Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy.

PURPOSE: Currently, no validated blood-based assays accurately predict treatment response or outcome in melanoma patients. We hypothesized that methylation of tumor-related genes detected in serum DNA could predict disease outcome and therapeutic response in patients receiving concurrent biochemotherapy (BC) for metastatic melanoma. PATIENTS AND METHODS: American Joint Committee on Cancer stage IV melanoma patients (N = 50) had blood drawn before administration of BC. Patients (n = 47) were classified as BC responders or nonresponders. Responders (n = 23) demonstrated a complete or partial response following BC; nonresponders (n = 24) demonstrated progressive disease. Hypermethylation of Ras association domain family 1 (RASSF1A), retinoic acid receptor-beta2 (RAR-beta2), and O6-methylguanine DNA methyltransferase (MGMT) genes were assessed by methylation-specific polymerase chain reaction. RESULTS: Circulating methylated RASSF1A was significantly less frequent for responders (three of 23 patients; 13%) than nonresponders (10 of 24 patients; 42%; P = .028). Patients with RASSF1A, RAR-beta2, or at least one serum methylated gene had significantly worse overall survival than patients with no methylated genes (log-rank, P = .013, .021, and .01, respectively). Methylated RASSF1A was the only factor that significantly correlated with overall survival and BC response (risk ratio, 2.38; 95% CI, 1.16 to 4.86; P = .018; odds ratio = 0.21; 95% CI, 0.05 to 0.90; P = .036). CONCLUSION: Detection of circulating methylated DNA in serum can predict response to BC and disease outcome.     

Estrogen receptor-alpha methylation predicts melanoma progression

The role of estrogen receptor alpha (ER-alpha) in melanoma is unknown. ER-alpha expression may be regulated in melanoma via hypermethylation of promoter CpG islands. We assessed ER-alpha hypermethylation in primary and metastatic melanomas and sera as a potential tumor progression marker. ER-alpha methylation status in tumor (n = 107) and sera (n = 109) from American Joint Committee on Cancer (AJCC) stage I to IV melanoma patients was examined by methylation-specific PCR. The clinical significance of serum methylated ER-alpha was assessed among AJCC stage IV melanoma patients receiving biochemotherapy with tamoxifen. Rates of ER-alpha methylation in AJCC stage I, II, and III primary melanomas were 36% (4 of 11), 26% (5 of 19), and 35% (8 of 23), respectively. Methylated ER-alpha was detected in 42% (8 of 19) of stage III and 86% (30 of 35) of stage IV metastatic melanomas. ER-alpha was methylated more frequently in metastatic than primary melanomas (P = 0.0003). Of 109 melanoma patients' sera in AJCC stage I, II, III, and IV, methylated ER-alpha was detected in 10% (2 of 20), 15% (3 of 20), 26% (5 of 19), and 32% (16 of 50), respectively. Serum methylated ER-alpha was detected more frequently in advanced than localized melanomas (P = 0.03) and was the only factor predicting progression-free [risk ratio (RR), 2.64; 95% confidence interval (95% CI), 1.36-5.13; P = 0.004] and overall survival (RR, 2.31; 95% CI, 1.41-5.58; P = 0.003) in biochemotherapy patients. Hypermethylated ER-alpha is a significant factor in melanoma progression. Serum methylated ER-alpha is an unfavorable prognostic factor.     

Clinical results using biochemotherapy as a standard of care in advanced melanoma

Phase II studies of biochemotherapy in metastatic melanoma patients have reported response rates of 47-63%. Even though these were highly selected patients, we were intrigued by these promising response rates and began using this regimen as standard care in advanced melanoma patients. We report the results of the first 65 patients with AJCC stage IV melanoma (n = 57) or unresectable stage III (n = 8) melanoma treated with concurrent biochemotherapy at Memorial Hospital. Treatment was repeated every 3 weeks and patients were assessed for antitumour effects after every other cycle. The overall response rate among the 63 patients evaluable for response was 29% (three complete responses, 15 partial responses). The median duration of responses was 3.7 months. The response rate among previously treated and previously untreated patients was 6% and 38%, respectively. The estimated median survival for all patients was 8.5 months; the median survival for previously untreated patients was 9.2 months. Tumour response did not correlate with survival. Our experience, which is a retrospective evaluation, does not provide support for the routine use of biochemotherapy as standard treatment. The low response rate among previously treated patients indicates that biochemotherapy is not useful as second-line therapy.     

Biochemotherapy for metastatic melanoma with limited central nervous system involvement

OBJECTIVES: Biochemotherapy outcomes were examined in stage IV melanoma patients with previously treated or active central nervous system (CNS) metastases prior to systemic therapy. PATIENTS AND METHODS: Patients who received biochemotherapy for metastatic melanoma with active or pretreated CNS metastases were compared to patients without evidence of CNS metastases in terms of response, time to progression (TTP), overall survival (OS), and treatment toxicity. RESULTS: Twenty-six (16%) of 159 total patients began biochemotherapy with previously treated or active CNS metastases (group I), compared to 133 (84%) who were radiographically free of CNS involvement (group II). A partial or complete response to biochemotherapy was seen in 13 (50%) group I patients, compared to 56 (42%) group II patients (p = 0.243). The median TTP and median survival were 5.5 and 7.0 months, respectively, for group I patients and 6.0 and 9.9 months, respectively, for group II patients (p = 0.222 and 0.434 for TTP and OS, respectively). Five (19%) group I patients survived longer than 24 months. Gamma Knife radiosurgery or surgical resection of CNS disease prior to biochemotherapy improved survival versus delayed treatment (p = 0.017 and 0.005, respectively). CONCLUSION: Patients with limited CNS metastases and widespread systemic disease can achieve prolonged survival with targeted treatment of CNS lesions and aggressive systemic therapy.     

Plasma Fas ligand, an inducer of apoptosis, and plasma soluble Fas, an inhibitor of apoptosis, in advanced melanoma

The transmembrane receptor Fas/APO-1, together with its protein-binding partner (Fas ligand), is a key regulator of programmed cell death and induces apoptosis when it binds Fas ligand (FasL) or soluble Fas ligand (sFasL). However, soluble Fas (sFas) blocks apoptosis by inhibiting binding between Fas and FasL or sFasL. At present, the status of sFas and sFasL in metastatic malignant melanoma remains unknown. This study sought to evaluate the relationship between plasma levels of sFas and/or sFasL and clinical response in 45 metastatic malignant melanoma patients treated by biochemotherapy. sFas and sFasL were measured by specific enzyme-linked immunosorbent assay (ELISA) tests in the sera from patients and 34 healthy donors. Overall, sFas and sFasL levels in patients were significantly higher (P < 0.0001) than in healthy donors. Before the biochemotherapy treatment the sFas level was about the same in biochemorefractory (n = 26) as in responder patients (n = 19). In contrast, the sFasL level was very high only in biochemorefractory patients. At the end of the treatment, in biochemorefractory patients the sFas level was extremely significantly increased (P < 0.0001) and a significant decrease in the plasma levels of sFasL was observed (P = 0.0002). In responder patients, no change in sFas and sFasL was detected. In conclusion, elevated levels of sFas and sFasL might be associated with poor prognosis in advanced melanoma; their possible role in the regulation of apoptosis in influencing the response to biochemotherapy should be further explored.     

Biochemotherapy for advanced melanoma

The outcome of chemotherapy for patients with stage IV melanoma is unsatisfactory, since durable responses are rarely achieved. More experimental treatments, such as vaccine approaches, antibody treatments, and gene therapy are being developed and are of high scientific interest; however, their efficacy in advanced melanoma patients has so far been very limited. Based on the observation of a small proportion of long-term responses, the use of biotherapy or biochemotherapy is currently preferred in many institutions as first-line treatment in stage IV melanoma. Various interleukin-2 (IL-2) dosing schedules and combinations with interferon alpha (IFN-alpha) have been tested in patients with advanced melanoma during the past decade. The response rates reported with IL-2 as a single agent or in combination with IFN-alpha varies from 10% to 41%, with a small, but remarkable proportion of durable responses. Subsequently, biochemotherapy regimens combining IL-2, IFN-alpha, and chemotherapy have been evaluated in phase II trials, which have suggested improved response rates. Recent randomized trials have investigated the role of biochemotherapy as compared to biotherapy alone or as compared to chemotherapy for the treatment of advanced melanoma. So far, none of the approaches has been proven to confer a survival benefit and thus the uniform desire is to include as many patients as possible in controlled clinical trials.     

Impact of gene polymorphisms on clinical outcome for stage IV melanoma patients treated with biochemotherapy: an exploratory study.

PURPOSE: Biochemotherapy can achieve high response rates in advanced melanoma, but the factors that influence regression and survival remain unknown. The present exploratory study tested the hypothesis that cytokine gene polymorphisms predict clinical outcome in stage IV melanoma patients treated with biochemotherapy. EXPERIMENTAL DESIGN: Ninety patients with stage IV melanoma were treated with biochemotherapy, including cisplatin, vinblastine, and dacarbazine combined with interleukin (IL)-2 and IFN-alpha either with or without tamoxifen. Cytokine gene polymorphisms for IFN-gamma (+874A-->T) and IL-10 (-1082G-->A) were assessed. X-ray repair cross-complementing gene 1 (XRCC1; Arg399Gln), xeroderma pigmentosum complementary group D (XPD; Lys751Gln), and excision repair cross-complementing gene 1 (ERCC1; codon 118) DNA repair polymorphisms were also determined. RESULTS: IFN-gamma (+874A-->T) gene polymorphism was statistically significantly associated with response (P = 0.001), progression-free survival (P = 0.0012), and overall survival (P < 0.001), whereas the IL-10 polymorphism was marginally associated with response (P = 0.03) and overall survival (P = 0.065). Multivariate analysis revealed that IFN-gamma (+874A-->T) independently predicted overall survival (P = 0.003). The ERCC1 polymorphism was weakly associated with overall survival (P = 0.045). Combining polymorphisms for IFN-gamma, IL-10, and ERCC1 stratified patients into four distinct groups with significantly different clinical outcome (P < 0.001), so that patients with more "favorable" polymorphisms had a better outcome. CONCLUSIONS: Cytokine gene polymorphisms predicted clinical outcome for advanced melanoma patients who received biochemotherapy. The combined effects of multiple genetic polymorphisms may provide more accurate prognostic information. Additional independent studies are needed to confirm these pilot findings.     

Allelic imbalance on 12q22-23 in serum circulating DNA of melanoma patients predicts disease outcome

Allelic imbalance (AI) encompassing the apoptotic protease-activating factor 1 (APAF-1) locus (12q22-23) is found frequently in metastatic melanoma. Circulating DNA with AI on 12q22-23 in serum was evaluated as a surrogate marker to predict biochemotherapy (BC) treatment response in melanoma patients. Sera were collected from 49 American Joint Committee on Cancer stage IV melanoma patients treated with BC. Serum AI of the 12q22-23 region was demonstrated to be present before and/or after BC. BC responders showed a significantly lower frequency of AI (5 of 24, 21%) compared with nonresponders (11 of 20, 55%; Fisher's exact test, P < 0.029). Serum AI on 12q22-23 was associated with worse prognosis (log-rank test, P < 0.046). These findings indicate that serial serum genetic analysis of tumor-related AI on 12q22-23 may have clinical use in predicting tumor response to therapy.     

Prognostic factors for survival after isolated limb perfusion for malignant melanoma

AIMS: Risk factors were determined for mortality within 1 year after isolated limb perfusion (ILP). METHODS: All of 439 patients who underwent ILP for melanoma of the extremities were studied. Ninety percent of the patients had MD Anderson stage IIB or III disease at the time of ILP. ILP was performed with melphalan with or without TNFalpha under mild hyperthermic (38-40 degrees C) or normothermic (37-38 degrees C) conditions in 80% of the cases. RESULTS: Sixty-nine patients died within this period, 64 of metastatic melanoma. The indication for ILP was an unresectable primary (n=3), a local recurrence (n=24) or adjuvant to excision of primary lesions (n=17) in patients with stage IIIB regional lymph node metastases. These patients or patients with stage IIIAB melanoma with satellites and/or in-transit metastases with regional lymph node metastases had a relative risk of 4.6 (95% CI 2.0-6.6) and 3.6 (95% CI 2.1-10) of dying within 1 year from ILP, respectively (p<0.001). In patients with stage IV disease (distant metastases), the relative risk was 22 (95% CI 3.8-127, p=0.001). CONCLUSION: Patients with advanced limb melanoma have an increased risk of death within 1 year after ILP when regional lymph node or distant metastases are present.     

Circulating DNA microsatellites: molecular determinants of response to biochemotherapy in patients with metastatic melanoma

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

A phase II study of biochemotherapy for advanced melanoma incorporating temozolomide, decrescendo interleukin-2 and GM-CSF

Metastatic malignant melanoma remains a very difficult disease to treat. Previous phase II studies using biochemotherapy (combination of platinum-containing chemotherapy with IL-2 and IFNalpha) have shown response rates of about 50%. However, a site of frequent relapse is in the central nervous system (CNS). Temozolomide is an oral alkylating agent that has equivalent activity to dacarbazine, but it has the advantage of CNS penetration. We report the results of a phase II study using a novel biochemotherapy regimen containing temozolomide, cisplatin, decrescendo IL-2, IFNalpha, and GM-CSF in the treatment of stage IV melanoma. Seventy-one patients with histologically confirmed metastatic melanoma were enrolled between June 1998 and October 1999. Prior chemotherapy or IL-2 was not permitted. The median age was 54 years (range 22-72). Twenty-one patients (30%) had a history of treated brain metastases. Patients received temozolomide 150 mg/m2 orally days 1-5, cisplatin 30 mg/m2 IV days 1-3, IFNalpha 5 MU/m2 SQ on days 1-5, and IL-2 was administered in a decrescendo fashion according to the following schedule: day 1: 18 MU/m2 continuous IV infusion over 6 hours; day 2: 18 MU/m2 continuous IV infusion over 12 hours; day 3: 9 MU/m2 subcutaneously q12 hours; day 4: 4.5 MU/m2 subcutaneously x 1. Patients were also given GM-CSF 250 microg subcutaneously days 6-25. The cycles were repeated every 4 weeks. Partial responses were seen in 10 of the 71 patients (14%) with a median duration of response of 9.4 months. There were no complete responses. The median survival for all patients was 8.6 months. Further studies of this novel biochemotherapy regimen are not indicated. Other schedules that incorporate temozolomide and/or GM-CSF and further studies to define the optimal method of delivering IL-2 should be pursued.     

Treatment of patients with progressive unresectable metastatic melanoma with a heterologous polyvalent melanoma whole cell vaccine

Unresectable metastatic melanoma has no elective treatment. Neither chemotherapy, intravenous IL-2 nor biochemotherapy clearly improves the overall survival. Recent assays with therapeutic vaccines have been recently yielded promising results. Here, we describe the application, clinical tolerance and antitumoural activity of a heterologous polyvalent melanoma whole cell vaccine in patients with metastatic melanoma. Twenty-eight AJCC stage III/IV melanoma patients with progressive unresectable metastatic disease were treated with our heterologous polyvalent melanoma whole cell vaccine between July 1, 1998 and July 1, 2002. All patients had already been unsuccessfully treated with high doses of IFN-alpha2 and/or polychemotherapy and/or biochemotherapy and/or perfusion of extremities, or could not receive other treatments due to their age or underlying illness. Twenty-three were assessable. The vaccine was constituted by 10 melanoma cell lines, derived from primary, lymph node and metastatic melanomas. Prior to intradermal inoculation, the cells were irradiated and mixed with BCG, and 50% were treated with DNFB. After a median follow-up of 19 months, 26% of patients responded: 3 CR (18, 16+, and 26+ months), 2 PR (8 and 22 months) and 1 MR (36+ months). The median survival of the whole group was 20.2 months. None of the 28 patients initially included in the study presented significant toxicity. This vaccination program had specific antitumoural activity in advanced metastatic melanoma patients and was well tolerated. The clinical responses and the median survival of our group of patients, together with the low toxicity of our polyvalent vaccine, suggest that this approach could be applied to earlier metastatic melanoma patients.     

Outpatient biochemotherapy with interleukin-2 and interferon alfa-2b in patients with metastatic malignant melanoma: results of two phase II cytokine working group trials.

PURPOSE: The Cytokine Working Group performed a randomized phase II trial of two outpatient biochemotherapy regimens to identify an outpatient regimen with high antitumor activity and less toxicity than inpatient regimens which might be compared with chemotherapy or inpatient biochemotherapy regimens in future phase III trials. PATIENTS AND METHODS: Eighty-one patients with metastatic malignant melanoma received dacarbazine 250 mg/m(2)/d intravenously (IV) and cisplatin 25 mg/m(2)/d IV on days 1, 2, and 3, plus interferon (IFN) alfa-2b 5 mU/m(2) subcutaneously (SC) on days 6, 8, 10, 13, and 15, given every 28 days. Interleukin-2 (IL-2) was given daily on days 6 to 10 and 13 to 15. In group 1, IV IL-2 was given at 18.0 MU/m(2), and in group 2, SC IL-2 was given at 5.0 mU/m(2). RESULTS: In group 1 (IV IL-2), there were five complete responses (CRs) and 11 partial responses (PRs) among 44 patients (objective response rate [ORR], 36%; 95% confidence interval [CI], 22% to 51%). In group 2 (SC IL-2), there was one CR and five PRs among the 36 patients (ORR, 17%; 95% CI, 4% to 29%). The median survival was 10.7 months in group 1 and 7.3 months in group 2. Eleven patients in group 1 and four patients in group 2 remain alive as of the last follow-up. Toxicities in both groups were similar. No patient required hospitalization for neutropenic fever. CONCLUSION: Biochemotherapy has activity in these outpatient regimens with acceptable toxicity. The antitumor activity observed with the IV IL-2 regimen seems similar to that of inpatient biochemotherapy regimens. If inpatient biochemotherapy regimens develop an established role in the management of melanoma, future phase III trial comparisons with this outpatient IV IL-2 regimen would be appropriate.     

Biochemotherapy of melanoma

Despite the evaluation of many different chemotherapy and immunotherapy drugs, the median survival in metastatic melanoma remains in the range of 6 to 9 months. Combination chemotherapy or combination immunotherapy has not produced a significant advantage over single-agent therapy but is associated with greater toxicity. Based on the potential for additive or synergistic activity with the combination of chemotherapy and biotherapy, many investigators have evaluated biochemotherapy in patients with advanced melanoma. Aggregate results suggest that biochemotherapy is tolerable and produces a response rate in the range of 50% with a complete response rate of 10%. Although these phase II results appear superior to previous results with chemotherapy or immunotherapy alone, the true benefits of biochemotherapy can only be determined with the results of randomized phase III trials; therefore, biochemotherapy should be considered an as yet experimental therapy. Many other issues regarding biochemotherapy, such as sequence, outpatient administration, and use in the adjuvant setting, for stage III melanoma are being actively evaluated.     

Long-term survival in metastatic melanoma patients treated with sequential biochemotherapy: report of a Phase II study

The overall survival for patients with metastatic melanoma is very poor, with a median survival of 8.5 months. In this Phase II trial, we assessed the efficacy, safety, and tolerability of a sequential biochemotherapy schedule, using dacarbazine as antiblastic agent and immunomodulant doses of interleukin-2 and interferon-alfa. Thirty-one eligible patients with metastatic melanoma received dacarbazine IV as antiblastic therapy and interluekin-2, plus interferon-alfa SC as sequential immunotherapy, for 6 months. Responding and nonprogressing patients were subsequently maintained on immunotherapy treatment for further 6 months. Twenty-nine patients had an adequate trial, and were assessable for both response and toxicities, with a median follow-up of 49 months. The overall response rate was 52 percent (3 CR and 12 PR), SD was 8 (27 percent) and PD were achieved in 6 patients (21 percent). The median survival duration of responders was 28 months, significantly longer (p < 0.001) than the 16 months of nonresponders. Therapy was well tolerated and produced a significant improvement in progressive-free survival. Further studies, thus, are recommended for larger groups of patients not only to confirm these results, but also to apply this biochemotherapy regimen as adjuvant postsurgical treatment in early stages of malignant melanoma.     

Evaluation of the serum L-dopa/L-tyrosine ratio as a melanoma marker

A wide range of molecules have been investigated as tumour markers in melanoma, most of which are not suitable for use by clinical oncologists for the detection of fast and unpredictable metastatic dissemination. We have already shown that the serum L-dopa/L-tyrosine ratio (an index of tyrosinase functional activity) correlates with the tumour burden and in some cases predicted disease progression in metastatic melanoma patients. We examined the potential value of this ratio for the follow-up, therapy monitoring and prognosis in melanoma compared with a reference marker (S100B, a melanoma-associated antigen). Sixty melanoma patients (24 stage I-II, 18 stage III, 18 stage IV, American Joint Committee on Cancer staging) were entered into the study, sampled two to eight times (before and after therapy) and were followed for up to 30 months. Serum L-dopa and L-tyrosine were determined by high performance liquid chromatography and S100B by an immunoluminometric assay. In stage III patients with elevated marker concentration, lymph node dissection decreased the S100B level (from 0.27 to < 0.13 microg/l, P=0.008), but not the L-dopa/L-tyrosine ratio. Chemotherapy decreased the L-dopa/L-tyrosine ratio by 38% (P =0.04) and the S100B level by 45% (P = 0.02) in stage IV responders. During follow-up, patients with marker levels within normal limits (n=19) had stable disease, except for two stage II patients. In patients with progressive disease (n=20), an increase in one or both markers was observed. Stage IV patients with high L-Dopa/L-Tyrosine ratio (above 20 x 10-5) at inclusion had shorter survival (3 months), while patients with low levels had longer survival (15 months). Levels of S100B had no impact on survival, as all stage IV patients (with levels below or above 0.38 microg/l) had the same survival (5 months). The serum L-dopa/L-tyrosine ratio may be influenced by successful therapy and levels at inclusion may correlate with prognosis in stage IV patients. Levels of these two markers in other biological fluids such as cerebrospinal fluid and tumour exudates may be useful diagnostically and prognostically in difficult cases.     

Metastasectomy for recurrent stage IV melanoma.

BACKGROUND AND OBJECTIVES: Many patients undergoing complete surgical resection of distant metastatic melanoma (American Joint Committee on Cancer [AJCC] stage IV) develop recurrent disease. We examined whether a second metastasectomy could prolong the survival of patients with recurrent stage IV melanoma. DESIGN AND PATIENTS: Retrospective review of our 8,750-patient melanoma database identified 211 patients who were rendered clinically free of disease by surgical resection of stage IV metastases during the 24-year study period (January 1971 through December 1995). Our study population comprised the 131 patients who developed recurrent stage IV disease and were followed for at least 24 months or until death. RESULTS: The median disease-free interval prior to recurrent stage IV disease was 8 months (range 0.6-91.8 months). There were 131 tumor-involved anatomic sites; the median number was one (range 1-3). Of these sites, 71 (54.2%) were soft tissue, 35 (26.7%) were pulmonary, 28 (21.4%) were gastrointestinal, 23 (17.6%) were cerebral, 13 (9.9%) were skeletal, and 2 (1.5%) were gynecologic. Median survival following treatment for recurrent stage IV melanoma was 18.2 months after complete metastasectomy, compared with 12.5 months or 5.9 months after a palliative surgical procedure or nonsurgical management, respectively. The 5-year survival rate was 20.0% (8/40) for patients in the complete surgical metastasectomy group, compared with 7.0% (3/43) and 2.1% (1/48) for those in the palliative surgical and nonsurgical groups, respectively. By multivariate analysis, the two most important prognostic factors for survival following diagnosis of recurrent stage IV melanoma were a prolonged disease-free interval to recurrence (P = 0.0001) and complete surgical metastasectomy of the recurrence (P = 0.0001). CONCLUSIONS: Metastasectomy can prolong the survival of patients with recurrent stage IV melanoma if all clinically evident tumor can be resected.     

Association of circulating tumor cells with serum tumor-related methylated DNA in peripheral blood of melanoma patients

Although previous studies have separately shown the utility of circulating tumor cells (CTC) or cell-free tumor-related DNA in blood of cancer patients, there has been no investigation of their association and/or the prognostic value of combining these assessments. To date, the true source of tumor-related DNA in serum remains unknown. We hypothesized that CTC is a possible origin of serum tumor-related methylated DNA and their combination can predict disease outcome. To test this hypothesis, we obtained matched pairs of peripheral blood lymphocytes and serum specimens simultaneously from 50 American Joint Committee on Cancer stage IV melanoma patients before administration of biochemotherapy. Peripheral blood leukocytes were analyzed for three mRNA markers of CTC: MART-1, GalNAc-T, and MAGE-A3. Sera were analyzed for two methylated DNA markers: RASSF1A and RAR-beta2. CTC were detected in 13 of 15 (86%) patients with serum tumor-related methylated DNA and only in 13 of 35 (37%) patients without methylated DNA (P = 0.001). The number of CTC markers detected significantly correlated with methylated DNA (P = 0.008). CTC and methylated DNA were significantly correlated with biochemotherapy-treated patients' outcome. Patients with both CTC and methylated DNA showed significantly poorer response to biochemotherapy (P = 0.02) and worse time to progression and overall survival (P = 0.009 and 0.02, respectively). The correlation between CTC and serum tumor-related methylated DNA and the significant effect of this correlation on disease outcome indicate that a composite molecular assessment in blood may be a useful determinant of disease status and efficacy of systemic therapy for melanoma.     

Biochemotherapy of metastatic melanoma in patients with or without recently diagnosed brain metastases

BACKGROUND: Brain metastases are an alarming complication of advanced melanoma, frequently contributing to patient demise. The authors performed a retrospective analysis to determine whether the treatment of metastatic melanoma with biochemotherapy would result in similar outcomes if brain metastases were first controlled with aggressive, central nervous system (CNS)-directed treatment. METHODS: Seventy melanoma patients were treated with biochemotherapy for metastatic melanoma between 1999 and 2005. Of these, 20 patients had recently diagnosed brain metastases, whereas 50 did not. Brain metastases (if present) were treated with stereotactic radiosurgery >or=28 days prior to systemic therapy. All patients were treated with biochemotherapy consisting of either dacarbazine or temozolomide in combination with a 96-hour continuous intravenous infusion of interleukin-2 and subcutaneous interferon-alpha-2B. The primary endpoint was survival from the time of the initial diagnosis of metastatic disease. RESULTS: Median survival from the time of the diagnosis of metastatic melanoma was 15.8 months for patients with brain metastases and 11.1 months for those without CNS involvement (P = .26 by the log-rank test; P = .075 by the Gehan Wilcoxon test). Dacarbazine-based and temozolomide-based regimens appeared similar with regard to their effect on overall survival and CNS disease progression. A plateau in further brain recurrences was observed in patients who survived for > 20 months. CONCLUSIONS: Data from the current study suggest that the outcome of biochemotherapy is comparable in patients with and those without brain metastases, if brain metastases are controlled with multidisciplinary treatment. Prolonged survival can be achieved in approximately 15% of patients, regardless of whether or not brain metastases are present.