Summary 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.
Summary 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.
Summary 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.
Abstract Introduction Preoperative chemotherapy (CT) and preoperative chemoradiation therapy (CRT) for resectable oesophageal cancer have been shown to improve overall survival in meta-analyses. ...There are limited data comparing these preoperative therapies. We report the outcomes of a randomised phase II trial comparing preoperative CT and CRT for resectable adenocarcinoma of the oesophagus and gastro-oesophageal junction. Methods Patients were randomised to receive preoperative CT with cisplatin (80 mg/m2 ) and infusional 5 fluorouracil (1000 mg/m2 /d) on days 1 and 21, or preoperative CRT with the same drugs accompanied by concurrent radiation therapy commencing on day 21 of chemotherapy and the 5 fluorouracil reduced to 800 mg/m2 /d. The radiation dose was 35 Gy in 15 fractions over 3 weeks. The endpoints were toxicity, response rates, resection (R) status, progression-free survival (PFS), overall survival (OS) and quality of life. Results Seventy-five patients were enroled on the study: 36 received preoperative CT and 39 preoperative CRT. Toxicity was similar for CT and CRT. Eight patients (11%) did not proceed to resection. The histopathological response rate (CRT 31% versus CT 8%, p = 0.01) and R1 resection rate (CRT 0% versus CT 11%, p = 0.04) favoured those receiving CRT. The median PFS was 14 and 26 months for CT and CRT respectively ( p = 0.37). The median OS was 29 months for CT compared with 32 months for CRT ( p = 0.83). Conclusions Despite no difference in survival, the improvement from preoperative CRT with respect to margin involvement makes this treatment a reasonable option for bulky, locally advanced resectable adenocarcinoma of the oesophagus.
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.
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.
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;
= .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;
= .39). Local failure rate was lower after WBRT (20.0%
33.6%;
= .03). At 12 months, 41.5% of patients in the WBRT group and 51.4% of patients in the observation group had died (
= .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 (
= .32). WBRT was associated with more grade 1 to 2 acute toxicity.
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.
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).
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.
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).
Neoadjuvant chemotherapy conferred a better OS than surgery alone and should be considered in all anatomical location and histological subtypes.
•Preoperative chemotherapy leads to better overall survival.•Disease-free survival was better too.•No differences were seen between squamous cell carcinoma and adenocarcinoma.•Greater effect for tumour located in the gastro-oesophageal junction.•No differences in postoperative morbidity or mortality.
Abstract 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 (⩽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 ⩾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.
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.
Abstract Background and purpose To investigate the hypothesis that primary tumor volume is prognostic independent of T and N stages in patients with non-small cell lung cancer (NSCLC) treated by ...definitive radiotherapy. Materials and methods Multicenter prospective observational study. Patient eligibility: pathologically proven stage I–III non-small cell lung cancer planned for definitive radiotherapy (minimum 50 Gy in 20 fractions) using CT-based contouring. Volumes of the primary tumor and enlarged nodes were measured according to a standardized protocol. Survival was adjusted for the effect of T and N stage. Results There were 509 eligible patients. Five-year survival rates for tumor volume grouped by quartiles were, for increasing tumor volume, 22%, 14%, 15% and 21%. Larger primary tumor volume was associated with shorter survival (HR = 1.060 (per doubling); 95% CI 1.01–1.12; P = 0.029). However, after adjusting for the effects of T and N stage, there was no evidence for an association (HR = 1.029, 95% CI, 0.96–1.10, P = 0.39). There was evidence, however, that larger primary tumor volume was associated with an increased risk of dying, independently of T and N stage, in the first 18 months but not beyond. Conclusions In patients treated by non-surgical means we were unable to show that lung tumor volume, overall, provides additional prognostic information beyond the T and N stage (TNM, 6th edition). There is evidence, however, that larger primary tumor volume adversely affects outcome only within the first 18 months. Larger tumor size alone should not by itself exclude patients from curative (chemo)radiotherapy.
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