Metastatic melanoma to the liver: A contemporary and comprehensive review of surgical,systemic, and regional therapeutic options

Effective management of hepatic metastases from ocular and cutaneous melanoma remains a major therapeutic challenge. Treatment options include hepatic resection, hepatic intra‐arterial (HIA) chemotherapy, chemoembolization, and hepatic perfusions. Evaluating the efficacy of these interventions is limited by the retrospective nature of most of the data, although controlled phase 3 studies are starting to emerge. Studies of hepatic resection are strongly suggestive of a survival benefit following surgery in selected patients. Effective systemic agents for metastatic cutaneous melanoma are available and supported by randomized controlled phase 3 trials. In contrast, no active systemic treatment has yet been identified for metastatic ocular melanoma. HIA and intravenous delivery of fotemustine have been compared in a randomized phase 3 trial in patients with unresectable metastases from melanoma, but no differences between the 2 approaches were observed. Hepatic arterial chemoembolization appears only to be moderately effective according to uncontrolled studies; targeting patients with less liver involvement may improve outcomes. A recent phase 3 study showed a significant improvement in hepatic progression‐free survival with percutaneous hepatic perfusion compared with best alternative care in patients with metastatic melanoma; however, the overall survival analysis was confounded by crossover of control patients to active treatment. In conclusion, hepatic resection offers the possibility of long‐term survival in carefully selected patients with liver‐limited metastases from melanoma. In patients with unresectable cutaneous melanoma, effective systemic therapy is the best treatment option. For patients with unresectable ocular melanoma, regional treatments are likely to assume a greater role until effective systemic treatments are identified. Cancer 2014;120:781–789 . © 2013 American Cancer Society.     

A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma

The main objective of this prospective multicentre randomized phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation with fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma cerebral metastases. Seventy-six patients were randomized to receive either fotemustine (arm A, n = 39) or fotemustine plus whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg/m(2) on days 1, 8 and 15, followed by a 5 week rest period, then every 3 weeks in non-progressive patients. In arm B, concomitant whole brain irradiation was performed at a total dose of 37.5 Gy (2.5 Gy/day on days 1-5 for three consecutive weeks). Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in cerebral response (arm A, 7.4%, arm B, 10.0%) or control rates (objective responses plus stable disease) after 7 weeks (arm A, 30%; arm B, 47%) or in overall survival (arm A, 86 days; arm B, 105 days). However, there was a significant difference in favour of arm B for the time to cerebral progression (P = 0.028, Wilcoxon test). In conclusion, fotemustine plus whole brain irradiation delayed the time to cerebral progression of melanoma cerebral metastases compared with fotemustine alone but without a significant improvement in terms of objective control or overall survival.     

Chemoimmunotherapy with bleomycin,vincristine, lomustine,dacarbazine (BOLD), and human leukocyte interferon for metastatic uveal melanoma

BACKGROUND: A Phase II trial comprising patients with metastatic uveal melanoma (Stage IVB) was undertaken to determine the activity of bleomycin, vincristine, lomustine, and dacarbazine (BOLD) chemotherapy with human leukocyte interferon, as well as the progression-free and overall survival of the patients according to the substage before treatment. METHODS: Twenty-two patients with histologically proven metastatic uveal melanoma received 15 mg of bleomycin (Days 2 and 5), 1 mg/m(2) vincristine (Days 1 and 4), 200 mg/m(2) dacarbazine (Days 1 to 5), and 80 mg lomustine (Day 1) every 4 weeks together with a leukocyte interferon preparation (3 x 10(6) IU daily for 6 weeks followed by 6 x 10(6) IU three times per week). RESULTS: Of 20 evaluable patients, 3 (15%; 95% confidence interval [CI] 0-38) obtained a partial objective response in hepatic and extrahepatic sites and 11 (55%; 95% CI 32-77) showed stable disease after receiving more than two cycles. The median progression-free survival was 4 months (95% CI 2-10) and the median overall survival was 12 months (95% CI 8-22). Eleven patients who had favorable pretreatment characteristics (Stage IVBa) survived a median of 17 months (95% CI 4-37) whereas 10 patients with less favorable characteristics (Stage IVBb) survived a median of 11 months (95% CI 1-23). Moderate toxicity occurred with this outpatient regimen. CONCLUSIONS: The BOLD/human leukocyte interferon regimen had modest activity against metastatic uveal melanoma in hepatic and extrahepatic sites. The median overall survival approached that reported for more aggressive intrahepatic therapy regimens. Substage differences can significantly impact study outcomes. Therefore, substage information should be reported to facilitate comparisons between studies.     

Regional chemotherapy of colorectal cancer metastatic to the liver

Ninety-three patients with biopsy-proven colorectal cancer metastatic to the liver were treated with hepatic arterial infusion of 5-fluorodeoxyuridine (FUDR). There were 52 men and 41 women (median age, 60 years). Forty-two patients (45%) had failed prior systemic chemotherapy. Catheters were operatively placed and multiple catheters were used if dictated by hepatic arterial anatomy in order to obtain perfusion of the entire liver. The drug was delivered by a totally implanted INFUSAID model 400 pump and patients received cyclic therapy consisting of 2 weeks of 0.3 mg/kg/d FUDR alternating with 2 weeks of saline. Patients with extrahepatic tumor or patients whose hepatic tumor failed to respond to FUDR were given a 30 minute intraarterial infusion of mitomycin C, 15 mg/m2, every 6 to 8 weeks in addition to FUDR. Fifty of the 93 evaluable patients presented with metastatic tumor confined to the liver. Of these 50 patients, 83% demonstrated a significant reduction in tumor size with a median duration of response of 13 months and a median survival of 25 months from diagnosis of liver metastases. Twenty-four of these 50 patients remain alive. Forty-three patients presented with extrahepatic metastases in addition to their liver tumor, and 74% had a response with a median duration of 6 months and a median survival of 14 months. Only six patients of those presenting with extrahepatic tumor remain alive. None of the 93 patients died solely of uncontrolled liver tumor, and only 9 died as a result of uncontrolled liver metastases and disseminated extrahepatic tumor. The duration of survival for both groups was determined by the uncontrolled progression of extrahepatic tumor. In patients with metastatic colorectal cancer involving only the liver, hepatic arterial FUDR alone and with the addition of mitomycin C provided excellent control of hepatic tumor. Survival appeared to be prolonged in this uncontrolled study.     

Fotemustine (S 10036) in the intra-arterial treatment of liver metastasis from malignant melanoma. A phase II Study

Fotemustine is a new nitrosourea which has shown some efficacy on disseminated malignant melanoma (DMM) (24.2% response rate (RR) among 153 patients in a Phase II trial) but little activity on hepatic metastasis (8.8% RR). In order to improve those poor results, hepatic intra-arterial infusion (HIAI) of fotemustine was performed. After two years, thirteen patients, all in good general condition, were evaluable. Seven were pretreated and six had extrahepatic metastasis on entry into the study. All patients had a surgically implanted intra-arterial catheter. The induction cycle consisted of 100 mg/m2/week for 3-4 weeks, followed by 5 weeks rest and maintenance therapy of 100 mg/m2 every 3 weeks for stabilized or responding patients. Two complete responses (CR) (72+ and 145+ weeks) and six partial responses (PR) (7-18.5 weeks) were observed. The hepatic RR reached 61.5%. A RR of 42.8% was registered on preexisting EHM (one CR and one PR on cerebral lesions). Nevertheless, this treatment is limited by the high progression rate of 46.1% in extrahepatic disease. Toxicity was mainly hematologic (grade III-IV), comprising 36% neutropenia and 15% thrombopenia. Hepatic intra-arterial infusion of fotemustine is efficient therapy for liver metastases of DMM, but combination schedules (IV + HIA) are warranted.     

肝动脉泵生物化疗治疗进展期黑色素瘤肝转移Ⅱ期临床研究

背景与目的：黑色素瘤肝转移全身治疗效果不佳,国外研究发现肝动脉灌注化疗可显著改善疗效,本研究进一步探讨肝动脉泵为基础的生物化疗治疗肝转移的疗效及对生存期的影响。方法：选择进展期黑色素瘤肝转移患者21例,予肝动脉泵置入,行淋巴细胞删除性化疗（福莫司汀＋达卡巴嗪）,化疗后立刻进行自体细胞因子诱导的杀伤细胞回输．并同时应用白介素-2、粒细胞巨噬细胞集落刺激因子治疗,28d为一周期。疗效评定采用实体瘤疗效评价标准。对21例患者的疾病控制率、不良反应发生率、无进展生存期、总生存期进行分析。结果：可评价疗效患者共17例,完全缓解1例,部分缓解1例,稳定6例．进展9例。疾病控制率47．06％（8／17）。中位无进展生存期3个月。中位生存期6个月。Ⅲ～Ⅳ级的不良反应占38．1％（8／21）。结论：对于进展期黑色素瘤肝转移患者。以肝动脉泵为基础的生物化疗可明显改善患者的疾病控制率。无进展生存期、总生存期有延长趋势,毒副作用可耐受,是一种有良好前景的治疗模式。     

Temozolomide in combination with fotemustine in patients with metastatic melanoma

Purpose  Temozolomide and fotemustine are both active drugs for treating metastatic melanoma. The present study was designed to assess the efficacy and safety of combination therapy with temozolomide + fotemustine in patients with metastatic melanoma. Methods  Forty patients (median age 50.5 and 22 males) with pathologically confirmed, unresectable, AJCO stage IV melanoma were enrolled into the study. The primary endpoints were tumor response and safety. Patients received oral temozolomide 125 mg/m² on days 1–7 and intravenous fotemustine 80 mg/m² on day 3 every 3 weeks. Results  Fourteen (35%) patients achieved an objective response, including 3 (7.5%) complete and 11 (27.5%) partial responses. Median overall survival time was 6.7 months and 6-month survival rate was 57.4%. Myelosupression, particularly thrombocytopenia, was the primary toxicity. Conclusion  The regimen, temozolomide combined with fotemustine, is an active and moderately safe first-line chemotherapy regimen with acceptable and easily manageable toxicities in patients with metastatic melanoma.     

Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma

Uveal melanoma is associated with a high mortality rate once metastases occur, with over >90% of metastatic patients dying within less than 1 year from metastases to the liver. The intraarterial hepatic (iah) administration of the alkylating agent fotemustine holds some promise with response rates of 36% and median survival of 15 months. Here, we investigated whether the DNA-repair-protein MGMT may be involved in the variability of response to fotemustine and temozolomide in uveal melanoma. Epigenetic inactivation of MGMT has been demonstrated to be a predictive marker for benefit from alkylating agent therapy in glioblastoma. We found a methylated MGMT promoter in 6% of liver metastases from 34 uveal melanoma patients. The mean MGMT activity measured in liver metastases with negligible liver tissue content was significantly lower than in liver tissue (146 versus 523 fmol/mg protein, p = 0.002). Expression of the MGMT protein was detectable in 50% of 88 metastases by immunohistochemistry on a tissue microarray. Expression was heterogeneous, and in accordance with MGMT activity data, usually lower than in the surrounding liver. Differential MGMT activity/expression between metastasis and liver tissue and more efficient depletion of MGMT with higher doses of alkylating agent therapy using iah delivery may provide the pharmacologic window for the higher response rate. However, these results do not support MGMT methylation status or protein expression as predictive markers for treatment outcome to iah chemotherapy with alkylating agents.     

Pilot study of hepatic intraarterial fotemustine chemotherapy for liver metastases from uveal melanoma: a single-center experience with seven patients

Background. Uveal melanoma is characterized by a high frequency of hepatic metastases. For patients with liver metastases, who have a median survival of 5 to 7 months, surgery and systemic conventional chemotherapy have little to offer. Methods. Between February 1995 and July 1999, seven patients with isolated hepatic metastases from uveal melanoma were enrolled into a pilot trial of intraarterial fotemustine therapy. An implantable Port-A-Cath catheter was inserted into the hepatic artery for regional chemotherapy via the gastroduodenal artery. Fotemustine 100 mg/m² was administered intraarterially over a 4-h period. The induction phase consisted of one administration per week for 4 weeks, followed by a 5-week rest period. Maintenance therapy with administration of fotemustine every 3 weeks continued until progression or toxicity. Results. Ten patients were evaluated for the trial. One patient was not eligible because of impaired liver function, and in two patients implantation of the port system was not possible for anatomic reasons. Seven patients received a median of 16 treatment cycles (range, 4–28) and all were evaluable for response. Two patients achieved a partial response (PR), three had stable disease (SD), and tumor progressed in two patients (PD). The median survival time from diagnosis of liver metastasis was 24 months (range, 4 to 50+ months). Two patients survived for more than 2 years and two patients are still alive. The toxicity was low and the treatment could be administered on an outpatient basis. Conclusion. Intraarterial fotemustine treatment of uveal melanoma metastatic to the liver is well tolerated, and in some patients is associated with prolonged survival. Received: May 22, 2000 / Accpted: October 13, 2000     

Uveal melanoma: natural history and treatment options for metastatic disease

In order to evaluate the natural history, prognostic parameters and treatment modalities for metastatic uveal melanoma, a review of the clinical data from the current literature was performed based on a Medline database search. Uveal melanoma represents approximately 5% of all melanomas. It is a distinct clinico-pathological entity, differing in many aspects from cutaneous melanoma. The clinical course is unpredictable and metastatic disease can develop very late after a long disease-free interval. Uveal melanoma metastasizes haematogenously, predominantly to the liver. The most Important prognostic parameters for primary uveal melanoma are tumour diameter, the patient's age and gender, histological features and tumour location. Systemic chemotherapy that is effective in cutaneous melanoma has failed to show activity in uveal melanoma. So far only the BOLD chemotherapy regimen (dacarbazine, lomustine, vincristine and bleomycin) combined with interferon-alpha has been shown to produce an objective tumour response in approximately 20% of previously untreated patients. For metastatic disease localized to the liver, intra-arterial application of fotemustine or carboplatin or chemoembolization with cisplatin have shown useful activity, resulting in a response in up to 40% of patients. Selected patients may benefit from palliative surgery. Immunotherapy with interleukin-2 or interferon-alpha has not shown consistent activity in metastatic uveal melanoma. In conclusion, patients with uveal melanoma metastatic to the liver should undergo one of the local treatment options. Carefully selected patients with extrahepatic disease or patients failing local treatment may benefit from systemic therapy using the BOLD regimen combined with interferon.     

Response, survival, and prognostic factors after hepatic arterial chemoembolization in patients with liver metastases from cutaneous melanoma

We reviewed the medical records of 42 patients with cutaneous melanoma metastatic to the liver who underwent hepatic artery chemoembolization (HACE) at our institution. HACE resulted in radiologic response (38.9%) or disease stabilization (47.2%) in most patients. The median overall survival (OS) and time to progression (TTP) of liver disease were 7.7 and 6 months, respectively. Patient's age, lactate dehydrogenase (LDH) levels, type of treatment, number of extrahepatic metastatic sites, and response to therapy were found to be significant predictors of OS after HACE. Prolonged survival was seen in patients who responded to HACE (p = .034).     

Determinants of unresectability and outcome of patients with occult colorectal hepatic metastases

BACKGROUND: Patients chosen for liver resection of colorectal liver metastases are a select group with minimal disease, favorable tumor biology and earlier presentation when compared to unresectable patients. Despite intense preoperative assessments, operative detection of occult unresectable disease is inevitable for a small group of patients. The aim of this study was to evaluate determinants of occult unresectability, and to establish if patients with occult unresectable disease demonstrate survival benefits similar to resected patients, or more similar to patients diagnosed with metastatic disease who were never explored. METHODS: A retrospective medical record review was performed on 171 patients with colorectal hepatic metastases who underwent exploration with the intent of performing a curative liver resection. Patient and tumor characteristics, operative findings and survival were evaluated. Univariate and multivariate analysis were performed to evaluate determinants of unresectability, and survival was determined by Kaplan-Meier analysis. RESULTS: One hundred forty-six patients were completely resected and 25 patients were found to have occult unresectable disease during exploration. Of these 25 patients, 10 had more extensive hepatic disease than expected which precluded resection, while 15 patients had unexpected extrahepatic disease. Of the 15 patients with extrahepatic disease, 7 had otherwise resectable liver metastases. Only bilobar disease was a statistically significant finding associated with occult unresectability on multivariate analysis (P = 0.05). Resected patients had a median survival of 37 months, while unresected patients had a median survival of 17 months (P < 0.005). At 3 and 5 years, the overall survival for resected patients was 52% and 29%. The survival at 3 years for patients with occult unresectable disease was only 5%, with no 5 year survivors. CONCLUSIONS: The majority of patients with occult unresectable colorectal hepatic metastases had bilobar disease or extrahepatic spread. Despite the process of patient selection that leads to an attempt for curative resection, patients with occult unresectable disease identified at exploration suffer from poor survival that approximates the outcome of patients never considered for resection.     

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.     

化疗及手术干预对结肠癌肝转移预后的影响

[目的]探讨化疗及手术干预对结直肠癌肝转移预后的影响。[方法]139例结直肠癌肝转移患者分为两组 ,肝动脉插管化疗组(HA)88例 ,全身静脉化疗组(SV)51例。术后3周开始化疗 ,4周1个疗程 ,共6个疗程。每1个疗程中 ,HA组丝裂霉素(MMC)20mg、5_Fu7g;SV组MMC10mg、5_Fu5.25g。术后随访3年 ,观察两组资料的1年、3年生存率。[结果]1年生存率HA组87.5%与SV组50.9%之间有极显著性差异(P<0.01) ,3年生存率HA组36.4%与SV组15%之间有极显著性差异(P<0.01)。[结论]结直肠癌肝转移手术后 ,肝动脉插管化疗的预后较全身静脉化疗好     

Randomised phase III trial of fotemustine versus fotemustine plus whole brain irradiation in cerebral metastases of melanoma]

PURPOSE: The main objective of this prospective multicenter randomised phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation versus fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma brain metastases. PATIENTS AND METHODS: Seventy-six patients (instead of the 106 planned patients; study was stopped after the interim analysis) were randomised receiving either fotemustine (arm A, n = 39) or fotemustine and whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg m(-2) on day 1, 8 and 15, followed by a 5-week rest period, then every 3 weeks in non-progressive patients. In arm B, a concomitant whole brain irradiation was performed at the total dose of 37.5 Gy (2.5 Gy/d(-1), days 1-5, 3 consecutive weeks). RESULTS: Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in brain response (arm A: 7.4%, B: 10.0%) or control rates (objective response plus stable disease) after seven weeks (arm A: 30%, B: 47%) and overall survival (arm A: 86d, B: 105d). However, there was a significant difference in favour of arm B for the time to brain progression (p = 0.028, Wilcoxon test). CONCLUSION: Fotemustine plus whole brain irradiation delayed the time to brain progression of melanoma cerebral metastases compared to fotemustine alone but without a significant improvement in terms of objective control or overall survival.     

Intra-arterial hepatic fotemustine for the treatment of liver metastases from uveal melanoma: experience in 101 patients.

BACKGROUND: Exclusive liver metastases occur in up to 40% of patients with uveal melanoma associated with a median survival of 2-7 months. Single agent response rates with commonly available chemotherapy are below 10%. We have investigated the use of fotemustine via direct intra-arterial hepatic (i.a.h.) administration in patients with uveal melanoma metastases. PATIENTS AND METHODS: A total of 101 patients from seven centers were treated with i.a.h. fotemustine, administered intra-arterially weekly for a 4-week induction period, and then as a maintenance treatment every 3 weeks until disease progression, unacceptable toxicity or patient refusal. RESULTS: A median of eight fotemustine infusions per patient were delivered (range 1-26). Catheter related complications occurred in 23% of patients; however, this required treatment discontinuation in only 10% of the patients. The overall response rate was 36% with a median overall survival of 15 months and a 2-year survival rate of 29%. LDH, time between diagnosis and treatment start and gender were significant predictors of survival. CONCLUSIONS: Locoregional treatment with fotemustine is well tolerated and seems to improve outcome of this poor prognosis patient population. Median survival rates are among the longest reported and one-third of the patients are still alive at 2 years.     

Hepatic artery infusion chemotherapy for metastatic colorectal carcinoma

Hepatic metastases are a major cause of morbidity and will affect up to 80,000 new patients annually in the United States. Up to 20% of these patients will die with metastatic disease localized to the liver. Hepatic arterial infusion (HAI) therapy has a sound anatomical and pharmacological rationale. A number of randomized clinical trials in patients with unresected metastases have demonstrated that HAI is associated with a complete response rate in 5% of patients and partial responses up to 60%. In comparison, systemic chemotherapy is associated with a partial response in 20% of cases. No investigation comparing systemic chemotherapy with HAI has demonstrated an improvement in survival following HAI, since all investigations either allowed crossover, were under-powered with respect to survival statistics, or included patients with extrahepatic disease in the HAI arm. However, a recent investigation utilizing HAI with systemic chemotherapy following hepatic resection demonstrates improved local and systemic disease control and overall survival. This approach offers new promise for the curative treatment of the patients with metastatic colorectal carcinoma.     

Stratégies thérapeutiques et traitements systémiques des métastases cérébrales du mélanome

Brain metastases affect 37% of patients suffering from metastatic melanoma, and their prognosis remains poor, with an overall survival lower than six months. At the moment, there is no standard therapeutic strategy for management of melanoma brain metastases. In some cases, having recourse to a systemic treatment is justified, for example, when brain metastases are combined with a progressive peripheral disease, or with unresecable brain lesions. In France, the use of fotemustine, which received the AMM approval, for metastatic melanoma treatment, is one of the treatments recommended in the case of brain metastases as this chemotherapy, that is active on the melanoma passes the blood-brain barrier. Temozolomide also shows some activity in the brain metastases treatment of melanoma that remains modest in monotherapy but seems interesting when it is combined with radiotherapy. The place of new drugs, in particular ipilimumab and vemurafenib, in the strategy of melanoma brain metastases treatment, still has to be defined and may improve the prognosis of these patients and their quality of life. The new targeted therapies, the widespread use of stereotactic radiosurgery and the improvement in neurosurgical operations would need a prospective clinical assessment, all the more so, in most of clinical studies, the presence of metastases is an exclusion criterion.     

A comparison between hepatic artery ligation and portal 5-Fu infusion versus 5-Fu intra arterial infusion for colorectal liver metastases.

AIM: A prospective randomized study was executed comparing two regimens of regional therapy for liver metastases from colorectal cancer. METHODS: Eighteen patients were allocated to hepatic artery occlusion for 16 h followed by intraportal 5-fluorouracil (5-Fu) infusion (1000 mg/m(2)) for 5 days every sixth week (HAO). Twenty-one patients received intra-arterial 5-Fu infusion+Leucovorin (100 mg) i.v. for 2 days every second week (HAI). The follow up every third month included CT and CEA. Thirteen patients had limited extrahepatic cancer. At tumor progression regional therapy was stopped and systemic chemotherapy or the best supportive care was administered. RESULTS: The study was discontinued after randomization of 39 patients. No significant difference in survival within patients with and without extrahepatic cancer was present. The mean survival was longer in the HAI group than for the HAO group (19 months versus 13 months, p=0.0147) (median 18 (8-37) versus 12 (2-26). PR and SD were registered in 8/18 in the HAO group and 17/21 patients in HAI group. The median time to progress was 4 (1-22) months versus 7 (1-23) months for the HAO and HAI group, respectively. CONCLUSION: Regional intraarterial infusion with 5-Fu gives significantly better survival than hepatic artery occlusion followed by portal infusion. A limited amount of extrahepatic cancer does not influence survival time. A trial comparing hepatic artery 5-FU infusion and Leucovorin versus the most effective systemic therapy is warranted.     

Temozolomide, thalidomide, and whole brain radiation therapy for patients with brain metastasis from metastatic melanoma: a phase II Cytokine Working Group study

BACKGROUND.

The combination of temozolomide (TMZ) and thalidomide was reported to produce a high response rate, including shrinkage of brain metastases, in patients with metastatic melanoma. The authors tested the efficacy of a regimen including TMZ, thalidomide, and whole brain radiation therapy (WBRT) in patients with brain (CNS) metastases from melanoma.

METHODS.

Patients with melanoma, CNS metastases documented by magnetic resonance imaging, and no prior systemic chemotherapy received WBRT, 30 Gray in 10 fractions, Days 1 to 5 and 8 to 12; TMZ, 75 mg/m²/day, Weeks 1 to 6; and thalidomide, 100 mg/day, Weeks 1 to 4, then escalated by 100 mg/day at Weeks 5, 7, and 9 as tolerated to a maximum of 400 mg/day. CNS and systemic tumor response was assessed at Week 10. Patients without CNS or clinically significant systemic disease progression received additional cycles of TMZ at 10‐week intervals.

RESULTS.

Thirty‐nine patients received treatment, and 3 exhibited CNS response (1 complete response, 2 partial responses) (response rate, 7.6%; 95% confidence interval, 0.7%‐16.1%), all unconfirmed by repeat imaging. Seven patients had stable CNS disease at 10 weeks. No patient exhibited a systemic response. Only 4 patients received 2 cycles of therapy, and just 1 received 3. Median time to progression was 7 weeks, and median overall survival was 4 months. Grade 3‐4 side effects included deep venous thrombosis (3), pulmonary embolism (1), and CNS events (12). Eighteen (45%) patients required admission for side effects (7) and/or symptomatic disease progression (11).

CONCLUSIONS.

The efficacy of TMZ, thalidomide, and WBRT in the treatment of CNS metastatic melanoma is low. Other treatment approaches should be considered for this patient population. Cancer 2008. © 2008 American Cancer Society.