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Brain metastases in children with melanoma
Abstract
BACKGROUND
Brain metastases complicate the course of malignant melanoma in at least 20% of adult cases. These events are commonly preceded by metastases to other sites. Due to the rarity of malignant melanoma in children, little is known about the incidence, clinical features, and outcome of children with melanoma who develop brain metastases.METHODS
The authors reviewed the records of 44 children with malignant melanoma treated at St. Jude Children's Research Hospital over a 33-year period. Eight (18%) developed brain metastases during the course of their disease. The authors reviewed the clinical and radiologic features of six of these cases, for whom complete clinical information and imaging studies were available.RESULTSThe median age at diagnosis of malignant melanoma was 15 years (range, 11-21 years). Brain metastases developed a median of 20 months (range, 0-50 months) after diagnosis and were preceded by metastases to other organs in 5 patients. In most cases, lesions were supratentorial and multiple. Most showed radiologic signs of intralesional hemorrhage. All patients received whole brain radiotherapy, and one had surgical resection. Three patients received chemotherapy. Five patients died a median of 5 months (range, 2-10 months) after diagnosis of brain involvement. One patient, who had a single brain metastasis at diagnosis, is alive more than 34 months later.CONCLUSIONS
Brain metastases develop in a significant proportion of children with malignant melanoma and are associated with a poor outcome. The incidence, features, and outcome in children do not appear to differ from those in adults. Cancer 1997; 79:2440-5. © 1997 American Cancer Society.
The current evidence on pediatric melanoma is heterogenous, especially regarding the prognosis of different histological subtypes. We sought to systematically review the evidence on pediatric melanoma, highlighting the major sources of heterogeneity and focusing on available data on single patients. A systematic search was performed from 1948 to January 25, 2021. Only studies reporting at least 1 case of cutaneous melanoma in patients aged ≤18 years were included. Unknown primary and uncertain malignant melanomas were excluded. Three couples of authors independently performed title/abstract screening and two different authors reviewed all the relevant full texts. The selected articles were manually crosschecked for overlapping data for qualitative synthesis. Subsequently data on single patients were extracted to perform a patient-level meta-analysis. PROSPERO Registration number: CRD42021233248. The main outcomes were melanoma-specific survival (MSS) and progression-free survival (PFS) outcomes. Separate analyses were done of cases with complete information on histologic subtype, focusing on superficial spreading (SSM), nodular (NM) and spitzoid melanomas, as well as of those classified as de-novo (DNM) and acquired or congenital nevus-associated melanomas (NAM). The qualitative synthesis covered 266 studies; however, data on single patients were available from 213 studies including 1,002 patients. Among histologic subtypes, NM had a lower MSS than both SSM and spitzoid melanoma, and a lower PFS than SSM. Spitzoid melanoma had a significantly higher progression risk than SSM and trended toward lower mortality. Focusing on nevus-associated status, DNM demonstrated better MSS after progression than congenital NAM, and no differences were highlighted in PFS. Our findings describe the existence of different biological patterns in pediatric melanoma. Specifically, spitzoid melanomas demonstrated intermediate behavior between SSM and NM and showed a high risk of nodal progression but low mortality. This raises the question of whether spitzoid lesions are being over-diagnosed as melanoma in childhood.
Pediatric solid tumor central nervous system (CNS) metastases are rare and distinct from CNS metastases from either pediatric leukemias or adult solid tumors, both of which occur at a much higher frequency. This suggests a fundamental difference between the adult and pediatric blood-brain barriers, perhaps reflecting an increased permeability to systemic treatments, or a tendency toward the use of myeloablative therapy in the pediatric population. Due to their low incidence (approximately 1–10%) in pediatric solid tumor cases, CNS metastases are not routinely screened for and typically present with neurologic symptoms and as a late finding. Treatment is often targeted to CNS symptoms and the primary tumor type, with options generally including surgery, chemotherapy (systemic, intrathecal, or intraventricular delivered through an implantable ventricular reservoir), radiation, stem cell therapy, or immunotherapy. Previous reports suggest an association between aggressive multimodal therapy and rare, long-term survival in pediatric patients with CNS metastases from multiple different primary tumor types. Certain factors have been found to be associated with the development of CNS metastases, including diagnostic lumbar punctures, the presence of pulmonary metastases, and certain subtypes of primary tumors. We thus recommend consideration of CNS screening in pediatric solid tumor patients with predisposing factors.
Brain metastases (BM) are the most commonly diagnosed type of central nervous system tumor in the United States. Estimates of the frequency of BM vary significantly, as there is no nationwide reporting system for metastases. BM may be the first sign of a previously undiagnosed cancer, or occur years or decades after the primary cancer was diagnosed. Incidence of BM varies significantly by primary cancer site. Lung, breast, and melanoma continue to be the leading cause of BM. These tumors are increasingly more common as new therapeutics, advanced imaging, and improved screening have led to lengthened survival after primary diagnosis for cancer patients. BM are difficult to treat, and for most individuals the diagnosis of BM generally portends a poor prognosis.
Brain metastases (BM) are a frequent occurrence in adults malignancies, with an expected 20–40% of adult patients expected to develop BM during their disease course. In comparison, the brain is a rare site of metastasis in pediatric extracranial solid tumors with an estimated incidence in the order of 1–10%. Nevertheless, with continuing improvements in systemic therapies leading to prolonged survival, the incidence of pediatric BM may rise. While there is a broad body of literature on the incidence and management of adult BM, including large randomized clinical trials, there is a paucity of published data on pediatric BM, limited primarily to small series and cases reports. Pediatric BM may present synchronously or more commonly in the setting of prior extracranial metastases, particularly to the lungs. Treatment has typically included surgical resection for isolated or symptomatic lesions, radiation therapy, chemotherapy, and possibly immunotherapy. Although the outcome for pediatric patients with BM is in general very poor, there are some reports of long-term survivors, suggesting that aggressive multimodal therapy may be warranted in a subset of patients.
From the standpoint of radiology, the brain is a unique organ, whose substance enclosed in a rather thin bone “shell” could be differentiated as gray and white matter due to its relative homogeneity and immobility as early as on images obtained using the first models of CT scanners. Subsequently, imaging techniques, particularly MRI, allowed for a more accurate visualization of cerebral structural features and better identification of pathological changes in the brain structure than with CT. Requirements of clinicians for quantitative and most importantly qualitative content of the obtained diagnostic findings are constantly growing. In terms of diagnostic requests of modern medicine, a mere statement of the fact of visualization of a focal brain lesion is definitely not enough in most cases. The actual clinical situation is such that a formal description of syntopical features of focal brain lesions is the distant past of continuously developing neuroimaging methods. Today, there is a demand for technology allowing to obtain information that brings findings of noninvasive radiation diagnostic methods as close as possible to the exact interpretation of the histologic nature of lesions, an objective assessment of the characteristics of their blood supply, etc., without any techniques with traumatic access to abnormal sites.
Each year in the United States, an average of one to two children per 10,000 develop cancer. Survival rates for children with cancer have continued to increase quite dramatically over the last several decades. Many cancer patients have symptomatic neurologic complications during the course of their illness; neurologic problems are a common reason for hospitalization of patients with systemic cancer, both in adults and in children. Therapeutic improvements, longer survival and improved imaging modalities have increased both the amount of time at risk and the possibility of detecting such complications. The incidence, timing, etiology and treatment of neurologic sequelae in children with cancer have not been extensively evaluated. The purpose of this review is to outline the major tumor- and treatment-related neurologic sequelae of pediatric cancer.
Each year in the United States, an average of one to two children per 10,000 develop cancer. Survival rates for children with cancer have continued to increase quite dramatically over the last several decades. Many cancer patients have symptomatic neurologic complications during the course of their illness, and neurologic problems are a common reason for hospitalization of both adult and pediatric patients with systemic cancer. Therapeutic improvements, longer survival times, and improved imaging modalities have increased both the amount of time at risk and the possibility of detecting such complications. The incidence, timing, etiology and treatment of neurologic sequelae in children with cancer has not been extensively evaluated. The purpose of this review is to outline the major tumor-and treatment-related neurologic sequelae of pediatric cancer.
Malignant melanoma is a relatively common neoplasm of melanocytes. The lesion is classically pigmented although amelanotic melanomas are known to occur. The tumour is prone to metastasize early with lymph node metastases presenting earlier than haematogenous metastases [1]. Melanomas presenting with unknown primaries are rare. We describe a case of a metastatic amelanotic melanoma with an unknown primary in a young woman.
Object:
Metastasis to the brain is frequent in adult cancer patients but rare among children. Advances in primary tumor treatment and the associated prolonged survival are said to have increased the frequency of brain metastasis in children. The authors present a series of cases of brain metastases in children diagnosed with a solid primary cancer, evaluate brain metastasis trends, and describe tumor type, patterns of occurrence, and prognosis.
Methods:
Patients with brain metastases whose primary cancer was diagnosed during childhood were identified in the 1990-2012 Tumor Registry at The University of Texas M.D. Anderson Cancer Center. A review of their hospital records provided demographic data, history, and clinical data, including primary cancer sites, number and location of brain metastases, sites of extracranial metastases, treatments, and outcomes.
Results:
Fifty-four pediatric patients (1.4%) had a brain metastasis from a solid primary tumor. Sarcomas were the most common (54%), followed by melanoma (15%). The patients' median ages at diagnosis of the primary cancer and the brain metastasis were 11.37 years and 15.03 years, respectively. The primary cancer was localized at diagnosis in 48% of patients and disseminated regionally in only 14%. The primary tumor and brain metastasis presented synchronously in 15% of patients, and other extracranial metastases were present when the primary cancer was diagnosed. The remaining patients were diagnosed with brain metastasis after initiation of primary cancer treatment, with a median presentation interval of 17 months after primary cancer diagnosis (range 2-77 months). At the time of diagnosis, the brain metastasis was the first site of systemic metastasis in only 4 (8%) of the 51 patients for whom data were available. Up to 70% of patients had lung metastases when brain metastases were found. Symptoms led to the brain metastasis diagnosis in 65% of cases. Brain metastases were single in 60% of cases and multiple in 35%; 6% had only leptomeningeal disease. The median Kaplan-Meier estimates of survival after diagnoses of primary cancer and brain metastasis were 29 months (95% CI 24-34 months) and 9 months (95% CI 6-11 months), respectively. Untreated patients survived for a median of 0.9 months after brain metastasis diagnosis (95% CI 0.3-1.5 months). Those receiving treatment survived for a median of 8 months after initiation of therapy (95% CI 6-11 months).
Conclusions:
The results of this study challenge the current notion of an increased incidence of brain metastases among children with a solid primary cancer. The earlier diagnosis of the primary cancer, prior to its dissemination to distant sites (especially the brain), and initiation of presumably more effective treatments may support such an observation. However, although the actual number of cases may not be increasing, the prognosis after the diagnosis of a brain metastasis remains poor regardless of the management strategy.
A review of published data on the overall frequency of metastatic brain tumorsHistology of the primary cancerPatient ageSexConclusions
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In contrast to the occurrence of brain metastases advanced malignant tumours in adult cancer patients, the dissemination of solid tumours to the brains of paediatric cancer patients is very uncommon. We present a neuro-pathological and clinical study of a group of children and adolescents with brain metastases (BM) from extracranial solid malignancies. The analysed patients were diagnosed with soft tissue sarcomas (three), germ cell tumours (three), or osteosarcoma, neuroblastoma, clear cell sarcoma of the kidney, or pleuropulmonary blastoma (one each). In our series, BM frequently coexisted with pulmonary metastases. Three different metastatic patterns were discernible: a solitary tumour, multiple lesions and diffuse parenchymal dissemination. Two cases showed haemorrhagic presentation. Most of the children died due to BM progression, while children with germ cell tumours showed the best prognosis. The histopathological pictures of BM can be different from the primary tumour, showing dedifferentiation or a diverse neoplastic component. The autopsy examination can still be helpful in the final diagnosis of certain cases with atypical clinical presentations.
Malignant melanoma (MM) is one of the least common types of childhood cancer, accounting for less than 1% of all pediatric malignancies. Neurocutaneous melanosis (NCM) is a rare phakomatosis consisting of congenital abnormal pigmentation of the skin and meninges. The meningeal lesions are particularly prone to malignant change.
The authors describe 5 patients with NCM and 1 with primary leptomeningeal melanoma (LMM) seen at 2 treatment centers in the north of England over a 13-year period (1984-1997).
The clinical features, progress, radiological findings, and treatment of these patients are discussed. All six died within eight months of their diagnosis, illustrating the difficulties faced in treating patients with these conditions. The authors reviewed the published literature on NCM, concentrating on the various therapeutic strategies that have been tried. Very little consistency in approach was found. Malignant skin lesions in NCM may be less responsive than primary malignant melanoma, but the small number of patients with primary LMM or brain metastases of MM make comparisons with NCM difficult. The authors' own series illustrates well the piecemeal nature of therapy for patients with these rare conditions.
The rate of incidence of MM melanoma in the U.K. is increasing, and it will represent an increasing proportion of the pediatric oncologist's workload. A consistent approach to the therapy of patients with metastatic MM and NCM is needed if we are to have any hope of offering more than palliative therapy to these children in the future.
The incidence of intracerebral metastasis is largely underestimated. They appear to be the most frequent cause of intracerebral tumors with an average incidence of probably more than 12/100 000 inhabitants per year. Depending on reports, 25 to 35% of cancer patients will develop brain metastasis. In neurosurgical series, the frequency of cerebral metastasis among surgical procedures for brain tumors increased from 3.5 to 12%. We reviewed the literature in order to better know the frequency of intracerebral metastasis depending on the type of primary cancer. The rate of other metastatic lesions, the duration between discovery of the primitive cancer and brain metastasis were found to be useful for selection of patients for neurosurgical treatment. Three types of cancers could be defined, regarding the incidence of brain metastasis. While occurrence of brain metastases is very high, surgery should often be useless; if brain metastases only occur in the late stage of a cancer, then, surgery should be discussed according to the general status of the patient; although brain metastasis is rare in a cancer, surgery will often be required for diagnosis and treatment.
Hematogenous brain metastases are uncommon in childhood. Three patients and a literature review that includes centers reporting up to 36 years of experience are presented in this study. The total of 2,040 patients includes our three examples of one neuroblastoma, one hepatoblastoma, and one adrenal carcinoma. Cerebral hematogenous metastases were reported in 4.4% of 429 patients with neuroblastoma, 1.9% of 574 rhabdomyosarcoma patients, 6.5% of 386 patients with osteosarcoma, 3.3% of 487 Ewing sarcoma patients, 3.6% of 44 melanoma patients, 13.5% of 37 patients with germ cell tumors, and 1.3% of the 78 patients with Wilms tumor. Five miscellaneous patients included three with a hepatoblastoma and one each with adrenal carcinoma and nephroma. All of the large series reports have been published in oncology journals.
Childhood and adolescent melanoma is rare, accounting for only 1.3% for all cases of cancer in patients under the age of 20 years. However, in 15-19 year olds, melanoma accounts for up to 7% of all cancers. Review of reported cases in this age group reveals that predisposing 'paediatric' conditions such as a giant congenital melanocytic naevi or xeroderma pigmentosum are rarely present. Furthermore, inactivating germ-line mutations of the gene CDKN2A have only been reported in 1.5% of cases of early onset melanoma. Epidemiological studies suggest that interactions between solar exposure, development of naevi, pigmentary traits, and a family history of melanoma are the main determinants of melanoma development during the first 20 years of life. As yet, there are no available staging or treatment strategies for this group of patients so treatment recommendations are based on the adult experience. To improve our understanding of the natural history of melanoma and to identify the most appropriate therapies for young patients with this disease, practising physicians are encouraged to enroll their patients, especially those with advanced stage disease, in cooperative group trials which incorporate newer staging systems and promising therapies.
Brain metastases of pediatric germ cell tumors are uncommon, and there is limited information regarding their incidence, clinical presentation, response to treatment, and influence on survival.
The authors reviewed the experience with brain metastases from pediatric germ cell tumors at St. Jude Children's Research Hospital (Memphis, TN) over a 40-year period.
Between March 1962 and February 2002, 16 of 206 patients with germ cell tumors (7.8%) had brain metastases at the time of initial presentation (n = 2), later in the course of the illness (n = 12), or at autopsy (n = 2). Twelve of 16 patients (75%) had symptoms referable to the brain (nausea/emesis, headaches, or seizures), and 14 (88%) had pulmonary metastases at the time brain metastases were identified. Patients with brain metastases were more likely to have an extragonadal primary tumor (P = 0.013), advanced-stage disease at initial presentation (P = 0.016), and choriocarcinoma within the primary tumor (P < 0.001). The incidence of brain metastases was significantly lower in the second 2 decades of the study period (5 of 135 patients [3.7%]) than in the first 2 decades (11 of 71 patients [15.5%]; P = 0.005). Two of the 16 patients in the current study are long-term survivors.
Brain metastases are uncommon in childhood germ cell tumors, and their incidence appears to be decreasing. In the current study, most patients with such metastases were symptomatic and had pulmonary metastases at the time brain metastases were identified. Patients with the highest risk of developing brain metastases include those with extragonadal tumors, those with high disease stage at initial presentation, and those with choriocarcinoma as a component of the primary tumor. The probability of survival is poor, although a small proportion of patients may become long-term survivors.
Malignant melanoma is rare in childhood and has never been reported to cause pancytopenia due to bone marrow metastases in a child. We report a 3-year-old boy with a large congenital melanocytic nevus who presented with bone pain and pancytopenia due to diffuse bone and bone marrow infiltration with metastatic melanoma without an identifiable primary site. Despite treatment with imatinib mesylate there was no response and the patient died with progressive disease. This case illustrates an unusual presentation of bone marrow failure secondary to malignant melanoma in a young child with symptomatic metastatic marrow infiltration, a rarely reported site of melanoma involvement in adults or children.
The treatment and prophylaxis of leptomeningeal leukemia and lymphoma in children has dramatically improved disease control and long-term survival. However, the treatment of other leptomeningeal cancers has been less successful and the neurologic morbidity associated with central nervous system-directed therapy has a significant long-term impact on quality of life. Further research is critical to identify new therapeutic strategies for children with or at high risk for leptomeningeal cancer.
Brain metastasis is a well described and common complication in adult patients with cancer. It is estimated that between 25–40%
of all adults with malignancies will develop brain metastasis [1–4]. This is particularly common in patients with melanoma,
lung cancer, breast cancer and gastrointestinal tract neoplasms [5, 6]. In pediatric patients with solid tumors, however,
the incidence of brain metastases is exceedingly rare. Most of the recent literature suggests that the overall incidence of
brain metastases in pediatric oncology patients ranges from 1–10% [1–4].
Metastatic disease to the central nervous system (CNS) is common and accounts for approximately 37% of intracranial neoplasms
[1]. Autopsy studies have shown that 24% of patients who die from cancer have intracranial metastasis and the estimated annual
incidence is approximately 170,000 cases per year [2]. Earlier detection and improved treatment of primary malignancies have
contributed to the increasingly important role of imaging to detect CNS dissemination.
The BJC is owned by Cancer Research UK, a charity dedicated to understanding the causes, prevention and treatment of cancer and to making sure that the best new treatments reach patients in the clinic as quickly as possible. The journal reflects these aims. It was founded more than fifty years ago and, from the start, its far-sighted mission was to encourage communication of the very best cancer research from laboratories and clinics in all countries. The breadth of its coverage, its editorial independence and it consistent high standards, have made BJC one of the world's premier general cancer journals. Its increasing popularity is reflected by a steadily rising impact factor.
PURPOSE
Interferon alfa-2b (IFN alpha-2b) exhibits antitumor activity in metastatic melanoma and on this basis has been evaluated as an adjuvant therapy following surgery for deep primary (T4) or regionally metastatic (N1) melanoma.
METHODS
A randomized controlled study of IFN alpha-2b (Schering-Plough, Kenilworth, NJ) administered at maximum-tolerated doses of 20 MU/m2/d intravenously (i.v.) for 1 month and 10 MU/m2 three times per week subcutaneously (SC) for 48 weeks versus observation, was conducted by the Eastern Cooperative Oncology Group (ECOG) in 287 patients.
RESULTS
A significant prolongation of relapse-free survival (P = .0023, one-sided) and prolongation of overall survival (P = .0237, one-sided) was observed with IFN alpha-2b therapy in this trial, which is now mature with a median follow-up time of 6.9 years. The impact of treatment on relapse rate is most pronounced early during the treatment interval. The overall benefit of treatment in this trial was analyzed stratified by tumor burden and the presence or absence of microscopic nonpalpable and palpable regional lymph node metastasis. The benefit of therapy with IFN alpha-2b was greatest among node-positive strata. Toxicity of IFN alpha-2b required dose modification in the majority of patients, but treatment at > or = 80% of the scheduled dose was feasible in the majority of patients through the IV phase of treatment, and for more than 3 months of SC maintenance therapy. Discontinuation of treatment due to toxicity was infrequent after the fourth month of therapy.
CONCLUSION
IFN alpha-2b prolongs the relapse-free interval and overall survival of high-risk resected melanoma patients. The increment in median disease-free survival (from 1 to 1.7 years) and overall survival (from 2.8 to 3.8 years) that results from this therapy is associated with a 42% improvement in the fraction of patients who are continuously disease-free after treatment with IFN (from 26% to 37%) in comparison to observation. IFN alpha-2b is the first agent to show a significant benefit in relapse-free and overall survival of high-risk melanoma patients in a randomized controlled trial.
Background. Cancers of individual organs generally are composed of various histologic types, each with its own frequency and demographic patterns. For childhood cancers in particular, a classification of cancers by histologic type is important for understanding the etiology and progression of the disease.Methods. Data from the Surveillance, Epidemiology, and End Results (SEER) Program on 9308 microscopically confirmed malignant neoplasms in children younger than age 15, newly diagnosed during 1973-1987, were made available for analysis. Tumors were grouped histologically according to a classification previously utilized in an international volume of childhood cancer incidence.Results. The most frequent histologic types were acute lymphocytic leukemia (23.6%), astrocytoma (9.6%), neuroblastoma (6.6%), and Wilms' tumor (6.4%). Acute lymphocytic leukemia accounted for 75% of childhood leukemia. The most common form of Hodgkin's disease was the nodular sclerosing subtype, which was diagnosed in 56% of all cases. Burkitt's and Burkitt-like disease accounted for approximately one third of non-Hodgkin's lymphoma, the sex ratio (male to female) being unusually high (5.7). Among the brain tumors, glioma was of interest because 198 cases (excluded from this analysis) were diagnosed without histologic confirmation—due, no doubt, to their inaccessibility for biopsy because they were located in the brain stem. The most common histologic type of soft tissue sarcoma was rhabdomyosarcoma, which accounted for 51% of the total, more than half of which were of the embryonal type. To the authors' knowledge, this report offers for the first time the relative frequencies of rare types of leukemias, such as megakaryoblastic leukemia, in childhood. This report also includes the frequencies of 21 rarer forms of soft tissue sarcoma. Five forms of childhood cancer had a 5-year relative survival rate of 85% or better. Of the cancers with the poorest outcome, three had relative survival rates of 46.5-49%; the relative survival rate for acute myelogenous leukemia was only 26.4%. The trends in survival over time for 21 types of childhood cancer also are included in this report.Conclusions. Further refinements in classification now are available through laboratory techniques utilizing molecular biology, immunology, and cytogenetics, which are of importance in etiologic studies, diagnosis, treatment, and prognosis. It would be important in the future for cancer registries to record the results of relevant laboratory tests for further analysis by subtype.
Thirty-one children and adolescents with malignant melanoma were treated at the Christie Hospital and Holt Radium Institute between 1945 and 1977. Locations of primary lesions included head-neck 14, trunk nine, and extremity eight. Twenty-five patients had clinically localized tumor at diagnosis, four had regional disease, and two had generalized tumor. Surgery was the primary modality of therapy. Fifteen patients survive without active disease from two years to more than 18 years, and 16 patients died of disease.
Background. Metastatic melanoma with an unidentified primary site represents 4% of all newly diagnosed cases of malignant melanoma in adults. Little is known of the incidence and clinicopathologic features of this clinical entity in the pediatric population.
Methods. We reviewed all previously diagnosed cases of malignant melanoma in children and adolescents (<21 years) who were treated at our institution and identified three patients who presented with metastatic melanocytic lesions with an unidentified primary site.
Results. This clinical presentation accounted for 9% of all malignant melanocytic lesions treated at our center over a 20-year period. The clinicopathologic features were similar to those seen in adults. Two patients died of progressive disease within two years of presentation; the third is alive and disease-free 18 years post-diagnosis.
Conclusions. Although uncommon in the pediatric population, malignant melanoma should be considered in the differential diagnosis of poorly differentiated disseminated malignancy that involves lymph nodes or viscera with no identifiable primary tumor.
One-hundred twenty five of 700 patients with malignant melanoma treated at Roswell Park Memorial Institute from 1972 to 1978 were found to have brain metastases. Seventy-three percent of the patients had multiple brain metastases. Male to female ratio was 1.9:1. The median survival of the untreated group of patients was 3 weeks as compared with that of 6 weeks for the patients maintained on steroids only, 9 weeks for those who received radiotherapy, 11 weeks for the patients treated with intraarterial chemotherapy, and 26 weeks for the patients who underwent successful surgical excision of a solitary lesion.
The authors report the results of a retrospective review of 13 patients who underwent 19 craniotomies for resection of metastatic malignant melanoma at the University of Colorado (Denver, CO) between 1983 and 1989. There was preoperative evidence of extracranial disease in 11 patients. Eight patients had more than one intracranial metastasis at operation. Intraoperative ultrasound was used in 18 of the 19 craniotomies to minimize surgical trauma to the brain. the 30-day mortality was zero. the 30-day morbidity was minimal. No patient acquired a new neurologic deficit as a result of surgery. All patients regained at least their preoperative level of functioning. Six of the patients who were living at the time of review have been followed for 4 to 25 months (median, 7.5 months). the seven patients who were dead at the time of review survived 4 to 18 months (median, 10 months). These results compare favorably with the survival of untreated patients with metastatic melanoma to the brain (median, 1 month), patients treated with radiation therapy alone (median, 2–4 months), and those treated with chemotherapy alone (median, 2–4 months). the excision of metastatic melanoma from the brain, although not curative, may increase survival in patients with this problem with little morbidity and mortality even in the presence of other metastases.
One hundred and twenty-two patients with clinically advanced, histologically confirmed, cutaneous malignant melanoma, seen at Wayne State University over a 12 year period were reviewed. The incidence of central nervous system metastases (CNS) diagnosed clinically was 46% and at autopsy 75%. Meningeal involvement was suspected clinically in 10.6% and found at autopsy in 52%. Motor dysfunction, mental confusion, cranial nerve disturbance, as well as headache, were the most common manifestations. EEG was found to be extremely sensitive in predicting and confirming CNS metastases even before clinical manifestation. Accuracy increased by performing an EEG serially or combining it with a brain scan. Best therapeutic results were noted after surgery for solitary CNS metastases. Palliative radiotherapy was effective in 37% of patients. Mean survival after neurological diagnosis was 4.0 months, but it varied depending on the site of the initial primary and the presence or absence of other visceral involvement. Concomitant liver metastases carried the worst prognosis. Patients with head, neck or trunk primaries who develop lung or liver metastases should be examined carefully and tested periodically with EEG. Persistent EEG abnormalities should strengthen the clinical suspicion of an underlying CNS metastases and may be an indication for further studies and possible therapy.
The immediate cause of death was determined for all patients dying at Memorial Hospital from 1973 to 1976 with biopsy-proven malignant melanoma. One-third of patients died of a central nervous system involvement. Pulmonary involvement and infections were the next most common causes of death. The addition of chemotherapy or chemoimmunotherapy to surgery did not change the causes of death. The incidence of postmortem, documented CNS metastases has also increased since prior studies 10 yr ago.
The records of all patients who received radiotherapy for melanoma metastatic to brain (63 patients) and epidural space (9 patients) at the American Oncologic Hospital from January 1971, through March 1980, were reviewed. Patients were evaluated according to the type of therapy received (corticosteroids, radiotherapy, surgery) and whether their brain metastases were radiographically solitary (60%) or multiple (40%). Forty-nine patients with brain metastases received corticosteroid therapy for 2 to 7 days or more before radiotherapy. Fifty-two percent of the patients with solitary and 30% of those with multiple brain metastases responded to radiotherapy. The use of large doses (greater than or equal to 500 rad) per fraction produced a significantly higher response rate than did the use of low doses (less than or equal to 400 rad) per fraction (P < .02), but only for those patients with solitary brain metastases. Patients with cord compression undergoing decompressive laminectomy had relief of neurologic symptoms, whereas those not paralyzed who received radiotherapy alone did not respond. Surgical excision with postoperative irradiation is recommended for the management of solitary brain metastases from melanoma. Surgical decompression is recommended for the management of epidural cord compression.
We report on a prospective phase TI study utilizing stereotactic radiosurgery for patients with intracranial parenchymal metastases. Fifty patients ranging in age from 38 to 77 years with 1 to 3 intraparenchymal brain metastases were treated with stereotactic radiosurgery either immediately following whole brain radiotherapy or at the time of intracranial disease progression following failure of whole brain radiotherapy. Twenty patients treated with adjuvant therapy received a median radiosurgical dose of 20 Gy. Thirty patients treated with salvage therapy received a median radiosurgical dose of 20 Gy. No immediate neurotoxicity was seen following radiosurgery however, 4 patients (8%) developed symptomatic radiation necrosis. Median survival was 6.5 and 6.0 months for patients treated with adjuvant and salvage radiosurgery respectively. In patients with oligometastatic brain metastases manifesting intracranial disease progression after whole brain radiotherapy, salvage radiotherapy appears to offer improved palliation when compared to retreatment with whole brain radiotherapy. The results of patients treated with up-front adjuvant radiosurgery when compared to historical controls treated with whole brain radiotherapy only are less clear as to benefit and require a phase III study before definitive recommendations can be made.
The CT appearance of metastatic malignant melanoma is varied, but it can show features suggesting the correct diagnosis. Intracerebral hemorrhage alone, associated with an adjacent tumor nodule or mixed diffusely with a tumor, occurred in 10 of 33 patients. Identification of a tumor nodule is important, since it may be the site of recurrent hemorrhage if not removed completely at surgery. Unusual presentations such as meningeal carcinomatosis and lesions simulating primary gliomas also occurred.
122 patients with clinically advanced, histologically confirmed, cutaneous malignant melanoma, seen at Wayne State University over a 12 year period were reviewed. The incidence of central nervous system metastases (CNS) diagnosed clinically was 46% and at autopsy 75%. Meningeal involvement was suspected clinically in 10.6% and found at autopsy in 52%. Motor dysfunction, mental confusion, cranial nerve disturbance, as well as headache, were the most common manifestations. EEG was found to be extremely sensitive in predicting and confirming CNS metastases even before clinical manifestation. Accuracy increased by performing an EEG serially or combining it with a brain scan. Best therapeutic results were noted after surgery for solitary CNS metastases. Palliative radiotherapy was effective in 37% of patients. Mean survival after neurological diagnosis was 4.0 months, but it varied depending on the site of the initial primary and the presence or absence of other visceral involvement. Concomitant liver metastases carried the worst prognosis. Patients with head, neck or trunk primaries who develop lung or liver metastases should be examined carefully and tested periodically with EEG. Persistent EEG abnormalities should strengthen the clinical suspicion of an underlying CNS metastases and may be an indication for further studies and possible therapy.
We have attempted to describe virtually all forms of malignant melanoma which affect man except those arising in the eye. The vast majority of malignant melanomas clearly fall into one of three kinds: (1) malignant melanoma of the superficial-spreading type, (2) malignant melanoma of the lentigo-maligna type, and (3) malignant melanoma of the nodular type. The developmental biology of a primary neoplasm is illustrated by discussing and illustrating the evolution of these three dominant forms of melanoma. Primary malignant melanoma of the superficial-spreading type and of the lentigo-maligna type develop through a characteristic biphasic growth pattern: an initial radial-growth phase, followed by a vertical-growth phase. The radial-growth phase of these melanomas is only rarely associated with the development of metastases, while the vertical-growth phase is commonly associated with subsequent metastatic disease. The phenomenon of the vertical-growth phase is apparently, therefore, a qualitative step in the development of a primary malignant melanoma. Malignant melanoma of the nodular type is an example of a primary tumor without a precursor developmental stage such as a radial-growth phase.
Although chemotherapy has been generally of limited clinical benefit in the treatment of metastatic malignant melanoma (MMM), fotemustine (FM) is a newly developed drug which is active against this disease. Twenty-four patients with histologically proven MMM were treated with fotemustine, with or without dacarbazine (DITC) according to different phase II trials. In the first schedule, three patients received FM alone on days 1, 8, 15 followed by a 5-week rest period. The second schedule consisted of FM administered on days 1 and 8 alternating with DTIC on days 15 and 16, followed by a 5-week rest period (19 patients). The third schedule, given to two patients, consisted of DTIC followed 4 h later by FM. The overall response rate was 8.3%. Response in those who were treated with alternating drugs, included one partial response (PR) in the brain which lasted 4 months, and one PR in brain metastases with complete response (CR) in lymph nodes for 4 months. Clinical and radiological evidence of regression was observed mainly in brain metastases (22.2%), reflecting the intracerebral activity of the drug. It seems that fotemustine is superior to any other drug currently available in the treatment of these metastases.
Three patients with metastatic malignant melanoma, 2 of whom were males with primary lesion on the shoulder, and a female with primary lesion on the ankle, with Clark's level III-IV, completely responded to interferon-DTIC, but failed in the brain. Radiologically, all the lesions were peripheral in location, and none showed any bleeding tendency. Clinically, these lesions seemed to be resistant to radiotherapy, chemotherapy or steroid treatment, and were the cause of death after a very short survival period. Interferon apparently is inactive against melanoma brain metastases, but does cause CNS symptoms. Because CNS metastases are sometimes the sole site of clinical relapse, and are frequently disabling, prophylactic cranial irradiation (PCI) needs to be studied in high risk patients.
A retrospective study was undertaken of factors affecting survival in 129 patients with cerebral metastases from malignant melanoma referred to the Department of Radiation Oncology from June 1982 to January 1990. Their ages ranged from 19 to 83 years and the time interval from diagnosis of the primary tumour to development of cerebral metastases ranged from one month to 17 years. Cerebral metastases were apparently solitary in 59 (46%) and multiple in 70 (54%) patients respectively. Craniotomy with resection of tumour was performed in 49 patients, of whom 24 had a solitary cerebral metastasis as the only evidence of disease. Most patients (94%) received a course of radiotherapy. Median survival of the whole group after detection of cerebral metastases was 5 months (range less than 1-87+). Univariate analysis indicated that a solitary cerebral metastasis, absence of extracranial disease and tumour resection predicted improved survival, but only surgical intervention was of independent prognostic significance in a multivariate analysis. The effect of cranial irradiation on survival could not be assessed, but the dose of radiation did not influence survival. Of the 10 patients who survived for more than 2 years, eight had total resection of a solitary cerebral metastasis.
The authors report the results of a retrospective review of 13 patients who underwent 19 craniotomies for resection of metastatic malignant melanoma at the University of Colorado (Denver, CO) between 1983 and 1989. There was preoperative evidence of extracranial disease in 11 patients. Eight patients had more than one intracranial metastasis at operation. Intraoperative ultrasound was used in 18 of the 19 craniotomies to minimize surgical trauma to the brain. The 30-day mortality was zero. The 30-day morbidity was minimal. No patient acquired a new neurologic deficit as a result of surgery. All patients regained at least their preoperative level of functioning. Six of the patients who were living at the time of review have been followed for 4 to 25 months (median, 7.5 months). The seven patients who were dead at the time of review survived 4 to 18 months (median, 10 months). These results compare favorably with the survival of untreated patients with metastatic melanoma to the brain (median, 1 month), patients treated with radiation therapy alone (median, 2-4 months), and those treated with chemotherapy alone (median, 2-4 months). The excision of metastatic melanoma from the brain, although not curative, may increase survival in patients with this problem with little morbidity and mortality even in the presence of other metastases.
From 1972 to 1987, 35 patients underwent resection of a single brain metastasis from melanoma; 19 received postoperative radiation therapy (RT) (group A), and 16 did not (group B). Group A had a longer interval to CNS relapse compared with group B, but survival was similar. However, 4/17 (24%) from group A and 11/13 (85%) from group B died of neurologic causes. We conclude that patients with single brain metastasis from melanoma have improved control of CNS disease when postoperative RT is administered, and survival depends upon control of systemic disease.
Malignant melanoma is rare in children, representing 1% to 3% of all pediatric malignancies. Thirty-three children with malignant melanoma were treated at St Jude Children's Research Hospital from 1967 to 1988. Their ages ranged from 1 day to 20 years (median, 12 years); 23 were boys and 10 were girls; and 5 of the 33 (15%) were black. Four of the 33 children had been treated for a previous malignancy. In 3, melanoma arose within a bathing trunk nevus. The extremity was the most common site (13), followed by the trunk (9), head and neck (7), and perineum (1). In 3 patients the primary site could not be determined. Upon initial presentation to St Jude Hospital, 17 patients had localized disease (stage I), 10 had regional node involvement (stage II), and the remaining 6 patients had disseminated disease (stage III). Using both Clark's level and Breslow's thickness as indicators, the incidence, initial stage, prognosis, and survival were compared. By Clark's level, 7 patients, (6 of whom were stage I) were level II or III, and 22 patients were level IV or V. Though 16 of 22 level IV and V patients were initially stage I, 10 patients eventually developed progressive disease. Similar observations were noted when using Breslow's thickness to evaluate the primary. In 5 of 27 evaluable patients, Breslow's depth of invasion was less than 1.5 mm. All 5 of these patients were diagnosed with stage I disease and have not shown progressive disease.
Five patients with advanced malignant melanoma, treated with viral oncolysate, had solitary central nervous system metastases that were removed surgically. Histologic examination revealed striking and significant mononuclear inflammatory cell infiltrates, consisting of a mean of 60% plasma cells and a lesser proportion of lymphocytes at the edges of the lesions, within their supporting fibrovascular trabeculae, and among the tumor cells. Comparable inflammatory changes were not found in solitary metastatic malignant melanomas removed surgically from the brains of 19 patients not treated with viral oncolysate. Similarly, multiple metastatic malignant melanomas obtained postmortem from the brains of 12 patients not treated with viral oncolysate showed minimal inflammatory responses. Ultrastructural examination of material from a single treated patient revealed morphologic abnormalities of the blood-brain barrier, changes that were perhaps conducive to infiltration of the neoplasm by inflammatory cells. The authors suggest that administration of viral oncolysate enhances the inflammatory cell response to metastatic malignant melanoma in the brain.
A number of partial or complete remissions have been induced within the past 3 years in patients with metastatic melanoma treated with biomodulators, such as low-dose cyclophosphamide (CY) and interleukin-2 (IL-2), or active specific immunotherapy. Six of the most successfully treated patients, with prolonged remissions in skin, lymph nodes, liver and/or lung, all had relapses in the brain. At the time of relapse in the CNS, remissions were continuing in the other viscera. A large single intracerebral metastasis was found in four of the six patients; the other two patients had three metastases each, one of which also had meningeal seeding. Resection was performed in the four patients with single lesions, without postoperative radiotherapy. Intrathecal IL-2 successfully controlled meningeal disease. To date, the median survival of the group exceeds 7 months, in contrast to the usual reported median of 1 to 4 months, reflecting the predominance of resectable single lesions. Immunological therapy failed to prevent or treat metastases to the CNS, but may have influenced the patients' reactivity to the disease, producing single rather than diffuse metastases. If melanoma is to be cured now by any systemic therapy, particularly biomodulation, new regional strategies must be devised to overcome the blood-brain barrier. By analogy with autoimmune disease of the CNS such as multiple sclerosis, in which excessive cell-mediated immunity is found, several possible immunological maneuvers are suggested.
One hundred consecutive patients with cerebral metastases from malignant melanoma were studied in relation to survival from the time of diagnosis of central nervous system (CNS) involvement, response to treatment, characteristics of their primary lesion, and the course of the disease from initial diagnosis to the development of intracranial tumor. After treatment, clinical and investigational evidence of objective regression of cerebral lesions was demonstrable in ten patients who survived with a median of 11.5 months from diagnosis of CNS involvement. In 11 additional patients, CNS disease remained clinically stable for a median period of 7 months. Median survival for the entire group of 100 patients was 2.5 months. However, eight patients (8%) survived longer than 1 year from the time of diagnosis of cerebral metastases, four of whom (4%) survived longer than 2 years; the longest survivor being disease-free and incomplete neurologic remission at more than 82 months. Patients with malignant melanoma metastatic to the brain should be informed of the therapeutic options available for their disease.
A subgroup of 59 patients selected on the basis of favorable prognostic factors from a larger group of 194 patients treated for intracranial metastases of melanoma was analyzed with a view to assessing the relative efficacy of different accelerated fractionation regimens. The most effective modification of the previously standard therapy was a shortening of the overall treatment time, although this was also associated with the use of larger doses per fraction. Patients who had brain metastases only at the time of treatment showed a longer survival time than those with coexistent metastases in other organs and survived longer if treated with 10 fractions within 1 week rather than 20 fractions in 2 weeks. The same was found in patients who underwent complete resection of intracranial tumor before irradiation. A complete surgical resection also increased the probability of eliminating intracranial disease, but overall the median survival increased by less than 2 months. It is concluded that a short overall treatment time is more important than large fraction sizes in attempts to improve the treatment of metastatic intracranial melanomas with favorable prognosis.
Etiology of malignant melanoma in persons younger than 20 years of age was examined using data from two sources: medical records of 78 patients with this diagnosis at six hospitals, and information on 101 individuals included in 10 U.S. population-based SEER cancer registry areas between 1973-1976. Annual melanoma incidence rate was 3.4 per million in boys, 3.9 per million in girls, and 10-fold greater in white children than in black children. Melanoma was seven times more frequent in the second decade of life than the first. Skin was the primary site of melanoma in approximately 90% of the children in the two study series. The predominant cutaneous sites were head, neck, and trunk among boys, and arms and legs among girls. These variations by age, race, and sex suggest the etiologic role of cumulative skin exposure to sunlight, particularly in two patients with xeroderma pigmentosum. In 14 patients in the hospital series, melanoma was reported to develop within pigmented nevi that were present at birth.
Sixty patients from two Radiation Therapy Oncology Group (RTOG) studies with cerebral metastases from malignant melanoma were analyzed to determine the response to whole brain irradiation. General performance status, neurologic function, and specific neurologic symptoms were evaluated for rate and duration of improvement. Also analyzed was the influence of chemotherapy and steroids, although neither was a controlled factor. Results indicate a significant benefit from radiation therapy in terms of symptomatic and neurologic function improvement. Symptomatic improvement was observed in 76%, with 31% completely improved. Of the four most frequent symptoms, complete or partial improvement was observed as follows: headache--27 of 37 patients (73%); motor loss--14 of 23 patients (61%); impaired mentation--13 of 24 patients (62%); and convulsions--10 of 12 patients (83%). Improvement in neurologic function class was observed in 18 of 44 patients (41%). Median survival for Study 1 patients was 10 weeks (range 1-200) and that of Study II patients 14 weeks (range 1-76). These results are comparable to those found in radiation therapy of brain metastases from all other primary tumors.
Two hundred seventy-five cranial computed tomography (CT) scans performed on 179 patients with malignant melanoma were reviewed. Of the 101 patients with confirmed cerebral metastases, CT demonstrated lesions in 93. In 72% of these, areas of increased attenuation were present in the precontrast scan. These lesions also enhanced after contrast infusion. There was a direct correlation between the extent of bleeding in the neoplasm and the density of the metastasis, at least 20% red blood cells per high power field were consistently present within lesions of increased attenuation. Cerebral metastases were occasionally associated with subdural or intracranial hemorrhage. Meningeal melanomatosis was recognized by CT only when associated with adjacent parenchymal metastases. In nine (11%) of 74 patients without clinical evidence of brain involvement, CT revealed cerebral metastases; this suggests that a staging CT scan might be useful on patients with diffuse or advanced local extracranial disease prior to definitive therapy.
To determine the value of computed tomographic (CT) scans in the staging of asymptomatic melanoma patients who presented with or developed local-regional disease as the first site of recurrence and had both a normal chest radiograph and serum lactate dehydrogenase (LDH) level.
The records of 99 patients with local-regional disease were reviewed. Of these, 89 met the study criteria and are the subjects of this analysis. Radiologic findings were categorized into the following four groups: (1) true-positive (TP), when the scan identified either regional or distant disease that was not appreciated on physical examination; (2) false-positive (FP), when the scan showed a radiologic abnormality that either did not change for at least 6 months or was proven to be histologically benign; (3) false-negative (FN), when a patient had symptoms suggestive of or suspicious for metastases and was subsequently found to have metastases, but all imaging studies were nondiagnostic; and (4) true-negative (TN), when all imaging studies were negative for metastases in an asymptomatic patient.
Findings on CT scan were TP for six patients (7%), FP for 20 (22%), and TN for 63 (71%). Of the six patients with TP findings, CT of the chest identified disease that was not visible on chest radiograph in only one and CT of the abdomen or pelvis showed metastases in five. CT or magnetic resonance imaging (MRI) of the brain showed no evidence of brain metastases in any patient, although it showed asymptomatic skull metastases in one patient. The most common FP findings were hypodense hepatic lesions and noncalcified lung nodules.
TP findings are observed in approximately 7% of patients with local-regional disease, which indicates a low yield but definite usefulness of CT scans in this subset of patients. Because FP are more common than TP findings, histologic diagnosis of recurrence is advisable. CT scan or MRI of the brain is not necessary in asymptomatic patients. CT of the chest adds little to a chest radiograph. In light of today's more cost-conscious health-care environment, our results are of practical importance.
Cutaneous melanoma is an uncommon malignancy in children and for this reason, there is little information available regarding the timing and patterns of recurrence in children with this disease. This study reviews the experience at a single institution (Duke University Melanoma Clinic) in treating children with malignant melanoma.
Eighty-five patients < or = 18 years of age with malignant melanoma have been treated. All but three patients were over the age of 10; 73% of them were > 14. As for adults, treatment consisted of wide local excision of all primary lesions with primary closure or split-thickness skin graft, as needed. In addition, 22 patients underwent dissection of regional lymph nodes. Patients whose tumors had aggressive pathologic characteristics were treated with an adjuvant immunotherapy protocol. Patients with recurrence at distant sites were offered combination chemotherapy.
Patients and pathologic characteristics of sex, race, primary site, histologic type, tumor thickness, and Clark level were similar to those observed in adults. Actuarial survival rates (79% versus 77% at 5 years) of the pediatric and adult Stage I melanoma patients were also not significantly different. Children had a greater incidence of recurrence after initial treatment, although recurrence tended to happen after a longer disease-free interval than for adults. Half of the 79 children who were first seen with Stage I disease have suffered a relapse, but more than one-third were disease free for > or = 5 years after initial treatment. Of the 18 patients who were disease free for > or = 7 years, 12 (67%) ultimately had recurrent disease, including five patients who had recurrences > 13 years after initial diagnosis.
The early age at which malignant melanoma may occur and the significant potential for very late recurrence mandate that pediatricians and other primary care physicians consider the diagnosis of melanoma even in young patients with new skin lesions and that patients treated for melanoma be carefully followed for a lifetime.
Cancers of individual organs generally are composed of various histologic types, each with its own frequency and demographic patterns. For childhood cancers in particular, a classification of cancers by histologic type is important for understanding the etiology and progression of the disease.
Data from the Surveillance, Epidemiology, and End Results (SEER) Program on 9308 microscopically confirmed malignant neoplasms in children younger than age 15, newly diagnosed during 1973-1987, were made available for analysis. Tumors were grouped histologically according to a classification previously utilized in an international volume of childhood cancer incidence.
The most frequent histologic types were acute lymphocytic leukemia (23.6%), astrocytoma (9.6%), neuroblastoma (6.6%), and Wilms' tumor (6.4%). Acute lymphocytic leukemia accounted for 75% of childhood leukemia. The most common form of Hodgkin's disease was the nodular sclerosing subtype, which was diagnosed in 56% of all cases. Burkitt's and Burkitt-like disease accounted for approximately one third of non-Hodgkin's lymphoma, the sex ratio (male to female) being unusually high (5.7). Among the brain tumors, glioma was of interest because 198 cases (excluded from this analysis) were diagnosed without histologic confirmation--due, no doubt, to their inaccessibility for biopsy because they were located in the brain stem. The most common histologic type of soft tissue sarcoma was rhabdomyosarcoma, which accounted for 51% of the total, more than half of which were of the embryonal type. To the authors' knowledge, this report offers for the first time the relative frequencies of rare types of leukemias, such as megakaryoblastic leukemia, in childhood. This report also includes the frequencies of 21 rarer forms of soft tissue sarcoma. Five forms of childhood cancer had a 5-year relative survival rate of 85% or better. Of the cancers with the poorest outcome, three had relative survival rates of 46.5-49%; the relative survival rate of acute myelogenous leukemia was only 26.4%. The trends in survival over time for 21 types of childhood cancer also are included in this report.
Further refinements in classification now are available through laboratory techniques utilizing molecular biology, immunology, and cytogenetics, which are of importance in etiologic studies, diagnosis, treatment, and prognosis. It would be important in the future for cancer registries to record the results of relevant laboratory tests for further analysis by subtype.
The Southwest Oncology Group entered 62 patients with Stage IV or inoperable Stage III (one patient) melanoma into SWOG protocol 8804 and treated them with cisplatin 100 mg/m2 and DTIC 750 mg/m2 i.v. infusion over 15-30 minutes. There were 18 patients with brain metastases and four ocular primaries. Five patients, all without bain metastases, were ineligible. Responses of 8 patients could not be determined, and 11 patients received only one course of treatment. Of the eligible patients, 46 (81%) had some hematologic toxicities, with 31 of these (67%) having grade III or worse. There were 23 patients (40%) with renal toxicities. The miscellaneous toxicities were muscle weakness, flu-like symptoms, and fatigue. Five patients died while on treatment. There were no complete responses. Eight patients had partial responses ranging from 1.5 to 10.5 months, although two patients were still alive at 30.4 and 30.9 months. The estimated response rate for patients with brain metastases was 11%. The estimated response rate for patients without brain metastases was 13%. If one unconfirmed partial response is included, the overall response rate is 14% with a 95% confidence interval of 6% to 26%. It is concluded that DTIC and cisplatin have definite activity in melanoma, but, at least in this population, the toxicity is treatment-limiting and requires close attention to patient care.
To determine local tumor control rates and survival of patients with melanoma metastases to the brain, the authors reviewed the results of 23 consecutive patients with a total of 32 tumors (19 patients had a solitary tumor and four had multiple tumors) who underwent adjuvant stereotactic radiosurgery. Tumor locations included the cerebral hemisphere (24 cases), brain stem (four cases), basal ganglia (two cases), and cerebellum (two cases). Fifteen patients had associated cranial symptomatology and eight had incidental metastases. All patients had tumors of 3 cm or less in diameter (mean tumor volume 2.5 cu cm), and all received fractionated whole-brain radiation therapy (30 Gy) in addition to radiosurgery (mean tumor margin dose 16 Gy). Nineteen patients were managed with both modalities at the time of diagnosis; four underwent radiosurgery 3 to 12 months after fractionated whole-brain radiotherapy. The mean patient follow-up period was 12 months (range 3 to 38 months).
After radiosurgery, eight patients improved, 13 remained stable, and two deteriorated. One patient subsequently required craniotomy because of intratumoral hemorrhage; this patient and three others are living 13 to 38 months after radiosurgery. Nineteen patients died, 18 from progression of their systemic disease and one from another hemorrhage into a new brain metastasis. The local tumor control rate was 97%. Only two patients subsequently developed new intracranial metastases. The median survival period after diagnosis was 9 months (range 3 to 38 months). The authors believe that stereotactic radiosurgery coupled with fractionated whole-brain irradiation is an effective management strategy for cerebral metastases from a melanoma. Multi-institutional trials are warranted to confirm that stereotactic radiosurgery results equal or surpass the outcome achieved with craniotomy and tumor resection.
Forty-eight cases of melanoma occurring in patients under 20 years of age were reviewed from a 23-year period at a single center. Fourteen of the patients were preadolescent children and 44 were Caucasian. Histological review of 44 available primary tumors showed only superficial spreading and nodular types. Thickness ranged from 0.23 mm to 8.50 mm, with a median of 1.03 mm. Ulceration was present in 7%, necrosis in 35%, evidence of regression in 16%, and antecedent nevus in 49% of the cases. The overall 5-year survival is 77%, with a median follow-up of 48 months. There is no detectable survival difference between preadolescent children and adolescents. Several treatment failures occurred after improper biopsy and/or inaccurate original diagnosis of Spitz's nevus. Of 38 stage I and II patients given definitive surgical treatment by the authors, the 5-year survival is 90%. Although histological confusion with Spitz's nevi occasionally occurs, melanoma in this age group can be treated with good results.
Interferon alfa-2b (IFN alpha-2b) exhibits antitumor activity in metastatic melanoma and on this basis has been evaluated as an adjuvant therapy following surgery for deep primary (T4) or regionally metastatic (N1) melanoma.
A randomized controlled study of IFN alpha-2b (Schering-Plough, Kenilworth, NJ) administered at maximum-tolerated doses of 20 MU/m2/d intravenously (i.v.) for 1 month and 10 MU/m2 three times per week subcutaneously (SC) for 48 weeks versus observation, was conducted by the Eastern Cooperative Oncology Group (ECOG) in 287 patients.
A significant prolongation of relapse-free survival (P = .0023, one-sided) and prolongation of overall survival (P = .0237, one-sided) was observed with IFN alpha-2b therapy in this trial, which is now mature with a median follow-up time of 6.9 years. The impact of treatment on relapse rate is most pronounced early during the treatment interval. The overall benefit of treatment in this trial was analyzed stratified by tumor burden and the presence or absence of microscopic nonpalpable and palpable regional lymph node metastasis. The benefit of therapy with IFN alpha-2b was greatest among node-positive strata. Toxicity of IFN alpha-2b required dose modification in the majority of patients, but treatment at > or = 80% of the scheduled dose was feasible in the majority of patients through the IV phase of treatment, and for more than 3 months of SC maintenance therapy. Discontinuation of treatment due to toxicity was infrequent after the fourth month of therapy.
IFN alpha-2b prolongs the relapse-free interval and overall survival of high-risk resected melanoma patients. The increment in median disease-free survival (from 1 to 1.7 years) and overall survival (from 2.8 to 3.8 years) that results from this therapy is associated with a 42% improvement in the fraction of patients who are continuously disease-free after treatment with IFN (from 26% to 37%) in comparison to observation. IFN alpha-2b is the first agent to show a significant benefit in relapse-free and overall survival of high-risk melanoma patients in a randomized controlled trial.
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