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Lutz S.,Blanchard Valley Regional Cancer Center | Berk L.,H. Lee Moffitt Cancer Center and Research Institute | Chang E.,University of Texas M. D. Anderson Cancer Center | Chow E.,University of Toronto | And 13 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011

Purpose: To present guidance for patients and physicians regarding the use of radiotherapy in the treatment of bone metastases according to current published evidence and complemented by expert opinion. Methods and Materials: A systematic search of the National Library of Medicine's PubMed database between 1998 and 2009 yielded 4,287 candidate original research articles potentially applicable to radiotherapy for bone metastases. A Task Force composed of all authors synthesized the published evidence and reached a consensus regarding the recommendations contained herein. Results: The Task Force concluded that external beam radiotherapy continues to be the mainstay for the treatment of pain and/or prevention of the morbidity caused by bone metastases. Various fractionation schedules can provide significant palliation of symptoms and/or prevent the morbidity of bone metastases. The evidence for the safety and efficacy of repeat treatment to previously irradiated areas of peripheral bone metastases for pain was derived from both prospective studies and retrospective data, and it can be safe and effective. The use of stereotactic body radiotherapy holds theoretical promise in the treatment of new or recurrent spine lesions, although the Task Force recommended that its use be limited to highly selected patients and preferably within a prospective trial. Surgical decompression and postoperative radiotherapy is recommended for spinal cord compression or spinal instability in highly selected patients with sufficient performance status and life expectancy. The use of bisphosphonates, radionuclides, vertebroplasty, and kyphoplasty for the treatment or prevention of cancer-related symptoms does not obviate the need for external beam radiotherapy in appropriate patients. Conclusions: Radiotherapy is a successful and time efficient method by which to palliate pain and/or prevent the morbidity of bone metastases. This Guideline reviews the available data to define its proper use and provide consensus views concerning contemporary controversies or unanswered questions that warrant prospective trial evaluation. Copyright © 2011 Elsevier Inc.


Glynne-Jones R.,Mount Vernon Center for Cancer Treatment | Chau I.,Royal Marsden Hospital
European Journal of Cancer, Supplement | Year: 2013

Neoadjuvant treatment in terms of preoperative radiotherapy reduces local recurrence in rectal cancer, but this improvement has little if any impact on overall survival. Currently performed optimal quality-controlled total mesorectal excision (TME) surgery for patients in the trial setting can be associated with very low local recurrence rates of less than 10% whether the patients receive radiotherapy or not. Hence metastatic disease is now the predominant issue. The concept of neoadjuvant chemotherapy (NACT) is a potentially attractive additional or alternative strategy to radiotherapy to deal with metastases. However, randomised phase III trials, evaluating the addition of oxaliplatin at low doses plus preoperative fluoropyrimidine-based chemoradiotherapy (CRT), have in the main failed to show a significant improvement on early pathological response, with the exception of the German CAO/ARO/AIO-04 study. The integration of biologically targeted agents into preoperative CRT has also not fulfilled expectations. The addition of cetuximab appears to achieve relatively low rates of pathological complete responses, and the addition of bevacizumab has raised concerns for excess surgical morbidity. As an alternative to concurrent chemoradiation (which delivers only 5-6. weeks of chemotherapy), potential options include an induction component of 6-12. weeks of NACT prior to radiotherapy or chemoradiation, or the addition of chemotherapy after short-course preoperative radiotherapy (SCPRT) or chemoradiation (defined as consolidation chemotherapy) which utilises the "dead space" of the interval between the end of chemoradiation and surgery, or delivering chemotherapy alone without any radiotherapy. © 2013 Elsevier Ltd.


Vinayan A.,Mount Vernon Center for Cancer Treatment | Glynne-Jones R.,Mount Vernon Center for Cancer Treatment
Best Practice and Research: Clinical Gastroenterology | Year: 2016

Radical concurrent chemoradiotherapy with 5FU and Mitomycin C is the standard-of-care for squamous-cell carcinoma of the anus (SCCA). Phase III trials combined radiation doses of 50-60 Gy with concurrent Fluoropyrimidines, Mitomycin C and Cisplatin in various doses and schedules. CRT is highly successful for early T1/T2 cancers, but results in appreciable late morbidities and still fails to control larger and node-positive tumours.Compliance to chemotherapy is important for local control. Modern radiotherapy techniques such as intensity-modulated radiotherapy (IMRT), rotational IMRT, image-guided radiotherapy (IGRT) have enabled smaller margins and highly conformal plans, resulting in decreased radiation doses to the organs at risk and ensuring a shorter overall treatment time. These advances offer the potential for integrating higher doses of radiation, escalation of the currently used drugs and the safe use of other more novel agents with acceptable toxicity. In this chapter potential novel approaches are discussed in the context of SCCA. © 2016 Elsevier Ltd.


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.


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.


Glynne-Jones R.,Mount Vernon Center for Cancer Treatment | Counsell N.,University College London | Quirke P.,University of Leeds | Mortensen N.,University of Oxford | And 4 more authors.
Annals of Oncology | Year: 2014

Background: In stage III colon cancer, oxaliplatin/5-fluorouracil (5-FU)-based adjuvant chemotherapy (FOLFOX) improves disease-free survival (DFS) and overall survival (OS). In rectal adenocarcinoma following neoadjuvant chemoradiation (CRT), we examined the benefit of postoperative adjuvant capecitabine and oxaliplatin (XELOX) chemotherapy. Methods: Eligible patients were randomly assigned following fluoropyrimidine-based CRT and curative resection to observation or six cycles of XELOX. The primary end point was DFS; secondary end points were acute toxicity and OS. 390 patients were required in each arm, to detect an improvement in 3-year DFS from 40% to 50.5%, with 85% power and two-sided 5% significance level. Results: The study closed prematurely in 2008 because of poor accrual. Only 113 patients were randomly assigned to either observation (n = 59) or XELOX (n = 54). Compliance was poor, 93% allocated chemotherapy started and 48% completed six cycles. Protocolised dose reductions in XELOX were 39%, and levels of G3/G4 toxicity 40%. After a median follow-up of 44.8 months, 16 patients (27%) in the observation arm had relapsed or died compared with 12 patients (22%) in XELOX. The 3-year DFS rate was 78% with XELOX and 71% with observation [hazard ratio (HR) for DFS = 0.80; 95% confidence interval (CI) 0.38-1.69; P = 0.56]. The 3-year OS for XELOX and observation were 89% and 88%, respectively (HR for OS = 1.18; 95% CI 0.43-3.26; P = 0.75). Conclusions: The observed improvement in DFS for adjuvant XELOX and similar OS were not statistically significant, as expected given the small number of patients and consequent low power. Our findings support the need for trials that test the role of neoadjuvant chemotherapy. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Aggarwal A.,Mount Vernon Center for Cancer Treatment | Duke S.,Mount Vernon Center for Cancer Treatment | Glynne-Jones R.,Mount Vernon Center for Cancer Treatment
Current Oncology Reports | Year: 2013

Anal cancer is an uncommon malignancy. There have been some intriguing developments in the past 3 years, in terms of our understanding of the molecular biology and processes that lead to anal cancer. There have also been some notable successes in prevention, imaging and treatment. Nonsurgical treatment is highly effective. The primary aim of such treatment is to achieve loco-regional control with chemoradiation (CRT), and preserve anal function without a colostomy. Randomised phase III trials presented or published over the past 3 years have explored novel strategies of neoadjuvant chemotherapy, maintenance chemotherapy, radiotherapy dose escalation and replacement of mitomycln C (MMC) with cisplatin in CRT. All have failed to improve on the current standard of care; i.e. MMC/ 5 fluorouracil (5FU) chemoradiation. However, more conformal strategies such as intensity modulated radiotherapy (IMRT) appear feasible to deliver with reduced toxicity, and may offer an opportunity to dose-escalate both to gross tumour and areas of potential nodal spread. Preliminary outcome data suggest no loss of efficacy. We evaluate the relevant recent literature published over the past 2 years, and summarize interesting and important new findings, with the aim of bringing the reader up-to-date on anal cancer. © 2013 Springer Science+Business Media New York.


Glynne-Jones R.,Mount Vernon Center for Cancer Treatment | Sebag-Montefiore D.,University of Leeds | Adams R.,University of Cardiff | Gollins S.,North Wales Cancer Treatment Center | And 3 more authors.
Cancer | Year: 2013

Background: Only 2 prospective studies have previously reported prognostic factors for anal cancer, European Organization for Research and Treatment of Cancer trial 22861 (EORTC 22861) and Radiation Therapy Oncology Group trial 98-11 (RTOG 98-11). Both of those trials reported that clinically positive lymph nodes and male sex predicted poorer overall survival (OS). The EORTC 22861 trial indicated that the same factors were prognostic for locoregional control. In the current report, the authors investigated potential prognostic factors from the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I), in which patients were randomized to receive either radiotherapy alone or chemoradiation (CRT) with concurrent 5-fluorouracil/ mitomycin C. METHODS: In the ACT I trial, associations between several baseline characteristics and 3 endpoints were investigated: locoregional failure (LRF), anal cancer death (ACD), and OS. The analyses were restricted to 292 patients who received CRT, which subsequently became standard treatment. A score was derived using multivariable Cox regression to identify the set of factors that, together, had the best prognostic performance. This score was then validated with a large, independent prospective trial (the ACT II trial). RESULTS: Palpable, clinically positive lymph nodes were associated with LRF (P =.012), a greater risk of ACD (P =.031), and decreased OS (P =.006) in multivariable analyses. Men had worse outcomes than women for LRF (P =.036), ACD (P =.039), and OS (P =.008). On average, a lower hemoglobin level had an adverse effect on ACD (P =.008), and a higher white blood cell count had an adverse effect on OS (P =.001). However, external validation of the score was poor for LRF (area under the curve [AUC] = 54%) but was better for ACD (AUC = 67%) and OS (AUC = 63%). CONCLUSIONS: The results from this analysis of the ACT I trial supported evidence for palpable lymph nodes and male sex as prognostic factors for LRF and OS, and lower hemoglobin levels and a higher white blood cell count were identified as prognostic factors for ACD and OS, respectively. Cancer 2013. © 2012 American Cancer Society. This analysis of the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I) complements 2 other studies, adding further evidence that palpable inguinal lymph node status and sex are independently prognostic of overall survival, locoregional failure, and anal cancer death. In addition, after adjusting for sex and lymph node status, presenting hemoglobin level is identified as another prognostic factor for anal cancer death. Copyright © 2012 American Cancer Society.


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.


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.

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