Prognostic factors derived from a prospective database dictate clinical biology of anal cancer Anal carcinoma: impact of TN category of disease on survival, disease relapse, and colostomy failure in US Gastrointestinal Intergroup RTOG 98-11 phase 3 trial. Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. Evaluation of planned treatment breaks during radiation therapy for anal cancer: update of RTOG 92-08. Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I) "Mind the gap"--the impact of variations in the duration of the treatment gap and overall treatment time in the first UK Anal Cancer Trial (ACT I). Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Node-negative T1-T2 anal cancer: radiotherapy alone or concomitant chemoradiotherapy? RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial. Can radiobiological parameters derived from squamous cell carcinoma of the head and neck be used to predict local control in anal cancer treated with chemoradiation? Intensity-modulated radiotherapy vs. conventional radiotherapy in the treatment of anal squamous cell carcinoma: a propensity score analysis.
Only 4 prospect i ve r and omized phase 3 trials have been reported for anal cancer . A prognostic factor analysis for anal cancer from a prospect i ve data base has been published from only 1 study ( N = 110 ) . To confirm and uncover new prognostic factors , we analyzed the prospect i ve data base of intergroup RTOG 98‐11 PURPOSE The long-term up date of US GI Intergroup RTOG 98 - 11 anal cancer trial found that concurrent chemoradiation ( CCRT ) with fluorouracil ( 5-FU ) plus mitomycin had a significant impact on disease-free survival ( DFS ) and overall survival ( OS ) compared with induction plus concurrent 5-FU plus cisplatin . The intent of the current analysis was to determine the impact of tumor node ( TN ) category of disease on survival ( DFS and OS ) , colostomy failure ( CF ) , and relapse ( local-regional failure [ LRF ] and distant metastases [ DM ] ) in this patient group . METHODS AND MATERIAL S DFS and OS were estimated univariately by using the Kaplan-Meier method , and 6 TN categories were compared by the log-rank test ( T2N0 , T3N0 , T4N0 , T2N1 - 3 , T3N1 - 3 , and T4N1 - 3 ) . Time to relapse and colostomy were estimated by the cumulative incidence method , and TN categories were compared using Gray 's test . RESULTS Of 682 patients , 620 were analyzable for outcomes by TN category . All endpoints showed statistically significant differences among the TN categories of disease ( OS , P<.0001 ; DFS , P<.0001 ; LRF , P<.0001 ; DM , P=.0011 ; CF , P=.01 ) . Patients with the poorest OS , DFS , and LRF outcomes were those with T3 - 4N-positive ( + ) disease . CF was lowest for T2N0 and T2N+ ( 11 % , 11 % , respectively ) and worst for the T4N0 , T3N+ , and T4N+ categories ( 26 % , 27 % , 24 % , respectively ) . CONCLUSIONS TN category of disease has a statistically significant impact on OS , DFS , LRF , DM , and CF in patients treated with CCRT and provides excellent prognostic information for outcomes in patients with anal carcinoma . Significant challenges remain for patients with T4N0 and T3 - 4N+ categories of disease with regard to survival , relapse , and CF and lesser challenges for T2 - 3N0/T2N+ categories PURPOSE Concomitant radiochemotherapy ( RCT ) is the st and ard for locally advanced anal canal carcinoma ( LAACC ) . Questions regarding the role of induction chemotherapy ( ICT ) and a higher radiation dose in LAACC are pending . Our trial was design ed to determine whether dose escalation of the radiation boost or two cycles of ICT before concomitant RCT lead to an improvement in colostomy-free survival ( CFS ) . PATIENTS AND METHODS Patients with tumors ≥ 40 mm , or < 40 mm and N1 - 3M0 were r and omly assigned to one of four treatment arms : ( A ) two ICT cycles ( fluorouracil 800 mg/m(2)/d intravenous [ IV ] infusion , days 1 through 4 and 29 to 32 ; and cisplatin 80 mg/m(2 ) IV , on days 1 and 29 ) , RCT ( 45 Gy in 25 fractions over 5 weeks , fluorouracil and cisplatin during weeks 1 and 5 ) , and st and ard-dose boost ( SD ; 15 Gy ) ; ( B ) two ICT cycles , RCT , and high-dose boost ( HD ; 20 - 25 Gy ) ; ( C ) : RCT and SD boost ( reference arm ) ; and ( D ) RCT and HD boost . RESULTS Two hundred eighty-three of 307 patients achieved full treatment . With a median follow-up period of 50 months , the 5-year CFS rates were 69.6 % , 82.4 % , 77.1 % , and 72.7 % in arms A , B , C , and D , respectively . Considering the 2 × 2 factorial analysis , the 5-year CFS was 76.5 % versus 75.0 % ( P = .37 ) in groups A and B versus C and D , respectively ( ICT effect ) , and 73.7 % versus 77.8 % in groups A and C versus B and D , respectively ( RT-dose effect ; P = .067 ) . CONCLUSION Using CFS as our main end point , we did not find an advantage for either ICT or HD radiation boost in LAACC . Nevertheless , the results of the most treatment-intense arm B should prompt the design of further intensification studies PURPOSE On initial publication of GI Intergroup Radiation Therapy Oncology Group ( RTOG ) 98 - 11 [ A Phase III R and omized Study of 5-Fluorouracil ( 5-FU ) , Mitomycin , and Radiotherapy Versus 5-Fluorouracil , Cisplatin and Radiotherapy in Carcinoma of the Anal Canal ] , concurrent chemoradiation ( CCR ) with fluorouracil ( FU ) plus mitomycin ( MMC ) decreased colostomy failure ( CF ) when compared with induction plus concurrent FU plus cisplatin ( CDDP ) , but did not significantly impact disease-free survival ( DFS ) or overall survival ( OS ) for anal canal carcinoma . The intent of the up date d analysis was to determine the long-term impact of treatment on survival ( DFS , OS , colostomy-free survival [ CFS ] ) , CF , and relapse ( locoregional failure [ LRF ] , distant metastasis ) in this patient group . PATIENTS AND METHODS Stratification factors included sex , clinical node status , and primary size . DFS and OS were estimated univariately by the Kaplan-Meier method , and treatment arms were compared by log-rank test . Time to relapse and CF were estimated by the cumulative incidence method and treatment arms were compared by using Gray 's test . Multivariate analyses used Cox proportional hazard models to test for treatment differences after adjusting for stratification factors . RESULTS Of 682 patients accrued , 649 were analyzable for outcomes .  DFS and OS were statistically better for RT + FU/MMC versus RT + FU/CDDP ( 5-year DFS , 67.8 % v 57.8 % ; P = .006 ; 5-year OS , 78.3 % v 70.7 % ; P = .026 ) . There was a trend toward statistical significance for CFS ( P = .05 ) , LRF ( P = .087 ) , and CF ( P = .074 ) . Multivariate analysis was statistically significant for treatment and clinical node status for both DFS and OS , for tumor diameter for DFS , and for sex for OS . CONCLUSION CCR with FU/MMC has a statistically significant , clinical ly meaningful impact on DFS and OS versus induction plus concurrent FU/CDDP , and it has borderline significance for CFS , CF , and LRF . Therefore , RT + FU/MMC remains the preferred st and ard of care PURPOSE Radiation Therapy Oncology Group ( RTOG ) 92 - 08 began as a single arm , Phase II trial for patients with anal cancer consisting of radiation ( RT ) + 5-flourouracil + mitomycin-C with a m and atory 2-week break and was amended after completion to evaluate the same treatment regimen without a treatment break . Long-term efficacy and late toxicity reporting are the specific aims of this study . METHODS AND MATERIAL S Survivals were estimated with the Kaplan-Meier method . Overall survival ( OS ) was compared with RTOG 87 - 04 with the log-rank test . Time to local failure , regional failure , locoregional failure ( LRF ) , distant metastases , second primary , and colostomy failure were estimated by the cumulative incidence method . LRF was compared with RTOG 87 - 04 using the Gray 's test . RESULTS Forty-seven patients entered in the m and atory treatment break cohort . The study was reopened in 1995 to the no m and atory treatment break cohort completing accrual with 20 patients in 1996 . Of 67 total patients , 1 patient in the m and atory treatment break portion of the study did not receive any protocol treatment and is excluded from analyses . After adjusting for tumor size , neither cohort showed a statistically significant difference in OS or LRF compared with the RTOG 87 - 04 mitomycin-C arm . No patient in either cohort experienced a Grade 3 or higher late toxicity . CONCLUSIONS No statistically significant differences were seen in OS or LRF when compared to the mitomycin-C arm of RTOG 87 - 04 , but the sample sizes for the m and atory break cohort and the no m and atory break cohort are small . Late toxicity was low and similar for the treatment cohorts Background : The first UKCCCR Anal Cancer Trial ( 1996 ) demonstrated the benefit of chemoradiation over radiotherapy ( RT ) alone for treating epidermoid anal cancer , and it became the st and ard treatment . Patients in this trial have now been followed up for a median of 13 years . Methods : A total of 577 patients were r and omised to receive RT alone or combined modality therapy using 5-fluorouracil and mitomycin C. All patients were scheduled to receive 45 Gy by external beam irradiation . Patients who responded to treatment were recommended to have boost RT , with either an iridium implant or external beam irradiation . Data on relapse and deaths were obtained until October 2007 . Results : Twelve years after treatment , for every 100 patients treated with chemoradiation , there are an expected 25.3 fewer patients with locoregional relapse ( 95 % confidence interval ( CI ) : 17.5–32.0 fewer ) and 12.5 fewer anal cancer deaths ( 95 % CI : 4.3–19.7 fewer ) , compared with 100 patients given RT alone . There was a 9.1 % increase in non-anal cancer deaths in the first 5 years of chemoradiation ( 95 % CI + 3.6 to + 14.6 ) , which disappeared by 10 years . Conclusions : The clear benefit of chemoradiation outweighs an early excess risk of non-anal cancer deaths , and can still be seen 12 years after treatment . Only 11 patients suffered a locoregional relapse as a first event after 5 years , which may influence the choice of end points in future studies PURPOSE The United Kingdom Coordinating Committee on Cancer Research anal cancer trial demonstrated the benefit of combined modality treatment ( CMT ) using radiotherapy ( RT ) , infusional 5-fluorouracil , and mitomycin C over RT alone . The present study retrospectively examines the impact of the recommended 6-week treatment gap and local RT boost on long-term outcome . METHODS AND MATERIAL S A total of 577 patients were r and omly assigned RT alone or CMT .  After a 6-week gap responders received a boost using either additional external beam radiotherapy ( EBRT ) ( 15 Gy ) or iridium-192 implant ( 25 Gy ) . The effect of boost , the gap between initial treatment ( RT alone or CMT ) and boost ( Tgap ) , and overall treatment time ( OTT ) were examined for their impact on outcome . RESULTS Among the 490 good responders , 436 ( 89 % ) patients received a boost after initial treatment . For boosted patients , the risk of anal cancer death decreased by 38 % ( hazard ratio [ HR ] : 0.62 , 99 % CI 0.35 - 1.12 ; p=0.04 ) , but there was no evidence this was mediated via a reduction in locoregional failure ( LRF ) ( HR : 0.90 , 99 % CI 0.48 - 1.68 ; p=0.66 ) . The difference in Tgap was only 1.4 days longer for EBRT boost , compared with implant ( p=0.51 ) . OTT was longer by 6.1 days for EBRT ( p=0.006 ) . Tgap and OTT were not associated with LRF . Radionecrosis was reported in 8 % of boosted , compared with 0 % in unboosted patients ( p=0.03 ) . CONCLUSIONS These results question the benefit of a radiotherapy boost after a 6-week gap . The higher doses of a boost may contribute more to an increased risk of late morbidity , rather than local control Squamous cell carcinoma of the anus ( SCCA ) is a rare cancer but its incidence is increasing throughout the world , and is particularly high in the human immunodeficiency virus positive ( HIV+ ) population . A multidisciplinary approach is m and atory ( involving radiation therapists , medical oncologists , surgeons , radiologists and pathologists ) . SCCA usually spreads in a loco-regional manner within and outside the anal canal . Lymph node involvement at diagnosis is observed in 30 - 40 % of cases while systemic spread is uncommon with distant extrapelvic metastases recorded in 5 - 8 % at onset , and rates of metastatic progression after primary treatment between 10 % and 20 % . SCCA is strongly associated with human papilloma virus ( HPV , types 16 - 18 ) infection . The primary aim of treatment is to achieve cure with loco-regional control and preservation of anal function , with the best possible quality of life . Treatment dramatically differs from adenocarcinomas of the lower rectum . Combinations of 5FU-based chemoradiation and other cytotoxic agents ( mitomycin C ) have been established as the st and ard of care , leading to complete tumour regression in 80 - 90 % of patients with locoregional failures in the region of 15 % . There is an accepted role for surgical salvage . Assessment and treatment should be carried out in specialised centres treating a high number of patients as early as possible in the clinical diagnosis . To date , the limited evidence from only 6 r and omised trials [ 1,2,3,4,5,6,7 ] , the rarity of the cancer , and the different behaviour/natural history depending on the predominant site of origin , ( the anal margin , anal canal or above the dentate line ) provide scanty direction for any individual oncologist . Here we aim to provide guidelines which can assist medical , radiation and surgical oncologists in the practical management of this unusual cancer PURPOSE To evaluate the influence of concomitant chemotherapy on loco-regional control ( LRC ) and cancer-specific survival ( CSS ) in patients with T1-T2 N0 M0 anal cancer treated conservatively by primary radiotherapy ( RT ) .  MATERIAL S AND METHODS Between 1976 and 2008 , 146 patients with T1 ( n=29 ) or T2 ( n=117 ) N0 M0 anal cancer were treated curatively by RT alone ( n=71 ) or by combined chemoradiotherapy ( CRT ) ( n=75 ) consisting of mitomycin C±5-fluorouracil . Univariate and multivariate analyses were performed to assess patient- , tumor- and treatment-related factors influencing LRC and CSS . RESULTS With a median follow-up of 62.5 months ( interquartilerange , 26 - 113 months ) , 122 ( 84 % ) patients were locally controlled . The five-year actuarial LRC , CSS and overall survival for the population were 81.4%±3.6 % , 91.9%±2.6 % , and 75.4%±3.9 % , respectively . The five-year LRC and CSS for patients treated with RT alone and with CRT were 75.5%±6.0 % vs. 86.8%±4.1 % ( p=0.155 ) and 88.5%±4.5 % vs. 94.9%±2.9 % ( p=0.161 ) , respectively . In the multivariate analysis , no clinical or therapeutic factors were found to significantly influence the LRC and CSS , while the addition of chemotherapy was of borderline significance ( p=0.065 and p=0.107 , respectively ) . CONCLUSIONS In the management of node negative T1-T2 anal cancer , LRC and CSS tend to be superior in patients treated by combined CRT , even though the difference was not significant . R and omized studies are warranted to assess definitively the role of combined treatment in early-stage anal carcinoma PURPOSE A multi-institutional phase 2 trial assessed the utility of dose-painted intensity modulated radiation therapy ( DP-IMRT ) in reducing grade 2 + combined acute gastrointestinal and genitourinary adverse events ( AEs ) of 5-fluorouracil ( 5FU ) and mitomycin-C ( MMC ) chemoradiation for anal cancer by at least 15 % compared with the conventional radiation/5FU/MMC arm from RTOG 9811 . METHODS AND MATERIAL S T2 - 4N0 - 3M0 anal cancer patients received 5FU and MMC on days 1 and 29 of DP-IMRT , prescribed per stage : T2N0 , 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes ( PTVs ) in 28 fractions ; T3 - 4N0 - 3 , 45 Gy elective nodal , 50.4 Gy ≤ 3 cm or 54 Gy > 3 cm metastatic nodal and 54 Gy anal tumor PTVs in 30 fractions . The primary endpoint is described above . Planned secondary endpoints assessed all AEs and the investigator 's ability to perform DP-IMRT . RESULTS Of 63 accrued patients , 52 were evaluable . Tumor stage included 54 % II , 25 % IIIA , and 21 % IIIB . In primary endpoint analysis , 77 % experienced grade 2 + gastrointestinal/genitourinary acute AEs ( 9811 77 % ) . There was , however , a significant reduction in acute grade 2 + hematologic , 73 % ( 9811 85 % , P=.032 ) , grade 3 + gastrointestinal , 21 % ( 9811 36 % , P=.0082 ) , and grade 3 + dermatologic AEs 23 % ( 9811 49 % , P<.0001 ) with DP-IMRT . On initial pretreatment review , 81 % required DP-IMRT replanning , and final review revealed only 3 cases with normal tissue major deviations . CONCLUSIONS Although the primary endpoint was not met , DP-IMRT was associated with significant sparing of acute grade 2 + hematologic and grade 3 + dermatologic and gastrointestinal toxicity . Although DP-IMRT proved feasible , the high pretreatment planning revision rate emphasizes the importance of real-time radiation quality assurance for IMRT trials BACKGROUND Chemoradiation became the st and ard of care for anal cancer after the ACT I trial . However , only two-thirds of patients achieved local control , with 5-year survival of 50 % ; therefore , better treatments are needed . We investigated whether replacing mitomycin with cisplatin in chemoradiation improves response , and whether maintenance chemotherapy after chemoradiation improves survival . METHODS In this 2 × 2 factorial trial , we enrolled patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease from 59 centres in the UK . Patients were r and omly assigned to one of four groups , to receive either mitomycin ( 12 mg/m(2 ) on day 1 ) or cisplatin ( 60 mg/m(2 ) on days 1 and 29 ) , with fluorouracil ( 1000 mg/m(2 ) per day on days 1 - 4 and 29 - 32 ) and radiotherapy ( 50.4 Gy in 28 daily fractions ) ; with or without two courses of maintenance chemotherapy ( fluorouracil and cisplatin at weeks 11 and 14 ) . The r and om allocation was generated by computer and patients assigned by telephone . R and omisation was done by minimisation and stratified by tumour site , T and N stage , sex , age , and renal function . Neither patients nor investigators were masked to assignment . Primary endpoints were complete response at 26 weeks and acute toxic effects ( for chemoradiation ) , and progression-free survival ( for maintenance ) . The primary analyses were done by intention to treat . This study is registered at controlled-trials.com , number 26715889 . FINDINGS We enrolled 940 patients : 472 were assigned to mitomycin , of whom 246 were assigned to no maintenance , 226 to maintenance ; 468 were assigned to cisplatin , of whom 246 were assigned to no maintenance , 222 to maintenance . Median follow-up was 5.1 years ( IQR 3.9 - 6.9 ) . 391 of 432 ( 90.5 % ) patients in the mitomycin group versus 386 of 431 ( 89.6 % ) in the cisplatin group had a complete response at 26 weeks ( difference -0.9 % , 95 % CI -4.9 to 3.1 ; p=0.64 ) . Overall , toxic effects were similar in each group ( 334/472 [ 71 % ] for mitomycin vs 337/468 [ 72 % ] for cisplatin ) . The most common grade 3 - 4 toxic effects were skin ( 228/472 [ 48 % ] vs 222/468 [ 47 % ] ) , pain ( 122/472 [ 26 % ] vs 135/468 [ 29 % ] ) , haematological ( 124/472 [ 26 % ] vs 73/468 [ 16 % ] ) , and gastrointestinal ( 75/472 [ 16 % ] vs 85/468 [ 18 % ] ) . 3-year progression-free survival was 74 % ( 95 % CI 69 - 77 ; maintenance ) versus 73 % ( 95 % CI 68 - 77 ; no maintenance ; hazard ratio 0.95 , 95 % CI 0.75 - 1.21 ; p=0.70 ) . INTERPRETATION The results of our trial -- the largest in anal cancer to date --show that fluorouracil and mitomycin with 50.4 Gy radiotherapy in 28 daily fractions should remain st and ard practice in the UK . FUNDING Cancer Research UK OBJECTIVES Parameters have been derived in head and neck cancer to account for the additional biological effective dose provided by synchronous chemotherapy . The purpose of this study was to establish whether such parameters could be used to predict local control differences in anal cancer . METHODS In anal cancer two r and omised trials of radiotherapy vs chemoradiotherapy and two trials r and omising between different synchronous chemotherapy regimens  were identified . To predict differences in local control between the arms of the first two studies , a global value of 9.3 Gy for the chemotherapy biologically effective dose was employed . For the last two trials , values specific to differing chemotherapy schedules were derived . These values were added to the calculated biological effective dose for the radiotherapy component in order to predict local control outcomes in anal cancer trials . RESULTS The predicted difference in local control using the global value of 9.3 Gy for the addition of synchronous chemotherapy in the trials of radiotherapy vs radiotherapy and synchronous chemotherapy was 24.6 % compared with the observed difference of 21.4 % . Using schedule-specific values for the contribution of chemotherapy , the predicted differences in local control in the two trials of differing synchronous chemotherapy schedules were 7.2 % and 12 % compared with the observed 18 % and 0 % . CONCLUSION The methods initially proposed require modification to result in adequate prediction . If the decreased cisplatin dose intensity employed in anal cancer is modelled , more satisfactory predictions for such trials can be achieved . ADVANCES IN KNOWLEDGE This revised modelling may be hypothesis generating BACKGROUND AND PURPOSE Definitive chemoradiation is the st and ard management for anal squamous cell carcinoma ( ASCC ) ; more conformal pelvic radiotherapy using intensity modulated radiotherapy ( IMRT ) minimizes toxicity but may increase locoregional recurrences ( LRR ) . We compared IMRT and conventional radiotherapy ( CRT ) outcomes in ASCC patients . MATERIAL AND METHODS We retrospectively review ed records of 223 ASCC patients treated at Memorial Sloan-Kettering Cancer Center from 1991 to 2010 . Forty-five patients received  IMRT and 178 CRT . We determined locoregional recurrence-free survival ( LRFS ) , distant metastases-free survival ( DMFS ) , and overall survival ( OS ) for each radiation modality . A propensity score analysis was performed using potentially confounding variables . Locoregional and distant patterns of failure for CRT and IMRT were compared . RESULTS Patients treated with IMRT had significantly higher N stage ( P<.01 ) , and were less likely to be treated with induction chemotherapy ( P=.01 ) . The 2-year LRFS , DMFS , and OS were 87 % , 86 % , and 93 % , respectively , for IMRT ; and 82 % , 88 % , 90 % , respectively , for CRT ; with no significant difference in outcomes by univariate analysis or in a propensity score analysis adjusted for disparity between the groups . CONCLUSIONS This large , single-institution experience of definitive chemoradiation for ASCC using CRT vs. IMRT demonstrates that outcomes are not compromised by more conformal radiotherapy . In the absence of prospect i ve , multi-institutional , r and omized trials of IMRT in ASCC , these retrospective data , using methods to minimize bias , can help to establish the role of IMRT in the definitive therapy of ASCC
BACKGROUND AND PURPOSE A recent up date of the RTOG 9811 , reported differing relapse rates for early and late anal squamous cell carcinoma following chemoradiotherapy ( CRT ) .
There may be a role for dose-individualization , however the dose-response relationship for anal cancer is not currently known .
Intensity-modulated radiotherapy ( IMRT ) has been widely adopted with multiple series published .
The aim is to fit a tumor control probability ( TCP ) model to the published IMRT data .