Biochemotherapy for melanoma

Systemic therapy for advanced melanoma includes chemotherapy, either with dacarbazine (DTIC) alone or a multiagent combination chemotherapy, and biologic therapy with recombinant interferon-a and/or interleukin-2. However, none of these treatment options has produced long-term control of the disease except on rare occasions. Combined chemo-immunotherapy (biochemotherapy) has shown high objective response rates (approximately 50%) and a significant though small proportion of long-term complete responders in metastatic melanoma. It has, however, been associated with greater toxicity. Overall results of sequential versus concurrent biochemotherapy are similar, but the toxicity appears to be less severe in patients treated with the concurrent regimen. At this time, biochemotherapy is under evaluation in a well-designed prospective, randomized trial to identify whether there is benefit to this strategy, compared with chemotherapy alone.     

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.     

Biochemotherapy in patients with advanced vulvovaginal mucosal melanoma

Patients with advanced vulvovaginal mucosal melanoma generally have a dismal prognosis, and no effective systemic therapy for the disease has been reported. The objective of this retrospective clinical study was to assess the clinical benefit of biochemotherapy in this patient population. We evaluated the medical records of all patients with advanced vulvovaginal mucosal melanoma treated with biochemotherapy at our institution. Our search yielded 11 patients with adequate documentation for study inclusion: eight patients had undergone treatment with cisplatin (CDDP), vinblastine (VB), dacarbazine (DTIC), interferon-alpha (IFN) and interleukin-2 (IL-2), one with CDDP, VB, DTIC and IFN, one with CDDP, temozolomide and IFN, and one with CDDP, VB, DTIC, tamoxifen, IFN and IL-2. All IL-2 treatments were administered intravenously. The median follow-up duration was 10 months (range, 2-44 months). Four patients (36%) showed partial responses, but none showed a complete response. Two patients did not return for follow-up evaluation after the completion of treatment. The median time to disease progression in all 11 patients was 3 months; however, the median time to disease progression in those with a partial response or stable disease was 6 months. One patient was alive at the last documented follow-up visit (51 months). The median overall survival duration from the start of biochemotherapy was 10 months. Biochemotherapy appears to have significant activity against advanced vulvovaginal melanoma, and should be considered as a systemic treatment option for advanced, metastatic, vulvovaginal melanoma.     

Biochemotherapy in patients with metastatic anorectal mucosal melanoma

BACKGROUND: Patients with metastatic anorectal melanoma generally have an unfavorable prognosis, but no effective systemic therapy has been reported. METHODS: The authors retrospectively evaluated the medical records of all patients with metastatic anorectal melanoma treated with biochemotherapy between January 1991 and December 2001 at the University of Texas M. D. Anderson Cancer Center (Houston, TX). RESULTS: The search yielded 18 patients. Of these patients, 14 had undergone treatment with cisplatin (CDDP), vinblastine (VB), dacarbazine (DTIC), interferon alpha-2b (IFN), and interleukin 2 (IL-2); 2 had undergone treatment with CDDP, VB, DTIC, and IFN; 1 had undergone treatment with CDDP, IFN, and IL-2; and 1 had undergone treatment with CDDP, VB, temozolomide, IFN, and IL-2. All IL-2 treatments were administered intravenously. The median follow-up time was 12.2 months (range, 3.5-43.7 months). Eight patients (44%) had major responses, including two (11%) complete responses (CRs). Three patients were lost to follow-up evaluation after the completion of treatment. The median time to progression among the 15 remaining patients was 6.2 months. Four patients, including 1 with a CR, were alive at their last documented follow-up visits (survival: 14.0, 20.7, 31.3, and 43.7 months, respectively). The median overall survival was 12.2 months. Among 13 patients who received biochemotherapy as first-line systemic therapy, 6 patients (46%) had major responses, including two (15%) CRs. The median time to progression for this group was 6.2 months, and the median overall survival was 12.9 months. CONCLUSIONS: Biochemotherapy had substantial activity against metastatic anorectal melanoma and should be considered for use in the treatment of metastatic disease from primary anorectal melanoma.     

Biochemotherapy in the treatment of metastatic melanoma in selected patients

Introduction  Bioimmunochemotherapy (BCT) is a combination of biological agents and cytostatics that has shown an increase in response rate (RR) in metastatic melanoma patients. The aim of the study is to evaluate RR, progression-free survival (PFS), overall survival (OS) and treatment toxicity. Materials and methods  Retrospective analysis of 11 metastatic melanoma patients treated from January 2002 to June 2008 with cisplatin 20 mg/m² i.v. days 1–4, dacarbazine 800 mg/m² i.v. day 1, vinblastine 1.5 mg/m² i.v. days 1–4, interleukin (IL)-2 9 MIU/m² s.c. 5–8 days and interferon (IFN)-α-2b 5 MIU/m² s.c. days 5–9, 11, 13 and 15, with the support of granulocyte colony-stimulating factor (G-CSF) and antibiotics. Patients with ECOG 0, age ≤65 years and with measurable disease were included. The planned number of courses was 4. RR was measured by Revised Evaluation Criteria in Solid Tumour (RECIST) criteria (computed tomography [CT]±proton emission tomography [PET]). Toxicity was measured according to the National Cancer Institute (NCI) common toxicity criteria. Results  Observed RRs were 18% complete response (CR), 27% partial response (PR), 9% stable disease (SD) and 46% disease progression. The median PFS was 4 months (95% CI, 0–10 m), with a 23% one-year PFS. Median OS was 4.6 months (95% CI, 0.9–19 m), with a 29% one-year OS. Eighty-three percent of patients experienced grade 3–4 toxicity, mainly due to neutropenia, thrombocytopenia and flu-like syndrome. Conclusions  Treatment with BCT shows an increase in RR, some achieving durable CR; nevertheless it cannot be considered a standard treatment and should be employed only in selected patients.     

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.     

Biochemotherapy for the treatment of metastatic malignant melanoma: a systematic review

BACKGROUND: The incidence of malignant melanoma has increased in recent years. Current therapies for metastatic melanoma include chemotherapy and a variety of immunotherapeutic choices. With no established standard treatment option, the evaluation of biochemotherapy is warranted. METHODS: A systematic review of the literature was conducted to locate randomized controlled trials, meta-analyses, systematic reviews, and evidence-based practice guidelines published up to April 2007. RESULTS: Nine eligible randomized controlled trials were identified, including six comparing chemotherapy alone to biochemotherapy (chemotherapy combined with interleukin-2 and interferon). Response rates were significantly higher with biochemotherapy in only two trials, although when data were pooled, biochemotherapy was superior to chemotherapy on response (relative risk, 1.52; 95% confidence interval, 1.24-1.87; p<0.0001) but did not delay time to progression (Hazard ratio, 0.80; 95% confidence interval, 0.63-1.01; p=0.06). Biochemotherapy was not associated with a statistically significant survival benefit in any of the individual trials or in a pooled analysis (Hazard ratio, 0.95; 95% confidence interval, 0.78-1.17; p=0.64). Biochemotherapy is a toxic therapy, and patients are likely to experience serious hematologic, gastrointestinal, cutaneous, and constitutional toxicities, although when conducted in the correct setting, grade 3 and 4 effects appear to be manageable, and treatment-related death can be minimized. CONCLUSION: The results of available studies are inconsistent with regard to benefit (response, time-to-progression, and survival) and show consistently high toxicity rates. Therefore, biochemotherapy is not recommended for the treatment of metastatic malignant melanoma in adults.     

Biochemotherapy of metastatic malignant melanoma. Predictive value of tumour-infiltrating lymphocytes.

The therapeutic efficacy of biochemotherapy in metastatic malignant melanoma still carries a low remission rate, but with some durable responses. It would therefore be of considerable importance if patients with a high probability of responding could be identified using predictive tests. The response to interferon-alpha (IFN-alpha) correlates with the occurrence of CD4(+) lymphocytes identified by fine-needle aspirates from melanoma metastases (H?kansson et al, 1996). The present investigation studies a possible correlation between tumour-infiltrating CD4(+) lymphocytes in malignant melanoma metastases and the therapeutic effect of biochemotherapy. A total of 25 patients with systemic and 16 with regional metastatic melanoma were analysed before initiation of biochemotherapy (cis-platinum 30 mg/m(2) d.1-3, DTIC 250 mg/m(2) d.1-3 i.v. and IFN-alpha 2 b 10 million IU s.c. 3 days a week, q. 28d.). A monoclonal antibody, anti-CD4, was used to identify tumour-infiltrating lymphocytes in fine-needle aspirates before start of treatment. The presence of these lymphocytes was correlated to response, time to progression and overall survival. A statistically significant correlation (P = 0.01) was found between the occurrence of CD4(+) lymphocytes and tumour regression during biochemotherapy in patients with systemic disease. Out of 14 patients with moderate to high numbers of infiltrating CD4(+) lymphocytes, 12 achieved tumour regression. In contrast, among patients with low numbers of these cells in metastatic lesions, 8 out of 11 had progressive disease. We also found a significantly longer time to progression (P < 0.003) and overall survival (P < 0.01) among patients with moderate to high numbers of these cells compared to patients with low numbers of these cells before initiation of biochemotherapy. Furthermore, in patients with regional disease, we found a significantly longer time to progression (P = 0.01) and a trend toward a longer overall survival time (P = 0.09). Based on these results and as previously shown with IFN-alpha therapy alone, there seems to be a need for CD4(+) lymphocytes infiltrating the tumours before the start of biochemotherapy to make the treatment successful. Determination of these cells in fine-needle aspirates seems to be a method to predict responders to biochemotherapy, thus increasing the cost-benefit of this treatment strategy considerably, both in terms of patient adverse reactions and health care costs.     

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.     

胃癌的生物化疗

胃癌（Gastric carcinoma）具有明显的地域性,尤其是东亚三国（日本、韩国和中国）为高发区,约占全球总数的2／3,近年来发病率略呈下降趋势。可是在我国,胃癌仍高居各种恶性肿瘤之首。     

Biochemotherapy with low doses of subcutaneous interleukin-2 in patients with melanoma: results of a phase II trial

Introduction Metastatic melanoma has an ominous prognosis. Bio-chemotherapy regimens can increase the response rate but with a high degree of toxicity due, mainly, to the use of high-dose intravenous interleukin-2. Objectives To test the feasibility and activity profile of a bio-chemotherapy regimen of low-dose subcutaneous interleukin-2. Material and methods Administration scheme: dacarbazine at 200 mg/m²/d on days 1–4, cisplatin at 20 mg/m²/d intravenous on days 1–4, vinblastine at 1.5 mg/m²/d on days 1–4, IL-2 at 4.5 MUI/m²/d subcutaneous on days 5–8, IFN-alpha at 5 MU subcutaneous on days 5–9, 11, 13, 15 of every 21-day cycle. Results Objective response was obtained in 11 patients (39.3%; 95%CI: 21–59) including 4 with complete response (14.5%; 95%CI: 4–33). With an extended follow-up of 49 months and 60 months, respectively, 2 patients continue with complete response. The main toxicities were haematological: grade 3–4 neutropenia in 8.2% of cycles, thrombocytopenia in 1.2% and anaemia in 3.2%. Conclusions The regimen is safe and has a good activity profile. The presence of long-term survivors, despite the use of lower doses and subcutaneous IL-2, is encouraging.     

Biochemotherapy with temozolomide, cisplatin, vinblastine, subcutaneous interleukin-2 and interferon-alpha in patients with metastatic melanoma

The aim of this study was to determine the efficacy and tolerability of a biochemotherapy regimen, including low-dose subcutaneous interleukin-2 and temozolomide, in patients with metastatic melanoma. Treatment consisted of temozolomide (150 mg/m per day on days 1-5), cisplatin (20 mg/m per day intravenously on days 1-4), vinblastine (1.5 mg/m per day on days 1-4), interleukin-2 (4.5 MU/m per day subcutaneously on days 5-8) and interferon-alpha2b (5 MU subcutaneously on days 5-9, 11, 13, 15, every 28 days). Thirty-six patients were included. Patients with poor prognostic factors were not excluded. Seventeen patients (47%) had been treated previously in an adjuvant setting with interferon-alpha. Four patients (11%) had been treated previously with chemotherapy and six (17%) had been treated with other biochemotherapy regimens. The distribution by American Joint Committee on Cancer staging was as follows: M1a in two patients (6%), M1b in 11 patients (31%) and M1c in 23 patients (64%). At inclusion, seven patients (19.4%) had cerebral metastases that had previously been treated with whole brain radiotherapy. For thirty-four evaluable patients, seven (20.5%) achieved an objective response. Overall, metastatic disease was substantially decreased or temporarily stabilized in 11 patients (32.4%; 95% confidence interval, 17.4-50.5). Responses were observed for all locations. The central nervous system was the initial site of relapse in two responding patients. The median survival was 10 months. The main toxicities noted were haematological (grades 3-4): neutropenia (1.8%), thrombocytopenia (1.8%) and anaemia (1.2%). It can be concluded that this regimen is well tolerated and has a modest activity despite the poor prognosis of our patient population. The low haematological toxicity rate obtained suggests that higher doses could be tried.     

Biochemotherapy with thymosin {alpha}l, interleukin-2 and dacarbazine in patients with metastatic melanoma: Clinical and immunological effects

BACKGROUND: DTIC and interleukin-2 (IL-2), as single agents, have a limitedanti-tumor activity in patients with metastatic melanoma. Experimentally,thymosin     

生物化疗对原发性肝癌的疗效及血清IL-2、IL-12水平的影响

目的　探讨生物化疗对原发性肝癌 (PLC)的疗效及其对患者血清IL -2、IL -12水平的影响。方法　 60例PLC患者 ,随机分为 2个组 ,即单纯经肝动脉栓塞化疗 (TACE)组 (以下简称TACE组 ) 3 5例 ,生物化疗 (BIO )组 (以下简称BIO组 ) 2 5例。BIO组于TACE后第 3天开始接受IL -2 (IL -2 10 0万U /天× 10天 ,静脉点滴 )及IFN -γ(5 0万U /天× 10天 ,肌肉注射 )治疗。采用酶联免疫吸附法 (ELISA)检测治疗前后血清IL -2、IL -12水平 ,同时观测肿瘤体积变化情况。结果　BIO组用药后血清IL-2、IL -12水平显著高于TACE组 (P <0 .0 1)。 43例不能手术的患者中无完全缓解 (CR )者 ,BIO组 18例中部分缓解 (PR ) 4例(2 2 .2 % ) ,无变化 (SD) 11例 (61.1% ) ,进展 (PD ) 3例 (16.7% ) ,有效率为 83 .3 % ;TACE组 2 5例中PR 2例 (8.0 % ) ,SD 15例(60 .0 % ) ,PD 8例 (3 2 .0 % ) ,有效率为 68.0 % ;BIO组疗效 (83 .3 % )优于TACE组 (68.0 % ) (P <0 .0 5 )。 2组PR和PD率比较有显著性差异 (P <0 .0 5 ) ,2组SD率比较无显著性差异 (P >0 .0 5 )。结论　生物化疗是治疗PLC的 1种积极有效的方法 ,可作为不能手术PLC患者的可行性治疗方法 ,也可作为PLC术后的 1种良好的辅助治疗手段 ;IL -2和IFN -γ的联合应用是 1种较好的生     

恶性肿瘤患者化疗及生物化学治疗后淋巴细胞亚群的变化

目的　观察恶性肿瘤患者化疗和生物化学治疗前后淋巴细胞亚群的变化及其临床意义。方法　利用流式细胞仪测定 3 2例化疗前后和 2 6例生物化学治疗前后的淋巴细胞亚群及其活性。结果　化疗结束后 1个月患者CD2 5 及NK细胞较化疗前明显降低 (P <0 0 5 ) ,CD4 和CD8 细胞无明显变化 (P >0 0 5 )。化疗后应用免疫治疗组CD2 5 及NK细胞较化疗前明显升高 (P <0 0 1及P <0 0 5 )。结论　化疗对恶性肿瘤患者细胞免疫功能有明显抑制作用 ,化疗结束后应用生物反应调节剂对恶性肿瘤患者的细胞免疫功能有明显改善作用。