Challenges of chemosensitivity testing.
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Antineoplastic Agents↗
Biomedical subjects
Agop Y Bedikian
Publications and source records attributed to Agop Y Bedikian.
Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group.
PURPOSE: Chemotherapy resistance in melanoma has been linked to antiapoptotic effects mediated by Bcl-2 protein. We evaluated whether targeting Bcl-2 using an antisense oligonucleotide (oblimersen sodium) could improve the efficacy of systemic chemotherapy in patients with advanced melanoma. PATIENTS AND METHODS: We randomly assigned chemotherapy-naïve patients with advanced melanoma to treatment with dacarbazine (1,000 mg/m2) alone or preceded by a 5-day continuous intravenous infusion of oblimersen sodium (7 mg/kg/d) every 3 weeks for up to eight cycles. Patients were stratified by Eastern Cooperative Oncology Group performance status, liver metastases, disease site, and serum lactate dehydrogenase (LDH). The primary efficacy end point was overall survival. RESULTS: Among 771 patients randomly assigned, the addition of oblimersen to dacarbazine yielded a trend toward improved survival at 24-month minimum follow-up (median, 9.0 v 7.8 months; P = .077) and significant increases in progression-free survival (median, 2.6 v 1.6 months; P < .001), overall response (13.5% v 7.5%; P = .007), complete response (2.8% v 0.8%), and durable response (7.3% v 3.6%; P = .03). A significant interaction between baseline serum LDH and treatment was observed; oblimersen significantly increased survival in patients whose baseline serum LDH was not elevated (median overall survival, 11.4 v 9.7 months; P = .02). Neutropenia and thrombocytopenia were increased in the oblimersen-dacarbazine group; however, there was no increase in serious infections or bleeding events. CONCLUSION: The addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes in patients with advanced melanoma and increased overall survival in patients without an elevated baseline serum LDH.
Adolescent↗
Metastatic uveal melanoma therapy: current options.
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Combined Modality Therapy↗
Pharmacokinetics and urinary excretion of vincristine sulfate liposomes injection in metastatic melanoma patients.
Vincristine sulfate liposomes injection (VSLI) is a liposomal formulation of vincristine encapsulated in sphingosomes composed of sphinogomyelin and cholesterol (58/42; mol/mol). The pharmacokinetics and urinary excretion of VSLI were evaluated in 12 patients with metastatic melanoma after single-dose (2.0 mg/m2 every 2 weeks = 1 cycle) and multiple-dose (cycle 3, pharmacokinetics only) administrations (intravenous infusion over 1 hour). After VSLI infusion, total (released and encapsulated) vincristine concentrations in plasma remained relatively constant for 3 to 12 hours and thereafter declined, with interpatient variability seen in the rate of decline resulting in monoexponential or biexponential profiles. The area under the plasma concentration-time curve from time zero to infinity of total vincristine in plasma ranged from 4933 to 40495 h.ng/mL and total clearance ranged from 131 to 445 mL/h. The volume of distribution at steady state was 2650 +/- 731 mL, indicating VSLI was mainly confined within the plasma. The released vincristine concentrations in plasma were below the level of quantitation in 95% of samples. The pharmacokinetic parameters were similar between cycles 1 and 3, and trough plasma levels of total vincristine were below the level of quantitation of 1 ng/mL. Approximately 8% of the injected dose was excreted in the urine as unchanged vincristine (7%) or N-desformylvincristine (0.8%). Overall, VSLI exhibited a longer circulation half-life and higher area under the plasma concentration-time curve compared to conventional vincristine, whereas its route of elimination remained unchanged.
Adult↗
A phase II trial of arsenic trioxide in patients with metastatic melanoma.
BACKGROUND: Arsenic trioxide induces growth inhibition and apoptosis in human melanoma cell lines. Therefore, a Phase II trial was conducted to evaluate the efficacy and toxicity of single-agent arsenic trioxide in patients with Stage IV melanoma. METHODS: Twenty patients, 10 with metastatic melanoma of cutaneous origin and 10 with metastatic melanoma of choroidal origin, received arsenic trioxide 0.25 mg/kg/day for 5 days, followed by a maintenance dose of 0.35 mg/kg/day twice a week. All patients with melanoma of cutaneous origin and four patients with melanoma of choroidal origin had received prior therapy. RESULTS: Single-agent arsenic trioxide did not induce clinical response in this patient population. Eight patients (five with melanoma of cutaneous origin, and three with melanoma of choroidal origin) had disease stabilization for at least six weeks. The median overall survival duration for patients with melanoma of cutaneous origin was 7.9 months, and that of patients with melanoma of choroidal origin has not been reached at a median follow-up duration of 11.8 months. Grade 3 toxicity included neutropenia, fatigue, abdominal pain, and arthralgia. Grade 4 toxicity did not occur. CONCLUSIONS: Single-agent arsenic trioxide was generally well tolerated; however, no tumor regression was observed in this patient population. Future clinical trials should evaluate arsenic trioxide in combination with other anticancer drugs that may improve its clinical activity in melanoma.
Adult↗
Pilot study of high-dose, concurrent biochemotherapy for advanced melanoma.
BACKGROUND: Durable complete response rates ranging from 5% to 20% have been reported in association with biochemotherapy for patients with metastatic melanoma, with response rates on the low end of this range being observed in trials that used lower doses and less intense treatment schedules. In the current study, the authors addressed the feasibility of increasing the doses of agents used in concurrent biochemotherapy. METHODS: Three patients with metastatic melanoma were enrolled at each of six concurrent biochemotherapy dose levels. The doses were as follows: dacarbazine 800 mg/m(2) or 1000 mg/m(2) (Day 1); cisplatin 25 mg/m(2) or 30 mg/m(2) (Days 1-4); vinblastine 1.6 mg/m(2) or 1.8 mg/m(2) (Days 1-5); interleukin-2 9 million units (MU) per m(2) or 12 MU/m(2) as a 24-hour continuous infusion (Days 1-4); and interferon-alpha-2b 5 MU/m(2), 10 MU/m(2), or 15 MU/m(2) (Days 1-5) and 5 MU/m(2) (Days 7, 9, and 11) administered subcutaneously. RESULTS: Of the 19 patients who were enrolled, 18 were evaluable for toxicity and response. Sixty-nine treatment courses were administered in total (median, 4 courses per patient; range, 1-6 courses per patient), with reduction of the dose of at least 1 agent being required in 7 courses (10%). Twenty-six courses were delayed by a median of 7 days (range, 3-29 days), with interferon-alpha-2b administration frequently omitted because of thrombocytopenia, most often after Day 5. Blood product support was required in 40 courses. Dose-limiting toxic effects included global encephalopathy, renal and hepatic dysfunction, pancreatitis, and ileus. There was 1 complete response, and there were 10 partial responses. The median time to disease progression was 6.9 months, and the median survival duration was 12.2 months. CONCLUSIONS: Although dose intensification can be achieved safely in patients with advanced melanoma, other strategies should be pursued to enhance the clinical activity of biochemotherapy as a response induction regimen.
Adult↗
Biochemotherapy in patients with metastatic anorectal mucosal melanoma.
BACKGROUND: Patients with metastatic anorectal melanoma generally have an unfavorable prognosis, but no effective systemic therapy has been reported. METHODS: The authors retrospectively evaluated the medical records of all patients with metastatic anorectal melanoma treated with biochemotherapy between January 1991 and December 2001 at the University of Texas M. D. Anderson Cancer Center (Houston, TX). RESULTS: The search yielded 18 patients. Of these patients, 14 had undergone treatment with cisplatin (CDDP), vinblastine (VB), dacarbazine (DTIC), interferon alpha-2b (IFN), and interleukin 2 (IL-2); 2 had undergone treatment with CDDP, VB, DTIC, and IFN; 1 had undergone treatment with CDDP, IFN, and IL-2; and 1 had undergone treatment with CDDP, VB, temozolomide, IFN, and IL-2. All IL-2 treatments were administered intravenously. The median follow-up time was 12.2 months (range, 3.5-43.7 months). Eight patients (44%) had major responses, including two (11%) complete responses (CRs). Three patients were lost to follow-up evaluation after the completion of treatment. The median time to progression among the 15 remaining patients was 6.2 months. Four patients, including 1 with a CR, were alive at their last documented follow-up visits (survival: 14.0, 20.7, 31.3, and 43.7 months, respectively). The median overall survival was 12.2 months. Among 13 patients who received biochemotherapy as first-line systemic therapy, 6 patients (46%) had major responses, including two (15%) CRs. The median time to progression for this group was 6.2 months, and the median overall survival was 12.9 months. CONCLUSIONS: Biochemotherapy had substantial activity against metastatic anorectal melanoma and should be considered for use in the treatment of metastatic disease from primary anorectal melanoma.
Adult↗
Phase II evaluation of paclitaxel by short intravenous infusion in metastatic melanoma.
In four clinical trials in mostly chemotherapy-naive patients with metastatic melanoma, paclitaxel was found to be effective with a response rate of 16%. In vitro studies have shown that following exposure of cancer cells to paclitaxel for 1 h, sensitivity to repeat paclitaxel doses decreased markedly at 48-72 h and returned at 120 h. In this phase II study we assessed the efficacy of paclitaxel at a dose of 90 mg/m per day given intravenously over 80 min on days 1, 5 and 9 every 3 weeks, initially in two groups of 14 patients with metastatic choroidal and non-choroidal melanoma. One patient in the non-choroidal melanoma group had a confirmed response, and 23 additional patients were therefore accrued to this group. (One patient withdrew consent for treatment within a week from start of therapy. The patient was considered to have received inadequate treatment and a replacement was registered.) A total of 52 patients with a median age of 55 years (range 21-79 years) were treated. Forty-four patients completed two or more courses of paclitaxel and were evaluable for response. We observed >50% tumour regression in six patients. All the responses except one were amongst the 32 evaluable patients with non-choroidal melanoma. The response rate in this group was 15.6%. During the 219 courses of paclitaxel delivered, the side effects were mild, manageable and mostly reversible. No grade 3 acute allergic reactions were observed. Paclitaxel given by short intravenous infusion is marginally active against previously treated non-choroidal melanoma.
Adult↗
The role of taxanes in the treatment of metastatic melanoma.
The management of patients with metastatic malignant melanoma remains difficult. Conventional chemotherapy has been disappointingly ineffective. Dacarbazine (DTIC) is considered to be one of the most active single agents with a response rate of approximately 15-20%. Many patients who initially respond to treatment subsequently relapse. Clearly, there is a need for improvement, and the evaluation of new agents is warranted. This article reviews current phase II studies of single-agent taxanes and their combinations in patients with metastatic melanoma, and examines the likely impact of taxanes on treatment strategies. Response rates from phase II trials with single-agent taxanes vary from 3.3% to 17%. Prolonged durations of disease control are observed. Combinations of taxanes with DTIC, temozolomide, cisplatin, carboplatin and tamoxifen have demonstrated response rates from 12% to 41%, suggesting that they are at least as effective as various other combination regimens. Encouraging results have been produced in the second-line metastatic setting. Taxanes, both as single agents and in combinations, may be a treatment option for some patients with metastatic melanoma, especially in the second-line setting.
Antineoplastic Combined Chemotherapy Protocols↗
Phase II evaluation of temozolomide in metastatic choroidal melanoma.
Temozolomide (Temodar) has demonstrated clinical activity against melanoma equivalent to that of intravenous dacarbazine (DTIC). Phase I clinical studies have shown that low dose chronic administration of temozolomide permits the delivery of higher dose intensities than a 5 day dose schedule. Temozolomide is hydrolysed to its active metabolite monomethyltriazenoimidazole carboxamide (MTIC) upon absorption from the gastrointestinal tract, while DTIC is inactive until it is metabolized in the liver to MTIC. In view of this, a higher concentration of MTIC will pass through the liver during the first pass when its source is temozolomide rather than DTIC. To determine if these characteristics of temozolomide will translate into a higher response rate than that achieved with DTIC, we conducted a phase II clinical trial of temozolomide in patients with uveal melanoma metastatic to the liver. Temozolomide was administered orally at a starting dose of 75 mg/m2 per day for 21 days every 4 weeks. Fourteen patients were enrolled in the trial. No complete or partial responses were observed. Stabilization of disease was achieved in two patients. The treatments were well tolerated. We conclude that, like DTIC, temozolomide at the dose and schedule studied in this trial is not effective for the control of metastatic melanoma of uveal origin.
Adolescent↗
Sphincter-sparing local excision and adjuvant radiation for anal-rectal melanoma.
PURPOSE: To evaluate the outcome and toxicity of a sphincter-sparing treatment strategy in the management of patients with anal-rectal melanoma. PATIENTS AND METHODS: Between 1989 and 2000, 23 patients with invasive anal-rectal melanoma were managed with sphincter-sparing surgical resection and adjuvant radiation. Surgery consisted of primary local excision, as well as dissection for patients with documented regional nodal disease. Adjuvant radiation was delivered using a hypofractionated regimen of 30 Gy in five fractions over 2.5 weeks. Adjuvant systemic therapy was delivered to nine patients: cytotoxic chemotherapy in seven and immunotherapy in two. RESULTS: After a median follow-up of 32 months, 15 patients had relapsed and 15 patients had died. The actuarial 5-year overall, disease-specific, disease-free, and distant metastasis-free survival rates were 31%, 36%, 37%, and 35%, respectively. The actuarial 5-year local and regional nodal control rates were 74% and 84%, respectively. No patient had locoregional failure as the sole site of failure and no patient required salvage abdominoperineal resection (APR). By univariate analysis, patients with nodal disease at presentation had a decreased actuarial 5-year disease-specific (0% v 45%, P =.004), disease-free (0% v 45%, P <.001), and distant metastasis-free survival (0% v 42%, P <.001). The actuarial complication-free survival rate was 71%. Two patients developed mild scrotal edema (grade 1), and four patients developed moderate proctitis requiring prolonged medical management (grade 2). CONCLUSION: Sphincter-sparing local excision and adjuvant radiation is well tolerated and can effectively control local-regional disease while avoiding the functional morbidity of APR.
Adult↗
Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial.
PURPOSE: The addition of cytokines to chemotherapy has produced encouraging results in advanced melanoma. In this phase III trial, we compared the effects of chemotherapy (cisplatin, vinblastine, and dacarbazine [CVD]) with those of sequential biochemotherapy consisting of CVD plus interleukin-2 and interferon alfa-2b. PATIENTS AND METHODS: Metastatic melanoma patients who had not previously received chemotherapy were stratified by prognostic factors and given chemotherapy or biochemotherapy. CVD consisted of dacarbazine (days 1 and 22) and cisplatin and vinblastine (days 1 to 4 and 22 to 25). Biochemotherapy involved CVD with vinblastine reduced 25% plus interleukin-2 by 24-hour continuous infusion (on days 5 to 8, 17 to 20, and 26 to 29) and interferon alfa-2b by subcutaneous injection (on days 5 to 9, 17 to 21, and 26 to 30). Response was assessed every 6 weeks. RESULTS: Among 190 patients enrolled, 91 were assessable for biochemotherapy and 92 for chemotherapy. Ten percent of the patients were alive a median of 52 months from start of therapy. Response rates were 48% for biochemotherapy and 25% for chemotherapy (P =.001); six patients given biochemotherapy and two given chemotherapy had complete responses. Median time to progression (TTP) was 4.9 months for biochemotherapy and 2.4 months for chemotherapy (P =.008); median survival was 11.9 and 9.2 months, respectively (P =.06). The influence of treatment on TTP and survival was confirmed in multivariate analyses with other prognostic factors not included in the original stratification. Biochemotherapy produced substantially more constitutional, hemodynamic, and myelosuppressive toxic effects. CONCLUSION: Cytokines substantially augment the antitumor activity of chemotherapy at the expense of considerable toxicity in patients with metastatic melanoma.
Adult↗
Adjuvant irradiation for axillary metastases from malignant melanoma.
PURPOSE: To evaluate the outcome and treatment-related toxicity for patients with axillary lymph node metastases from malignant melanoma treated with surgery and radiation, with or without systemic therapy. MATERIALS AND METHODS: The medical records of 89 consecutive patients with axillary lymph node metastases from malignant melanoma were retrospectively reviewed. All patients underwent axillary dissection and postoperative radiation to a median dose of 30 Gy at 6 Gy/fraction delivered twice weekly. In 3 patients referred with microscopic residual disease, a single boost (4-6 Gy) was given to a reduced field. All but 2 patients were referred because their axillary dissections revealed features believed to predict a 30-50% risk of subsequent axillary recurrence: lymph nodes >/=3 cm in size (54 patients), >/=4 lymph nodes positive (44), the presence of extracapsular extension (69), recurrent disease after initial surgical resection (23), or multiple risk factors (77). Fifty-one patients received systemic therapy before or after radiation therapy. RESULTS: At a median follow-up of 63 months, 47 patients had relapsed and 43 patients had died. The actuarial overall and disease-free survival rates at 5 years were 50% and 46%, respectively. The actuarial axillary control and distant metastasis-free survival rates at 5 years were 87% and 49%, respectively. Univariate analysis revealed that the probability of axillary control was inferior when the axillary disease measured >6 cm in size (72% vs. 93%, p = 0.02), the location of the primary tumor was unknown (74% vs. 93%, p = 0.02), the axillary failure occurred within 18 months from diagnosis of the primary melanoma (84% vs. 100%, p = 0.04), or the Breslow thickness was >4 mm (80% vs. 96%, p = 0.04). Additionally, there was an inferior distant metastasis-free and disease-free survival when there were >2 nodes positive for metastatic disease, the primary lesion had a Breslow thickness >4 mm, or the axillary failure occurred within 18 months from diagnosis of the primary melanoma. On multivariate analysis, the significantly inferior distant metastasis-free and disease-free survival seen when >2 nodes were positive or the recurrence occurred within 18 months remained significant. The small number of axillary failures precluded multivariate analysis for axillary control; however, stratified analysis suggested that size >6 cm was the factor most closely associated with subsequent axillary failure. Twenty-six patients developed treatment-related arm edema. Classification according to the severity of edema yielded 5-year actuarial arm edema rates of 21%, 19%, and 1%, for Grade 1 (transient or asymptomatic), Grade 2 (requiring medical intervention), or Grade 3 (requiring surgical intervention) edema, respectively. CONCLUSION: Adjuvant radiation therapy using a hypofractionated regimen resulted in an 87% 5-year axillary control rate, superior to the 50-70% local control achieved with surgery alone for lymph node metastases from melanoma when high-risk features are present. Improvements are needed for patients with bulky nodal masses >6 cm in size. Mild-to-moderate arm edema was common, but manageable. The degree to which radiotherapy adds to the risk of arm edema after axillary dissection alone cannot be addressed in the present analysis.
Adult↗
Phase II trial of 9-nitrocamptothecin (RFS 2000) for patients with metastatic cutaneous or uveal melanoma.
The camptothecin derivative 9-nitrocamptothecin (9-NC) has demonstrated clinical activity in patients with ovarian and pancreatic carcinomas. Preclinical studies have shown promising activity of 9-NC for melanoma. We have thus conducted a phase II clinical trial of 9-NC for patients with metastatic cutaneous and uveal melanoma. Twenty-eight patients were enrolled in the trial, with diagnoses evenly divided between the two types of melanoma. 9-NC was administered orally at a starting dose of 1.5 mg/m(2)/day for 5 consecutive days of each week. No complete or partial responses were observed. Stabilization of disease was achieved in four individuals (15%) for durations of 3, 4, 6 and 8 months. Hematologic toxicity was moderate. Gastrointestinal side effects were common with 43% of the patients experiencing grade 3 or 4 diarrhea and 18% reporting grade 3 or 4 vomiting. In contrast to other 9-NC clinical trials, no patients developed chemical cystitis with gross hematuria. We conclude that, in keeping with the general chemoresistance of melanoma, 9-NC at the dose and schedule studied in this trial is significantly toxic and is not active for metastatic melanoma of cutaneous or uveal origin.
Adult↗