Is there still a role for cytotoxic chemotherapy after targeted therapy and immunotherapy in metastatic melanoma?A case report and literature review

Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However,a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, even in the absence of a response to modern targeted therapies and immunotherapies; accordingly, determining predictive biomarkers of the response to chemotherapies for metastatic melanoma remains a priority to guide treatment in these patients. We report a case study of a patient with B-Raf proto-oncogene serine/threonine kinase-mutated metastatic melanoma harbouring many genetic mutations. The patient did not respond to prior targeted therapies or immunotherapies but experienced a dramatic objective radiological and clinical response to subsequent dacarbazine-based chemotherapy. In the era of targeted therapies and immunotherapies for metastatic melanoma, cytotoxic chemotherapies may still represent an interesting therapeutic weapon in a well-defined subgroup of patients presenting with specific genetic and molecular features.     

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.     

Total abdominal perfusion (TAP) in the treatment of abdominal metastatic melanoma

Total abdominal perfusion (TAP) is a recently described technique in which the abdominal organs are isolated from the systemic circulation and perfused by means of an external pump. Administering chemotherapy into the circuit provides higher locoregional drug exposure with lower systemic toxicity. Two patients with melanoma metastatic to the abdomen were treated using this technique. The first patient suffered from intractable upper gastrointestinal bleeding due to unresectable melanoma metastasis of the duodenum. He underwent TAP with melphalan and cisplatinum. His bleeding stopped and the tumor regressed. This patient's response lasted for 6 months. The second patient had an unresectable liver metastasis. She underwent TAP with melphalan and DTIC, resulting in a complete response with disappearance of the liver mass, which lasted until her death in 13 months. Our conclusion is that TAP should be considered as a technique for regional chemotherapy, which may be used in the treatment of unresectable metastatic melanoma of the abdomen. © 1994 Wiley-Liss, Inc.     

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.     

Consolidation electrochemotherapy with bleomycin in metastatic melanoma during treatment with dabrafenib

Background

Small molecules that inhibit V600 mutated BRAF protein, such as vemurafenib and dabrafenib, are effective in treatment of metastatic melanoma.

Case report

We here describe the clinical course of a V600E BRAF mutated metastatic melanoma patient with systemic disease, who developed tumor progression on superficial soft-tissue metastases during treatment with dabrafenib. Bleomycin electrochemotherapy during dabrafenib treatment was administered to control the soft-tissue progressing metastases and ensured sustained local control without significant toxicity.

Conclusions

The new combined approach maintained the patient quality of life and allowed for the prosecution of the target therapy, which proved to be still effective on systemic disease, up to 17 months.     

替莫唑胺联合舒尼替尼治疗转移性黏膜黑色素瘤的疗效及安全性

目的:探索替莫唑胺(temozolomide,TMZ)联合舒尼替尼(sunitinib,SUN)在转移性黏膜黑色素瘤治疗中的应用价值.方法:回顾性纳入我中心2008年8月至2016年12月间接受TMZ联合SUN治疗的晚期黏膜黑色素瘤患者.患者均无BRAF/NRAS突变,服用TMZ (200 mg/m2,d 1～5)和SUN (37.5 mg,d 1～28)治疗,28 d为一个疗程,治疗直至病情进展或毒副反应无法耐受.主要观察客观有效率(ORR)、疾病无进展生存期(PFS)、总生存期(OS)和毒副反应发生率.结果:纳入的27例患者中,原发肠道4例、泌尿生殖道9例、鼻咽部5例、口腔7例、食管2例,有19例患者既往接受过抗肿瘤治疗,TMZ联合SUN治疗的中位治疗周期为3.0.治疗后ORR 19.2％,疾病控制率(DCR) 81.5％,中位PFS(3.0±0.7)个月,中位OS(7.1±0.9)个月.全组患者中有4例存在KIT突变,提示存在KIT突变/扩增的患者使用KIT抑制剂可能获益.联合治疗耐受性良好,仅2例患者因出现血小板抑制Ⅳ级,将SUN调整剂量为25 mg.Ⅲ～Ⅳ级副反应包括血小板下降(19.2％)、白细胞下降(19.2％)和肝功能损害(3.9％),未发生治疗相关性死亡事件.结论:TMZ联合SUN是治疗转移性黏膜黑色素瘤的有效方案,且安全性良好.     

Late recurrence of stage I malignant melanoma

Although the introduction of well-established risk factors has made the clinical course and prognosis of malignant melanoma disease much more predictable, in a considerable number of patients the disease's course is still not as expected. One group to which this applies are stage I melanoma patients who develop metastatic disease after 10 years or more of a disease-free interval. In our series of 94 such patients, 6 developed late relapse of their disease. The subsequent survival of these patients did not relate to any of the primary tumors' characteristics, but to the pattern of the late recurrence. Four patients with visceral metastases were dead within 1 to 5 years following relapse, one patient with lymph node involvement is alive with metastases, and another patient with skin metastases has no signs of disease following surgery and immunotherapy. Our conclusion is that malignant melanoma patients should be placed under close follow-up for the rest of their lives.     

Surgical approach to malignant melanoma in the gastrointestinal tract

The gastrointestinal (GI) tract is a common site for malignant melanoma. Diagnosis of lesions in the GI tract is usually delayed until complications occur, such as obstruction, bleeding, or perforation of the GI tract. Of 348 patients with malignant melanoma treated during a 10-year period, 11 had GI involvement either in a metastatic form or as a primary melanoma. Three of these patients were treated surgically for metastatic lesions in the small bowel causing intussusception, two for peritonitis secondary to perforation of the small bowel, and one for massive bleeding from metastatic melanoma in the stomach. Another patient had a primary melanoma in the esophagus and underwent esophagectomy. Three patients had primary melanomas of the anal canal and one of the rectum. Three of them underwent abdominoperineal resections, and two had bilateral groin dissection in addition. Six of the patients are alive 6 months to 4 years following diagnosis. The remaining five died of metastatic melanoma from 6 months to 4 years post-surgery.     

The role of surgery in treatment of stage IV melanoma

The prognosis for patients with melanoma has not improved over the last 30 years. So far, almost without exception, clinical trials conducted with single or multiple agent chemotherapy, biological therapy (interferon-alpha, interleukin-2), and biochemotherapy have failed to demonstrate consistent survival benefit. Without effective alternate treatments, surgery must be considered the primary treatment of melanoma, independent of disease stage. Although surgery is clearly favored as the treatment of localized melanoma, consensus opinion and clinician preference become divided once melanoma progresses beyond its primary site. Many physicians will adopt an attitude of resignation and hesitancy when treating metastatic melanoma. As a result, patients with advanced disease are often treated with medications that produce little survival or palliative benefit at the expense of significant toxicity. Numerous studies have demonstrated clear and durable survival advantages for patients undergoing complete resection of metastatic melanoma. Further, surgical resection can produce an immediate decrease in tumor burden with minimal morbidity and mortality at a reasonable cost.     

Individualized therapy of disseminated cancer using malignant melanoma as a model

Approximately 20 to 25% of patients with malignant melanoma will die of metastatic disease. The current standards of care for advanced metastatic melanoma (stage IV, AJCC classification) are poor. To date, randomized trials have failed to demonstrate that one regimen is better than another. It is therefore crucial that patients with disseminated malignant melanoma be recruited into clinical trials. In recent years, there have been impressive advances in our knowledge of the biology and nature of cancer development and the growth and progression to metastasis. The approach “from bench to bedside” is current reality in the treatment of several solid tumors and hematologic malignancies. The identification of new targets to facilitate individualized melanoma treatment is now an important issue. This article will give an overview of recent developments in clinical trials of targeted therapies in metastatic melanoma patients. Presented as Session VII of the First International Symposium on Cancer Metastasis and the Lymphovascular System. April 28–30, 2005, San Francisco, CA; Chaired by Axel Hauschild.     

A Primary Sacral Melanoma of Unknown Origin: A Case Report

Malignant melanoma caused by malignant transformation of melanocytes is associated with high mortality and is difficult to manage. Metastasis is not uncommon (up to 31% of all cases) and is closely associated with a poor prognosis. Although rare (4–5%), extracutaneous melanoma has been reported; however, primary malignant melanoma of the sacrum is extremely rare (only three case reports to date). Here, we present a 51-year-old patient who underwent surgical treatment for a lesion of the spinal canal and associated bony structures; extensive aggressive resection was required. She underwent partial sacrectomy and lumbo-iliac fixation (to maintain spinal stability). Pathology revealed malignant melanoma. We discuss the diagnosis, surgical intervention, and postoperative follow-up, which may assist clinicians. Although metastatic malignant melanoma is usually fatal, primary extracutaneous melanoma of the spine may respond well to surgery and adjuvant radiotherapy.     

The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study

Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had >50% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies.     

Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma

This paper is a report of response rate (RR) and survival of 34 metastatic melanoma patients who received a dinitrophenyl (DNP)-modified autologous melanoma cell vaccine. In all, 27 patients started the vaccine as a primary treatment for metastatic melanoma and seven started it as an adjuvant, with no evidence of disease at the time, but had developed new metastases. Interleukin-2 (IL-2) was administered in 24 out of the 34 patients: 19 who progressed on vaccine alone and five who had the combination from start. Interleukin-2 was administered in the intravenous, bolus high-dose regimen (seven patients) or as subcutaneous (s.c.) low-dose treatment (17). Overall response for the entire group was 35% (12 patients out of 34), 12% having a complete response (CR) and 23% a partial response (PR). However, only two patients had tumour responses while on the vaccine alone, whereas the other 10 demonstrated objective tumour regression following the combination with IL-2 (two CR, eight PR), lasting for a median duration of 6 months (range 3-50 months). Of the 12 responding patients, 11 attained strong skin reactivity to the s.c. injection of irradiated, unmodified autologous melanoma cells. None of the patients with a negative reactivity experienced any tumour response. Patients with positive skin reactions survived longer (median survival - 54 months). The results suggest enhanced RRs to the combination of IL-2 and autologous melanoma vaccine. Skin reactivity to unmodified autologous melanoma cells may be a predictor of response and improved survival, and therefore a criterion for further pursuing of immunotherapeutic strategies.     

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.     

Conventional fractionated radiotherapy for 51 patients with lentigo maligna and lentigo maligna melanoma

Lentigo maligna (LM) and lentigo maligna melanoma (LMM) are distinct entities from other forms of melanoma, occurring predominantly on the skin of the head and neck in elderly people, having a slow growth rate and a low metastatic potential (10%). Twenty-three patients with LM were treated with conventional fractionated irradiation, 18 were locally controlled and two failed locally both of whom, however, were salvaged with further treatment. Three patients are not evaluable because of short follow-up time. Median time to complete regression of the lesion is seven months. Twenty-eight patients with LMM have been irradiated, 23 are locally controlled, two locally recurred (both retrieved with subsequent treatment), and three are inevaluable because of short follow-up time. One patient with a level 5 LMM has developed regional and distant metastases. It is concluded that irradiation is a simple effective method of treatment for this form of melanoma.     

Revisiting the role of systemic therapies in patients with metastatic melanoma to the CNS

The CNS is a common site of metastasis in patients with malignant melanoma. Locoregional control either with surgery or radiotherapy is first-line treatment for patients with brain metastasis should they be suitable candidates. For those patients who are not and those who progress after previous treatment, there is an unmet clinical need for effective systemic therapies. Systemic cytotoxics, such as temozolamide and fotemustine, have only modest activity, resulting in a median progression-free survival ranging from 1–2 months, in patients with metastatic melanoma to the brain. Newer systemic treatments such as vemurafenib and ipilimumab have been approved for the treatment of melanoma, but evidence regarding their activity in brain metastases is inconclusive due to the limited access of patients to clinical trials. This is now being revised and more data are emerging supporting the inclusion of patients with brain metastasis in trials. In this review, the authors present data regarding the efficacy of systemically administered therapies in patients with metastatic melanoma to the brain.     

Radiotherapy for metastatic melanoma presenting in pregnancy

We describe the study of a patient with metastatic melanoma to axillary nodes presenting during pregnancy. The factors considered in her management are discussed, including issues related to staging, the decision not to terminate the pregnancy and the relative efficacy and fetal toxicity of the available treatment options. An overview of the known effects of radiotherapy on the fetus is presented and the technical alterations that were used to decrease the toxicity of radiotherapy are discussed.     

Phase 2 trial of carboplatin,weekly paclitaxel,and biweekly bevacizumab in patients with unresectable stage IV melanoma

BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in the growth and metastatic progression of melanoma. Exposure of melanoma cells to chemotherapy induces VEGF overproduction, which in turn may allow melanoma cells to evade cell death and become chemotherapy resistant. Therefore, in patients with metastatic melanoma, the combination of chemotherapy with an agent that specifically targets VEGF might be able to control tumor growth and progression more effectively than chemotherapy alone. METHODS: A 2‐stage phase 2 clinical trial was conducted in patients with unresectable stage IV (metastatic) melanoma to assess antitumor activity and the toxicity profile of the combination of carboplatin (area under the curve 6 iv on Day 1 of a 28‐day cycle), paclitaxel (80 mg/m² iv on Days 1, 8, and 15), and bevacizumab (10 mg/kg iv on Days 1 and 15). Treatment was continued until progression or intolerable toxicity. RESULTS: Fifty‐three patients (62.3% male) were enrolled. Nine (17%) patients achieved partial remission, and another 30 (57%) achieved stable disease for at least 8 weeks. Median progression‐free survival and median overall survival were 6 months and 12 months, respectively. One patient died after 8 treatment cycles from intracranial hemorrhage into undiagnosed brain metastases. The most common severe (grade ≥3) toxicities were neutropenia (53%), thrombocytopenia (11%), hypertension (9%), and anemia (8%). CONCLUSIONS: This combination of carboplatin, paclitaxel, and bevacizumab appears to be moderately well tolerated and clinically beneficial in patients with metastatic melanoma. Further study of this combination is warranted. Cancer 2009. © 2008 American Cancer Society.     

Antitumor activity of delimotecan against human metastatic melanoma: Pharmacokinetics and molecular determinants

Delimotecan (MEN 4901/T‐0128) is a new cytotoxic prodrug constituted by a camptothecin analog (T‐2513) bound to carboxymethyl dextran through a triglycine linker. A significant antitumor activity of delimotecan against human metastatic melanoma xenograft model Me15392 is reported. Dacarbazine, the drug approved for the treatment of metastatic melanoma, was ineffective in this melanoma model. Pharmacokinetic studies, together with the expression analysis of mRNA for enzymes involved in delimotecan metabolism, showed that T‐2513 and other cytotoxic metabolites of delimotecan (SN 38 and T‐0055) are generated in greater quantities in the tumor tissue than in toxicity target tissues, such as liver, thus accounting for the antitumoral activity. Moreover, we demonstrated that human metastatic melanoma cells are able to phagocytose delimotecan and cleave it to release the cytotoxic moieties T‐2513 in the tumoral environment. Further flow cytometric analysis showed a higher recruitment of macrophages in xenografted human metastatic melanoma, when compared with other human tumors. Thus, the antitumoral activity of delimotecan exerted on metastatic melanoma is due to several factors: (i) the ability of melanoma cells to phagocytose and metabolise delimotecan; (ii) the accumulation of delimotecan in tumoral mass; (iii) the recruitment of macrophage cells to the melanoma nodule and (iv) the expression in melanoma cells of a pattern of enzymes that converts delimotecan into cytotoxic metabolites. Based on these results, delimotecan might be exploited as a new anticancer agent for the therapy of metastatic melanoma because of its high efficacy and good selectivity, and therefore clinical trials for this indication are warranted. © 2009 UICC