Vad And Related Regimens

With no overall improvement in outcome seen with the alkylator-based combination regimens developed in the 1970s and 1980s, regimens utilizing anthracy-clines administered by continuous infusion were developed, with the rationale that continuous drug exposure would more effectively target slowly cycling plasma cells. One such regimen is VAD: vincristine 0.4 mg/day and doxorubicin (Adriamycin) 9 mg/m2/day as a continuous infusion, with pulses of dexametha-sone (orally or IV intravenously) 40 mg/day on days 1-4, 9-11, 17-20 in repeating 28- to 35-day cycles.37 Approximately two-thirds of previously untreated patients will respond to VAD, usually within two to three cycles.38-40 Unfortunately, despite the continuous infusion of chemotherapy in VAD and other regimens41-43 (see Table 83.2), the majority of these responses are partial,38-40, 42, 44 as seen with earlier bolus regimens. Also, long-term survival of nontrans-planted myeloma patients treated with VAD is not significantly better than that seen with MP.3' 20 VAD is a reasonable option in patients with renal insufficiency because, in contrast to melphalan, neither vincristine nor doxorubicin requires dosage adjustment for impaired creatinine clearance. The widespread popularity of VAD since its advent in the 1980s until the last few years is accounted for by another factor as well: the dramatic increase in the use of HDC/ASCS. Several groups have reported a clear negative impact on stem cell mobilization and subsequent engraft-ment (particularly platelets) from prior melphalan therapy.45-47 Accordingly, VAD (two to four cycles) was often the initial regimen used in patients for whom HDC/ASCS was planned. More recently, TD has supplanted VAD as the most widely used regimen in such patients.

Central line placement and use of an ambulatory pump for regimens like VAD are inconvenient and are associated with infections and thrombotic complications. This, and the recognition that infusional regimens have not changed the overall course of MM compared to MP, has led to interest in more convenient bolus or oral variations on VAD (see Table 83.2). Randomized studies have shown that both "bolus

VAD," with the standard doses of each drug given as an IV injection on days 1-4, and also the DVd regimen have similar efficacy to traditional VAD.48' 49 DVd consists of pegylated doxorubicin (Doxilâ„¢) 40 mg/m2 IVPB on day 1, Vincristine 2 mg IVP on day 1, and dex-amethasone 40 mg/day on days 1-4. In a Phase II study, DVd induced major responses in 88% of newly diagnosed patients and was well tolerated overall.49 It is noteworthy that grade 3-4 palmar-plantar ery-throdysesthesia, a Doxil-related toxicity not seen with traditional VAD, occurred in approximately 20% of patients. The VECD protocol, using bolus injections of vincristine 1.5 mg day 1 and epirubicin 20 mg/m2 days 2 and 3 with 1-hour infusions of cyclophosphamide 200 mg/m2 days 1-3 and oral dexamethasone 20 mg/m2 days 1-5, is yet another regimen with comparable efficacy to VAD.50 Bolus VAD or VECD are less expensive than either standard infusional VAD51 or DVd. In a preliminary cost analysis, DVd was shown to be less costly than VAD if the latter was administered on an inpatient basis.52 Given the significantly higher drug costs associated with DVd,52 this might not hold true at centers where both regimens are given in the outpatient setting.

Oral VAD variants have also been developed, and these are likely to have similar efficacy to traditional VAD.53, 54 The lack of availability of oral anthracyclines in the United States at present makes these less relevant for standard practice, however.

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