Determinants of outcome in melanoma patients with cerebral metastases.

PURPOSE: To analyze prognostic factors, effects of treatment, and survival for patients with cerebral metastases from melanoma. PATIENTS AND METHODS: All melanoma patients with cerebral metastases treated at the Sydney Melanoma Unit between 1952 and 2000 were identified. From 1985 to 2000, patients were diagnosed and treated using consistent modern techniques and this cohort was analyzed in detail. Multivariate analysis of prognostic factors for survival was performed. RESULTS: A total of 1137 patients with cerebral metastases were identified; 686 were treated between 1985 and 2000. For these 686 patients, the median time from primary diagnosis to cerebral metastasis was 3.1 years (range, 0 to 41 years). A total of 646 patients (94%) have died as a result of melanoma. The median survival from the time of diagnosis of cerebral metastasis was 4.1 months (range, 0 to 17.2 years). Treatment was as follows: surgery and postoperative radiotherapy, 158 patients; surgery alone, 47 patients; radiotherapy alone, 236 patients; and supportive care alone, 210 patients. Median survival according to treatment received for these four groups was 8.9, 8.7, 3.4, and 2.1 months, respectively; the differences between surgery and nonsurgery groups were statistically significant. On multivariate analysis, significant factors associated with improved survival were surgical treatment (P <.0001), no concurrent extracerebral metastases (P <.0001), younger age (P =.0007), and longer disease-free interval (P =.036). Prognostic factors analysis confirmed the important influence of patient selection on treatment received. CONCLUSION: This large series documents the characteristics of patients who developed cerebral metastases from melanoma. Median survival was dependent on treatment, which in turn was dependent on patient selection.     

Hepatic arterial Fotemustine chemotherapy in patients with liver metastases from cutaneous melanoma is as effective as in ocular melanoma.

AIM: Hepatic metastases from melanoma are associated with poor prognosis. Systemic chemotherapy and biological treatments remain unsatisfactory. This study investigated the impact of hepatic arterial chemotherapy in patients with ocular and cutaneous melanoma. METHODS: In a retrospectively analysed observational study, 36 consecutive patients with hepatic metastases from ocular or cutaneous melanoma were assigned for surgical hepatic port-catheter implantation. Fotemustine was delivered weekly for a 4-week period, followed by a 5-week rest and a maintenance period every 3 weeks until progression. Overall survival, response and toxicity were analysed and compared. RESULTS: After port-catheter implantation 30/36 patients were finally treated (18 with ocular and 12 with cutaneous melanoma). A median of 8 infusions per patient were delivered (range 3-24). 30% thrombocytopenia grade >or=3, 7% neutropenia grade >or=3 but no nausea or vomiting grade >or=3 were encountered. Nine out of 30 patients achieved partial remission, 10/30 stable disease; 11/30 patients were progressive. Median survival for all treated patients was 14 months. Partial remission and stable disease were associated with a survival advantage compared to progressive disease (19 vs. 5 months). No significant difference in survival was observed for ocular versus cutaneous melanoma. Serum LDH was a significant predictor of both response and survival. CONCLUSIONS: Hepatic arterial Fotemustine chemotherapy was well tolerated. Meaningful response and survival rates were achieved in ocular as well as cutaneous melanoma. Careful patient selection in consideration of extra-hepatic involvement is crucial for the effectiveness of this treatment. Independent from the primary melanoma site, it is debatable if patients with highly elevated serum-LDH may benefit from this approach.     

Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy

BACKGROUND:

Patients with metastatic poorly differentiated endocrine carcinoma (PDEC) usually have a short survival. The chemotherapy combination of cisplatin and etoposide is frequently used as first‐line palliative chemotherapy. There are, however, no published studies concerning second‐line treatment of the disease. Temozolomide has shown clinical effect in well‐differentiated endocrine carcinomas. This study was performed to evaluate the effect of temozolomide in PDEC patients who had progressed on first‐line treatment.

METHODS:

Twenty‐five patients with PDEC (mainly gastrointestinal) were treated with temozolomide alone or in combination with capecitabine. A subset of patient also received bevacizumab. MGMT methylation was analyzed in tissue specimens. Data were collected retrospectively.

RESULTS:

One patient had a complete response, and 7 patients had partial response (33% response rate). Median duration of response was 19 months. Another 9 (38%) patients had a stable disease, after progression at inclusion, with a median duration of 18 months. Median progression‐free survival for all patients was 6 months, and median overall survival was 22 months. Only 1 patient had a MGMT methylation.

CONCLUSIONS:

Treatment with temozolomide alone or in combination with capecitabine and bevacizumab resulted in objective response or stabilization in 71% of PDEC patients who failed on first‐line chemotherapy. These results indicated that temozolomide may be used as second‐line treatment in PDEC. Cancer 2011;. © 2011 American Cancer Society.     

Stereotactic radiosurgical treatment in 103 patients for 153 cerebral melanoma metastases

PURPOSE: To report on the outcome of patients with melanoma brain metastases treated with stereotactic radiosurgery (SRS). PATIENTS AND METHODS: One hundred three patients with 153 intracranial melanoma metastases consecutively underwent Linac-based SRS between November 1991 and October 2001. The Kaplan-Meier method, univariate comparisons with log-rank test, and multivariate analyses with classification and regression tree models were performed. Calculations were based on last imaging date rather than the date of the last visit. RESULTS: Median age was 51 years (range, 18-93 years). Median Karnofsky performance status was 90. Sixty-one patients (59%) had single brain metastasis at presentation. Treatment sequence was SRS alone (61 patients), SRS + whole-brain radiotherapy (WBRT) (12 patients), and salvage SRS after WBRT (30 patients). The median tumor volume was 1.9 cm(3) (range, 0.06-22.3 cm(3)). The median SRS minimum peripheral dose and isodose was 18 Gy (range, 10-24 Gy) and 85% (range, 60%-100%), respectively. The median follow-up was 6 months for all patients and 13 months (range, 2-46 months) for patients alive at the time of analysis. The 1-year local control (LC) for all patients treated with SRS was 49%. Among the patients treated with initial SRS alone, the 1-year LC was better for patients with tumors < or =2 cm(3) than with tumors >2 cm(3): 75.2% vs. 42.3% (p < 0.05). The 1-year distant brain metastasis-free survival incidence was 14.7% for the 73 patients receiving either initial SRS alone or SRS +WBRT. The initial number of brain lesions (single vs. multiple) was the only factor with a significant effect on distant brain metastasis-free survival at 1 year: 23.5% for single metastases and 0% for multiple lesions (p < 0.05). The 1-year overall survival was 25.2%. Stratification by Score Index for Radiosurgery (SIR) revealed a significant effect on survival, which was 29% at 1 year for SIR >6 and 10% for SIR <==6 (relative hazard ratio, 2.1; p < 0.05) in classification and regression-tree multivariate analysis involving age, Karnofsky performance status, primary tumor control, tumor volume, SRS dose, SIR (>6 vs. < or =6), and systemic disease status. CONCLUSIONS: Initial SRS alone was an effective treatment modality for smaller cerebral melanoma metastases, achieving a 75% incidence of 1-year LC for < or =2 cm(3) single brain metastases and should be considered in patients with SIR >6. The role of WBRT in melanoma brain metastases cannot be addressed, owing to retrospective bias toward administering this treatment to patients with more aggressive disease. A prospective study is needed to assess the role of WBRT in patients with melanoma brain metastasis.     

A phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma

Temozolomide is an alkylating agent with activity in the treatment of melanoma metastatic to the brain. Lomustine is a nitrosurea that crosses the blood brain barrier and there is evidence to suggest that temozolomide may reverse resistance to lomustine. A multicentre phase I/II study was conducted to assess the maximum-tolerated dose (MTD), safety and efficacy of the combination of temozolomide and lomustine in melanoma metastatic to the brain. Increasing doses of temozolomide and lomustine were administered in phase I of the study to determine the MTD. Patients were treated at the MTD in phase II of the study to six cycles, disease progression or unacceptable toxicity. Twenty-six patients were enrolled in the study. In phase I of the study, the MTD was defined as temozolomide 150 mg m(-2) days 1-5 every 28 days and lomustine 60 mg m(-2) on day 5 every 56 days. Dose-limiting neutropaenia and thrombocytopaenia were observed at higher doses. Twenty patients were treated at this dose in phase II of the study. No responses to therapy were observed. Median survival from starting chemotherapy was 2 months. The combination of temozolomide and lomustine in patients with brain metastases from melanoma does not demonstrate activity. The further evaluation of this combination therefore is not warranted.     

Impact of regional chemotherapy for melanoma metastases

Metastatic malignant melanoma requires sophisticated delineation of therapeutic approaches in order that palliation of the disease should be managed effectively. To date, systemic chemotherapy for melanoma metastases appears to be of only limited benefit, since tumoricidal drug levels can hardly be achieved in a way to overcome primary or secondary drug resistance of melanoma cells. With respect to topographically defined patterns of metastasis, therapeutic approaches introducing regional chemotherapy have recently promised improved palliation in the management of advanced solid tumors including melanoma. Among these approaches, isolated limb perfusion has become a well-established procedure in the treatment of melanoma which has metastasized to the extremities. The adjuvant setting of this technique is currently under investigation, and suggests a beneficial outcome in perfused high-risk patients. Intraarterial infusion techniques with or without regional venous drug hemofiltration might provide high cytotoxic tissue levels at the target region, thus subsequently leading to enhanced cell kill rates evidenced in terms of clinical responses. Angioocclusive approaches using persistent (chemoembolization) or transient (microspheres, liposomes) blocking techniques with subsequent reduction of the arterial/arteriolar blood flow may optimize the pharmacological advantage of regional drug delivery. In addition to cytoreductive surgery and systemic chemotherapy, the above-mentioned approaches of regional chemotherapy offer a new perspective in the palliative management of metastatic melanoma.     

The treatment of brain metastases in melanoma patients

The incidence of central nervous system (CNS) metastases in patients with melanoma ranges from 10% to 40% in clinical studies and is even higher in autopsy series with as many as two-thirds of patients with metastatic melanoma having CNS involvement. Treatment options for patients with cerebral metastases are limited and depend largely on the number and the size of the lesions and on the extracranial extension of metastatic disease. This report gives the results of different treatment modalities in patients with melanoma metastases to the brain. As data from prospective randomized studies are lacking, the general recommendations based on clinical series reports are: (i) the combination of surgery and whole-brain radiotherapy (WBRT) is superior to WBRT alone for the treatment of single brain metastasis in patients with limited or absent systemic disease and good neurological condition. (ii) Radio surgery, alone or in conjunction with WBRT, yields results which are comparable to those reported after surgery followed by WBRT, provided that the lesion's diameter does not exceed 3 cm. With the use of WBRT after surgery or radio surgery the local control seems better (with the combined approach), but the overall survival does not improve. (iii) WBRT alone or in combination with chemotherapy is the treatment of choice in patients with single brain metastasis not amenable to surgery or radio surgery, with an active systemic disease, and in patients with multiple brain metastases. Chemotherapy may be also offered to patients with a good performance status, or after recurrence to local therapy.     

Management of brain metastases in patients with melanoma

PURPOSE OF REVIEW: Melanoma is the third most common metastatic brain tumor in the United States and is a major cause of morbidity and mortality. The development of more effective therapies for melanoma brain metastases is a major unmet clinical need and is summarized in this review. RECENT FINDINGS: Management strategies include symptomatic treatment with corticosteroids and anticonvulsants, and definitive therapy in the form of whole-brain radiation therapy, surgical resection, stereotactic radiosurgery, and systemic therapy. The data on whole-brain radiation therapy show little impact on survival, but there is evidence that it may improve neurologic deficits. Surgery may provide a survival advantage in combination with whole-brain radiation therapy in the management of a single brain melanoma metastasis, compared with whole-brain radiation therapy alone. Stereotactic radiosurgery may offer a survival advantage (in a select group of patients with limited disease) when used alone or in combination with whole-brain radiation therapy, compared with whole-brain radiation therapy alone. Fotemustine, temozolomide, and thalidomide are three agents with high central nervous system penetration that are being actively investigated as part of systemic therapy. SUMMARY: The currently available therapeutic options offer palliative relief of symptoms in most patients and a survival advantage in selected patients with melanoma and brain metastases. An urgent need exists to further define these treatments in the context of randomized trials, several of which are under way in the United States and abroad.     

Survival and prognostic factors in patients with brain metastases from malignant melanoma

AIM: We wanted to determine the factors influencing survival in a retrospective review of patients with melanoma brain metastases to permit more specific recommendations regarding therapy. PATIENTS AND METHODS: We reviewed the data of 100 patients treated at the Department of Dermatology and Radiation Oncology, University of Zurich, and the Klinik im Park, Zurich. Information on potential prognostic factors (age, sex, location of the primary tumor, Clark level, Breslow index, histological type, number of brain metastases, stage at initial diagnosis, location of brain metastases, and therapy) was collected from the medical records of 100 patients treated between 1966 and 2002. Univariate and multivariate analyses were performed to identify significant prognostic factors. RESULTS: The overall median survival time was 4.8 months, with 6-month, 1-year and 2-year survival percentages of 36, 14 and 5%, respectively. Univariate analysis indicated that survival correlated significantly with radiotherapy (partial and whole brain), surgery, stereotactic radiosurgery, chemotherapy, Clark level and Breslow index. Treatment with temozolomide (p = 0.052) and number of brain metastases (p = 0.07) failed to be statistically significant. Multivariate analysis confirmed radiotherapy (partial and whole brain), surgery, stereotactic radiosurgery, chemotherapy and the location of brain metastases as independent and significant prognostic factors of survival. The remaining factors did not reach statistical significance in multivariate analysis. CONCLUSION: Radiotherapy, chemotherapy and especially surgery and stereotactic radiosurgery seem to significantly prolong survival, as shown by multivariate analysis. Treatment with temozolomide will possibly play an important role in the future management of patients with brain metastases from cutaneous melanoma, but further prospective studies to verify this assumption are urgently needed.     

结直肠癌肝转移的术前化疗

结直肠癌在西方国家占肿瘤患者死亡的第2位,发病率为56.1/10万。我国结直肠癌发病率约为20.6/10万,占肿瘤患者死亡的第5位。Parkin等[1]报道,2002年,全世界新诊断结直肠癌为l 020 000例,占发病率第3位,死亡529 000例,占死亡率第4位。     

Neoadjuvant chemotherapy for patients with liver metastases from colorectal cancer

Colorectal cancer is the second most common type of cancer in industrialized countries. Despite improved resection procedures and optimized adjuvant chemotherapy, local or distant recurrences occur in 22-25% of patients with stage II/III colon cancer. Approximately 30% of patients have advanced disease at presentation. The liver is the most common site of colorectal metastases and, interestingly, 20-30% of patients with colorectal cancer have liver-only metastases. The combined modality of chemotherapy and surgery increases overall survival and the chance of cure for metastatic patients, even if there is no agreement in terms of the best schedule and how long the treatment must last. In this paper, we review the role and the rationale of neoadjuvant chemotherapy within a multimodal approach, and discuss remaining questions and future directions.     

The role of chemotherapy in the treatment of patients with brain metastases from solid tumors

Chemotherapy for brain metastases has been considered ineffective because the drugs do not penetrate the intact blood brain barrier. Alternate explanations for past failures of chemotherapy include observations that 1) many solid tumors which metastasize to brain are drug-resistant regardless of location, 2) brain metastases often occur following failure of primary chemotherapeutic regimens to control systemic metastases, and 3) previous trials of chemotherapy employed agents other than those known to be most effective against the primary malignancy. Furthermore, laboratory studies have demonstrated that cytoxic levels of many drugs can be measured in tumor tissue from primary and metastatic brain tumors. These clinical and pharmacologic observations suggest that chemotherapy would be expected to have limited value unless known effective combination regimens are employed as first-line therapy in chemosensitive malignancies. Recent reports of chemotherapy for patients with brain metastases from small cell lung carcinoma, gestational choriocarcinoma, germ cell malignancies, and breast carcinoma do describe response rates in the brain similar to those in other organ sites. In conclusion, chemotherapy for cerebral metastases can be expected to be effective only when effective drugs for systemic metastases are available. While the blood-brain barrier may be an additional detriment to successful treatment, other factors may be more important.     

The role of chemotherapy in the treatment of patients with brain metastases from solid tumors

Brain metastases are the most frequent cancer in the central nervous system, being ten times more common than primary brain tumors. Patients generally have a poor outcome with a median survival of 4 months after diagnosis of the metastases. Therapeutic options include surgery, stereotactic, radiosurgery, whole-brain radiotherapy (WBRT), and chemotherapy. Patients with a limited number of brain metastases and well-controlled systemic cancer benefit from brain metastases-specific therapies, including surgery, radiosurgery, and conventional radiation. The role of chemotherapy for brain metastases remains limited. There is concern about drug delivery because of the blood-brain barrier. However, higher response rates are noted with initial therapies, suggesting that part of the poor response rate may be related to the late onset of brain metastases and the use of second- and third-line regimens. Recent studies have demonstrated objective responses with systemic therapy in a variety of cancer types, especially when combined with WBRT. Individual therapeutic strategies for central nervous system metastases must be chosen based on performance status, the extent of intracranial disease, and the chemosensitivity of the underlying tumor, as well as the control of the systemic cancer. In this article we review important prognostic factors and challenges in using chemotherapy. We specifically review recent advances in the treatment of brain metastases from breast and lung cancer as well as melanoma. Future treatment advances will require a multidisciplinary approach integrating surgical, radiation, and chemotherapeutic options to improve neurological function and quality of life, rather than just focusing on survival endpoints.     

Integration of gamma knife surgery in the management of cerebral metastases from melanoma

The aim of this study was to investigate the effect of gamma knife surgery on the local control of cerebral metastases from melanoma and to assess survival. In 29 patients, 105 of 178 cerebral metastases were treated with gamma knife surgery. Only five patients had metastases confined to the brain. Of the 96 metastases with magnetic resonance imaging follow-up, 61.5% regressed by more than 50% of the pretreatment volume, 25% regressing by more than 90% and 13.5% completely. The median survival from gamma knife surgery was 5.7 months (longest survival, 38 months). In multivariate analyses, a larger number of lesions requiring treatment (P < 0.001), recursive partitioning analysis class (P = 0.009) and a long time interval from initial melanoma diagnosis to detection of cerebral metastases (P = 0.001) influenced survival. It can be concluded that gamma knife surgery is a useful adjunct in the management of cerebral metastases from melanoma and has a significant impact on local control. Its greatest potential may be achieved in conjunction with systemic chemotherapy, especially in the presence of extracerebral metastases.     

Management of metastatic melanoma patients with brain metastases

Brain metastases seem to be an almost inevitable complication in patients with metastatic melanoma. Except for the rare patients who can undergo successful surgical resection of brain metastases, current management strategies do not appear adequate and result in a poor outcome (median survival, 2–4 months). In recent small series, stereotactic radiosurgery or gamma-knife treatment has suggested improvement in local control compared with whole brain radiation therapy. We have recently shown prolonged survival (11.1 months) using a multimodality treatment approach in 44 sequential patients with melanoma brain metastases. A subsequent study demonstrated that the outcome of biochemotherapy for metastatic melanoma is not affected by the presence or absence of brain metastases. Our results suggest that the outcome of patients with melanoma brain metastases can be improved using a multidisciplinary management strategy.