Nodal radiation therapy for metastatic melanoma

Purpose: The aim of this retrospective study was to review our experience of radiation therapy to regional nodes in patients with proven nodal metastases, with respect to regional control, late toxicity, and overall survival.

Methods and Materials: All patients with a histological diagnosis of malignant melanoma, with involvement of the regional nodes but without distant metastases, who commenced nodal irradiation between January 1985 and July 1995 at Peter MacCallum Cancer Institute were studied. The study population of 113 patients was divided into two categories: those with no residual macroscopic disease following nodal surgery (adjuvant group, 42 patients) and those who had no surgery (8) or had macroscopic residual disease following nodal surgery (63) (palliative group, 71 patients).

Results: In the adjuvant group at 5 years following commencement of nodal irradiation 26% were estimated to be failure-free. Of the 74% who had experienced treatment failure by 5 years, an estimated 20% failed first with nodal relapse, 52% with distant metastases, and 2% with both nodal relapse and distant metastases. The estimated 5-year overall survival for this group was 33%. In the palliative group 16 patients (23%) had an objective complete response. Altogether 48 patients (68%) had a symptomatic response. At 5 years the overall survival in this group was 8% and an estimated 4% were failure-free. Of the 96% who had failed by 5 years, 68% failed first in the regional nodes, 25% had distant metastases as the first failure, and 3% had both nodal relapse and distant metastases.

Conclusion: We recommend adjuvant postoperative radiation therapy for patients with proven nodal metastases and high risk of regional recurrence (multiple nodes, extracapsular extension, or recurrent nodal disease) in addition to adjuvant interferon.     

Adrenal metastases of malignant melanoma: Characteristic computed tomography appearances

Malignant melanoma is an extremely aggressive form of cancer. Adrenal metastases are found in 50% of cases of malignant melanoma, and are most often clinically and biochemically silent. Clinical presentation varies, and the diagnosis of adrenal metastases is often made incidentally, and frequently years after treatment of the primary lesion. An adrenal mass lesion seen on a CT scan, greater than 5 cm in diameter, with central or irregular areas of necrosis/haemorrhage (and no lipomatous component) is characteristic of a metastasis from malignant melanoma, in the setting of normal gland function. If these features are bilateral, they are pathognomonic. Oval, low‐attenuation (on CT) adrenal masses less than 3 cm in diameter should not be considered benign in a patient with any prior history of melanoma. Careful imaging review of the adrenal glands should be undertaken in all patients with malignant melanoma. Early diagnosis of these distant metastases has important prognostic and therapeutic implications. The four cases presented illustrate the spectrum of presentations and clinical course of adrenal metastases from malignant melanoma. The accompanying CT images show the characteristic appearances of adrenal metastases.     

The thorax as the initial site for systemic relapse in malignant melanoma: a prospective survey of 324 patients.

Thirteen of 324 patients with malignant melanoma followed during a 24 month period experienced dissemination. The thorax was the initial site for relapse in 12, all of whom were asymptomatic. Ten gave no evidence of extrathoracic disease. Retrospective analysis of previous x-rays originally interpreted as negative revealed metastases in 33%. Life table analysis demonstrated a significantly longer survival for the subset with isolated intrathoracic metastases treated surgically than for their counterparts with metastases no longer amenable to surgery and treated by other modalities. We conclude that the thorax is the site of predilection for initial systemic relapse in malignant melanoma, that detection of early, surgically resectable metastases correlates with longer patient survival, and that routine chest roentgenography is inadequate in reliably uncovering such early disease. These data suggest the potential value of more vigorous radiographic surveillance (with either computed tomography or conventional full lung tomography) in patients at high risk for relapse.     

Nail-bed melanoma

In our series of 348 patients treated over a 10-year period, six (1.7%) had their primary lesions in the nail bed. Five of the subungual melanomas occurred in the toes and one in the thumb. Four of the lesions were of the acral lentiginous type. The delay in diagnosis was 7 months to 6 years. Four of the patients presented with advanced, neglected tumors. One had distant metastases at diagnosis. The treatment was mainly surgical. Digital amputation was carried out for local control. Five patients underwent lymph node dissection and in three of them regional metastases were found. Of the four patients with regional and distant metastases at the time of diagnosis, three died within 6 to 60 months and the fourth is alive with metastatic spread. Of the two patients with melanoma confined to the nail bed, one is free of disease 50 months following diagnosis and the other suffered from a local recurrence and has been free of disease for 30 months following wide excision and limb perfusion.     

Laparoscopic surgery for melanoma metastases to the adrenal gland

The probability of developing cutaneous melanoma is now predicted to be one in 55 for males and one in 88 for females. Although melanoma is relatively uncommon compared with other malignancies such as breast (one in seven) or prostate cancer (one in six), the incidence is growing at an alarming rate. The development of novel strategies for the management of advanced disease will become even more urgent and require continued and controlled investigations over the next 10 years. Surgery is effective for the palliation of isolated resectable metastases. However, most patients with Stage IV melanoma have widespread disease and are not cured by metastasectomy. For the few individuals with isolated adrenal metastases from melanoma, complete resection appears to confer a survival advantage. New data are emerging about the efficacy and outcome of laparoscopic adrenalectomy for malignant lesions. However, the natural history of laparoscopic surgery for these lesions is still unknown. The indications for and limitations of laparoscopic adrenalectomy for metastatic melanoma are discussed.     

Palliative isolated limb perfusion for advanced limb disease in stage IV melanoma patients

INTRODUCTION: Two to three percent of the patients with extremity melanoma develop in-transit metastases in the course of their disease. When local treatments fail, isolated limb perfusion (ILP) is a reasonable option, but is generally only applied to patients without evidence of distant metastases. We assessed the value of ILP in stage IV melanoma patients with symptomatic unresectable limb melanoma at our institutions. PATIENTS AND METHODS: A computerized database, containing all patient, tumor, ILP, and follow-up data of 505 ILPs performed in 451 patients between 1978 and 2001, allowed the selection of eight (1.8%) stage IV patients who underwent a palliative ILP for unresectable melanoma lesions on the limbs. All patients had high tumor burden limb disease, according to the combined Fraker and Rossi criteria. RESULTS: The overall tumor response rate was 88%, with 13% complete and 75% partial response rates. One patient did not respond to ILP. Three partial responding patients attained a complete remission (CR) after excision of the remaining limb lesions. The median duration of hospital stay was 12 days and acute regional toxicity was mild with slight erythema and edema in six and no signs of reaction in two patients. The median limb recurrence-free interval after CR was 6 months and the median duration from the time of distant metastases to death was 15 months. Overall ILP leads to the desired palliative effect in six patients (75%). CONCLUSION: ILP should be considered as a palliative treatment in selected stage IV melanoma patients with symptomatic advanced limb disease.     

Adrenal glands metastases from malignant melanoma. Laparoscopic bilateral adrenalectomy

Adrenal metastases from Malignant Melanoma (MM) represent a debated therapeutical problem particularly in the case of disseminated disease. Surgical treatment, however, seems to be able to provide improvement on survival. Laparoscopic adrenalectomy is considered a gold standard procedure in benign adrenal disease but its value in malignancy, in terms of oncological effectiveness, is not known. A case of bilateral adrenal malignant melanoma metastases is reported. The patient, affected by superficial spreading melanoma of the right foot, eleven years after the primary developed a right adrenal metastasis. The relapse was treated by laparoscopic right adrenalectomy. One year later the patient had a new metastasis in the left adrenal gland and was submitted to laparoscopic left adrenalectomy. The two step laparoscopic bilateral adrenalectomy showed to be quite easy to perform, providing a complete removal of the whole glands, without adrenal tissue crushing and without neoplastic tissue dissemination in abdominal cavity. The postoperative course was excellent and the patient was discharged within about 72 hours after the two procedures. In literature only few reports indicate the feasibility of laparoscopic adrenalectomy for malignancy. In the reported case of malignant melanoma metastasis, minimally invasive adrenalectomy was very satisfactory and the good results obtained suggest its routine use.     

Risk factors related to late metastases in 1,372 melanoma patients disease free more than 10 years

In many centers, Stage I–II melanoma patients are considered “cured” after 10 years of disease‐free survival and follow‐up visits are interrupted. However, melanoma may relapse also later. We retrospectively analyzed a cohort of 1,372 Stage I–II melanoma patients who were disease‐free 10 years after diagnosis. The aim of this study was to characterize patients who experienced a late recurrence and to compare them to those who remained disease‐free to identify possible predictive factors. Multivariate Cox proportional‐hazards regression analyses were carried out to evaluate the influence of different factors on the risk of recurrence. Seventy‐seven patients out of 1,372 (5.6%) relapsed, 52 in regional sites and 25 in distant ones. The majority of patients (31 out of 52) experienced late recurrence in regional lymph nodes. Brain and lung were the most common site of single distant recurrence (24% each). Patients with multiple distant metastases showed a brain and lung involvement in, respectively, 40 and 48% of cases. A Cox proportional‐hazards regression model analysis showed the independent role of age under 40 years, Breslow thickness >2 mm, and Clark Level IV/V in increasing the risk of Late Recurrence. These patients should be followed‐up for longer than 10 years. The pattern of recurrence suggests that melanoma cells can be dormant preferentially in lymph nodes, brain and lung. A particular attention should be reserved to these anatomic sites during the follow‐up after 10 years of disease‐free.     

A ten-year follow-up on stage II Malignant Melanoma patients treated postsurgically with newcastle disease virus oncolysate

Newcastle disease virus oncolysate was examined as an adjunctive immunotherapeutic agent in the postsurgical management of 83 cases of Stage II malignant melanoma. At this time, all the patients have been under observation for at least 10 years, and over 60% are alive and free of recurrent disease. Older studies in the United States report postsurgical survival figures for Stage II cases of 5-15%. More contemporary studies indicate a 33% survival at 10 years. The unusual disease-free survival periods in the present study, including exceptional survivals in 21 patients with head and neck disease and six cases with cerebral metastases, suggest a unique role for the administration of Newcastle disease virus oncolysate in the management of Stage II malignant melanoma patients.     

85例皮肤恶性黑色素瘤手术治疗分析

目的：评价皮肤恶黑手术治疗结果并结合文献进行探讨．方法：85例皮肤恶黑，原发灶切除30例，瘤床广泛切除16例，截肢21例．其他17例。淋巴结清扫32例，其中预防性清扫7例。结果：81例获随访，1例复发，5例卫星灶．12例途中转移，15例淋巴结转移，38例血行转移．37例无瘤生存，1例带瘤生存，总生存率46．9％。结论：卫星灶、途中转移、淋巴结转移发生提示预后不良。手术切缘应根据肿瘤厚度确定。     

An evaluation of the surgical management of melanoma of the brain

Thirty-two patients with histologically proved metastatic malignant melanoma of the brain were evaluated. Intracranial surgery was performed in 19 and was considered not indicated in 13 patients. Following intracranial surgery, satisfactory improvement in neurologic deficits was observed in 14 (74%) patients. The median survival after occurrence of brain metastases was 5–6 months (1 – 15 months) for the surgical group; and for the nonsurgical group, patients with multiple brain metastases and multiple visceral involvement did not survive beyond a median of 1 month (range 0.5–6 months). Intratumor hemorrhage with substantial intracerebral hematoma was present in 7 (41%) out of 17 craniotomies. The overall incidence of intratumor hemorrhage found at autopsy was 59% for the entire series. Among ail the cases with intratumor hemorrhage, only 2 patients who received chemotherapy after craniotomy developed thrombocytopenia with fatal intracranial hemorrhage. The latter cause-and-effect correlation could not be assessed in the other patients. As a result of this retrospective study, we have observed that patients with malignant melanoma and evidence of single brain metastasis without multiple visceral involvement seemed to benefit more from palliative surgery. Moreover, intratumor hemorrhage was a frequent occurrence and should be considered in the differential diagnosis of a patient with malignant melanoma and rapid deterioration of neurologic deficits.     

Temozolomide With or Without Radiotherapy in Melanoma With Unresectable Brain Metastases

Summary Brain metastases are a common complication in patients suffering from metastatic malignant melanoma. We analyzed efficacy and toxicity of the alkylating agent temozolomide with excellent CNS penetration and known activity in brain metastasis in 35 patients with unresectable melanoma brain metastases. Patients received 200 mg/m² temozolomide on days 1 to 5 every 28 days as first or second-line therapy. This therapy regimen was combined with radiotherapy of the brain metastases in 22/35 patients. Grade III and IV toxicity was observed in 8/35 patients (leukopenia, granulocytopenia, thrombocytopenia, anemia, nausea and obstipation). Complete remission was observed in 1/34, partial remission in 2/34 and stable disease in 9/34 patients. In 5/34 a mixed response was assessed, 17/34 had disease progression and in one patient tumor response was not evaluable. The median progression free time was 5 (0–8) months for all patients, the median survival time for all patients from start of therapy was 8 (0–28) months, 9 (2–28) months in patients with concurrent stereotactic radiotherapy and 7 (3–17) months in patients with concurrent whole brain radiotherapy. Our results demonstrate that temozolomide can be combined with radiotherapy for the treatment of brain metastases in malignant melanoma, and that this combination may prolong survival in this patient group.     

Spontaneous regression of malignant melanoma

The case of a 47-year-old white female patient has been described with malignant melanoma that started as a node on her right ankle twelve years ago and regressed spontaneously. During the last two years of her life, dissemination of the melanoma appeared in the form of subcutaneous nodes, which regressed spontaneously in successive crops. In the course of her disease there was evidence of distant metastases to the brain. Spontaneous regression seems to have been enhanced by immunotherapy, when most of the metastases had regressed, including those in the brain.     

Post-menopausal bleeding: a rare presentation of metastatic uveal melanoma

Uveal melanoma differs from cutaneous melanoma in many ways, including its pattern of metastasis, and exhibits latency with clinical evidence of metastasis sometimes appearing many years after primary diagnosis. Most patients develop metastasis within the liver, but some may present with metastasis to other sites. We report a case of uveal melanoma that presented with post-menopausal bleeding due to metastasis. Further investigation revealed widespread metastatic disease and the patient was not fit for chemotherapy. She died two months after presentation: autopsy revealed metastases in many sites, including the uterus, right ovarian fibroma, kidney, mesentery, liver, lung, thyroid, bone marrow and skin. The immediate cause of death was cardiac tamponade due to a malignant effusion secondary to cardiac metastasis. This case illustrates the widespread metastatic potential of uveal melanoma and highlights the potential for unusual presentation of metastatic disease from this eye tumor.(Pathology Oncology Research Vol 12, No 3, 184–187)     

Smoking and the development of metastases from malignant melanoma

Investigations on 2583 malignant melanoma patients indicated that in both men and women, although there did not appear to be a causal relationship between cigarette smoking and melanoma, smoking did facilitate the spread of metastases. Significantly more ex-smokers or smokers than life-long non-smokers first presented for melanoma treatment with established metastases. Also, in patients with localized disease, metastases appeared within 10 years more often in exsmokers than in life-long non-smokers.     

Characteristics associated with early and late melanoma metastases

BACKGROUND:

Differences in risk factors for metastases at different time intervals after treatment have been described in several malignancies; however, to the authors' knowledge, no extensive study examining this issue in melanoma has been conducted to date.

METHODS:

The authors performed a nested case‐control study of patients with melanoma who presented with only local disease. Patients in the case group included 549 patients who developed metastases ≥6 months after surgery. Of these, 320 patients developed metastasis within 3 years after undergoing definitive surgery (early metastases [EM]), and 70 patients developed metastasis ≥8 years after undergoing definitive surgery (late metastases [LM]). For each case, a control patient was chosen who had melanoma but who did not develop metastases in the same interval. Univariate and conditional multivariate logistic regression were used in the analysis of 34 clinical and tumor characteristics.

RESULTS:

Multivariate analysis confirmed previously established risk factors for metastases, such as increasing tumor thickness. In addition, the authors discovered that a personal history of nonmelanoma skin cancer (P = .006) and a history of cancer other than skin cancer (P = .020) also were associated with metastasis. In comparing the 320 EM patients with the 70 LM patients, EM patients were more likely to have thicker lesions (P < .001), ulcerated lesions (P = .016), and a history of nonmelanoma skin cancer (P = .024).

CONCLUSIONS:

In this study, 2 potentially novel risk factors for melanoma metastases were identified, and different profiles of risk factors were constructed for EM versus LM. These differences may be important in future risk identification and stratification for clinical trials and for the management and treatment of patients with melanoma. Cancer 2010. © 2010 American Cancer Society.     

The value of preoperative screening procedures in stage I and II malignant melanoma.

Fifty patients with melanoma (30 with clinical Stage I disease and 20 with clinical Stage II disease) were analyzed retrospectively along with the screening test done prior to surgery. While the value of the chest X ray is unquestioned in preoperative screening, the same cannot be said of liver, brain, and bone scans. The bone marrow biopsy, however, done with a Janshidi needle was of value in detecting one patient with bone-marrow metastases who on examination had clinical Stage II disease and precluded surgery in this same individual. Therefore, we feel that in the preoperative scanning of patients with Stage I or Stage II human malignant melanoma, and especially in the latter, the bone-marrow biopsy should be done routinely in addition to a hematological profile, liver profile, and chest X ray.     

Radiotherapy for cutaneous malignant melanoma: rationale and indications

The use of radiation as adjuvant therapy for patients with cutaneous malignant melanoma has been hindered by the unsubstantiated belief that melanoma cells are radioresistant. An abundance of literature has now demonstrated that locoregional relapse of melanoma is common after surgery alone when certain clinicopathologic features are present. Features associated with a high risk of primary tumor recurrence include desmoplastic subtype, positive microscopic margins, recurrent disease, and thick primary lesions with ulceration or statellitosis. Features associated with a high risk of nodal relapse include extracapsular extension, involvement of four or more lymph nodes, lymph nodes measuring at least 3 cm, cervical lymph node location, and recurrent disease. Numerous studies support the efficacy of adjuvant irradiation in these clinical situations. Although data in the literature remain sparse, evidence also indicates that elective irradiation is effective in eradicating subclinical nodal metastases after removal of the primary melanoma. Consequently, there may be an opportunity to integrate radiotherapy into the multimodality treatment of patients at high risk of subclinical nodal disease, particularly those with an involved sentinel lymph node. Such patients are known to have a low rate of additional lymph node involvement, and thus in this group, a short course of radiotherapy may be an adequate substitute for regional lymph node dissection. This will be the topic of future research.     

The effect of pregnancy on hormone levels and receptors in malignant melanoma

As previous studies indicate, some cases of malignant melanoma are clearly hormonally dependent as demonstrated by their stimulation by pregnancy and regression following delivery. A case of melanoma initiated during pregnancy and stimulated by a subsequent pregnancy was studied with biochemical receptor studies before and after endocrine manipulation. The negative steriod receptor studies obtained late in the patient's disease at time of endocrine manipulation predicted the lack of response. Results of this study indicate investigations are needed to define the relationship between malignant melanoma and pregnancy.     

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.