Clinical outcomes of image guided adaptive hypofractionated weekly radiotherapy for bladder cancer in those unsuitable for radical treatment Accepted Manuscript Clinical outcomes of image guided adapt[.]
Accepted Manuscript Clinical outcomes of image guided adaptive hypofractionated weekly radiotherapy for bladder cancer in those unsuitable for radical treatment S Hafeez, PhD FRCR, F McDonald, MD FRCR, S Lalondrelle, MD FRCR, H McNair, PhD, K Warren-Oseni, DCR(T), K Jones, BSc, V Harris, MD FRCR, H Taylor, MSc, V Khoo, MD FRCR, K Thomas, MSc, V Hansen, PhD, D Dearnaley, MD FRCR, A Horwich, MD FRCR, R Huddart, PhD FRCR PII: S0360-3016(17)30302-4 DOI: 10.1016/j.ijrobp.2017.01.239 Reference: ROB 24077 To appear in: International Journal of Radiation Oncology • Biology • Physics Received Date: 21 October 2016 Revised Date: 23 January 2017 Accepted Date: 31 January 2017 Please cite this article as: Hafeez S, McDonald F, Lalondrelle S, McNair H, Warren-Oseni K, Jones K, Harris V, Taylor H, Khoo V, Thomas K, Hansen V, Dearnaley D, Horwich A, Huddart R, Clinical outcomes of image guided adaptive hypofractionated weekly radiotherapy for bladder cancer in those unsuitable for radical treatment, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/j.ijrobp.2017.01.239 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT Clinical outcomes of image guided adaptive hypofractionated weekly radiotherapy for bladder cancer in those unsuitable for radical treatment Hafeez S PhD FRCR1,2, McDonald F MD FRCR2 , Lalondrelle S MD FRCR2, McNair H PhD1,2, Warren-Oseni K DCR(T)2 , Jones K BSc2, Harris V MD FRCR2, Taylor H MSc 2, Khoo V MD FRCR 2, Thomas K MSc 2, Hansen V PhD 2, Dearnaley RI PT D MD FRCR 1,2, Horwich A MD FRCR1,2, Huddart R PhD FRCR1,2 Institute of Cancer Research, UK 2The Royal Marsden NHS Foundation Trust, UK Acknowledgments TE D M AN U SC We acknowledge NHS funding to the NIHR Biomedical Research Centre for Cancer EP and to Cancer Research UK (CRUK) Keywords Bladder cancer, image-guided, hypofractionated, adaptive, radiotherapy, AC C organ preservation Conflict of Interest Notification No conflicts of interest Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT Summary This prospective study demonstrates that hypofractionated radiotherapy delivered with a plan of the day approach is well tolerated in those unfit for radical bladder cancer treatment It provides opportunity for local disease and symptom control in AC C EP TE D M AN U SC RI PT patients for whom cystectomy, trimodality or daily radiotherapy is not appropriate Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT Clinical outcomes of image guided adaptive hypofractionated weekly M AN U SC RI PT radiotherapy for bladder cancer in those unsuitable for radical treatment organ preservation TE D Keywords Bladder cancer, image-guided, hypofractionated, adaptive, radiotherapy, EP Conflict of Interest Notification AC C No conflicts of interest Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT Abstract Purpose/objectives We report on the clinical outcomes of a phase II study assessing image guided hypofractionated weekly radiotherapy in bladder cancer patients unsuitable for RI PT radical treatment Methods and materials Fifty-five patients with T2-T4aNx-2M0-1 bladder cancer not suitable for cystectomy or A ‘plan of the day’ radiotherapy SC daily radiotherapy treatment were recruited approach was used, treating whole (empty) bladder to 36Gy in weekly fractions M AN U Acute toxicity was assessed weekly during radiotherapy, at and 12 weeks using Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Late toxicity was assessed at months and 12 months using Radiation Therapy Oncology Group TE D (RTOG) grading Cystoscopy was used to assess local control at months Cumulative incidence function was used to determine local progression at at years Death without local progression was treated as a competing risk Overall AC C Results EP survival were estimated using the Kaplan-Meier method Median age was 86 years (range 68-97 years) 87% patients completed their prescribed course of radiotherapy Genito-urinary and gastro-intestinal grade acute toxicity was seen in 18% (10/55) and 4% (2/55) patients respectively No grade genito-urinary or gastro-intestinal toxicity was seen Grade >3 late toxicity (any) at and 12 months was seen in 6.5% (2/31) and 4.3% (1/23) patients respectively Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT Local control following radiotherapy was 92% of assessed patients (60% total population) Cumulative incidence of local progression at year and years for all patients was 7% (95%CI 2%-17%) and 17% (95%CI 8%-29%) respectively Overall RI PT survival at year was 63% (95% CI 48%-74%) Conclusion Hypofractionated radiotherapy delivered weekly with a plan of the day approach offers good local control with acceptable toxicity in a patient population not suitable AC C EP TE D M AN U SC for radical bladder treatment Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT 1.0 Introduction Under utilization of curative therapy in those with muscle invasive bladder cancer (MIBC) is well documented [1-3] High cancer specific mortality is particularly evident RI PT in older patients reflecting their poorer access to effective treatment [2] There is good evidence that symptomatic local disease can be relieved for the duration of survival with hypofractionated radiotherapy (21Gy in fractions on alternate days) when either cystectomy or radical radiotherapy is unsuitable [4] As SC local disease control is related to total radiotherapy dose delivered, a higher biological effective dose is anticipated to improve outcomes [5, 6] A number of M AN U retrospective studies report successful treatment of MIBC with 30-36Gy in weekly fractions [7-10] Each fraction of this regime represents ~17% of the prescription dose so a geographical miss could potentially compromise tumour control and TE D tolerability Image guided adaptive radiotherapy (IGRT) strategies in bladder cancer show significant dosimetric gains for tumour coverage and normal tissue sparing [11-15] EP Implementation is therefore anticipated improve local control and toxicity but prospective studies are lacking Here we report on the long term clinical outcomes of AC C ‘plan of the day’ hypofractionated radiotherapy in a non-randomised phase II study in patients unsuitable for radical treatment Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT 2.0 Materials and methods Between January 2009 and March 2014, fifty-five patients with pathological evidence of MIBC unsuitable for cystectomy or daily radiotherapy because of stage, comorbidity or personal preference were recruited prospectively to an institutional RI PT Clinical Research and Ethics Committee approved protocol (NCTXXXXXXXX; ISRCTNXXXXX) Details of planning and plan selection have been previously presented and are SC summarized in Supplementary Table [12, 16] Normal tissue constraints are given in Supplementary Table Treatment was delivered using plan selection from library M AN U of three, 3D conformal plans treating whole empty bladder to 36Gy in fractions over weeks Acute toxicity was collected using the Common Terminology Criteria for Adverse TE D Events (CTCAE), version 3.0 at baseline, weekly during radiotherapy, and then at and 12 weeks following completion of treatment Local response was assessed at three months with cystoscopy and biopsy where possible Local response was EP defined as absence of pathological or clinical MIBC at cystoscopy, pathological or AC C radiological down staging to non-invasive disease, or stable radiological disease Late toxicity was scored at months and 12 months using the Radiation Therapy Oncology Group (RTOG) late radiation morbidity-scoring schema Patients were subsequently followed up as clinically indicated with cystoscopic surveillance and imaging where appropriate Overall survival (OS) was estimated using Kaplan-Meier method and was defined as time from start of radiotherapy to death from any cause Surviving patients and those lost to follow-up were censored at the last assessment date Cumulative incidence Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT competing risk (CICR) method was used to calculate local progression at and years Local progression was defined as interval from radiotherapy start to disease relapse within the bladder (pathological, radiological or clinical) Death without local progression was treated as a competing risk CICR analysis was performed using R RI PT version 3.3.1 All other analyses were carried out using STATA v13.1 (StataCorp LP, TX, USA) 2.1 Statistical considerations SC Sample size was calculated assuming the rate of local control was no more than 40% at months (null hypothesis) Using a single stage design with one-sided alpha of power M AN U 0.05 (assuming true rate of control is 60%), 56 patients were estimated for 90% Considering expected loss to follow-up prior to the 3-month evaluation, recruitment target was set at 67 patients The study closed prior to this because of a AC C EP TE D competing study (HYBRID study; NCT01810757) [17] Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT 3.0 Results Patient characteristics are shown in Table Target coverage and normal tissue sparing have been previously presented [12] Seven patients stopped treatment early because of deterioration in general health Four deaths occurred during RI PT radiotherapy unrelated to treatment (3 from pneumonia and from urinary sepsis) 3.1 Treatment related toxicity Radiotherapy was well tolerated with no grade genito-urinary or gastro-intestinal SC toxicity seen at any time M AN U At baseline (pre-radiotherapy) grade and grade urinary toxicity was evident in 10 (19%) and (9%) patients During treatment acute genito-urinary grade and grade toxicity was seen in 22 (40%) and 10 (18%) patients respectively (Figure 1) At weeks following radiotherapy patients (20% of those assessed) had grade urinary TE D toxicity and patients (5% of those assessed) had grade urinary toxicity At 12 weeks following radiotherapy patients (27% of those assessed) reported grade EP toxicity and patient (4.5% of those assessed) had grade urinary toxicity Acute gastro-intestinal grade and grade toxicity was seen in 21 (38%) and (4%) AC C patients respectively Change in acute toxicity over time is shown in Supplementary Figure Supplementary Figure shows total number of patients available for assessment at each time point Other acute grade toxicity occurred in 23 (42%) patients (predominately fatigue or anaemia) Other acute grade toxicity occurred in (4%) patients (hyponatraemia and syncope) One grade acute toxicity event occurred (ventricular arrthymia), unrelated to radiotherapy No known radiotherapy treatment related deaths occurred during the follow-up period Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT RTOG late toxicity scores at and 12 months were available for 31 and 23 patients respectively Grade late toxicity of any type at and 12 months was seen in 6/31 (19%) and 3/23 (13%) patients respectively Grade late toxicity of any type at and 12 months was seen in 2/31 (6.5%) and 1/23 (4.3%) patients respectively RI PT (Figure 2) At months, patients (16.1%) reported grade 2, and patients (6.5%) reported grade RTOG bladder toxicity At 12 months, patients (8.7%) reported grade and patient (4.3%) reported grade RTOG bladder toxicity All late bladder symptom scoring (grade and grade 3) were as a result of cystitis like symptoms No episodes of >grade hematuria were SC (frequency, urgency and dysuria) M AN U reported at or 12 months No >3 grade late bowel toxicity was seen Two patients experienced grade toxicity at months (6.5%) and patient (4.3%) had grade toxicity at 12 months All late TE D RTOG bowel symptoms scoring (grade 2) were as a result of diarrhea 3.2 Response assessment and outcome Response to radiotherapy months after completing treatment was assessed in 36 This was performed by cystoscopy in 30 patients 33/36 (92%) of EP patients assessed patients (60% of all patients) achieved local disease control within the AC C bladder at months 28/30 (93%) achieved complete response as assessed on cystoscopy This means local control at months was achieved in a minimum of 51% (28/55) of all patients (based on assuming failure in all patients not assessed by cystoscopy) Cumulative incidence of local progression was 7% (95%CI 2%-17%) and 17% (95%CI 8%-29%) for all patients at year and years respectively Results for patients stratified by stage are presented in Figure After median follow-up of years, a total of 38 deaths were recorded Estimated survival at year was 62% (95% CI 48% to 74%) (Figure 4) Table summarizes the Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT outcome grouped by stage 4.0 Discussion Our study demonstrates that patients with high median age and comorbidity index, RI PT deemed unsuitable for radical treatment can be treated with hypofractionated weekly radiotherapy delivered with a plan of the day approach with acceptable morbidity rates SC As cancer specific mortality is highest in those >80 years, the assumption that death from competing medical conditions rather than from MIBC to justify no active M AN U treatment does not necessarily hold true [2] Intervention (cystectomy, radiotherapy or TURBT alone) for older patients significantly reduces risk of death from MIBC compared to watchful waiting [2, 3] Watchful waiting alone, we contend also would have been sub-optimal management given that 85% of our patient population had Our data also supports TE D potentially curable disease (T2 or T3 only disease) intervention for this population as long-term survival and progression free survival EP was achieved in a third of patients From the linear quadratic equation, 36Gy in fractions is approximately 48Gy AC C assuming α/β of 10 for tumour control when delivered in 2Gy per fraction (EQD2) It delivers higher total dose than other commonly used radiotherapy regimes in the non-radical setting The EQD2 of 20Gy in fractions, 21Gy in fractions and 30Gy in 10 fractions are 23Gy, 30Gy and 33Gy respectively Although fewer fractions are less burdensome, to achieve balance between efficacy, toxicity, and convenience, patients’ prescriptions should be individualized Turgeon et al., delivered 50Gy in 20 fractions with a non-IGRT IMRT achieving EQD2 of 52Gy [18] Their patient population (median age 70) were also suitable for Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT concurrent chemotherapy (gemcitabine) which clinically improves local control and from radiobiological modeling has equivalent additional >10Gy benefit [19] They achieved 83% complete response 43% of which had assessment with cystoscopy RI PT and biopsy Biopsy assessment was not mandated within our study, as this would necessitate rigid cystoscopy and anesthetic in a high-risk population The absence of pathological correlation (biopsy at the time cystoscopy) lends itself to tumour under SC staging, however any downstaging achieved (i.e partial response) has potential M AN U patient benefit [20] Even though most patients (72%) had no significant urinary symptoms (grade 0-1) prior to radiotherapy, urinary symptom scores did not deteriorate during radiotherapy as may have been anticipated given improved targeting with plan of the day TE D approach [12] There is some suggestion of possible improvement in scores following radiotherapy than at baseline reflecting potential early symptom control EP Given year survival is 62% (95% CI 48% to 74%); the risk of developing late toxicity is an important consideration especially in the context of large fraction size used, but AC C the observed rate of late toxicity (>grade 2) was low The dosimetric advantage with plan of the day is likely to have contributed to both high complete response and low non-urinary toxicity rates [12] We acknowledge that due to the nature of the trial population a proportion of patients did not contribute toxicity information Such missing data are inevitable and illustrates the difficulties of assessing a less fit population A weakness of this work is that it is a single centre, single arm study We shall address this within a randomised multi-centre trial (XXXX study; hypofractionated 10 Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT bladder radiotherapy with or without image guided adaptive planning XXXXX [17] Unlike the reported phase II study, this trial will allow treatment delivery using volumetric intensity modulated arc therapy As well as improving conformity, it will shorten treatment delivery time, so reducing opportunity for intra-fraction organ from on line re-optimisation strategies in development [22] RI PT motion and filling [21] Further opportunity to spare normal tissue is likely to come In conclusion hypofractionated bladder radiotherapy of 36Gy in weekly fractions SC delivered with image guidance presents an important disease control option in appropriately selected patients and meets clinical need for a somewhat neglected M AN U patient population Exclusion from radical treatment on the basis of age alone would be unacceptable as functional decline is specific to the individual This approach is not advocated as an alternative to radical treatment but as a means of potential AC C EP TE D disease control in those with competing comorbidities 11 Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT Tables Table Patient characteristics Table Status at last follow-up RI PT Figures Figure Worst symptoms or acute toxicity as graded by CTCAE v3.0 Figure Worst late toxicity at and 12 months as graded by RTOG competing risk, for all patients and stratified by stage SC Figure Cumulative incidence of local progression using death from other causes as Supplementary on line M AN U Figure Kaplan Meier plots for rates of overall survival and stratified by stage Table CTV to PTV expansion details Table Dose constraints guidance used for 3D conformal planning for total TE D prescription dose of 36Gy in fractions Figure Change in acute toxicity over time AC C EP Figure Number of patients assessed at each time point 12 Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT References RI PT Gray PJ, Fedewa SA, Shipley WU, Efstathiou JA, Lin CC, Zietman AL, Virgo KS: Use of potentially curative therapies for muscle-invasive bladder cancer in the United States: results from the National Cancer Data Base Eur Urol 2013, 63(5):823-829 Noon AP, Albertsen PC, Thomas F, Rosario DJ, Catto JW: Competing mortality in patients diagnosed with bladder cancer: evidence of undertreatment in the elderly and female patients Br J Cancer 2013, 108(7):1534-1540 Hollenbeck BK, Miller DC, Taub D, Dunn RL, Underwood W, 3rd, Montie JE, Wei JT: Aggressive treatment for bladder cancer is associated with improved overall survival among patients 80 years old or older Urology 2004, 64(2):292-297 Duchesne GM, Bolger JJ, Griffiths GO, Trevor Roberts J, Graham JD, Hoskin PJ, Fossa SD, Uscinska BM, Parmar MK: A randomized trial of hypofractionated schedules of palliative radiotherapy in the management of bladder carcinoma: results of medical research council trial BA09 Int J Radiat Oncol Biol Phys 2000, 47(2):379-388 Majewski W, Maciejewski B, Majewski S, Suwinski R, Miszczyk L, Tarnawski R: Clinical radiobiology of stage T2-T3 bladder cancer Int J Radiat Oncol Biol Phys 2004, 60(1):60-70 Pos FJ, Hart G, Schneider C, Sminia P: Radical radiotherapy for invasive bladder cancer: What dose and fractionation schedule to choose? Int J Radiat Oncol Biol Phys 2006, 64(4):1168-1173 Rostom AY, Tahir S, Gershuny AR, Kandil A, Folkes A, White WF: Once weekly irradiation for carcinoma of the bladder Int J Radiat Oncol Biol Phys 1996, 35(2):289-292 Scholten AN, Leer JW, Collins CD, Wondergem J, Hermans J, Timothy A: Hypofractionated radiotherapy for invasive bladder cancer Radiother Oncol 1997, 43(2):163-169 McLaren DB, Morrey D, Mason MD: Hypofractionated radiotherapy for muscle invasive bladder cancer in the elderly Radiother Oncol 1997, 43(2):171-174 Jose CC, Price A, Norman A, Jay G, Huddart R, Dearnaley DP, Horwich A: Hypofractionated radiotherapy for patients with carcinoma of the bladder Clin Oncol (R Coll Radiol) 1999, 11(5):330333 Burridge N, Amer A, Marchant T, Sykes J, Stratford J, Henry A, McBain C, Price P, Moore C: Online adaptive radiotherapy of the bladder: small bowel irradiated-volume reduction Int J Radiat Oncol Biol Phys 2006, 66(3):892-897 XXXXX Vestergaard A, Muren LP, Lindberg H, Jakobsen KL, Petersen JB, Elstrom UV, Agerbaek M, Hoyer M: Normal tissue sparing in a phase II trial on daily adaptive plan selection in radiotherapy for urinary bladder cancer Acta Oncol 2014, 53(8):997-1004 Tuomikoski L, Collan J, Keyrilainen J, Visapaa H, Saarilahti K, Tenhunen M: Adaptive radiotherapy in muscle invasive urinary M AN U SC AC C 10 EP TE D 11 12 13 14 13 Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT 20 21 RI PT AC C EP 22 SC 19 M AN U 16 17 18 TE D 15 bladder cancer - An effective method to reduce the irradiated bowel volume Radiother Oncol 2011 Hafeez S, Warren-Oseni K, McNair HA, Hansen VN, Jones K, Tan M, Khan A, Harris V, McDonald F, Lalondrelle S et al: Prospective Study Delivering Simultaneous Integrated High-dose Tumor Boost (≤70 Gy) With Image Guided Adaptive Radiation Therapy for Radical Treatment of Localized Muscle-Invasive Bladder Cancer International Journal of Radiation Oncology*Biology*Physics 2016, 94(5):1022-1030 XXXXX https://http://www.clinicaltrials.gov/ct2/show/NCT01810757 Turgeon GA, Souhami L, Cury FL, Faria SL, Duclos M, Sturgeon J, Kassouf W: Hypofractionated intensity modulated radiation therapy in combined modality treatment for bladder preservation in elderly patients with invasive bladder cancer Int J Radiat Oncol Biol Phys 2014, 88(2):326-331 Plataniotis GA, Dale RG: Assessment of the radiation-equivalent of chemotherapy contributions in 1-phase radio-chemotherapy treatment of muscle-invasive bladder cancer Int J Radiat Oncol Biol Phys 2014, 88(4):927-932 Efstathiou JA, Spiegel DY, Shipley WU, Heney NM, Kaufman DS, Niemierko A, Coen JJ, Skowronski RY, Paly JJ, McGovern FJ et al: Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience Eur Urol 2012, 61(4):705-711 Foroudi F, Wilson L, Bressel M, Haworth A, Hornby C, Pham D, Cramb J, Gill S, Tai KH, Kron T: A dosimetric comparison of 3D conformal vs intensity modulated vs volumetric arc radiation therapy for muscle invasive bladder cancer Radiat Oncol 2012, 7:111 Vestergaard A, Hafeez S, Muren LP, Nill S, Hoyer M, Hansen VN, Gronborg C, Pedersen EM, Petersen JB, Huddart R et al: The potential of MRI-guided online adaptive re-optimisation in radiotherapy of urinary bladder cancer Radiother Oncol 2016, 118(1):154-159 14 Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT Table Patient characteristics Age Median 86 years (range 68-97) Male 31 Female 24 Stage at presentation* 36 T3N0M0 11 SC T2N0M0 RI PT Gender T4N0M0 3 TanyNanyM1 M AN U TanyN1-N3M0 Histological subtype Transitional cell carcinoma** Squamous cell carcinoma 49 Other TE D Adenocarcinoma EP Grade High (grade 3) 52 AC C Intermediate (grade 2) Unknown WHO performance status at baseline** 16 12 Unknown 17 Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT Charlson comorbidity index (†age adjusted) 21 (0) 11 (0) 12 (0) 3 (2) (18) >5 (35) Number of fractions delivered ^ SC 3 at baseline assessment; 17 patients did not have performance status documented at baseline assessment but were deemed fit for proposed treatment by recruiting clinician (i.e AC C presumed PS 0-3) † Modified Charlson-Deyo score (measure of comorbidity across multiple organ sites, captured using International Classification of Diseases, 9th revision, Clinical Modification codes) was retrospectively calculated for each patient excluding his or her diagnosis of bladder cancer at presentation Age-adjusted Charlson index score, for each decade after 40 years an additional point is added ^3 patients were planned to 30Gy in fractions because of either advanced disease or limited performance status Forty-eight patients completed their prescribed course of radiotherapy treatment Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT Table Status at last follow-up after median follow-up of years Number of patients Total patient number Initial Initial Initial T2N0M0 T3-T4N0M0 TanyN+M1 Alive 12 17 (30.9%) Disease free 10 15 (27.3%) 0 Regional disease (pelvis) 0 Metastases 0 Dead 24 Metastases 10 Other malignancy 1 Other causes* 13 RI PT (1.8%) (0%) (1.8%) SC (bladder) 38 (69.0%) 17 (30.9%) (3.6%) 19 (34.5%) M AN U Localised disease (%) *No known deaths from radiotherapy occurred; 19 other causes of death were due to pneumonia (8 patients), cardiac events (4 patients), urinary sepsis (2 patients), unknown cause of death (2 patients), sepsis from idiopathic myelosuppression and bowel obstruction (1 patient), peripheral vascular disease (1 patient), superior vena cava obstruction AC C EP TE D (1 patient) .. .Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT Clinical outcomes of image guided adaptive hypofractionated weekly radiotherapy for bladder cancer in those unsuitable for radical treatment. .. appropriate Hypofractionated bladder IGRT ACCEPTED MANUSCRIPT Clinical outcomes of image guided adaptive hypofractionated weekly M AN U SC RI PT radiotherapy for bladder cancer in those unsuitable for radical. .. lacking Here we report on the long term clinical outcomes of AC C ‘plan of the day’ hypofractionated radiotherapy in a non-randomised phase II study in patients unsuitable for radical treatment Hypofractionated