Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial.

BACKGROUND: Adjuvant radiotherapy is recommended for patients with melanoma after lymphadenectomy. We previously showed this treatment reduced risk of repeat lymph-node field cancer in patients with a high risk of recurrence but had no effect on overall survival. Here, we aim to update the relapse and survival data from that trial and assess quality of life and toxic effects. METHODS: In the ANZMTG 01.02/TROG 02.01 randomised controlled trial, we enrolled patients who had undergone lymphadenectomy for a palpable lymph-node field relapse and were at high risk of recurrence at 16 hospitals (11 in Australia, three in New Zealand, one in Netherlands, and one in Brazil). We randomly assigned patients (1:1) to adjuvant radiotherapy (48 Gy in 20 fractions, given over a maximum of 30 days) or observation, stratified by institution, areas of lymph-node field (parotid and cervical, axilla, or groin), number of involved nodes (≤3 vs >3), maximum involved node diameter (≤4 cm vs >4 cm), and extent of extracapsular extension (none, limited, or extensive). Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocation, but participants were unaware of each other's treatment allocation. In this follow-up, we assessed outcomes every 3 months from randomisation for the first 2 years, then every 6 months up to 5 years, then annually. The primary endpoint was lymph-node field relapse as a first relapse, assessed in patients without major eligibility infringements (determined by an independent data monitoring committee). We assessed late adverse effects (occurring >90 days after surgery or start of radiotherapy) with standard criteria in the as-treated population. This study is registered with ClinicalTrials.gov, number NCT00287196. FINDINGS: Between March 21, 2003, and Nov 15, 2007, we randomly assigned 123 patients to adjuvant radiotherapy (109 eligible for efficacy assessments) and 127 to observation (108 eligible). The final follow-up date was Nov 15, 2011. Median follow-up was 73 months (IQR 61-91). 23 (21%) relapses occurred in the adjuvant radiotherapy group compared with 39 (36%) in the observation group (adjusted hazard ratio [HR] 0·52 [95% CI 0·31-0·88], p=0·023). Overall survival (HR 1·27 [95% CI 0·89-1·79], p=0·21) and relapse-free survival (0·89 [0·65-1·22], p=0·51) did not differ between groups. Minor, long-term toxic effects from radiotherapy (predominantly pain, and fibrosis of the skin or subcutaneous tissue) were common, and 20 (22%) of 90 patients receiving adjuvant radiotherapy developed grade 3-4 toxic effects. 18 (20%) of 90 patients had grade 3 toxic effects, mainly affecting skin (nine [10%] patients) and subcutaneous tissue (six [7%] patients). Over 5 years, a significant increase in lower limb volumes was noted after adjuvant radiotherapy (mean volume ratio 15·0%) compared with observation (7·7%; difference 7·3% [95% CI 1·5-13·1], p=0·014). No significant differences in upper limb volume were noted between groups. INTERPRETATION: Long-term follow-up supports our previous findings. Adjuvant radiotherapy could be useful for patients for whom lymph-node field control is a major issue, but entry to an adjuvant systemic therapy trial might be a preferable first option. Alternatively, observation, reserving surgery and radiotherapy for a further recurrence, might be an acceptable strategy. FUNDING: National Health and Medical Research Council of Australia, Cancer Council Australia, Melanoma Institute Australia, and the Cancer Council South Australia.

Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial.

BACKGROUND: The use of radiotherapy after therapeutic lymphadenectomy for patients with melanoma at high risk of further lymph-node field and distant recurrence is controversial. Decisions for radiotherapy in this setting are made on the basis of retrospective, non-randomised studies. We did this randomised trial to assess the effect of adjuvant radiotherapy on lymph-node field control in patients who had undergone therapeutic lymphadenectomy for metastatic melanoma in regional lymph nodes. METHODS: This randomised controlled trial included patients from 16 hospitals in Australia, New Zealand, the Netherlands, and Brazil. To be eligible for this trial, patients had to be at high risk of lymph-node field relapse, judged on the basis of number of nodes involved, extranodal spread, and maximum size of involved nodes. After lymphadenectomy, randomisation was done centrally by computer and patients assigned by telephone in a ratio of 1:1 to receive adjuvant radiotherapy of 48 Gy in 20 fractions or observation, with institution, lymph-node field, number of involved nodes, maximum node diameter, and extent of extranodal spread as minimisation factors. Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocation. The primary endpoint was lymph-node field relapse (as a first relapse), analysed for all eligible patients. The study is registered at ClinicalTrials.gov, number NCT00287196. The trial is now closed and follow-up discontinued. FINDINGS: 123 patients were randomly allocated to the adjuvant radiotherapy group and 127 to the observation group between March 20, 2002, and Sept 21, 2007. Two patients withdrew consent and 31 had a major eligibility infringement as decided by the independent data monitoring committee, resulting in 217 eligible for the primary analysis (109 in the adjuvant radiotherapy group and 108 in the observation group). Median follow-up was 40 months (IQR 27-55). Risk of lymph-node field relapse was significantly reduced in the adjuvant radiotherapy group compared with the observation group (20 relapses in the radiotherapy group vs 34 in the observation group, hazard ratio [HR] 0·56, 95% CI 0·32-0·98; p=0·041), but no differences were noted for relapse-free survival (70 vs 73 events, HR 0·91, 95% CI 0·65-1·26; p=0·56) or overall survival (59 vs 47 deaths, HR 1·37, 95% CI 0·94-2·01; p=0·12). The most common grade 3 and 4 adverse events were seroma (nine in the radiotherapy group vs 11 in the observation group), radiation dermatitis (19 in the radiotherapy group), and wound infection (three in the radiotherapy group vs seven in the observation group). INTERPRETATION: Adjuvant radiotherapy improves lymph-node field control in patients at high risk of lymph-node field relapse after therapeutic lymphadenectomy for metastatic melanoma. Adjuvant radiotherapy should be discussed with patients at high risk of relapse after lymphadenectomy. FUNDING: National Health and Medical Research Council of Australia, Cancer Australia, Melanoma Institute Australia, Cancer Council of South Australia.

Merkel cell carcinoma: 27-year experience at the Peter MacCallum Cancer Centre.

PURPOSE: To retrospectively evaluate the treatment outcome of patients with Merkel cell carcinoma after local and/or regional treatment. METHODS AND MATERIALS: Patients presenting to our center between January 1980 and July 2006 with Merkel cell carcinoma and without distant metastases were reviewed. The primary endpoint was locoregional control. Secondary endpoints were distant recurrence, survival and treatment toxicity. RESULTS: A total of 176 patients were identified. The median age was 79 years. The median follow-up was 2.2 years for all patients and 3.9 years for those alive at the last follow-up visit. The most common primary site was the head and neck (56%), and 62 patients(35%) had regional disease at presentation. The initial surgery to the primary tumor involved (wide) local excision in 140 patients and biopsy only in 28 patients (8 patients had no identifiable primary tumor); 33 patients underwent nodal surgery. Of the 176 patients, 165 (94%) underwent radiotherapy (RT) and 29 of them also underwent concurrent chemotherapy. The median radiation dose was 50 Gy (range, 18-60). Locoregional recurrence developed in 33 patients(19%), with a median interval to recurrence of 8 months. Distant metastases developed in 43 patients(24%). Age, primary tumor size, and RT (no RT vs. < 45 Gy vs. ≥ 45 Gy) were predictive of locoregional control on univariate analysis. However, only RT remained significant on multivariate analysis. The estimated 5-year actuarial rate for locoregional control, progression-free survival, and overall survival was 76%, 60%, and 45%, respectively. CONCLUSION: The locoregional control rate for Merkel cell carcinoma in our study was comparable to those from other series using combined modality treatment with RT an integral part of treatment.

The management of primary cutaneous melanoma in Victoria in 1996 and 2000.

OBJECTIVE: To describe tumour characteristics and clinical management of melanomas newly diagnosed in 1996 and in 2000--before and after publication of the clinical practice "Guidelines for the management of cutaneous melanoma" by the Australian Cancer Network (1997), and their endorsement by the National Health and Medical Research Council (NHMRC) and republication (1999). DESIGN AND SETTING: Survey of clinicians involved in the management of patients with melanoma sampled from the Victorian Cancer Registry. The Registry is notified of all cases of cancer diagnosed by pathology laboratories and hospitals in both the public and private health sectors in the state of Victoria. PATIENTS: People with a cutaneous melanoma newly diagnosed in 1996 and 2000. All invasive melanomas > 1.50 mm in thickness were included, and for each year random samples were selected of 100 each of invasive melanomas 0.76-1.50 mm in thickness, invasive melanomas < or = 0.75 mm, and in-situ melanomas, plus 50 melanomas of unknown thickness. MAIN OUTCOME MEASURES: Biopsy method, adequacy of pathology reporting, adequacy of definitive excision (compared with margins recommended by the Guidelines), and follow-up procedures. RESULTS: The use of partial biopsies increased between 1996 and 2000. Recommended margins of definitive excision were used in only 33.6% of cases. Margins were smaller than recommended for 36% of in-situ melanomas, risking recurrence of primary melanoma. Documented follow-up examinations for subsequent primary skin malignancy were uncommon (6%). CONCLUSIONS: Many aspects of the management of primary cutaneous melanoma appear not to meet the recommendations of the published Guidelines. Further studies to explore the reasons for failure to meet the Guideline recommendations are needed.

Concurrent adjuvant radiotherapy and interferon-alpha2b for resected high risk stage III melanoma -- a retrospective single centre study.

Interferon-alpha2b (IFNalpha2b) is the only form of systemic adjuvant therapy for stage III melanoma with documented survival benefit. Radiotherapy can also be utilized in the adjuvant setting in patients at high risk of nodal basin recurrence. As IFNalpha2b is associated with substantial toxicity, we sought to determine both the systemic and radiation-related toxicities in patients treated with combined adjuvant IFNalpha2b and regional adjuvant radiotherapy delivered in the setting of a single institution. Eighteen consecutive patients who commenced adjuvant IFNalpha2b between November 1997 and August 2002 were analysed retrospectively for toxicities associated with the combination of IFNalpha2b and adjuvant radiotherapy (40-50 Gy in 15-25 fractions) to nodal basins delivered during the maintenance phase of IFNalpha2b therapy (median dose during radiotherapy of 6.5 MU/m three times per week). Seven out of 18 patients who received concurrent radiotherapy and IFNalpha2b displayed grade 3 skin reactions. Severe radiation-induced toxicity was seen in three further patients, one who developed radiation pneumonitis, one who developed severe oral mucositis, and one who developed wound dehiscence that took 10 months to resolve. Non-radiation-related toxicity to IFNalpha2b therapy was typical for this dose and schedule. We conclude that concurrent use of adjuvant radiotherapy and IFNalpha2b may enhance radiation-induced toxicity. However, overall we found concurrent radiation and IFNalpha2b could be safely delivered with appropriate clinical monitoring.

High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group Study--TROG 96:07.

PURPOSE: The effectiveness of synchronous carboplatin, etoposide, and radiation therapy was prospectively assessed in a group of patients with high-risk Merkel cell carcinoma (MCC) of the skin. PATIENTS AND METHODS: Patients were eligible if they had disease localized to the primary site and nodes, and were required to have at least one of the following high risk features: recurrence after initial therapy, involved nodes, primary tumor size greater than 1 cm, gross residual disease after surgery, or occult primary with nodes. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks and synchronous carboplatin (area under the curve, 4.5) and intravenous etoposide 80 mg/m2 days 1 to 3 was given in weeks 1, 4, 7, and 10. The median age of the group was 67 (range, 43-86) years, and there were 39 males and 14 females. Involved nodes (stage II) were present in 33 cases (62%). The sites involved were head and neck (22 patients), occult primary (13 patients), upper limb (eight patients), lower limb (eight patients), and trunk (two patients). RESULTS: Fifty-three patients were entered between 1996 and 2001. The median potential follow-up was 48 months. There were no treatment related deaths. The 3-year overall survival, locoregional control, and distant control were 76%, 75%, and 76%, respectively. Tumor site and the presence of nodes were factors that were predictive for local control and survival. Multivariate analysis indicated that the major factor influencing survival was the presence of nodes; however, this was not a significant factor in locoregional control. CONCLUSION: High levels of locoregional control and survival have been achieved with the addition of chemotherapy to radiation treatment for high-risk MCC of the skin. The role of chemoradiotherapy for high-risk MCC warrants further investigation.