Neoadjuvant chemotherapy or chemoradiotherapy for adenocarcinoma of the esophagus.

BACKGROUND: The optimal treatment strategy for patients with esophageal adenocarcinoma (EAC) remains undetermined. This study compared outcomes in patients undergoing neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) for EAC. METHODS: Patients who underwent nCT or nCRT followed by surgery for EAC were identified from a prospective database (2000-2017) and included. After propensity score matching, the impact of the treatments on postoperative complications, in-hospital mortality, pathological outcomes, and survival rates were compared. RESULTS: Of the 396 eligible patients, 262 patients were analysed following matching with 131 patients in both groups. There were no significant differences between the nCT and nCRT groups for overall complications (59% vs 57%, P = 0.802) or in-hospital mortality (2% vs 0%, P = 0.156). Patients who had nCRT had more R0 resections (93% vs 83%, P = 0.013), and higher pathological complete response rates (15% vs 5%, P < 0.001). No differences in 5-year overall survival rates (nCT vs nCRT; 44% vs 33%, P = 0.645) were found. CONCLUSION: In this study no differences between nCT and nCRT were seen in postoperative complications and in-hospital mortality in patients treated for EAC. Inspite of improved complete resection and pathological response there was no difference in the overall survival between the treatment modalities.

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.

Utility of 30-day mortality as a quality metric for palliative radiation treatment: A population-based analysis from Queensland, Australia.

INTRODUCTION: Palliative radiotherapy (PRT) is frequently used to treat symptoms of advanced cancer, however benefits are questionable when life expectancy is limited. The 30-day mortality rate after PRT is a potential quality indicator, and results from a recent meta-analysis suggest a benchmark of 16% as an upper limit. In this population-based study from Queensland, Australia, we examined 30-day mortality rates following PRT and factors associated with decreased life expectancy. METHODS: Retrospective population data from Queensland Oncology Repository was used. Study population data included 22,501 patients diagnosed with an invasive cancer who died from any cause between 2008 and 2017 and had received PRT. Thirty-day mortality rates were determined from the date of last PRT fraction to date of death. Cox proportional hazards models were used to identify factors independently associated with risk of death within 30 days of PRT. RESULTS: Overall 30-day mortality after PRT was 22.2% with decreasing trend in more recent years (P = 0.001). Male (HR = 1.20, 95% CI = 1.13-1.27); receiving 5 or less radiotherapy fractions (HR = 2.97, 95% CI = 2.74-3.22 and HR = 2.17, 95% CI = 2.03-2.32, respectively) and receiving PRT in a private compared to public facility (HR = 1.61, 95% CI = 1.51-1.71) was associated with decreased survival. CONCLUSION: The 30-day mortality rate in Queensland following PRT is higher than expected and there is scope to reduce unnecessarily protracted treatment schedules. We encourage other Australian and New Zealand centres to examine and report their own 30-day mortality rate following PRT and would support collaboration for 30-day mortality to become a national and international quality metric for radiation oncology centres.

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.

Longitudinal trajectory of quality of life for patients with melanoma brain metastases: A secondary analysis from a whole brain radiotherapy randomized clinical trial.

Purpose: Brain metastases are common in patients with advanced melanoma. This study describes 12-month quality of life (QoL) trajectories following local management of 1-3 melanoma brain metastases. Methods: This study assessed QoL data collected during a multi-center, prospective, open-label, phase III randomized controlled trial comparing the efficacy of adjuvant whole brain radiotherapy (WBRT) with observation after local treatment of 1-3 melanoma brain metastases. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Core (QLQ-C30) and Brain Tumour (BN-20) questionnaires at baseline and every 2 months, for 12 months.Using growth mixture modelling, QoL trajectories were identified for global health status, QLQ-C30 and BN-20 subscales for patients with baseline and at least one follow-up assessment. Multivariable logistic regression was used to examine associations between trajectories, demographic, and clinical factors. Results: After combining QoL data from observation and WBRT arms, QLQ-C30 and BN-20 trajectories were calculated for 139 and 137 patients respectively. Depending on the QoL domain, 9-54 % of patients reported a deterioration in QoL. Older age (≥65 years) was significantly associated with deterioration in global health status (OR = 2.88, 95 %CI = 1.27-6.54), physical (OR = 3.49, 95 %CI = 1.29-9.41), role (OR = 4.15, 95 %CI = 1.77-9.71), social (OR = 4.42, 95 % CI = 1.57-12.46), cognitive (OR = 6.70, 95 % CI = 1.93-23.29) and motor functioning (OR = 4.95, 95 %CI = 1.95-12.61) and increased future uncertainty (OR = 0.20, 95 %CI = 0.07-0.53). Female sex (OR = 0.10, 95 %CI = 0.02-0.41), not having neurosurgery at baseline (OR = 0.09, 95 %CI = 0.02-0.52), 2-3 brain metastases (OR = 5.75, 95 %CI = 1.76-18.85) or receiving adjuvant WBRT (OR = 6.77, 95 %CI = 2.00-22.99) were associated with poorer physical, emotional, cognitive and social outcomes respectively. Conclusions: Poorer QoL outcomes in the first 12 months after diagnosis of melanoma brain metastases were observed in patients aged ≥ 65 years, females, having 2-3 brain metastases, non-surgical treatment of metastases or adjuvant WBRT.Clinical Trial Registration Number:Whole Brain Radiotherapy Trial (WBRTMel) was registered with the Australian Clinical Trials Registry (ACTRN12607000512426) and ClinicalTrials.gov (NCT01503827).Study Support:This project was funded by Cancer Australia PdCCRS (Grants No. 512358, 1009485, and 1084046) and the National Helath and Medical Research Coucil of Australia (NHMRC; Grant No. 1135285).ADT was supported by a Cancer Australia Priority-driven Collaborative Cancer Research Scheme. Project #1046923. RLM was supported by an NHMRC Fellowship #1194703 and a University of Sydney, Robinson Fellowship. JFT was supported by an NHMRC Program Grant #1093017.

Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis.

BACKGROUND: In a previous meta-analysis, we identified a survival benefit from neoadjuvant chemotherapy or chemoradiotherapy before surgery in patients with resectable oesophageal carcinoma. We updated this meta-analysis with results from new or updated randomised trials presented in the past 3 years. We also compared the benefits of preoperative neoadjuvant chemotherapy compared with neoadjuvant chemoradiotherapy. METHODS: To identify additional studies and published abstracts from major scientific meetings, we searched Medline, Embase, and Central (Cochrane clinical trials database) for studies published since January, 2006, and also manually searched for abstracts from major conferences from the same period. Only randomised studies analysed by intention to treat were included, and searches were restricted to those databases citing articles in English. We used published hazard ratios (HRs) if available or estimates from other survival data. We also investigated treatment effects by tumour histology and relations between risk (survival after surgery alone) and effect size. FINDINGS: We included all 17 trials from the previous meta-analysis and seven further studies. 12 were randomised comparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1854), nine were randomised comparisons of neoadjuvant chemotherapy versus surgery alone (n=1981), and two compared neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy (n=194) in patients with resectable oesophageal carcinoma; one factorial trial included two comparisons and was included in analyses of both neoadjuvant chemoradiotherapy (n=78) and neoadjuvant chemotherapy (n=81). The updated analysis contained 4188 patients whereas the previous publication included 2933 patients. This updated meta-analysis contains about 3500 events compared with about 2230 in the previous meta-analysis (estimated 57% increase). The HR for all-cause mortality for neoadjuvant chemoradiotherapy was 0.78 (95% CI 0.70-0.88; p<0.0001); the HR for squamous-cell carcinoma only was 0.80 (0.68-0.93; p=0.004) and for adenocarcinoma only was 0.75 (0.59-0.95; p=0.02). The HR for all-cause mortality for neoadjuvant chemotherapy was 0.87 (0.79-0.96; p=0.005); the HR for squamous-cell carcinoma only was 0.92 (0.81-1.04; p=0.18) and for adenocarcinoma only was 0.83 (0.71-0.95; p=0.01). The HR for the overall indirect comparison of all-cause mortality for neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy was 0.88 (0.76-1.01; p=0.07). INTERPRETATION: This updated meta-analysis provides strong evidence for a survival benefit of neoadjuvant chemoradiotherapy or chemotherapy over surgery alone in patients with oesophageal carcinoma. A clear advantage of neoadjuvant chemoradiotherapy over neoadjuvant chemotherapy has not been established. These results should help inform decisions about patient management and design of future trials. FUNDING: Cancer Australia and the NSW Cancer Institute.

Individual patient data meta-analysis of neoadjuvant chemotherapy followed by surgery versus upfront surgery for carcinoma of the oesophagus or the gastro-oesophageal junction.

INTRODUCTION: Which neoadjuvant treatment for locally advanced thoracic oesophagus (TE) or gastro-oesophageal junction carcinoma is best remains an open question. Randomised controlled trials variously accrued patients with adenocarcinoma and squamous cell carcinoma, making strong conclusions hard to obtain. The primary objective of this individual participant data meta-analysis was to investigate the effect of neoadjuvant chemotherapy on overall survival (OS). PATIENTS AND METHODS: Eligible trials should have closed to accrual before 2016 and compared neoadjuvant chemotherapy and surgery (CS) to surgery alone. All relevant published and unpublished trials were identified via searches of electronic databases, conference proceedings and clinical trial registers. The main end-point was OS. Investigators were contacted to obtain the individual patient data, which was recorded, harmonised and checked. A random-effects Cox model, stratified by trial, was used for meta-analysis and subgroup analyses were preplanned. RESULTS: 16 trials were identified as eligible. Individual patient data were obtained from 12 trial and 2478 patients. CS was associated with an improved OS versus surgery, hazard ratio (HR) = 0.83 [0.72-0.96], p < 0.0001, translating to an absolute benefit of 5.7% at 5-years from 16.8% to 22.5%. Treatment effects did not vary substantially between adenocarcinoma (HR = 0.73 [0.62-0.87]) and squamous cell carcinoma (HR = 0.91 [0.76-1.08], interaction p = 0.26). A somewhat more pronounced effect was observed in gastro-oesophageal junction (HR = 0.68 [0.50-0.93]) versus TE (HR = 0.87 [0.75-1.00], interaction p = 0.07). CS was also associated with a greater disease-free survival (HR = 0.74 [0.64-0.85], p < 0.001). CONCLUSIONS: Neoadjuvant chemotherapy conferred a better OS than surgery alone and should be considered in all anatomical location and histological subtypes.

Enhanced toxicity with concurrent cetuximab and radiotherapy in head and neck cancer.

PURPOSE: To report toxicity data from the first 13 consecutive patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), ineligible for cisplatin, treated with concurrent cetuximab and radiotherapy (RT) at our institution. MATERIALS AND METHODS: Data were collected prospectively between August 2007 and May 2008. Planned treatment consisted of a cetuximab loading dose (400mg/m(2)) via intravenous infusion 1 week prior and then weekly (250mg/m(2)) with 70Gy in 35 daily fractions over 7 weeks. RESULTS: Median age was 68 years (range 52-82 years). The predominant primary sites were hypopharyngeal (5) and oropharyngeal (5). Ineligibility for cisplatin consisted of renal impairment (5), hearing impairment (4) and of other major co-morbidities (4). Of the 13 patients, 10 (77%) had grade 3/4 skin reactions and 10 (77%) grade 3/4 mucositis. Six (46%) patients required admission for management of severe skin reactions and/or mucositis with 4 (31%) requiring a treatment break, median 10 days (9-15days). Only 4 (31%) patients managed to complete the planned 8 cycles of cetuximab. Of the 9 patients with 12-week post-therapy data, 7 (78%) achieved a complete response. CONCLUSIONS: Our early experience with cetuximab/RT has demonstrated a higher rate of toxicity compared with the recently reported randomised trial, resulting in low treatment compliance and delays in completing RT.

A phase II trial of chemoradiation therapy with weekly oxaliplatin and protracted infusion of 5-fluorouracil for esophageal cancer.

BACKGROUND: Chemoradiation therapy using regimens containing cisplatin and 5-fluorouracil are most commonly used for inoperable cancer of the esophagus. Cisplatin is relatively toxic and is not suitable for many patients. Little data exists using platinum analogues together with protracted infusion 5-fluorouracil and radiation therapy in the curative setting. METHODS: Fourteen patients with localised oesophageal cancer suitable for curative chemoradiation therapy registered on the study. Chemotherapy consisted of 5-fluorouracil 225 mg/m(2) daily throughout radiation therapy, with oxaliplatin 60 mg/m(2) weekly. The radiation dose was 56 to 60 Gy in 28 to 30 fractions. RESULTS: The median age of the patients was 70.5 years. Therapy was associated with excessive grade 3 and 4 non-hematologic toxicity. There was one treatment related death. The median progression-free survival was 31.5 months and median overall survival 32.6 months. Six patients achieved a prolonged complete endoscopic and radiological response. CONCLUSIONS: Although weekly oxaliplatin in combination with infusional 5 fluorouracil produces durable remissions in esophageal cancer, the regimen used in this trial was not acceptable for routine use. Future protocols should incorporate lower chemotherapy doses.

Whole brain radiotherapy (WBRT) after local treatment of brain metastases in melanoma patients: Statistical Analysis Plan.

BACKGROUND: The WBRTMel trial is a multinational, open-label, phase III randomised controlled trial comparing whole brain radiotherapy (WBRT) to observation following local treatment of one to three melanoma brain metastases with surgery and/or stereotactic irradiation. The primary trial endpoint was to determine the effect of adding WBRT to local treatment on distant intracranial control, and the secondary endpoints were neurocognitive function, quality of life (QoL), performance status, overall survival, death from intracranial causes, death from melanoma and cost-effectiveness. OBJECTIVE: The objective of this update is to outline and publish the pre-determined statistical analysis plan (SAP) before the database lock and the start of analysis. METHODS: The SAP describes basic analysis principles, methods for dealing with a range of commonly encountered data analysis issues and the specific statistical procedures for analysing efficacy and safety outcomes. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses regarding the clinical and QoL outcomes. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid analysis bias arising from knowledge of the data. RESULTS: The resulting SAP is consistent with best practice and will allow open and transparent reporting. CONCLUSION: We have developed a SAP for the WBRTMel trial which will be followed to ensure high-quality standards of internal validity to minimise analysis bias. TRIAL REGISTRATION: ANZ Clinical Trials Registry, ACTRN12607000512426 . Registered on 9 October 2007. ClinicalTrials.gov, NCT01503827 . Registered on 4 January 2012. Trial group reference numbers ANZMTG 01.07, TROG 08.05.

Adjuvant Whole-Brain Radiation Therapy Compared With Observation After Local Treatment of Melanoma Brain Metastases: A Multicenter, Randomized Phase III Trial.

PURPOSE: The brain is a common site of metastasis for patients with high-risk melanoma. Although surgery or stereotactic radiosurgery are highly effective local treatments for a small number of metastases, there is a high risk of developing additional brain metastases. The role of adjuvant whole-brain radiotherapy (WBRT) in reducing new metastases is controversial, with a lack of high-level evidence specifically for melanoma. METHODS: In this randomized phase III trial, patients who had local treatment of one to three melanoma brain metastases were randomly assigned to WBRT or observation. The primary end point was distant intracranial failure within 12 months, and secondary end points included time to intracranial failure, survival, and time to deterioration in performance status. RESULTS: Between April 2009 and September 2017, 215 patients were randomly assigned from 24 centers. Median follow-up was 48.1 months (range, 39.6 to 68 months). Forty-two percent of patients in the WBRT group and 50.5% of those in the observation developed distant intracranial failure within 12 months (odds ratio, 0.71; 95% CI, 0.41 to 1.23; P = .22) and the rates over the entire follow-up period were 52.0% and 57.9%, respectively (odds ratio, 0.79; 95% CI, 0.45 to 1.36; P = .39). Local failure rate was lower after WBRT (20.0% v 33.6%; P = .03). At 12 months, 41.5% of patients in the WBRT group and 51.4% of patients in the observation group had died (P = .28), with no difference in the rate of neurologic death. Median time to deterioration in performance status was 3.8 months after WBRT and 4.4 months with observation (P = .32). WBRT was associated with more grade 1 to 2 acute toxicity. CONCLUSION: After local treatment of one to three melanoma brain metastases, adjuvant WBRT does not provide clinical benefit in terms of distant intracranial control, survival, or preservation of performance status.

Role of functional imaging in head and neck squamous cell carcinoma: fluorodeoxyglucose positron emission tomography and beyond.

Positron emission tomography (PET) has emerged as an integral diagnostic tool in the management of head and neck squamous cell carcinoma (HNSCC). This article reviews the usefulness and ongoing dilemmas of fluorine-18 fluorodeoxyglucose (18-F FDG) PET and FDG PET/CT in HNSCC. In addition, it examines the potential role of novel markers and biologic characterization of disease, which in the future may assist in targeted therapeutic strategies.

Hypofractionated radiotherapy for the palliation of advanced head and neck cancer in patients unsuitable for curative treatment--"Hypo Trial".

BACKGROUND AND PURPOSE: The primary purpose of the trial was to assess rate of tumour response to a hypofractionated course of radiotherapy in patients with incurable squamous cell carcinoma of the head and neck (HNSCC). Secondary objectives included radiation toxicity, symptom control, quality of life (QoL) and progression-free and overall survival. PATIENTS AND METHODS: Patients were planned to receive 30 Gy in 5 fractions at 2/week, at least 3 days apart, with an additional boost of 6 Gy for small volume disease (< or =3 cm) in suitable patients. Thirty-seven patients were enrolled between August 2004 and March 2006. Median age was 68 (43-87) years, 81% were male and the predominant primary site was oropharynx (32%). The majority (73%) presented with Stage III-IV disease. RESULTS: Thirty-five patients received radiotherapy, 1 died prior to treatment and one refused treatment. Of the 35 patients receiving radiotherapy, 31 (88%) received > or =30 Gy. Of the 35 patients who received treatment the overall objective response was 80%. Grade 3 mucositis and dysphagia were experienced in 9/35 (26%) and 4/35 (11%), respectively. QoL and symptom control were assessable in 21 patients. Thirteen (62%) reported an overall improvement in QoL and 14 (67%) experienced an improvement in pain. The median time to progression and death was 3.9 and 6.1 months, respectively. CONCLUSION: The "Hypo Trial" regimen provided effective palliative treatment in HNSCC unsuitable for curative treatment. Compliance was excellent and resulted in high response rates, symptom control and improvement in QoL with acceptable toxicity. However, progression free and overall survival was short.

A prospective phase II study of adjuvant postoperative radiation therapy following nodal surgery in malignant melanoma-Trans Tasman Radiation Oncology Group (TROG) Study 96.06.

BACKGROUND: The role of adjuvant postoperative therapy after resection of localised malignant melanoma involving regional lymph nodes remains controversial. There are no randomised trials that confirm that postoperative radiation conveys a benefit in terms of regional control or survival. METHODS: Two hundred and thirty-four patients with melanoma involving lymph nodes were registered on a prospective study to evaluate the effect of postoperative radiation therapy. The regimen consisted of 48Gy in 20 fractions to the nodal basin using recommended treatment guidelines for each of the major node sites. The primary endpoints were regional in-field relapse and late toxicity. Secondary endpoints were adjacent relapse, distant relapse, overall survival, progression-free survival and time to in-field progression. RESULTS: Adjuvant radiation therapy was well tolerated by all of the patients. As the first site of relapse, regional in-field relapses occurred in 16/234 patients (6.8%). The overall survival was 36% at 5 years. The progression-free survival and regional control rates were 27% and 91%, respectively, at 5 years. Patients with more than 2 nodes involved had a significantly worse outcome in terms of distant relapse, overall and progression-free survival. CONCLUSION: We believe that adjuvant radiation therapy following nodal surgery could offer a possible benefit in terms of regional control. These results require confirmation in a randomised trial.

Whole brain irradiation following surgery or radiosurgery for solitary brain metastases: mature results of a prematurely closed randomized Trans-Tasman Radiation Oncology Group trial (TROG 98.05).

We evaluated the effect of adjuvant whole brain irradiation (WBI) after surgery or radiosurgery for solitary brain metastases in a Phase III multicentre trial with randomization to 30-36 Gy WBI or observation. The study was closed early due to slow accrual after 19 patients (WBI 10, observation 9). There was no difference in CNS failure-free survival or overall survival between the arms. There was a trend to reduced CNS relapse with WBI (30% versus 78%, P=0.12). Limited analysis of quality of life and neurocognitive function data revealed no evidence of difference between the arms. Our results are not inconsistent with two larger randomized trials and support the use of upfront WBI to decrease brain recurrence in this setting.

Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05).

BACKGROUND AND PURPOSE: Despite numerous randomized trials investigating radiotherapy (RT) fractionation schedules for painful bone metastases, there are very few data on RT for bone metastases causing pain with a neuropathic component. The Trans-Tasman Radiation Oncology Group undertook a randomized trial comparing the efficacy of a single 8 Gy (8/1) with 20 Gy in 5 fractions (20/5) for this type of pain. MATERIALS AND METHODS: Eligible patients had radiological evidence of bone metastases from a known malignancy with no change in systemic therapy within 6 weeks before or anticipated within 4 weeks after RT, no other metastases along the distribution of the neuropathic pain and no clinical or radiological evidence of cord/cauda equina compression. All patients gave written informed consent. Primary endpoints were pain response within 2 months of commencement of RT and time to treatment failure (TTF). The hypothesis was that 8/1 is at least as effective as 20/5 and the planned sample size was 270 patients. RESULTS: Between February 1996 and December 2002, 272 patients were randomized (8/1:20/5=137:135) from 15 centres (Australia 11, New Zealand 3, UK 1). The commonest primary cancers were lung (31%), prostate (29%) and breast (8%); index sites were spine (89%), rib (9%), other (2%); 72% of patients were males and the median age was 67 (range 29-89). The median overall survival (95% CI) for all randomized patients was 4.8 mo (4.2-5.7 mo). The intention-to-treat overall response rates (95% CI) for 8/1 vs 20/5 were 53% (45-62%) vs 61% (53-70%), P=0.18. Corresponding figures for complete response were 26% (18-34%) vs 27% (19-35%), P=0.89. The estimated median TTFs (95% CI) were 2.4 mo (2.0-3.3 mo) vs 3.7 mo (3.1-5.9 mo) respectively. The hazard ratio (95% CI) for the comparison of TTF curves was 1.35 (0.99-1.85), log-rank P=0.056. There were no statistically significant differences in the rates of re-treatment, cord compression or pathological fracture by arm. CONCLUSIONS: 8/1 was not shown to be as effective as 20/5, nor was it statistically significantly worse. Outcomes were generally poorer for 8/1, although the quantitative differences were relatively small.

Role of radiotherapy in the pre-operative management of carcinoma of the esophagus.

The use of radiotherapy in the management of carcinoma of the esophagus and gastro-esophageal junction has undergone much evolution over the past 2 decades. Advances to define its role have been slow with meta-analyses often providing the most useful data. In spite of this many institutions around the world are divided about the role of radiotherapy in this disease and attribute different roles to radiotherapy based on clinical stage, tumor site and histology. The purpose of this review is to try to define the role of radiotherapy given our current knowledge base and to review which current and future trials may fill the gaps of knowledge that we currently have. It will also highlight the difficulties in making firm recommendations about the use of radiotherapy especially in a time when technology and treatments are rapidly evolving.

Long-term results of positron emission tomography-directed management of the neck in node-positive head and neck cancer after organ preservation therapy.

OBJECTIVES: The current study presents the long-term results from a study designed to evaluate a restaging positron emission tomography (PET) directed policy whereby neck dissections were omitted in all node positive head and neck squamous cell carcinoma (N+HNSCC) patients with PET-negative lymph nodes after definitive radiotherapy (RT), with or without chemotherapy. METHODS: A post-therapy nodal response assessment with PET and computed tomography (CT) was performed in patients who achieved a complete response at the primary site after definitive radiotherapy. Patients with PET-negative lymph nodes were observed regardless of residual CT abnormalities. RESULTS: One hundred and twelve patients, the majority of whom (83 patients, 74%) had oropharyngeal primaries, were treated on protocol. Median follow-up was 62months. Negative and positive predictive values for the restaging PET was 97.1% and 77.8% respectively, with only one patient who was PET-negative after treatment experiencing an isolated nodal relapse. CONCLUSION: PET-guided management of the neck following organ preservation therapy effectively spares neck dissections in patients with N+HNSCC without compromising isolated nodal control or overall survival.

Second primary oesophageal cancer following radiation for breast cancer.

The management of 12 women who presented with a second primary oesophageal cancer following radiotherapy for breast cancer was reviewed. It was concluded that nine cases fitted the classical description of a radiation-induced malignancy. Most cases were successfully managed with combined modality therapy in spite of their previous radiotherapy.