Jill Ainslie

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.

The role of radiotherapy in the management of primary cutaneous neuroendocrine tumors (merkel cell or trabecular carcinoma): Experience at the peter maccallum cancer institute (Melbourne, Australia)

Clinical presentation, treatment, and radiation response data are presented for 20 patients with primary cutaneous neuroendocrine tumors (Merkel cell or trabecular carcinoma). Thirty-six sites were irradiated, 26 sites were local recurrences after surgery or metastases, only 3 primary tumors were irradiated de novo. In 22 out of 23 sites (96%) a complete response of measurable tumor was observed and 1 partial response (4%), an overall response rate of 100%. Thirteen sites were irradiated prophylactically with no measurable disease present and no recurrences have been seen in these areas. There was only 1 recurrence in an irradiated site (after a low radiation dose). Forty percent (8/20) either had distant metastases at presentation (5 patients) or developed them after radiotherapy (3 patients) and five of these patients have died of metastatic disease. Follow-up time ranged from 1-77 months, and actuarial 5-year survival was 63%. In view of these findings we would advocate the wider study of primary radiotherapy after biopsy or excision biopsy for the primary lesion, and prophylactic nodal irradiation with the object of avoiding extensive surgery in these often elderly patients.

NODAL RADIATION THERAPY FOR METASTATIC MELANOMA

PURPOSE The aim of this retrospective study was to review our experience of radiation therapy to regional nodes in patients with proven nodal metastases, with respect to regional control, late toxicity, and overall survival. METHODS AND MATERIALS All patients with a histological diagnosis of malignant melanoma, with involvement of the regional nodes but without distant metastases, who commenced nodal irradiation between January 1985 and July 1995 at Peter MacCallum Cancer Institute were studied. The study population of 113 patients was divided into two categories: those with no residual macroscopic disease following nodal surgery (adjuvant group, 42 patients) and those who had no surgery (8) or had macroscopic residual disease following nodal surgery (63) (palliative group, 71 patients). RESULTS In the adjuvant group at 5 years following commencement of nodal irradiation 26% were estimated to be failure-free. Of the 74% who had experienced treatment failure by 5 years, an estimated 20% failed first with nodal relapse, 52% with distant metastases, and 2% with both nodal relapse and distant metastases. The estimated 5-year overall survival for this group was 33%. In the palliative group 16 patients (23%) had an objective complete response. Altogether 48 patients (68%) had a symptomatic response. At 5 years the overall survival in this group was 8% and an estimated 4% were failure-free. Of the 96% who had failed by 5 years, 68% failed first in the regional nodes, 25% had distant metastases as the first failure, and 3% had both nodal relapse and distant metastases. CONCLUSION We recommend adjuvant postoperative radiation therapy for patients with proven nodal metastases and high risk of regional recurrence (multiple nodes, extracapsular extension, or recurrent nodal disease) in addition to adjuvant interferon.

Treatment of nonmelanoma skin cancer at a large Australian center.

One thousand one hundred fifty‐four cases of nonmelanoma skin cancer (NMSC) referred to the Consultative Skin Clinic at Peter MacCallum Cancer Institute (PMCI) (Melbourne, Australia) in 1980 were reviewed. The median age was 68 years, and the male to female ratio was 1.5:1. Final diagnosis was basal cell carcinoma (BCC) in 901 patients (78%), squamous cell carcinoma (SCC) in 242 patients (21%), and basosquamous carcinoma in 11 patients (1%). Seven hundred twelve (62%) were biopsy proven. Comparison of clinical and histologic diagnoses showed that BCC were correctly diagnosed clinically in 85% of cases but only 53% of SCC were correctly diagnosed. The distribution of sites was as follows: head and neck 871 (75%), limbs 131 (11%), trunk 50 (4%), and multiple sites 102 (9%). One thousand eighty‐nine (94%) had primary lesions and 65 (6%) had recurrent lesions. The lesions were treated with surgery in 55% of cases, superficial radiotherapy in 39%, other types of radiotherapy in 3%, cryotherapy in 1%, and 5‐fluorouracil in 0.2%. Recurrent lesions, lesions on the eyelids, ears or nose, and T4 lesions were significantly associated with increased failure rates. Superficial radiotherapy was associated with a 2.3‐fold increase in failure rate compared to surgery when other prognostic factors were taken into account (P = 0.01, 95% confidence interval = 1.2–43). Nonsuperficial radiotherapy was associated with an 11.5‐fold increase in failure rate compared to surgery (P < 0.0001, 95% confidence interval = 4.9–27.1), but several of these cases were treated for palliative purposes only. The results of, and indications for treatment with surgery or radiotherapy at PMCI are discussed.

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.

Adjuvant radiotherapy and regional lymph node field control in melanoma patients after lymphadenectomy: Results of an intergroup randomized trial (ANZMTG 01.02/TROG 02.01)

LBA9084 Background: Adjuvant radiotherapy (RT) is an option for patients with isolated regional recurrence of melanoma considered to be at high risk of further regional recurrence after lymphadenectomy. This is the first completed study to assess the effects of RT on regional recurrence, survival, morbidity and quality of life (QOL) in these patients. METHODS Multicenter randomized study of patients with isolated regional recurrence at increased risk (>25%) of regional recurrence. Eligibile patients included ≥1 parotid, ≥ 2 cervical or axillary or ≥ 3 groin nodes or extra nodal spread of tumor or maximum metastatic node diameter ≥3cm in neck or axilla or ≥4cm in the groin. Patients were randomized to observation or regional nodal basin RT (48Gy in 20 fractions) after lymphadenectomy. Regional recurrence was the primary end point and morbidity, QOL, patterns of relapse, disease free and overall survival were secondary end points. The target sample size was 220 patients, which would enable a difference in 3 year regional relapse (cumulative incidence) rates of 30% versus 15% to be detected with a power of 80% (using a two sided logrank test at the 5% level of significance). RESULTS 250 pts were randomized from 16 centers from March 2002 to September 2007. There were 123 in the RT group and 127 in OBS group. 2 pts withdrew consent and 31 were excluded from analysis of the main objective following an independent blinded review of eligibility compliance by two reviewers. 227 pts were available for analysis of the main objective (109 RT, 108 OBS). Median follow-up was 27 mo. There was a statistically significant improvement in lymph node field control with radiotherapy, 20 RT pts and 34 OBS pts relapsed (HR 1.77 1.02-3.08 p=0.041). Median survival times were 2.6 years (RT) and 3.9 years (OBS) p=0.14. CONCLUSIONS Adjuvant RT improved regional control in melanoma patients at high risk of regional relapse after lymphadenectomy. An effect on survival was not demonstrated. No significant financial relationships to disclose.

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 others 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.

ANALYSIS OF TOXICITY OF MERKEL CELL CARCINOMA OF THE SKIN TREATED WITH SYNCHRONOUS CARBOPLATIN/ETOPOSIDE AND RADIATION: A TRANS-TASMAN RADIATION ONCOLOGY GROUP STUDY

PURPOSE The acute and late toxicities of synchronous carboplatin, etoposide, and radiation therapy were prospectively assessed in a group of patients with high-risk Merkel cell carcinoma of the skin. PATIENTS AND METHODS Forty patients from six different centers throughout Australia were entered into a Phase II study under the auspices of the Trans-Tasman Radiation Oncology Group. The trial was activated in 1996 and continues to accrue. Patients are eligible if they have disease localized to the primary site and nodes and are required to have at least one of the following high-risk features: recurrence after initial therapy, involved nodes, primary 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 curve [AUC] 4.5) and etoposide (80 mg/M(2) i.v.) were given on days 1-3 during weeks 1, 4, 7, and 10. The median age of the group was 67 years (43-78). RESULTS The median duration of follow-up was 22 months (2-45). There were no treatment-related deaths. Grade 3 or 4 skin toxicity occurred in 63% of patients (95% CI 48, 78). The most serious acute effect was on neutrophils with Grade 3 or 4 (neutrophils < 1 x 10(9)/L), occurring in 60% (95% CI 45, 75) of cases. Complications from neutropenia (fever and sepsis) occurred in 16 patients (40% of cases). The median time for neutropenic complications was 27 days (9-35), and 10/16 (62%) cases of neutropenic fever occurred after the second cycle of chemotherapy. The probability of Grade 3 or 4 late effects on platelets (<50 x 10(9)/L) and hemoglobin (<8 g/dl) was 10% (95% CI 1, 20) and 6% (95% CI 2, 15), respectively. Of the 40 patients, 35 were able to complete 4 cycles of chemotherapy. There were no factors predictive for neutropenic toxicity at a p value < 0.05. CONCLUSIONS The protocol has acceptable toxicity, and the treatment has been deliverable in a multi-institutional trial setting. Neutropenia is likely to occur with synchronous carboplatin/etoposide and radiation in this population of patients. The risk of a febrile neutropenia was greatest at the time of the second cycle of chemotherapy, when there was moist desquamation of skin or mucosal membranes that provided a portal for infection. This should be considered in the design of subsequent protocols with chemoradiotherapy.

Use of a radon mould technique for skin cancer: results from the Peter MacCallum Cancer Institute (1975–1984)

During the period from 1975 to 1984, 642 patients had non-melanoma skin cancers (NMSC) treated by a radon mould technique following the principles of the Manchester system. The results of 77 out of 642 (12%) with histologically verified lesions are presented. The sites of the lesions were as follows: head and neck 25 (32%), upper limbs 38 (49%), lower limbs 13 (17%) and trunk one case only. The histological diagnosis was squamous cell carcinoma 48 (62%), basal cell carcinoma in 22 (29%) and other in seven (9%). There were nine out of 77 (12%) failures, four with persistent disease, which did not clear after initial treatment (and for whom the radon mould was an inappropriate choice of technique), and five (6%) recurrences after clearance of the initial lesion. There was a sharp rise in failures after 1979 when there was a change of radon supplier, but no calibration error was substantiated. It is clearly beneficial for institutions to cross-check the manufacturers brachytherapy source data. There have been no further recurrences or any symptomatic late morbidity. This is a safe, effective and practical radiotherapeutic technique for superficial lesions (not exceeding a depth of 4 mm) in areas of poor radiation tolerance, and may obviate the need for a prolonged fractionated course of external-beam radiation in selected patients. Alternatives to radon are discussed.

Long-term prospective assessment of quality of life and lymphedema after inguinal or inguinal and pelvic lymphadenectomy for recurrent melanoma in the groin

Book Society of Surgical Oncology 69 Annual Cancer Symposium Boston, Massachusetts