Inoperable Melanoma Research Articles

Phase I study of the combination of docetaxel, temozolomide and cisplatin in patients with metastatic melanoma

In a search for more effective combination chemotherapy for the treatment of metastatic melanoma, we conducted a phase I trial of a novel combination of docetaxel, temozolomide, and cisplatin. Patients with inoperable or recurrent metastatic melanoma with a Zubrod performance status of 2 or less and adequate organ function were eligible. The dose of docetaxel was escalated between cohorts of patients, and the doses of temozolomide and cisplatin were fixed. A standard 3 + 3 dose escalation design was used to determine the maximum tolerated dose (MTD). Among 23 patients who were enrolled, 21 were evaluable for toxicity. Eighteen patients (78%) had stage IV-M1c disease. The dose-limiting toxicities were myelosuppression and pulmonary embolism. The MTD was 30 mg/m(2) docetaxel on days 1, 8, and 15 when given with 150 mg/m(2) temozolomide on days 1-5, and 20 mg/m(2) cisplatin on days 1-4, repeating every 4 weeks. Among 19 patients evaluated for response, 6 (32%) had partial responses and 5 (26%) had stable disease. Among 14 chemo-naive patients, 6 (43%) had a partial response and 4 (29%) had stable disease. Nine patients developed brain metastases by the time of the last follow-up evaluation, and the median time to brain metastases for all 19 evaluable patients has not been reached. This combination was well tolerated and appears to be a promising treatment for patient with metastatic melanoma.

Final results of a phase I study of daily PI-88 as a single agent and in combination with dacarbazine (D) in patients with metastatic melanoma

8532 Background: PI-88 is a heparan sulfate mimetic that inhibits angiogenesis and metastasis directly and via release of tissue factor pathway inhibitor (TFPI). PI-88 has shown some efficacy in an intermittent dosage regimen (250 mg/day 4 days/week) in melanoma (Thomson et al, ASCO 2005). This study tested PI-88 7 days per week alone (group 1) and in combination with 3 weekly D (group 2). Methods: Eligibility included inoperable metastatic melanoma, no prior chemotherapy, PS 0–1, adequate organ function, no recent use of heparin, negative anti-heparin antibody (AHA), no concurrent use of anti-coagulants or anti-platelet agents, no history of GI bleeding. Group 1 cohorts received daily PI-88 in doses of 140 mg, 190 mg and 250 mg. Group 2 received PI-88 commencing at the level below the single agent MTD plus D 1,000 mg/m2 every 21 days. Group 1 pts who had PD could continue PI-88 with the addition of D. FDG-PET scans were performed prior to and after 6 weeks PI-88 in Group 1. Free TFPI was measured in serum prior to and up to 2hr post first dose PI-88 in group 1. Results: Group 1 - DLT occurred in 0/3 (140 mg), 0/3 (190 mg) and 2/3 (250 mg) pts. Group 2 - DLT occurred in 1/6 (140 mg) and 0/4 (190 mg) pts. All DLTs were AHA positive grade III/IV thrombocytopenia with in 1 pt (250 mg) cerebral venous sinus thrombosis. No other major toxicities and no increase in expected DTIC toxicities were observed. 4 group 1 pts had pre/post PET scans. One pt had 50% fall in SUVmax with radiologic SD for 4 months. No radiologic responses occurred with PI-88 alone. 3/9 pts in group 2 had radiologic PR. 2/5 group1 pts who had D added to PI-88 had PR. Free TFPI increased from 6.9 ± 1.9 ng/ml just prior PI-88 to 56.1 ± 19.4 30 min post PI-88. The elevated levels were maintained at 60 and 120 min. Elevation of free TFPI did not correlate with PI-88 dose. Conclusion: The recommended phase II dose of continuous daily PI-88 is 190mg alone and in combination with D 1,000 mg/m2 every 3 weeks. An ongoing randomised study is comparing D 1,000 mg/m2 plus PI-88 190mg/day to single-agent D. No significant financial relationships to disclose.

A biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, temozolomide (Temodal), interferon-alfa and interleukin-2 for metastatic melanoma: a phase II study

Our objective was to evaluate the toxicity and antitumor efficacy of concurrent biochemotherapy in metastatic melanoma patients and the effectiveness of adding temozolomide to protect the brain from metastases. Twenty-three patients with advanced inoperable melanoma were hospitalized for 5-6 days for the following treatment: cisplatin 20 mg/m daily for 4 days, vinblastine 1.6 mg/m daily for 4 days and oral temozolomide 250 mg/m daily for 5 days, with 18 x 10 IU/m intravenous interleukin-2 by continuous infusion for 4 days (the dose was cut daily by 50%) and 5 x 10 U/m interferon-alfa subcutaneously daily for 5 days, repeated at 28-day intervals for a maximum of nine courses. According to the standard World Health Organization response criterion, the objective response rate was 43.4% and the median survival was 18.6 months. All but one patient survived for more than 12 months, and no responding patient progressed first in the brain. Substituting dacarbazine by temozolomide in the MD Anderson melanoma section protocol appears to offer protection against dissemination of brain metastases, equal activity in the periphery and a possible lower incidence of toxicity due to the oral route.

Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-α

Metastatic melanoma is commonly treated with chemotherapy and/or biological agents used separately. In this study we have investigated the efficacy of combined chemotherapy using cisplatin, vinblastine, DTIC (CVD) and biological therapy using interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) in patients with metastatic melanoma. All patients had advanced, inoperable melanoma without prior treatment with chemotherapy or biotherapy, a performance status of ECOG 0-2 and no evidence of symptomatic brain metastases. The CVD regimen consisted of cisplatin 20 mg/m2/d x 4, vinblastine 1.6 mg/m2/d x 5 and DTIC 800 mg/m2 x 1, repeated at 21-day intervals. The biotherapy regimen included IL-2, 9 x 10(6) IU/ m2/d x 4 days and IFN-alpha 5 x 10(6) U/m2/d SC x 5 days. The CVD and biotherapy regimens were integrated initially, in an alternating manner at 6-week intervals and subsequently, in a sequential fashion where patients were randomized to receive either CVD immediately followed by biotherapy (CVD/Bio) or the reverse sequence (Bio/CVD). Patients were admitted to the hospital for IL-2 administration and for monitoring and treatment of IL-2 induced side effects. The phase II results of the integrated therapy (biochemotherapy) studies were retrospectively compared to our previously reported results with the CVD regimen used alone. The alternating biochemotherapy program was used in 40 patients and the sequential biochemotherapy was used in 62 patients. The alternating regimen produced 2 CRs and 11 PRs for an overall response rate of 33% among 39 evaluable patients. The sequential biochemotherapy produced 14 CRs and 23 PRs for an overall response rate of 60% (95% CI, 47% to 72%). The sequence of CVD/Bio resulted in a higher response rate (11 CRs + 11 PRs (69%)) compared to the Bio/CVD sequence (3 CRs + 12 PRs (50%)). Although the duration of PRs was short (median, 8 months), the median duration of CRs was 3+years and 10 of 16 CRs are currently disease free for periods of 3+ to 6+ years. The median survival of patients receiving sequential biochemotherapy was 13 months compared to 9 months for the CVD treated group (P = 0.04). Treatment with biochemotherapy was associated with severe toxicity including intense myelosuppression, infections, IL-2 induced constitutional toxicity and hypotension. However, the IL-2 induced toxicities were generally manageable on a regular ward, except for 15% of the patients who required transfer to an intensive care unit for treatment of complications associated with the treatment. The sequential combination of CVD with IL-2 + IFN-alpha appears to have produced an increase in the number of durable responses in patients with metastatic melanoma. The toxicity of this program, although severe, was manageable. The biochemotherapy regimen produced an apparent increase in the median survival compared to that observed with the CVD regimen. However, a prospective comparison of these two regimens will be required to confirm these observations.

Sequential chemo-immunotherapy treatment of metastatic malignant melanoma

Twelve patients with recurring metastatic inoperable malignant melanoma (performance status ECOG 0-1), received the following chemotherapy: tamoxifen p.o., carmustine i.v., dacarbazine i.v., and cisplatin i.v., followed by immunotherapy: interleukin-2 s.c. and interferon-alpha s.c. The treatment cycle was repeated every 6 weeks. Total response rate was 66.6%, with 25% (3 patients) achieving complete cure that has persisted for a period of 17.75 months (mean). In addition, different responses to treatment were observed between the local recurrence lesions and the metastatic lesions. Medium to severe side effects were observed, all but one of them being reversible (neurotoxicity), such as fever, anemia, leukopenia: nephrotoxicity, neurotoxicity, and dyspnea.

Results of regional isolated perfusion for locally inoperable melanoma of the limbs

In the period 1978-1990, 49 patients with locally inoperable melanoma of the limbs were treated with regional isolated perfusion according to four different perfusion schedules. Perfusion resulted in a complete remission in 28 patients (57%), with a median duration of 10 (1-55+) months, and a partial remission in 10 (21%), with a median duration of 3 (1-9) months. In patients treated with a double (normothermic or sequential hyperthermic) perfusion schedule the complete remission rate was higher. Regional lymph node involvement reduced the chance of achieving complete remission. Twelve patients with complete remission (43%) showed a relapse in the perfused area. The corresponding 3-year limb recurrence-free interval was 46%. This interval was mainly influenced by the number of lesions at the moment of perfusion. Three of the patients who failed to respond eventually required amputation of the affected limb. The median follow-up of the surviving patients was 23 (5-142) months. At the time of analysis 23 patients were still alive, 12 of whom had no evidence of disease. Patients with complete remission had a slightly, though statistically not significant better 3-year survival rate than patients without complete remission (49% vs 33%). Regional isolated perfusion halted progression in all of these 49 patients and resulted in a complete remission for 57%. It is, therefore, an important modality in the management of patients with locally inoperable melanoma and provides a valuable alternative to amputation.

Regional Isolated Limb Perfusion in Patients with Malignant Melanoma

In this overview the Amsterdam/Rotterdam ‘controlled’ normothermic (tissue temperatures 37-38 °C) perfusion technique is described. The benefit of the widely used so-called ‘mild’ hyperthermia (39-40°C) is queried. A plea is made to report acute regional toxicity after perfusion according to Wieberdink’s grading system for uniformity. Perfusion has a well-established role in the treatment of locally inoperable melanoma. As an adjunct to surgery, benefit has also been shown in resectable stage II–III recurrent melanoma. For stage I primary melanoma the results of the ongoing EORTC/WHO adjuvant trials are eagerly awaited. In measurable disease an overall response rate of about 80% (with equal proportions of complete and partial remissions) can be obtained by single normothermic or ‘mild’ hyperthermic perfusion. Perfusion strategies that have been investigated to improve the complete response rate are discussed: the application of other cytostatics than melphalan, the role of repeat perfusions, perfusion with melphalan at borderline ‘true’ hyperthermic temperatures (40.5-42°C), sequential perfusion applying ‘true’ hyperthermia (42-43°C) and melphalan separately, and perfusion with the combination of rTNF-alpha, Inter-feron-gamma and melphalan. The ideal of a 100% complete remission rate has been approached in several perfusion strategies but the duration of remission is still rather short. The main issue for the immediate future will therefore be prolongation of the limb recurrence-free interval.

Use of I-131 labeled, murine Fab against a high molecular weight antigen of human melanoma: preliminary experience.

High molecular weight antigen (HMWA) is a tumor-associated proteoglycan of human malignant melanoma. I-131 labeled Fab fragments of these specific antibodies were used for preliminary feasibility studies for radioimmunodetection and therapy of human subjects who had inoperable metastatic melanoma. Ten patients received tracer doses of 5-13 mCi (185-481 MBq) of I-131 (anti-HMWA) Fab. All patients (8/8) who had melanoma lesions greater than 1 cm by correlative diagnostic methods had one or more lesions that had localization to tumor of the radiolabeled Fab. In all, 17 of 23 (74%) documented metastases were seen. There were no false positives in this series. Two patients who had avid uptake received potentially radiotherapeutic doses of 142 mCi (5,254 MBq) (one patient) and 181 mCi (6,697 MBq) and 193 (7,141 MBq) (total: 374 mCi or 13,838 MBq) (one patient). For both of these patients, whole body imaging studies showed that the localization of the high dose I-131 Fab was predominantly in tumor. The patient who received the larger dose showed a greater than 50% reduction in the size of pelvic and pericaval nodes, with stabilization of disease at the smaller nodal size for a period of three months. On whole body images, the anti-Fab HMWA appears to be more tumor selective than Fab preparations that target the p97 antigen for melanoma, and there is less uptake in liver.

Intra-arterial infusion therapy with 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (NSC 45388) for malignant melanoma.

Seventeen patients with advanced regional malignant melanoma were treated with intra-arterial 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC) in an attempt to improve the response rate to this drug. There were 6 partial objective (greater than 50% reduction) responders and one complete remission for an overall response rate of 41%. The local control of melanoma by this modality of treatment was impressive, and toxicity was less than that which is usually seen with systemic chemotherapy with DTIC. Our studies suggest intra-arterial therapy is preferrable to systemic therapy for the isolated inoperable melanoma lesion.

Immunotherapy of Malignant Melanoma.

Meeting Abstracts1 May 1972Immunotherapy of Malignant Melanoma.M. Mastrangelo, M.D., R. S. Bornstein, M.D., H. Sulit, M.D., D. Chee, Ph.D., J. VV. Yarbro, M.D., F.A.C.P., R. T. Prehn, M.D.M. Mastrangelo, M.D.Search for more papers by this author, R. S. Bornstein, M.D.Search for more papers by this author, H. Sulit, M.D.Search for more papers by this author, D. Chee, Ph.D.Search for more papers by this author, J. VV. Yarbro, M.D., F.A.C.P.Search for more papers by this author, R. T. Prehn, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-76-5-877_4 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptExtensive investigation of the immunology of animal and human neoplasia suggests that host immunity may be a significant factor in host resistance to cancer. Furthermore, this immunological response may be capable of augmentation. The frequency of spontaneous regressions and the often noted occurrence of metastatic disease many years after removal of the primary lesion have suggested that host factors may play a role in the control of human melanoma. The lack of efficacy of conventional means of therapy has lent impetus to an immunological approach to the treatment of inoperable melanoma. Several uncontrolled studies utilizing intralesional injection of BCG vaccine... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Philadelphia, Pa. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byBCG in der Immuntherapie von Tumoren — Eine kurze historische ÜbersichtLocal immunotherapy — Experimental and clinical researchBCG and Cancer 1 May 1972Volume 76, Issue 5Page: 877-878KeywordsBacille calmette guerinCancer immunotherapyImmunityImmunologyLesionsMelanomaVaccines Issue Published: 1 May 1972 PDF downloadLoading ...