Melanoma by Howard L. Kaufman & Janice M. Mehnert

Author:Howard L. Kaufman & Janice M. Mehnert
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

3 Combination Chemotherapy

Given the low response rates to single chemotherapy agents, combinations of three to four chemotherapy agents have been investigated in the treatment of advanced-stage melanoma. A number of regimens have been investigated including combinations of cisplatin, vinblastine or vindesine, and dacarbazine (CVD) and what is known as the Dartmouth regimen (carmustine (BCNU), dacarbazine, cisplatin, and tamoxifen). Initial excitement for these regimens was primarily due to the observed increased response rates; however, follow-up studies incorporating multiple treatment centers demonstrated response rates similar to those seen with single-agent dacarbazine. Initial responses with CVD treatment demonstrated an overall response rate of 40 %, almost double that seen with dacarbazine treatment [62]. A multicenter phase III trial of CVD versus CVD plus interleukin-2 and interferon-α2b demonstrated a more modest response rate for CVD of 21 % [6]. And, in a study evaluating the CVD regimen setting as second-line chemotherapy, response rate in patients treated with CVD was 9.6 % with the best responses being PRs [46].

The Dartmouth regimen was investigated in a number of clinical trials. Initial trials included tamoxifen (TAM), but there was some concern of its side effects, specifically increased incidence of deep venous thrombosis and PEs, despite the increased overall response rates [70]. Further studies then compared the chemotherapy regimen alone contained within the Dartmouth regimen (carmustine (BCNU), vindesine, and dacarbazine) versus chemotherapy plus TAM. McClay et al. [70] demonstrated decreases in response rate in the absence of TAM, while two phase III trials demonstrated no differences in response rates, PFS, and OS with or without TAM added to chemotherapy [18, 86]. Margolin et al. [69] demonstrated similar objective response rates for the Dartmouth regimen, 15 % (12/79; 95 % CI, 8–25 %) as seen with single-agent treatment with dacarbazine. Chapman et al. [15] investigated the Dartmouth regimen versus the standard chemotherapy treatment, dacarbazine, in a multicenter phase III clinical trial which demonstrated that there were no differences in overall survival, although a nonsignificant increased tumor response was noted in patients treated with the Dartmouth regimen. In total, no long-term or survival benefits were observed with the Dartmouth regimen, and there were significant, increased toxicities with this regimen, suggesting that it should not replace dacarbazine as a standard chemotherapy regimen.

The combination chemotherapy regimen of bleomycin, vincristine, lomustine (CCNU), and dacarbazine (BOLD) has also been investigated in the treatment of advanced-stage melanoma. A multicenter phase II clinical trial investigated the use of BOLD plus IFN-α, evaluating the use of combination chemotherapy plus immunotherapy. Forty-three patients with stage IV disease were enrolled on the clinical trial with diverse disease characteristics, including nine patients with brain metastases, and a 27 % response rate was observed, including one complete response and ten partial responses [79]. Subset analysis in treatment-naïve patients with brain metastases demonstrated a 40 % response rate [79]. A previous study had demonstrated response rates of 62 % using BOLD plus IFN-α [80], which included patients with both stage III and stage IV disease. Additionally, there was some variations between studies using natural, leukocyte-derived IFN-α and recombinant IFN-α.

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