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The data from this study indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate in patients with poor prognosis metastatic melanoma.

Although biochemotherapy appears to be a promising treatment for metastatic melanoma, its impact remains unpredictable. Microsatellite markers for loss of heterozygosity (LOH) appear to have prognostic significance when identified in primary tumors and serum and/or plasma from cancer patients. However, their association with response to systemic therapy has yet to be assessed. To determine whether microsatellite markers are associated with response to therapy, serum from 41 patients with metastatic melanoma, drawn before the initiation of biochemotherapy, was analyzed for LOH with nine microsatellite markers. During a median follow-up of 13 months, the overall response rate for these 41 patients was 56%, including 13 (32%) complete responses and 10 (24%) partial responses. LOH was detected in sera from 12 (29%) of the 41 patients. The response rate of these 12 patients was 17% (95% confidence interval [CI] = 5% to 45%), whereas that of the 29 patients without LOH was 72% (95% CI = 54% to 85%) (P =.001). All statistical tests were two-sided. The presence of LOH was statistically significant and independently associated with disease progression (multivariable analysis, P =.003). Circulating tumor DNA markers may be useful in assessing prognosis for advanced melanoma patients and their response to biochemotherapy.

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BACKGROUND In vitro cell culture data and preclinical models suggest that tamoxifen modulates tumor cell sensitivity to a wide range of therapeutic agents. In the current study, the authors examined whether high‐dose tamoxifen (HDT) improved the overall and complete response in patients with metastatic melanoma who were treated with concurrent biochemotherapy. METHODS Forty‐nine patients were treated with a biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo interleukin‐2, interferon‐α‐2b, and tamoxifen. The study had a 2‐step design, beginning with a tamoxifen dose escalation from 40 mg to 320 mg (17 subjects) to evaluate safety and tolerability, followed by Phase II accrual of 32 patients to HDT (320 mg) to assess clinical efficacy. Efficacy was compared with a similar modified biochemotherapy regimen with low‐dose tamoxifen (LDT). Pharmacokinetic studies were performed to determine in vivo tamoxifen levels. RESULTS Tamoxifen dose escalation was completed without any reported dose‐limiting toxicity. The overall response rate in the HDT group was 50% (95% confidence interval, 33.2%–66.8%), with a complete response rate of 6% and a median survival of 9.5 months. The overall response rate was not improved and the complete response and survival appeared inferior compared with that of patients recently treated with concurrent biochemotherapy and LDT. Serum tamoxifen levels were found to correlate with the dose administered, with a mean of 0.9 μM at the 40‐mg dose to 4.6 μM at the 320‐mg dose. Ultrafiltered protein‐free sera demonstrated low (< 0.01 μM) concentrations of tamoxifen. CONCLUSIONS The addition of HDT to a regimen of concurrent biochemotherapy did not appear to improve response rates or overall survival, despite reaching the targeted plasma concentration. Unknown drug interactions or high protein binding of tamoxifen may account for the lack of clinical effectiveness. Cancer 2001;92:609–19. © 2001 American Cancer Society.

A healthy woman sought preconceptional genetic counseling regarding a family history of a mitochondrial myopathy in her brother and retinitis pigmentosa (RP) in her two maternal aunts. Several questions were raised: (1) What is the likelihood of a familial mitochondrial condition? (2) What molecular tests or prenatal screening can we offer? (3) How would these tests help assess the likelihood of a familial mitochondrial condition? A mitochondrial mutation previously identified in the brother consisted of a heteroplasmic 2.9 kb deletion. We detected this deletion in the peripheral blood of the brother by PCR amplification of the deletion breakpoint, but not in his mother, the consultand, nor in one of the two aunts affected with RP. Although the molecular analysis was encouraging to the consultand, a familial mitochondrial disorder could not be eliminated with certainty. The pros and cons of prenatal testing for mitochondrial disorders are discussed in general, and as specifically related to this family.