The CARTS study: Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery A COX-2 inhibitor combined with chemoradiation of locally advanced rectal cancer: a phase II trial Concurrent chemoradiation with capecitabine and weekly irinotecan as preoperative treatment for rectal cancer: results from a phase I/II study 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 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) Four-week neoadjuvant intensity-modulated radiation therapy with concurrent capecitabine and oxaliplatin in locally advanced rectal cancer patients: a validation phase II trial. Preoperative capecitabine and pelvic radiation in locally advanced rectal cancer--is it equivalent to 5-FU infusion plus leucovorin and radiotherapy? A phase II study of capecitabine and irinotecan in combination with concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer Preoperative Chemoradiotherapy with Concomitant Small Field Boost Irradiation for Locally Advanced Rectal Cancer: A Multi-Institutional Phase II Study (KROG 04-01) Nonoperative Management of Rectal Cancer With Complete Clinical Response After Neoadjuvant Therapy The hazard of accelerated tumor clonogen repopulation during radiotherapy. Restorative and Nonrestorative Surgery for Low Rectal Cancer After High-Dose Radiation Local Excision After Preoperative Chemoradiotherapy for Rectal Cancer: Results of a Multicenter Phase II Clinical Trial Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx. Biologic basis for altered fractionation schemes Diffusion-weighted MRI in locally advanced rectal cancer Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. Preoperative chemotherapy and pelvic radiation for tethered or fixed rectal cancer: a phase II dose escalation study. Improved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: the lyon R96-02 randomized trial. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. Phase I trial of preoperative hypofractionated intensity-modulated radiotherapy with incorporated boost and oral capecitabine in locally advanced rectal cancer. Prospective trial of preoperative concomitant boost radiotherapy with continuous infusion 5-fluorouracil for locally advanced rectal cancer. 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. Dose-effect relationship in chemoradiotherapy for locally advanced rectal cancer: a randomized trial comparing two radiation doses. Preoperative chemoradiation downstages locally advanced ultrasound-staged rectal cancer. High-dose radiotherapy and concurrent UFT plus l-leucovorin in locally advanced rectal cancer: A phase I trial Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Randomized phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer: Radiation Therapy Oncology Group Trial 0012. 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. Neoadjuvant bevacizumab, oxaliplatin, 5-fluorouracil, and radiation for rectal cancer. 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. Acute gastrointestinal toxicity and tumor response with preoperative intensity modulated radiation therapy for rectal cancer. Radiation dose-response model for locally advanced rectal cancer after preoperative chemoradiation therapy. Phase II Trial of Preoperative Chemoradiation With a Hyperfractionated Radiation Boost in Locally Advanced Rectal Cancer Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response. Phase I dose escalating trial of hyperfractionated pre-operative chemoradiation for locally advanced rectal cancer. Preoperative intensity-modulated and image-guided radiotherapy with a simultaneous integrated boost in locally advanced rectal cancer: report on late toxicity and outcome. 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. 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
Background The CARTS study is a multicenter feasibility study , investigating the role of rectum saving surgery for distal rectal cancer . Methods / Design Patients with a clinical T1 - 3 N0 M0 rectal adenocarcinoma below 10 cm from the anal verge will receive neoadjuvant chemoradiation therapy ( 25 fractions of 2 Gy with concurrent capecitabine ) . Transanal Endoscopic Microsurgery ( TEM ) will be performed 8 - 10 weeks after the end of the preoperative treatment depending on the clinical response . Primary objective is to determine the number of patients with a ( near ) complete pathological response after chemoradiation therapy and TEM . Secondary objectives are the local recurrence rate and quality of life after this combined therapeutic modality . A three-step analysis will be performed after 20 , 33 and 55 patients to ensure the feasibility of this treatment protocol . Discussion The CARTS- study is one of the first prospect i ve multicentre trials to investigate the role of a rectum saving treatment modality using chemoradiation therapy and local excision . The CARTS study is registered at clinical trials.gov ( NCT01273051 Background and aim The aim of this study was to investigate the possible effect of a COX-2 inhibitor in addition to chemoradiation of locally advanced rectal cancer . Material s and methods The study included 35 patients with rectal adenocarcinoma . All patients had a tumor localised ≤10 cm from the anal verge and a circumferential margin ≤5 mm on a magnetic resonance scan . The patients were scheduled to receive external radiation with a tumor dose of 60 Gy supplemented with an endorectal boost of 5 Gy . Concurrent with radiation , the patients received uracil-tegafur 300 mg/m2 daily . Celexocib was scheduled throughout the radiation period in a dose of 400 mg × 2 daily . Results A macular papular rash was seen in 17 ( 49 % ) of the patients leading to stop of medication with celecoxib . Thirty-three patients were operated , and all patients responded to treatment . Complete pathological remission was found in 21 % of the patients and further 24 % had only microscopic residual tumor cells . The results did not suggest any difference according to the accomplishment of the COX-2 medication . Conclusion The addition of a COX-2 inhibitor to chemotherapy-enhanced radiation treatment of rectal cancer was not feasible due to a high incidence of rash in the present study The aim of this study was to investigate the efficacy and safety of chemoradiation using capecitabine and irinotecan as neoadjuvant therapy for patients with rectal cancer .  Conventional radiation was given at daily fractions of 1.8 Gy on 5 days a week for a total dose of 55.8 ( 50.4 + 5.4 ) Gy . Concurrently , irinotecan 40 mg m−2 once weekly and capecitabine continuously at dose levels of 500 , 650 , 750 and 825 mg m−2 twice daily were administered . Surgery was performed 4–6 weeks following completion of chemoradiation . A total of 28 patients ( 3 UICC II , 25 UICC III ) were enrolled and all received treatment . Dose-limiting toxicity was diarrhoea grade IV and h and –foot syndrome at the 825 mg m−2 dose level . The maximum tolerated dose of capecitabine was 750 mg m−2 . Diarrhoea was the most common toxicity : grade III in nine patients . Two patients died , one due to pneumonia and one due to sudden cardiac death . A complete response and only microfocal residual tumour disease was achieved in four and three patients ( 27 % ) . In all , 25 of 28 patients undergoing surgery , 24 ( 96 % ) had R0 resection . Preoperative chemoradiation based on continuous daily capecitabine and weekly irinotecan appears to tolerated and effective in patients with rectal cancer Background Neoadjuvant radiochemotherapy ( RCT ) is now part of the armamentarium of cancer of the lower and middle rectum . It is recommended in current clinical practice prior to surgical excision if the lesion is classified T3/T4 or N+ . Histological complete response , defined by the absence of persistent tumor cell invasion and lymph node ( ypT0N0 ) after pathological examination of surgical specimen has been shown to be an independent prognostic factor of overall survival and disease-free survival . Surgical excision is usually performed between 6 and 8 weeks after completion of CRT and pathological complete response rate ranges around 12 % . In retrospective studies , a lengthening of the interval after RCT beyond 10 weeks was found as an independent factor increasing the rate of pathological complete response ( between 26 % and 31 % ) , with a longer disease-free survival and without increasing the operative morbidity . The aim of the present study is to evaluate in 264 patients the rate of pathological complete response rate of rectal cancer after RCT by lengthening the time between RCT and surgery . Methods / design The current study is a multicenter r and omized trial in two parallel groups comparing 7 and 11 weeks of delay between the end of RCT and cancer surgery of rectal tumors . At the end of the RCT , surgery is planified and r and omization is performed after patient ’s written consent for participation . The histological complete response ( ypT0N0 ) will be determined with analysis of the complete residual tumor and double reading by two pathologists blinded of the group of inclusion . Patients will be followed in clinics for 5 years after surgery . Participation in this trial does not change patient ’s management in terms of treatment , investigations or visits . Secondary endpoints will include overall and disease free survival , rate of sphincter conservation and quality of mesorectal excision .  The number of patients needed is 264.Trial registration Clinical Trial.gov : Background . Preoperative radiochemotherapy is a cornerstone in patients with non- resectable locally advanced rectal cancer ( LARC ) . To improve outcome ( number of R0 resections and survival ) high-dose radiotherapy ( RT ) was combined with oral UFT/l-leucovorin to allow tumour regression before radical intended surgery . Methods . Pelvic RT was delivered with megavoltage photons using a 5 field technique . RT was CT-based , given 5 days a week through one posterior field and two lateral fields ( 48.6 Gy/27 fractions ) to encompass the primary tumour and the regional lymph nodes . In addition , the tumour bed received a concurrent boost ( 5.4 Gy/27 fractions ) and a final boost ( 6 Gy/3 fractions ) ; thus GTV received 60 Gy/30 fractions . Concurrent with RT patients received a daily dose of oral UFT 300 mg/m2 plus l-leucovorin 22.5 mg 5/7days ( divided in three doses ) . Results . From September 2000 to November 2004 , 52 patients ( median age 60 years ( 32–83 ) ; median PS 0 ( 0–2 ) ) with LARC ( 36 primary , 16 recurrent ) were included in this phase II study . All but three patients received the planned 60 Gy , median duration of RT was 42 days ( 25–49 ) . Toxicity was very modest ; only four patients had a dose reduction of UFT . No hematological toxicity of clinical significance was seen . Non-hematological toxicity grade 1 ( GI-toxicity , fatigue and /or dysuria ) was frequently observed but only four patients experienced grade 3 toxicity ( diarrhoea and /or nausea/vomiting ) . Forty patients ( 77 % ) were operated ( 30 R0 , 5 R1 , 5 R2 ) median 55 days ( 27–112 ) after completion of RT . Seven ( 13 % ) patients had a pathological complete response ( pCR ) . Thirty-one patients ( 60 % ) died after median 25.4 months ( 1.6–45.2 months ) . Twenty-one patients ( 40 % ) are still alive June 2007 . Conclusions . Preoperative high-dose RT and concomitant UFT produces major regression in most patients with non-resectable LARC and thus a good chance of cure PURPOSE To vali date tolerance and pathological complete response rate ( pCR ) of a 4-week preoperative course of intensity-modulated radiation therapy ( IMRT ) with concurrent capecitabine and oxaliplatin ( CAPOX ) in patients with locally advanced rectal cancer . METHODS AND MATERIAL S Patients with T3 to T4 and /or N+ rectal cancer received preoperative IMRT ( 47.5 Gy in 19 fractions ) with concurrent capecitabine ( 825 mg/m(2 ) b.i.d . , Monday to Friday ) and oxaliplatin ( 60 mg/m(2 ) on Days 1 , 8 , and 15 ) . Surgery was scheduled 4 to 6 weeks after the completion of chemoradiation . Primary end points were toxicity and pathological response rate . Local control ( LC ) , disease-free survival ( DFS ) , and overall survival ( OS ) were also analyzed . RESULTS A total of 100 patients were evaluated .  Grade 1 to 2 proctitis was observed in 73 patients ( 73 % ) . Grade 3 diarrhea occurred in 9 % of the patients . Grade 3 proctitis in 18 % of the first 50 patients led to reduction of the dose per fraction to 47.5 Gy in 20 treatments . The rate of Grade 3 proctitis decreased to 4 % thereafter ( odds ratio , 0.27 ) . A total of 99 patients underwent surgery . A pCR was observed in 13 % of the patients , major response ( 96 - 100 % of histological response ) in 48 % , and pN downstaging in 78 % . An R0 resection was performed in 97 % of the patients . After a median follow-up of 55 months , the LC , DFS , and OS rates were 100 % , 84 % , and 87 % , respectively . CONCLUSIONS Preoperative CAPOX-IMRT therapy ( 47.5 Gy in 20 fractions ) is feasible and safe , and produces major pathological responses in approximately 50 % of patients PURPOSE The aim of this retrospective case-matching study was to compare the treatment outcomes and acute toxicity of preoperative radiotherapy ( RT ) with capecitabine vs. preoperative RT with intermittent 5-fluorouracil ( 5-FU ) infusion , leucovorin , and mitomycin C in rectal cancer . METHODS AND MATERIAL S We matched 34 patients who were treated with preoperative concurrent capecitabine and 50 Gy of RT by their clinical T stage ( T3 or T4 ) and the tumor location ( < or=7 cm or > 7 cm from the anal verge ) with another 68 patients who were treated with preoperative intermittent 5-FU infusion , leucovorin , mitomycin C , and 50 Gy of RT  for a comparison of the pathologic tumor response , local control , distant failure , and survival rates . RESULTS The pathologic complete response rate was 21 % with capecitabine and 18 % with 5-FU and leucovorin ( p = 0.72 ) . The rate of T downstaging after chemoradiation was 59 % for both groups . The rate of sphincter-sparing resection was 38 % after capecitabine plus RT and 43 % after 5-FU plus RT ( p = 0.67 ) . At 3 years , there was no significant difference in the local control rate ( 93 % for capecitabine and 92 % for 5-FU and leucovorin ) , relapse-free rate ( 74 % for capecitabine and 73 % for 5-FU and leucovorin ) , or disease-specific survival rate ( 86 % for capecitabine and 77 % for 5-FU and leucovorin ) . The acute toxicity profile was comparable , with little Grade 3 and 4 toxicity . CONCLUSIONS When administered with concurrent preoperative RT , both capecitabine and intermittent 5-FU infusion with leucovorin modulation provided comparable pathologic tumor response , local control , relapse-free survival , and disease-specific survival rates in rectal cancer We sought to evaluate the efficacy and safety data of a combination regimen using weekly irinotecan in combination with capecitabine and concurrent radiotherapy ( CapIri-RT ) as neoadjuvant treatment in rectal cancer in a phase-II trial . Patients with rectal cancer clinical stages T3/4 Nx or N+ were recruited to receive irinotecan ( 50 mg m−2 weekly ) and capecitabine ( 500 mg m−2 bid days 1–38 ) with a concurrent RT dose of 50.4 Gy . Surgery was scheduled 4–6 weeks after the completion of chemoradiation . A total of 36 patients ( median age 62 years ; m/f : 27:9 ) including three patients with local recurrence were enclosed onto the trial . The median distance of the tumour from the anal verge was 5 cm . The main toxicity observed was ( NCI-CTC grade s 1/2/3/4 ( n ) ) : Anaemia 23/9/−/− ; leucocytopenia 12/7/7/2 , diarrhoea 13/15/4/− , nausea/vomiting 9/10/2/− , and increased activity of transaminases 3/3/1/−. One patient had a reversible episode of ventricular fibrillation during chemoradiation , most probably caused by capecitabine . The relative dose intensity was ( median/mean ( % ) ) : irinotecan 95/91 , capecitabine 100/92 ) . Thirty-four patients underwent surgery ( anterior resection n=25 ; abdomino-perineal resection n=6 ; Hartmann 's procedure n=3 ) . R0-resection was accomplished in all patients . Two patients died in the postoperative course from septic complications . Pathological complete remission was observed in five out of 34 resected patients ( 15 % ) , and nine patients showed microfoci of residual tumour ( 26 % ) . After a median follow-up of 28 months one patient had developed a local recurrence , and five patients distant metastases . Three-year overall survival for all patients with surgery ( excluding three patients treated for local relapse or with primary metastatic disease ) was 80 % . In summary , preoperative chemoradiation with CapIri-RT exhibits promising efficacy whereas showing managable toxicity . The local recurrence and distant failure rates observed after a median 28 months are low compared with st and ard 5-fluorouracil based therapy Purpose This study was design ed to determine the effect of concomitant small field boost irradiation given during preoperative chemoradiotherapy for patients with locally advanced rectal cancer . Methods The study prospect ively enrolled 38 patients scheduled for preoperative chemoradiotherapy . Pelvic radiotherapy of 43.2 Gy/24 fractions was delivered and boost radiotherapy of 7.2 Gy/12 fractions was concomitantly administered during the latter half of the pelvic radiotherapy treatment period . Two cycles of a bolus 5-fluorouracil and leucovorin injection in the first and fifth weeks of radiotherapy were administered . The median time to surgery after completion of chemoradiotherapy was six weeks . Tumor responses to chemoradiotherapy were assessed by using magnetic resonance volumetry and postchemoradiotherapy pathology tests to determine tumor downstaging and tumor regression rate . Results Thirty-six of 38 patients ( 94.7 percent ) underwent the scheduled surgery . The mean tumor volume reduction rate was 70.3 percent , and the clinical response rate was 66.7 percent . The downstaging rates were 41.7 percent for T classification , 85.2 percent for N classification , and 72.2 percent for stage . Tumor regression grade s after preoperative chemoradiotherapy were Grade 1 in 5 patients ( 13.9 percent ) , Grade 2 in 24 patients ( 66.7 percent ) , Grade 3 in 3 patients ( 8.3 percent ) , and Grade 4 in 4 patients ( 11.1 percent ) . Ten patients ( 26.3 percent ) experienced ≥ Grade 3 acute toxicity . Conclusions Our data suggest that concomitant boost irradiation does not improve clinical outcomes compared with other published preoperative chemoradiotherapy regimens . In addition , the clinicians choosing to use concomitant small field boost irradiation should be cautious to minimize the risk of unplanned sphincter ablation Introduction : Nonoperative management ( NOM ) of rectal cancer after a complete clinical response ( cCR ) to neoadjuvant therapy is controversial . In this article , we retrospectively review ed the outcomes of patients managed with selective NOM after a cCR to neoadjuvant treatment  and compared these with patients who underwent st and ard rectal resection with a pathological complete response ( pCR ) . Methods : Patients completing neoadjuvant chemoradiotherapy ( CRT ) for stage I to III rectal cancer between January 2006 and August 2010 were retrospectively review ed .  Median follow-up was calculated in months after completion of CRT . Results : Thirty-two patients ( median follow-up 28 months ) were treated by NOM after a cCR . Among 265 treated by CRT and rectal resection  , 57 patients ( 22 % ) had a pCR and formed the control group ( median follow-up 43 months ) . Factors associated with selective use of NOM included lower pretreatment stage , older age , and distal tumor location ( P < 0.05 ) . In the NOM group , 6 recurred locally ( median 11 months , range 7–14 ) , 3 of whom also had concurrent distant recurrence . All 6 local failures were controlled by salvage rectal resection with no further local recurrence of disease ( median follow-up 17 months ) . In the rectal resection/pCR group , there were no local failures . The 2-year distant disease-free survival ( 88 % vs 98 % , P = 0.27 ) and overall survival ( 96 % vs 100 % , P = 0.56 ) were similar for NOM and rectal resection/pCR groups . Conclusions : Rectal resection was successfully avoided in 81 % of patients selected for NOM . When combined with salvage surgery , NOM appears to achieve similar local and distant disease control compared with patients with a pCR treated by rectal resection . Longer follow-up and prospect i ve trials are warranted to evaluate this promising treatment option When analysis of results of radiotherapy for nearly 500 patients with oropharyngeal cancer showed evidence for rapid tumor regrowth during extensions of treatment from about 5 weeks to about 8 weeks , we search ed the literature on radiotherapy for head and neck cancer to determine whether it revealed similar evidence of accelerated tumor regrowth . Estimates of doses to achieve local control in 50 % of cases ( TCD50 ) were made from published local control rates , and the dependence of these doses on overall treatment duration was evaluated . In parallel , published scattergrams were analyzed to estimate the rate of tumor regrowth over the period of 4 - 10 weeks from initiation of therapy . Both analyses suggested that , on average , clonogen re population in squamous cell carcinomas of the head and neck accelerates only after a lag period of the order of 4 + /- 1 weeks after initiation of radiotherapy and that a dose increment of about 0.6 Gy per day is required to compensate for this re population . Such a dose increment is consistent with a 4-day clonogen doubling rate , compared with a median of about 60 days in published reports of unperturbed tumor growth rates . The values presented here are average values for a large number of patients : it is necessary , not only to verify the results of these retrospective analyses in prospect i ve studies , but also to develop methods to predict the time of onset and rate of accelerated tumor clonogen re population in the individual patient Abstract PURPOSE : This prospect i ve , nonr and omized study evaluates , with a seven-year median follow-up , the morbidity and the functional and oncologic results of conservative surgery after high-dose radiation for cancer of the lower third of the rectum of patients who would otherwise have undergone abdominoperineal resection . METHODS : Between June 1990 and June 1996 , 43 patients with distal rectal adenocarcinoma were treated by preoperative radiotherapy ( 40 + 20 Gy delivered with three fields ) and curative surgery . The mean distance from the anal verge was 50 ( range , 25–60 ) mm , and none of the tumors was fixed ( 15 percent T2N0 , 53 percent T3N0 , 32 percent T3N1 ) . RESULTS : Postoperative mortality ( 2 percent ) and morbidity ( 35 percent ) were not increased by high-dose preoperative radiation . Conservative surgery was done in 30 patients ( 70 percent : 26 coloanal anastomoses and 4 low stapled anastomoses ) . After conservative surgery , long-term functional results showed 30 percent complete continence and 20 percent serious incontinence . Four patients had local recurrence as first development ( 13 percent ) . The seven-year overall survival rate was 53 percent , 62 percent after conservative surgery and 31 percent after abdominoperineal resection . The univariate analysis underscores the tumor response impact on long-term survival ( pT<3 = 81 percent ; pT3 = 35 percent ; P = 0.0008 ) . CONCLUSIONS : These long-term results confirm the feasibility of conservative surgery for low rectal carcinoma after high-dose radiation . A prospect i ve multicentric trial began in France in June 1996 to evaluate the reproducibility of these results BACKGROUND : Transanal local excision has been suggested as an attractive approach for patients with rectal cancer who show a major clinical response after preoperative chemoradiotherapy . OBJECTIVE : To evaluate the impact of transanal local excision on the local recurrence of rectal cancer in patients who had a major clinical response after preoperative chemoradiotherapy .  DESIGN : Sequential 2-stage phase II study for early efficacy . SETTING : Multicenter study . PATIENTS : Patients with clinical T3 or low-lying T2 rectal adenocarcinoma that showed a major clinical response after a preoperative chemoradiotherapy .  Eligible patients underwent a full-thickness transanal local excision . According to their histopathology , the patients staged as ypT0 - 1 were observed , while the remaining patients were recommended to undergo a subsequent total mesorectal excision . MAIN OUTCOME MEASURES : A local recurrence rate of ⩽5 % was set as a successful rate for stopping the trial early after the first stage . RESULTS : The study group included 63 patients . Before chemoradiotherapy , patients were staged as clinical T3 ( n = 42 ) and T2 ( n = 21 ) . After the local excision , 43 patients fulfilled the criteria to be observed with no further treatment . Nine of the remaining 20 patients for whom a subsequent total mesorectal excision was recommended refused surgery . Two of these patients who refused surgery had intraluminal local recurrence ; both had a ypT2 tumor and underwent salvage surgery . The estimated cumulative 3-year overall survival , disease-free survival and local disease-free survival were 91.5 % ( 95 % CI : 75.9–97.2 ) , 91.0 % ( 95 % CI : 77.0–96.6 ) and 96.9 % ( 95 % CI : 80.3–99.5 ) , respectively . LIMITATIONS : The time of follow-up is still short and the sample size is limited . CONCLUSIONS : Our data suggest that local excision is a good option for patients with a major clinical response after chemoradiotherapy . A longer period of follow-up is required to confirm these findings Concomitant boost schedules are characterized by delivering the boost ( 10 - 12 fractions ) as second daily treatments during rather than following the basic wide field irradiations . This results in shortening the overall time to administer 69 - 72 Gy from 7 1/2 - 8 weeks to 6 weeks , which we hoped would improve the tumor control rate by reducing the opportunity for tumor clonogens to regenerate during treatment . From August 1985 to August 1988 , 79 patients with T2 - 4 carcinomas of the oropharynx ( 72 patients ) or nasopharynx ( 7 patients ) were treated according to 1 of the 3 variants of the concomitant boost technique .  The median age of patients was 60 years ( range : 19 - 84 years ) and the male-to-female ratio was 2.6 . The overall 2-year actuarial primary and nodal control rates by radiotherapy alone were 74 % and 76 % , respectively . The ultimate 2-year control rates after surgical salvage were 82 % and 84 % , respectively . If the boost given during the last 2 - 2 1/2 weeks of basic treatment , a slightly better primary control rate ( p = 0.11 ) result ed than if the boost was delivered during the first 2 - 2 1/2 weeks or twice a week throughout the basic treatment . The 2-year actuarial primary control rate of the 13 patients receiving induction chemotherapy prior to radiotherapy was significantly lower than that of patients treated with radiation only ( 81 % vs 34 % , p = 0.01 ) , but this could be partly attributed to a more advanced stage in the chemotherapy group . The acute mucosal reactions were , as expected , more severe than those observed with conventional fractionation . Fifty patients developed confluent mucositis covering more than half of the boost area . Such reactions lasted for more than 6 weeks in seven patients . Late complications , however , so far observed , have been few . Three patients experienced chronic mucosal tenderness , 1 chronic mucosal ulceration , 2 transient bone exposure , and 1 carotid rupture following salvage surgery . The results so far appear to be better than the outcome of conventional radiotherapy . Its real value will be determined in a prospect i ve r and omized study Conventional is commonly not universally correct , and so with dose fractionation in radiotherapy . Fractionation spares slowly responding tissues more than tissues and tumors that show an early response , suggesting that therapeutic gains may be further increased by reducing fractional doses below 1.8 to 2 Gy . The overall duration of a course of radiotherapy  should not be the same for all tumors in all sites because the time of onset of regeneration after the start of radiotherapy varies from tissue to tissue and among tumors . Although growth kinetics and dose‐response characteristics are known to vary , inability to identify and quantify them prospect ively frustrates rational selection of patients for individualized fractionation regimens . In general , curative radiotherapy should be delivered in as short an overall time as possible using the smallest practical dose per fraction . Although 2 Gy , 5 times per week may be a reasonable “ average ” treatment , greater individualization should be a research goal Background and purpose The aim of this study was to assess the predictive potential of diffusion-weighted magnetic resonance imaging ( MRI ) for the selection of favorable pathological responders after radiochemotherapy for locally advanced rectal cancer . Patients and methods In 59 patients with locally advanced rectal cancer , the apparent diffusion coefficient ( ADC ) in the tumor was obtained at 3 Tesla before radiochemotherapy and surgery . The predictive potential for pathological complete response ( pCR ) and good response ( GR ) was assessed . GR was defined as pCR and near-pCR based on the tumor regression grade . Results The GR group consisted of 13 patients ( 22 % ) with 9 complete responders . Both the preradiochemotherapy ADC values and relative change in ADC ( ΔADC ) were predictive for pathological response . Preradiochemotherapy ADC values showed a positive predictive value of 42 % for pCR and 67 % for GR using a similar cut-off value of 0.97 * 10−3 mm2/s . For ΔADC , the optimal threshold for predicting GR or pCR was a 41 % increase of the ADC . With this threshold , positive predictive values of 64 % and 91 % were found for pCR and GR , respectively . Conclusion Low preradiochemotherapy ADC values and high ΔADC correspond to pathological good response . Diffusion-weighted MRI may be used as an additional tool for selecting good treatment responders after radiochemotherapy . ZusammenfassungHintergrundZiel dieser prospektiven Studie war die Evaluierung des prädiktiven Werts der  diffusionsgewichteten Magnetresonanztomographie ( MRT )  für ein pathologisch günstiges Ansprechen nach Radiochemotherapie ( RCT ) bei lokal fortgeschrittenem Rektumkarzinom . Patienten und Method enBei 59 Patienten mit lokal fortgeschrittenem Rektumkarzinom wurde vor RCT und vor Operation der scheinbare Diffusionskoeffizient ( „ apparent diffusion coefficient “ , ADC ) des Tumors ermittelt . Das prädiktive Potenzial des ADC zur Ermittlung einer pathologisch kompletten Remission ( pKR ) oder einer guten Remission ( GR ) wurde evaluiert . Die GR wurde als pKR und Beinahe-pKR auf der Basis pathologischer Tumorregressions grade definiert . ErgebnisseDie GR-Gruppe best and aus 13 Patienten ( 22 % ) mit 9 pKR . Sowohl die ADC-Werte vor RCT als auch die relative ADC-Änderung ( ΔADC ) waren prädiktiv für die pathologische Remission . Die ADC-Werte vor RCT zeigten einen positiven prädiktiven Wert von 42 % für pKR und 67 % für GR mit einem Cut-off-Wert von 0,97 * 10−3 mm2/s . Für ΔADC lag die optimale Schwelle zur Vorhersage von GR oder pKR bei einer 41%igen Erhöhung des ADC . Mit dieser Schwelle wurde ein positiver prädiktiver Wert von 64 % für pKR bzw . 91 % für GR ermittelt . SchlussfolgerungSowohl niedrige ADC-Werte vor RCT als auch eine hohe relative Änderung gehen einher mit einem guten pathologischen Ansprechen . Die diffusionsgewichtete MRT könnte in einem Protokoll zur Verwendung gelangen , mit dem Patienten mit gutem Ansprechen nach RCT ausgewählt werden PURPOSE We assessed the impact of  tumor regression grading  ( TRG ) and its value in correlation to established prognostic factors in a cohort of rectal carcinoma patients treated by preoperative chemoradiotherapy ( CRT ) .  PATIENTS AND METHODS TRG was evaluated on surgical specimens of 385 patients treated within the preoperative CRT arm of the CAO/ARO/AIO-94 trial :  50.4 Gy was delivered , fluorouracil was given in the first and fifth week , and surgery was performed 6 weeks thereafter . TRG was determined by the amount of viable tumor versus fibrosis , ranging from TRG 4 when no viable tumor cells were detected , to TRG 0 when fibrosis was completely absent . TRG 3 was defined as regression more than 50 % with fibrosis outgrowing the tumor mass , TRG 2 was defined as regression less than 50 % , and TRG 1 was defined basically as a morphologically unaltered tumor mass . We performed an initially unplanned , hypothesis-generating analysis with respect to the prognostic value of this TRG system . RESULTS TRG 4 , 3 , 2 , 1 , 0 was found in 10.4 % , 52.2 % , 13.8 % , 15.3 % , and 8.3 % of the resected specimens , respectively . Five-year disease-free survival ( DFS ) after CRT and curative resection was 86 % for TRG 4 , 75 % for grouped TRG 2 + 3 , and 63 % for grouped TRG 0 + 1 ( P = .006 ) . On multivariate analysis , the pathologic T category and the nodal status after CRT were the most important independent prognostic factors for DFS . CONCLUSION In this exploratory analysis , complete ( TRG 4 ) and intermediate pathologic response ( TRG 2 + 3 ) suggested improved DFS after preoperative CRT . TRG assessment should be implemented in pathologic evaluation and prospect ively vali date d in further studies PURPOSE To study the impact of preoperative radiation dose escalation and postoperative adjuvant chemotherapy on the outcome of tethered and fixed rectal carcinoma . METHODS AND MATERIAL S We have treated 156 patients with 3 consecutive preoperative chemoradiation protocol s with escalating treatment intensity . Schedule 1 consisted of 40 Gy radiation with concurrent 5-fluorouracil ( 5-FU ) infusion and mitomycin C. Schedule 2 used a s and wich design with preoperative ( 40 Gy ) and postoperative ( 18 Gy ) radiation with concomitant 5-FU infusion , leucovorin , and mitomycin C. In schedule 3 , the preoperative radiation dose was increased to 50 Gy and adjuvant 5-FU/leucovorin chemotherapy was added following surgery . There were 54 , 27 , and 75 patients treated in schedules 1 , 2 , and 3 , respectively . RESULTS The resectability was 91 % for schedule 1 and 100 % for both schedules 2 and 3 . A dose-response relationship was observed between the radiation dose and the tumor downstaging and local control . The pathological complete response ( T0N0M0 ) rates for schedules 1 , 2 , and 3 were 4 % , 15 % , and 25 % , respectively . The respective rates of tumor downstaging were 41 % , 33 % , and 68 % , respectively . The 5-year local relapse-free rates were 67 % for schedule 1 ( 40 Gy ) , 96 % for schedule 2 ( 58 Gy ) , and 92 % for schedule 3 ( 50 Gy ) ( p = 0.0011 ) . The addition of postoperative chemotherapy appeared to improve both the survival and the relapse-free survival . The 5-year survival was increased from 52 % to 84 % ( p = 0.0004 ) and the 5-year progression-free survival was improved from 48 % to 74 % ( p = 0.0008 ) . CONCLUSION Preoperative 5-FU infusion , leucovorin , mitomycin C , and 50-Gy pelvic radiation , followed by postoperative bolus 5-FU/leucovorin chemotherapy , appeared to be an effective treatment for tethered/fixed rectal cancers . However , its therapeutic efficacy could only be vali date d in r and omized studies PURPOSE The potential advantage of high-dose preoperative radiotherapy to increase tumor response and improve the chance of sphincter preservation for low rectal cancer remains controversial . The aim of this trial was to evaluate the role of escalating the dose of preoperative radiation to increase sphincter-saving procedures . PATIENTS AND METHODS Patients with rectal carcinoma located in the lower rectum , staged T2 or T3 , Nx , or M0 with endorectal sonography , and not involving more than two-thirds circumference , were r and omly assigned to one of two groups : preoperative external-beam radiotherapy ( EBRT ; 39 Gy in 13 fractions over 17 days ) versus the same EBRT with boost ( 85 Gy in three fractions ) using endocavitary contact x-ray . RESULTS Between 1996 and 2001 , 88 patients were enrolled onto the study . A significant improvement was seen in favor of the contact x-ray boost for complete clinical response ( 24 % v 2 % ) and for a complete or near-complete sterilization of the operative specimen ( 57 % v 34 % ) . A significant increase in sphincter preservation was observed in the boost group ( 76 % v 44 % ; P = .004 ) . At a median follow-up of 35 months , there was no difference in morbidity , local relapse , and 2-year overall survival . CONCLUSION A dose escalation with endocavitary irradiation provides increased tumor response and sphincter preservation with no detrimental effect on treatment toxicity and early clinical outcome PURPOSE Neoadjuvant chemoradiotherapy is considered a st and ard approach for T3 - 4 M0 rectal cancer . In this situation , we compared neoadjuvant radiotherapy plus capecitabine with dose-intensified radiotherapy plus capecitabine and oxaliplatin . PATIENTS AND METHODS We r and omly assigned patients to receive 5 weeks of treatment with radiotherapy 45 Gy/25 fractions with concurrent capecitabine 800 mg/m(2 ) twice daily 5 days per week ( Cap 45 ) or radiotherapy 50 Gy/25 fractions with capecitabine 800 mg/m(2 ) twice daily 5 days per week and oxaliplatin 50 mg/m(2 ) once weekly ( Capox 50 ) . The primary end point was complete sterilization of the operative specimen ( ypCR ) . RESULTS Five hundred ninety-eight patients were r and omly assigned to receive Cap 45 ( n = 299 ) or Capox 50 ( n = 299 ) . More preoperative grade 3 to 4 toxicity occurred in the Capox 50 group ( 25 v 1 % ; P < .001 ) . Surgery was performed in 98 % of patients in both groups . There were no differences between groups in the rate of conservative surgery ( 75 % ) or postoperative deaths at 60 days ( 0.3 % ) . The ypCR rate was 13.9 % with Cap 45 and 19.2 % with Capox 50 ( P = .09 ) . When ypCR was combined with yp few residual cells , the rate was respectively 28.9 % with Cap 45 and 39.4 % with Capox 50 ( P = .008 ) . The rate of positive circumferential rectal margins ( between 0 and 2 mm ) was 19.3 % with Cap 45 and 9.9 % with Capox 50 ( P = .02 ) . CONCLUSION The benefit of oxaliplatin was not demonstrated and this drug should not be used with concurrent irradiation . Cap 50 merits investigation for T3 - 4 rectal cancers PURPOSE To determine the safety and efficacy of preoperative hypofractionated radiotherapy using intensity-modulated radiotherapy ( IMRT ) and an incorporated boost with concurrent capecitabine in patients with locally advanced rectal cancer . METHODS AND MATERIAL S The eligibility criteria included adenocarcinoma of the rectum , T3-T4 and /or N1-N2 disease , performance status 0 or 1 , and age > or = 18 years .  Photon IMRT and an incorporated boost were used to treat the whole pelvis to 45 Gy and the gross tumor volume plus 2 cm to 55 Gy in 25 treatments within 5 weeks . The study was design ed to escalate the dose to the gross tumor volume in 5-Gy increments in 3-patient cohorts . Capecitabine was given orally 825 mg/m(2 ) twice daily for 7 days each week during RT . The primary endpoint was the maximal tolerated radiation dose , and the secondary endpoints were the pathologic response and quality of life . RESULTS Eight patients completed RT at the initial dose level of 55 Gy . The study was discontinued because of toxicity-six Grade 3 toxicities occurred in 3 ( 38 % ) of 8 patients . All patients went on to definitive surgical resection , and no patient had a pathologically complete response . CONCLUSION This regimen , using hypofractionated RT with an incorporated boost , had unacceptable toxicity despite using st and ard doses of capecitabine and IMRT . Additional research is needed to determine whether IMRT is able to reduce the side effects during and after pelvic RT with conventional dose fractionation RATIONALE To evaluate the response to a concomitant boost given during st and ard chemoradiation for locally advanced rectal cancer . METHODS AND MATERIAL S Concomitant boost radiotherapy was administered preoperatively to 45 patients with locally advanced rectal cancer in a prospect i ve trial . Treatment consisted of 45 Gy to the pelvis with 18 mV photons at 1.8 Gy/fraction using a 3-field belly board technique with continuous infusion 5FU chemotherapy ( 300mg/m(2 ) ) 5 days per week . The boost was given during the last week of therapy with a 6-hour inter-fraction interval to the tumor plus a 2 - 3 cm margin . The boost dose equaled 7.5 Gy/5 fractions ( 1.5 Gy/fraction ) ; a total dose of 52.5 Gy/5 weeks was given to the primary tumor . Pretreatment tumor stage , determined by endorectal ultrasound and CT scan , included 29 with T3N0 [ 64 % ] , 11 T3N1 , 1 T3Nx , 2 T4N0 , 1 T4N3 , and 1 with TxN1 disease . Mean distance from the anal verge was 5 cm ( range 0 - 13 cm ) . Median age was 55 years ( range 33 - 77 years ) . The population consisted of 34 males and 11 females . Median time of follow-up is 8 months ( range 1 - 24 months ) . RESULTS Sphincter preservation ( SP ) has been accomplished in 33 of 42 ( 79 % ) patients resected to date . Three patients did not undergo resection because of the development of metastatic disease in the interim between the completion of chemoradiation ( CTX/XRT ) and preoperative evaluation . The surgical procedures included proctectomy and coloanal anastomosis ( n = 16 ) , low anterior resection ( n = 13 ) , transanal resection ( n = 4 ) . Tumor down-staging was pathologically confirmed in 36 of the 42 ( 86 % ) resected patients , and 13 ( 31 % ) achieved a pathologic CR . Among the 28 tumors ( 67 % ) located < 6 cm from the anal verge , SP was accomplished in 21 cases ( 75 % ) . Although perioperative morbidity was higher , toxicity rates during CTX/XRT were comparable to that seen with conventional fractionation . Compared to our contemporary experience with conventional CTX/XRT ( 45Gy ; 1.8 Gy per fraction ) , improvements were seen in SP ( 79 % vs. 59 % ; p = 0.02 ) , SP for tumors < 6 cm from the anal verge ( 75 % vs. 42 % ; p = 0.003 ) , and down-staging ( 86 % vs. 62 % ; p = 0.003 ) . CONCLUSION The SP rate with concomitant boost radiation has been highly favorable with rates of response which are higher than those previously reported for chemoradiation without administration of a boost . Further evaluation of this radiotherapeutic strategy appears warranted BACKGROUND Improving the response to preoperative therapy may increase the likelihood of successful resection of locally advanced rectal cancers . Historically , the pathologic complete response ( pCR ) rate has been < approximately 10 % with preoperative radiation therapy alone and < approximately 20 % with concurrent chemotherapy and radiation therapy . METHODS AND MATERIAL S Thirty-seven patients were enrolled on a prospect i ve Phase I/II protocol conducted jointly at Washington University , St. Louis and the Catholic University of the Sacred Heart , Rome evaluating a three-dimensionally ( 3D ) planned boost as part of the preoperative treatment of patients with unresectable or recurrent rectal cancer .  Preoperative treatment consisted of 4500 cGy in 25 fractions over 5 weeks to the pelvis , with a 3D planned 90 cGy per fraction boost delivered once or twice a week concurrently ( no time delay ) with the pelvic radiation . Thus , on days when the boost was treated , the tumor received a dose of 270 cGy in one fraction while the remainder of the pelvis received 180 cGy . When indicated , nonaxial beams were used for the boost . The boost treatment was twice a week ( total boost dose 900 cGy ) if small bowel could be excluded from the boost volume , otherwise the boost was delivered once a week ( total boost dose 450 cGy ) . Patients also received continuous infusion of 5-fluorouracil ( 1500 mg/m(2)-week ) concurrently with the radiation as well as postoperative 5-FU/leucovorin . RESULTS All 37 patients completed preoperative radiotherapy as planned within 32 - -39 elapsed days . Twenty-seven underwent proctectomy ; reasons for unresectability included persistent locally advanced disease ( 6 cases ) and progressive distant metastatic disease with stable or smaller local disease ( 4 cases ) . Actuarial 3-year survival was 82 % for the group as a whole . Among resected cases the 3-year local control and freedom from disease relapse were 86 % and 69 % , respectively . Twenty-four of the lesions ( 65 % ) achieved an objective clinical response by size criteria , including 9 ( 24 % ) with pCR at the primary site ( documented T0 at surgery ) . The most important factor for pCR was tumor volume : small lesions with planning target volume ( PTV ) < 200 cc showed a 50 % pCR rate ( p = 0.02 ) . There were no treatment associated fatalities . Nine of the 37 patients ( 24 % ) experienced Grade 3 or 4 toxicities ( usually proctitis ) during preoperative treatment . There were an additional 7 perioperative and 2 late toxicities . The most important factors for small bowel toxicity ( acute or late ) were small bowel volume ( > or = 150 cc at doses exceeding 4000 cGy ) and large tumor ( PTV > or = 800 cc ) . For rectal toxicity the threshold is PTV > or = 500 cc . CONCLUSION 3D planned boost therapy is feasible . In addition to permitting the use of nonaxial beams for improved dose distributions , 3D planning provides tumor and normal tissue dose-volume information that is important in interpreting outcome . Every effort should be made to limit the treated small bowel to less than 150 cc . Tumor size is the most important predictor of response , with small lesions of PTV < 200 cc most likely to develop complete responses PURPOSE Locally advanced rectal cancer represents a major therapeutic challenge . Preoperative chemoradiation therapy is considered st and ard , but little is known about the dose-effect relationship . The present study represents a dose-escalation phase III trial comparing 2 doses of radiation . METHODS AND MATERIAL S The inclusion criteria were resectable T3 and T4 tumors with a circumferential margin of ≤5 mm on magnetic resonance imaging . The patients were r and omized to receive  50.4 Gy  in 28 fractions to the tumor and pelvic lymph nodes ( arm A ) or the same treatment supplemented with an endorectal boost given as high-dose-rate brachytherapy ( 10 Gy in 2 fractions ; arm B ) . Concomitant chemotherapy , uftoral 300 mg/m2 and L-leucovorin 22.5 mg/d , was added to both arms on treatment days . The primary endpoint was complete pathologic remission . The secondary endpoints included tumor response and rate of complete resection ( R0 ) . RESULTS The study included 248 patients . No significant difference was found in toxicity or surgical complications between the 2 groups . Based on intention to treat , no significant difference was found in the complete pathologic remission rate between the 2 arms ( 18 % and 18 % ) . The rate of R0 resection was different in T3 tumors ( 90 % and 99 % ; P=.03 ) . The same applied to the rate of major response ( tumor regression grade , 1 + 2 ) , 29 % and 44 % , respectively ( P=.04 ) . CONCLUSIONS This first r and omized trial comparing 2 radiation doses indicated that the higher dose increased the rate of major response by 50 % in T3 tumors . The endorectal boost is feasible , with no significant increase in toxicity or surgical complications BACKGROUND This prospect i ve study assessed the effect of preoperative radiation and chemotherapy on the pathologic staging of advanced rectal cancer . METHODS Twenty patients with rectal cancer were treated with combined chemoradiation prior to operation , after pretreatment staging of all lesions with transrectal ultrasound ( TRUS ) . Perirectal fat invasion served as minimal criteria for preoperative neoadjuvant therapy . The pretreatment stage of these rectal lesions as defined by TRUS was then compared with the pathological stage of the surgical specimen following resection . Cancers were treated with high-dose radiation ( 45 to 54 Gy ) in 19 of 20 patients . One patient received in excess of 60 Gy because of tumor characteristics . Chemotherapy consisted of 5-fluorouracil delivered as a continuous infusion or bolus therapy . Four to 8 weeks after neoadjuvant therapy , 13 abdominal perineal resections , 5 low anterior resections , and 2 completion proctectomies were performed . RESULTS Following resection , rectal cancer was downstaged in 14 of 20 patients . No tumor was present in the rectal wall in 8 of 20 patients . Complete pathological response was present in 7 of 20 patients . Local recurrence occurred in 2 of 20 patients . Disease-free survival in the remaining 17 of 20 patients ranges from 9 to 51 months ( average 26 ) . CONCLUSIONS Preoperative chemoradiation in the surgical management of advanced rectal cancer results in demonstrable tumor downstaging A phase I trial of preoperative high dose pelvic radiotherapy and oral UFT/l-leucovorin in patients with locally advanced and unresectable rectal cancer patients to evaluate toxicity and efficacy was performed . Eighteen patients ( 14 with primary unresectable tumours and four with locally recurrent tumours ) were treated . All patients were evaluable for acute toxicity and efficacy . Patients received increasing doses of UFT ( 150 to 300 mg/m2/day UFT and a fixed dose of 22.5 mg/day l-leucovorin ) with each fraction , five days a week for 30 days , concomitantly with pelvic radiotherapy ( 60 Gy in 30 fractions using concomitant boost technique ) . All patients received the planned dose of radiotherapy . No hematological toxicity was observed . Only one patient developed grade 3 toxicity ( diarrhea ) . Fourteen patients ( 78 % ) had surgery ( 11 R0 and 3 R1 ) after median 40 days . Two patients ( 11 % ) had a complete pathological response . Ten patients are alive after median follow-up of 49 months . Toxicity , resection rate and survival are very encouraging and the study continues as a phase II trial BACKGROUND Fluorouracil-based chemoradiotherapy is regarded as a st and ard perioperative treatment in locally advanced rectal cancer . We investigated the efficacy and safety of substituting fluorouracil with the oral prodrug capecitabine . METHODS This r and omised , open-label , multicentre , non-inferiority , phase 3 trial began in March , 2002 , as an adjuvant trial comparing capecitabine-based chemoradiotherapy with fluorouracil-based chemoradiotherapy , in patients aged 18 years or older with pathological stage II-III locally advanced rectal cancer from 35 German institutions . Patients in the capecitabine group were scheduled to receive two cycles of capecitabine ( 2500 mg/m(2 ) days 1 - 14 , repeated day 22 ) , followed by chemoradiotherapy ( 50·4 Gy plus capecitabine 1650 mg/m(2 ) days 1 - 38 ) , then three cycles of capecitabine . Patients in the fluorouracil group received two cycles of bolus fluorouracil ( 500 mg/m(2 ) days 1 - 5 , repeated day 29 ) , followed by chemoradiotherapy ( 50·4 Gy plus infusional fluorouracil 225 mg/m(2 ) daily ) , then two cycles of bolus fluorouracil . The protocol was amended in March , 2005 , to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy ( 50·4 Gy plus capecitabine 1650 mg/m(2 ) daily ) followed by radical surgery and five cycles of capecitabine ( 2500 mg/m(2 ) per day for 14 days ) and patients in the fluorouracil group received chemoradiotherapy ( 50·4 Gy plus infusional fluorouracil 1000 mg/m(2 ) days 1 - 5 and 29 - 33 ) followed by radical surgery and four cycles of bolus fluorouracil ( 500 mg/m(2 ) for 5 days ) . Patients were r and omly assigned to treatment group in a 1:1 ratio using permuted blocks , with stratification by centre and tumour stage . The primary endpoint was overall survival ; analyses were done based on all patients with post-r and omisation data . Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12·5 % margin . This trial is registered with Clinical Trials.gov , number NCT01500993 . FINDINGS Between March , 2002 , and December , 2007 , 401 patients were r and omly allocated ; 392 patients were evaluable ( 197 in the capecitabine group , 195 in the fluorouracil group ) , with  a median follow-up of 52 months ( IQR 41 - 72 ) . 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group ( 76 % [ 95 % CI 67 - 82 ] vs 67 % [ 58 - 74 ] ; p=0·0004 ; post-hoc test for superiority p=0·05 ) . 3-year disease-free survival was 75 % ( 95 % CI 68 - 81 ) in the capecitabine group and 67 % ( 59 - 73 ) in the fluorouracil group ( p=0·07 ) . Similar numbers of patients had local recurrences in each group ( 12 [ 6 % ] in the capecitabine group vs 14 [ 7 % ] in the fluorouracil group , p=0·67 ) , but fewer patients developed distant metastases in the capecitabine group ( 37 [ 19 % ] vs 54 [ 28 % ] ; p=0·04 ) . Diarrhoea was the most common adverse event in both groups ( any grade : 104 [ 53 % ] patients in the capecitabine group vs 85 [ 44 % ] in the fluorouracil group ; grade 3 - 4 : 17 [ 9 % ] vs four [ 2 % ] ) . Patients in the capecitabine group had more h and -foot skin reactions ( 62 [ 31 % ] any grade , four [ 2 % ] grade 3 - 4 vs three [ 2 % ] any grade , no grade 3 - 4 ) , fatigue ( 55 [ 28 % ] any grade , no grade 3 - 4 vs 29 [ 15 % ] , two [ 1 % ] grade 3 - 4 ) , and proctitis ( 31 [ 16 % ] any grade , one [ < 1 % ] grade 3 - 4 vs ten [ 5 % ] , one [ < 1 % ] grade 3 - 4 ) than did those in the fluorouracil group , whereas leucopenia was more frequent with fluorouracil than with capecitabine ( 68 [ 35 % ] any grade , 16 [ 8 % ] grade 3 - 4 vs 50 [ 25 % ] any grade , three [ 2 % ] grade 3 - 4 ) . INTERPRETATION Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer . FUNDING Roche Pharma AG ( Grenzach-Wyhlen , Germany ) PURPOSE To evaluate the rate of pathologic complete response and toxicity of neoadjuvant chemoradiation for advanced T3/T4 distal rectal cancers in a r and omized phase II study PATIENTS AND METHODS Patients with clinical T3/T4 distal rectal cancers were r and omly assigned in a phase II study to receive combined neoadjuvant chemoradiotherapy followed by surgical resection . Patients were r and omly assigned to receive continuous venous infusion ( CVI ) fluorouracil ( FU ) 225 mg/m2 per day , 7 days per week , plus pelvic hyperfractionated radiation 55.2 to 60 Gy at 1.2 Gy bid ( arm 1 ) or CVI FU 225 mg/m2 per day Monday to Friday , 120 hours per week plus irinotecan 50 mg/m2 once weekly for 4 weeks plus pelvic radiation therapy 50.4 to 54 Gy at 1.8 Gy per day ( arm 2 ) . Surgery was performed 4 to 10 weeks after completion of neoadjuvant therapy . The primary end point of this study was pathologic complete response ( pCR ) . Secondary end points included acute and late normal tissue morbidity . RESULTS A total of 106 patients were entered onto the study , with 103 assessable for response . The overall resectability rate was 93 % . The median time to surgery was 7 weeks . Tumor downstaging was observed in 78 % of patients in both arms . The pCR rate for all assessable patients was 26 % in each arm . For patients who had surgery , the pCR rate was also the same ( 28 % ) in both arms . Acute and late toxicity was also similar . Grade 3 and 4 acute hematologic and nonhematologic toxicity occurred in 13 % and 38 % in arm 1 and 12 % and 45 % in arm 2 , respectively . CONCLUSION Although the overall complete response rate and toxicity seems similar in both arms , this is the first multi-institutional study to establish a relatively high ( 28 % ) pCR rate after neoadjuvant therapy PURPOSE Three Phase II studies of preoperative radiotherapy and concurrent 5FU chemotherapy were undertaken . The primary endpoints were acute toxicity and pathologic complete response rate ( pCR ) . Secondary endpoints were local recurrence-free survival ( LRFS ) , disease-free survival ( DFS ) , and overall survival ( OS ) . METHODS AND MATERIAL S A total of 134 patients with adenocarcinoma of the rectum ( clinical T3/T4 or N1/N2 ) were treated . The initial cohort received 40 Gy in 20 fractions , the second 46 Gy in 23 fractions , and the third 50 Gy in 25 fractions . 5FU ( 225 mg/m2/day ) was given continuously throughout radiotherapy .  A total of 121 patients underwent surgical resection .  RESULTS Treatment was well tolerated . Grade 3/4 acute toxicity was observed in 13 % , 4 % , and 14 % of patients in the 40 Gy , 46 Gy , and 50 Gy cohorts , respectively ( p = 0.20 ) . pCR was documented in 15 % , 23 % , and 33 % of patients , respectively ( p = 0.07 ) . The 2-year actuarial LRFS was 72 % , 90 % , and 89 % ( p = 0.02 ) ; DFS was 62 % , 84 % , and 78 % ( p = 0.02 ) ; and OS was 72 % , 94 % , and 92 % , respectively ( p = 0.03 ) . CONCLUSIONS All treatment schedules were well tolerated . There was a trend toward increased pCR with higher doses . A statistically significant increase in LRFS , DFS , and OS was seen with radiation doses of 46 Gy and greater , but there was no difference between 46 Gy and 50 Gy PURPOSE To evaluate the feasibility and pathologic complete response rate of induction bevacizumab + modified infusional fluorouracil , leucovorin , and oxaliplatin ( FOLFOX ) 6 regimen followed by concurrent bevacizumab , oxaliplatin , continuous infusion 5-fluorouracil ( 5-FU ) , and radiation for patients with rectal cancer . METHODS AND MATERIAL S Eligible patients received 1 month of induction bevacizumab and mFOLFOX6 . Patients then received 50.4 Gy of radiation and concurrent bevacizumab ( 5 mg/kg on Days 1 , 15 , and 29 ) , oxaliplatin ( 50 mg/m(2)/week for 6 weeks ) , and continuous infusion 5-FU ( 200 mg/m(2)/day ) . Because of gastrointestinal toxicity , the oxaliplatin dose was reduced to 40 mg/m(2)/week . Resection was performed 4 - 8 weeks after the completion of chemoradiation . RESULTS The trial was terminated early because of toxicity after 26 eligible patients were treated . Only 1 patient had significant toxicity ( arrhythmia ) during induction treatment and was removed from the study . During chemoradiation , Grade 3/4 toxicity was experienced by 19 of 25 patients ( 76 % ) . The most common Grade 3/4 toxicities were diarrhea , neutropenia , and pain . Five of 25 patients ( 20 % ) had a complete pathologic response . Nine of 25 patients ( 36 % ) developed postoperative complications including infection ( n = 4 ) , delayed healing ( n = 3 ) , leak/abscess ( n = 2 ) , sterile fluid collection ( n = 2 ) , ischemic colonic reservoir ( n = 1 ) , and fistula ( n = 1 ) . CONCLUSIONS Concurrent oxaliplatin , bevacizumab , continuous infusion 5-FU , and radiation causes significant gastrointestinal toxicity . The pathologic complete response rate of this regimen was similar to other fluorouracil chemoradiation regimens . The high incidence of postoperative wound complications is concerning and consistent with other reports utilizing bevacizumab with chemoradiation before major surgical resections BACKGROUND Preoperative chemoradiotherapy , total mesorectal excision surgery , and adjuvant chemotherapy with fluorouracil is the st and ard combined modality treatment for rectal cancer . With the aim of improving disease-free survival ( DFS ) , this phase 3 study ( CAO/ARO/AIO-04 ) integrated oxaliplatin into st and ard treatment . METHODS This was a multicentre , open-label , r and omised , phase 3 study in patients with histologically proven carcinoma of the rectum with clinical ly staged T3 - 4 or any node-positive disease . Between July 25 , 2006 , and Feb 26 , 2010 , patients were r and omly assigned to two groups : a control group receiving st and ard fluorouracil-based combined modality treatment , consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil ( 1000 mg/m(2 ) days 1 - 5 and 29 - 33 ) , followed by surgery and four cycles of bolus fluorouracil ( 500 mg/m(2 ) days 1 - 5 and 29 ; fluorouracil group ) ; and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil ( 250 mg/m(2 ) days 1 - 14 and 22 - 35 ) and oxaliplatin ( 50 mg/m(2 ) days 1 , 8 , 22 , and 29 ) , followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin ( 100 mg/m(2 ) days 1 and 15 ) , leucovorin ( 400 mg/m(2 ) days 1 and 15 ) , and infusional fluorouracil ( 2400 mg/m(2 ) days 1 - 2 and 15 - 16 ; fluorouracil plus oxaliplatin group ) . R and omisation was done with computer-generated block-r and omisation codes stratified by centre , clinical T category ( cT1 - 4 vs cT4 ) , and clinical N category ( cN0 vs cN1 - 2 ) without masking . DFS is the primary endpoint . Secondary endpoints , including toxicity , compliance , and histopathological response are reported here . Safety and compliance analyses included patients as treated , efficacy endpoints were analysed according to the intention-to-treat principle . This study is registered with Clinical Trials.gov , number NCT00349076 . FINDINGS Of the 1265 patients initially enrolled , 1236 were evaluable ( 613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil  group ) . Preoperative grade 3 - 4 toxic effects occurred in 140 ( 23 % ) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 ( 20 % ) of 624 patients who actually received fluorouracil chemoradiotherapy .  Grade 3 - 4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy ( 73 patients [ 12 % ] vs 52 patients [ 8 % ] ) , as was grade 3 - 4 nausea or vomiting ( 23 [ 4 % ] vs nine [ 1 % ] ) . 516 ( 85 % ) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy , and 571 ( 94 % ) had the full dose of radiotherapy ; as did 495 ( 79 % ) and 601 ( 96 % ) of 624 patients who received fluorouracil-based chemoradiotherapy , respectively . A pathological complete response was achieved in 103 ( 17 % ) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 ( 13 % ) of 606 patients who underwent surgery in the fluorouracil group ( odds ratio 1·40 , 95 % CI 1·02 - 1·92 ; p=0·038 ) . In the fluorouracil and oxaliplatin group , 352 ( 81 % ) of 435 patients who began adjuvant chemotherapy completed all cycles ( with or without dose reduction ) , as did 386 ( 83 % ) of 463 patients in the fluorouracil group . INTERPRETATION Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did st and ard treatment . Longer follow-up is needed to assess DFS . FUNDING German Cancer Aid ( Deutsche Krebshilfe ) BACKGROUND Preoperative chemoradiotherapy ( preopCRT ) for locally advanced rectal cancer is associated with grade 3 or higher acute gastrointestinal ( GI ) toxicity . This study was conducted to determine whether intensity-modulated radiation therapy ( IMRT ) significantly reduces acute GI toxicity , compared to 3-dimensional conformal RT ( 3D-CRT ) in preopCRT for rectal cancer . METHODS A retrospective analysis was conducted of 48 patients treated between January 2002 and August 2010 with preopCRT for rectal cancer .  3D-CRT or IMRT was administered at a planned dose of 45 - 50.4 Gy to patients positioned prone on a bowel-displacement device . Data regarding patient and tumor characteristics , treatment , acute toxicity , and tumor response were collected . Comparisons of acute toxicity and treatment response between 3D-CRT and IMRT were performed with the Chi-square or Fisher 's exact test . RESULTS There were no significant differences in radiation dose , median age , race , gender , stage , type of concurrent chemotherapy , pathologic complete response ( pCR ) , or type of surgery ( lower anterior or abdominal perineal resection ) between 3D-CRT and IMRT . There was a significant reduction in grade 2 or higher GI toxicity ( 3D-CRT , 60.7 % ; IMRT , 30 % ; P = .036 ) and grade 2 or higher diarrhea ( 3D-CRT , 42.8 % ; IMRT , 10 % ; P = .014 ) . Two patients who underwent 3D-CRT required a treatment break ( grade 3 diarrhea and grade 3 dehydration ) . Radiation duration was significantly less ( IMRT , 35 days ; 3D-CRT , 39 days ; P ≤ .0001 ) . pCR rates were 16.7 % for 3D-CRT and 21.4 % for IMRT ( nonsignificant [ NS ] ) ; pCR+microscopic residual rates were 57.1 % for IMRT and 27.8 % for 3D-CRT ( P = .093 ) . CONCLUSION Maximal bowel displacement with IMRT yields favorable acute GI toxicity and pathologic downstaging profiles , as compared to 3D-CRT in preoperative CRT for rectal cancer and warrants further prospect i ve investigation PURPOSE Preoperative chemoradiation therapy ( CRT ) is part of the st and ard treatment of locally advanced rectal cancers . Tumor regression at the time of operation is desirable , but not much is known about the relationship between radiation dose and tumor regression . In the present study we estimated radiation dose-response curves for various grade s of tumor regression after preoperative CRT . METHODS AND MATERIAL S A total of 222 patients , treated with consistent chemotherapy and radiation therapy techniques , were considered for the analysis . Radiation therapy consisted of a combination of external-beam radiation therapy and brachytherapy . Response at the time of operation was evaluated from the histopathologic specimen and grade d on a 5-point scale ( TRG1 - 5 ) . The probability of achieving complete , major , and partial response was analyzed by ordinal logistic regression , and the effect of including clinical parameters in the model was examined . The radiation dose-response relationship for a specific grade of histopathologic tumor regression was parameterized in terms of the dose required for 50 % response , D50,i , and the normalized dose-response gradient , γ50,i . RESULTS A highly significant dose-response relationship was found ( P=.002 ) . For complete response ( TRG1 ) , the dose-response parameters were D50,TRG1=92.0 Gy ( 95 % confidence interval [ CI ] 79.3 - 144.9 Gy ) , γ50,TRG1=0.982 ( CI 0.533 - 1.429 ) , and for major response ( TRG1 - 2 ) D50,TRG1&2=72.1 Gy ( CI 65.3 - 94.0 Gy ) , γ50,TRG1&2=0.770 ( CI 0.338 - 1.201 ) . Tumor size and N category both had a significant effect on the dose-response relationships . CONCLUSIONS This study demonstrated a significant dose-response relationship for tumor regression after preoperative CRT for locally advanced rectal cancer for tumor dose levels in the range of 50.4 - 70 Gy , which is higher than the dose range usually considered Purpose : The purpose of this phase II study was to prospect ively determine the efficacy of preoperative chemoradiation with a hyperfractionated ( Hfx ) RT boost to 61.8 Gy in locally advanced rectal cancer . Methods : Eligibility stipulated that the primary lesion had to be either T4 ; or T3 and > 4 cm or 40 % of the bowel circumference .  Radiation ( RT ) consisted of 45 Gy to the pelvis ( 1.8 Gy per fraction ) followed by 1.2 Gy twice daily ( to the gross tumor volume ) to a total RT dose of 61.8 Gy . There was 5-FU infused at 1 g/m2/24 hours for 4 days during the 1st and 6th weeks of RT ( concurrent with the Hfx boost ) . Surgical resection was planned 4 to 6 weeks later . Adjuvant chemotherapy ( bolus 5-FU/leucovorin ) was scheduled for 4 cycles at 28-day intervals . Results : There were 22 patients , ages 22 to 81 years ( median , 64 ) enrolled in the study . Of the 20 patients evaluable for response , 10 ( 50 % ) had evidence of clinical downstaging and 5 patients ( 25 % ) had ≥90 % fibrosis in the resected specimen . With a median f/u of 40 months ( 7–158 ) , the 4 years actuarial rate for all patients ( n = 22 ) of OS was 64 % , of DFS 62 % , and of LC 84 % . 3/21 patients ( 14 % ) had positive margins , all of whom developed a local failure ( P < 0.001 ) . Conclusion : This regimen of high dose preoperative chemoRT with a Hfx RT boost ( to 61.8 Gy ) in patients with bulky , locally advanced rectal cancer results in clinical downstaging in half of the patients with significant fibrosis in the operative specimen AIMS With the aim of improving locoregional control , the use of preoperative chemoradiotherapy ( CRT ) for rectal cancer has increased . A pathological complete response ( pCR ) is often used as a surrogate marker for the efficacy of different CRT schedules . By analysing factors affecting pCR , this analysis aims to guide the development of future trials . MATERIAL S AND METHODS Search es of Medline , EMBASE and the electronic American Society of Clinical Oncology abstract data bases were carried out to identify prospect i ve phase II and phase III trials using preoperative CRT to treat rectal cancer . Trials were eligible for inclusion if they defined : the CRT drugs , the radiation dose and the pCR rate . Phase I patients were excluded from the analysis . A multivariate analysis examined the effect of the above variables on the pCR rate and in addition the use of neoadjuvant chemotherapy , the type of publication ( peer review ed vs abstract ) , the year of publication and whether the cancers were stated to be inoperable , fixed or threatening the circumferential resection margin were included . The method of analysis used was weighted linear modelling of the pCR rate . RESULTS Sixty-four phase II and seven phase III trials were identified including a total of 4732 patients . Statistically significant factors associated with pCR were the use of two drugs , the method of fluoropyrimidine administration ( with continuous intravenous 5-fluorouracil being the most effective ) and a higher radiotherapy dose . Although the use of two drugs was associated with a higher rate of pCR , no single schedule seemed to be more effective . None of the other factors analysed significantly influenced pCR . CONCLUSIONS A higher rate of pCR is seen in studies using two drugs , infusional 5-fluorouracil and a radiotherapy dose of 45 Gy and above PURPOSE To determine the acute toxicity , post-operative complications , pathologic response and extent of downstaging to high dose pre-operative radiation using a hyperfractionated radiation boost and concurrent chemotherapy in a prospect i ve Phase I trial . MATERIAL S & METHODS To be eligible for this study , patients had to have adenocarcinoma of the rectum less than 12 cm from the anal verge with either Stage T4 or T3 but greater than 4 cm or greater than 40 % of the bowel circumference . All patients received  45 Gy pelvic radiation ( 1.8 Gy per fraction ) . Subsequent radiation was given to the region of the gross tumor with a 2 cm margin . This " boost " treatment was given at 1.2 Gy twice daily to a total dose of 54.6 Gy for Level I , 57 Gy for Level II , and 61.8 Gy for Level III . 5-FU was given at 1g/m2 over 24 hours for a four day infusion during the first and sixth weeks of radiation , with the second course concurrent with the hyperfractionated radiation . Surgical resection was carried out 4 - 6 weeks following completion of chemoradiation ( in curative cases ) and additional adjuvant chemotherapy consisting of 5-FU and Leucovorin was given for an additional 4 monthly cycles Days 1 through 5 beginning four weeks post surgery . RESULTS Twenty-seven patients , age 40 - 82 ( median 61 ) , completed the initial course of chemoradiation and are included in the analysis of toxicity . The median follow-up is 27 months ( range 8 - 68 ) . Eleven patients were treated to a dose of 54.6 Gy , nine patients to 57 Gy , and seven patients to 61.8 Gy . Twenty-one patients had T3 tumors , and six patients T4 tumors . Grade III acute toxicity from chemoradiation included proctitis ( 5 patients ) , dermatitis ( 9 ) , diarrhea ( five ) , leukopenia ( 1 ) , cardiac ( 1 ) . Grade IV toxicities included one patient with diarrhea ( on dose Level I ) and one patient ( on dose Level III ) with cardiac toxicity ( unrelated to radiation ) . Surgical resection consisted of abdominal perineal resection in 16 and low anterior resection in 7 . Four patients did not undergo a curative resection ; three initially presented with metastases and one developed metastasis during the pre-operative regimen . Post-operative complications included pelvic or perineal abscess in two ( on dose Levels I & II ) , and delayed wound healing in two ( one of whom , on dose Level III , developed perineal wound dehiscence requiring surgical reconstruction ) . Of the 23 patients who had a curative resection , four manifested pathologic complete responses ( 17.4 % ) . Thirteen of 23 patients ( 57 % ) had evidence of pathologic downstaging and only 1/23 patients ( on dose Level I ) had a positive resection margin . Of these 23 patients ( with a minimum follow-up of 8 months ) , the patient with positive margins was the only one who developed a local failure ( Fisher 's Exact p=.04 ) . The 3-year actuarial OS , DFS and LC rates are 82 % , 72 % and 96 % , respectively . Twelve of 13 patients ( 92 % at 3 years ) > or = 61 years vs. 5/10 patients ( 45 % at 3 years ) < 61 years remained disease-free ( log-rank p=0.017 ) . CONCLUSION This regimen of high dose pre-operative chemoradiation employing a hyperfractionated radiation boost is feasible and tolerable and results in significant downstaging in locally advanced rectal cancer . The vast majority of patients ( 96 % ) achieved negative margins , which appears to be a prerequisite for local control ( p= 0.04 ) . Older age ( > or = 61 years ) was a significant predictor for improved DFS . This regimen ( at dose Level III , 61.8 Gy ) is currently being tested in a Phase II setting BACKGROUND AND PURPOSE The addition of chemotherapy to preoperative radiotherapy has been established as the st and ard of care for patients with cT3 - 4 rectal cancer . As an alternative strategy , we explored intensity-modulated and image-guided radiotherapy ( IMRT-IGRT ) with a simultaneous integrated boost ( SIB ) in a prospect i ve phase II study . Here , we report outcome and late toxicity after a median follow-up of 54 months . METHODS AND MATERIAL S A total of 108 patients were treated preoperatively with  IMRT-IGRT , delivering a dose of 46 Gy in fractions of 2 Gy . Patients ( n=57 ) displaying an anticipated circumferential resection margin ( CRM ) of less than 2 mm based on magnetic resonance imaging received a SIB to the tumor up to a total dose of 55.2 Gy . RESULTS The absolute incidence of grade ≥3 late gastrointestinal and urinary toxicity was 9 % and 4 % , respectively , with a 13 % rate of any grade ≥3 late toxicity . The actuarial 5-year local control ( LC ) , progression-free survival ( PFS ) and overall survival ( OS ) were 97 % , 57 % , and 68 % . On multivariate analysis , R1 resection and pN2 disease were associated with significantly impaired OS . CONCLUSIONS The use of preoperative IMRT-IGRT with a SIB result ed in a high 5-year LC rate and non-negligible late toxicity PURPOSE The optimal chemotherapy regimen administered concurrently with preoperative radiation therapy ( RT ) for patients with rectal cancer is unknown . National Surgical Adjuvant Breast and Bowel Project trial R-04 compared four chemotherapy regimens administered concomitantly with RT . PATIENTS AND METHODS Patients with clinical stage II or III rectal cancer who were undergoing preoperative RT ( 45 Gy in 25 fractions over 5 weeks plus a boost of 5.4 Gy to 10.8 Gy in three to six daily fractions ) were r and omly assigned to one of the following chemotherapy regimens : continuous intravenous infusional fluorouracil ( CVI FU ; 225 mg/m(2 ) , 5 days per week ) , with or without intravenous oxaliplatin ( 50 mg/m(2 ) once per week for 5 weeks ) or oral capecitabine ( 825 mg/m(2 ) twice per day , 5 days per week ) , with or without oxaliplatin ( 50 mg/m(2 ) once per week for 5 weeks ) . Before r and om assignment , the surgeon indicated whether the patient was eligible for sphincter-sparing surgery based on clinical staging . The surgical end points were complete pathologic response ( pCR ) , sphincter-sparing surgery , and surgical downstaging ( conversion to sphincter-sparing surgery ) . RESULTS From September 2004 to August 2010 , 1,608 patients were r and omly assigned . No significant differences in the rates of pCR , sphincter-sparing surgery , or surgical downstaging were identified between the CVI FU and capecitabine regimens or between the two regimens with or without oxaliplatin . Patients treated with oxaliplatin experienced significantly more grade 3 or 4 diarrhea ( P < .001 ) . CONCLUSION Administering capecitabine with preoperative RT achieved similar rates of pCR , sphincter-sparing surgery , and surgical downstaging compared with CVI FU . Adding oxaliplatin did not improve surgical outcomes but added significant toxicity . The definitive analysis of local tumor control , disease-free survival , and overall survival will be performed when the protocol -specified number of events has occurred Background . Consensus is that patients with locally advanced rectal cancer ( LARC ) should receive long-term chemoradiotherapy ( CRT ) before surgery . With the intent to offer the patients intensified concomitant chemotherapy ( CT ) to improve outcome and to assess tolerability and toxicity of oxaliplatin ( Ox ) a phase I trial of high dose pelvic radiotherapy ( RT ) , fixed dose of oral UFT/l-leucovorin and increasing doses of weekly Ox were performed . Methods . Pelvic RT with 48.6 Gy/27 fractions was given to the primary tumour and the regional lymph nodes and a concurrent boost of 5.4 Gy/27 fractions with a final boost of 6 Gy/3 fractions was given to the gross tumour volume ( GTV ) ( 60 Gy/30 fractions ) . Concurrent with RT patients received a daily dose of UFT 300 mg/m2 plus fixed dose l-leucovorin 22.5 mg 5/7 days and increasing weekly doses of Ox with 10 mg/m2/week from a start dose of 30 mg/m2/week to a maximum of 60 mg/m2/week . In addition , before and after CRT the patients received one course of TEGAFOX ( UFT 300 mg/m2 with l/leucovorin 22.5 mg Days 1–14 and Ox 130 mg/m2 given on Day 1 ) . Surgery was planned at least six weeks after the completion of the CRT . Results . From May 2005 to March 2009 , 18 patients with LARC ( 16 primary , two recurrent ) were included in this phase I trial  . Toxicity was low with only 5–17 % grade 3–4 toxicity . Fifteen patients ( 83 % ) were operated ( 14 R0 resection and 1 R1 resection ) after completion of CRT . Five ( 33 % ) patients had a pathological complete response ( ypCR ) . When ypCR was combined with yp few residual cells , the rate was 60 % . Thirteen patients are still alive December 2011 . Conclusion . Preoperative high-dose RT and concomitant UFT with increasing doses of Ox up to 60 mg/m2/week was feasible with low toxicity , high ypCR rates and promising OS in patients with non-resectable LARC
PURPOSE We conducted a systematic review and meta- analysis to quantify the pathological complete response ( pCR ) rate after preoperative (chemo)radiation with doses of ⩾60Gy 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 .