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Breugom A.J.,Leiden University | Swets M.,Leiden University | Bosset J.-F.,Besancon University Hospital njoz | Collette L.,European Organisation for Research | And 9 more authors.
The Lancet Oncology | Year: 2015

Background: The role of adjuvant chemotherapy for patients with rectal cancer after preoperative (chemo)radiotherapy and surgery is uncertain. We did a meta-analysis of individual patient data to compare adjuvant chemotherapy with observation for patients with rectal cancer. Methods: We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library, CENTRAL, and conference abstracts to identify European randomised, controlled, phase 3 trials comparing observation with adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with non-metastatic rectal cancer. The primary endpoint of interest was overall survival. Findings: We analysed data from four eligible trials, including data from 1196 patients with (y)pTNM stage II or III disease, who had an R0 resection, had a low anterior resection or an abdominoperineal resection, and had a tumour located within 15 cm of the anal verge. We found no significant differences in overall survival between patients who received adjuvant chemotherapy and those who underwent observation (hazard ratio [HR] 0.97, 95% CI 0.81-1.17; p=0.775); there were no significant differences in overall survival in subgroup analyses. Overall, adjuvant chemotherapy did not significantly improve disease-free survival (HR 0.91, 95% CI 0.77-1.07; p=0.230) or distant recurrences (0.94, 0.78-1.14; p=0.523) compared with observation. However, in subgroup analyses, patients with a tumour 10-15 cm from the anal verge had improved disease-free survival (0.59, 0.40-0.85; p=0.005, pinteraction=0.107) and fewer distant recurrences (0.61, 0.40-0.94; p=0.025, pinteraction=0.126) when treated with adjuvant chemotherapy compared with patients undergoing observation. Interpretation: Overall, adjuvant fluorouracil-based chemotherapy did not improve overall survival, disease-free survival, or distant recurrences. However, adjuvant chemotherapy might benefit patients with a tumour 10-15 cm from the anal verge in terms of disease-free survival and distant recurrence. Further studies of preoperative and postoperative treatment for this subgroup of patients are warranted. Funding: None. © 2015 Elsevier Ltd. Source

Diez P.,Mount Vernon Center for Cancer Treatment | Vogelius I.S.,Vejle Sygehus | Vogelius I.S.,University of Wisconsin - Madison | Bentzen S.M.,University of Wisconsin - Madison
International Journal of Radiation Oncology Biology Physics | Year: 2010

Purpose: A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high). Methods and Materials: Nine published prostate cancer dose escalation studies including 6,539 patients were identified in the MEDLINE and CINAHL databases and reviewed to assess the relationship between dose and biochemical control. A novel method of analysis is presented in which the normalized dose-response gradient, γ50, is estimated for each study and subsequently synthesized across studies. Our method does not assume that biochemical control rates are directly comparable between studies. Results: Nonrandomized studies produced a statistically significantly higher γ50 than randomized studies for intermediate- to high-risk patients (γ50 = 1.63 vs. γ50 = 0.93, p = 0.03) and a borderline significantly higher (γ50 = 1.78 vs. γ50 = 0.56, p = 0.08) for low-risk patients. No statistically significant difference in γ50 was found between low- and intermediate- to high-risk patients (p = 0.31). From the pooled data of low and intermediate- to high-risk patients in randomized trials, we obtain the overall best estimate of γ50 = 0.84 with 95% confidence interval 0.54-1.15. Conclusions: Nonrandomized studies overestimate the steepness of the dose-response curve as compared with randomized trials. This is probably the result of stage migration, improved treatment techniques, and a shorter follow-up in higher dose patients that were typically entered more recently. This overestimation leads to inflated expectations regarding the benefit from dose-escalation and could lead to underpowered clinical trials. There is no evidence of a steeper dose response for intermediate- to high-risk compared with low-risk patients. © 2010 Elsevier Inc. All rights reserved. Source

Glynne-Jones R.,Mount Vernon Center for Cancer Treatment
Recent Results in Cancer Research | Year: 2014

The limitation of the traditional method of stratifying patients with rectal cancer for prognosis using magnetic resonance imaging (MRI) and computerised tomography (CT) - TNM staging - is that cT3 tumors comprise the vast majority of rectal cancers. There is a wide variability in outcomes for cT3. Despite this observation, many still advocate routine short course preoperative radiotherapy (SCPRT) or chemoradiation (CRT) for all patients staged as cT3N0 regardless of tumour location, proximity to other structures or extent, despite the fact that advances in imaging with MRI now offer the ability to predict potential outcomes in terms of the risk of local and metastatic recurrence for the individual. Preoperative CRT is designed to reduce local recurrence. The majority of local recurrences historically reflected inadequate quality of the mesorectal resection. Currently, optimal quality-controlled surgery in terms of total mesorectal excision (TME) in the trial setting can be associated with much lower local recurrence rates of less than 10 % whether patients receive radiotherapy or not. Because of the high risk of metastatic disease in selected patients, integrating more active chemotherapy is now attractive. Chemoradiotherapy (CRT) achieves shrinkage and sometimes eradication of tumour - i.e. a pathological complete response (pCR), and reduces local recurrence, but has no impact on overall survival. CRT also increases surgical morbidity and impacts on anorectal, urinary and sexual function with an increased risk of second malignancies. Hence, the predominant aims of CRT have been to shrink/downstage a tumour to allow an R0 resection to be performed, or to increase the chances of performing sphincter-sparing surgery. However, it remains unclear why shrinkage/downstaging is meaningful to a patient unless the tumour is initially borderline resectable or unresectable (i.e. the CRM is threatened) or the aim is to perform a lesser operation (i.e. sphincter-sparing or local excision) or for organ-sparing, i.e. to avoid surgery altogether. If it is important to shrink the cancer - ie there is a predicted threat to the CRM, then CRT is currently the treatment of choice. If the cancer is resectable and the aim is simply to lower the risk of local recurrence and preoperative CRT does not impact on survival, can CRT be omitted in selected cases? The answer is yes - with the proviso that we are using good quality MRI and the surgeon is performing good quality TME surgery within the mesorectal plane. © 2014 Springer International Publishing Switzerland. Source

Chow E.,Odette Cancer Center | Hoskin P.,Mount Vernon Center for Cancer Treatment | Mitera G.,Odette Cancer Center | Zeng L.,Odette Cancer Center | And 6 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: To update the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases by surveying international experts regarding previous uncertainties within the 2002 consensus, changes that may be necessary based on practice pattern changes and research findings since that time. Methods and Materials: A two-phase survey was used to determine revisions and new additions to the 2002 consensus. A total of 49 experts from the American Society for Radiation Oncology, the European Society for Therapeutic Radiology and Oncology, the Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists, and the Canadian Association of Radiation Oncology who are directly involved in the care of patients with bone metastases participated in this survey. Results: Consensus was established in areas involving response definitions, eligibility criteria for future trials, reirradiation, changes in systemic therapy, radiation techniques, parameters at follow-up, and timing of assessments. Conclusion: An outline for trials in bone metastases was updated based on survey and consensus. Investigators leading trials in bone metastases are encouraged to adopt the revised guideline to promote consistent reporting. Areas for future research were identified. It is intended for the consensus to be re-examined in the future on a regular basis. © 2012 Elsevier Inc. Source

Glynne-Jones R.,Mount Vernon Center for Cancer Treatment | Carvalho C.,Champalimaud Cancer Center
Seminars in Radiation Oncology | Year: 2016

Preoperative radiotherapy has an accepted role in reducing the risk of local recurrence in locally advanced resectable rectal cancer, particularly when the circumferential resection margin is breached or threatened, according to magnetic resonance imaging. Fluoropyrimidine-based chemoradiation can obtain a significant down-sizing response and a curative resection can then be achieved. Approximately, 20% of the patients can also obtain a pathological complete response, which is associated with less local recurrences and increased survival. Patients who achieve a sustained complete clinical response may also avoid radical surgery. In unresectable or borderline resectable tumors, around 20% of the patients still fail to achieve a sufficient down-staging response with the current chemoradiation schedules. Hence, investigators have aspired to increase pathological complete response rates, aiming to improve curative resection rates, enhance survival, and potentially avoid mutilating surgery. However, adding additional cytotoxic or biological agents have not produced dramatic improvements in outcome and often led to excess surgical morbidity and higher levels of acute toxicity, which effects on compliance and in the global efficacy of chemoradiation. © 2016 Elsevier Inc. Source

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