg twice daily. RESULTS Two of the 20 patients had a partial response (10%) and an additional 5 of 20 (25%) had stable disease. The duration of response in the two responders was 10 and 27 months, respectively. For the patients with stable disease, the median duration was 4 months (range 3-11 months). The overall median progression-free survival was 1.9 months with a median and a 1-year survival of 3.9 months and 20%, respectively. Toxicity was manageable and as previously described for sorafenib, including hypertension and skin rash. CONCLUSION Sorafenib has activity in ATC, but at a low frequency and similar to our previous experience with fosbretabulin. One patient with a response had previously progressed on fosbretabulin. Toxicities were both predictable and manageable.