Ian Rabinowitz

Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer

Purpose: This phase II randomized trial evaluated the efficacy and tolerability of anastrozole combined with gefitinib or anastrozole with placebo in women with hormone receptor–positive metastatic breast cancer (MBC). Experimental Design: Postmenopausal women with hormone receptor–positive measurable or evaluable MBC who had not received prior endocrine therapy for this disease stage or who developed metastatic disease during/after adjuvant tamoxifen were eligible. The primary response variable was progression-free survival (PFS) and secondary response variables included clinical benefit rate, objective response rate, overall survival, safety and tolerability, and pharmacokinetics. Tumor biomarker evaluation was an exploratory objective. Results: Forty-three patients were randomized to anastrozole plus gefitinib and 50 patients were randomized to anastrozole plus placebo of a planned total of 174 patients (enrollment was prematurely discontinued due to slow recruitment). PFS for patients receiving the combination of anastrozole and gefitinib was longer than for patients receiving anastrozole plus placebo [hazard ratio (gefitinib/placebo), 0.55; 95% confidence interval, 0.32-0.94; median PFS, 14.7 versus 8.4 months]. The clinical benefit rate was 49% versus 34%, and the objective response rate was 2% versus 12% with anastrozole plus gefitinib and anastrozole plus placebo, respectively. No evidence of interaction between baseline biomarker levels and relative treatment effect was found. No unexpected adverse events were observed. Conclusion: This small randomized study showed that anastrozole in combination with gefitinib is associated with a marked advantage in PFS compared with anastrozole plus placebo, and that the combination was tolerated in postmenopausal women with hormone receptor–positive MBC. Further investigation of epidermal growth factor receptor inhibition in combination with endocrine therapy may be warranted. Clin Cancer Res; 16(6); 1904–14

Biomarkers, fatigue, sleep, and depressive symptoms in women with breast cancer: a pilot study.

PURPOSE/OBJECTIVES To evaluate the changes in reports of fatigue, sleep disturbances, and depressive symptoms and serum cortisol, melatonin, serotonin, and bilirubin during adjuvant chemotherapy in women with breast cancer and to determine whether any correlations exist between the symptom parameters and biomarkers. DESIGN Prospective longitudinal, correlational, repeated-measures pilot study. SETTING Large southwestern, university-based, National Cancer Institute-designated cancer center. SAMPLE 22 subjects (11 women with stage II breast cancer receiving adjuvant chemotherapy and 11 cancer-free women who were matched by age, ethnicity, and menopausal status). METHODS Questionnaires (fatigue, sleep, depressive symptoms), wrist sleep actigraphy, and laboratory analysis of serum samples. All subjects (i.e., women with breast cancer receiving chemotherapy and a comparison group of cancer-free women who were matched by age, ethnicity, and menopausal status) were admitted to a general clinical research center for two nights during cycles 1 and 4 for data collection. MAIN RESEARCH VARIABLES Biomarkers (serum cortisol, melatonin, serotonin, and bilirubin), fatigue, sleep, and depressive symptoms. FINDINGS Mean fatigue scores of the subjects with cancer were significantly higher than the healthy comparison group. Subjects with cancer had a significantly lower mean actual sleep time compared to the comparison group at cycle 1. No significant difference was found between the groups at cycle 4. Depression scores also differed significantly between the cancer group and comparison group. Select biomarkers changed over time and were associated with subjective parameters of fatigue, sleep, and depressive symptoms. CONCLUSIONS Findings suggest that fatigue, sleep, and depressive symptoms are more prevalent in women with cancer than a cancer-free comparison group. Biomarkers changed over time and provide a possible explanatory mechanism for the three related symptoms. IMPLICATIONS FOR NURSING Data help to explain a mechanism that may underlie fatigue, sleep, and depressive symptoms and provide a theoretical framework from which to establish evidence-based interventions for symptom management.

Clinicopathologic Features of Agranulocytosis in the Setting of Levamisole-Tainted Cocaine

Levamisole is a known contaminant of cocaine and, via this route, has been associated with otherwise unexplained agranulocytosis. Levamisole is currently present in the majority of cocaine samples seized by the US Drug Enforcement Agency. We identified 20 cases of unexplained agranulocytosis in our practice locations of Albuquerque, NM, and Vancouver, Canada. Epidemiologic investigation revealed recent or ongoing cocaine use in 14 cases (70%). Certain morphologic features, including circulating plasmacytoid lymphocytes, increased bone marrow plasma cells, and mild megakaryocytic hyperplasia, were associated with the cocaine-exposed group. Of 5 patients tested, 3 (60%) were HLA-B27+ and showed antineutrophil antibodies, consistent with known associations of levamisole-induced agranulocytosis. One patient, who was positive for cocaine and levamisole by toxicology testing, died of infectious complications. Inadvertent consumption of levamisole via cocaine is a severely under-appreciated risk factor for agranulocytosis, and specific laboratory features are suggestive of this etiology.

Phase IB study of the combination of docetaxel, gemcitabine, and bevacizumab in patients with advanced or recurrent soft tissue sarcoma: the Axtell regimen.

BACKGROUND To assess the response of patients with soft tissue sarcoma (STS) to the combination of docetaxel, bevacizumab, and gemcitabine. Vascular endothelial growth factor (VEGF)-A levels and expression of VEGF-A and VEGF receptors 1 and 2 were evaluated. PATIENTS AND METHODS Thirty-eight chemotherapy-naive patients with STS were enrolled. A dose-finding study for gemcitabine from 1000, 1250, then 1500 mg/m(2) was done in nine patients (three cohorts), followed by an expansion cohort of 27 patients. Dose of docetaxel was 50 mg/m(2), bevacizumab was 5 mg/kg, and gemcitabine was 1500 mg/m(2), every 2 weeks. Serum VEGF-A was measured by enzyme-linked immunosorbent assay and tissue VEGF-A and its receptors by immunohistochemistry. RESULTS The median follow-up was 36 months. The overall response rate observed was 31.4%, with 5 complete and 6 partial responses, and 18 stable diseases lasting for a median of 6 months. There was no significant hematologic toxicity. The adverse events with the highest grade were attributed to bevacizumab. There was no correlation of VEGF pathway biomarkers with outcome. CONCLUSIONS The combination of gemcitabine, docetaxel, and bevacizumab is safe and effective in patients with STS. The most concerning adverse events were consequences of bevacizumab administration. The benefit of bevacizumab in this patient population remains unclear.BACKGROUND To assess the response of patients with soft tissue sarcoma (STS) to the combination of docetaxel, bevacizumab, and gemcitabine. Vascular endothelial growth factor (VEGF)-A levels and expression of VEGF-A and VEGF receptors 1 and 2 were evaluated. PATIENTS AND METHODS Thirty-eight chemotherapy-naive patients with STS were enrolled. A dose-finding study for gemcitabine from 1000, 1250, then 1500 mg/m2 was done in nine patients (three cohorts), followed by an expansion cohort of 27 patients. Dose of docetaxel was 50 mg/m2, bevacizumab was 5 mg/kg, and gemcitabine was 1500 mg/m2, every 2 weeks. Serum VEGF-A was measured by enzyme-linked immunosorbent assay and tissue VEGF-A and its receptors by immunohistochemistry. RESULTS The median follow-up was 36 months. The overall response rate observed was 31.4%, with 5 complete and 6 partial responses, and 18 stable diseases lasting for a median of 6 months. There was no significant hematologic toxicity. The adverse events with the highest grade were attributed to bevacizumab. There was no correlation of VEGF pathway biomarkers with outcome. CONCLUSIONS The combination of gemcitabine, docetaxel, and bevacizumab is safe and effective in patients with STS. The most concerning adverse events were consequences of bevacizumab administration. The benefit of bevacizumab in this patient population remains unclear.

Epstein–Barr virus-associated inflammatory pseudotumor of the spleen: report of two cases and review of the literature

We report two rare examples of Epstein–Barr virus (EBV)-associated inflammatory pseudotumor of the spleen. One patient presented with night sweats, abdominal pain, and weight loss and was found to have a splenic mass on CT scan suspected of lymphoma. The splenic mass in second patient was found incidentally at the time of work up for kidney stones. The pathologic examination of these splenectomy specimens showed similar histologic features. However, the spindle cells were composed of EBV-infected follicular dendritic cells in one case whereas the second case lacked significant follicular dendritic cell proliferation and showed only focal EBV-infected cells suggesting that these proliferations are heterogenous in nature.

A phase I study of flavopiridol in combination with gemcitabine and irinotecan in patients with metastatic cancer.

Background:Flavopiridol (HMR 1275) is a synthetic flavone with antineoplastic properties through inhibition of cyclin-dependent kinase inhibitor. Flavopiridol synergizes in a sequence-dependent fashion with chemotherapy. Major adverse events of flavopiridol in single agent phase I studies are secretory diarrhea, neutropenia, thrombosis, and fatigue. Patients and Methods:Patients with advanced solid tumors were treated with gemcitabine 800 mg/m2 and irinotecan 80 mg/m2 on day 1, followed by flavopiridol, starting dose of 30 mg/m2 on day 2 with increment of 15 mg/m2 per dose level, repeated on days 8 and 9 for the first 6 patients (3-week cycle), and then repeated on days 15 and 16 for the remainder patients (4-week cycle). The protocol had to be amended for inability to redose after 1 week. Results:Fourteen women and 7 men with advanced solid tumors were enrolled. The median age was 51 years and the median number of prior chemotherapies was 3 (0–9). Neutropenic sepsis (1 patient), grade 3 diarrhea (1 patient), and neutropenia (2 patients) preventing retreatment on day 8 were observed among the 6 subjects treated on the first schedule. The recommended phase II dose of flavopiridol was 45 mg/m2 in combination with irinotecan and gemcitabine every 2 weeks. Dose-limiting toxicities were electrolyte imbalance with fatigue (1 patient), and renal failure and dyspnea with hypoxia (1 patient each), seen at 45 and 60 mg/m2 doses, respectively. The most common side effects were fatigue (81%), nausea (71%), diarrhea (67%), transient myelosuppression (43%), and vomiting (24%). Conclusions:The every 2 week dosing is well tolerated with a phase II recommended dose of 45 mg/m2 of flavopiridol in combination with irinotecan (80 mg/m2) and gemcitabine (800 mg/m2).

A Phase I Protocol of Hydralazine and Valproic Acid in Advanced, Previously Treated Solid Cancers

Smokers experience aberrant gene promoter methylation in their bronchial cells, which may predispose to the development of neoplasia. Hydralazine is a DNA demethylating agent, and valproic acid is a histone deacetylase inhibitor, and both have modest but synergistic anticancer activity in vitro. We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers. Twenty females and nine males were enrolled, with a median age of 57 years and a median ECOG performance status of 0. Grade 1 lymphopenia and fatigue were the most common adverse effects. Three subjects withdrew for treatment-related toxicities occurring after the DLT observation period, including testicular edema, rash, and an increase in serum lipase accompanied by hyponatremia in one subject each. A true MTD of hydralazine in combination with therapeutic doses of valproic acid was not reached in this trial, and the planned upper limit of hydralazine investigated in this combination was 400 mg/day without grade 3 or 4 toxicities. A median number of two treatment cycles were delivered. One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments. This trial supports further investigation of epigenetic modification as a new therapeutic strategy.

Alternative administration of camptothecin analogues

In order to improve the therapeutic index of camptothecin (CPT) analogues, alternative administration of CPT analogues is being evaluated. Topotecan, irinotecan, rubitecan, lurtotecan and 9-aminocamptothecin have been administered orally with response rates equivalent to that seen after intravenous administration, where applicable. Oral availability and administration of some of the newer CPT analogues, including diflomotecan (BN80915) and grimatecan (ST1481), have also shown promising results. Aerosolisation of liposomal 9-nitrocamptothecin has been studied in patients with advanced malignancies involving the lung, demonstrating systemic antitumour activity. Intrathecal administration of topotecan has been studied in children with refractory neoplastic meningitis. It is well tolerated and associated with some antitumour activity. Intraperitoneal administration of topotecan as consolidation therapy in patients with ovarian cancer has shown promising results. Transdermal administration of rubitecan has been studied in mice. So far, no CPT has been approved for an alternative route of administration.

Interaction between statins and rituximab in non-Hodgkin's lymphoma.

TO THE EDITOR: I read with interest the editorial by Carver et al in Journal of Clinical Oncology on the approach to doxorubicin cardiotoxicity in the elderly patients treated for non-Hodgkin’s lymphoma. The authors stated they have a “low threshold to add statins in light of the possible protective effect of this drug class on anthracylcine cardiotoxicity.” However, I would caution the authors (and readers) to consider recent data before adopting this practice. In a laboratory study, statins were found to significantly decrease rituximab-mediated complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity of B-cell lymphomas. These studies suggested that statins, through cholesterol depletion, induced conformational changes in CD20 that result in impaired binding of the anti-CD20 monoclonal antibody. It is firmly established that rituximab has a major beneficial impact in the outcome of patients with nonHodgkin’s lymphoma. Impairing the binding of rituximab to the tumor cells by adding a statin may negate some of the benefit of this drug, and needs to be weighed against any potential cardiac benefit derived from this approach as outlined by the authors. Furthermore, although there are no clinical data to support holding statins during rituximab administration, it may be prudent to consider doing so, even in patients already on this class of drug. Patients could be restarted on their statin one or two half-lives after the last dose of rituximab has been administered. At the very least, physicians should discuss this potentially negative interaction with their patients.

Disease-specific survival for patients with multiple myeloma: significant improvements over time in all age groups

Abstract This study analyzed the survival of patients with multiple myeloma. Surveillance, Epidemiology, and End Results (SEER) and Centers for Disease Control and Prevention (CDC) databases were queried to calculate myeloma cause-specific survival curves by the Kaplan and Meier product-limit method. The Cox proportional hazards model was used to assess univariate and multivariate predictors of myeloma cause-specific survival. The outcome of interest was death due to myeloma. Results from a Cox proportional hazards model restricted to age and time period at diagnosis demonstrated that the magnitude of improvement in survival by time period varied by age at diagnosis. Among patients under 60 years at diagnosis, hazard ratios for myeloma cause-specific death decreased by more 50% from the first interval of observation to the last. Hazard ratios decreased during the study period by 39% among patients 60–69 years of age and by 27% among patients who were 70 years of age and older. Survival is improving in patients with myeloma of all ages.