生物化疗、化疗或生物疗法用于治疗恶性黑色素瘤的回顾性分析

背景与目的:近年来恶性黑色素瘤发病率有明显上升趋势,恶性黑色素瘤对单纯放、化疗不甚敏感,然而,它是一种免疫原性较高的肿瘤,联合免疫治疗可以提高疗效,因此,恶性黑色素瘤治疗的合理性在于它的综合治疗.本研究回顾性分析观察Ⅲ、Ⅳ期恶性黑色素瘤患者应用生物化学、生物或化学治疗的近期和远期疗效.方法:分析102例Ⅲ、Ⅳ期恶性黑色素瘤患者化学治疗(达卡巴嗪、顺铂、福莫司汀)、生物治疗(白细胞介素-2、干扰素α-2b、树突状细胞)或生物化疗(上述两者联合续贯)的临床疗效.中位随访时间2年(1至4年).结果:近期疗效:生物化疗组36例,有效率(RR)为69.44%,与生物治疗组(34例,RR29.41%)和化学治疗组(32例,RR 46.89%)相比,差异有显著性(P＜0.05).远期疗效生物化疗组的中位生存时间(MST)为2年9个月,与生物治疗组(MST为2年2个月)和化学治疗组(MST为1年2个月)相比,差异有显著性(P＜0.05).然而,毒副作用在生物化疗明显高于其他两组,但经一般处理,患者均可耐受.结论:恶性黑色素瘤患者经生物化学治疗可明显提高有效率并延长生存时间.     

恶性黑色素瘤的生物治疗现状

本文介绍了近年来细胞因子、过继免疫治疗、肿瘤疫苗及单抗交联物等生物治疗方案在恶性黑色素瘤治疗中的应用概况。     

恶性黑色素瘤的生物治疗和生物化学治疗

为观察生物冶疗和生物化学治疗对恶性黑色素瘤病人术后存活的影响.取136例恶性黑色素瘤病人,男性80例,女性56例,中位年龄48岁(18岁～80岁).肿瘤部位以头面部和四肢最多见(占全部病例的69.9%),躯干,消化道和生殖系统分别占11.0%,8.1%和8.5%,较少见部位包括乳腺1例,子宫2例,食道3例,全组病人入院后分别接受手术及放疗,化疗,生物治疗和生物化学治疗,资料完整者111例,其中23例术后应用生物治疗(包括TAK细胞,IL-2和IFN-α);34例术后接受生物化学治疗(单药或多药化疗联合生物反应调节剂);48例术后应用放疗或化疗.化疗药物包括DDP(100mg/M2),CBP(350mg/M2),DTIC(125mg/M2×3)     

恶性黑色素瘤生物治疗研究进展

黑色素瘤是较常见的恶性肿瘤,近年来已经成为发病率增长最快的肿瘤之一.自2011年依匹单抗等药物经FDA批准上市后,黑色素瘤相关治疗的研究与发展就一直处于各类肿瘤研究的前列.现我国黑色素瘤患者死亡病例与新发病例的比例明显高于全球平均水平,但治疗情况却与国外差距悬殊,生存率相差甚远,8种FDA批准的药物在我国也均未上市.文章就目前黑色素瘤治疗相关药物临床应用进展、耐药机制研究及新型免疫药物的开发予以综述.     

恶性黑色素瘤的靶向治疗

目前恶性黑色素瘤(MM)主要的靶向治疗方法包括信号传导通路抑制剂、靶向凋亡、蛋白酶体抑制剂、抗血管生成治疗等.MM靶向治疗研究的发展方向是根据患者对靶向治疗敏感性的差异选择更加个体化的靶向治疗方法和技术.     

恶性黑色素瘤药物治疗研究进展

近年来随着治疗策略的变化,新的联合用药方案的提出以及新药问世,带动了一系列恶性黑色素瘤的临床试验,并取得了一些可喜的结果。全文就化疗、免疫制剂、生物化疗和靶向药物在恶性黑色素瘤中应用进展作一综述。     

恶性黑色素瘤38例临床分析

回顾分析了16年间收治的38例恶性黑色素瘤的临床资料.结果1年生存率54.1%（20/37）,3年生存率28.1%（9/32）,5年生存率24%（6/25）,7年以上生存率16.7%（3/18）.初步研究结果提示,恶性黑色素瘤应早期发现,早期诊断,早期切除,并配合化疗、放疗和免疫综合性治疗,可有效提高患者的治愈率及生存率.     

恶性黑色素瘤化疗研究进展

恶性黑色素瘤(Malignant melanoma,MM)是一种恶性程度极高的实体肿瘤,它极具侵袭性,预后差。尽管晚期黑色素瘤的治疗已经进入靶向和免疫治疗的时代,但是化疗仍然不可摒弃。恶性黑色素瘤的化疗经历了从单药化疗、两药或三药甚至四药的联合化疗、再到生物化疗这一发展过程。本文综述恶性黑色素瘤化疗研究进展,对主要的化疗方案进行比较,展望化疗未来发展的方向。     

恶性黑色素瘤38例临床分析

回顾分析了16年间收治的38例恶性黑色素瘤的临床资料。结果1年生存率54.1%(20/37),3年生存率28.1%(9/32),5年生存率24%(6/25),7年以上生存率16.7%(3/18)。初步研究结果提示,恶性黑色素瘤应早期发现,早期诊断,早期切除,并配合化疗、放疗和免疫综合性治疗,可有效提高患者的治愈率及生存率。     

过继性生物-化疗对难治性恶性黑色素瘤的治疗

组成肿瘤包块细胞的异质性(不同代龄、不同分化程度、不同周期，甚至两种类型)，构成了对同一种治疗的不同敏感性和低抗性，决定了对恶性肿瘤应采用多种方法综合治疗和有计划治疗的策略。     

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 biochemotherapy for the treatment of metastatic malignant melanoma

The use of interleukin-2 (IL-2) and interferon-alpha (IFNalpha) in combination with chemotherapy for the treatment of advanced malignant melanoma has generated considerable interest. In particular, the relatively high number of durable complete responses has suggested this may be a significant advance in the treatment of malignant melanoma. We report our experience at the University of Colorado in 43 patients, including many with poor prognostic factors. Patients received cisplatin 20 mg/m2 on days 1-4, vinblastine 1.6 mg/m2 on days 1-4, dacarbazine 800 mg/m2 on day 1, IL-2 9 x 10(6) IU/m2 per day intravenously over 24h on days 1-4 and IFNalpha 5 x 10(6) IU/m2 per day subcutaneously on days 1-5 every 3 weeks. The median follow-up for all patients was 34 months. Responses were seen in 20 patients (47%, 95% confidence interval 31-62%) and comprised five complete responses (CRs) (12%) and 15 partial responses (PRs) (35%). Two patients achieving a CR remain disease free at 45 and 47 months follow-up. In addition three patients who obtained a surgical CR and another with only minor residual changes on computed tomography scan have not progressed at 27, 30, 40 and 27 months, respectively. Toxicity was manageable, but all patients had at least one grade 3 or 4 toxicity, predominantly hypotension and neutropenia. There were no treatment-related deaths. In conclusion, the response rate and duration is within the range previously reported for biochemotherapy. The results of ongoing randomized studies are awaited to better define the value of biochemotherapy in the treatment of advanced melanoma.     

On the effect of biochemotherapy in metastatic malignant melanoma: an immunopathological evaluation

Although immunotherapy and biochemotherapy have shown promise, producing a subset of durable responses, for the majority of patients with metastatic melanoma the prognosis is still poor. Therefore there is a great need for predictive tests to identify patients with a high probability of responding. Furthermore, there is also a need for a better understanding of the mechanisms of action during treatment in order to be able to monitor the relevant antitumour reactivity during treatment and to optimize the efficacy of future immunotherapy and biochemotherapy. In the present study histopathological regression criteria were used to study the efficacy of biochemotherapy. Thirty-two patients with metastatic malignant melanoma (18 with regional disease and 14 with systemic disease) were treated with biochemotherapy (cisplatin 30 mg/m2 intravenously on days 1-3, dacarbazine 250 mg/m2 intravenously on days 1-3 and interferon-alpha2b 10 million IU subcutaneously 3 days a week, every 28 days). Pre-treatment fine needle aspirates were obtained from metastases to analyse the number of tumour-infiltrating CD4+ lymphocytes. Therapeutic efficacy was evaluated in metastases resected after treatment using histopathological criteria of tumour regression. Comparisons were also made with metastases from 17 untreated patients, all with regional disease. Regressive changes of 25% or more (of the section area) were found in two of the 17 untreated patients with regional disease compared with 13 of the 18 patients with regional disease and 10 of the 14 patients with systemic disease after biochemotherapy. Fifty per cent of the patients with regional disease showed a high degree of regressive changes (75-100% of the section area) after biochemotherapy. These results demonstrate the occurrence of an antitumour reactivity in the majority of patients. Patients with extensive regressive changes in 75-100% of the analysed biopsies were also found to have a longer overall survival (P = 0.019). In patients with regional disease there was a close correlation between a larger number of CD4+ lymphocytes pre-treatment and a higher degree of regressive changes post-treatment (P < 0.05). Thus, immunohistochemical analysis of tumour biopsies shortly after treatment seems to be a good surrogate endpoint. This technique also allows detailed analysis of antitumour reactivity and escape mechanisms.     

High-dose interleukin-2 in patients with metastatic melanoma whose disease progressed after biochemotherapy

The objective of this study was to report our experience with 38 consecutive patients with metastatic melanoma treated with high-dose (HD) bolus interleukin (IL)-2 after disease progression on or after biochemotherapy as the only earlier treatment for metastatic disease. We conducted a retrospective review of all patients with metastatic melanoma treated with HD IL-2 at the Oncology Center of Hospital Sirio-Libanes between October 2000 and December 2009. The treatment consisted of IL-2, of 600,000 U/kg every 8 h for up to 14 doses, followed by 1-week rest and readmission for the second cycle. Responders received up to four additional cycles. Median follow-up was 9 months. The overall response rate was 23.6%, and we found no correlation between earlier response to biochemotherapy and response to HD IL-2. The median survival was 9.5 months for all patients and 36.1 months for the responders. The most frequent grade 3 or 4 adverse events were hypotension, diarrhea, and respiratory distress, and one patient died from septic shock. We concluded that HD IL-2 has clinically meaningful antitumor activity in patients with metastatic melanoma whose disease has progressed after biochemotherapy. This is a treatment alternative in patients with no central nervous system involvement and who are fit enough to tolerate it, regardless of the initial response to biochemotherapy.     

High-dose tamoxifen added to concurrent biochemotherapy with decrescendo interleukin-2 in patients with metastatic melanoma

BACKGROUND: In vitro cell culture data and preclinical models suggest that tamoxifen modulates tumor cell sensitivity to a wide range of therapeutic agents. In the current study, the authors examined whether high-dose tamoxifen (HDT) improved the overall and complete response in patients with metastatic melanoma who were treated with concurrent biochemotherapy. METHODS: Forty-nine patients were treated with a biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo interleukin-2, interferon-alpha-2b, and tamoxifen. The study had a 2-step design, beginning with a tamoxifen dose escalation from 40 mg to 320 mg (17 subjects) to evaluate safety and tolerability, followed by Phase II accrual of 32 patients to HDT (320 mg) to assess clinical efficacy. Efficacy was compared with a similar modified biochemotherapy regimen with low-dose tamoxifen (LDT). Pharmacokinetic studies were performed to determine in vivo tamoxifen levels. RESULTS: Tamoxifen dose escalation was completed without any reported dose-limiting toxicity. The overall response rate in the HDT group was 50% (95% confidence interval, 33.2%-66.8%), with a complete response rate of 6% and a median survival of 9.5 months. The overall response rate was not improved and the complete response and survival appeared inferior compared with that of patients recently treated with concurrent biochemotherapy and LDT. Serum tamoxifen levels were found to correlate with the dose administered, with a mean of 0.9 microM at the 40-mg dose to 4.6 microM at the 320-mg dose. Ultrafiltered protein-free sera demonstrated low (< 0.01 microM) concentrations of tamoxifen. CONCLUSIONS: The addition of HDT to a regimen of concurrent biochemotherapy did not appear to improve response rates or overall survival, despite reaching the targeted plasma concentration. Unknown drug interactions or high protein binding of tamoxifen may account for the lack of clinical effectiveness.     

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.