Time trends of cutaneous melanoma in Queensland, Australia and Central Europe.

BACKGROUND: The objective of this study was to describe recent developments in cutaneous melanoma from the German speaking countries in Europe (Germany, Austria, and Switzerland) and from Queensland, Australia. METHODS: All incident invasive cutaneous melanoma cases recorded between 1986 and 1996 by the Queensland Melanoma Register and by the Central Malignant Melanoma Registry of the German Dermatological Society were included in the analysis. Weighted linear trend analyses were performed to assess significant changes over the years using yearly sample sizes as weights. RESULTS: In Central Europe, the median tumor thickness decreased from 1.2 mm in 1986 to 0.8 mm in 1996 (P < 0.001), whereas it varied insignificantly between 0.5 mm and 0.6 mm in Queensland. The percentage of patients with Clark Level II invasion increased significantly in Queensland (P < 0.001; 1996, 61.1%) and in Central Europe (P = 0.041; 1996, 24.5%). The percentage of superficial spreading melanomas rose in Central Europe (P = 0.043; 1996, 64.4%), whereas it decreased slightly in Queensland (P = 0.032; 1996, 75%). In Queensland and in Central Europe, younger people and women presented more frequently with thinner melanomas (

Where the sun never shines: anorectal melanoma.

BACKGROUND: Melanoma occurring in the anorectal region is recognized to be an uncommon tumour with a poor prognosis. Queensland has the highest incidence rate of cutaneous melanoma in the world. The purpose of the present study was to determine if the very high incidence of cutaneous melanoma in Queensland has any bearing on the incidence of anorectal melanoma, and to compare this with published studies from other parts of the world. An assessment of the authors' results in the treatment of anorectal melanoma was made by a review of patients presenting during the last decade throughout Queensland. METHODS: All cases of melanoma occurring in Queensland are accumulated in the Melanoma Register, administered by the Queensland Melanoma Project, and data from this were used to derive the results in the present study. Queensland population data were provided by the Australian Bureau of Statistics. RESULTS: During the study period 1985-95 in Queensland there were 21,391 cases of cutaneous melanoma which occurred in an average population, during that time, of 2.89 million. During the same time there were nine cases of anorectal melanoma, giving a relative incidence therefore of 0.04%. This contrasts with published relative incidences of 0.2% for white people in North America, 11% for Southwestern Native Americans, and 14.2% for Northern Pakistan (P < 0.0001). However, the population-based incidence rates of anorectal melanoma for Queensland, United States white people, Southwestern Native Americans and Northern Pakistan are not significantly different from each other. All patients in the present series presented with large tumours, and none survived beyond 25 months despite standard surgical and adjuvant therapy. CONCLUSIONS: The protection against cutaneous melanoma afforded by skin pigmentation is not apparent in the anal area. Anorectal melanoma is no more or less frequent in Queensland, even with the very high incidence rate of cutaneous melanoma. Sun exposure appears to be neither protective nor a risk factor. The outcome of therapy for this condition remains disappointing in the authors' experience.

Recombinant interferon-alpha2a plus 5-fluorouracil for the treatment of metastatic melanoma.

The therapy of metastatic melanoma is limited by poor responses to known chemotherapeutic agents. The report of Mulder et al. (Proc ASCO 1992; 11: 347) raised the possibility of the known interaction between 5-fluorouracil and interferon-alpha2a improving response rates in melanoma. This study was designed to examine the effects of 5-fluorouracil plus interferon-alpha2a alone without the confounding effects of dacarbazine. Doses were chosen based on the earlier study rather than the higher doses used in colon cancer. Therapy for metastatic melanoma with 5-fluorouracil and interferon-alpha2a is manageable in terms of toxicity. The major toxicities were lethargy, nausea/anorexia and flu-like symptoms. These were thought to be primarily attributable to interferon-alpha2a. Only one case of severe diarrhoea occurred. The response rate of 14% is similar to the reported results of interferon-alpha2a treatment alone. On these data, there is no evidence of synergy using this dose and schedule.

Radiation therapy for nodal disease in malignant melanoma.

Radiation therapy has been widely used for palliative management of inoperable metastatic malignant melanoma. For patients with nodal disease, response rates of approximately 70% have been reported. There are limited data concerning the role of adjuvant irradiation following therapeutic lymph node dissection. In this review, 57 patients with isolated resectable and nonresectable nodal disease have been treated with radiation. The overall response rate is 84% for bulky disease. Large fractions are beneficial. The median disease-free survivals were 11 months after adjuvant treatment and 7 months for those with inoperable disease. The median overall survivals were 20 months and 18 months, respectively. Local control in long-term survivors was excellent. Sixty-five percent of patients developed distant metastases. There is a need for additional studies with the use of adjuvant radiation therapy following lymph node dissection.

Interferon-alpha 2a does not improve response or survival when combined with dacarbazine in metastatic malignant melanoma: results of a multi-institutional Australian randomized trial.

Following extensive phase II trials of the combination of dacarbazine and interferon-alpha 2a we performed a prospective, randomized, controlled trial of this combination versus dacarbazine alone as systemic therapy for symptomatic, measurable metastatic malignant melanoma. The two treatment arms were well matched for age, sex, performance, status, relapse-free survival, prior therapy and sites of disease. Therapy consisted of dacarbazine given in combination in escalating doses of 200 mg/m2, 400 mg/m2 and 800 mg/m2 i.v. every 3 weeks, or alone at 800 mg/m2 i.v. every 3 weeks. Interferon was administered subcutaneously starting at 3 mU daily on days 1-3, 9 mU daily on days 4-70, then 9 mU three times per week. Therapy was continued for at least 6 months unless overt progressive disease was observed. Eighty seven patients were randomized to the combination and 83 patients to dacarbazine alone. Response rates were respectively, complete 7% and 2%, and partial 14% and 15%, for a total response rate of 21% (95% confidence limits 13-31%) and 17% (95% confidence limits 10-27%). Median duration of response was 258 and 286 days, and survival of the whole groups 229 and 269 days respectively. Toxicity was worse in the combination arm, with more patients experiencing fatigue, nausea and anorexia, flu-like symptoms and neutropenia. However quality of life was not significantly different in either group, except that fatigue, as measured at week 12 by LASA scales, and activity, as measured by the functional living index, were both improved in the combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic value of quality of life scores in a trial of chemotherapy with or without interferon in patients with metastatic malignant melanoma.

In a multi-centre randomised clinical trial comparing dacarbazine (DTIC) plus recombinant interferon-alfa2a (IFN) versus DTIC alone for patients with metastatic malignant melanoma, aspects of quality of life (QL) were measured prospectively by patients using linear analogue self assessment (LASA) scales including the GLQ-8 and by doctors using Spitzer's QL Index. QL scores and performance status at the time of randomisation were available for 152 of 170 eligible patients. These scores carried significant prognostic information. In univariate analyses, Spitzer QL Index assessed by the doctor and LASA scores for physical wellbeing (PWB), mood, pain, appetite, nausea and vomiting, GLQ-8 total and overall QL were significant (P < 0.01) predictors of subsequent survival. QL Index and LASA scales for mood, appetite, and overall QL remained independently significant (all P < 0.05) in multivariate models allowing for significant prognostic factors other than QL (liver metastases and performance status). These findings closely parallel those in patients with metastatic breast cancer. They add further validity to the QL Index and LASA scores, provide the first evidence of the prognostic significance of the GLQ-8, and argue strongly for the routine assessment of QL in future therapy trials.

Increasing incidence of cutaneous melanoma in Queensland, Australia.

BACKGROUND: Queensland, Australia, had the world's highest incidence rates of invasive cutaneous melanoma in the 1970s. PURPOSE: The purpose of this study was to monitor trends in melanoma incidence in Queensland. METHODS: We studied two time periods in which ascertainment was comparable. RESULTS: In the 7.5 years up to 1987, the incidence of invasive melanoma in Queensland increased by more than one half in women (to 42.89 per 100,000) and more than doubled in men (to 55.81 per 100,000), with the most dramatic increase seen in men over age 50 years. This higher increase in men is a reversal of the previously higher rates in women. In Queensland, cumulative risks of total cutaneous melanoma (in persons aged 0-74 years), including preinvasive melanoma, have increased to one in 14 in men and to one in 17 in women. There were large increases in age-standardized incidence rates of thin lesions (less than 0.75 mm) in both sexes but not of in situ lesions, and there were also increases in thicker lesions, especially on the backs of males. CONCLUSIONS: Although increased awareness and earlier diagnosis appear to have accompanied increased incidence, increased exposure to solar UV radiation during the past 50 years appears to be the most likely explanation for the rise in incidence rates. IMPLICATIONS: A better understanding is needed of the causes of melanoma and of the complex relationships between constitutional factors, ambient UV radiation, and sun-exposure behavior.

Desmoplastic melanoma: patterns of recurrence.

Desmoplastic melanoma is a rare type of malignant melanoma, recognized since 1971. Other variants of desmoplastic melanoma include neural transforming melanoma and neurotropic melanoma. The pathology and clinical features of 58 patients whose tumor had the features of desmoplastic melanoma, neural transforming melanoma, and neurotropic melanoma, either separately or in combination, were examined to assess patterns of recurrent disease. The tumor was situated on the head and neck in 41% of patients and was amelanotic in 71% of patients. There was an associated superficial melanoma in 48% of patients. There was a combination of the 3 histologic patterns, commonly found in the 1 melanoma. Local recurrence occurred in 29% of patients and malignant cranial neuropathies were documented in 4 patients. Nineteen percent of patients have died from disseminated disease. Neurotropic melanomas had a lower incidence of visceral recurrence. Desmoplastic and neural transforming melanomas had similar rates of local and visceral recurrence. When this specific variant of melanoma is compared with larger series of malignant melanoma in general, they appear to be more advanced locally, with a higher incidence of local recurrence. When considered in relation to the thicker nondesmoplastic melanomas, the survival is no worse and may be more favorable. Surgeons should excise the primary tumor and local recurrences with wide margins and adopt close follow-up. On the head and neck, symptoms and signs relating to trigeminal or facial nerve innervation may herald a developing malignant cranial neuropathy.

Exclusion of the familial melanoma locus (MLM) from the PND/D1S47 and MYCL1 regions of chromosome arm 1p in 7 Australian pedigrees.

Familial melanoma (MLM) is sometimes found associated with the dysplastic nevus syndrome (DNS). Considerable controversy exists over the possible assignment of a cutaneous malignant melanoma/dysplastic nevus gene, designated CMM, to the distal short arm of chromosome 1, linked to the PND and D1S47 loci. To date, no support for linkage of MLM alone to these markers has been found; likewise no study has been able to exclude the entire region between PND and D1S47 from linkage to MLM. We have carried out linkage studies between markers on 1p and MLM in seven Australian kindreds; three of these are the largest reported worldwide. We have been able to exclude localization of an MLM gene from a 40-cM region that spans the interval between D1S47 and PND and extends approximately 15 cM on either side of these markers. In addition, we can exclude a region of about 20 cM around the MYCL1/D1S57 loci.

Treatment of advanced malignant melanoma with recombinant interferon alfa-2a in combination with DTIC: long-term follow-up of two phase II studies.

The present studies were designed to examine whether treatment of disseminated melanoma with a combination of recombinant interferon alpha (rIFN alpha-2a) and DTIC may provide better results than either agent alone. Two dose levels of rIFN alpha-2a were examined with the same dose and schedule of DTIC administration. In the first study 76 patients were treated with rIFN alpha-2a (3 x 10(6) IU days 1-3, 9 x 10(6) IU days 4-70 then 9 x 10(6) IU TIW) plus DTIC (i.v. 200 mg/m2, escalating to 800 mg/m2 each 21 d) for 6 months or longer or until failure. Responses were seen in 26% of patients overall (7CR, 13PR) with the highest responses being seen in those assessed as having a good prognosis and in patients with skin and/or lung metastases. It was notable that males showed a better response than females and that patients with metastases in lymph nodes showed low responses. Response rates in 30 patients treated with high-dose rIFN alpha-2a (18 x 10(6) IU days 7-70) were not superior to that seen at the lower dose and was accompanied by significant increase in bone marrow toxicity. The duration of responses appeared longer than expected from responses to DTIC alone and four patients remain progression free at periods in excess of 3 years. Failure in nine of the responders was due to the development of brain metastases which emphasizes the need for additional treatment approaches to treat micrometastases at this site. The results of a randomized control study comparing DTIC alone with DTIC plus 'low' dose rIFN alpha-2a are awaited with interest.

Desmoplastic, neural transforming and neurotropic melanoma: a review of 45 cases.

An analysis of the clinicopathological features of 45 cases of desmoplastic, neural transforming and neurotropic melanoma assessed by a single pathologist are reported. The age range of 27 males and 18 females was 17-88 years. Twenty primary lesions (44%) were on the head and neck and fourteen (31%) were on the trunk. Thirty lesions (67%) were amelanotic. The initial clinical diagnosis was incorrect for 16 patients. Mean thickness was 4.5 mm. Recurrence occurred in 17 patients (38%). Local recurrence has occurred in 12 patients. This was related to a primary where: pathological diagnosis was incorrect; excision was less than 1 cm; the site was on the head and neck; Clarke level was V; and Breslow thickness was greater than 4 mm. Four patients had cranial nerve neuropathies due to recurrent neurotropic melanoma. Four patients are alive with inoperable disease and five have died from disseminated melanoma. These tumours can be difficult to recognize clinically and pathologically, with poor results if not adequately treated primarily. Therefore, the need for surgeons to be aware of this tumour and its clinicopathological features is important. Close follow-up is essential.

Clinical evaluation of interferons in malignant melanoma.

The evaluation of interferons in the treatment of malignant melanoma has been mainly in the treatment of advanced disease using interferons as the sole agent or in combination with other agents. Studies of the value of interferons as adjuvant therapy in high-risk primary melanoma patients are necessary, but no results have been published to date. Human interferon alpha produces low response rates as a sole agent, but in combination with cimetidine, a 30% response rate has been achieved. Recombinant alpha interferons give responses of 15%-20% in advanced melanomas, and combination with cimetidine does not enhance the response rate. Recombinant alpha interferons have been used in combination with other interferons, cimetidine, monoclonal antibodies, and cytotoxics, with either no or small improvement in response rates. DTIC with recombinant interferon alpha-2a has been shown to produce objective response rates of 26%, with low toxicity and maintenance of quality of life. A randomized trial with DTIC as the sole agent, compared with combination treatment, is being conducted to determine the significance of this finding.

Recombinant interferon alfa-2a in advanced malignant melanoma. A phase I-II study in combination with DTIC.

There is a rising incidence of malignant melanoma world-wide and, despite major improvements in its early diagnosis and treatment, the 10-year death rate remains at 20-25%. Evidence that the immune system has a role in the control of melanoma growth has encouraged immunological intervention. The results of phase II trials of recombinant interferon alfa-2a in advanced melanoma justified further studies. A review of trials of various interferons used as sole agents showed an overall objective response rate of 16.3%, one-third of the responses being complete responses of long duration. The use of cimetidine together with recombinant interferon alfa-2a remains controversial. Trials of both beta- and gamma-interferons are incomplete and information on their effect in advanced melanoma is not yet available. Recombinant interferon alfa-2a in combination with chemotherapy is now being used in trials and the early results are encouraging. In a combined series from Brisbane and Newcastle, Australia involving 44 patients treated with recombinant interferon alfa-2a and DTIC, 13 objective responses including 6 complete responses have been obtained. These response rates compare favourably with those of earlier trials using interferon alone. Further work is necessary to determine the best combined dosage and method of administration for optimum immunobiological effect.

Adenovirus replication as an in vitro probe for drug sensitivity in human tumors.

The feasibility of using adenovirus 5 as an in vitro probe for chemosensitivity in short-term cultures of human tumors was evaluated using human melanoma cell lines and primary cultures of melanoma biopsies. A convenient immunoperoxidase method was developed for quantitating viral replication 2 days after infection. Two different approaches were explored: the host cell reactivation assay (HCR) using drug-treated virus; and the viral capacity assay using drug-treated cells. The HCR assay detected sensitivity to 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC) in Mer- (methyl excision repair deficient) cell lines as decreased ability of the cells to replicate MTIC-treated virus. This test should be applicable to DNA-damaging agents and repair-deficient tumors. Adenovirus replicated readily in nonproliferating primary cultures of melanoma biopsies; application of the HCR assays to this material identified one Mer- sample of 11 tested. Herpes viruses were not suitable for use in HCR because herpes simplex virus type 1 failed to distinguish Mer- from Mer+ melanoma cells; and nonproductive infection of MTIC-sensitive lymphoid cells with Epstein-Barr virus yielded an MTIC-resistant cell line. The second assay (viral capacity) involved determination of the inhibition of replication of untreated virus in treated cells. This approach correctly predicted sensitivity to hydroxyurea and deoxyadenosine in melanoma cell lines when compared with clonogenic survival assay. Viral capacity was also inhibited by cytosine arabinoside, fluorouracil, vincristine, adriamycin, 6-mercaptopurine and ionising radiation, and may therefore be useful for detecting sensitivity to a wide range of antitumor agents.