Continuing reassessment of the risks of erythropoiesis-stimulating agents in patients with cancer.

PURPOSE: Erythropoiesis-stimulating agents (ESA) are approved for the treatment of anemia in patients with nonmyeloid malignancies whose anemia is due to the effect of concomitantly administered chemotherapy. Since the 1993 approval of epoetin alfa in patients with cancer, the risk of thrombovascular events, decreased survival, and poorer tumor control have been increasingly recognized. The risks of ESAs in patients with cancer and the design of trials to assess these risks have been the topic of discussion at two Oncologic Drugs Advisory Committees in 2004 and 2007. EXPERIMENTAL DESIGN: Evaluation of randomized clinical trials comparing use of ESAs to transfusion support alone in patients with active cancer. RESULTS: Six studies (Breast Cancer Erythropoeitin Survival Trial, Evaluation of NeoRecormon on outcome in Head And Neck Cancer in Europe, Danish Head and Neck Cancer, Lymphoid Malignancy, CAN-20, and Anemia of Cancer) investigating ESAs in oncology patients showed decreased survival, decreased duration of locoregional tumor control, and/or increased risk of thrombovascular events. In these six studies, ESA dosing was targeted to achieve and maintain hemoglobin values in excess of current recommendations, and in three of the six studies, ESAs were administered to patients not receiving chemotherapy. CONCLUSIONS: ESAs increase the risk of thrombovascular events and result in decreased survival and poorer tumor control when administered to achieve hemoglobin levels of > or =12 g/dL in patients with nonmyeloid malignancies. No completed or ongoing randomized, controlled trial has addressed safety issues of ESAs in patients with chemotherapy-associated anemia using currently approved dosing regimens in an epidermal tumor type. Additional studies are needed to better characterize these risks.

Long-term assessment of cardiac function after dose-dense and -intense sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) as adjuvant therapy for high risk breast cancer.

OBJECTIVES: This study evaluated the incidence of late cardiotoxicity after dose-dense and -intense adjuvant sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) for breast cancer (BC) with > or = 4 involved ipsilateral axillary lymph nodes. METHODS: Patients were enrolled from 1994 to 2001 after definitive BC surgery if > or =4 axillary nodes were involved. Planned treatment was A 90 mg/m(2) q 14 days x 3, T 250 mg/m(2) q 14 days x 3, C 3 g/m(2 )q 14 days x 3 with filgrastim (G) support. Left ventricular ejection fraction (LVEF) was monitored using equilibrium radionuclide angiography (ERNA) before the initiation of chemotherapy, and after three cycles of each chemotherapeutic agent. At a median follow-up of 7 years, we obtained ERNA scans on 32 patients to evaluate the long-term cardiotoxicity of this regimen. RESULTS: Eighty-five eligible patients enrolled on the treatment protocol. Clinical heart failure developed in one patient. Seven (8%) patients had LVEF < 50% at the end of therapy. No cardiac-related deaths occurred. Thirty-two (46%) of 69 surviving patients have consented to late cardiac imaging. At a median follow-up of 7 years, the median absolute change in LVEF from baseline was -5.5%; [range (-8%) to (+36%)], and from the end of chemotherapy was -2.0%; [range (-25%) to (+16%)]. Four patients (12%) had a LVEF < 50%; two of these four patients had an LVEF of < 50% at the end of chemotherapy. CONCLUSIONS: Late development of asymptomatic decline in cardiac function may occur after dose-dense and -intense adjuvant therapy, but is uncommon.

Palmar-plantar erythrodysesthesia in patients receiving capecitabine and intratumor thymidine phosphorylase and dihydropyrimidine dehydrogenase: is there a pharmacologic explanation?

BACKGROUND: Palmar-plantar erythordysesthesia (PPE) is the most common toxicity of capecitabine. Preclinical studies have shown that radiation therapy (RT) upregulates thymidine phosphorylase (TP), which could in turn increase the efficacy of capecitabine. Capecitabine is degraded by dihydropyrimidine dehydrogenase (DPD), and a deficiency in this enzyme can increase the toxicity of capecitabine. However, the effect of radiation therapy on frequency of PPE and association with TP and DPD has not been fully characterized. PATIENTS AND METHODS: Toxicity data were collected prospectively in 33 patients and retrospectively in 25 patients with locally advanced pancreatic cancer enrolled in 3 clinical trials who received capecitabine/RT followed by capecitabine alone. Tumor specimens on 33 patients were procured via endoscopic ultrasonography standards 1 week befoer RT and 2 weeks after RT to evaluate TP and DPD messenger RNA levels. Roche grading was used to assess PPE. RESULTS: Among 58 patients, 14 (24%) developed PPE. The capecitabine group tended to have a higher incidence of PPE than the capecitabine/RT group (17.2% vs. 10.3%; P = .12). Grade 2/3 PPE, was observed in 15.5% of patients receiving capecitabine and 1.7% of patients receiving capecitabine/RT (P = .0078; overall: 17.2%). Median cumulative dose of capecitabine for first development of PPE was 235,000 mg/m2 in the capecitabine/RT group, and 3,185,000 mg/m2 in the capecitabine group, with the relative frequency of an event occurring in the capecitabine/RT arm versus capecitabine of 0.59. Time to occurrence of first episode of PPE was a median of 5 weeks with capecitabine/RT and 6 weeks with capecitabine. Log-rank test showed that neither age, sex, performance status, nor ethnicity were associated with development of PPE. There was no clear difference in tumor responses of patients who had PPE versus those who did not have PPE. Mean tumor TP level was higher among patients with versus without PPE (275.77 vs. 215.29; P = .32). Mean tumor DPD level was lower among patients with versus without PPE (55.18 vs. 63.58; P = .49). Mean TP-DPD ratio was higher among patients with versus without PPE (10.29 vs. 3.04; P = .31). CONCLUSION: No significant association of PPE with higher tumor thymidine phosphorylase or lower tumor DPD levels was found. There was no difference in the incidence, severity, or time to occurrence of PPE with capecitabine/RT versus capecitabine, indicating no effect of RT. Further studies to evaluate the underlying mechanism of PPE are required.