"Immunoscore â€” a scoring system to determine specific lymphocyte populations in the core of the tumor and at its invasive margins â€” is emerging as a prognostic marker in colorectal cancer (CRC), according to researchers.
A new study sh"...
Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at the N7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.
The pharmacokinetics of melphalan after IV administration has been extensively studied in adult patients. Following injection, drug plasma concentrations declined rapidly in a biexponential manner with distribution phase and terminal elimination phase half-lives of approximately 10 and 75 minutes, respectively. Estimates of average total body clearance varied among studies, but typical values of approximately 7 to 9 mL/min/kg (250 to 325 mL/min/m²) were observed. One study has reported that on repeat dosing of 0.5 mg/kg every 6 weeks, the clearance of melphalan decreased from 8.1 mL/min/kg after the first course, to 5.5 mL/min/kg after the third course, but did not decrease appreciably after the third course. Mean (±SD) peak melphalan plasma concentrations in myeloma patients given IV melphalan at doses of 10 or 20 mg/m²were 1.2 ± 0.4 and 2.8 ± 1.9 mcg/mL, respectively.
The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into cerebrospinal fluid (CSF) is low. The extent of melphalan binding to plasma proteins ranges from 60% to 90%. Serum albumin is the major binding protein, while α 1-acid glycoprotein appears to account for about 20% of the plasma protein binding. Approximately 30% of the drug is (covalently) irreversibly bound to plasma proteins. Interactions with immunoglobulins have been found to be negligible.
Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, no other melphalan metabolites have been observed in humans. Although the contribution of renal elimination to melphalan clearance appears to be low, one study noted an increase in the occurrence of severe leukopenia in patients with elevated BUN after 10 weeks of therapy.
A randomized trial compared prednisone plus IV melphalan to prednisone plus oral melphalan in the treatment of myeloma. As discussed below, overall response rates at week 22 were comparable; however, because of changes in trial design, conclusions as to the relative activity of the 2 formulations after week 22 are impossible to make.
Both arms received oral prednisone starting at 0.8 mg/kg/day with doses tapered over 6 weeks. Melphalan doses in each arm were:
Arm 1: Oral melphalan 0.15 mg/kg/day x 7 followed by 0.05 mg/kg/day when WBC began to rise.
Arm 2: IV melphalan 16 mg/m² q 2 weeks x 4 (over 6 weeks) followed by the same dose every 4 weeks.
Doses of melphalan were adjusted according to the following criteria:
Table 1. Criteria for Dosage Adjustment in a Randomized Clinical
|WBC/mm³||Platelets||Percent of Full Dose|
|≥ 4,000||≥ 100,000||100|
|≥ 3,000||≥ 75,000||75|
|≥ 2,000||≥ 50,000||50|
|< 2,000||< 50,000||0|
One hundred seven patients were randomized to the oral melphalan arm and 203 patients to the IV melphalan arm. More patients had a poor-risk classification (58% versus 44%) and high tumor load (51% versus 34%) on the oral compared to the IV arm (P < 0.04). Response rates at week 22 are shown in the following table:
Table 2. Response Rates at Week 22
|Initial Arm||Evaluable Patients||Respondersn (%)||P|
|Oral melphalan||100||44 (44%)||P > 0.2|
|IV melphalan||195||74 (38%)|
Because of changes in protocol design after week 22, other efficacy parameters such as response duration and survival cannot be compared.
Severe myelotoxicity (WBC ≤ 1,000 and/or platelets ≤ 25,000) was more common in the IV melphalan arm (28%) than in the oral melphalan arm (11%).
An association was noted between poor renal function and myelosuppression; consequently, an amendment to the protocol required a 50% reduction in IV melphalan dose if the BUN was ≥ 30 mg/dL. The rate of severe leukopenia in the IV arm in the patients with BUN over 30 mg/dL decreased from 50% (8/16) before protocol amendment to 11% (3/28) (P = 0.01) after the amendment.
Before the dosing amendment, there was a 10% (8/77) incidence of drug-related death in the IV arm. After the dosing amendment, this incidence was 3% (3/108). This compares to an overall 1% (1/100) incidence of drug-related death in the oral arm.
Last reviewed on RxList: 1/21/2009
This monograph has been modified to include the generic and brand name in many instances.
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