Bryan Burmeister

Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis

BACKGROUND Resectable oesophageal cancer is often treated with surgery alone or with preoperative (neoadjuvant) chemoradiotherapy or chemotherapy. We aimed to clarify the benefits of neoadjuvant chemoradiotherapy or chemotherapy versus surgery alone by a meta-analysis of randomised trial data. METHODS Eligible trials were identified first from earlier published meta-analyses and systematic reviews. We also used MEDLINE, Cancerlit, and EMBASE databases to identify additional studies and published abstracts from major scientific meetings since 1980. Only randomised studies with an analysis by an intention-to-treat principle were included, and searches were restricted to those databases citing articles in English. We used published hazard ratios if available or estimates from other survival data or survival curves. Treatment effects by type of tumour and treatment sequencing were also investigated. FINDINGS Ten randomised comparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1209) and eight of neoadjuvant chemotherapy versus surgery alone (n=1724) in patients with local operable oesophageal carcinoma were identified. The hazard ratio for all-cause mortality with neoadjuvant chemoradiotherapy versus surgery alone was 0.81 (95% CI 0.70-0.93; p=0.002), corresponding to a 13% absolute difference in survival at 2 years, with similar results for different histological tumour types: 0.84 (0.71-0.99; p=0.04) for squamous-cell carcinoma (SCC), and 0.75 (0.59-0.95; p=0.02) for adenocarcinoma. The hazard ratio for neoadjuvant chemotherapy was 0.90 (0.81-1.00; p=0.05), which indicates a 2-year absolute survival benefit of 7%. There was no significant effect on all-cause mortality of chemotherapy for patients with SCC (hazard ratio 0.88 [0.75-1.03]; p=0.12), although there was a significant benefit for those with adenocarcinoma (0.78 [0.64-0.95]; p=0.014). INTERPRETATION A significant survival benefit was evident for preoperative chemoradiotherapy and, to a lesser extent, for chemotherapy in patients with adenocarcinoma of the oesophagus. The findings provide an evidence-based framework for the use of neoadjuvant treatment in management decisions.

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.

Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial

BACKGROUND Resection remains the best treatment for carcinoma of the oesophagus in terms of local control, but local recurrence and distant metastasis remain an issue after surgery. We aimed to assess whether a short preoperative chemoradiotherapy regimen improves outcomes for patients with resectable oesophageal cancer. METHODS 128 patients were randomly assigned to surgery alone and 128 patients to surgery after 80 mg/m(2) cisplatin on day 1, 800 mg/m(2) fluorouracil on days 1-4, with concurrent radiotherapy of 35 Gy given in 15 fractions. The primary endpoint was progression-free survival. Secondary endpoints were overall survival, tumour response, toxic effects, patterns of failure, and quality of life. Analysis was done by intention to treat. FINDINGS Neither progression-free survival nor overall survival differed between groups (hazard ratio [HR] 0.82 [95% CI 0.61-1.10] and 0.89 [0.67-1.19], respectively). The chemoradiotherapy-and-surgery group had more complete resections with clear margins than did the surgery-alone group (103 of 128 [80%] vs 76 of 128 [59%], p=0.0002), and had fewer positive lymph nodes (44 of 103 [43%] vs 69 of 103 [67%], p=0.003). Subgroup analysis showed that patients with squamous-cell tumours had better progression-free survival with chemoradiotherapy than did those with non-squamous tumours (HR 0.47 [0.25-0.86] vs 1.02 [0.72-1.44]). However, the trial was underpowered to determine the real magnitude of benefit in this subgroup. INTERPRETATION Preoperative chemoradiotherapy with cisplatin and fluorouracil does not significantly improve progression-free or overall survival for patients with resectable oesophageal cancer compared with surgery alone. However, further assessment is warranted of the role of chemoradiotherapy in patients with squamous-cell tumours.

Randomized Trial of Short-Course Radiotherapy Versus Long-Course Chemoradiation Comparing Rates of Local Recurrence in Patients With T3 Rectal Cancer: Trans-Tasman Radiation Oncology Group Trial 01.04

PURPOSE To compare the local recurrence (LR) rate between short-course (SC) and long-course (LC) neoadjuvant radiotherapy for rectal cancer. PATIENTS AND METHODS Eligible patients had ultrasound- or magnetic resonance imaging-staged T3N0-2M0 rectal adenocarcinoma within 12 cm from anal verge. SC consisted of pelvic radiotherapy 5 × 5 Gy in 1 week, early surgery, and six courses of adjuvant chemotherapy. LC was 50.4 Gy, 1.8 Gy/fraction, in 5.5 weeks, with continuous infusional fluorouracil 225 mg/m(2) per day, surgery in 4 to 6 weeks, and four courses of chemotherapy. RESULTS Three hundred twenty-six patients were randomly assigned; 163 patients to SC and 163 to LC. Median potential follow-up time was 5.9 years (range, 3.0 to 7.8 years). Three-year LR rates (cumulative incidence) were 7.5% for SC and 4.4% for LC (difference, 3.1%; 95% CI, -2.1 to 8.3; P = .24). For distal tumors (< 5 cm), six of 48 SC patients and one of 31 LC patients experienced local recurrence (P = .21). Five-year distant recurrence rates were 27% for SC and 30% for LC (log-rank P = 0.92; hazard ratio [HR] for LC:SC, 1.04; 95% CI, 0.69 to 1.56). Overall survival rates at 5 years were 74% for SC and 70% for LC (log-rank P = 0.62; HR, 1.12; 95% CI, 0.76 to 1.67). Late toxicity rates were not substantially different (Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer G3-4: SC, 5.8%; LC, 8.2%; P = .53). CONCLUSION Three-year LR rates between SC and LC were not statistically significantly different; the CI for the difference is consistent with either no clinically important difference or differences in favor of LC. LC may be more effective in reducing LR for distal tumors. No differences in rates of distant recurrence, relapse-free survival, overall survival, or late toxicity were detected.

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.

Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial

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/m(2)) and infusional 5 fluorouracil (1000 mg/m(2)/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/m(2)/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 enrolled 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.

Results of a prospective study of positron emission tomography–directed management of residual nodal abnormalities in node‐positive head and neck cancer after definitive radiotherapy with or without systemic therapy

The purpose of this study was to present our prospectively evaluated positron emission tomography (PET)‐directed policy for managing the neck in node‐positive head and neck squamous cell carcinoma (N+HNSCC) after definitive radiotherapy (RT) with or without concurrent systemic therapy.

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.

Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: Systematic review with meta-analysis combining individual patient and aggregate data

BACKGROUND The prognosis of patients with gastroesophageal adenocarcinoma is poor. There is conflicting evidence regarding effects of preoperative chemotherapy on survival and other outcomes. METHODS We conducted a meta-analysis with aggregate and individual patient data (IPD) to assess the effect of preoperative chemotherapy for gastroesophageal adenocarcinoma on survival and other outcomes. Two independent reviewers identified eligible randomised controlled trials (RCTs) comparing chemotherapy+/-radiotherapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma. IPD was solicited from all trials. Meta-analyses were performed using the two stage method. RESULTS We identified 14 RCTs (2422 patients). For eight RCTs (1049 patients; 43.3%) we obtained IPD. Preoperative chemotherapy was associated with longer overall survival (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.73-0.89; p<0.0001). There were larger treatment effects in tumours of the gastroesophageal junction and for chemoradiotherapy compared to chemotherapy, but the tests for subgroup differences were not statistically significant. Preoperative chemotherapy was associated with longer disease-free survival, higher likelihood of R0 resection and more favourable post-treatment tumour stage, but not perioperative complications. CONCLUSION Preoperative chemotherapy for locoregional gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should be offered to all eligible patients. There appear to be larger survival advantages in tumours of the gastroesophageal junction and for chemoradiotherapy, but these findings require prospective confirmation.

Positron emission tomography and pathological evidence of response to neoadjuvant therapy in adenocarcinoma of the esophagus

Our aim was to determine if fluorodeoxyglucose positron emission tomography (FDG-PET) could be correlated with a pathological response in patients with esophageal adenocarcinoma receiving neoadjuvant chemotherapy and/or chemoradiation therapy. Patients with resectable, histologically proven adenocarcinoma of the esophagus were entered in the study. Preoperative chemotherapy comprised two cycles of cisplatin and 5-fluorouracil. Radiation therapy commenced with the second cycle on day 22. FDG-PET images were obtained pre-treatment and on completion of intended neo-adjuvant treatment. Quantification was achieved by the calculation of both standardized uptake values (SUV) and tumor/liver ratios (TLR). Evidence of histopathological response was identified according to the Mandard tumor regression scoring system. There were 45 patients, 22 receiving neoadjuvant chemotherapy and 23 chemoradiation therapy. Forty patients underwent surgical resection. Seven patients (16%) had a histopathological response. The mean percentage change in SUV in the histological responders group was -56.8% (SD 29) and in the non-responders -27.8% (SD 32.1) (P = 0.035). The mean percentage change in TLR was -49.1% (SD 44.8) in the responders and in the non-responders -27.3% (SD 31.3) (P = 0.128). There was no difference between the two methods of assessment, however there was less variation with SUV. There was no correlation between the FDG-PET response and the histopathological response. Presently an FDG-PET scan performed 3-6 weeks after neoadjuvant therapy for adenocarcinoma of the esophagus should not be used as a marker of the potential result of the treatment. The optimal timing of a second FDG-PET remains unclear.