Phase II trial of imatinib mesylate in patients with metastatic melanoma.

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.

Phase II evaluation of bryostatin-1 in metastatic melanoma.

In this phase II study we assessed the efficacy of bryostatin-1 (NSC 339555) in metastatic melanoma patients when given intravenously either once a week at a dose of 25 microg/m2 per day over 24 h for 3 weeks or at 40 microg/m2 per day over 72 h every 2 weeks. Treatment courses were repeated every 4 weeks. Patients who had received one prior chemotherapy regimen for advanced melanoma, with or without biotherapy, were randomized to one or the other bryostatin-1 dose schedules until 12 patients were registered to each arm. Because there was one confirmed response among the 12 patients who received the 72 h dose schedule, 25 more patients were added to that arm. No prophylactic medications were given. Objective tumour measurements were used to assess the efficacy of the regimen. The National Cancer Institutes common toxicity criteria were used to grade reactions. In total, 49 patients with metastatic melanoma, none having symptomatic brain metastasis, were studied. Of these, 12 patients received the 24 h bryostatin-1 regimen, while the remaining 37 received the 72 h regimen. One patient receiving the 72 h regimen had a partial response lasting over 7 months. Muscle pain occurred in over 90% of the patients and was the dose-limiting side effect of the 72 h regimen. Grade 3/4 nausea and vomiting were more common on the 24 h regimen than on the 72 h one (35% versus 5% of patients). There was no therapy-related thrombocytopenia. Neutropenia was mild and mainly limited to patients receiving the 72 h regimen. Bryostatin-1 has limited activity against melanoma when given by 72 h intravenous infusion.

Unexpected cytokines in serum of malignant melanoma patients during sequential biochemotherapy.

Biochemotherapy, which combines traditional chemotherapy with immune modulating biologicals, produces an unexpectedly high response rate (>50%) in advanced melanoma patients. We hypothesize that immunological mechanism(s) are responsible for the increased response rate, and particularly that macrophage activation is involved in tumor reduction. Patients were randomized to receive chemotherapy, composed of cisplatin, vinblastine, and dacarbazine (CVD), or biochemotherapy, which is CVD followed by interleukin (IL)-2 and IFN-alpha2b (CVD-BIO). Laboratory analysis was performed on sera from 41 patients from each arm. Measurements of macrophage activation (neopterin), nitric oxide production (nitrite), and tumor necrosis factor-alpha (TNF-alpha), IL-1alpha, IL-1beta, IFN-gamma, IL-6, IL-10, and soluble IL-2 receptor (sIL-2R) were performed. Six of the nine biological responses (nitrite, neopterin, IFN-gamma, IL-6, soluble IL-2R, and IL-10) significantly (P < 0.0002) increased in the CVD-BIO patients but not in the CVD patients. The increased IL-6 (P = 0.04) and IL-10 (P = 0.05) correlated with patient response, but only when the minor responders were included in the analysis. Evidence of macrophage activation was found in CVD-BIO patients and not in those receiving CVD alone. In addition, an unusual cytokine elaboration composed of IL-6, IFN-gamma, IL-10, nitrite, neopterin, and sIL-2R, but not the expected TNF-alpha and IL-1, was detected. A trend of higher increase in IL-6 and IL-10 in patients having clinical response was found, suggesting an incomplete Th2 pattern of cytokine elaboration. These data show that macrophage activation does not appear to be critical in the response to CVD-BIO, but that IL-10 and IL-6 induced by the BIO component of the CVD-BIO were associated with tumor regression, and that their biology should be pursued further in the analysis of mechanism(s) of response.

A phase II study of "decrescendo" interleukin-2 plus interferon-alpha-2a in patients with progressive metastatic melanoma after chemotherapy.

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.

Pilot study of intra-arterial cisplatin and intravenous vinblastine and dacarbazine in patients with melanoma in-transit metastases.

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.

Phase II trial of escalated dose of tirapazamine combined with cisplatin in advanced malignant melanoma.

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.

Phase II trial of doxil for patients with metastatic melanoma refractory to frontline therapy.

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.

Enhancement of cell-mediated immunity in melanoma patients immunized with murine anti-idiotypic monoclonal antibodies (MELIMMUNE) that mimic the high molecular weight proteoglycan antigen.

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.

DNA damage in peripheral blood mononuclear cells correlates with response to biochemotherapy in melanoma.

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.

Nitric oxide and neopterin levels and clinical response in stage III melanoma patients receiving concurrent biochemotherapy.

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.

Hypercalcemia due to parathyroid hormone-related protein secretion by melanoma.

About 1-2% of melanoma patients develop hypercalcemia. We report hypercalcemia without bone metastasis in a 46-year-old woman with advanced melanoma. The hypercalcemia was associated with elevated serum parathyroid hormone-related protein (PTHrP) levels. An even higher concentration (10 times the serum level) in pleural effusion caused by pleural metastases implied that the source of the increased circulating PTHrP was the melanoma. Immunohistochemical staining of paraffin sections, performed using a monoclonal antibody (9H7) against the peptide sequence 109-141 of human PTHrP, detected PTHrP in the cytoplasm and nucleoli of melanoma cells in an autopsy specimen but not in specimens from this patient prior to onset of hypercalcemia. Considering the evidence, it is very likely that PTHrP production by melanoma caused hypercalcemia in this patient.

Active immunotherapy with ultraviolet B-irradiated autologous whole melanoma cells plus DETOX in patients with metastatic melanoma.

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.

Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma.

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.

Prognostic factors for survival of patients treated systemically for disseminated melanoma.

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.

Phase II study of neoadjuvant concurrent biochemotherapy in melanoma patients with local-regional metastases.

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.

Phase II trial of tirapazamine combined with cisplatin in chemotherapy of advanced malignant melanoma.

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.

Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system.

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.

Development and results of biochemotherapy in metastatic melanoma: the University of Texas M.D. Anderson Cancer Center experience.

PURPOSE: Systemic therapy for metastatic melanoma includes chemotherapy, either with dacarbazine alone or a multiagent combination regimen, and biologic therapy with recombinant interferon-alpha and/or recombinant interleukin-2. However, neither of these treatment options has produced long-term control of disease except on rare occasions. We have therefore developed a combined biochemotherapy program in an effort to improve long-term control of metastatic melanoma. PATIENTS AND METHODS: Between October 1990 and October 1993, we treated 115 patients with a triple-drug chemotherapy regimen--CVD (cisplatin, vinblastine, dacarbazine)--in combination with biotherapy using recombinant interleukin-2 and recombinant interferon-alpha. This program of biochemotherapy has evolved from an initial protocol of sequential use of CVD followed by biotherapy, called sequential biochemotherapy, to a more recent protocol of concurrent administration of all five drugs, called concurrent biochemotherapy. Sixty-two patients have been treated with the sequential regimen and 53 patients with the concurrent regimen. RESULTS: Among the 114 evaluable patients, we have observed 24 complete responses (21%) and 45 partial responses (39%) for an overall response rate of 60%. From the group of 24 complete responders, 12 patients (10% of the total) have achieved long-term remissions and have remained disease free for periods of time ranging from 4+ to 6+ years. CONCLUSION: Although the overall results of sequential versus concurrent biochemotherapy are similar, the toxicity appears to be less severe in patients treated with the concurrent regimen. The overall median survival of patients treated with biochemotherapy appears to be longer compared with our previous experience with CVD chemotherapy used alone (12 vs 9 months). Based on the encouraging results obtained with biochemotherapy, phase III studies have been initiated to compare prospectively biochemotherapy with chemotherapy (CVD regimen) alone.

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

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Phase Ia/Ib trial of anti-GD2 chimeric monoclonal antibody 14.18 (ch14.18) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in metastatic melanoma.

We performed a phase Ia/Ib trial of chimeric anti-GD2 monoclonal antibody 14.18 (ch14.18) in combination with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to determine the maximum tolerated dose as well as immunologic and biologic responses to the regimen. Sixteen patients with metastatic malignant melanoma received escalating doses of ch14.18 (15-60 mg/m2) administered intravenously for 4 h on day 1. Twenty-four hours later, subcutaneous injections of rhGM-CSF were administered daily for a total of 14 days. Significant side effects were related to ch14.18 infusion and consisted of moderate to severe abdominal and/or extremity pain, blood pressure changes, headache, nausea, diarrhea, peripheral nerve dysesthesias, myalgias, and weakness. Dose-limiting toxicity was observed at 60 mg/m2 and consisted of severe hypertension, hypotension, and atrial fibrillation in one patient each, respectively. Significant increases in white blood cell count, granulocyte count, eosinophil count, and monocyte count occurred after rhGM-CSF treatment. Significant enhancement of in vitro and in vivo monocyte and neutrophil tumoricidal activity and antibody-dependent cellular cytotoxicity along with significant elevations in C-reactive protein and neopterin were observed. Despite these immunological and biological changes, no antitumor activity was seen. In short, the combination of ch14.18 and rhGM-CSF resulted in toxicity similar to that observed with ch14.18 alone without improvement in tumor response.