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Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP)

Overview

CyclophosphamideThe CHOP regimen incorporates cyclophosphamide (Bristol-Myers Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, Pfizer’s Neosar/Cyclostin, generics), doxorubicin (Pfizer’s Adriamycin/Adriblastine, Bristol-Myers Squibb’s Rubex, Kyowa’s Adriacin, generics), vincristine (Eli Lilly’s Oncovin), and prednisone (generics). This combination is frequently used in non-Hodgkin’s lymphoma; its use is becoming less widespread in chronic lymphocytic leukemia.

Mechanism of Action

•  Cyclophosphamide is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication.

•  Doxorubicin is an anthracycline. Anthracyclines interact with several different cellular targets, most importantly topoisomerase II. By inhibiting this DNA regulation enzyme, anthracyclines exert their cyto-toxic effect. Another mechanism leading to cell death, known as DNA intercalation, involves insertion of the anthracycline molecule between base pairs. This phenomenon causes single- and double-stranded breaks in DNA that inhibit cell proliferation. The free radicals generated by the reductive metabolism of anthracyclines may also damage cellular structures.

•  Vincristine is a vinca alkaloid. Vinca alkaloids interact with tubulin and disrupt microtubular function in the mitotic spindle. This action leads to metaphase arrest, resulting in mitotic arrest and cell death.

•  Prednisone is a corticosteroid and reduces inflammatory responses and suppresses the immune system.

Clinical Performance

DoxorubicinThe dosage of cyclophosphamide and doxorubicin in CHOP regimens can vary (300-750 mg/m2 cyclophosphamide and 25-50 mg/m2 doxorubicin). When lower doses of these drugs are used, it may be referred to as mini-CHOP.

A randomized clinical trial was designed to compare the anthracycline-containing regimens CHOP (incorporating the lower doses of cyclophosphamide and doxorubicin) and CAP (cyclophosphamide, doxorubicin, prednisone) with fludarabine in 938 previously untreated Binet stage B and C chronic lymphocytic leukemia patients. Patients were randomly assigned to receive six monthly courses of CHOP, CAP, or fludarabine. Those patients who received fludarabine or CAP and had stable or progressive disease after three cycles were switched to either CAP or fludarabine, respectively. The CHOP regimen used in this study consisted of lower doxorubicin doses, so responses were assessed after six courses of treatment and patients with stable or progressive disease were switched to fludarabine.

The response rates obtained following six courses of therapy (or at switch during the six courses) showed that both fludarabine and CHOP were clearly superior to CAP. CR rates of 29.6%, 15.2%, and 40.1% and PR rates of 41.9%, 43%, and 31% were achieved in patients receiving CHOP, CAP, and fludarabine, respectively, regardless of stage. Accrual to the CAP arm was prematurely closed

when results of the first interim analysis showed significantly reduced response rates compared with CHOP and fludarabine.

The median follow-up in this study was 70 months and median survival was 67 months, 70 months, and 69 months in the CHOP, CAP, and fludarabine arms, respectively, with five-year survival rates of 57.3%, 59.8%, and 58.4%, respectively. Although distinct differences in remission rates were observed, they did not translate into differences in survival. This effect was generated by the fact that patients who did not respond to their initial therapy were switched to another arm of the study, and the majority of patients received subsequent therapy over the course of their disease, thus obscuring the interpretation of survival data. Similar conclusions have been outlined in other large, prospective multicenter trials.

A higher frequency and severity of nausea, vomiting, and hair loss in patients receiving anthracycline-containing regimens were observed, whereas myelosuppression predominated in the fludarabine group. However, the increased rate of infection associated with myelosuppression in fludarabine-treated patients reported in previous trials was not observed in this study. The authors suggested that this absence may be explained by the fact that this patient group was previously untreated.

Additional studies have shown that standard doses of CHOP did not result in any advantage in terms of response duration or survival when compared with chlorambucil plus prednisone. A meta-analysis of 2,022 chronic lymphocytic leukemia patients in ten trials of combination chemotherapy (CHOP or COP [cyclophosphamide, oncovin, prednisone]) versus chlorambucil plus or minus corticosteroids was carried out to compare overall long-term survival rates (chronic lymphocytic leukemia Trialists’ Collaborative Group, 1999). No benefit was seen for combination chemotherapy over single-agent chlorambucil in terms of five-year survival rates.

The combination of the toxicity associated with CHOP and the response rates gained with other agents have convinced physicians that CHOP should be reserved for those patients who fail chlorambucil or fludarabine therapy.

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