Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer

Bujko, Krzysztof; Nowacki, Marek P.; Nasierowska‐Guttmejer, Anna; Michalski, Wojciech; Bębenek, Marek; Kryj, Mariusz

doi:10.1002/bjs.5506

Cited by 1,067 publications

(649 citation statements)

References 26 publications

(22 reference statements)

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“…86)). (Figure 1) In this register based study we found a low ypT0 rate, (8%) compared to other studies that have shown rates of 13-45% (84)(85)(86). Our results may reflect the broad inclusion of rectal cancer patients in Swedish normal clinical practice with a high proportion of T4 tumours and the inclusion of patients with LRT, and SRT with delay but without chemotherapy.…”

Section: Study IIIsupporting

confidence: 51%

Response to neoadjuvant treatment in rectal cancer surgery

Loftås

2016

Linköping University Medical Dissertations

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Rectal cancer is one of the three most common malignancies in Sweden with an annual incidence of about 2000 cases. Current treatment consists of surgical resection of the rectum including the loco-regional lymph nodes in the mesorectum. In advanced cases, neoadjuvant chemo-radiotherapy (CRT) prior to the operative treatment reduces local recurrences and enables surgery. The neoadjuvant treatment can also eradicate the tumour completely, i.e. complete response. This research project was designed to investigate the effects of preoperative radiotherapy/ CRT and analyze methods to predict response to CRT. Study I investigated the expression of the FXYD-3 protein with immunohistochemistry in rectal cancer, with or without preoperative radiotherapy. The results from the total cohort showed that, strong FXYD-3 expression was correlated to infiltrative tumour growth (p = 0.02). In the radiotherapy group, strong FXYD-3 expression was related to an unfavourable prognosis (p = 0.02). Tumours with strong FXYD-3 expression had less tumour necrosis (p = 0.02) after radiotherapy. FXYD-3 expression in the primary tumour was increased compared to normal mucosa (p=0.008). We concluded that FXYD-3 expression was a prognostic factor in patients receiving preoperative radiotherapy for rectal cancer. Study II investigated FXYD-3 expression in tumours that developed local recurrences following surgery and compared this with expression in tumours that did not develop local recurrences. There was no difference in the expression of FXYD-3 between the group that developed local recurrences and the group that did not develop local recurrences. There was no difference in survival between those with strong or weak FXYD-3 expression. We concluded that this study could not confirm the findings from study 1 i.e. that FXYD-3 expression has prognostic significance in rectal cancer. Study III was a register-based study on the incidence and effects of complete response to neoadjuvant treatment. Eight per cent of the patients with adequate CRT to achieve complete response also had a complete histological response of the luminal tumor in the resected bowel. Sixteen per cent of that group had remaining lymph node metastases in the operative specimen. Chemotherapy together with radiotherapy doubled the chance of complete response in the luminal tumour. Patients with remaining lymph node metastases had a lower survival rate compared to those without. We concluded that residual nodal involvement after neoadjuvant treatment was an important factor for reduced survival after complete response in the luminal tumour. Study IV followed up the results from the previous study by re-evaluating magnetic resonance imaging (MRI)- images in patients with complete tumour response. Two experienced MRI radiologists performed blinded re-staging of post CRT MR- images from patients with complete response in the luminal tumour. One group with lymph node metastases and another one without were studied and the results compared with the pathology reports. The sensitivity, spe...

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Section: Study IIIsupporting

confidence: 51%

Response to neoadjuvant treatment in rectal cancer surgery

Loftås

2016

Linköping University Medical Dissertations

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“…In the study from Bujko et al, RT dose and fractionation and time interval until surgery were different in both groups (535 Gy followed by immediate surgery versus 50.4 Gy followed by surgery after a waiting period of 4-6 weeks). 21 In this study, therefore, it remains unclear whether the observed differences in tumor response between both arms are attributable to the addition of chemotherapy or to a different RT schedule and a different waiting period until surgery.…”

Section: Discussionmentioning

confidence: 86%

Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer: A systematic review and meta‐analysis

Ceelen

Fierens

Nieuwenhove

et al. 2009

Intl Journal of Cancer

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Combining chemotherapy with preoperative radiotherapy (RT) has a sound radiobiological rationale. We performed a systematic review and meta-analysis of trials comparing preoperative RT with preoperative chemoradiation (CRT) in rectal cancer patients. The Cochrane Central Register of Controlled Trials, Web of Science, Embase and Medline (Pubmed) were searched from 1975 until June 2007. Dichotomous parameters were summarized using the odds ratio while time to event data were analyzed using the pooled hazard ratio for death. From the primary search result of 324 trials, 4 relevant randomized trials were identified. The addition of chemotherapy significantly increased grade III and IV acute toxicity (p 5 0.002) while no differences were observed in postoperative morbidity or mortality. Preoperative CRT significantly increased the rate of pathological complete response (p < 0.001) although this did not translate into a higher sphincter preservation rate (p 5 0.29). The local recurrence rate was significantly lower in the CRT group (p < 0.001). No statistically significant differences were observed in disease free survival (p 5 0.89) or overall survival (p 5 0.79). Compared to preoperative RT alone, preoperative CRT improves local control in rectal cancer but is associated with a more pronounced treatment related toxicity. The addition of chemotherapy does not benefit sphincter preservation rate or long-term survival. Future trials should address improvements in the rate of distant metastasis and overall survival by incorporating more active chemotherapy. ' UICCKey words: rectal cancer; radiotherapy; surgery The incidence of fatal cases of colorectal cancer in Europe exceeds 200,000 per year. 1 Because of the specific anatomy and biology of rectal cancer, surgery alone historically has been associated with local recurrence in up to 1 in 4 patients. 2 Locally recurrent disease is usually incurable, causes important morbidity and suffering and gives rise to systemic metastases. In the last few decades, improvements in surgical technique have dramatically lowered the incidence of locally recurrent disease. Careful pathological studies have clearly demonstrated that the major cause of local recurrence is the persistence of tumor foci within the mesorectum. 3,4 Intact removal of the entire mesorectum (total mesorectal excision or TME) in cancers of the mid or lower third of the rectum was pioneered by Heald and has resulted in local recurrence rates lower than 5-10%. [5][6][7] Parallel to improvements in surgical technique, adjuvant therapy regimens have been tested in clinical trials in an effort to reduce local recurrence rates. Neoadjuvant radiotherapy (RT) has been shown to significantly decrease local recurrence rate and improve survival provided a biologically equivalent dose (BED) of at least 30 gray (Gy) is administered. 8 The advantages of preoperative over postoperative RT include enhanced effectiveness in well-oxygenated tissue, downstaging of advanced tumors and better treatment compliance. 9 The theoretical ...

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“…At the present time, different radiation schedules are used: in northern Europe, 25 Gy in five fractions (short course) is commonly applied, whereas 45 Gy in 25 fractions (long course) with chemotherapy is preferred in southern Europe and North America. Bujko et al (2006) randomised 310 patients with cT3 rectal cancer to 5 Gy Â 5, followed by surgery or conventional preoperative 50.4 Gy plus bolus 5FU1leucovorin daily over 5 weeks, followed by surgery and reported similar local control and survival results. The ability to predict complete pathologic response or sensitivity to radiation based on IHC would have a significant impact on the selection of patients for preoperative radiotherapy or chemoradiation therapy schedules.…”

Section: Discussionmentioning

confidence: 96%

Combined analysis of VEGF and EGFR predicts complete tumour response in rectal cancer treated with preoperative radiotherapy

et al. 2008

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The ability to predict complete pathologic response or sensitivity to radiation before treatment would have a significant impact on the selection of patients for preoperative radiotherapy or chemo-radiation therapy schedules. The aim of this study was to determine the value of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), p53, Bcl-2 and apoptosis proteaseactivating factor-1 (APAF-1) as predictors of complete pathologic tumour regression in patients undergoing preoperative radiotherapy for advanced rectal cancer. Pretreatment tumour biopsies from predominantly cT3 patients undergoing a preoperative high-dose-rate brachytherapy protocol were immunostained for EGFR, VEGF, p53, Bcl-2 and APAF-1. Immunoreactivity was evaluated by three pathologists. Cut-off scores for tumour marker positivity were obtained by receiver-operating characteristic (ROC) curve analysis. The association of marker expression with complete pathologic response was analysed in univariate and multivariable analysis. Multi-marker phenotypes of the independent protein markers were evaluated. In multivariable analysis, loss of VEGF (P-value ¼ 0.009; odds ratio (OR) (95% CI) ¼ 0.24 (0.08 -0.69)) and positive EGFR (P-value ¼ 0.01; OR (95% CI) ¼ 3.82 (1.37 -10.6)) both demonstrated independent predictive value for complete pathologic response. The odds of complete response were 12.8 for the multi-marker combination of VEGF-negative and EGFR-positive tumours. Of the 34 EGFR-negative-and VEGFpositive cases, 32 (94.1%) had no complete pathologic response. The combined analysis of VEGF and EGFR is predictive of complete pathologic response in patients undergoing preoperative radiotherapy. In addition, the findings of this study have identified a subgroup of simultaneous EGFR-negative and VEGF-positive patients who are highly resistant to radiotherapy and should perhaps be considered candidates for innovative neoadjuvant combined modalities.

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Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer

Abstract: Neoadjuvant chemoradiation did not increase survival, local control or late toxicity compared with short-course radiotherapy alone.

Cited by 1,067 publications

References 26 publications

Response to neoadjuvant treatment in rectal cancer surgery

Response to neoadjuvant treatment in rectal cancer surgery

Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer: A systematic review and meta‐analysis

Combined analysis of VEGF and EGFR predicts complete tumour response in rectal cancer treated with preoperative radiotherapy

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