Melanoma of the clavicular region: multimodal treatment.

HYPOTHESIS: Treatment for melanoma that has metastasized to the supraclavicular nodes should be intensive and use a multimodality approach. DESIGN: Retrospective analysis of clinical records. SETTING: Six primary care centers, 2 of which were referral centers. PATIENTS: Eighteen patients diagnosed as having a rare pattern of advanced melanoma metastatic to the clavicular region. INTERVENTION: Combined radiotherapy, chemotherapy, and thorough surgical excision of the affected nodal basins. MAIN OUTCOME MEASURE: Length of survival from time of diagnosis and treatment to time of follow-up. RESULTS: Median survival among the 18 patients was 28 months with a 22% survival rate at 5 years after diagnosis. Among patients who received radiotherapy to the clavicular node basin, mean length of survival was 88.7 months with a 50% 5-year survival rate compared with a mean length of survival of 33.8 months and an 8.3% 5-year survival rate in patients who did not receive radiotherapy (P<.001). Mean survival among patients who had supraclavicular node dissection was 45.8 months with a 23.1% survival rate at 5 years after diagnosis, compared with a mean survival of 52 months and a 20% 5-year survival rate among patients who did not receive therapeutic lymphadenectomy. Of the 11 patients who had therapeutic lymphadenectomy, 2 also received radiotherapy to the supraclavicular nodal basin and continued to be disease-free at 82 and 130 months. All long-term survivors had been treated with intra-arterial chemotherapy. CONCLUSION: In a series of patients with malignant melanoma metastatic to the clavicular lymph nodes, multimodality treatment using radiotherapy, chemotherapy, and thorough surgical excision of affected nodal basins provided an appreciable 5-year survival rate.

Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593.

PURPOSE: Patients with primary cutaneous melanoma > or = 1.5 mm in thickness are at high risk of having regional micrometastases at the time of initial surgical treatment. A phase III international study was designed to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent regional recurrence and influence survival. PATIENTS AND METHODS: A total of 832 assessable patients from 16 centers entered the study; 412 were randomized to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild hyperthermia. Median age was 50 years, 68% of patients were female, 79% of melanomas were located on a lower limb, and 47% had a thickness > or = 3 mm. RESULTS: Median follow-up duration is 6.4 years. There was a trend for a longer disease-free interval (DFI) after ILP. The difference was significant for patients who did not undergo elective lymph node dissection (ELND). The impact of ILP was clearly on the occurrence-as first site of progression - of in-transit metastases (ITM), which were reduced from 6.6% to 3.3%, and of regional lymph node (RLN) metastases, with a reduction from 16.7% to 12.6%. There was no benefit from ILP in terms of time to distant metastasis or survival. Side effects were higher after ILP, but transient in most patients. There were two amputations for limb toxicity after ILP. CONCLUSION: Prophylactic ILP with melphalan cannot be recommended as an adjunct to standard surgery in high-risk primary limb melanoma.

Isolated hyperthermia chemotherapy perfusion for limb melanoma.

Safe techniques for regional chemotherapy of the limbs by perfusion are now available. The method is effective in obtaining regionally confined high levels of toxic drugs or chemotherapeutic agents in the isolated areas. The best responses have been observed in limb melanoma with recurrent or intransit disease. Chemotherapy by perfusion as an adjunct to surgical excision reduces the local recurrence and the regional and lymph node metastases. Our survivals for adjunctive perfusion for Stage I melanomas with Level V and lesions 5 mm thick and thicker are better than usually reported. Regional chemotherapy has had an important role in reduction of major amputations for the control of limb melanoma. Multiple chemotherapeutic limb perfusions can further extent survival in patients with recurring melanoma.

Regional chemotherapy for melanoma. A 35-year experience.

OBJECTIVE: The authors present their 35-year experience with intra-arterial chemotherapeutic regional perfusion of 1139 patients with melanomas, using an extracorporeal oxygenated circuit and heart-lung apparatus. SUMMARY BACKGROUND DATA: Intra-arterial chemotherapy produces improved responses in many tumors. By isolating and sustaining the area with extracorporeal oxygenated circulation, high doses can be delivered to the tumor area, limited only by local toxicity. Drug levels up to 10 times those achieved by systemic administration are obtained. METHODS: Techniques for hyperthermic perfusion were developed for limbs, pelvis, head, neck, and skin of the breast. Melphalan (Burroughs Wellcome, Research Triangle Park, NC) was used in 753 patients. Combinations with melphalan or other drugs were used in remaining cases at temperature of 38 to 40 C for 30 to 60 minutes. RESULTS: Chemotherapy perfusion followed by tumor excision or node dissection, was performed where indicated. The cumulative 10-year survival for patients with localized melanomas was 70%. For patients with local recurrences or satellites within 3 cm, survival was 61%. For those with regionally confined intransit tumors, survival was 30%; for those with regional node involvement, 38%; for those with intransit and nodal metastases, 16%; for those with distant metastases and perfusion--mainly to save functional limbs--survival was 7%. Multiple perfusions were performed in 158 patients with recurrent disease on 366 occasions. Patients with indolent regionally confined melanomas were benefited by prolongation of useful life. CONCLUSIONS: Safe perfusion techniques are available for most anatomic regions. Increased chemotherapeutic doses are delivered to isolated areas limited only by local toxicity. Adjunct perfusion in poor prognosis stage I cases is useful in reducing local recurrence, and intransit or lymph node metastases. Regional perfusion reduces the need for major amputation. Multiple perfusion can be useful in treating recurrent chronic melanoma.

Multiple perfusions for melanoma.

From 1957 to 1992, 1139 patients had regional perfusion alone, or combined with excisional surgery for malignant melanoma. Of these, 158 patients had multiple perfusions for recurrent disease, including 155 for limb melanoma and three for head and neck melanoma. One-hundred-and-twenty patients were perfused twice, 28 treated three times, eight treated four times, and two treated five times. At first perfusion, 39 patients were classified as disease stages I and II, 98 at stage III, and 21 at stage IV. Melphalan was used in 70% of perfusions, either alone or in combination. Nitrogen mustard was used sparingly in only a few patients. Fifty-one patients with stage III disease had the greatest number of perfusions (127). Cumulative survival from date of first perfusion at 5 and 10 years were: stage 1,68 and 36%; stage IIIA, 25 and 16%; stage IIIB, 32 and 10%; stage IIIAB, 29 and 11% and stage IV, 14 and 0%. When compared with the entire series, the percent survival was decreased by 2 to 3 times, however, 21 patients remain alive and disease-free. For stages I and II, patients are alive and disease-free from 5 to 33 years. For stage IIIA, 6 patients were alive at the last follow-up, however, the status of two are currently unknown. For stage IIIB survival times range from 8 to 106 months with two patients alive without recurrence. For stage IIIAB, two patients are alive and disease-free at 15 and 26 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic evaluation of intracranial metastasis in malignant melanoma.

BACKGROUND: Malignant melanoma (MM) is often reported as the third most common cause of intracranial metastasis (IM) after carcinoma of the breast and lung. Most patients with advanced MM will have widespread extracranial disease, but the majority will die from intracerebral spread. METHODS: A retrospective review of 117 patients with documented IM from MM over the past 25 years was undertaken. Various factors (including age, race, sex distribution, primary lesions with Clark's level, Breslow's thickness, primary sites and staging at initial presentation, diagnosis of IM and its various treatment methods, survival data, and autopsy findings) were analyzed. Prognostic indicators were clarified from this analysis as a predictor of central nervous system (CNS) metastasis. An ideal treatment plan was also analyzed in order to predict a better survival. RESULTS: Fifty-eight percent of patients were male; 42% were female. Seventy-one percent of the primary lesions were of Clark's level IV and V, with mean Breslow's thickness of 3.5 mm. Median time interval between the initial diagnosis and development of IM was 3.5 years. Complete surgical resection of the intracranial lesion in the brain resulted in the longest mean survival of 10.3 months, whereas mean survival for the group with no treatment was only 3 weeks. Patients with primary lesions of the head and neck had the lowest mean survival of 3.3 months, whereas those whose primary sites were unknown had the longest mean survival of 7.5 months. One- and 2-year survival were 9% and 3%, respectively. All but one of the 30 patients at autopsy were found to have visceral metastasis, namely of the lung, liver, and bone. CONCLUSION: An aggressive search for metastasis should be undertaken in patients at high risk of developing CNS metastasis, e.g., male, head and neck primary, Clark's level IV and V, Breslow's thickness of > 3 mm, and presence of visceral metastases, mainly lung. A complete surgical resection should be attempted whenever possible, with adjunctive use of whole-brain irradiation, along with systemic chemotherapy for further control of recurrence and to prolong survival.

Adoptive immunotherapy of advanced renal cell cancer using PHA-stimulated autologous lymphocytes.

Patients with advanced renal cell carcinoma, previously failed maximal treatment with standard chemo-hormonal-radiation therapies, were treated with plant lectin phytohemagglutinin (PHA)-stimulated autologous peripheral blood lymphocytes in a 10-year study with a 16-year follow up period. In a phase I-II setting, 52 patients were given subcutaneously 40-80 x 10(6) PHA-stimulated lymphocytes weekly for 3 weeks and then escalated to a maximum number of 80 x 10(9) lymphocytes over the next 9 weeks at 3 week intervals. In vitro blastogenesis under study conditions (10 micrograms/ml PHA for 72 hr) measured by [3H]thymidine uptake was optimal with lymphocyte stimulating indexes approaching 300. Lymphocytes obtained from patients with breast cancer, melanoma and renal cell carcinoma responded to PHA similarly to those from normal volunteers. All patients that responded developed erythematous reactions at the sites of injection; malaise, joint paint and chill-fever for 24-48 hr. The patients that responded the best were those with at least 1 positive reaction out of 4 skin tests (tuberculosis, yeast, dermatophytin, mumps) prior to therapy. All toxicity was transient and did not exceed Grade I based on criteria of the Southwest Oncology Group. The majority of patients developed a lymphopenia in the first 24 hr followed by a lymphocytosis 48-72 hr later. For some patients the lymphocytosis was as much as 30% atypical lymphocytes. Of 41 evaluable patients, there were 5 complete responses, 8 partial responses, 3 stable diseases, and 25 progressive disease. The overall response rate was 32% and the median survival was 2.8 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Acral lentiginous melanoma.

Between 1958 and 1990, 82 patients with acral lentiginous melanoma were treated by the Tulane Surgical Service with regional perfusion, excision of lesion, and lymph node dissection. The patient group comprised 27 white men, 29 white women, 18 black men, and 8 black women, with an average age of 61 years. More foot lesions than hand lesions were reported, and all the lack men had foot lesions. In stage I patients, overall 5-year survival rates were 65% at 5 years and 44% at 10 years, with differences by race and gender. The black men did poorest, with a 13% 10-year survival rate. Survival rates were worse with increasing disease stage when calculated using univariate analysis. The 5-year survival rate of all patients with stage III and stage IV disease was 26%. A multivariate analysis was performed in 78 of 82 patients in whom all variables of Clark's level, age, race, stage, and sex were known. A strong relationship was observed between decreasing survival time and increasing Clark's level, with stage of marginal significance. In a multivariate analysis of patients with stage I disease, an increasing level of invasion was found to be significant, with a trend for a relationship to thickness. A trend toward decreased survival time was observed in men and blacks.

Vaginal melanoma and the role of regional chemotherapy.

Vaginal melanoma is a rare cancer usually diagnosed as a locally advanced disease. Aggressive surgical management of the primary tumor and local-regional recurrences, combined with the use of adjuvant radiation and chemotherapy, improves disease-free interval and, perhaps, survival times. Techniques of regional chemotherapy allow the delivery of high doses of chemotherapy to the tumor bed, while minimizing systemic toxicities. These treatments can be used to decrease tumor size, render bulky tumors resectable, and decrease the need for radical procedures. Additionally, they may help eradicate clinically inapparent local-regional disease and have a favorable effect on survival times.

Treatment of abdominal malignant neoplasms using regional chemotherapy with hemofiltration.

The regional delivery of high-dose chemotherapy for malignant neoplasms of the limb with the isolated regional perfusion technique was first described in the late 1950s. Recently, the use of concomitant hemofiltration for rapid systemic drug removal permits the use of higher regional drug levels in treating patients with advanced abdominal malignant neoplasms without complete vascular isolation. Twenty-five patients successfully underwent 42 treatments of high-dose intra-arterial chemotherapy with concomitant hemofiltration at Tulane University Medical Center Hospital, New Orleans, La, from 1989 through 1990. One patient (4%) achieved a complete response. Two patients (8%) had partial responses following high-dose intra-arterial chemotherapy with concomitant hemofiltration and their residual disease was resected for cure. Seven patients (28%) achieved a partial response, 11 (44%) had stable disease, and four (16%) had progression of disease.

Oxyphilic (Hürthle cell) adenoma arising in a black thyroid gland.

We report this case to further document in the literature morphologic changes encountered in a black thyroid gland. It is only through an expanding data base that future conclusions may be reached regarding the role, if any, of minocycline in some of these alterations.

Regional perfusion for the treatment of subungual melanoma.

Thirty-one patients with subungual melanoma representing 2.6 per cent of all patients with limb melanoma were treated by isolated regional perfusion. Acral lentiginous melanoma prevalent on subungual and volar skin was the most common histologic type. The subungual lesions primarily occurred on the lower limbs (61%) and great toe (48%). At diagnosis, most patients had advanced disease; 53 per cent of stage I patients had lesions with level IV invasion or greater. The median thickness of the primary lesion was 2.35 mm. All patients were treated by isolated regional perfusion and amputation of the involved digit, as well as regional lymph-node dissection where clinically indicated. The mean survival rate for all stages at five years was 35 per cent. Patients with stage I disease had the best survival rates, 61 per cent at five years and 54 per cent at ten years; however, patients with advanced disease, stage III (M.D. Anderson classification), had only a 17 per cent survival rate at five years and 8 per cent at 10 years. Women had slightly better survival rates than men, and patients with upper-limb lesions had the better prognosis.

Bone and liver imaging in regionally advanced melanoma.

The clinical records of 94 patients with regionally advanced melanoma (nodal disease or regional satellites) were reviewed to determine the value of preoperative bone and liver imaging. Of 68 bone scans obtained, none were suggestive of metastases. of 97 liver imaging studies (computed tomography, scintiscan, or sonography) in 88 patients, only two were found to have demonstrable metastases. Liver enzyme elevation was present in both of these patients. Bone and liver imaging in the absence of signs or symptoms of dissemination by history, physical examination, chest x-ray, and enzyme determination for regionally advanced melanoma appears to be of little value unless the patient is involved in a protocol study.

Radiation dose and breast cancer risk in patients treated for cancer of the cervix.

The relationship between breast cancer and radiation treatment for cervical cancer was evaluated in an international study of 953 women who subsequently developed breast cancer and 1,806 matched controls. Radiation doses to the breast (average 0.31 Gy) and ovaries (average 32 Gy) were reconstructed for exposed subjects on the basis of their original radiotherapy records. Overall, 88% of the breast cancer cases and 89% of the controls received radiation treatment [relative risk (RR) = 0.88; 95% confidence interval (CI) = 0.7-1.2]. Among women with intact ovaries (561 cases, 1,037 controls), radiotherapy was linked to a significant 35% reduction in breast cancer risk, attributable in all likelihood to the cessation of ovarian function. Ovarian doses of 6 Gy were sufficient to reduce breast cancer risk but larger doses did not reduce risk further. This saturation-type response is probably due to the killing of a critical number of ovarian cells. Cervical cancer patients without ovaries (145 cases, 284 controls) were analyzed separately because such women are at especially low natural risk for breast cancer development. In theory, any effect of low-dose breast exposure, received incidentally during treatment for cervical cancer, should be more readily detectable. Among women without ovaries, there was a slight increase in breast cancer risk (RR = 1.07; 95% CI = 0.6-2.0), and a suggestion of a dose response with the RR being 1.0, 0.7, 1.5 and 3.1 for breast doses of 0, 0.01-0.24, 0.25-0.49 and 0.50+ Gy, respectively. However, this trend of increasing RR was not statistically significant. If low-dose radiation increases the risk of breast cancer among women over age 40 years, it appears that the risk is much lower than would be predicted from studies of younger women exposed to higher doses.

Isolated regional perfusion for treatment of limb melanoma in the American black.

Since 1957, 961 patients with invasive malignant melanoma of the limbs were treated by regional perfusion. Forty-eight patients were black, representing 5 per cent of all patients with regional melanoma treated during this period. Thirty-one of the 48 patients were men, and 17 were women. Only 21 of the 48 patients had stage I lesions (M.D. Anderson classification), of whom 63 per cent had level IV or greater invasion. The average depth of invasion was 3.70 mm. Of 21 patients with stage III disease, 15 came to diagnosis with an intact primary lesion in addition to regional disease, and the majority of lesions arose on a plantar site with level V invasion. Eighty per cent of the patients had acral lentiginous melanoma. All melanoma patients were treated by isolated regional perfusion with wide excision of the primary plus regional lymph node dissection for biopsy-proven regional disease. At 10 years, survival rates were 71 per cent for stage I patients and 12.5 per cent for those with stage III disease. When black patients having had acral melanoma on a plantar or palmar site were compared with white patients of a similar stage of disease, however, it was found that black patients had equivalent long-term survival rates.

A randomized multicenter trial comparing mitoxantrone, cyclophosphamide, and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast carcinoma.

Three hundred thirty-one women with metastatic breast cancer were randomized to receive combination chemotherapy with either cyclophosphamide, Novantrone (mitoxantrone; Lederle Laboratories, Wayne, NJ), and fluorouracil (CNF) or cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and fluorouracil (CAF). Patients could not have had prior chemotherapy, although adjuvant chemotherapy was acceptable. Initial doses were 500 mg/m2 of cyclophosphamide and 500 mg/m2 of fluorouracil with either 10 mg/m2 of mitoxantrone or 50 mg/m2 of doxorubicin, administered intravenously (IV) on day 1 and repeated every 3 weeks. There were no statistically significant differences in pretreatment or prior therapy characteristics between the groups. For patients assigned to the CNF and CAF groups, respectively, 25 (18%) were premenopausal, 39 (40%) were estrogen receptor (ER) negative, 39 (38%) had a disease-free interval less than 1 year, and 24 (26%) had received prior adjuvant chemotherapy. All patients were compared for response rate, duration of response, time to progression or death, time to treatment failure (TTF), and survival. None of these parameters were statistically significant favoring one regimen over the other. The response rate (complete [CR] and partial response [PR]) was 29% for the CNF group (95% confidence interval of 22% to 37%) and 37% for the CAF group (95% confidence interval of 29% to 45%). The median response duration and TTF were 171 days and 125 days for the CNF group and 254 days and 147 days for the CAF group, respectively. The median survival times for the CNF group and the CAF group were 377 and 385 days, respectively. The major dose-limiting toxicity for both regimens was leukopenia, manifested as granulocytopenia. The incidence of stomatitis/mucositis was 10% in the CNF group and 19% in the CAF group. Alopecia occurred in 49% of CNF patients (severely for 4%) and in 86% of CAF patients (severely for 39%). Nausea/vomiting occurred in 80% of CNF patients and in 81% of CAF patients; the degree of severity was also comparable. There was significantly less cardiotoxicity observed in the CNF group compared with the CAF group. Although CNF is somewhat less effective in overall response rate, survival curves are identical. CNF can be offered to patients who reject anthracycline-containing regimens because of fear of alopecia.

Radiation dose and second cancer risk in patients treated for cancer of the cervix.

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.

A role for topical 5-fluorouracil therapy in melanoma.

Topical 5-fluorouracil (Efudex) has been shown to be of great value in the treatment of skin cancers, Marjolin ulcers, and advanced squamous cell carcinoma of the mouth and esophagus. It has been advocated for use on patients with melanocytic dysplasia and lentigo maligna melanoma. This report confirms the use of topical 5-FU for lentigo maligna melanoma and melanocytic dysplasia. In melanomas with poor prognosis, preoperative treatment with topical 5-FU converts the cellular infiltrate from acute inflammatory cells to round cells which have been shown to be T-cells. We believe this preoperative stimulation of the patients' own immune reaction to the tumor may be of great significance in improving the surgical results for melanomas with a poor prognosis.