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1.
Ann Oncol ; 17(4): 571-7, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16469753

ABSTRACT

BACKGROUND: The addition of cytokines to chemotherapy (CT) has obtained encouraging but contradictory results in metastatic melanoma. In this phase III trial, we compared the effects of CT [cisplatin, vindesine and dacarbazine (CVD)] with those of concurrent biochemotherapy (bioCT) consisting of CVD plus interleukin-2 and interferon-alpha2b. PATIENTS AND METHODS: A total of 151 untreated metastatic melanoma patients were randomized, 75 on arm A (cisplatin 30 mg/m2 on days 1-3, vindesine 2.5 mg/m2 on day 1 and dacarbazine 250 mg/m2 on days 1-3), and 76 on arm B (same CVD scheme plus interferon-alpha2b on days 1-5 and interleukin-2 on days 1-5 and 8-15, both administered subcutaneously), either recycled every 3 weeks. Response was assessed every two cycles. RESULTS: Ten percent of the patients were alive at a median of 52 months from start of therapy. We observed a response rate (RR) of 21% on arm A versus 33% on arm B; three patients (4%) given bioCT had complete responses (CRs). Median time to progression (TTP) was identical; median overall survival (OS) time was 12 months on arm A and 11 months on arm B. CONCLUSIONS: BioCT is not better than CT alone; the trend in favor of the bioCT in terms of RR did not translate into better TTP or OS. Therefore, bioCT cannot be recommended as standard first-line therapy for metastatic melanoma.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Interferon-alpha/therapeutic use , Interleukin-2/therapeutic use , Melanoma/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Dacarbazine/administration & dosage , Female , Humans , Injections, Subcutaneous , Interferon alpha-2 , Interferon-alpha/administration & dosage , Interleukin-2/administration & dosage , Male , Melanoma/pathology , Middle Aged , Neoplasm Metastasis , Recombinant Proteins , Vinblastine/administration & dosage
2.
Int J Gynecol Cancer ; 11(5): 359-64, 2001.
Article in English | MEDLINE | ID: mdl-11737466

ABSTRACT

The purpose of this study was to review the clinical course of patients diagnosed with vulvar melanoma. Charts of patients diagnosed between 1970 and 1997 were reviewed for demographics, lesion characteristics, disease duration and extent, and treatments. Actuarial survival curves were computed by the Kaplan Meier method and compared by Cox proportional hazards regressions. Fifty-one patients (median age 54) with vulvar melanoma presented with a vulvar mass (39%), pain (30%), bleeding (24%), and itching (20%). Anatomical distribution was mucosa of the vulva (65%), vulvar epidermal site (21%), or unspecified vulva (14%), with 20% having multifocal disease at diagnosis. Histologic types were superficial spreading or nodular (50% each). Median lesion characteristics were diameter 2 cm, Breslow index 4.4 mm, and Clark level IV. Distribution of patients per American Joint Committee on Cancer (AJCC) stage was 29%, 50%, 16%, and 7% for stages I, II, III and IV, respectively. Inguinal node metastases were unilateral in 16% and bilateral in 7%. Despite complete surgical resection, 32 patients (63%) recurred. Median survival for all patients was 41 months (range, 5-324), with 91% 5-year survival for patients with stage I and 31% for stage >or= IIA (P = 0.0002). As with cutaneous melanoma, the AJCC classification, Breslow's thickness, and Clark's levels are the major predictors of overall survival (P = 0.0001 each) and disease-free survival (P

Subject(s)
Melanoma/mortality , Melanoma/pathology , Neoplasm Recurrence, Local , Vulvar Neoplasms/mortality , Vulvar Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Female , Humans , Medical Records , Melanoma/surgery , Middle Aged , Neoplasm Staging , Prognosis , Proportional Hazards Models , Retrospective Studies , Survival Analysis , Texas/epidemiology , Vulvar Neoplasms/surgery
3.
Cancer ; 88(7): 1703-9, 2000 Apr 01.
Article in English | MEDLINE | ID: mdl-10738230

ABSTRACT

BACKGROUND: The authors tested a biotherapy regimen involving recombinant interferon-alpha-2a (rIFN-alpha-2a) and recombinant human interleukin-2 (rhIL-2), given in a "decrescendo" schedule over 5 days, for its activity and toxicity in 21 patients who previously had received chemotherapy for advanced melanoma. METHODS: Patients (15 men and 6 women) were given intravenous rhIL-2 at a dose of 18 MIU/m(2) over 6 hours, followed by 18 MIU/m(2) over 12 hours, then 18 MIU/m(2) over 24 hours, and finally 4.5 MIU/m(2)/day for 3 consecutive days. rIFN-alpha-2a (10 MIU/m(2)) was given subcutaneously on Days 1-5. Courses were repeated every 4 weeks. Tumor sites were measured every 8 weeks. Toxicity was recorded using National Cancer Institute Common Toxicity Criteria. RESULTS: No major objective responses were noted. The median number of courses given was two. The median time to progression was 2 months and the median survival was 6 months (range, 2-25 months). However, 2 patients with melanoma involving >/= 2 visceral organs (1 with a high baseline serum lactate dehydrogenase level) and a third with soft tissue metastases achieved durable control of disease and were alive a median of 30+ months later. A fourth patient had a palliative response with reversal of melanosis and a survival of 7 months. This regimen was well tolerated and resulted in no serious long term adverse effects. CONCLUSIONS: The response rate for this regimen was no greater than 10% with Type I and II errors each not exceeding 10%. Nevertheless, occasional durable control of disease and the nonoverlapping toxicity profile with prior chemotherapy support consideration of this regimen in these patients who have limited second-line treatment options.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Interferon-alpha/administration & dosage , Interleukin-2/administration & dosage , Melanoma/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Blood Cell Count , Cytokines/therapeutic use , Female , Humans , Interferon alpha-2 , Interferon-alpha/adverse effects , Interleukin-2/adverse effects , Male , Middle Aged , Neoplasm Metastasis , Recombinant Proteins , Salvage Therapy
4.
Melanoma Res ; 9(5): 483-9, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10596915

ABSTRACT

For melanoma, in-transit metastases (ITMs) are a harbinger of systemic disease in over 70% of patients and thus warrant a systemic approach to management. In this study, previously untreated patients with ITMs (n=15) received a systemic regimen of 'CVD' in 21 day cycles (median, three cycles) as follows: dacarbazine 800 mg/m2 intravenously (i.v.) on day 1, vinblastine 1.6 mg/m2 i.v. on days 1-5, and cisplatin (CDDP) 100 mg/m2 by 24 h intra-arterial (i.a.) infusion in 1l of heparinized saline via the iliac or subclavian artery on day 3. There were three clinical complete responses (CRs) in patients with a modest burden of ITMs (< 3 cm in size) and seven partial responses (PRs), yielding a 67% response rate (95% confidence interval, 38-88%). One of the clinical CRs had microscopic residual disease at surgery (a pathological PR). The times to progression (TTP) for the CRs were 5, 21 and 38+ months; the median TTP for the PRs was 4.5 months (range, 2-10 months). Overall median survival was 31 months. Systemic toxicities were similar to those induced by i.v. CVD. However, patients noted more pronounced paraesthesia in the infused extremity. Also, two patients experienced severe CDDP-induced burns, one patient developed brachial plexopathy, and one patient had a haemorrhage in an occult brain metastasis. The high clinical activity of this regimen will have to be confirmed in more patients before a first-pass i.a. advantage can be claimed. Furthermore, the dose, schedule and technique of i.a. CDDP delivery must be further refined before it can be routinely incorporated in regimens as an alternative to isolated regional hyperthermic perfusion, which is technically more difficult and is not readily available in community-based hospitals.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Cisplatin/adverse effects , Dacarbazine/administration & dosage , Dacarbazine/adverse effects , Disease-Free Survival , Female , Humans , Infusions, Intra-Arterial , Lymphatic Metastasis , Male , Melanoma/mortality , Melanoma/secondary , Middle Aged , Neoplasm, Residual , Pilot Projects , Skin Neoplasms/mortality , Skin Neoplasms/secondary , Survival Rate , Treatment Outcome , Vinblastine/administration & dosage , Vinblastine/adverse effects
5.
Anticancer Drugs ; 10(8): 735-9, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10573206

ABSTRACT

A phase II study was undertaken to determine the efficacy of tirapazamine combined with cisplatin in patients with metastatic melanoma between April 1996 and April 1997. Tirapazamine 390 mg/m2, administered i.v. over 2 h, followed in 1 h by cisplatin 75 mg/m2 over 1 h, were used every 21 days to treat chemotherapy-naive patients with metastatic melanoma. Objective tumor measurements were used to assess efficacy of the regimen. NCI common toxicity criteria were used to grade toxicities. Forty-eight patients with metastatic melanoma of cutaneous or mucosal origin, none with symptomatic brain metastasis, were treated. Nine patients had a partial response, with an overall response rate of 20% (95% confidence interval: 9-33%). The median duration of response was 6 months. Grade 3 nausea, vomiting, anorexia, muscle cramps and fatigue occurred in fewer than 10% of patients. Neutropenia and thrombocytopenia were rare. This outpatient single-day administered tirapazamine-cisplatin regimen has definite activity in chemotherapy-naive patients with metastatic melanoma. Further studies in combination with other agents active against this disease are warranted.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Cisplatin/adverse effects , Dose-Response Relationship, Drug , Female , Humans , Male , Melanoma/pathology , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Time Factors , Tirapazamine , Treatment Outcome , Triazines/administration & dosage , Triazines/adverse effects
6.
Oncol Rep ; 6(5): 1097-9, 1999.
Article in English | MEDLINE | ID: mdl-10425308

ABSTRACT

Treatment options for patients with stage IV melanoma are limited. Based on differences in the toxicity and activity profiles of pegylated liposomal doxorubicin (doxil) compared to standard doxorubicin, we have conducted a phase II trial of doxil for patients with metastatic melanoma. Doxil was administered as a 60-90 min intravenous infusion every 21 days. The starting dose was 60 mg/m2 for the initial nine patients, but was subsequently reduced to 50 mg/m2 for the remainder due to toxicity issues. Thirty-two patients were enrolled in the trial. Ninety-one percent had received prior systemic therapy. There were no complete responses and two partial responses for an overall response rate of 6%. The dominant side effects included hand-foot syndrome, rash (occasionally severe), and stomatitis, consistent with reports from other trials using similar doses and schedules. We conclude that doxil does not demonstrate sufficient activity in metastatic melanoma to warrant further investigation into its use in this setting.


Subject(s)
Antineoplastic Agents/administration & dosage , Doxorubicin/administration & dosage , Melanoma/drug therapy , Aged , Female , Humans , Infusions, Intravenous , Male , Melanoma/pathology , Middle Aged , Neoplasm Metastasis , Treatment Outcome
7.
Cancer ; 85(5): 1055-9, 1999 Mar 01.
Article in English | MEDLINE | ID: mdl-10091788

ABSTRACT

BACKGROUND: Treatment of solid tumors rarely has been associated with tumor lysis syndrome. However, to the authors' knowledge the clinical scenario has not been reported previously in melanoma patients. METHODS: A patient with bulky metastatic melanoma was treated with concurrent biochemotherapy using interleukin-2, interferon-alpha, and a combination of cisplatin, vinblastine, and dacarbazine. RESULTS: Within 24 hours of the initiation of treatment, brisk tumor lysis occurred and led to a fatal outcome. CONCLUSIONS: Improvements in the treatment of solid tumors may increase the incidence of tumor lysis syndrome for tumors once believed to be marginally responsive. Oncologists should remain cognizant of this problem as more active regimens become available.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Tumor Lysis Syndrome/etiology , Acute Disease , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aspartate Aminotransferases/blood , Calcium/blood , Cisplatin/adverse effects , Creatinine/blood , Dacarbazine/adverse effects , Fatal Outcome , Humans , Interferon-alpha/adverse effects , Interleukin-2/adverse effects , L-Lactate Dehydrogenase/blood , Male , Melanoma/blood , Middle Aged , Phosphorus/blood , Skin Neoplasms/blood , Tumor Lysis Syndrome/blood , Uric Acid/blood , Vinblastine/adverse effects
8.
Melanoma Res ; 9(6): 575-81, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10661768

ABSTRACT

In order to evaluate the natural history, prognostic parameters and treatment modalities for metastatic uveal melanoma, a review of the clinical data from the current literature was performed based on a Medline database search. Uveal melanoma represents approximately 5% of all melanomas. It is a distinct clinico-pathological entity, differing in many aspects from cutaneous melanoma. The clinical course is unpredictable and metastatic disease can develop very late after a long disease-free interval. Uveal melanoma metastasizes haematogenously, predominantly to the liver. The most Important prognostic parameters for primary uveal melanoma are tumour diameter, the patient's age and gender, histological features and tumour location. Systemic chemotherapy that is effective in cutaneous melanoma has failed to show activity in uveal melanoma. So far only the BOLD chemotherapy regimen (dacarbazine, lomustine, vincristine and bleomycin) combined with interferon-alpha has been shown to produce an objective tumour response in approximately 20% of previously untreated patients. For metastatic disease localized to the liver, intra-arterial application of fotemustine or carboplatin or chemoembolization with cisplatin have shown useful activity, resulting in a response in up to 40% of patients. Selected patients may benefit from palliative surgery. Immunotherapy with interleukin-2 or interferon-alpha has not shown consistent activity in metastatic uveal melanoma. In conclusion, patients with uveal melanoma metastatic to the liver should undergo one of the local treatment options. Carefully selected patients with extrahepatic disease or patients failing local treatment may benefit from systemic therapy using the BOLD regimen combined with interferon.


Subject(s)
Melanoma/drug therapy , Uveal Neoplasms/drug therapy , Combined Modality Therapy , Disease Susceptibility , Follow-Up Studies , Humans , Melanoma/epidemiology , Melanoma/secondary , Melanoma/surgery , Palliative Care , Prognosis , Uveal Neoplasms/epidemiology , Uveal Neoplasms/pathology , Uveal Neoplasms/surgery
9.
Clin Cancer Res ; 4(10): 2363-70, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9796966

ABSTRACT

The purpose of this study was to determine whether a combination of two anti-idiotypic antibodies that mimic the high molecular weight proteoglycan antigen found on most melanoma tumors was capable of enhancing cellular immunity in vaccinated high-risk patients with melanoma. Twenty-eight stage I-IV high-risk patients with melanoma were immunized with a mixture of variable concentrations of MELIMMUNE-1 and MELIMMUNE-2, along with the adjuvant SAF-m, using two immunization schedules. Peripheral blood mononuclear cells were collected before the first immunization and 4 weeks after the final immunization and tested for in vitro proliferation to MELIMMUNE-1 and MELIMMUNE-2 and for cytotoxicity against 51Cr-labeled target cell lines. Additionally, supernatants from in vitro proliferation cultures were tested for interleukin 10 and IFN-gamma levels. Significant in vitro proliferation to MELIMMUNE-1 and MELIMMUNE-2 were observed in postimmunization samples but not in prevaccination samples. The mean stimulation index for MELIMMUNE-2 (33.7 +/- 0.6) was significantly higher than that for MELIMMUNE-1 (13.9 +/- 0.3; P < 0.025). Supernatants obtained from 78% of the in vitro stimulated cultures pre- or postvaccination contained significant levels of interleukin 10 (range, 0.43-142 pg/ml), whereas IFN-gamma levels were elevated in 53% of postvaccination samples (range, 3-245 pg/ml) but not prevaccination samples. More importantly, we were able to generate specific CTL responses in 43% of the patients, which correlated with elevated IFN-gamma levels. These results indicate that MELIMMUNE enhances cell-mediated immunity in patients with melanoma.


Subject(s)
Antibodies, Anti-Idiotypic/immunology , Antibodies, Monoclonal/immunology , Antigens, Neoplasm/immunology , Melanoma/immunology , Neoplasm Proteins/immunology , Proteoglycans/immunology , Cytokines/blood , HLA-A2 Antigen/analysis , Humans , Immunization , Lymphocyte Activation , Melanoma-Specific Antigens , Molecular Weight , T-Lymphocytes, Cytotoxic/immunology , Tumor Cells, Cultured
10.
J Clin Oncol ; 16(9): 2921-9, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9738559

ABSTRACT

PURPOSE: In patients with stage IV melanoma, durable responses have been reported with treatment regimens that involve high-dose interleukin-2 (IL-2). We analyze long-term results of 631 melanoma patients from 12 institutions who had received IL-2 alone, in combination with interferon alfa 2a or 2b (IFNalpha), or with cytotoxic drugs. METHODS: Case records that contained pretreatment parameters, response data, and updated survival information were collected. After univariate analysis, the multivariate evaluation of the impact of pretreatment parameters on response and survival was performed by logistic regression and Cox's regression, respectively. RESULTS: Patients were divided into four groups according to treatment: IL-2 alone (n=117), IL-2 and chemotherapy (n=49), IL-2 and IFNalpha (n=153), and IL-2, chemotherapy, and IFNalpha (n=312). The median survival of all patients was 10.5 months and the 2- and 5-year survival rates were 19.9% and 10.4%, respectively. Independent prognostic factors for response and survival were entirely different, treatment group being the only significant factor for response, and serum lactate dehydrogenase (LDH), metastatic site, and performance predicting survival. The addition of IFNalpha to IL-2 was associated with prolonged survival, but the effect of additional chemotherapy was less obvious. CONCLUSION: Serum LDH, metastatic site, and performance status are useful stratification factors for randomized trials in metastatic melanoma. The improved long-term survival rates observed in melanoma patients treated with IL-2/IFNalpha-containing regimens are notable in contrast to the reported 5-year survival rates of 2% to 6% achieved with chemotherapy, but because selection bias cannot be ruled out, the impact of IL-2, as well as all other components of the treatment regimens, on survival needs to be confirmed in prospective randomized trials.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Interleukin-2/therapeutic use , Melanoma/drug therapy , Adult , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Female , Humans , Interferon alpha-2 , Interferon-alpha/administration & dosage , Interleukin-2/administration & dosage , L-Lactate Dehydrogenase/blood , Male , Melanoma/secondary , Middle Aged , Multivariate Analysis , Neoplasm Staging , Prognosis , Recombinant Proteins , Regression Analysis , Survival Analysis
11.
Melanoma Res ; 8(2): 145-8, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9610867

ABSTRACT

The combination of cisplatin-based chemotherapy with interleukin-2 (IL-2) and interferon, referred to as biochemotherapy, has shown encouraging results in patients with advanced melanoma. Toxicity is high, however and no objective parameters exist to distinguish between patients who are likely to respond and those who are not. The purpose of this pilot study was to determine whether in vitro cisplatin-induced damage to the glutathione S-transferase-pi (GST-pi) gene in peripheral blood mononuclear cells (PBMCs) before therapy correlated with the histological response in melanoma patients with local-regional metastases who received concurrent biochemotherapy before definitive surgery. Before therapy, PBMCs from 16 patients were exposed to cisplatin at concentrations of 25, 50 or 100 microM for 3 h and the extent of damage to the GST-pi gene was quantitated by polymerase chain reaction (PCR). Patients were subsequently treated on a biochemotherapy regimen consisting of cisplatin 20 mg/m2 intravenously (i.v.) on days 1-4, vinblastine 1.5 mg/m2 i.v. on days 1-4, dacarbazine 800 mg/m2 i.v. on day 1, IL-2 9 MIU/m2 per day i.v. by continuous infusion on days 1-4 (total of 96 h), and interferon alpha2a 5 MU/m2 subcutaneously on days 1-5. The 16 patients were categorized into two groups: major responders (n = 7) and non-major responders (n = 9). Although we observed a wide interpatient variation, a statistically significant correlation existed between the histological response and the degree of DNA damage caused in the PBMCs at all three cisplatin concentrations tested (P = 0.024 for 25 microM; P = 0.036 for 50 microM; P = 0.007 for 100 microM). Our pilot study suggests that determination of in vitro cisplatin-induced DNA damage using a gene-specific PCR assay may be useful in predicting the histological response to biochemotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , DNA Damage , Glutathione Transferase/genetics , Interferon-alpha/therapeutic use , Interleukin-2/therapeutic use , Leukocytes, Mononuclear/drug effects , Melanoma/therapy , Skin Neoplasms/therapy , Cisplatin/administration & dosage , Combined Modality Therapy , Dacarbazine/administration & dosage , Disease Progression , Humans , Interferon alpha-2 , Leukocytes, Mononuclear/enzymology , Melanoma/blood , Melanoma/pathology , Neoplasm Staging , Polymerase Chain Reaction , Recombinant Proteins , Skin Neoplasms/blood , Skin Neoplasms/pathology , Vinblastine/administration & dosage
12.
Melanoma Res ; 8(2): 149-55, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9610868

ABSTRACT

The combination of cisplatin-based chemotherapy with interleukin-2 (IL-2) and interferon-alpha (IFN-alpha), referred to as biochemotherapy, has produced overall response rates of greater than 50% in advanced melanoma patients, with durable complete responses in the range of 5-10%. The mechanism of action of biochemotherapy is unknown. Preclinical work suggests synergistic interactions between the cytotoxic agents, especially cisplatin, and the biological agents in killing melanoma cells. Immune effector cells activated by the components of the biochemotherapy may also be involved, as direct cytotoxic effectors and/or as sources of secondary cytokines, which can induce nitric oxide (NO) production in a wide variety of cell types. In addition, high levels of neopterin, a marker of monocyte/macrophage activation, have been found in patients undergoing immunotherapy or biochemotherapy for melanoma. Based on these data, we hypothesized that the degree of elevation of serum NO metabolic products and neopterin during treatment would correlate with the response to biochemotherapy in melanoma patients. Blood samples were obtained before and during preoperative biochemotherapy with cisplatin, vinblastine, dacarbazine, IL-2 and IFN-alpha in 45 melanoma patients with locoregionally advanced disease. NO was measured as nitrite after enzymatic reduction, using the colorimetric assay of Griess, and neopterin was measured by radioimmunoassay. Our results demonstrate a higher day 5 nitrite level (of borderline statistical significance, P = 0.057) in major responders to the therapy than in those who did not achieve a major response, while there was no difference in the elevation in neopterin level during therapy between major and non-major responders. These results suggest that induction of NO during biochemotherapy may be playing a role in the mechanism of action of this therapy, while the role of monocyte/macrophage activation is still in question.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Interferon-alpha/therapeutic use , Interleukin-2/therapeutic use , Melanoma/therapy , Neopterin/blood , Nitric Oxide/blood , Skin Neoplasms/therapy , Adult , Aged , Cisplatin/administration & dosage , Combined Modality Therapy , Dacarbazine/administration & dosage , Female , Humans , Male , Melanoma/blood , Melanoma/pathology , Middle Aged , Neoplasm Staging , Skin Neoplasms/blood , Skin Neoplasms/pathology , Vinblastine/administration & dosage
13.
Clin Cancer Res ; 4(3): 619-27, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9533529

ABSTRACT

Our objective was to determine the clinical activity, toxicity, and immunological effects of active immunotherapy using UVB-irradiated (UVR) autologous tumor (AT) cells plus adjuvant DETOX in metastatic melanoma patients. Eligibility included nonanergic patients fully recovered after resection of 5 or more grams of metastatic melanoma. Treatment consisted of intradermal injections of 10(7) UVR-AT plus 0.25 ml of DETOX every 2 weeks x 6, then monthly. Peripheral blood mononuclear cells (PBMCs) were harvested for cytotoxicity assays, and skin testing was performed for delayed-type hypersensitivity (DTH) determinations before the first, fourth, seventh, and subsequent treatments. Forty-two patients were treated, 18 in the adjuvant setting and 24 with measurable disease. Among the latter group, there were two durable responses in soft-tissue sites and in a bone metastasis. Treatment was well tolerated. Thirty-five patients were assessable for immunological parameters; 10 of these patients, including the 2 responders, demonstrated early induction of PBMC cytotoxicity against AT cells that persisted up to 10 months on treatment before falling to background levels. In five of seven patients, the fall-off heralded progressive disease. Late induction of a weak DTH reaction to AT cells was observed in eight patients. Active immunotherapy with UVR-AT + DETOX had modest but definite clinical activity in advanced melanoma. The induction of both PBMC cytotoxicity and DTH reactivity to AT cells supported a specific systemic immune effect of treatment, although the former more closely followed disease course in this study.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Cancer Vaccines , Cytoskeletal Proteins/therapeutic use , Immunotherapy , Lipid A/analogs & derivatives , Melanoma/immunology , Melanoma/therapy , Skin Neoplasms/immunology , Skin Neoplasms/therapy , Ultraviolet Rays , Adult , Aged , Aged, 80 and over , Antigens, CD/blood , Bone Neoplasms/immunology , Bone Neoplasms/secondary , Bone Neoplasms/therapy , Cytotoxicity, Immunologic , Drug Combinations , Female , Humans , Hypersensitivity, Delayed , Immunity, Active , Immunoglobulin G/blood , Lipid A/therapeutic use , Male , Melanoma/mortality , Melanoma/pathology , Middle Aged , Neoplasm Staging , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Soft Tissue Neoplasms/immunology , Soft Tissue Neoplasms/therapy , Survival Rate , Time Factors
14.
J Clin Oncol ; 16(5): 1752-9, 1998 May.
Article in English | MEDLINE | ID: mdl-9586888

ABSTRACT

PURPOSE: To evaluate the antitumor activity and toxicity of concurrent biochemotherapy that uses cisplatin, vinblastine, and docarbazine (DTIC) (CVD) in combination with interferon alfa-2a (IFN-alpha) and interleukin-2 (IL-2) in patients with metastatic melanoma. PATIENTS AND METHODS: Between October 1992 and October 1993, 53 patients with a documented diagnosis of metastatic melanoma with measurable lesions and an Eastern Oncology Cooperative Group (ECOG) performance status of 2 or less were enrolled onto this study. Patients were required to have no clinically significant cardiac dysfunction and to be free from symptomatic brain metastases. The treatment consisted of cisplatin 20 mg/m2 daily for 4 days; vinblastine 1.6 mg/m2 daily for 4 days; and DTIC 800 mg/m2 intravenously (i.v.) day 1 with IL-2 9 x 10(6) IU/m2 i.v. by continuous infusion daily for 4 days and IFN-alpha 5 x 10(6) U/m2 subcutaneously daily for 5 days, repeated at 21-day intervals. Response was assessed after two cycles and patients who responded were continued on treatment for a total of six cycles. RESULTS: Among 53 assessable patients, 11 patients (21%) achieved a complete response (CR) and 23 patients (43%) achieved a partial response (PR), for an overall objective response rate of 64%. The median time to disease progression for all patients was 5 months. The median survival of all patients entered onto the trial was 11.8 months. Among the 11 patients who achieved a CR, five patients (9%) have remained in continuous CR for 50+ to 61+ months. The toxicity of biochemotherapy consisted of severe myelosuppression, significant nausea and vomiting, and moderately severe hypotension that required inpatient hospital care for each 5-day cycle of treatment. There were no treatment-related deaths. CONCLUSION: Concurrent biochemotherapy for patients with advanced melanoma is capable of producing high CR and overall response rates and resulted in durable complete remissions in a small fraction of patients. Toxicity, although severe, was manageable in a routine inpatient hospital environment.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/drug therapy , Melanoma/secondary , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Cisplatin/adverse effects , Dacarbazine/administration & dosage , Dacarbazine/adverse effects , Disease Progression , Female , Humans , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Interleukin-2/administration & dosage , Interleukin-2/adverse effects , Male , Melanoma/mortality , Middle Aged , Survival Rate , Vinblastine/administration & dosage , Vinblastine/adverse effects
15.
J Clin Oncol ; 16(3): 1103-11, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9508197

ABSTRACT

PURPOSE: The current American Joint Commission on Cancer (AJCC) staging system distinguishes between soft tissue and visceral metastases in advanced (stage IV) melanoma. We sought to verify these staging criteria and to identify prognostic variables that could be used to evaluate the impact of systemic therapy on long-term survival during the prior decade. PATIENTS AND METHODS: We conducted a retrospective study of patients with advanced cutaneous melanoma enrolled in clinical trials between 1979 and 1989 at The University of Texas M.D. Anderson Cancer Center. Pretreatment age, sex, number of organs with metastases, serum levels of lactate dehydrogenase (LDH) and albumin, and period of enrollment were analyzed using a Cox proportional hazards model of survival. RESULTS: In univariate and multivariate analyses that involved 318 stage IV patients, normal serum levels of LDH and albumin, soft tissue and/or single visceral organ metastases (especially lung), female sex, and enrollment late in the decade were independent positive predictors for survival. In multivariate analyses, the current AJCC criteria did not significantly predict outcome. Systemic treatment response did not bias these results, and only 4% of patients had a complete response. Patients who lived more than 2 years (11%) had a mix of favorable prognostic characteristics and a high frequency of systemic or surgically induced complete response. CONCLUSION: This study supports the use of stratification parameters that reflect the favorable prognostic impact of soft tissue or single visceral organ metastases and normal serum levels of LDH and albumin at time of enrollment in advanced melanoma trials. Improved survival over the prior decade probably reflects advances in diagnostic and palliative interventions.


Subject(s)
Melanoma/secondary , Melanoma/therapy , Adult , Aged , Female , Humans , Male , Melanoma/mortality , Melanoma/pathology , Middle Aged , Neoplasm Staging , Prognosis , Proportional Hazards Models , Retrospective Studies , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Skin Neoplasms/therapy , Survival Analysis
16.
Cancer ; 82(2): 403-11, 1998 Jan 15.
Article in English | MEDLINE | ID: mdl-9445199

ABSTRACT

BACKGROUND: The aim of this study was to determine the efficacy of novobiocin and rifampin as oral antibiotic prophylaxis for the prevention of catheter-related infection in melanoma patients treated with interleukin-2 (IL-2) plus interferon-alpha and chemotherapy (biochemotherapy). METHODS: Patients with advanced melanoma who were treated with biochemotherapy at the University of Texas M. D. Anderson Cancer Center were randomized in a crossover study to receive either oral antibiotic prophylaxis consisting of novobiocin and rifampin or observation alone over a 35-day course period. Patients were subsequently "crossed over" to the opposite arm of the study for an additional 35-day period, with each serving as his or her own control. RESULTS: Twenty-six patients were enrolled. Nine patients (35%) failed to tolerate oral antibiotics because of severe nausea and vomiting; 17 patients (65%) were crossed over and considered evaluable. During the control patient courses, 71% of evaluable patients had infectious complications, 41% had a catheter-associated bacteremia, and 53% had a local catheter infection. In contrast, of the patients treated with antibiotic prophylaxis, only 12% had an infectious complication (P = 0.001), 12% had a local catheter infection (P = 0.008), and 6% had catheter-associated bacteremias (P = 0.04). Thirty-six episodes of catheter infections occurred during the 17 control courses, whereas only 3 episodes occurred during antibiotic prophylaxis (P < 0.001). CONCLUSIONS: Although more than one-third of patients receiving IL-2 treatment with biochemotherapy failed to tolerate novobiocin and rifampin, this oral antibiotic regimen was efficacious in preventing the infectious complications, especially those associated with vascular catheters, in this high risk patient population.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacterial Infections/prevention & control , Catheters, Indwelling/adverse effects , Interleukin-2/therapeutic use , Melanoma/therapy , Novobiocin/therapeutic use , Rifampin/therapeutic use , Administration, Oral , Adult , Anti-Bacterial Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bacteremia/etiology , Bacteremia/prevention & control , Catheterization, Central Venous/adverse effects , Catheterization, Central Venous/instrumentation , Catheterization, Peripheral/adverse effects , Catheterization, Peripheral/instrumentation , Chemoprevention , Cross-Over Studies , Equipment Contamination , Female , Humans , Immunologic Factors/therapeutic use , Interferon-gamma/therapeutic use , Male , Melanoma/drug therapy , Middle Aged , Nausea/chemically induced , Novobiocin/administration & dosage , Prospective Studies , Rifampin/administration & dosage , Vomiting/chemically induced
17.
Melanoma Res ; 8(6): 549-56, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9918417

ABSTRACT

Our results with concurrent biochemotherapy in patients with stage IV melanoma have been encouraging. Based on these data, we conducted a phase II study to determine the clinical and histological response rate to neoadjuvant concurrent biochemotherapy in patients with local-regional metastases of cutaneous melanoma (stage III). A total of 65 patients with biopsy-proven, measurable and potentially resectable local-regional disease (nodal, satellite/in-transit metastases and/or local recurrence) were treated with cisplatin 20 mg/m2 intravenously (i.v.) on days 1 to 4, vinblastine 1.5 mg/m2 i.v. on days 1 to 4, dacarbazine 800 mg/m2 i.v. on day 1 only, interleukin-2 9 MIU/m2 per day i.v. by 96 h continuous infusion on days 1 to 4, and interferon-alpha 2a 5 MU/m2 subcutaneously on days 1 to 5, repeated every 3 weeks. Patients underwent surgery after two to four courses of biochemotherapy. Those with tumour regression after two preoperative courses received two additional postoperative courses. Of the 64 patients assessable for clinical response, 28 (44%) had a partial response. Of the 62 patients whose response was assessed histologically, four (6.5%) had no evidence of viable tumour in the surgical specimen (pathological complete remission, pCR) and 27 (43.5%) had a partial response, giving an overall response rate of 50%. Tumour burden did not correlate with response, although patients who achieved a pCR had a significantly lower tumour burden (P = 0.02). Our phase II study indicates that neoadjuvant biochemotherapy is an active treatment for melanoma patients with local-regional metastases. However, it is unclear if biochemotherapy is more active than chemotherapy alone; phase III randomized trials are ongoing to answer this question in patients with stage IV disease.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/drug therapy , Neoadjuvant Therapy , Skin Neoplasms/drug therapy , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Dacarbazine/administration & dosage , Dacarbazine/therapeutic use , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Interferon alpha-2 , Interferon-alpha/administration & dosage , Interferon-alpha/therapeutic use , Interleukin-2/administration & dosage , Interleukin-2/therapeutic use , Male , Melanoma, Amelanotic/drug therapy , Middle Aged , Neoplasm Metastasis , Recombinant Proteins , Time Factors , Treatment Outcome , Vinblastine/administration & dosage , Vinblastine/therapeutic use
18.
Ann Oncol ; 8(4): 363-7, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9209666

ABSTRACT

PURPOSE: A phase II study was undertaken to determine the efficacy of tirapazamine (TPZ) combined with cisplatin (cDDP) in patients with metastatic melanoma. PATIENTS AND METHODS: Between June 1994 and November 1995, 48 patients with metastatic melanoma were treated with TPZ (260 mg/m2, administered intravenously over two hours) followed in one-hour by cDDP (75 mg/m2 over one hour) every 21 days. Sixteen patients had received prior chemotherapy, and 13 of these had failed to respond to prior cDDP. None of the patients had symptomatic brain metastasis. RESULTS: Nine patients had partial responses, with an overall response rate of 19% (95% confidence interval (95% CI) of 9%-33%). The median duration of response was six months. None of the responders had received prior chemotherapy. Responses were seen in 8 (33%, confidence interval of 16%-55%) of 24 patients with primary cutaneous melanoma who had received no prior chemotherapy and in the only patient with previously untreated conjunctival melanoma. There were no responders among the seven patients with choroidal melanoma and 16 patients with previously treated cutaneous melanoma. Two patients with partial responses were rendered free of gross disease surgically three months after completing eight courses of TPZ-cDDP; they remain free of tumor recurrence. Responses were seen in lymph nodes (27%), lung (26%), skin (20%), adrenal gland (20%), soft tissues (17%) and liver (17%). Common toxicities included muscle cramps, fatigue, gastrointestinal effects and peripheral neuropathy. Fatigue, nausea, vomiting, anorexia, and muscle cramps were grade 3 or 4 in less than 10% of the courses. Neutropenia and thrombocytopenia were rare. CONCLUSION: The TPZ-cDDP combination has definite activity against chemotherapy-naïve patients with cutaneous melanoma and warrant further studies in combination with other cytotoxic agents.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Female , Humans , Male , Melanoma/secondary , Middle Aged , Tirapazamine , Triazines/administration & dosage
19.
J Clin Oncol ; 15(3): 1039-51, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9060544

ABSTRACT

PURPOSE: To critically review the accuracy of the current American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma and propose a more useful staging system. METHODS: Retrospective evaluation of the published data as well as a reanalysis of the University of Alabama and Sydney Melanoma Unit (UAB/SMU) data bases (n = 4,568) for patients with primary melanoma was performed to examine specifically the impact of level of invasion and ulceration on the prognostic value of tumor thickness. In addition, an overlay graphic technique was used to compare the Kaplan-Meier survival curves of patients with local recurrences, satellites, in-transit metastases, and nodal metastases reported in the literature. RESULTS: Tumor thickness and ulceration remained the most powerful prognostic indicators in patients with stage I and II disease. Level of invasion provided statistically significant prognostic information only in the subgroup of patients with tumor thickness < or = 1 mm, but the absolute 10-year survival differences were small and inconsistent (level II, 95%; level III, 85%; level IV, 89%). The best statistical fit for tumor thickness cutoffs was at 1 versus 2 versus 4 mm. The overlay graphic technique showed that patients who developed satellite lesions or local recurrence had prognoses similar to those of patients with stage III disease. The most important prognostic factor for patients with nodal metastases was number of involved nodes rather than size. CONCLUSION: Our analysis showed that the current AJCC staging system has many inaccuracies that should be modified to conform to published data. On the basis of our analysis and review of the literature, we propose a new and more accurate staging system.


Subject(s)
Melanoma/pathology , Neoplasm Staging/methods , Skin Neoplasms/pathology , Humans , Lymphatic Metastasis , Melanoma/secondary , Neoplasm Staging/standards , Professional Staff Committees/standards , Retrospective Studies , Skin Neoplasms/secondary
20.
Semin Oncol ; 24(1 Suppl 4): S24-31, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9122731

ABSTRACT

Recombinant interferon alpha (rIFN-alpha) has shown antitumor activity in metastatic malignant melanoma both as single-agent therapy and in combination with chemotherapeutic agents. As a single agent, rIFN-alpha yields an objective response rate of approximately 15%, which is comparable with other biologic agents, such as recombinant interleukin-2 (rIL-2) and single-agent chemotherapy. The most effective application of rIFN-alpha to the treatment of metastatic melanoma seems to be as a component of drug regimens that combine rIFN-alpha with rIL-2 or with combination chemotherapy regimens. The combination of rIFN-alpha with rIL-2 appears to have greater antitumor activity than either agent alone. Likewise, rIFN-alpha may potentiate the antitumor activity of combination chemotherapy regimens. Chemoimmunotherapy using dual biologic agents is currently the most promising therapy for metastatic melanoma with objective response rates of more than 50%. The greatest success of chemoimmunotherapy is its ability to produce durable complete remission in approximately 10% of treated patients. These regimens produce long-term remissions and offer hope to patients with advanced melanoma.


Subject(s)
Interferon-alpha/therapeutic use , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Interferon alpha-2 , Interferon-alpha/administration & dosage , Interleukin-2/administration & dosage , Neoplasm Metastasis , Recombinant Proteins/administration & dosage
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