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Impact of radiotherapy boost on pathological complete response in patients with locally advanced rectal cancer: A systematic review and meta-analysis

Open AccessPublished:September 30, 2014DOI:https://doi.org/10.1016/j.radonc.2014.08.035

      Abstract

      Purpose

      We conducted a systematic review and meta-analysis to quantify the pathological complete response (pCR) rate after preoperative (chemo)radiation with doses of ⩾60 Gy in patients with locally advanced rectal cancer. Complete response is relevant since this could select a proportion of patients for which organ-preserving strategies might be possible. Furthermore, we investigated correlations between EQD2 dose and pCR-rate, toxicity or resectability, and additionally between pCR-rate and chemotherapy, boost-approach or surgical-interval.

      Methods and materials

      PubMed, EMBASE and Cochrane libraries were searched with the terms ‘radiotherapy’, ‘boost’ and ‘rectal cancer’ and synonym terms. Studies delivering a preoperative dose of ⩾60 Gy were eligible for inclusion. Original English full texts that allowed intention-to-treat pCR-rate calculation were included. Study variables, including pCR, acute grade ⩾3 toxicity and resectability-rate, were extracted by two authors independently. Eligibility for meta-analysis was assessed by critical appraisal. Heterogeneity and pooled estimates were calculated for all three outcomes. Pearson correlation coefficients were calculated between the variables mentioned earlier.

      Results

      The search identified 3377 original articles, of which 18 met our inclusion criteria (1106 patients). Fourteen studies were included for meta-analysis (487 patients treated with ⩾60 Gy). pCR-rate ranged between 0.0% and 44.4%. Toxicity ranged between 1.3% and 43.8% and resectability-rate between 34.0% and 100%. Pooled pCR-rate was 20.4% (95% CI 16.8–24.5%), with low heterogeneity (I2 0.0%, 95% CI 0.00–84.0%). Pooled acute grade ⩾3 toxicity was 10.3% (95% CI 5.4–18.6%) and pooled resectability-rate was 89.5% (95% CI 78.2–95.3%).

      Conclusion

      Dose escalation above 60 Gy for locally advanced rectal cancer results in high pCR-rates and acceptable early toxicity. This observation needs to be further investigated within larger randomized controlled phase 3 trials in the future.

      Keywords

      Colorectal cancer is the third most common cancer and often diagnosed in an advanced stage. Treatment of locally advanced rectal cancers (LARC) then consists of neoadjuvant chemoradiation therapy (CRT) followed by total mesorectal excision (TME). The clinical outcome after CRT is largely dependent on tumor response to CRT [
      • Maas M.
      • Nelemans P.J.
      • Valentini V.
      • Das P.
      • Rodel C.
      • Kuo L.J.
      • et al.
      Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
      ,
      • Vecchio F.M.
      • Valentini V.
      • Minsky B.D.
      • Padula G.D.
      • Venkatraman E.S.
      • Balducci M.
      • et al.
      The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer.
      ]. Overall, ∼15% of patients experience a pathological complete response (pCR) at the standard radiation dose (45–50.4 Gy) [
      • Maas M.
      • Nelemans P.J.
      • Valentini V.
      • Das P.
      • Rodel C.
      • Kuo L.J.
      • et al.
      Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
      ,
      • Sanghera P.
      • Wong D.W.
      • McConkey C.C.
      • Geh J.I.
      • Hartley A.
      Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response.
      ]. Complete response is relevant since this could select a proportion of patients for which organ-preserving strategies might be possible, either by local excision ([
      • Bokkerink G.M.
      • de Graaf E.J.
      • Punt C.J.
      • Nagtegaal I.D.
      • Rutten H.
      • Nuyttens J.J.
      • et al.
      The CARTS study: chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery.
      ,
      • Pucciarelli S.
      • De Paoli A.
      • Guerrieri M.
      • La Torre G.
      • Maretto I.
      • De Marchi F.
      • et al.
      Local excision after preoperative chemoradiotherapy for rectal cancer: results of a multicenter phase II clinical trial.
      ], ISRCTN14422743) or a “wait-and-scan” strategy [
      • Maas M.
      • Beets-Tan R.G.
      • Lambregts D.M.
      • Lammering G.
      • Nelemans P.J.
      • Engelen S.M.
      • et al.
      Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer.
      ,
      • Smith J.D.
      • Ruby J.A.
      • Goodman K.A.
      • Saltz L.B.
      • Guillem J.G.
      • Weiser M.R.
      • et al.
      Nonoperative management of rectal cancer with complete clinical response after neoadjuvant therapy.
      ,
      • Habr-Gama A.
      • Gama-Rodrigues J.
      • Sao Juliao G.P.
      • Proscurshim I.
      • Sabbagh C.
      • Lynn P.B.
      • et al.
      Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control.
      ]. Since response to radiotherapy is dose dependent in rectal cancer, dose escalation may lead to higher complete response rates [
      • Chan A.K.
      • Wong A.O.
      • Langevin J.
      • Jenken D.
      • Heine J.
      • Buie D.
      • et al.
      Preoperative chemotherapy and pelvic radiation for tethered or fixed rectal cancer: a phase II dose escalation study.
      ,
      • Overgaard M.
      • Overgaard J.
      • Sell A.
      Dose-response relationship for radiation therapy of recurrent, residual, and primarily inoperable colorectal cancer.
      ,
      • Wiltshire K.L.
      • Ward I.G.
      • Swallow C.
      • Oza A.M.
      • Cummings B.
      • Pond G.R.
      • et al.
      Preoperative radiation with concurrent chemotherapy for resectable rectal cancer: effect of dose escalation on pathologic complete response, local recurrence-free survival, disease-free survival, and overall survival.
      ]. A recent mathematical prediction model on pCR-rate indicated that 50% of patients could reach pCR after 92 Gy and that response exponentially increased after 60 Gy [
      • Appelt A.L.
      • Ploen J.
      • Vogelius I.R.
      • Bentzen S.M.
      • Jakobsen A.
      Radiation dose-response model for locally advanced rectal cancer after preoperative chemoradiation therapy.
      ]. This was in line with a prediction-curve based on a large systematic review on dose response in patients with LARC [
      • Sanghera P.
      • Wong D.W.
      • McConkey C.C.
      • Geh J.I.
      • Hartley A.
      Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response.
      ,
      • Appelt A.L.
      • Ploen J.
      • Vogelius I.R.
      • Bentzen S.M.
      • Jakobsen A.
      Radiation dose-response model for locally advanced rectal cancer after preoperative chemoradiation therapy.
      ]. Nevertheless, dose-escalation trials using ⩾60 Gy have not been systematically reviewed yet. Therefore, we conducted a systematic review and meta-analysis to quantify the pCR-rate after preoperative (chemo)radiation with doses of ⩾60 Gy in patients with LARC. Furthermore, correlations between pCR-rate, acute grade ⩾3 toxicity, chemotherapy, boost technique and surgical interval were studied.

      Methods

      Search strategy

      The PRISMA guidelines for systematic review and meta-analysis were used to conduct this review [
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      ]. We searched the electronic PubMed, EMBASE and Cochrane databases with the last search performed on April 10th 2014. Synonym terms for ‘radiotherapy’, ‘boost’ and ‘rectal cancer’ were used (see Supplement). The search was limited to articles published after 1988, because adjuvant treatment became progressively replaced by neo-adjuvant (chemo)radiation since. Duplicates were removed and additional papers were retrieved through cross referencing.

      Study selection

      All studies in primary LARC patients (T3-4NxM0/fixed tumors) receiving a preoperative physical radiation dose of ⩾60 Gy (with at least 45 Gy external beam radiation therapy (EBRT)) to the whole tumor were eligible for inclusion. Original researches, in English, with available full texts were included. Studies without our primary endpoint, palliative intent, or with previously irradiated patients were excluded, as well as studies using contact radiotherapy and/or X-ray treatment (CXR).

      Data extraction and quality assessment

      The primary outcome was the proportion of patients scheduled for preoperative ⩾60 Gy radiation that reached pCR. pCR was defined as absence of residual cancer cells in the resected specimen. This was calculated by intention-to-treat i.e. the number of patients with pCR divided by all patients scheduled for preoperative ⩾60 Gy radiation. If not so provided by the authors, pCR-rate was calculated from the data. Corresponding authors were contacted in case of insufficient information.
      Secondary outcomes were acute grade ⩾3 toxicity, and resectability rate. All toxicity scores were redefined to the National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE v4.0) [

      Cancer EOfRaTo. Common terminology criteria for adverse events, v1.0–v4.03; 1994.

      ], and presented as the percentages of patients experiencing acute grade ⩾3 toxicity. Resectability rate was defined as the percentage of patients with resectable tumors after (chemo-)radiation divided by all patients scheduled for preoperative ⩾60 Gy radiation. Furthermore, we extracted study-design, -size, demographics, the radiation protocol (total dose (EQD2-dose with alfa/beta = 10 [
      • Appelt A.L.
      • Ploen J.
      • Vogelius I.R.
      • Bentzen S.M.
      • Jakobsen A.
      Radiation dose-response model for locally advanced rectal cancer after preoperative chemoradiation therapy.
      ]), boost dose, radiation approach, margins, chemotherapy regimen (agent(s), administration protocol and doses), and time-to-surgery. Extraction was performed by two authors independently (J.P.M.B. and A.M.dH.). In case of discrepancy consensus was reached between authors.

      Critical appraisal

      Study quality was assessed by pre-defined criteria (Table 2) based on items listed in the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement [
      • von Elm E.
      • Altman D.G.
      • Egger M.
      • Pocock S.J.
      • Gotzsche P.C.
      • Vandenbroucke J.P.
      • et al.
      The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
      ]. Also study design, data presentation, and clinical characteristics that may have influenced the primary outcome were used. Quality assessment was also performed independently by two authors (J.P.M.B. and A.M.dH.). Studies were eligible for meta-analysis if at least a valid pCR-rate could be calculated.
      Table 2Critical appraisal and eligibility assessment for meta-analysis. y = yes, – = no, na = not applicable.
      Author, yearIdentification of LARC subgroup with ⩾60 Gy (y/n)Standard chemotherapy protocol (y/n/na)Surgical interval reported (y/n)Standardized pathologic response assessment (y/n)Reasons for drop-out and/or not undergoing surgery (y/n/na)TNM stage reported (y/n/partly)Acute grade ⩾3 toxicity for boost patients only (y/n)pCR recalculation possible (y/n)Meta-analysis inclusion
      Marks et al., 1993NnaYNnaNNN
      Meade et al., 1995YNYYYYYYYes
      Movsas et al., 1998YYYNYNYN
      Mohiuddin et al., 2000
      Additional data obtained through the corresponding author.
      NNYNYNYYYes
      Rouanet et al., 2002
      Additional data obtained through the corresponding author.
      NnaYNnaYNYYes
      Pfeiffer et al., 2005
      Additional data obtained through the corresponding author.
      YNYNYNYYYes
      Jakobsen et al., 2006
      Additional data obtained through the corresponding author.
      YYNYnayYYYes
      Mohiuddin et al., 2006
      Additional data obtained through the corresponding author.
      YYYYYPartlyYYYes
      Movsas et al., 2006YYYYYNNYYes
      Ho-Pun-Cheung et al., 2007NnaYYnaNNN
      Sun Myint et al., 2007NNYNnaNNY
      Jakobsen et al., 2008
      Additional data obtained through the corresponding author.
      YYYYYPartlyYYYes
      Vestermark et al., 2008
      Additional data obtained through the corresponding author.
      YYYYYNYYYes
      Lindebjerg et al., 2009
      Additional data obtained through the corresponding author.
      YYYYnaPartlyNYYes
      Maluta et al., 2010YYYYnaYYYYes
      Jakobsen et al., 2012
      Additional data obtained through the corresponding author.
      YNYYYPartlyNYYes
      Vestermark et al., 2012
      Additional data obtained through the corresponding author.
      YNYYYPartlyYYYes
      Engineer et al., 2013YnaNNYNYYYes
      low asterisk Additional data obtained through the corresponding author.

      Statistical methods

      The R statistical environment (version 3.0.2, R Development Core Team, 2011) with ‘metafor’ package (version 1.9-1) was used for statistical analysis [
      • Viechtbauer W.
      Conducting meta-analyses in R with the metafor package.
      ]. Potential publication bias was checked by funnel plots and rank correlation tests (Kendall’s tau). pCR-rate, grade ⩾3 toxicity and resectability rate were logit transformed, pooled, re-transformed and presented as proportions with 95% confidence interval (CI). Heterogeneity was assessed by the I2 statistic (i.e. estimated proportion of unexplained inter-study variance) prior to pooling. Random effects models, using a restricted maximum likelihood estimator, were used in case of large inter-study variance (I2 ⩾ 65%) to calculate a pooled estimate. Otherwise mixed- (25 < I2<65%) or (⩽25%) fixed effects models were used. Robustness of the pooled estimate was addressed by two sensitivity analyses (SA). The first SA excluded studies with pCR-rates lower than the 15% which we took as a reference standard based on large meta-analyses [
      • Maas M.
      • Nelemans P.J.
      • Valentini V.
      • Das P.
      • Rodel C.
      • Kuo L.J.
      • et al.
      Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
      ,
      • Sanghera P.
      • Wong D.W.
      • McConkey C.C.
      • Geh J.I.
      • Hartley A.
      Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response.
      ], i.e. negative outliers. The second SA only included studies with an EQD2-dose of ⩾60 Gy. Correlations between EQD2-dose and pCR-rate, toxicity and resectability, as well as between pCR-rate and chemotherapy, boost-approach and surgical-interval were visualized in scatter plots and formally tested by Pearson’s correlation test. P-values were considered significant if the p-value was below 0.05.

      Results

      In total 3377 articles were identified. After removing duplicates, 2765 articles were screened on title and abstract. Seventy-one remaining articles were screened on full text, of which 54 were excluded for the following reasons: no full text available (n = 20), studies not involving patients (n = 4), not including patients with LARC (n = 10), no curative setting (n = 3), only included previously irradiated patients (n = 1), preoperative dose of <60 Gy (n = 5), already included (non-unique) patient-population (n = 3), non-English articles (n = 2) and studies without our primary endpoint pCR (n = 6). One additional article was identified by cross-referencing. Finally, 18 studies (1106 patients) were included for systematic review, consisting of 7 prospective single/multiple arm studies, 3 RCTs, 2 NRCTs and 6 phase I/II trials (see Table 1 and Fig. 1) [
      • Marks G.
      • Mohiuddin M.
      • Masoni L.
      The reality of radical sphincter preservation surgery for cancer of the distal 3 cm of rectum following high-dose radiation.
      ,
      • Meade P.G.
      • Blatchford G.J.
      • Thorson A.G.
      • Christensen M.A.
      • Ternent C.A.
      Preoperative chemoradiation downstages locally advanced ultrasound-staged rectal cancer.
      ,
      • Movsas B.
      • Hanlon A.L.
      • Lanciano R.
      • Scher R.M.
      • Weiner L.M.
      • Sigurdson E.R.
      • et al.
      Phase I dose escalating trial of hyperfractionated pre-operative chemoradiation for locally advanced rectal cancer.
      ,
      • Mohiuddin M.
      • Regine W.F.
      • John W.J.
      • Hagihara P.F.
      • McGrath P.C.
      • Kenady D.E.
      • et al.
      Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response.
      ,
      • Rouanet P.S.-A.B.
      • Lemanski C.
      • Senesse P.
      • Gourgou S.
      • Quenet F.
      • et al.
      Restorative and nonrestorative surgery for low rectal cancer after high-dose radiation: long-term oncologic and functional results.
      ,
      • Pfeiffer P.
      High-dose radiotherapy and concurrent UFT plus l-leucovorin in locally advanced rectal cancer: a phase I trial.
      ,
      • Jakobsen A.
      • Mortensen J.P.
      • Bisgaard C.
      • Lindebjerg J.
      • Hansen J.W.
      • Rafaelsen S.R.
      Preoperative chemoradiation of locally advanced T3 rectal cancer combined with an endorectal boost.
      ,
      • Mohiuddin M.
      • Winter K.
      • Mitchell E.
      • Hanna N.
      • Yuen A.
      • Nichols C.
      • et al.
      Randomized phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer: radiation therapy oncology group trial 0012.
      ,
      • Movsas B.
      • Diratzouian H.
      • Hanlon A.
      • Cooper H.
      • Freedman G.
      • Konski A.
      • et al.
      Phase II trial of preoperative chemoradiation with a hyperfractionated radiation boost in locally advanced rectal cancer.
      ,
      • Ho-Pun-Cheung A.
      • Assenat E.
      • Thezenas S.
      • Bibeau F.
      • Rouanet P.
      • Azria D.
      • et al.
      Cyclin D1 gene G870A polymorphism predicts response to neoadjuvant radiotherapy and prognosis in rectal cancer.
      ,
      • Sun Myint A.
      • Lee C.D.
      • Snee A.J.
      • Perkins K.
      • Jelley F.E.
      • Wong H.
      High dose rate brachytherapy as a boost after preoperative chemoradiotherapy for more advanced rectal tumours - the clatterbridge experience.
      ,
      • Jakobsen A.
      • Mortensen J.P.
      • Bisgaard C.
      • Lindebjerg J.
      • Rafaelsen S.R.
      • Bendtsen V.O.
      A COX-2 inhibitor combined with chemoradiation of locally advanced rectal cancer: a phase II trial.
      ,
      • Vestermark L.W.
      • Jacobsen A.
      • Qvortrup C.
      • Hansen F.
      • Bisgaard C.
      • Baatrup G.
      • et al.
      Long-term results of a phase II trial of high-dose radiotherapy (60 Gy) and UFT/l-leucovorin in patients with non-resectable locally advanced rectal cancer (LARC).
      ,
      • Lindebjerg J.
      • Spindler K.L.
      • Ploen J.
      • Jakobsen A.
      The prognostic value of lymph node metastases and tumour regression grade in rectal cancer patients treated with long-course preoperative chemoradiotherapy.
      ,
      • Maluta S.
      • Romano M.
      • Dall’oglio S.
      • Genna M.
      • Oliani C.
      • Pioli F.
      • et al.
      Regional hyperthermia added to intensified preoperative chemo-radiation in locally advanced adenocarcinoma of middle and lower rectum.
      ,
      • Jakobsen A.
      • Ploen J.
      • Vuong T.
      • Appelt A.
      • Lindebjerg J.
      • Rafaelsen S.R.
      Dose-effect relationship in chemoradiotherapy for locally advanced rectal cancer: a randomized trial comparing two radiation doses.
      ,
      • Vestermark L.W.
      • Jensen H.A.
      • Pfeiffer P.
      High-dose radiotherapy (60 Gy) with oral UFT/folinic acid and escalating doses of oxaliplatin in patients with non-resectable locally advanced rectal cancer (LARC): a phase I trial.
      ,
      • Engineer R.
      • Mohandas K.M.
      • Shukla P.J.
      • Shrikhande S.V.
      • Mahantshetty U.
      • Chopra S.
      • et al.
      Escalated radiation dose alone vs. concurrent chemoradiation for locally advanced and unresectable rectal cancers: results from phase II randomized study.
      ]. Five-hundred-thirty-nine patients (48.7% of identified patients) were scheduled for ⩾60 Gy radiation with median of 21 patients per study (range 1–109). Median age ranged between 42 and 68 years. T-stage was reported in 9 studies for 342 of 539 patients (63.5%), with range 9.0–100%. Nodal status was reported in 6 studies for 321 patients (59.6%), with a range of 30.0–89.0%.
      Table 1Characteristics of the included studies (pSA = prospective single arm study, I/II = phase I/II trial, (N)RCT = (non)randomized controlled trial, BID = bis in die (twice daily), Br HDR = brachytherapy high-dose rate, EQD2 = Equivalent 2 Gy dose, 5-FU = Fluorouracil, UFT = Tegafur-uracil, Leu = Leucovorin, Oxi = Oxaliplatin, TEGAFOX = Uracil/ftorafur/leucovorin/Oxaliplatin, Cap = Capecitabine, n d.d. = in n daily doses, /d = per day, /wk = per week, SIB = simultaneous integrated boost, pCR = pathologic complete response).
      Author, yearStudy designTotal number of study patients (n)Unique boost treated patients (n)Median age (yr) of total study populationFractions (standard)Dose (standard) (Gy)Fractions (boost)Total dose (Gy)EQD2 dose (total)Boost approachBoost timingChemo-therapy in boost treated patientsChemotherapy doseMaximal tumor distance from anal verge (cm)T3 (%)T4 (%)N+ (%)Interval to surgery (planned/median)Resectability rate (%)Percentage acute grade ⩾3 toxicity for ⩾60 Gy (sub)group (% grade 3/grade 4)Number of pCR events (boost patients only)Percentage pCR (n)
      Marks et al., 1993pSA525731 × 1.8/22 × 2.545.05 x16061–64EBRTSIB0–34–8/–100.0– (–/–)
      Meade et al., 1995NRCT2016825 × 1.845.09 × 1.86060EBRTSequential5-FU (+Leu)225 mg/m2 d.d. (+30 mg/m2 d.d.)90.010.030.04–8/–100.0100 (–/100)00.0
      Movsas et al., 1998I/II2776125 × 1.845.014 × 1.2 BID6260EBRTSequential5-FU1000 mg/m2/d for 4 days in weeks 1 and 41278.032.04–6/–85.7 (71.4/14.3)
      Mohiuddin et al., 2000
      Additional data obtained through the corresponding author.
      NRCT3396438 × 1.2 BID50.012 × 1.2 BID6056EBRTSequential5-FU225 mg/m2 d.d.6–8/–77.033 (33/0)444.4
      Rouanet et al., 2002
      Additional data obtained through the corresponding author.
      pSA43366418 × 2.137.810.5 × 2.16060EBRTSequential684.016.030.02/–100.0– (–/–)716.3
      Pfeiffer et al., 2005
      Additional data obtained through the corresponding author.
      I/II18146527 × 248.63 × 26060EBRTSIB + sequentialUFT + Leu150–300 mg/m2/d + 22.5 mg/d6/5.778.05.6 (5.6/0)17.1
      Jakobsen et al., 2006
      Additional data obtained through the corresponding author.
      pSA50506127 × 254.03 × 2; 5 Br HDR6566BrachySequentialUFT + Leu100 mg/m2 3 d.d. + 7.5 mg 3 d.d.10100.00.070.0–/–96.06.0 (6.0/0)1326.0
      Mohiuddin et al., 2006
      Additional data obtained through the corresponding author.
      RCT106165738 × 1.2 BID45.612 × 1.2 BID6056EBRTSIB5-FU225 mg/m2 d.d.971.029.04–10/792.042.6 (–/–)531.3
      Movsas et al., 2006II22216425 × 1.845.014 × 1.2 BID6260EBRTSequential5-FU1000 mg/m2/d for 4 days in weeks 1 and 6129.091.04–6/–100.013.6 (–/–)00.0
      Ho-Pun-Cheung et al., 2007pSA70296425 × 1.845.09 × 1.86060EBRTSequential10/–– (–/–)
      Sun Myint et al. 2007pSA161625 × 1.845.01 × 10 Br HDR7561BrachySequential5-FU / Cap750/1000 mg/m2 for 4 days in weeks 1 and 5 or 825 mg/m2/d6–8/–– (–/–)743.8
      Jakobsen et al., 2008
      Additional data obtained through the corresponding author.
      pSA35356527 × 254.03 × 2; 5 Br HDR6566EBRT + BrachySequentialUFT + Leu100 mg/m2 3 d.d. + 22.5 mg 3 d.d.1077.033.077.08/–94.25.7 (5.7/0)720.0
      Vestermark et al., 2008
      Additional data obtained through the corresponding author.
      II52366027 × 248.63 × 26060EBRTSIB + sequentialUFT + Leu100 mg/m2 3 d.d. + 22.5 mg 3 d.d.6/7.975.05.3 (5.3/0)38.3
      Lindebjerg et al., 2009
      Additional data obtained through the corresponding author.
      MA13586527 × 260.03 × 2 + 5 Br HDR60–6566EBRT + BrachySIB + sequential5-FU + Leu100 mg/m2 3 d.d. + 22.5 mg d.d.108/–100.0– (–/–)112.5
      Maluta et al., 2010II76766025 × 250.05 × 26060EBRTSequential5-FU + Oxi200 m/m2/d + 45 mg/m2/wk1289.011.054.04–6/–100.01.3 (1.3/0)1823.7
      Jakobsen et al., 2012
      Additional data obtained through the corresponding author.
      RCT2431096328 × 1.850.42 × 5 Br HDR6062BrachySequentialUFT + Leu (Denmark) or 5-FU (Canada)100 mg/m2 3 d.d. + 22.5 mg 3 d.d. (Denmark) or 225/mg/m2/d (Canada)1084.016.089.08/–92.610 (10/0)2018.3
      Vestermark et al., 2012
      Additional data obtained through the corresponding author.
      I18166227 × 248.63 × 26060BrachySIB + sequentialTEGAFOX (UFT/Leu/Oxi)pre-RT 100 mg/m2 3 d.d. + 7.5 mg 3 d.d. on day 1–14 + Oxi 130 mg/m2.

      Concurrent 100 mg/m2 3 d.d. + 22.5 mg 3 d.d. + 30–60 mg/m2/wk increasing with 10 mg/m2/wk
      ⩾6/8.5– (–/–)531.3
      Engineer et al., 2013RCT90444225 × 1.845.011 × 1.86564EBRTSequential6–8/1034.04.8 (4.8/0)511.4
      low asterisk Additional data obtained through the corresponding author.
      Figure thumbnail gr1
      Fig. 1Flow-chart of the study selection procedure.
      Treatment characteristics are summarized in Table 1. Total radiation dose varied between 60 and 75 Gy (EQD2 58.4–66.3 Gy), as an accumulation of standard EBRT (45–54 Gy) and boost dose (6–30 Gy). Twelve studies used EBRT only, 6 studies used brachytherapy only and two combined EBRT and brachytherapy. A simultaneous integrated boost (SIB) approach was used in two studies whereas four studies used a combination of SIB and sequential approaches. Target margins were mentioned in all but one study [
      • Rouanet P.S.-A.B.
      • Lemanski C.
      • Senesse P.
      • Gourgou S.
      • Quenet F.
      • et al.
      Restorative and nonrestorative surgery for low rectal cancer after high-dose radiation: long-term oncologic and functional results.
      ]. Most studies used 3–5 field box techniques with almost similar elective fields, predominantly defined by 1–1.5 cm anterior to the sacral wall, 1–2 cm outside the bony pelvis, the L5-S1 border and 3–5 cm caudal of the tumor. No studies used Intensity Modulated Radiotherapy (IMRT).
      All but two studies administered 5-Fluorouracil (5-FU) based chemotherapy [
      • Rouanet P.S.-A.B.
      • Lemanski C.
      • Senesse P.
      • Gourgou S.
      • Quenet F.
      • et al.
      Restorative and nonrestorative surgery for low rectal cancer after high-dose radiation: long-term oncologic and functional results.
      ,
      • Ho-Pun-Cheung A.
      • Assenat E.
      • Thezenas S.
      • Bibeau F.
      • Rouanet P.
      • Azria D.
      • et al.
      Cyclin D1 gene G870A polymorphism predicts response to neoadjuvant radiotherapy and prognosis in rectal cancer.
      ], namely 5-FU, Uracil-Tegafur (UFT) or Capecitabine, at varying doses (see Table 1). Leucovorin was added in six studies and Oxaliplatin in two.
      One study did not report toxicity at all [
      • Lindebjerg J.
      • Spindler K.L.
      • Ploen J.
      • Jakobsen A.
      The prognostic value of lymph node metastases and tumour regression grade in rectal cancer patients treated with long-course preoperative chemoradiotherapy.
      ]. In the other studies toxicity was mostly scored according to NCI (10 studies), Radiation Therapy Oncology Group (RTOG, 2 studies), or Response Evaluation Criteria in Solid Tumors list (RECIST, one study) criteria. Four studies did not report specifically which toxicity criteria were used, but did report if toxicity demanded treatment. Transformation to NCI criteria was chosen since it was predominant.
      Interval to surgery varied between 2 and 10 weeks (median 7) after chemoradiation. Resectability ranged between 34.0 and 100%. Five studies reached 100% resectability [
      • Meade P.G.
      • Blatchford G.J.
      • Thorson A.G.
      • Christensen M.A.
      • Ternent C.A.
      Preoperative chemoradiation downstages locally advanced ultrasound-staged rectal cancer.
      ,
      • Rouanet P.S.-A.B.
      • Lemanski C.
      • Senesse P.
      • Gourgou S.
      • Quenet F.
      • et al.
      Restorative and nonrestorative surgery for low rectal cancer after high-dose radiation: long-term oncologic and functional results.
      ,
      • Movsas B.
      • Diratzouian H.
      • Hanlon A.
      • Cooper H.
      • Freedman G.
      • Konski A.
      • et al.
      Phase II trial of preoperative chemoradiation with a hyperfractionated radiation boost in locally advanced rectal cancer.
      ,
      • Lindebjerg J.
      • Spindler K.L.
      • Ploen J.
      • Jakobsen A.
      The prognostic value of lymph node metastases and tumour regression grade in rectal cancer patients treated with long-course preoperative chemoradiotherapy.
      ,
      • Maluta S.
      • Romano M.
      • Dall’oglio S.
      • Genna M.
      • Oliani C.
      • Pioli F.
      • et al.
      Regional hyperthermia added to intensified preoperative chemo-radiation in locally advanced adenocarcinoma of middle and lower rectum.
      ]. Others ranged between 75.0 and 96.0% and one was limited to 34.0% [
      • Engineer R.
      • Mohandas K.M.
      • Shukla P.J.
      • Shrikhande S.V.
      • Mahantshetty U.
      • Chopra S.
      • et al.
      Escalated radiation dose alone vs. concurrent chemoradiation for locally advanced and unresectable rectal cancers: results from phase II randomized study.
      ]. Three studies did not report resectability rate. Most common reasons to omit surgery were disease progression, distant metastasis or patient refusal. Surgical complication data were scarce for the ⩾60 Gy sub(group) specifically. Six studies reported wound infection, dehiscence or delayed healing problems in 0.0–16.0% [
      • Rouanet P.S.-A.B.
      • Lemanski C.
      • Senesse P.
      • Gourgou S.
      • Quenet F.
      • et al.
      Restorative and nonrestorative surgery for low rectal cancer after high-dose radiation: long-term oncologic and functional results.
      ,
      • Jakobsen A.
      • Mortensen J.P.
      • Bisgaard C.
      • Lindebjerg J.
      • Hansen J.W.
      • Rafaelsen S.R.
      Preoperative chemoradiation of locally advanced T3 rectal cancer combined with an endorectal boost.
      ,
      • Movsas B.
      • Diratzouian H.
      • Hanlon A.
      • Cooper H.
      • Freedman G.
      • Konski A.
      • et al.
      Phase II trial of preoperative chemoradiation with a hyperfractionated radiation boost in locally advanced rectal cancer.
      ,
      • Vestermark L.W.
      • Jacobsen A.
      • Qvortrup C.
      • Hansen F.
      • Bisgaard C.
      • Baatrup G.
      • et al.
      Long-term results of a phase II trial of high-dose radiotherapy (60 Gy) and UFT/l-leucovorin in patients with non-resectable locally advanced rectal cancer (LARC).
      ,
      • Maluta S.
      • Romano M.
      • Dall’oglio S.
      • Genna M.
      • Oliani C.
      • Pioli F.
      • et al.
      Regional hyperthermia added to intensified preoperative chemo-radiation in locally advanced adenocarcinoma of middle and lower rectum.
      ,
      • Jakobsen A.
      • Ploen J.
      • Vuong T.
      • Appelt A.
      • Lindebjerg J.
      • Rafaelsen S.R.
      Dose-effect relationship in chemoradiotherapy for locally advanced rectal cancer: a randomized trial comparing two radiation doses.
      ], one patient required small bowel resection [
      • Meade P.G.
      • Blatchford G.J.
      • Thorson A.G.
      • Christensen M.A.
      • Ternent C.A.
      Preoperative chemoradiation downstages locally advanced ultrasound-staged rectal cancer.
      ], and two studies reported surgical complications in all patients [
      • Meade P.G.
      • Blatchford G.J.
      • Thorson A.G.
      • Christensen M.A.
      • Ternent C.A.
      Preoperative chemoradiation downstages locally advanced ultrasound-staged rectal cancer.
      ,
      • Engineer R.
      • Mohandas K.M.
      • Shukla P.J.
      • Shrikhande S.V.
      • Mahantshetty U.
      • Chopra S.
      • et al.
      Escalated radiation dose alone vs. concurrent chemoradiation for locally advanced and unresectable rectal cancers: results from phase II randomized study.
      ]. Eight studies used some form of standardized pathologic response assessment, of which four explicitly used the Mandard tumor regression grade (TRG) [
      • Mandard A.M.
      • Dalibard F.
      • Mandard J.C.
      • Marnay J.
      • Henry-Amar M.
      • Petiot J.F.
      • et al.
      Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations.
      ].
      After critical appraisal 14 studies remained eligible for meta-analysis, representing 90.4% (487 of 539) of patients (Table 2). Unexplained inter-study variance (I2) was low for pCR pooling (0.0%, 95% CI 0.0–84.0%) and intermediate for grade ⩾3 toxicity and resectability pooling (66.2%, 95% CI 25.5–89.6%, and 80.3%, 95% CI 56.1–92.9%, respectively). Consequently, a fixed effects model was used to calculate the pCR-rate estimate, and a random effects model for the grade ⩾3 toxicity and resectability estimates. pCR-rate varied considerably between studies, from 0.0 to 44.4%. The pooled pCR-rate estimate was 20.4% (95% CI 16.8–24.5%) (see Fig. 2). The funnel plot did not show asymmetry (Kendall’s tau = −0.07, p = 0.74) [
      • Begg C.B.
      • Mazumdar M.
      Operating characteristics of a rank correlation test for publication bias.
      ] (see Supplement). Additionally, the first sensitivity analysis, excluding negative outlier pCR-rates below 15%, estimated the pCR-rate at 22.9% (95% CI 18.7–27.6%) and the second sensitivity analysis, using only studies with EQD2 doses of ⩾60 Gy, estimated the pCR-rate at 18.1% (95% CI 13.9–23.2%) (see Fig. 2).
      Figure thumbnail gr2
      Fig. 2Meta-analysis forest plot of pCR-rates and pooled estimate in comparison to a reference line of control group (14.8%)
      [
      • Sanghera P.
      • Wong D.W.
      • McConkey C.C.
      • Geh J.I.
      • Hartley A.
      Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response.
      ]
      (pCR = pathological complete response).
      Acute grade ⩾3 toxicity for boost patients was reliably reported in 11 of 18 studies. Data on late toxicity specifically for boost patients were scarce and therefore not further discussed in this paper. Acute toxicity consisted mostly of gastro-intestinal complaints, dermatitis, leukopenia/neutropenia and pain. Grade ⩾3 toxicity was low (⩽10%) in seven studies, higher in three (13.6, 33.0 and 42.6%) and a single-patient study had 100% (see Table 1) [
      • Meade P.G.
      • Blatchford G.J.
      • Thorson A.G.
      • Christensen M.A.
      • Ternent C.A.
      Preoperative chemoradiation downstages locally advanced ultrasound-staged rectal cancer.
      ]. There was no asymmetry in the funnel plot (Kendall’s tau = −0.1, p = 0.76) (see Supplement). The acute grade ⩾3 toxicity estimate was 10.3% (95% CI 5.4–18.6%) (see Fig. 3). The resectability estimate was 89.5% (95% CI 78.2–95.3%) (see Fig. 3).
      Figure thumbnail gr3
      Fig. 3Forest plot of available acute grade ⩾3 toxicity and resectability with pooled estimate.
      Total EQD2 dose did not correlate with acute grade ⩾3 toxicity (Pearson −0.17, p > 0.62) or resectability (Pearson −0.29, p < 0.33). pCR-rate was not correlated with total EQD2 dose (Pearson 0.44, p > 0.88), chemotherapy (5-FU only vs. 5-FU + Oxaliplatin) (Pearson 0.06, p > 0.83), boost-approach type (EBRT, Brachy or EBRT/Brachy combination) (Pearson 0.06, p > 0.85), nor with length of interval between radiotherapy and surgery (Pearson 0.10, p > 0.74).

      Discussion

      This meta-analysis shows a pCR-rate of 20.4% after preoperative ⩾60 Gy radiation in patients with LARC, which was associated with low (10.3%) acute grade ⩾3 toxicity and a high resectability rate (89.5%). Furthermore, no correlation between pCR-rate and toxicity, resectability, boost approach, chemotherapy or surgical interval was found.
      The calculated pCR-rate estimate of this meta-analysis is in line with the prediction of the previously mentioned mathematical and clinical dose–response prediction models. These models further predict an exponential pCR-rate increase, i.e. degree of tumor cell destruction, which occurs after linear dose-escalation above 60 Gy. This is visualized by their S-shaped dose–response curve [
      • Sanghera P.
      • Wong D.W.
      • McConkey C.C.
      • Geh J.I.
      • Hartley A.
      Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response.
      ,
      • Appelt A.L.
      • Ploen J.
      • Vogelius I.R.
      • Bentzen S.M.
      • Jakobsen A.
      Radiation dose-response model for locally advanced rectal cancer after preoperative chemoradiation therapy.
      ]. We also showed that dose-escalation ⩾60 Gy yielded comparable toxicity-rates as observed in direct and indirect control groups after standard dose [
      • Mohiuddin M.
      • Winter K.
      • Mitchell E.
      • Hanna N.
      • Yuen A.
      • Nichols C.
      • et al.
      Randomized phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer: radiation therapy oncology group trial 0012.
      ,
      • Jakobsen A.
      • Ploen J.
      • Vuong T.
      • Appelt A.
      • Lindebjerg J.
      • Rafaelsen S.R.
      Dose-effect relationship in chemoradiotherapy for locally advanced rectal cancer: a randomized trial comparing two radiation doses.
      ,
      • Engineer R.
      • Mohandas K.M.
      • Shukla P.J.
      • Shrikhande S.V.
      • Mahantshetty U.
      • Chopra S.
      • et al.
      Escalated radiation dose alone vs. concurrent chemoradiation for locally advanced and unresectable rectal cancers: results from phase II randomized study.
      ,
      • Swellengrebel H.A.
      • Marijnen C.A.
      • Verwaal V.J.
      • Vincent A.
      • Heuff G.
      • Gerhards M.F.
      • et al.
      Toxicity and complications of preoperative chemoradiotherapy for locally advanced rectal cancer.
      ] or after SIB boost technique of 55.2 Gy [
      • Engels B.
      • Platteaux N.
      • Van den Begin R.
      • Gevaert T.
      • Sermeus A.
      • Storme G.
      • et al.
      Preoperative intensity-modulated and image-guided radiotherapy with a simultaneous integrated boost in locally advanced rectal cancer: report on late toxicity and outcome.
      ]. Wiltshire et al. [
      • Wiltshire K.L.
      • Ward I.G.
      • Swallow C.
      • Oza A.M.
      • Cummings B.
      • Pond G.R.
      • et al.
      Preoperative radiation with concurrent chemotherapy for resectable rectal cancer: effect of dose escalation on pathologic complete response, local recurrence-free survival, disease-free survival, and overall survival.
      ] also found a non-linear relation between dose-increase and toxicity, since their 40 Gy, 46 Gy, and 50 Gy dose levels were associated with 13%, 4%, and 14% acute grade ⩾3 toxicity, respectively. Although we looked at a larger dose interval, toxicity remained comparable. None of the studies included in this meta-analysis used IMRT. However, modern radiation and/or planning techniques may further contribute to reduced toxicity due to dose reduction to healthy tissue (especially bowel-dose) [
      • Parekh A.
      • Truong M.T.
      • Pashtan I.
      • Qureshi M.M.
      • Martin N.E.
      • Nawaz O.
      • et al.
      Acute gastrointestinal toxicity and tumor response with preoperative intensity modulated radiation therapy for rectal cancer.
      ]. Furthermore, we observed no confounding between type of concurrent chemotherapy (or radio-sensitizer) and pCR-rate. This was also previously illustrated in several studies that found comparable pCR-rates for different sources of 5-FU [
      • Hofheinz R.D.
      • Wenz F.
      • Post S.
      • Matzdorff A.
      • Laechelt S.
      • Hartmann J.T.
      • et al.
      Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial.
      ,
      • Chan A.K.
      • Wong A.O.
      • Jenken D.A.
      Preoperative capecitabine and pelvic radiation in locally advanced rectal cancer–is it equivalent to 5-FU infusion plus leucovorin and radiotherapy?.
      ,
      • Yerushalmi R.
      • Idelevich E.
      • Dror Y.
      • Stemmer S.M.
      • Figer A.
      • Sulkes A.
      • et al.
      Preoperative chemoradiation in rectal cancer: retrospective comparison between capecitabine and continuous infusion of 5-fluorouracil.
      ,
      • Das P.
      • Lin E.H.
      • Bhatia S.
      • Skibber J.M.
      • Rodriguez-Bigas M.A.
      • Feig B.W.
      • et al.
      Preoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: a matched-pair analysis.
      ,
      • Saif M.W.
      • Hashmi S.
      • Zelterman D.
      • Almhanna K.
      • Kim R.
      Capecitabine vs continuous infusion 5-FU in neoadjuvant treatment of rectal cancer. A retrospective review.
      ], or when Leucovorin was added as a synergistic agent [
      • Bin Q.
      • Li J.
      • Liao C.
      • Cao Y.
      • Gao F.
      Oral uracil-tegafur plus leucovorin vs fluorouracil bolus plus leucovorin for advanced colorectal cancer: a meta-analysis of five randomized controlled trials.
      ]. Neither is there consistent evidence that combination chemotherapy of 5-FU with Oxaliplatin [
      • Gerard J.P.
      • Azria D.
      • Gourgou-Bourgade S.
      • Martel-Laffay I.
      • Hennequin C.
      • Etienne P.L.
      • et al.
      Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2.
      ,
      • Arbea L.
      • Martinez-Monge R.
      • Diaz-Gonzalez J.A.
      • Moreno M.
      • Rodriguez J.
      • Hernandez J.L.
      • et al.
      Four-week neoadjuvant intensity-modulated radiation therapy with concurrent capecitabine and oxaliplatin in locally advanced rectal cancer patients: a validation phase II trial.
      ,
      • Dipetrillo T.
      • Pricolo V.
      • Lagares-Garcia J.
      • Vrees M.
      • Klipfel A.
      • Cataldo T.
      • et al.
      Neoadjuvant bevacizumab, oxaliplatin, 5-fluorouracil, and radiation for rectal cancer.
      ,
      • Martin LK
      • Bekaii-Saab T
      Optimizing neoadjuvant therapy for rectal cancer with oxaliplatin.
      ,
      • O’Connell M.J.
      • Colangelo L.H.
      • Beart R.W.
      • Petrelli N.J.
      • Allegra C.J.
      • Sharif S.
      • et al.
      Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from national surgical adjuvant breast and bowel project trial R-04.
      ] or Irinotecan [
      • Hofheinz R.D.
      • von Gerstenberg-Helldorf B.
      • Wenz F.
      • Gnad U.
      • Kraus-Tiefenbacher U.
      • Muldner A.
      • et al.
      Phase I trial of capecitabine and weekly irinotecan in combination with radiotherapy for neoadjuvant therapy of rectal cancer.
      ,
      • Klautke G.
      • Kuchenmeister U.
      • Foitzik T.
      • Ludwig K.
      • Prall F.
      • Klar E.
      • et al.
      Concurrent chemoradiation with capecitabine and weekly irinotecan as preoperative treatment for rectal cancer: results from a phase I/II study.
      ,
      • Willeke F.
      • Horisberger K.
      • Kraus-Tiefenbacher U.
      • Wenz F.
      • Leitner A.
      • Hochhaus A.
      • et al.
      A phase II study of capecitabine and irinotecan in combination with concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer.
      ] significantly improved pCR-rates, since only the German CAO/ARO/AIO-04 trial found 17% vs. 13% pCR (odds ratio 1.40, 95% CI 1.02–1.92; p = 0.038) with and without Oxaliplatin respectively [
      • Rodel C.
      • Liersch T.
      • Becker H.
      • Fietkau R.
      • Hohenberger W.
      • Hothorn T.
      • et al.
      Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial.
      ]. Nevertheless, it is evident that these combined therapies increase acute grade ⩾3 toxicity (mostly gastro-intestinal complaints, dermatitis and peripheral neuropathy). Therefore, we are confident that neither chemotherapy type nor its dose influenced the pooled pCR-rate estimate, which restrained us from calculating a biological effective dose for each chemotherapy type and its dose-level. We excluded studies using contact radiotherapy (CXR) since dose distribution is considerably different from other radiation methods. However, this technique could be used to deliver high doses to distal, small (less advanced), well-selected (remaining) lesions. Broad experience shows that CXR can however be safely combined with external-beam radiotherapy [
      • Gerard J.P.
      • Chapet O.
      • Ramaioli A.
      • Romestaing P.
      Long-term control of T2–T3 rectal adenocarcinoma with radiotherapy alone.
      ,
      • Gerard J.P.
      • Ortholan C.
      • Benezery K.
      • Ginot A.
      • Hannoun-Levi J.M.
      • Chamorey E.
      • et al.
      Contact X-ray therapy for rectal cancer: experience in Centre Antoine-Lacassagne, Nice, 2002–2006.
      ,
      • Maingon P.
      • Guerif S.
      • Darsouni R.
      • Salas S.
      • Barillot I.
      • d’Hombres A.
      • et al.
      Conservative management of rectal adenocarcinoma by radiotherapy.
      ,
      • Sun Myint A.
      • Grieve R.J.
      • McDonald A.C.
      • Levine E.L.
      • Ramani S.
      • Perkins K.
      • et al.
      Combined modality treatment of early rectal cancer: the UK experience.
      ,
      • Gerard J.P.
      • Romestaing P.
      • Chapet O.
      Radiotherapy alone in the curative treatment of rectal carcinoma.
      ], and could improve ‘good response’ rates and sphincter preservation rates in those tumors [
      • Gerard J.P.
      • Chapet O.
      • Nemoz C.
      • Hartweig J.
      • Romestaing P.
      • Coquard R.
      • et al.
      Improved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: the lyon R96–02 randomized trial.
      ].
      The strength of this study is that it provides a reliable and robust pCR-rate estimate based on a systematic study selection and intention-to-treat analysis. Furthermore, the low heterogeneity between studies allowed to use a fixed-effects model to calculate a robust pCR-rate estimate, since this is a powerful tool to reveal a pattern of the true effects-size among more studies. Also, this could then be compared to a well-based estimate for a ‘control’ population [
      • Maas M.
      • Nelemans P.J.
      • Valentini V.
      • Das P.
      • Rodel C.
      • Kuo L.J.
      • et al.
      Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
      ,
      • Sanghera P.
      • Wong D.W.
      • McConkey C.C.
      • Geh J.I.
      • Hartley A.
      Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response.
      ]. Nevertheless, inter-study pCR variability was present and most likely depends on case-mix. However, such notable spread is not only present in our selected ‘boost population’ but is also present within the identified control populations presented by Maas et al. and Sanghera et al. [
      • Maas M.
      • Nelemans P.J.
      • Valentini V.
      • Das P.
      • Rodel C.
      • Kuo L.J.
      • et al.
      Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
      ,
      • Sanghera P.
      • Wong D.W.
      • McConkey C.C.
      • Geh J.I.
      • Hartley A.
      Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response.
      ]. Furthermore, all doses from different radiation treatments (EBRT-SIB, -sequential or brachytherapy) were recalculated to EQD2 doses to provide an optimal comparison method and dose–response analysis over all approaches together.
      The limitations of this study concern study selection, reporting, pathological assessment and timing of surgery. Firstly, our critical appraisal excluded four studies from the meta-analysis because pCR-rates could not be recalculated from the provided data, leading to a smaller number of patients to pool. Nevertheless, we do not expect that those excluded studies would dramatically have influenced the pooled pCR-rate estimate since these studies represented only 9.6% (n = 52) of the original identified sample of 539 patients. Nor did studies with <60 Gy EQD2-doses influence pCR-rate estimates. This robustness was indicated by the small positive 2.5% and negative 2.3% pCR-rate shift after sensitivity analyses that excluded ‘negative outliers’ or studies with EQD2 doses ⩾60 Gy, respectively. However, small numbers are unfortunately inherent to feasibility, dose-finding and early phase (I–II) trials which leaves the opportunity to further strengthen the evidence by conducting larger randomized dose-escalation trials. Secondly, we were not able to study the association between T- or N-stage and pCR-rates since for most studies response rate according to T-/N-stage was not reported. Third, the pCR-rate estimate might still be underestimated since pathologic response could only be obtained from operated patients. Despite our intention-to-treat analysis, and although the resectability rate was high, more patients might have experienced a complete response. However, we conservatively assumed all non-surgical patients to have non-pCR which might be incorrect since in some patients surgery was omitted for other reasons such as a worsened condition, newly diagnosed metastasis or patient’s refusal. Fourth, the pathologic assessment was different between studies, and therefore prone to bias. Ten of 14 included studies standardized assessment, of which 3 explicitly used Mandard’s score [
      • Mandard A.M.
      • Dalibard F.
      • Mandard J.C.
      • Marnay J.
      • Henry-Amar M.
      • Petiot J.F.
      • et al.
      Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations.
      ]. Others only mentioned that one pathologist assessed if there was ‘absence of viable tumor cells’ in the specimen. Fifth, destruction of solitary tumor cells may continue long after termination of radiotherapy, indicating that timing of surgery impacts response assessment. Three studies have shown increased pCR-rates when surgery was postponed from 8 to 11 weeks post-radiation (from 11.5 to 14.0%) [
      • Sloothaak D.A.
      • Geijsen D.E.
      • van Leersum N.J.
      • Punt C.J.
      • Buskens C.J.
      • Bemelman W.A.
      • et al.
      Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer.
      ], and when shorter surgical intervals are compared to intervals of >6–8, or >7, weeks (from 13.7 to 19.5%, and 16 to 28.0% respectively) [
      • Petrelli F.
      • Sgroi G.
      • Sarti E.
      • Barni S.
      Increasing the interval between neoadjuvant chemoradiotherapy and surgery in rectal cancer: a meta-analysis of published studies.
      ,
      • Wolthuis A.M.
      • Penninckx F.
      • Haustermans K.
      • De Hertogh G.
      • Fieuws S.
      • Van Cutsem E.
      • et al.
      Impact of interval between neoadjuvant chemoradiotherapy and TME for locally advanced rectal cancer on pathologic response and oncologic outcome.
      ]. A relative risk of 1.42 (1.19–1.68) for pCR was reported for intervals longer than 6–8 weeks as compared to intervals shorter than 6–8 weeks. Nevertheless, in our data we did not see an association between interval-length and pCR-rate, presumably because pCR-rate varied largely at each interval length with only a few studies available per interval-length point in the analysis. Such variation is common, and therefore often observed in systematic reviews on pCR-rates following CRT [
      • Maas M.
      • Nelemans P.J.
      • Valentini V.
      • Das P.
      • Rodel C.
      • Kuo L.J.
      • et al.
      Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
      ,
      • Sanghera P.
      • Wong D.W.
      • McConkey C.C.
      • Geh J.I.
      • Hartley A.
      Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response.
      ,
      • Foster J.D.
      • Jones E.L.
      • Falk S.
      • Cooper E.J.
      • Francis N.K.
      Timing of surgery after long-course neoadjuvant chemoradiotherapy for rectal cancer: a systematic review of the literature.
      ]. To further investigate the impact of prolonged intervals on pCR-rate and sphincter preservation, several randomized clinical trials are currently recruiting (GRECCAR6/NCT01648894 [
      • Lefevre J.H.
      • Rousseau A.
      • Svrcek M.
      • Parc Y.
      • Simon T.
      • Tiret E.
      • et al.
      A multicentric randomized controlled trial on the impact of lengthening the interval between neoadjuvant radiochemotherapy and surgery on complete pathological response in rectal cancer (GRECCAR-6 trial): rationale and design.
      ] and NCT01037049). Nonetheless, if such presumed time-effects allow extrapolation to when doses are escalated, pCR-rates and organ-preservation might even further benefit when longer intervals prove to be safe. Sixth, only a single study reported interval between radiotherapy and brachytherapy, which did not allow further meta-analysis. Finally, accelerated treatment (higher dose per fraction, i.e. simultaneous integrated boost) increases the biological effective dose which may benefit response [
      • Thames Jr., H.D.
      • Peters L.J.
      • Withers H.R.
      • Fletcher G.H.
      Accelerated fractionation vs. hyperfractionation: rationales for several treatments per day.
      ,
      • Withers H.R.
      Biologic basis for altered fractionation schemes.
      ], especially when tumor-regrowth time is short [
      • Ang K.K.
      • Peters L.J.
      • Weber R.S.
      • Maor M.H.
      • Morrison W.H.
      • Wendt C.D.
      • et al.
      Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx.
      ,
      • Withers H.R.
      • Taylor J.M.
      • Maciejewski B.
      The hazard of accelerated tumor clonogen repopulation during radiotherapy.
      ]. Nevertheless, some of these accelerated schedules remain challenging because of considerable toxicity [
      • Movsas B.
      • Hanlon A.L.
      • Lanciano R.
      • Scher R.M.
      • Weiner L.M.
      • Sigurdson E.R.
      • et al.
      Phase I dose escalating trial of hyperfractionated pre-operative chemoradiation for locally advanced rectal cancer.
      ,
      • Mohiuddin M.
      • Winter K.
      • Mitchell E.
      • Hanna N.
      • Yuen A.
      • Nichols C.
      • et al.
      Randomized phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer: radiation therapy oncology group trial 0012.
      ,
      • Freedman G.M.
      • Meropol N.J.
      • Sigurdson E.R.
      • Hoffman J.
      • Callahan E.
      • Price R.
      • et al.
      Phase I trial of preoperative hypofractionated intensity-modulated radiotherapy with incorporated boost and oral capecitabine in locally advanced rectal cancer.
      ,
      • Kim D.Y.
      • Kim T.H.
      • Jung K.H.
      • Chang H.J.
      • Lim S.B.
      • Choi H.S.
      • et al.
      Preoperative chemoradiotherapy with concomitant small field boost irradiation for locally advanced rectal cancer: a multi-institutional phase II study (KROG 04–01).
      ,
      • Myerson R.J.
      • Valentini V.
      • Birnbaum E.H.
      • Cellini N.
      • Coco C.
      • Fleshman J.W.
      • et al.
      A phase I/II trial of three-dimensionally planned concurrent boost radiotherapy and protracted venous infusion of 5-FU chemotherapy for locally advanced rectal carcinoma.
      ] and peri/post-operative complications [
      • Myerson R.J.
      • Valentini V.
      • Birnbaum E.H.
      • Cellini N.
      • Coco C.
      • Fleshman J.W.
      • et al.
      A phase I/II trial of three-dimensionally planned concurrent boost radiotherapy and protracted venous infusion of 5-FU chemotherapy for locally advanced rectal carcinoma.
      ,
      • Janjan N.A.
      • Crane C.N.
      • Feig B.W.
      • Cleary K.
      • Dubrow R.
      • Curley S.A.
      • et al.
      Prospective trial of preoperative concomitant boost radiotherapy with continuous infusion 5-fluorouracil for locally advanced rectal cancer.
      ]. It is likely that such toxicity originates from irradiation of surrounding tissues instead of the tumor, as a result of a previously acquired treatment plan not taking into account tumor-shrinkage during the course of radiation. The most optimal schedule for high doses thus remains to be investigated in the future.
      In the future disease monitoring will become progressively important. To discover that some patients do not respond, and will thus not benefit from additional radiation, should not be kept until surgery. Response should rather be monitored all along neo-adjuvant treatment to prevent over-treatment and create the opportunity to adjust an ongoing treatment. This demands sensitive response-prediction tools employable concurrently to CRT. Such a non-invasive method capable of differentiating pathological good (TRG1–2) from bad/none responders (TRG3–5) early during CRT is diffusion-weighted MRI (DWI) [
      • Intven M.
      • Reerink O.
      • Philippens M.E.
      Diffusion-weighted MRI in locally advanced rectal cancer: pathological response prediction after neo-adjuvant radiochemotherapy.
      ,
      • Lambrecht M.
      • Vandecaveye V.
      • De Keyzer F.
      • Roels S.
      • Penninckx F.
      • Van Cutsem E.
      • et al.
      Value of diffusion-weighted magnetic resonance imaging for prediction and early assessment of response to neoadjuvant radiochemotherapy in rectal cancer: preliminary results.
      ]. At the same time, this creates opportunity to identify those tumors likely to benefit from a sequential radiation boost. Whereas the oncological outcome benefit for patients that reach pCR seems favorable, contradictory outcomes have been published after reaching a near pCR, ranging from good prognosis (comparable to pCR) [
      • Vecchio F.M.
      • Valentini V.
      • Minsky B.D.
      • Padula G.D.
      • Venkatraman E.S.
      • Balducci M.
      • et al.
      The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer.
      ,
      • Beddy D.
      • Hyland J.M.
      • Winter D.C.
      • Lim C.
      • White A.
      • Moriarty M.
      • et al.
      A simplified tumor regression grade correlates with survival in locally advanced rectal carcinoma treated with neoadjuvant chemoradiotherapy.
      ,
      • Agarwal A.
      • Chang G.J.
      • Hu C.Y.
      • Taggart M.
      • Rashid A.
      • Park I.J.
      • et al.
      Quantified pathologic response assessed as residual tumor burden is a predictor of recurrence-free survival in patients with rectal cancer who undergo resection after neoadjuvant chemoradiotherapy.
      ] to poor prognosis (comparable to poor pathological response) [
      • Swellengrebel H.A.
      • Bosch S.L.
      • Cats A.
      • Vincent A.D.
      • Dewit L.G.
      • Verwaal V.J.
      • et al.
      Tumour regression grading after chemoradiotherapy for locally advanced rectal cancer: a near pathologic complete response does not translate into good clinical outcome.
      ,
      • Gosens M.J.
      • Klaassen R.A.
      • Tan-Go I.
      • Rutten H.J.
      • Martijn H.
      • van den Brule A.J.
      • et al.
      Circumferential margin involvement is the crucial prognostic factor after multimodality treatment in patients with locally advanced rectal carcinoma.
      ,
      • Rodel C.
      • Martus P.
      • Papadoupolos T.
      • Fuzesi L.
      • Klimpfinger M.
      • Fietkau R.
      • et al.
      Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer.
      ,
      • Gavioli M.
      • Luppi G.
      • Losi L.
      • Bertolini F.
      • Santantonio M.
      • Falchi A.M.
      • et al.
      Incidence and clinical impact of sterilized disease and minimal residual disease after preoperative radiochemotherapy for rectal cancer.
      ]. For these patients, with a proven radiation-sensitivity but near complete response, early response-assessment could form a future tool to select them to undergo additional boost radiation in order to further improve their response toward a cCR, which is in turn associated with better prognosis and anticipated improved quality-of-life if followed by an organ-preservation strategy.
      Dose escalation above 60 Gy for locally advanced rectal cancer results in high pCR-rates and acceptable early toxicity. This observation needs to be further investigated within larger randomized controlled phase 3 trials in the future.

      Conflict of interest statement

      There are no actual or potential conflicts of interest to declare.

      Appendix A. Supplementary data

      References

        • Maas M.
        • Nelemans P.J.
        • Valentini V.
        • Das P.
        • Rodel C.
        • Kuo L.J.
        • et al.
        Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
        Lancet Oncol. 2010; 11: 835-844
        • Vecchio F.M.
        • Valentini V.
        • Minsky B.D.
        • Padula G.D.
        • Venkatraman E.S.
        • Balducci M.
        • et al.
        The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer.
        Int J Radiat Oncol Biol Phys. 2005; 62: 752-760
        • Sanghera P.
        • Wong D.W.
        • McConkey C.C.
        • Geh J.I.
        • Hartley A.
        Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response.
        Clin Oncol. 2008; 20: 176-183
        • Bokkerink G.M.
        • de Graaf E.J.
        • Punt C.J.
        • Nagtegaal I.D.
        • Rutten H.
        • Nuyttens J.J.
        • et al.
        The CARTS study: chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery.
        BMC Surg. 2011; 11: 34
        • Pucciarelli S.
        • De Paoli A.
        • Guerrieri M.
        • La Torre G.
        • Maretto I.
        • De Marchi F.
        • et al.
        Local excision after preoperative chemoradiotherapy for rectal cancer: results of a multicenter phase II clinical trial.
        Dis Colon Rectum. 2013; 56: 1349-1356
        • Maas M.
        • Beets-Tan R.G.
        • Lambregts D.M.
        • Lammering G.
        • Nelemans P.J.
        • Engelen S.M.
        • et al.
        Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer.
        J Clin Oncol. 2011; 29: 4633-4640
        • Smith J.D.
        • Ruby J.A.
        • Goodman K.A.
        • Saltz L.B.
        • Guillem J.G.
        • Weiser M.R.
        • et al.
        Nonoperative management of rectal cancer with complete clinical response after neoadjuvant therapy.
        Ann Surg. 2012; 256: 965-972
        • Habr-Gama A.
        • Gama-Rodrigues J.
        • Sao Juliao G.P.
        • Proscurshim I.
        • Sabbagh C.
        • Lynn P.B.
        • et al.
        Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control.
        Int J Radiat Oncol Biol Phys. 2014; 88: 822-828
        • Chan A.K.
        • Wong A.O.
        • Langevin J.
        • Jenken D.
        • Heine J.
        • Buie D.
        • et al.
        Preoperative chemotherapy and pelvic radiation for tethered or fixed rectal cancer: a phase II dose escalation study.
        Int J Radiat Oncol Biol Phys. 2000; 48: 843-856
        • Overgaard M.
        • Overgaard J.
        • Sell A.
        Dose-response relationship for radiation therapy of recurrent, residual, and primarily inoperable colorectal cancer.
        Radiother Oncol. 1984; 1: 217-225
        • Wiltshire K.L.
        • Ward I.G.
        • Swallow C.
        • Oza A.M.
        • Cummings B.
        • Pond G.R.
        • et al.
        Preoperative radiation with concurrent chemotherapy for resectable rectal cancer: effect of dose escalation on pathologic complete response, local recurrence-free survival, disease-free survival, and overall survival.
        Int J Radiat Oncol Biol Phys. 2006; 64: 709-716
        • Appelt A.L.
        • Ploen J.
        • Vogelius I.R.
        • Bentzen S.M.
        • Jakobsen A.
        Radiation dose-response model for locally advanced rectal cancer after preoperative chemoradiation therapy.
        Int J Radiat Oncol Biol Phys. 2013; 85: 74-80
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • Mulrow C.
        • Gotzsche P.C.
        • Ioannidis J.P.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
        Ann Intern Med. 2009; 151: W65-W94
      1. Cancer EOfRaTo. Common terminology criteria for adverse events, v1.0–v4.03; 1994.

        • von Elm E.
        • Altman D.G.
        • Egger M.
        • Pocock S.J.
        • Gotzsche P.C.
        • Vandenbroucke J.P.
        • et al.
        The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
        Lancet. 2007; 370: 1453-1457
        • Viechtbauer W.
        Conducting meta-analyses in R with the metafor package.
        J Stat Softw. 2010; 36: 1-48
        • Marks G.
        • Mohiuddin M.
        • Masoni L.
        The reality of radical sphincter preservation surgery for cancer of the distal 3 cm of rectum following high-dose radiation.
        Int J Radiat Oncol Biol Phys. 1993; 27: 779-783
        • Meade P.G.
        • Blatchford G.J.
        • Thorson A.G.
        • Christensen M.A.
        • Ternent C.A.
        Preoperative chemoradiation downstages locally advanced ultrasound-staged rectal cancer.
        Am J Surgery. 1995; 170 (discussion 12–3): 609-612
        • Movsas B.
        • Hanlon A.L.
        • Lanciano R.
        • Scher R.M.
        • Weiner L.M.
        • Sigurdson E.R.
        • et al.
        Phase I dose escalating trial of hyperfractionated pre-operative chemoradiation for locally advanced rectal cancer.
        Int J Radiat Oncol Biol Phys. 1998; 42: 43-50
        • Mohiuddin M.
        • Regine W.F.
        • John W.J.
        • Hagihara P.F.
        • McGrath P.C.
        • Kenady D.E.
        • et al.
        Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response.
        Int J Radiat Oncol Biol Phys. 2000; 46: 883-888
        • Rouanet P.S.-A.B.
        • Lemanski C.
        • Senesse P.
        • Gourgou S.
        • Quenet F.
        • et al.
        Restorative and nonrestorative surgery for low rectal cancer after high-dose radiation: long-term oncologic and functional results.
        Dis Colon Rectum. 2002; 45: 305-313
        • Pfeiffer P.
        High-dose radiotherapy and concurrent UFT plus l-leucovorin in locally advanced rectal cancer: a phase I trial.
        Acta Oncol. 2005; 44: 224-229
        • Jakobsen A.
        • Mortensen J.P.
        • Bisgaard C.
        • Lindebjerg J.
        • Hansen J.W.
        • Rafaelsen S.R.
        Preoperative chemoradiation of locally advanced T3 rectal cancer combined with an endorectal boost.
        Int J Radiat Oncol Biol Phys. 2006; 64: 461-465
        • Mohiuddin M.
        • Winter K.
        • Mitchell E.
        • Hanna N.
        • Yuen A.
        • Nichols C.
        • et al.
        Randomized phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer: radiation therapy oncology group trial 0012.
        J Clin Oncol. 2006; 24: 650-655
        • Movsas B.
        • Diratzouian H.
        • Hanlon A.
        • Cooper H.
        • Freedman G.
        • Konski A.
        • et al.
        Phase II trial of preoperative chemoradiation with a hyperfractionated radiation boost in locally advanced rectal cancer.
        Am J Clin Oncol. 2006; 29: 435-441
        • Ho-Pun-Cheung A.
        • Assenat E.
        • Thezenas S.
        • Bibeau F.
        • Rouanet P.
        • Azria D.
        • et al.
        Cyclin D1 gene G870A polymorphism predicts response to neoadjuvant radiotherapy and prognosis in rectal cancer.
        Int J Radiat Oncol Biol Phys. 2007; 68: 1094-1101
        • Sun Myint A.
        • Lee C.D.
        • Snee A.J.
        • Perkins K.
        • Jelley F.E.
        • Wong H.
        High dose rate brachytherapy as a boost after preoperative chemoradiotherapy for more advanced rectal tumours - the clatterbridge experience.
        Clin Oncol (R Coll Radiol). 2007; 19: 711-719
        • Jakobsen A.
        • Mortensen J.P.
        • Bisgaard C.
        • Lindebjerg J.
        • Rafaelsen S.R.
        • Bendtsen V.O.
        A COX-2 inhibitor combined with chemoradiation of locally advanced rectal cancer: a phase II trial.
        Int J Colorectal Dis. 2008; 23: 251-255
        • Vestermark L.W.
        • Jacobsen A.
        • Qvortrup C.
        • Hansen F.
        • Bisgaard C.
        • Baatrup G.
        • et al.
        Long-term results of a phase II trial of high-dose radiotherapy (60 Gy) and UFT/l-leucovorin in patients with non-resectable locally advanced rectal cancer (LARC).
        Acta Oncol. 2008; 47: 428-433
        • Lindebjerg J.
        • Spindler K.L.
        • Ploen J.
        • Jakobsen A.
        The prognostic value of lymph node metastases and tumour regression grade in rectal cancer patients treated with long-course preoperative chemoradiotherapy.
        Colorectal Dis. 2009; 11: 264-269
        • Maluta S.
        • Romano M.
        • Dall’oglio S.
        • Genna M.
        • Oliani C.
        • Pioli F.
        • et al.
        Regional hyperthermia added to intensified preoperative chemo-radiation in locally advanced adenocarcinoma of middle and lower rectum.
        Int J Hyperthermia. 2010; 26: 108-117
        • Jakobsen A.
        • Ploen J.
        • Vuong T.
        • Appelt A.
        • Lindebjerg J.
        • Rafaelsen S.R.
        Dose-effect relationship in chemoradiotherapy for locally advanced rectal cancer: a randomized trial comparing two radiation doses.
        Int J Radiat Oncol Biol Phys. 2012; 84: 949-954
        • Vestermark L.W.
        • Jensen H.A.
        • Pfeiffer P.
        High-dose radiotherapy (60 Gy) with oral UFT/folinic acid and escalating doses of oxaliplatin in patients with non-resectable locally advanced rectal cancer (LARC): a phase I trial.
        Acta Oncol. 2012; 51: 311-317
        • Engineer R.
        • Mohandas K.M.
        • Shukla P.J.
        • Shrikhande S.V.
        • Mahantshetty U.
        • Chopra S.
        • et al.
        Escalated radiation dose alone vs. concurrent chemoradiation for locally advanced and unresectable rectal cancers: results from phase II randomized study.
        Int J Colorectal Dis. 2013; 28: 959-966
        • Mandard A.M.
        • Dalibard F.
        • Mandard J.C.
        • Marnay J.
        • Henry-Amar M.
        • Petiot J.F.
        • et al.
        Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations.
        Cancer. 1994; 73: 2680-2686
        • Begg C.B.
        • Mazumdar M.
        Operating characteristics of a rank correlation test for publication bias.
        Biometrics. 1994; 50: 1088-1101
        • Swellengrebel H.A.
        • Marijnen C.A.
        • Verwaal V.J.
        • Vincent A.
        • Heuff G.
        • Gerhards M.F.
        • et al.
        Toxicity and complications of preoperative chemoradiotherapy for locally advanced rectal cancer.
        Br J Surg. 2011; 98: 418-426
        • Engels B.
        • Platteaux N.
        • Van den Begin R.
        • Gevaert T.
        • Sermeus A.
        • Storme G.
        • et al.
        Preoperative intensity-modulated and image-guided radiotherapy with a simultaneous integrated boost in locally advanced rectal cancer: report on late toxicity and outcome.
        Radiother Oncol. 2014; 110: 155-159
        • Parekh A.
        • Truong M.T.
        • Pashtan I.
        • Qureshi M.M.
        • Martin N.E.
        • Nawaz O.
        • et al.
        Acute gastrointestinal toxicity and tumor response with preoperative intensity modulated radiation therapy for rectal cancer.
        Gastrointest Cancer Res. 2013; 6: 137-143
        • Hofheinz R.D.
        • Wenz F.
        • Post S.
        • Matzdorff A.
        • Laechelt S.
        • Hartmann J.T.
        • et al.
        Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial.
        Lancet Oncol. 2012; 13: 579-588
        • Chan A.K.
        • Wong A.O.
        • Jenken D.A.
        Preoperative capecitabine and pelvic radiation in locally advanced rectal cancer–is it equivalent to 5-FU infusion plus leucovorin and radiotherapy?.
        Int J Radiat Oncol Biol Phys. 2010; 76: 1413-1419
        • Yerushalmi R.
        • Idelevich E.
        • Dror Y.
        • Stemmer S.M.
        • Figer A.
        • Sulkes A.
        • et al.
        Preoperative chemoradiation in rectal cancer: retrospective comparison between capecitabine and continuous infusion of 5-fluorouracil.
        J Surg Oncol. 2006; 93: 529-533
        • Das P.
        • Lin E.H.
        • Bhatia S.
        • Skibber J.M.
        • Rodriguez-Bigas M.A.
        • Feig B.W.
        • et al.
        Preoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: a matched-pair analysis.
        Int J Radiat Oncol Biol Phys. 2006; 66: 1378-1383
        • Saif M.W.
        • Hashmi S.
        • Zelterman D.
        • Almhanna K.
        • Kim R.
        Capecitabine vs continuous infusion 5-FU in neoadjuvant treatment of rectal cancer. A retrospective review.
        Int J Colorectal Dis. 2008; 23: 139-145
        • Bin Q.
        • Li J.
        • Liao C.
        • Cao Y.
        • Gao F.
        Oral uracil-tegafur plus leucovorin vs fluorouracil bolus plus leucovorin for advanced colorectal cancer: a meta-analysis of five randomized controlled trials.
        Colorectal Dis. 2011; 13: 837-845
        • Gerard J.P.
        • Azria D.
        • Gourgou-Bourgade S.
        • Martel-Laffay I.
        • Hennequin C.
        • Etienne P.L.
        • et al.
        Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2.
        J Clin Oncol. 2010; 28: 1638-1644
        • Arbea L.
        • Martinez-Monge R.
        • Diaz-Gonzalez J.A.
        • Moreno M.
        • Rodriguez J.
        • Hernandez J.L.
        • et al.
        Four-week neoadjuvant intensity-modulated radiation therapy with concurrent capecitabine and oxaliplatin in locally advanced rectal cancer patients: a validation phase II trial.
        Int J Radiat Oncol Biol Phys. 2012; 83: 587-593
        • Dipetrillo T.
        • Pricolo V.
        • Lagares-Garcia J.
        • Vrees M.
        • Klipfel A.
        • Cataldo T.
        • et al.
        Neoadjuvant bevacizumab, oxaliplatin, 5-fluorouracil, and radiation for rectal cancer.
        Int J Radiat Oncol Biol Phys. 2012; 82: 124-129
        • Martin LK
        • Bekaii-Saab T
        Optimizing neoadjuvant therapy for rectal cancer with oxaliplatin.
        J Natl Compr Can Netw. 2013; 11 (quiz): 298-307
        • O’Connell M.J.
        • Colangelo L.H.
        • Beart R.W.
        • Petrelli N.J.
        • Allegra C.J.
        • Sharif S.
        • et al.
        Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from national surgical adjuvant breast and bowel project trial R-04.
        J Clin Oncol. 2014; 32: 1927-1934
        • Hofheinz R.D.
        • von Gerstenberg-Helldorf B.
        • Wenz F.
        • Gnad U.
        • Kraus-Tiefenbacher U.
        • Muldner A.
        • et al.
        Phase I trial of capecitabine and weekly irinotecan in combination with radiotherapy for neoadjuvant therapy of rectal cancer.
        J Clin Oncol. 2005; 23: 1350-1357
        • Klautke G.
        • Kuchenmeister U.
        • Foitzik T.
        • Ludwig K.
        • Prall F.
        • Klar E.
        • et al.
        Concurrent chemoradiation with capecitabine and weekly irinotecan as preoperative treatment for rectal cancer: results from a phase I/II study.
        Br J Cancer. 2006; 94: 976-981
        • Willeke F.
        • Horisberger K.
        • Kraus-Tiefenbacher U.
        • Wenz F.
        • Leitner A.
        • Hochhaus A.
        • et al.
        A phase II study of capecitabine and irinotecan in combination with concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer.
        Br J Cancer. 2007; 96: 912-917
        • Rodel C.
        • Liersch T.
        • Becker H.
        • Fietkau R.
        • Hohenberger W.
        • Hothorn T.
        • et al.
        Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial.
        Lancet Oncol. 2012; 13: 679-687
        • Gerard J.P.
        • Chapet O.
        • Ramaioli A.
        • Romestaing P.
        Long-term control of T2–T3 rectal adenocarcinoma with radiotherapy alone.
        Int J Radiat Oncol Biol Phys. 2002; 54: 142-149
        • Gerard J.P.
        • Ortholan C.
        • Benezery K.
        • Ginot A.
        • Hannoun-Levi J.M.
        • Chamorey E.
        • et al.
        Contact X-ray therapy for rectal cancer: experience in Centre Antoine-Lacassagne, Nice, 2002–2006.
        Int J Radiat Oncol Biol Phys. 2008; 72: 665-670
        • Maingon P.
        • Guerif S.
        • Darsouni R.
        • Salas S.
        • Barillot I.
        • d’Hombres A.
        • et al.
        Conservative management of rectal adenocarcinoma by radiotherapy.
        Int J Radiat Oncol Biol Phys. 1998; 40: 1077-1085
        • Sun Myint A.
        • Grieve R.J.
        • McDonald A.C.
        • Levine E.L.
        • Ramani S.
        • Perkins K.
        • et al.
        Combined modality treatment of early rectal cancer: the UK experience.
        Clini Oncol. 2007; 19: 674-681
        • Gerard J.P.
        • Romestaing P.
        • Chapet O.
        Radiotherapy alone in the curative treatment of rectal carcinoma.
        Lancet Oncol. 2003; 4: 158-166
        • Gerard J.P.
        • Chapet O.
        • Nemoz C.
        • Hartweig J.
        • Romestaing P.
        • Coquard R.
        • et al.
        Improved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: the lyon R96–02 randomized trial.
        J Clin Oncol. 2004; 22: 2404-2409
        • Sloothaak D.A.
        • Geijsen D.E.
        • van Leersum N.J.
        • Punt C.J.
        • Buskens C.J.
        • Bemelman W.A.
        • et al.
        Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer.
        Br J Surg. 2013; 100: 933-939
        • Petrelli F.
        • Sgroi G.
        • Sarti E.
        • Barni S.
        Increasing the interval between neoadjuvant chemoradiotherapy and surgery in rectal cancer: a meta-analysis of published studies.
        Ann Surg. 2013; 19: 2833
        • Wolthuis A.M.
        • Penninckx F.
        • Haustermans K.
        • De Hertogh G.
        • Fieuws S.
        • Van Cutsem E.
        • et al.
        Impact of interval between neoadjuvant chemoradiotherapy and TME for locally advanced rectal cancer on pathologic response and oncologic outcome.
        Ann Surg Oncol. 2012; 19: 2833-2841
        • Foster J.D.
        • Jones E.L.
        • Falk S.
        • Cooper E.J.
        • Francis N.K.
        Timing of surgery after long-course neoadjuvant chemoradiotherapy for rectal cancer: a systematic review of the literature.
        Dis Colon Rectum. 2013; 56: 921-930
        • Lefevre J.H.
        • Rousseau A.
        • Svrcek M.
        • Parc Y.
        • Simon T.
        • Tiret E.
        • et al.
        A multicentric randomized controlled trial on the impact of lengthening the interval between neoadjuvant radiochemotherapy and surgery on complete pathological response in rectal cancer (GRECCAR-6 trial): rationale and design.
        BMC cancer. 2013; 13: 417
        • Thames Jr., H.D.
        • Peters L.J.
        • Withers H.R.
        • Fletcher G.H.
        Accelerated fractionation vs. hyperfractionation: rationales for several treatments per day.
        Int J Radiat Oncol Biol Phys. 1983; 9: 127-138
        • Withers H.R.
        Biologic basis for altered fractionation schemes.
        Cancer. 1985; 55: 2086-2095
        • Ang K.K.
        • Peters L.J.
        • Weber R.S.
        • Maor M.H.
        • Morrison W.H.
        • Wendt C.D.
        • et al.
        Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx.
        Int J Radiat Oncol Biol Phys. 1990; 19: 1339-1345
        • Withers H.R.
        • Taylor J.M.
        • Maciejewski B.
        The hazard of accelerated tumor clonogen repopulation during radiotherapy.
        Acta Oncol. 1988; 27: 131-146
        • Freedman G.M.
        • Meropol N.J.
        • Sigurdson E.R.
        • Hoffman J.
        • Callahan E.
        • Price R.
        • et al.
        Phase I trial of preoperative hypofractionated intensity-modulated radiotherapy with incorporated boost and oral capecitabine in locally advanced rectal cancer.
        Int J Radiat Oncol Biol Phys. 2007; 67: 1389-1393
        • Kim D.Y.
        • Kim T.H.
        • Jung K.H.
        • Chang H.J.
        • Lim S.B.
        • Choi H.S.
        • et al.
        Preoperative chemoradiotherapy with concomitant small field boost irradiation for locally advanced rectal cancer: a multi-institutional phase II study (KROG 04–01).
        Dis Colon Rectum. 2006; 49: 1684-1691
        • Myerson R.J.
        • Valentini V.
        • Birnbaum E.H.
        • Cellini N.
        • Coco C.
        • Fleshman J.W.
        • et al.
        A phase I/II trial of three-dimensionally planned concurrent boost radiotherapy and protracted venous infusion of 5-FU chemotherapy for locally advanced rectal carcinoma.
        Int J Radiat Oncol Biol Phys. 2001; 50: 1299-1308
        • Janjan N.A.
        • Crane C.N.
        • Feig B.W.
        • Cleary K.
        • Dubrow R.
        • Curley S.A.
        • et al.
        Prospective trial of preoperative concomitant boost radiotherapy with continuous infusion 5-fluorouracil for locally advanced rectal cancer.
        Int J Radiat Oncol Biol Phys. 2000; 47: 713-718
        • Intven M.
        • Reerink O.
        • Philippens M.E.
        Diffusion-weighted MRI in locally advanced rectal cancer: pathological response prediction after neo-adjuvant radiochemotherapy.
        Strahlenther Onkol. 2013; 189: 117-122
        • Lambrecht M.
        • Vandecaveye V.
        • De Keyzer F.
        • Roels S.
        • Penninckx F.
        • Van Cutsem E.
        • et al.
        Value of diffusion-weighted magnetic resonance imaging for prediction and early assessment of response to neoadjuvant radiochemotherapy in rectal cancer: preliminary results.
        Int J Radiat Oncol Biol Phys. 2012; 82: 863-870
        • Beddy D.
        • Hyland J.M.
        • Winter D.C.
        • Lim C.
        • White A.
        • Moriarty M.
        • et al.
        A simplified tumor regression grade correlates with survival in locally advanced rectal carcinoma treated with neoadjuvant chemoradiotherapy.
        Ann Surg Oncol. 2008; 15: 3471-3477
        • Agarwal A.
        • Chang G.J.
        • Hu C.Y.
        • Taggart M.
        • Rashid A.
        • Park I.J.
        • et al.
        Quantified pathologic response assessed as residual tumor burden is a predictor of recurrence-free survival in patients with rectal cancer who undergo resection after neoadjuvant chemoradiotherapy.
        Cancer. 2013; 119: 4231-4241
        • Swellengrebel H.A.
        • Bosch S.L.
        • Cats A.
        • Vincent A.D.
        • Dewit L.G.
        • Verwaal V.J.
        • et al.
        Tumour regression grading after chemoradiotherapy for locally advanced rectal cancer: a near pathologic complete response does not translate into good clinical outcome.
        Radiother Oncol. 2014;
        • Gosens M.J.
        • Klaassen R.A.
        • Tan-Go I.
        • Rutten H.J.
        • Martijn H.
        • van den Brule A.J.
        • et al.
        Circumferential margin involvement is the crucial prognostic factor after multimodality treatment in patients with locally advanced rectal carcinoma.
        Clin Cancer Res. 2007; 13: 6617-6623
        • Rodel C.
        • Martus P.
        • Papadoupolos T.
        • Fuzesi L.
        • Klimpfinger M.
        • Fietkau R.
        • et al.
        Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer.
        J Clin Oncol. 2005; 23: 8688-8696
        • Gavioli M.
        • Luppi G.
        • Losi L.
        • Bertolini F.
        • Santantonio M.
        • Falchi A.M.
        • et al.
        Incidence and clinical impact of sterilized disease and minimal residual disease after preoperative radiochemotherapy for rectal cancer.
        Dis Colon Rectum. 2005; 48: 1851-1857