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Recommendations for planning and delivery of radical radiotherapy for localized urothelial carcinoma of the bladder

      Highlights

      • Homogenized guidelines for bladder radiotherapy were needed in literature.
      • A technical consensus for radiotherapy of bladder cancer is presented.
      • Planning acquisition, PTV margins and lymph-nodes radiotherapy are controversial.
      • Practical recommendations are available for the implementation of novel techniques.

      Abstract

      Purpose

      Curative radio-chemotherapy is recognized as a standard treatment option for muscle-invasive bladder cancer (MIBC). Nevertheless, the technical aspects for MIBC radiotherapy are heterogeneous with a lack of practical recommendations.

      Methods and materials

      In 2018, a workshop identified the need for two cooperative groups to develop consistent, evidence-based guidelines for irradiation technique in the delivery of curative radiotherapy. Two radiation oncologists performed a review of the literature addressing several topics relative to radical bladder radiotherapy: planning computed tomography acquisition, target volume delineation, radiation schedules (total dose and fractionation) and dose delivery (including radiotherapy techniques, image-guided radiotherapy (IGRT) and adaptive treatment modalities). Searches for original and review articles in the PubMed and Google Scholar databases were conducted from January 1990 until March 2020. During a meeting conducted in October 2020, results on 32 topics were presented and discussed with a working group involving 15 radiation oncologists, 3 urologists and one medical oncologist. We applied the American Urological Association guideline development’s method to define a consensus strategy.

      Results

      A consensus was obtained for all 34 except 4 items. The group did not obtain an agreement on CT enhancement added value for planning, PTV margins definition for empty bladder and full bladder protocols, and for pelvic lymph-nodes irradiation. High quality evidence was shown in 6 items; 8 items were considered as low quality of evidence.

      Conclusion

      The current recommendations propose a homogenized modality of treatment both for routine clinical practice and for future clinical trials, following the best evidence to date, analyzed with a robust methodology. The XXX group formulates practical guidelines for the implementation of innovative techniques such as adaptive radiotherapy.

      Keywords

      Radical cystectomy with cisplatin-based neoadjuvant chemotherapy is considered the standard of care to treat localized urothelial muscle-invasive bladder carcinoma (MIBC), providing 5-year overall survival (OS) rates of more than 50% among fit patients [
      • Grossman H.B.
      • Natale R.B.
      • Tangen C.M.
      • Speights V.O.
      • Vogelzang N.J.
      • Trump D.L.
      • et al.
      Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer.
      ,
      • Arcangeli G.
      • Strigari L.
      • Arcangeli S.
      Radical cystectomy versus organ-sparing trimodality treatment in muscle-invasive bladder cancer: A systematic review of clinical trials.
      ].
      Historically, “curative” radiotherapy was proposed as an alternative to radical cystectomy for patients deemed unfit for surgery and/or with inoperable MIBC [
      • Fosså S.D.
      • Waehre H.
      • Aass N.
      • Jacobsen A.B.
      • Olsen D.R.
      • Ous S.
      Bladder cancer definitive radiation therapy of muscle-invasive bladder cancer. A retrospective analysis of 317 patients.
      ,
      • Gospodarowicz M.K.
      • Rider W.D.
      • Keen C.W.
      • Connolly J.G.
      • Jewett M.A.
      • Cummings B.J.
      • et al.
      Bladder cancer: long-term follow-up results of patients treated with radical radiation.
      ].
      Concerns about morbi-mortality as well as impact on quality of life following radical cystectomy have led to the development of organ-preserving approaches even in patients fit for surgery. In this context, transurethral resection of bladder tumors (TURBT) followed by curative radiotherapy with concomitant chemotherapy (with or without neoadjuvant/adjuvant chemotherapy), known as the trimodal therapy strategy, has emerged as a relevant bladder-preserving approach. Although the only phase III randomized trial comparing radical cystectomy to trimodal therapy has failed to accrue [
      • Huddart R.A.
      • Birtle A.
      • Maynard L.
      • Beresford M.
      • Blazeby J.
      • Donovan J.
      • et al.
      Clinical and patient-reported outcomes of SPARE - a randomised feasibility study of selective bladder preservation versus radical cystectomy.
      ], trimodal therapy has long been proposed by several teams and recommended as an alternative for fit patients, with similar oncological results [
      • Arcangeli G.
      • Strigari L.
      • Arcangeli S.
      Radical cystectomy versus organ-sparing trimodality treatment in muscle-invasive bladder cancer: A systematic review of clinical trials.
      ,
      • Giacalone N.J.
      • Shipley W.U.
      • Clayman R.H.
      • Niemierko A.
      • Drumm M.
      • Heney N.M.
      • et al.
      Long-term outcomes after bladder-preserving tri-modality therapy for patients with muscle-invasive bladder cancer: an updated analysis of the massachusetts general hospital experience.
      ,
      • Mak R.H.
      • Hunt D.
      • Shipley W.U.
      • Efstathiou J.A.
      • Tester W.J.
      • Hagan M.P.
      • et al.
      Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of radiation therapy oncology group protocols 8802, 8903, 9506, 9706, 9906, and 0233.
      ], acceptable toxicity [
      • Efstathiou J.A.
      • Bae K.
      • Shipley W.U.
      • Kaufman D.S.
      • Hagan M.P.
      • Heney N.M.
      • et al.
      Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06.
      ] and an overall preserved quality of life and quality of conserved bladder function [
      • Zietman A.L.
      • Sacco D.
      • Skowronski U.
      • Gomery P.
      • Kaufman D.S.
      • Clark J.A.
      • et al.
      Organ conservation in invasive bladder cancer by transurethral resection, chemotherapy and radiation: results of a urodynamic and quality of life study on long-term survivors.
      ,
      • Lagrange J.-L.
      • Bascoul-Mollevi C.
      • Geoffrois L.
      • Beckendorf V.
      • Ferrero J.-M.
      • Joly F.
      • et al.
      Quality of life assessment after concurrent chemoradiation for invasive bladder cancer: results of a multicenter prospective study (GETUG 97*015).
      ,
      • Huddart R.A.
      • Hall E.
      • Lewis R.
      • Porta N.
      • Crundwell M.
      • Jenkins P.J.
      • et al.
      Patient-reported quality of life outcomes in patients treated for muscle-invasive bladder cancer with radiotherapy ± Chemotherapy in the BC2001 Phase III randomised controlled trial.
      ].
      Trimodal therapy can be proposed as an alternative to radical cystectomy in a well selected population of patients with tumor stage T2–T3 (+/−T4a) N0M0, no multifocal lesions, no hydronephrosis and no extensive in-situ carcinoma (CIS) outside the area of involvement[
      • Hindson B.R.
      • Turner S.L.
      • Millar J.L.
      • Foroudi F.
      • Gogna N.K.
      • Skala M.
      • et al.
      Australian & New Zealand Faculty of Radiation Oncology Genito-Urinary Group: 2011 consensus guidelines for curative radiotherapy for urothelial carcinoma of the bladder.
      ]. However, we note that these prognostic and predictive factors come from phase II prospective trials as well as retrospective studies with radiotherapy-only strategies in many cases [
      • Giacalone N.J.
      • Shipley W.U.
      • Clayman R.H.
      • Niemierko A.
      • Drumm M.
      • Heney N.M.
      • et al.
      Long-term outcomes after bladder-preserving tri-modality therapy for patients with muscle-invasive bladder cancer: an updated analysis of the massachusetts general hospital experience.
      ,
      • Fung C.Y.
      • Shipley W.U.
      • Young R.H.
      • Griffin P.P.
      • Convery K.M.
      • Kaufman D.S.
      • et al.
      Prognostic factors in invasive bladder carcinoma in a prospective trial of preoperative adjuvant chemotherapy and radiotherapy.
      ,

      Moonen L, v.d. Voet H, de Nijs R, Hart AAM, Horenblas S, Bartelink H. Muscle-invasive bladder cancer treated with external beam radiotherapy: pretreatment prognostic factors and the predictive value of cystoscopic re-evaluation during treatment. Radiother Oncol 1998;49:149–55. 10.1016/S0167-8140(98)00089-9.

      ,
      • Pollack A.
      • Zagars G.K.
      • Swanson D.A.
      Muscle-invasive bladder cancer treated with external beam radiotherapy: Prognostic factors.
      ,
      • Skołyszewski J.
      • Reinfuss M.
      • Weiss M.
      Radical external beam radiotherapy of urinary bladder carcinoma. An analysis of results in 500 patients.
      ], so they must be regarded with caution when it comes to proposing or declining an organ-preservation strategy. Besides, patients eligible for trimodal therapy must have an adequate bladder function; no consensus exists on this criteria, but this may include: bladder capacity >200 ml, no significant incontinence (≤1 pad/day), no significant irritative symptoms (no urgency, no daily pollakiuria, nocturnal pollakiuria ≤2/night) and no significant dysuria (IPSS score <8). Notably, the role of trimodal therapy for patients with high-risk non-muscle-invasive bladder cancer or with history of BCG failure remains controversial, and this strategy cannot be recommended in routine for these patients for now [
      • Rodrigues Pessoa R.
      • Mueller A.C.
      • Boxley P.
      • Flaig T.W.
      • Piper C.
      • Konety B.
      • et al.
      Systematic review and meta-analysis of radiation therapy for high-risk non-muscle invasive bladder cancer.
      ]. In any case, the feasibility of trimodal therapy should be validated during a multidisciplinary tumor board, involving urologists, medical oncologists, pathologists, radiologists and radiation oncologists.
      The aims of the current work were to review the modalities of curative radiotherapy within trimodal therapy for localized MIBC, to homogenize this treatment delivery across the group of institutions that are or will start performing this technique and subsequently to propose an optimal radiotherapy technical consensus.

      Methods

      In 2018, a workshop identified the need for two cooperative groups to develop evidence-based guidelines for the delivery of curative radiotherapy for localized MIBC, both for routine clinical practice and for the implementation of future clinical trials. In this perspective, the approach used to conduct the consensus methodology research was a consensus development panel [
      • Waggoner J.
      • Carline J.D.
      • Durning S.J.
      Is there a consensus on consensus methodology? Descriptions and recommendations for future consensus research.
      ].
      To do so, two radiation oncologists (JK and PS) first performed a review of the literature addressing several topics relative to radical bladder radiotherapy: planning Computed Tomography (CT) acquisition, target volume delineation, radiation schedules (total dose and fractionation), dose delivery (including radiotherapy techniques, image-guided radiotherapy (IGRT) and adaptive treatment modalities) and concurrent systemic treatment. Patient selection criteria for the indication of trimodal therapy was not in the scope of this review.
      Searches for original and review articles in the PubMed and Google Scholar databases were conducted from January 1990 until March 2020. General search terms (including both Medical Subject Headings (MeSH) and free text words) included the following: “bladder cancer”, “radiotherapy”, “trimodal therapy”, “chemoradiotherapy”, “bladder-sparing”, “dose constraints”, “image-guided radiotherapy”, and “adaptive radiotherapy”. Individual reference lists were reviewed for additional relevant references.
      Due to the heterogeneity of populations (e.g. patients with either resectable or unresectable tumors) and of regimens for bladder radical radiotherapy, the employed methodology was:
      • to focus uniquely on bladder-sparing trimodal therapy (not palliative) prospective trials of ≥20 patients to address the question of (chemo)radiotherapy regimens and correlated clinical outcomes;
      • to extend the review to relevant retrospective series of radical bladder radiotherapy (with or without chemotherapy) to address more technical aspects of the treatment (CT acquisition, target volumes delineation, and radiotherapy dose delivery).
      Once this review was performed, results on each topic were presented by JK and PS (Table 1, Table 2, Table 3) and discussed during a meeting conducted in October 2020 with a working group involving 15 radiation oncologists. Additionally, three urologists and one medical oncologist were solicited for their expertise in two topics regarding TURBT and concurrent systemic treatment, respectively. We applied the American Urological Association guideline development’s method to categorize the statements [

      AUA - Home - American Urological Association n.d. https://www.auanet.org/ (accessed November 30, 2020).

      ].
      Table 1Phase II and phase III trials (≥20 patients) of bladder-sparing trimodal therapy for muscle-invasive bladder cancer: patients and treatment.
      ReferenceName of study/armDesign/follow-upNStageWBRT: total doseWBRT: dose per fractionIndex tumor RT: total dose

      (if different)
      Index tumor RT:

      dose per fraction for the complement

      (if different)
      PLNRT: total dose

      (upper limit)
      PLNRT:

      dose per fraction
      Split

      vs

      Cont.
      OTT

      weeks
      Modality of RTARTConcurrent systemic treatmentNAD/AD chemotherapy
      Lagrange (2011)GETUG 97015Phase II

      8 years
      53T2-T4a

      N0/Nx
      63 Gy1.8–2 Gy qd45 Gy

      (L5-S1)
      1.8 Gy qdSplit6.52D/3DNoCDDP-5FU × 3CNo
      Tester (1993)RTOG 8512Phase II

      36 months
      48T2-T4

      N0/N1N2 (8%)
      60GyGy2 Gy qd40 Gy

      (L5-S1)
      2 Gy qdSplit92D/3DNoCDDP × 3CNo
      Shipley (1998)RTOG 8903Phase III

      5 years
      74T2-T4a

      N0/Nx
      39.6 Gy1.8 Gy qd64.8 Gy1.8 Gy qd39.6 Gy

      (S2-S3)
      1.8 Gy qdSplit92D/3DNoCDDP × 3CNAD: 50%

      MCV × 3C
      Gogna (2006)TROG 9701 &

      TROG 9906
      Phase II × 2

      23 months
      113T1-T4

      N0
      63–64 Gy (65%)

      50–50.4 Gy (25%)
      1.8 Gy-2 Gy qd

      63–64 Gy


      1.8 Gy qd
      Cont.6.5–72D/3DNoCDDP weeklyNo
      Hoskin (2010)RT vs RT + CON

      Arm B (exp)
      Phase III

      5 years
      164/327T1-T4b

      N0
      64 Gy (30%)

      (or 55 Gy (70%))
      2 Gy qd

      (or 2.75 Gy qd)
      Cont.6.5

      (or 4)
      2D/3DNoCON (arm B)No
      James (2012)BC 2001

      Arm B (exp)
      Phase III

      70 months
      182/320T2-T4a

      N0
      64 Gy (61%)

      (or 55 Gy (39%))
      2 Gy qd

      (or 2.75 Gy qd)
      Cont.6.5

      (or 4)
      2D/3DNo5FU - MMC × 2C

      (arm B)
      NAD: 31%
      Kragelj (2005)phase II

      10.3 years
      84T1-T4

      N0
      63.8–64 Gy1.8–2.2 Gy qd46–46.2 Gy

      (NR)
      1.8–2.2 Gy qdCont.6–6.52D/3DNoVinblastine weeklyNo
      Eapen (2004)phase II

      34 months
      200T1-T4b

      N0/N+ (7%)
      60 Gy2 Gy qd40 Gy

      (NR)
      2 Gy qdCont.62D/3DNoIntra-arterial CDDP × 2cNAD:

      intra-art. CDDP × 1C
      Tester (1996)RTOG 8802phase II

      3 years
      93T2-T4a

      N0/N+ (6%)
      39.6 Gy1.8 Gy qd64.8 Gy1.8 Gy qd39.6 Gy

      (L5-S1)
      1.8 Gy qdSplit92D/3DNoCDDP × 3CNAD:

      MCV × 3C
      Fellin (1997)phase II

      46 months
      56T2-T4

      N0
      41.4 Gy1.8 Gy qd64.8 Gy1.8 Gy qd41.4 Gy

      (S1-S2)
      1.8 Gy qdSplit92D/3DNoCDDP × 3CNAD:

      MCV × 2C
      Caffo (2011)phase II

      74 months
      26T2-T4

      N0
      36 Gy1.8 Gy qd54 Gy1.8 Gy qd36 Gy

      (S1-S2)
      1.8 Gy qdCont.62D/3DNoGem CDDP weeklyNo
      Arias (2000)phase II50T2-T4

      N0
      45 Gy1.8 Gy qd65 Gy2 Gy qd45 Gy

      (L5-S1)
      1.8 Gy qdSplit82D/3DNoCDDP d1-d5NAD:

      MVAC × 2C
      Coen (2019)RTOG 0712

      Arm Gem
      Phase II

      4.3 years
      35/70T2-T4a

      N0
      52 Gy2 Gy qd64 Gy2 Gy qd44 Gy

      (NR)
      2 Gy qdSplit92D/3DNoGem twice weeklyAD:

      Gem CDDP × 4C
      Lin (2009)Phase II

      47 months
      30T2-T4a

      N0
      50.4 Gy1.8 Gy qd64.8 Gy1.8 Gy qd45 Gy

      (S2-S3)
      1.8 Gy qdSplit72D/3DNoCDDP weekly (52%)

      CDDP-paclitaxel weekly (48%)
      NAD:

      CDDP-5FU × 3C (52%)

      CDDP-5FU-Paclitaxel × 3C (48%)
      Mokarim (1997)Phase II

      45 months
      35T2-T4

      N0
      40 Gy2 Gy qd60 Gy2 Gy qd40 Gy

      (L5-S1)
      2 Gy qdSplit82D/3DNoIntra-arterial CDDP - doxorubicin × 3CNo
      Tunio (2012)Phase III

      5 years
      230T2-T4

      N0
      45 Gy1.8 Gy qd65 Gy2 Gy qdArm A: 45 Gy

      (L5-S1)

      Arm B: No
      Arm A: 1.8 Gy qd

      Arm B: No
      Cont.72D/3DNoCDDP weeklyNo
      Murthy (2016)Phase II

      30 months
      44T1-T4

      N0
      64 Gy2 Gy qd68 Gy

      (55%)
      2.12 Gy qd (SIB)55 Gy

      (73%)

      (L5-S1)
      1.72 Gy qdCont.6.5IMRTYesCDDP weeklyNAD: 36%

      Gem Carboplatin
      Hagan (2003)RTOG 9706Phase I-II

      26 months
      47T2-T4a

      N0


      45.6 Gy

      I = 21.6gy

      C = 24 Gy
      I = 1.8 Gy qd

      C = 1.5 Gy bid
      64.8 Gy

      I = 40.8gy

      C = 24 Gy


      I = 1.8 Gy-1.6 Gy bid

      C = 1.5 Gy bid
      45.6 Gy

      I = 21.6gy

      C = 24 Gy

      (NR)


      I = 1.8 Gy qd

      C = 1.5 Gy bid
      Split82D/3DNoCDDP 2d/weekAD:

      MCV × 3C
      Kaufman (2009)RTOG 9906Phase I-II

      50 months
      80T2-T4a

      N0
      52.3 Gy

      I = 28.3 Gy





      C = 24 Gy
      I = d1-d5: 1.6 Gy-1.5 Gy bid

      d8-d17: 1.6 Gy qd

      C = 1.5 Gy bid
      64.3 Gy

      I = 40.3 Gy





      C = 24 Gy
      I = 1.6 Gy-1.5Gybid





      C = 1.5 Gy bid
      44.8 Gy

      I = 20.8 Gy

      C = 24 Gy

      (S1-S2)
      I = 1.6 Gy qd

      C = 1.5 Gy bid
      Split92D/3DNoCDDP – placitaxel weeklyAD:

      Gem CDDP x4C
      Mitin (2013)RTOG 0233Phase II

      5 years
      97T2-T4a

      N0
      52.3 Gy

      I = 28.3 Gy

      C = 24 Gy


      I = d1-d5: 1.6 Gy-1.5 Gy bid

      d8-d17: 1.6 Gy qd

      C = 1.5 Gy bid
      64.3 Gy

      I = 40.3 Gy





      C = 24 Gy


      I = 1.6 Gy-1.5Gybid





      C = 1.5 Gy bid
      44.8 Gy

      I = 20.8 Gy

      C = 24 Gy

      (NR)


      I = 1.6 Gy qd

      C = 1.5 Gy bid
      Split92D/3DNoArm A:

      CDDP Paclitaxel weekly

      Arm B:

      CDDP – 5FU weekly
      AD:

      Gem CDDP Paclitaxel × 4c
      Coen (2019)RTOG 0712

      Arm CDDP 5FU
      Phase II

      4.3 years
      35/70T2-T4a

      N0
      52.3 Gy

      I = 28.3 Gy

      C = 24 Gy


      I = d1-d5: 1.6 Gy-1.5 Gy bid

      d8-d17: 1.6 Gy qd

      C = 1.5 Gy bid
      64.3 Gy

      I = 40.3 Gy





      C = 24 Gy


      I = 1.6 Gy-1.5Gybid





      C = 1.5 Gy bid
      44.8 Gy

      I = 20.8 Gy

      C = 24 Gy

      (NR)


      I = 1.6 Gy qd

      C = 1.5 Gy bid
      Split92D/3DNoCDDP – 5FU weeklyAD:

      Gem CDDP × 4C
      Zapatero (2012)Phase II (protocol 2)

      5 years
      39T2-T4

      N0
      45.6 Gy

      I = 21.6 Gy

      C = 24 Gy


      I = 1.8 Gy qd

      C = 1.5 Gy bid
      64.8 Gy

      I = 40.8gy

      C = 24 Gy


      I = 1.8 Gy-1.6 Gy bid

      C = 1.5 Gy bid
      45.6 Gy

      I = 21.6gy

      C = 24 Gy

      (NR)


      I = 1.8 Gy qd

      C = 1.5 Gy bid
      Split82D/3DNoCDDP weeklyNo
      Hafeez (2016)Phase II

      19 months
      20T2T3

      N0
      52 Gy1.625 Gy qd70 Gy2.19 Gy qdCont.6.5IMRTYes5FU – MMC

      Gem (15%)
      NAD: 70%

      CDDP Gem
      Housset (1993)Phase II

      27 months
      54T2-T4

      N0-N1 (7%)
      44 Gy

      I = 24 Gy

      C = 20 Gy


      I = 3 Gy bid d1, 3, 15, 17

      C = 2.5 Gy bid d64, 66, 78, 80
      24 Gy

      (L5-S1)
      3 Gy bid d1, 3, 15, 17Split11.52D/3DNoCDDP 5FU × 4CNo
      Kaufman (2000)RTOG 9506Phase I/II

      29 months
      34T2-T4

      N0-Nx
      44 Gy

      I = 24 Gy

      C = 20 Gy


      I = 3 Gy bid d1, 3, 15, 17

      C = 2.5 Gy bid d64, 66, 78, 80
      24 Gy

      (NR)
      3 Gy bid d1, 3, 15, 17Split11.52D/3DNoCDDP 5FU × 4CNo
      James (2012)BC 2001

      Arm B
      Phase III

      70 months
      182/320T2-T4a

      N0
      55 Gy (39%)

      (or 64 Gy (61%))
      2.75 Gy qd

      (or 2 Gy)
      Cont.4

      (or 6.5)
      2D/3DNo5FU - MMC × 2C (arm B)NAD: 31%
      Hoskin (2010)RT vs RT + CON

      Arm B
      Phase III

      5 years
      164/327T1-T4b

      N0
      55 Gy (70%)

      (or 64 Gy (30%)
      2.75 Gy qd

      (or 2 Gy qd)
      Cont.4

      (or 6.5)
      2D/3DNoCON (arm B)No
      Choudhury (2011)GemXPhase II

      36 months
      50T2-T3

      N0
      52.5 Gy2.5 Gy qdCont.42D/3DNoGem weeklyNo
      Thompson (2017)GemX/neoGemXPhase II

      16 months
      78T2-T4

      N0
      52.5 Gy2.5 Gy qdCont.42D/3DNoGem weeklyNAD: 49%

      Gem CDDP or carboplatin
      Hussain (2004)Phase II

      51 months
      41T2-T4a

      N0Nx
      55 Gy2.5 Gy qdCont.42D/3DNo5FU – MMC × 2CNo
      WBRT: whole bladder RT; PLNRT: pelvic lymph nodes RT; cont.: continuous; OTT: overall treatment time; ART: adaptive RT; NAD/AD: neoadjuvant/adjuvant chemotherapy; exp: experimental arm; I: induction chemoradiotherapy; C: consolidation chemoradiotherapy; NR: non reported; CDDP: cisplatin; CON: carbogen and nicotinamide; MCV: Methotrexate, cisplatin, vinblastine; Gem: gemcitabine.
      Table 2Phase II/phase III trials (≥20 patients) of bladder-sparing trimodal therapy for muscle-invasive bladder cancer: outcomes and late toxicities.
      ReferenceName of studyComplete Response rate5-year OS5-year CSSSalvage cystectomy rate

      (immediate or delayed)
      Late G3 + GU toxicityLate G3 + GI toxicity
      Lagrange (2011)GETUG 97015NR43%

      (8-year OS 36%)
      NR33%
      Tester (1993)RTOG 851266%3-year OS 64%NR22%2%2%
      Shipley (1998)RTOG 890360%49%NR20%11%8%
      Gogna (2006)TROG 9701 TROG 990670%NR50%13%4%2%
      Hoskin (2010)RT vs RT + CON Arm B81%50%NR8%39%7%
      James (2012)BC 2001 Arm BNR48%NR11%Overall G3 + RTOG toxicity: 8%

      Overall G3 + LENT/SOMA toxicity: 54%
      Kragelj (2005)78%9-year OS 25%9-year CSS 51%8%9-year prevalence 66%9-year prevalence 11%
      Eapen (2004)83%50%62%15%1%0%
      Tester (1996)RTOG 880275%4-year OS 62%NR40%8%7%
      Fellin (1997)50%55%59%46%2%2%
      Caffo (2011)100%70%79%15%0%0%
      Arias (2000)68%48%NR20%NRNR
      Coen (2019)RTOG 0712 Arm Gem78%NRNR15%NRNR
      Lin (2009)77%60%NR17%3%0%
      Mokarim (1997)74%77%NR26%9% (WHO)0% (WHO)
      Tunio (2012)93%52%NRNR1%0%
      Murthy (2016)100%3-year OS 67%3-year CSS 73%9%4%0%
      Hagan (2003)RTOG 970674%3-year OS 61%NR17%13%6%
      Kaufman (2009)RTOG 990681%56%71%13%6%0%
      Mitin (2013)RTOG 023367%73%NR5%5% (CTCAE)1% (CTCAE)
      Coen (2019)RTOG 0712 Arm CDDP 5FU88%NRNR9%NRNR
      Zapatero (2012)80%60%NR23%NRNR
      Hafeez (2016)NRNRNRNR10%0%
      Housset (1993)74%3-year OS 59%3-year CSS 62%NRNRNR
      Kaufman (2000)RTOG 950667%3-year OS 83%NR29%6%15%
      James (2012)BC 2001 Arm BNR48%NR11%Overall G3 + RTOG toxicity: 8%

      Overall G3 + LENT/SOMA toxicity: 54%
      Hoskin (2010)RT vs RT + CON Arm B81%50%NR8%39%7%
      Choudhury (2011)GemX88%63%78%8%NRNR
      Thompson (2017)GemX/neoGemX92%2-year OS 68%NR9%0%4%
      Hussain (2004)71%36%2-year CSS 68%19%NRNR
      OS: overall survival; CSS: cancer-specific survival; GU: genito-urinary; GI: gastrointestinal.
      Table 3Strategies of adaptive radiotherapy for radical bladder radiotherapy.
      ART strategyReferenceType of studyNo. patientsRadiotherapy techniqueNumber of scanners for ART (CT/CBCT)Bladder repletion during CT planningVolumes and prescription doses (number of fractions)Iso or anisotropic marginsBladder repletion during treatmentAdditional time (min)Observed benefit
      Off-Line/CompositePos et al.

      (2005)
      P21RTC3DCT + 5 CBCTFullBladder: 60 Gy (25f)

      or 55 Gy (20f)

      PLN: 40 Gy (20f)
      Iso (15 mm)FullN/A
      • Mean irradiated volume reduced by 40% (PTVconv-PTVart)
      Foroudi et al.

      (2009)
      P5RTC3DCT + 5 CBCTEmptyBladder: 60 Gy (30f)Iso (15 mm)Empty7
      • Better coverage of CTV (V95%)
      Webster et al.

      (2013)
      R20RTC3DCT + 3 CBCTEmptyBladder: 52.5 Gy (20f)Iso (Composite 1: 5 mm/Composite 2: 10 mm)EmptyRecognized but not specified
      • Better coverage of CTV (V95%)
      • Mean irradiated volume reduced by 14,6% to 35%
      PoD non individualisedBurridge et al. (2006)R20RTC3DCTEmptyBladder: 52,5Gy (20f)AnisoEmptyRecognized but not specified
      • Meanirradiated small bowel volume reduced by 31 cm3 on average
      Vestergaard et al. (2010)R10RCMICTEmptyBladder: 60 Gy (30f)IsoEmptyN/A
      • Mean volume receiving 95% of prescribed dose reduced by 30 to 40%
      Murthy et al.

      (2011)
      R10TomotherapyCTBoth (empty for whole bladder treatment/full for SIB)Bladder: 64 Gy (32f)

      SIB: 68 Gy
      Iso (5 to 30 mm by 5 mm steps)Both21
      • Better target coverage with 5–15 mm margins PTV
      Webster et al.

      (2013)
      R20RTC3DCTEmptyBladder: 52,5Gy (20f)AnisoEmptyRecognized but not specified
      • Better coverage of CTV (V95%)
      • Mean irradiated volume reduced by 14,6 à 35%
      Murthy et al.

      (2016)
      P44TomotherapyCTBoth (empty if whole bladder treatment/full if SIB)Bladder: 64 Gy (32f)

      PLN: 55 Gy

      SIB: 68 Gy
      BothBothRecognized but not specified
      • Better locoregional control after 3 years
      • Reduction of grade 3 acute and late urinary toxicity
      Canlas et al.

      (2016)
      R8N/ACTEmptyBladder: 64 Gy (32f)AnisoEmptyRecognized but not specified
      • Mean irradiated healthy volume tissue reduced by (95% of prescribed dose)
      Murthy et al.

      (2019)
      R106RCMICTFullBladder: 64 Gy (32f)

      PLN: 55 Gy

      SIB: 68 Gy
      AnisoFullN/A
      • Acceptable toxicity (7,5% for grade 3–4 acute GU)
      PoD individualised based on CBCTWright et al.

      (2010)
      R2RCMICT + 4 CBCTEmptyBladder: 60 Gy (30f)

      SIB: 70 Gy
      AnisoN/AN/A
      • Better local control with SIB
      Vestergaard et al. (2010)R10RCMICT + 5 CBCTEmptyBladder: 60 Gy (30f)AnisoEmptyN/A
      • Mean volume receiving 95% of prescribed dose reduced by 30 to 40%
      Kron et al.

      (2010)
      P27RTC3DCT + 5 CBCTEmptyBladder: 64 Gy (32f)Iso (5 mm)N/AN/A
      • Lower integral dose due to more conformal irradiation despite the dose of IGRT
      Tolan et al.

      (2011)
      P11RCMICT + 15 CBCTFullBladder: 60–66 Gy

      (30-32f)

      PLN: 40–46 Gy
      Iso (5 mm)FullN/A
      • Mean irradiated volume reduced by half
      Foroudi et al.

      (2011)
      P27RTC3DCT + 5 CBCTEmptyBladder: 64 Gy (32f)Iso (5 mm)Empty11
      • Reduction of small bowel V45Gy and V5Gy by 29% and 15%
      • Similar coverage
      Kuyumcian et al. (2012)P27RTC3DCT + 5 CBCTEmptyBladder: 64 Gy (32f)Iso (5 mm)EmptyRecognized but not specified
      • Better distribution in selection plans (PTVsmall and large)
      Vestergaard et al. (2014)R13VMATCT + 4 CBCTEmptyBladder: 60 Gy (30f)

      SIB: 70 Gy
      AnisoEmptyN/A
      • Mean healthy volume tissue irradiated reduced by 36% with DVF-ART technique
      Vestergaard et al. (2014)P20VMATCT + 4 CBCTEmptyBladder: 60 Gy (30f)

      PLN: 48 Gy
      Iso (5 mm)Empty8
      • Mean healthy volume tissue irradiated reduced by 183 cm3 on average (30%)
      Foroudi et al.

      (2014)
      P50RTC3DCT + 5 CBCTEmptyBladder: 64 Gy (32f)Iso (7 mm)EmptyRecognized but not specified
      • Poor daily CTV coverage in 18% of cases
      Gronborg et al. (2015)P9VMATCT + 4 CBCTEmptyBladder: 60 Gy (30f)Iso (5 mm)EmptyRecognized but not specified
      • Mean irradiated volume of small bowel reduced by 113 cm3
      Tuomikoski et al. (2015)R10RCMI1 CT + 4 CBCT (RepeatCBCT)

      4 CT 15 min apart (RepeatCT)
      BothBladder: 60 Gy (30f)AnisoEmptyN/A
      • PTV volume reduced by 46% with CT-repeat method and 36% with CBCT-repeat
      PoD individualized based on repeat CTTuomikoski et al. (2011)P5VMAT4–5 CT (15 min apart after voiding + drinking)BothBladder: 45–50.4 Gy (25-28f)

      SIB: 55.8–65 Gy
      AnisoEmpty5–10
      • Mean irradiated volume of small bowel reduced by 155 cm3 on average
      • Risk of grade 2 acute toxicity reduced by 35 to 7%
      Lalondrelle et al. (2011)P

      A-POLO
      15RTC3D3 CT (T0, T15 and T30)Empty, medium and fullBladder: 36 Gy (6f)Iso (15 mm)Empty15–20
      • Better PTV coverage (V95%>95%), by 51% to 96%
      Meijer et al.

      (2012)
      P20RCMI2 CT (empty and full)FullBladder: 46 Gy (23f)

      SIB: 59.8 Gy
      IsoFull12
      • Reduction of dose to small bowel
      • No grade 3 toxicity
      Tuomikoski et al. (2013)P5VMAT4 CT (empty then filling)BothPartial bladder: 52,5Gy (21f)

      or

      Whole bladder: 44 Gy (22f) + SIB: 64 Gy
      Both (iso for 3 patients and aniso for 2)EmptyN/A
      • Reduction of dose to small bowel
      • No significant difference in target coverage
      Hutton et al.

      (2013)
      R

      A-POLO
      10N/A2 CT (T0 and T30 after voiding + drinking)BothBladder: 55 Gy (20f)AnisoEmpty4
      • Additional time of 4 min per fraction in case of ART
      McDonald et al. (2013)P

      A-POLO
      25RTC3D2 CT (T0 and T30 after voiding + drinking)BothBladder: 36 Gy (6f)AnisoEmpty14
      • Mean healthy volume tissue irradiated reduced by 219 cm3 on average
      • Frequency of PTV selected “small” and “medium” of 49% and 45% respectively
      Lutkenhaus et al. (2015)P10VMAT2 CTBothBladder and PLN: 40 Gy (20f)SIB: 55–60 GyIso (7 mm/9 mm if SIB)FullRecognized but not specified
      • Better pelvic lymph nodes coverage (V95%>99%)
      • Significant reduction of bowel volume receiving 30 Gy and 40 Gy
      Tuomikoski et al. (2015)R10RCMI1 CT + 4 CBCT (RepeatCBCT)

      4 CT 15 min intervals (RepeatCT)
      BothBladder: 60 Gy (30f)AnisoEmptyN/A
      • Greater PTV volume reduction by CT-based POD (46%) than CT–CBCT-based POD (36%)
      Hafeez et al.

      (2016)
      P

      A-POLO
      18RCMI2 CT (T30 and T60 after voiding + drinking)Full (2 filling times)Bladder: 52 Gy (32f)

      SIB: 70 Gy (32f)
      AnisoFull (voiding + drinking 30 min before treatment)13
      • Respectively 97.07+/-2.10% and 99.97+/-2.62% for mean D98 PTV SIB and whole bladder
      • No more toxicity with dose escalation
      Hafeez et al.

      (2017)
      P

      A-POLO
      55RTC3DCTFullBladder: 36 Gy (6f)N/AFullN/A
      • Local control: 92%
      • Acceptable grade 3 toxicity (18% for GU and 4% for GI)
      Re-Opt and PoDVestergaard et al. (2013)R7RCMICT + 5 CBCT (PoD)

      Daily CBCT (Re-Opt)
      EmptyBladder: 60 Gy (30f)Iso (3 mm for PoD/5 mm for Re-Opt)EmptyN/A
      • Reduction in the healthy volume tissue receiving 95% of prescribed dose by 66% for PoD and 41% for Re-Opt
      Kong et al.

      (2018)
      R10RCMI1 CT (non indiv PoD)

      1 CT + 5 CBCT (PoD indiv)

      Daily CBCT (Re-Opt)
      FullBladder: 46 Gy (23f)Iso (0, 5, 10 and 15 mm for PoD non indiv/5 mm for PoD indiv and Re-OptFullN/A
      • Reduction in the volume of healthy irradiated tissue by 25% (Re-Opt), 16% (PoD indiv) and 12% (non indiv PoD) versus conventional treatment
      Art: Adaptive Radiotherapy; CBCT: Cone Beam Computed Tomography; PoD: Plan Of the Day.
      For each topic, a blinded vote was performed among the experts to determine:
      • the evidence strength: A – high quality evidence (well-conducted randomized clinical trials (RCTs), exceptionally strong observational studies); B – moderate quality evidence (RCTs with some weaknesses, generally strong observational studies); and C – low quality evidence (observational studies that provide conflicting information or design problems (such as very small sample size).
      • the recommendation grade: strong (1), moderate (2) or weak (3).
      The final evidence strengths and recommendation grades corresponded to those proposed by the majority of the panelists. In the absence of majority reached following the first vote, a second blinded vote was proposed after a brief summary of the available data on the field by JK and PS.
      A summary of the guidelines from the working group is presented after the review (Table 4).
      Table 4Summary of guidelines from the working group for bladder radical radiotherapy.
      TopicsProposition of guidelinesEvidence strengthGrade of recommendation
      1. TURBT preceding radiotherapyA complete TURBT must be performed within 4–8 weeks before the start of radiotherapy.A1
      When TURBT has been performed more than 6 weeks before the start of RT, a second look should be performed to ensure that there is no tumor regrowth.B2
      2. Planning CT-scan acquisitionWhen standard planning is performed (i.e. without adaptive strategy):
      • if single-dose level whole bladder radiotherapy is planned, patients have to stop any absorption of fluids within 30 minutes before the planning CT and to void bladder immediately before planning CT.
      • when index tumor irradiation is planned, patients have to void bladder then drink 250–500 ml of water approximately 30 minutes before the planning CT.
      B2
      Ideally, rectum should be empty as well, with the same local practices as those used for prostate planning.C2
      Patients must be supine in comfortable position with adequate immobilization devices (knee and/or ankle supports).C1
      CT scan thickness should be ≤3 mm; the superior limit must be at the L3/L4 level (to encompass common iliac vessels), and the inferior limit must be 2 cm below ischial tuberosities.C1
      CT should be contrast-enhanced if renal function allows it, only in cases of: extravesicular extension at diagnosis, incomplete TURBT, delay of more than 6 weeks between the TURBT and the planning CT with no second look feasible before starting, or in case of pelvic lymph nodes (PLN) irradiation.CNo consensus
      4. Bladder MRI
      3. Delineation of target volumes
      • GTV
      Ideally, no GTV should be delineated as TURBT must be complete, but situations exist when TURBT cannot be complete, especially when tumor extends outside the wall of the bladder. In these cases, a GTV will be delineated using geographic information from: cystoscopy, contrast-enhanced planning-CT, imaging before or after TURBT (CT or MRI). Post-TURBT contrast-enhancement should be considered cautiously due to the frequent post-resection scarce.C1
      • CTV
      Whole bladder irradiation should be privileged.A1
      Standard CTV should encompass the whole bladder as a solid organ with inclusion of any residual gross lesion.A1
      We do not recommend systematic circumferential margin for CTV delineation.A margin should recommended:
      • if the index tumor is identifiable, an additional margin outside the bladder wall should be added regarding the lesion only: of 6 mm in case of no visible extra-vesicular extension, and of 10 mm in case of visible extra-vesicular extension (+/- in case of tumor > 35 mm, squamous differentiation or lymphovascular invasion).
      • if the index tumor is not identifiable, no additional margin should be added.
      B2
      Among males :
      • in case of clinical prostatic involvement, the whole prostate should be included in the CTV;
      • in the cases of CIS and/or multifocal lesions and/or trigone/bladder neck involvement, but with no clinical prostatic involvement, inclusion of the whole prostate in the CTV is optional;
      B2
      Among females :
      • the inclusion of proximal urethra (until the pelvic floor) in the cases of bladder neck and/or anterior vaginal wall involvement is optional;
      • anterior vaginal wall should not be routinely included in the CTV in the absence of visible invasion
      B2
      An index tumor CTV can be delineated in addition to the standard CTV when a bladder two-dose level approach is considered; it corresponds to the tumor bed and any residual GTV identified with the aid of imaging, cystoscopic data and if possible markers set following TURBT, with no additional margin.B2
      • PTV
      We recommend anisotropic CTV-to-PTV margins.B1
      Within a non-adaptive strategy, when bony alignment only is used, CTV-to-PTV margins should be of 1.5 to 2 cm in all directions except for superior and anterior directions where margins of 2 to 2.5 cm should be used.When a daily soft-tissue imaging realignment IGRT (such as CBCT) is used, it is reasonable to reduce these anisotropic margins to 1 to 1.5 cm and 1.5 to 2 cm, respectively.B1
      Margins should not differ between empty bladder and full bladder protocols.BNo consensus
      When PTV margins are applied on the index tumor CTV, daily soft tissue imaging should be systematically performed, and margins should take into account the localization of the tumor within the bladder: we recommend at least 1.5–2 cm in all directions for tumor of the superior wall or the anterior wall, and 1–1.5 cm in all directions in the other cases.B2
      4. Radiotherapy regimen
      • Dose/fractionation
      Continuous course chemoradiotherapy should be privileged, especially with >T2 tumors.B1
      Conventional fractionation or moderate accelerated hypofractionation are both relevant schedules for continuous schedules, with respective prescribed doses to the whole bladder of 64 Gy in 32 fractions, or 50–55 Gy in 20 fractions.A1
      When split-course schedule is chosen, the RT regimens should be in accordance to the MGH/RTOG protocols, with two courses of accelerated hypofractionated RT (induction then consolidation according to response), in order to avoid any extended overall treatment time, leading to an overall pure hyperfractionated regimen.A1
      • Dose escalation(innovative approach to be assessed in clinical trials)
      Dose escalation to index tumor is not recommended routinely, and should be reserved for solitary tumors with no CIS away from the index tumor; the site of the index tumor should be easily identifiable and should be outside the dome (ideally upon the trigone), with a ratio of index tumor CTV/whole bladder CTV <25%.B2
      If dose escalation is performed: a simultaneous integrated boost approach is encouraged, within a conventional fractionation schedule to the whole bladder, to a total escalated dose of 68 Gy in 32 fractionsC2
      If dose escalation is performed: adaptive-radiotherapy should be used, with associated dedicated repletion guidelinesB2
      In the absence of adaptive radiotherapy planning, the patient should have comfortably full bladder for planning CT and treatment.B2
      • PLN radiotherapy
      PLN radiotherapy is not recommended routinely.BNo consensus
      If performed: one can consider either small pelvic CTV or extended pelvic CTV, with usual vessels based delineation guidelines.BNo consensus
      If performed: it should be integrated only within a conventional fractionated schedule with simultaneous integrated boost, to a dose of 51.2–54.4 Gy in 32 fractions of 1.6–1.7 Gy.C2
      5. Radiotherapy delivery
      • IMRT/IGRT
      Radiotherapy for bladder cancer should be performed using both IMRT and IGRT based on soft-tissue imaging.B1
      • Adaptive radiotherapy (innovative approach to be assessed in clinical trials)
      Although no clinical benefit has been shown yet, adaptive radiotherapy should be privileged when possible, especially when a dose-escalation boost is performed.C2
      Among the different approaches, the optimal balance between dosimetric benefits and logistical/technical requirements seems to be a PoD approach, either non individualized or individualized with repeat CT, preferentially using the A-POLO approach.B2
      PoD strategies should be used with no more than 3 different plansB2
      PoD strategies should be implemented within a training program to improve the daily plan selection process.B2
      6. Concurrent systemic treatmentConcurrent systemic treatment (either chemotherapy or hypoxia modification) should be associated to radical RT for patients whether or not they are eligible for cisplatin.A1
      GTV = Gross Tumor Volume; CTV = Clinical Target Volume; PTV = Planning Target Volume; IMRT = Intensity Modulated RT; IGRT = Image Guided RT; TURBT = Transurethral Resection of Bladder Tumor; EQD2Gy = equivalent dose in 2-Gy fraction; PoD = Plan of the day; A-POLO = adaptive predictive organ localization.
      Evidence strength: A – high quality evidence (well-conducted randomized clinical trials (RCTs), exceptionally strong observational studies); B – moderate quality evidence (RCTs with some weaknesses, generally strong observational studies); C – low quality evidence (observational studies that provide conflicting information or design problems (such as very small sample size)).
      Grade of recommendation: strong (1), moderate (2) or weak (3).

      Results

      Transurethral resection of bladder tumors (TURBT) preceding radiotherapy

      TURBT is the first step of a trimodal therapy. TURBT can be performed either by monopolar or bipolar, en bloc or standard resection [

      Ouzaid I, Panthier F, Hermieu J-F, Xylinas E. Contemporary surgical and technical aspects of transurethral resection of bladder tumor. Transl Androl Urol 2019;8:21–4. 10.21037/tau.2019.01.04.

      ]. A wider margin of tumor-free urothelium around the lesion is required. The depth of the resection is crucial, often down to the peri-vesical fat, despite the risk of bladder perforation. As such, the bladder catheter is removed between Day 2 and Day 8 after the procedure. In the case of large tumors in patients not eligible for radical surgery, resection must be maximal if it cannot be complete.
      During the TURBT procedure, a special attention should be paid to bi-manual pelvic exam under anesthesia (EUA), as pre- and post-resection EUA constitute a component of the clinical staging of the lesion [
      • Rozanski A.T.
      • Benson C.R.
      • McCoy J.A.
      • Green C.
      • Grossman H.B.
      • Svatek R.S.
      • et al.
      Is exam under anesthesia still necessary for the staging of bladder cancer in the era of modern imaging?.
      ]; palpable tumor on the outer surface of the bladder following TURBT is in favor of T3 or T4 disease, depending on it is mobile or fixed, respectively.
      The quality of TURBT in a trimodal therapy setting has been assessed in several prospective studies, and achieving complete TURBT is crucial for oncological outcomes. Giacalone et al. [
      • Giacalone N.J.
      • Shipley W.U.
      • Clayman R.H.
      • Niemierko A.
      • Drumm M.
      • Heney N.M.
      • et al.
      Long-term outcomes after bladder-preserving tri-modality therapy for patients with muscle-invasive bladder cancer: an updated analysis of the massachusetts general hospital experience.
      ] compiled the pooled results from prospective trials led by the Massachussets General Hospital [
      • Shipley W.U.
      • Winter K.A.
      • Kaufman D.S.
      • Lee W.R.
      • Heney N.M.
      • Tester W.R.
      • et al.
      Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89–03.
      ,
      • Kaufman D.S.
      • Winter K.A.
      • Shipley W.U.
      • Heney N.M.
      • Chetner M.P.
      • Souhami L.
      • et al.
      The initial results in muscle-invading bladder cancer of RTOG 95-06: Phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response.
      ,
      • Hagan M.P.
      • Winter K.A.
      • Kaufman D.S.
      • Wajsman Z.
      • Zietman A.L.
      • Heney N.M.
      • et al.
      RTOG 97–06: Initial report of a Phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy.
      ,
      • Kaufman D.S.
      • Winter K.A.
      • Shipley W.U.
      • Heney N.M.
      • Wallace H.J.
      • Toonkel L.M.
      • et al.
      Phase I-II RTOG Study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy.
      ,
      • Mitin T.
      • Hunt D.
      • Shipley W.U.
      • Kaufman D.S.
      • Uzzo R.
      • Wu C.-L.
      • et al.
      Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial.
      ,
      • Michaelson M.D.
      • Hu C.
      • Pham H.T.
      • Dahl D.M.
      • Lee-Wu C.
      • Swanson G.P.
      • et al.
      A Phase 1/2 trial of a combination of paclitaxel and trastuzumab with daily irradiation or paclitaxel alone with daily irradiation after transurethral surgery for noncystectomy candidates with muscle-invasive bladder cancer (Trial NRG Oncology RTOG 0524).
      ,
      • Coen J.J.
      • Zhang P.
      • Saylor P.J.
      • Lee C.T.
      • Wu C.-L.
      • Parker W.
      • et al.
      Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712—A randomized phase II trial.
      ,
      • Zietman A.L.
      • Shipley W.U.
      • Kaufman D.S.
      • Zehr E.M.
      • Heney N.M.
      • Althausen A.F.
      • et al.
      A phase I/II trial of transurethral surgery combined with concurrent cisplatin, 5-fluorouracil and twice daily radiation followed by selective bladder preservation in operable patients with muscle invading bladder cancer.
      ]; complete TURBT was associated with increased bladder-intact disease-specific survival compared to incomplete resection (HR = 0.72, P = 0.02). The time interval between TURBT and radiotherapy has not been addressed specifically; in the studies previously cited, radiotherapy started between 4 and 8 weeks following TURBT [
      • Shipley W.U.
      • Winter K.A.
      • Kaufman D.S.
      • Lee W.R.
      • Heney N.M.
      • Tester W.R.
      • et al.
      Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89–03.
      ,
      • Kaufman D.S.
      • Winter K.A.
      • Shipley W.U.
      • Heney N.M.
      • Chetner M.P.
      • Souhami L.
      • et al.
      The initial results in muscle-invading bladder cancer of RTOG 95-06: Phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response.
      ,
      • Hagan M.P.
      • Winter K.A.
      • Kaufman D.S.
      • Wajsman Z.
      • Zietman A.L.
      • Heney N.M.
      • et al.
      RTOG 97–06: Initial report of a Phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy.
      ,
      • Kaufman D.S.
      • Winter K.A.
      • Shipley W.U.
      • Heney N.M.
      • Wallace H.J.
      • Toonkel L.M.
      • et al.
      Phase I-II RTOG Study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy.
      ,
      • Mitin T.
      • Hunt D.
      • Shipley W.U.
      • Kaufman D.S.
      • Uzzo R.
      • Wu C.-L.
      • et al.
      Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial.
      ,
      • Michaelson M.D.
      • Hu C.
      • Pham H.T.
      • Dahl D.M.
      • Lee-Wu C.
      • Swanson G.P.
      • et al.
      A Phase 1/2 trial of a combination of paclitaxel and trastuzumab with daily irradiation or paclitaxel alone with daily irradiation after transurethral surgery for noncystectomy candidates with muscle-invasive bladder cancer (Trial NRG Oncology RTOG 0524).
      ,
      • Coen J.J.
      • Zhang P.
      • Saylor P.J.
      • Lee C.T.
      • Wu C.-L.
      • Parker W.
      • et al.
      Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712—A randomized phase II trial.
      ,
      • Zietman A.L.
      • Shipley W.U.
      • Kaufman D.S.
      • Zehr E.M.
      • Heney N.M.
      • Althausen A.F.
      • et al.
      A phase I/II trial of transurethral surgery combined with concurrent cisplatin, 5-fluorouracil and twice daily radiation followed by selective bladder preservation in operable patients with muscle invading bladder cancer.
      ].

      Planning CT-scan acquisition

      Controversial data exist regarding the correlation between bladder filling and bladder motion during radiotherapy [
      • Dees-Ribbers H.M.
      • Betgen A.
      • Pos F.J.
      • Witteveen T.
      • Remeijer P.
      • van Herk M.
      Inter- and intra-fractional bladder motion during radiotherapy for bladder cancer: A comparison of full and empty bladders.
      ,
      • Pos F.J.
      • Koedooder K.
      • Hulshof M.C.C.
      • van Tienhoven G.
      • González González D.
      Influence of bladder and rectal volume on spatial variability of a bladder tumor during radical radiotherapy. Int.
      ,
      • Majewski W.
      • Wesolowska I.
      • Urbanczyk H.
      • Hawrylewicz L.
      • Schwierczok B.
      • Miszczyk L.
      Dose distribution in bladder and surrounding normal tissues in relation to bladder volume in conformal radiotherapy for bladder cancer.
      ]. When considering dose to organs at risk (OARs) according to bladder filling, Majewski et al. suggested that dose distribution in the rectum and in the bowels was significantly better with a “partially empty bladder” (80 mL), as compared to a “partially full bladder” (150 mL). As expected, dose distribution in OARs was also improved when partial bladder rather than whole bladder radiotherapy is performed [
      • Majewski W.
      • Wesolowska I.
      • Urbanczyk H.
      • Hawrylewicz L.
      • Schwierczok B.
      • Miszczyk L.
      Dose distribution in bladder and surrounding normal tissues in relation to bladder volume in conformal radiotherapy for bladder cancer.
      ]. Overall, Dees-Ribbers et al. suggest that both empty and full bladder protocols were acceptable, and treatment choice should be based upon dose constraints to OARs. The authors recommend that [
      • Dees-Ribbers H.M.
      • Betgen A.
      • Pos F.J.
      • Witteveen T.
      • Remeijer P.
      • van Herk M.
      Inter- and intra-fractional bladder motion during radiotherapy for bladder cancer: A comparison of full and empty bladders.
      ]:
      • for whole bladder single-dose level irradiation: empty bladder protocols should be used to reduce the irradiated volume;
      • for index tumor irradiation (i.e. irradiation of tumor bed and/or gross residual tumor, either for partial bladder radiotherapy or when a two-dose level approach is considered sequentially or concomitantly), full bladder protocols should be used to move healthy tissues away from the irradiated volume.

      Role of bladder multiparametric MRI for trimodal therapy

      The use of bladder multiparametric MRI (mp-MRI) within a trimodal therapy strategy can have several objectives:
      • at staging: insights in bladder mp-MRI have led to the development of VIRADS criteria, which assess the risk of extravesical extension [
        • Panebianco V.
        • Narumi Y.
        • Altun E.
        • Bochner B.H.
        • Efstathiou J.A.
        • Hafeez S.
        • et al.
        Multiparametric magnetic resonance imaging for bladder cancer: development of VI-RADS (vesical imaging-reporting and data system).
        ], accounting for the high sensitivity and specificity to detect ≤T2 versus T3 tumor (respectively 83% (95% CI 75–88) and 87% (95% CI 78–93) [
        • Gandhi N.
        • Krishna S.
        • Booth C.M.
        • Breau R.H.
        • Flood T.A.
        • Morgan S.C.
        • et al.
        Diagnostic accuracy of magnetic resonance imaging for tumour staging of bladder cancer: systematic review and meta-analysis.
        ]. This can be of interest in order: (i) to assess the ability to perform a complete TURBT and thus to confirm the indication of trimodal therapy; (ii) to help in the delineation of clinical target volume (cf. dedicated section), with decision or not to add a security margin regarding the lesion, depending on the risk of extravesical extension;
      • following TURBT: in case of inability to perform complete TURBT, post-TURBT bladder MRI can help to identify residual gross disease and perivesical extension [
        • van der Pol C.B.
        • Shinagare A.B.
        • Tirumani S.H.
        • Preston M.A.
        • Vangel M.G.
        • Silverman S.G.
        Bladder cancer local staging: multiparametric MRI performance following transurethral resection.
        ,
        • Lim C.S.
        • Tirumani S.
        • van der Pol C.B.
        • Alessandrino F.
        • Sonpavde G.P.
        • Silverman S.G.
        • et al.
        Use of Quantitative T2-weighted and apparent diffusion coefficient texture features of bladder cancer and extravesical fat for local tumor staging after transurethral resection.
        ]. In this case, due to frequent post-resection scar and artifacts generally persisting for 4–6 weeks after TURBT, MRI should be performed as far as possible from the TURBT, accounting for the need to start RT 4–8 weeks following TURBT.
      However, due to insufficient data on the role of mp-MRI to optimize the management of MIBC and more specifically bladder RT, we cannot make strong recommendation on its use [
      • Witjes J.A.
      • Bruins H.M.
      • Cathomas R.
      • Compérat E.M.
      • Cowan N.C.
      • Gakis G.
      • et al.
      European Association of Urology Guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 guidelines.
      ]. Therefore, in both cases discussed above, bladder mp-MRI can be recommended only if the waiting period for the examination does not delay patient management.

      Delineation of the target volumes

      Gross tumor volume (GTV)

      The GTV refers to any residual gross disease following TURBT, visualized on cystoscopy or on a contrast-enhanced CT or MRI scan.
      Ideally, no GTV should be delineated as TURBT should be complete, but situations exist when TURBT cannot be complete, especially when the tumor extends outside the wall of the bladder. In these cases, a GTV can be delineated using geographic information from: cystoscopy, contrast-enhanced planning-CT, imaging before or after TURBT (CT or MRI). If a GTV needs to be delineated, pre- and/or post-TURBT MRI, when available, should be fused with the planning CT (T2 weighted images).

      Clinical tumor volumes (CTV)

      General considerations

      The tumor CTV is usually the whole bladder contoured as a solid organ, with inclusion of any extravesical tumor spread. The rationale for including the whole bladder is the multifocality of lesions both at presentation and at recurrence [
      • Brausi M.
      • Collette L.
      • Kurth K.
      • van der Meijden A.P.
      • Oosterlinck W.
      • Witjes J.A.
      • et al.
      Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies.
      ], although partial bladder irradiation has been assessed in trials and will be discussed in this article. The question as to whether an additional CTV margin should be applied beyond the bladder wall to take into account the microscopic extravesical extension is not consensual. In a retrospective series of radical cystectomy correlating pre-operative imaging and definitive pathology, Jenkins et al. estimate that the overall accuracy of CT scans to predict extravesical extension is 44%, with understaging being more frequent than overstaging. The 90th percentiles of the maximum extravesical extension on histological specimen were 9.6 mm among patients with extravesical extension seen on pre-operative CT, and 6.3 mm among patients with organ-confined disease on CT. Squamous differentiation, lymphovascular invasion and tumor size >35 mm were correlated with the extent of extravesical extension [
      • Jenkins P.
      • Anjarwalla S.
      • Gilbert H.
      • Kinder R.
      Defining the clinical target volume for bladder cancer radiotherapy treatment planning.
      ].
      Extravesical extension can also be directly assessed on the bladder mp-MRI, if performed.

      Partial bladder irradiation versus whole bladder irradiation

      Partial bladder irradiation has been evaluated in an RCT [
      • Cowan R.A.
      • McBain C.A.
      • Ryder W.D.J.
      • Wylie J.P.
      • Logue J.P.
      • Turner S.L.
      • et al.
      Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose-escalated partial bladder radiotherapy.
      ]: 149 patients with T2T3N0 MIBC were randomized between whole bladder irradiation (52.5 Gy in 20 fractions) versus dose-escalated partial bladder irradiation of the index lesion (57.5 Gy in 20 fractions or 55 Gy in 16 fractions), without chemotherapy in both arms. The authors hypothesized an improvement in 5-year local control with dose-escalated partial bladder irradiation. Partial bladder irradiation resulted in a 61% reduction in the median irradiated bladder volume compared to the whole bladder arm, and allowed the delivery of an increased radiation dose without increased toxicity. However, this superiority study was negative as the experimental armit failed to show an improvement in local control or OS, and therefore, partial bladder irradiation (with or without dose-escalation to the tumor index) cannot be recommended outside of a clinical trial.

      Inclusion of proximal urethra/prostate/vagina anterior wall

      Among males with MIBC, occult pathological prostatic involvement has been found in 24–43% of cystoprostatectomy specimens: the pattern of involvement was mainly non-contiguous via in situ spread within prostatic urethra/ducts epithelium and more rarely contiguous via transmural invasion [
      • Ayyathurai R.
      • Gomez P.
      • Luongo T.
      • Soloway M.S.
      • Manoharan M.
      Prostatic involvement by urothelial carcinoma of the bladder: clinicopathological features and outcome after radical cystectomy.
      ,
      • Wood D.P.
      • Montie J.E.
      • Pontes J.E.
      • Medendorp S.V.
      • Levin H.S.
      Transitional cell carcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer.
      ,
      • Kefer J.C.
      • Voelzke B.B.
      • Flanigan R.C.
      • Wojcik E.M.
      • Waters W.B.
      • Campbell S.C.
      Risk assessment for occult malignancy in the prostate before radical cystectomy.
      ,
      • Shen S.S.
      • Lerner S.P.
      • Muezzinoglu B.
      • Truong L.D.
      • Amiel G.
      • Wheeler T.M.
      Prostatic involvement by transitional cell carcinoma in patients with bladder cancer and its prognostic significance.
      ,
      • Richards K.A.
      • Parks G.E.
      • Badlani G.H.
      • Kader A.K.
      • Hemal A.K.
      • Pettus J.A.
      Developing selection criteria for prostate-sparing cystectomy: a review of cystoprostatectomy specimens.
      ]. Among patients with prostatic involvement, stromal involvement occurred in 37–75% [
      • Ayyathurai R.
      • Gomez P.
      • Luongo T.
      • Soloway M.S.
      • Manoharan M.
      Prostatic involvement by urothelial carcinoma of the bladder: clinicopathological features and outcome after radical cystectomy.
      ,
      • Shen S.S.
      • Lerner S.P.
      • Muezzinoglu B.
      • Truong L.D.
      • Amiel G.
      • Wheeler T.M.
      Prostatic involvement by transitional cell carcinoma in patients with bladder cancer and its prognostic significance.
      ,
      • Richards K.A.
      • Parks G.E.
      • Badlani G.H.
      • Kader A.K.
      • Hemal A.K.
      • Pettus J.A.
      Developing selection criteria for prostate-sparing cystectomy: a review of cystoprostatectomy specimens.
      ,
      • Moschini M.
      • Shariat S.F.
      • Freschi M.
      • Soria F.
      • Abufaraj M.
      • Gandaglia G.
      • et al.
      Impact of prostate involvement on outcomes in patients treated with radical cystoprostatectomy for bladder cancer.
      ]. Three main risk factors of prostatic involvement have been identified: presence of CIS, multifocal disease and trigone/bladder neck involvement [
      • Kefer J.C.
      • Voelzke B.B.
      • Flanigan R.C.
      • Wojcik E.M.
      • Waters W.B.
      • Campbell S.C.
      Risk assessment for occult malignancy in the prostate before radical cystectomy.
      ,
      • Nixon R.G.
      • Chang S.S.
      • Lafleur B.J.
      • Smith J.A.J.A.
      • Cookson M.S.
      Carcinoma in situ and tumor multifocality predict the risk of prostatic urethral involvement at radical cystectomy in men with transitional cell carcinoma of the bladder.
      ]. In these cases, the inclusion of the whole prostate (with no additional margin) in the CTV can be discussed.
      Among females, proximal urethral involvement occurs in approximately 12% of patients, the only risk factor being bladder neck or anterior vaginal wall invasion [
      • Stein J.P.
      • Penson D.F.
      • Wu S.D.
      • Skinner D.G.
      Pathological guidelines for orthotopic urinary diversion in women with bladder cancer: A review of the literature.
      ,
      • Chen M.E.
      • Pisters L.L.
      • Malpica A.
      • Pettaway C.A.
      • Dinney C.P.
      Risk of urethral, vaginal and cervical involvement in patients undergoing radical cystectomy for bladder cancer: results of a contemporary cystectomy series from M.
      ]. Microscopic vaginal and cervical involvement remain rare (around 5%), and in most cases are associated with urethral involvement. This was correlated with stages T3b and T4 disease in a series of 115 women who underwent radical cystectomy [
      • Chen M.E.
      • Pisters L.L.
      • Malpica A.
      • Pettaway C.A.
      • Dinney C.P.
      Risk of urethral, vaginal and cervical involvement in patients undergoing radical cystectomy for bladder cancer: results of a contemporary cystectomy series from M.
      ]. Therefore, in case of bladder neck involvement and/or anterior vaginal wall involvement, the inclusion of proximal urethra (until pelvic floor) can be discussed in the CTV, with no additional margin. To delineate proximal urethra, an MRI is recommended. Due to the rarity of infraclinic vaginal involvement, anterior vaginal wall should not be routinely included in the CTV in the absence of visible invasion.

      Index tumor clinical tumor volume

      As well as the standard CTV, an index tumor CTV has been described which classically encompasses the tumor bed +/− any residual gross tumor with no additional margin for microscopic extension [
      • Cowan R.A.
      • McBain C.A.
      • Ryder W.D.J.
      • Wylie J.P.
      • Logue J.P.
      • Turner S.L.
      • et al.
      Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose-escalated partial bladder radiotherapy.
      ,

      Nakamura R, Kakuhara H, Kikuchi K, Segawa T, Oikawa H, Iwasaki K, et al. Partial Bladder boost using lipiodol marking during image-guided radiotherapy for bladder cancer. Anticancer Res 2018;38:4827–31. 10.21873/anticanres.12793.

      ,
      • Whalley D.
      • Caine H.
      • McCloud P.
      • Guo L.
      • Kneebone A.
      • Eade T.
      Promising results with image guided intensity modulated radiotherapy for muscle invasive bladder cancer.
      ,
      • Huddart R.A.
      • Hall E.
      • Hussain S.A.
      • Jenkins P.
      • Rawlings C.
      • Tremlett J.
      • et al.
      Randomized noninferiority trial of reduced high-dose volume versus standard volume radiation therapy for muscle-invasive bladder cancer: results of the BC2001 trial (CRUK/01/004).
      ]. This index tumor CTV can be utilized in two situations:
      • partial bladder irradiation (although partial irradiation is not recommended);
      • or when a two dose level approach is considered: either for index tumor dose escalation (with standard dose to the whole bladder) or for whole bladder dose de-escalation (with standard dose to the index tumor).
      The definition of an index tumor CTV should be limited to the following cases:
      • no multifocal lesions and/or no CIS away from the index tumor: the multifocality of CIS can be assessed by hexaminolevulinate photodynamic diagnosis-assisted TURBT, with systematic biopsies of suspicious areas on blue light examination, while randomized biopsies of optically healthy mucosae are usually not recommended [
        • Rouprêt M.
        • Pignot G.
        • Masson-Lecomte A.
        • Compérat E.
        • Audenet F.
        • Roumiguié M.
        • et al.
        French ccAFU guidelines - update 2020–2022: bladder cancer.
        ];
      • index tumor easily identifiable: either due to a macroscopic residual lesion following incomplete TURBT (i.e. GTV), or due to the presence of gold fiducial markers set during the TURBT with good consistency with the pre-TURBT imaging (contrast-enhanced CT or MRI) and the planning CT;
      • index lesion located outside the dome (due to the risk of geographical miss during dose delivery) and ideally upon the trigone;
      • ratio of index tumor CTV upon whole bladder <25% approximately, to allow a significant sparing of the rest of the bladder.
      Two strategies performed during TURBT have been suggested to help identify the index tumor for delineation or image-guidance purposes [
      • Nolan C.P.
      • Forde E.J.
      A review of the use of fiducial markers for image-guided bladder radiotherapy.
      ]:
      However, these strategies are still under investigation and should not be considered as a standard of care.

      Pelvic lymph node clinical tumor volume

      Pelvic lymph node (PLN) CTV definition is discussed along with potential indications of PLN irradiation in section 3.5.5.

      Planning target volume (PTV)

      CTV to PTV margins take into account set-up margins as well as internal motions relating to changes of position, volume and shape of the organ, both between each fraction (inter-fraction) and within a fraction (intra-fraction).

      Inter-fraction motion

      Inter-fraction motions of the bladder wall are complex, essentially depending on bladder and rectum filling [
      • Lotz H.T.
      • Remeijer P.
      • van Herk M.
      • Lebesque J.V.
      • de Bois J.A.
      • Zijp L.J.
      • et al.
      A model to predict bladder shapes from changes in bladder and rectal filling.
      ,
      • Lotz H.T.
      • Pos F.J.
      • Hulshof M.C.C.M.
      • van Herk M.
      • Lebesque J.V.
      • Duppen J.C.
      • et al.
      Tumor motion and deformation during external radiotherapy of bladder cancer.
      ,
      • Fokdal L.
      • Honoré H.
      • Høyer M.
      • Meldgaard P.
      • Fode K.
      • von der Maase H.
      Impact of changes in bladder and rectal filling volume on organ motion and dose distribution of the bladder in radiotherapy for urinary bladder cancer.
      ], with maximal shifts above 2 cm within the whole course of radiotherapy. This motion is anisotropic as superior and anterior bladder portions have greater amplitudes of motion [
      • Yee D.
      • Parliament M.
      • Rathee S.
      • Ghosh S.
      • Ko L.
      • Murray B.
      Cone beam CT imaging analysis of interfractional variations in bladder volume and position during radiotherapy for bladder cancer.
      ,
      • Tolan S.
      • Kong V.
      • Rosewall T.
      • Craig T.
      • Bristow R.
      • Milosevic M.
      • et al.
      Patient-specific PTV margins in radiotherapy for bladder cancer – A feasibility study using cone beam CT.
      ,
      • Pan Q.
      • Thariat J.
      • Bogalhas F.
      • Lagrange J.-L.
      Évaluation des mouvements des différentes portions anatomiques de la vessie, implications pour la radiothérapie guidée par l’image pour les cancers de vessie.
      ,
      • Mangar S.A.
      • Miller N.R.
      • Khoo V.S.
      • Hansen V.
      • McNair H.
      • Horwich A.
      • et al.
      Evaluating inter-fractional changes in volume and position during bladder radiotherapy and the effect of volume limitation as a method of reducing the internal margin of the planning target volume.
      ]. Changes in bladder volumes relative to the planned CTV have been widely described over the treatment and showed a weekly variation around 20–30%, mainly towards a decrease [
      • Pos F.J.
      • Koedooder K.
      • Hulshof M.C.C.
      • van Tienhoven G.
      • González González D.
      Influence of bladder and rectal volume on spatial variability of a bladder tumor during radical radiotherapy. Int.
      ,
      • Mangar S.A.
      • Miller N.R.
      • Khoo V.S.
      • Hansen V.
      • McNair H.
      • Horwich A.
      • et al.
      Evaluating inter-fractional changes in volume and position during bladder radiotherapy and the effect of volume limitation as a method of reducing the internal margin of the planning target volume.
      ,
      • Muren L.P.
      • Smaaland R.
      • Dahl O.
      Organ motion, set-up variation and treatment margins in radical radiotherapy of urinary bladder cancer.
      ]. However, some series have concluded an unpredictable pattern of volume variations, with cases of both larger and smaller bladders in the same patient over the course of radiotherapy [
      • Lalondrelle S.
      • Huddart R.
      • Warren-Oseni K.
      • Hansen V.N.
      • McNair H.
      • Thomas K.
      • et al.
      Adaptive-predictive organ localization using cone-beam computed tomography for improved accuracy in external beam radiotherapy for bladder cancer.
      ].
      Interestingly, Lotz et al. have assessed the variations in both GTV shape and position during a course of radiotherapy, estimating that variations in GTV shape were small compared to GTV translations (standard deviation of the GTV center of gravity 0.1–0.9 cm). Translations were largest in the cranio-caudal and antero-posterior directions, and were strongly correlated with the tumor location on the bladder wall (larger for tumors at the cranial and the anterior parts of the bladder) [
      • Lotz H.T.
      • Pos F.J.
      • Hulshof M.C.C.M.
      • van Herk M.
      • Lebesque J.V.
      • Duppen J.C.
      • et al.
      Tumor motion and deformation during external radiotherapy of bladder cancer.
      ].

      Intra-fraction motions

      Intra-fraction motions have been studied by repeated pre-treatment and post-treatment soft-tissue imaging, or by cine-MRI. Among 15 patients receiving 80 fractions, Lalondrelle et al. estimated using pre- and post-treatment cone beam CT (CBCT) that the bladder volume changed by 9 cc (SD 16 cc, range 32–52 cc) over a fraction (with a mean time of 13 min). This was associated with bladder wall translations, predominantly in cranial (mean 2.4 mm) and anterior direction (mean 2 mm) [
      • Lalondrelle S.
      • Huddart R.
      • Warren-Oseni K.
      • Hansen V.N.
      • McNair H.
      • Thomas K.
      • et al.
      Adaptive-predictive organ localization using cone-beam computed tomography for improved accuracy in external beam radiotherapy for bladder cancer.
      ]. Mangar et al. assessed intra-fraction bladder motion using cine-MRI in nine patients. An increase in volume of 1.6 cm3 per minute was observed during a fraction, corresponding to a bladder volume increase of 30%. For volumes up to 150 cc, this bladder filling was linearly correlated with a displacement of the superior, inferior and anterior bladder walls [
      • Mangar S.A.
      • Scurr E.
      • Huddart R.A.
      • Sohaib S.A.
      • Horwich A.
      • Dearnaley D.P.
      • et al.
      Assessing intra-fractional bladder motion using cine-MRI as initial methodology for Predictive Organ Localization (POLO) in radiotherapy for bladder cancer.
      ].

      Motion according to bladder filling

      The correlation of inter- and intra-fraction motions and bladder-filling protocols was investigated by Dees-Ribbers et al. Among 24 patients with pre and post-treatment CBCT, eight patients were treated with an empty bladder and sixteen with a full bladder. Both protocols showed similar intra- and inter-fraction motions, with largest movement in the cranial and anterior directions in both cases [
      • Dees-Ribbers H.M.
      • Betgen A.
      • Pos F.J.
      • Witteveen T.
      • Remeijer P.
      • van Herk M.
      Inter- and intra-fractional bladder motion during radiotherapy for bladder cancer: A comparison of full and empty bladders.
      ]. On the contrary, Pos et al. found that a large bladder volume and rectal diameter at planning CT was predictive of a large volume variation and a large tumor spatial variability [
      • Pos F.J.
      • Koedooder K.
      • Hulshof M.C.C.
      • van Tienhoven G.
      • González González D.
      Influence of bladder and rectal volume on spatial variability of a bladder tumor during radical radiotherapy. Int.
      ].

      Planning target volume margins (without adaptive strategies)

      CTV to PTV margins should be chosen to ensure that the CTV is covered in most of the fractions and ideally by the 95% isodose line [
      • van Herk M.
      • Remeijer P.
      • Rasch C.
      • Lebesque J.V.
      The probability of correct target dosage: dose-population histograms for deriving treatment margins in radiotherapy.
      ]. This global margin is highly dependent on the daily alignment method applied. Empirically, population-based CTV to PTV margins of 2 cm or more have been proposed, before the use of IGRT with soft tissue imaging realignment [
      • Turner S.L.
      • Swindell R.
      • Bowl N.
      • Marrs J.
      • Brookes B.
      • Read G.
      • et al.
      Bladder movement during radiation therapy for bladder cancer: Implications for treatment planning.
      ].
      Adapted margins have been proposed according to alignment method with two main strategies. First, several series assessed the percentage of patients for whom a given proportion of the wall displacements is covered by a margin from the CTV [
      • Pos F.J.
      • Koedooder K.
      • Hulshof M.C.C.
      • van Tienhoven G.
      • González González D.
      Influence of bladder and rectal volume on spatial variability of a bladder tumor during radical radiotherapy. Int.
      ,
      • Foroudi F.
      • Pham D.
      • Bressel M.
      • Wong J.
      • Rolfo A.
      • Roxby P.
      • et al.
      Bladder cancer radiotherapy margins: A comparison of daily alignment using skin.
      ,
      • Redpath A.T.
      • Muren L.P.
      CT-guided intensity-modulated radiotherapy for bladder cancer: Isocentre shifts, margins and their impact on target dose.
      ,
      • Henry A.M.
      • Stratford J.
      • McCarthy C.
      • Davies J.
      • Sykes J.R.
      • Amer A.
      • et al.
      X-ray volume imaging in bladder radiotherapy verification.
      ]. For example, Foroudi et al. estimated that bladder CTV coverage with a margin of 0.5, 1.0, 1.5, 2.0 and 2.5 cm was 0%, 19%, 56%, 93% and 96%, respectively based upon daily skin alignment. CTV coverage was 0%, 41%, 63%, 89% and 96% respectively, based upon daily bony alignment. It was 52%, 89%, 96%, 100% and 100%, respectively based upon daily soft-tissue alignment. Interestingly, with soft-tissue alignment, the overall insufficient coverage of CTV with a 1 cm margin is linked to insufficient coverage in the anterior and posterior directions in 90% of cases [
      • Foroudi F.
      • Pham D.
      • Bressel M.
      • Wong J.
      • Rolfo A.
      • Roxby P.
      • et al.
      Bladder cancer radiotherapy margins: A comparison of daily alignment using skin.
      ]. Another strategy to determine CTV to PTV margin is to assess, for each direction, and for a population of patients, uncertainties on systematic errors (Σ) and on random errors (σ) for each component (organ motion and set-up) of a given alignment method, as compared to a gold standard and to apply “Van Herk-like” recipes [
      • Muren L.P.
      • Smaaland R.
      • Dahl O.
      Organ motion, set-up variation and treatment margins in radical radiotherapy of urinary bladder cancer.
      ,
      • van Herk M.
      • Remeijer P.
      • Rasch C.
      • Lebesque J.V.
      The probability of correct target dosage: dose-population histograms for deriving treatment margins in radiotherapy.
      ,
      • Meijer G.J.
      • Rasch C.
      • Remeijer P.
      • Lebesque J.V.
      Three-dimensional analysis of delineation errors, setup errors, and organ motion during radiotherapy of bladder cancer.
      ]. The more precise the alignment method, the more the uncertainties on Σ and σ will decrease, and the more the CTV to PTV margin can decrease. Based on portal imaging alignment methods, Meijer et al. estimated that CTV to PTV margins should be 1 cm laterally and anteriorly, 1.2 cm caudally, 1.4 cm posteriorly and 2 cm cranially [
      • Meijer G.J.
      • Rasch C.
      • Remeijer P.
      • Lebesque J.V.
      Three-dimensional analysis of delineation errors, setup errors, and organ motion during radiotherapy of bladder cancer.
      ]. However, these recipes have been described for translation motions mainly, and therefore are not perfectly adapted to bladder motion which contains shape and volume modifications as well.

      Organs at risk

      The delineation of organs at risk should follow standard practices, for bowel bag, rectum, anal canal and femoral heads [
      • Gay H.A.
      • Barthold H.J.
      • O’Meara E.
      • Bosch W.R.
      • El Naqa I.
      • Al-Lozi R.
      • et al.
      Pelvic normal tissue contouring guidelines for radiation therapy: a Radiation Therapy Oncology Group consensus panel atlas.
      ].

      Radiotherapy regimen

      The regimens and clinical outcomes are summarized in Table 1, Table 2.

      Conventional fractionation

      A radiotherapy dose–response effect has been suggested in several series [
      • Majewski W.
      • Maciejewski B.
      • Majewski S.
      • Suwinski R.
      • Miszczyk L.
      • Tarnawski R.
      Clinical radiobiology of stage T2–T3 bladder cancer.
      ,
      • Pos F.J.
      • Hart G.
      • Schneider C.
      • Sminia P.
      Radical radiotherapy for invasive bladder cancer: what dose and fractionation schedule to choose?.
      ]. For example, Pos et al. estimated that an increase in total dose of 10 Gy was associated with a 1.44-fold increase in the 3-year local control [
      • Pos F.J.
      • Hart G.
      • Schneider C.
      • Sminia P.
      Radical radiotherapy for invasive bladder cancer: what dose and fractionation schedule to choose?.
      ]. In trimodal therapy prospective trials using conventional fractionation and no dose-escalation, the total prescribed dose to whole bladder was then relatively concordant, ranging from:
      The overall treatment time (OTT) ranged from 6 weeks (for continuous schedule) to 9 weeks (for split course schedules).
      In one study assessing dose escalation to the index tumor, total dose was 64 Gy on the whole bladder and 68 Gy on the index tumor [
      • Murthy V.
      • Masodkar R.
      • Kalyani N.
      • Mahantshetty U.
      • Bakshi G.
      • Prakash G.
      • et al.
      Clinical outcomes with dose-escalated adaptive radiation therapy for urinary bladder cancer: A prospective study.
      ].

      Altered fractionation

      When delivering radiotherapy, fractionation refers to two linked parameters, the dose per fraction and the OTT; altered fractionation therefore implies modification of one or of these two parameters, as compared to the conventional fractionation. A decrease of OTT (less than 6 weeks) typically aims to avoid clonogenic tumor repopulation (for tumors with high α/β ratio), with potential benefits on quality of life and cost-effectiveness, at the cost of increased acute toxicity; while a decrease of dose per fraction aims at reducing late toxicity [

      Joiner M, Kogel A van der. Basic clinical radiobiology. Hodder Arnold; 2009.

      ].
      OTT for the bladder has been suggested to have an impact on outcome as tumor clonogenic repopulation in urothelial carcinoma of the bladder was shown to accelerate after a lag period of about 5–6 weeks following the start of treatment. It was thus concluded that a dose increment of 0.36 Gy per day was required to compensate for this repopulation [
      • Maciejewski B.
      • Majewski S.
      Dose fractionation and tumour repopulation in radiotherapy for bladder cancer.
      ]. Similarly, the α/β ratio higher than 10 Gy [
      • van Leeuwen C.M.
      • Oei A.L.
      • Crezee J.
      • Bel A.
      • Franken N.A.P.
      • Stalpers L.J.A.
      • et al.
      The alfa and beta of tumours: a review of parameters of the linear-quadratic model, derived from clinical radiotherapy studies.
      ] suggests a low sensitivity to fractionation for urothelial bladder cancer cells.

      Pure hyperfractionated radiotherapy (without acceleration)

      Pure hyperfractionated radiotherapy refers to a regimen with OTT of at least 6 weeks, and dose per fraction <1.8 Gy. Several bladder-sparing prospective trials (from the Boston “2nd and 3rd generation” studies) can be considered as pure hyperfractionated regimens [
      • Hagan M.P.
      • Winter K.A.
      • Kaufman D.S.
      • Wajsman Z.
      • Zietman A.L.
      • Heney N.M.
      • et al.
      RTOG 97–06: Initial report of a Phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy.
      ,
      • Kaufman D.S.
      • Winter K.A.
      • Shipley W.U.
      • Heney N.M.
      • Wallace H.J.
      • Toonkel L.M.
      • et al.
      Phase I-II RTOG Study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy.
      ,
      • Mitin T.
      • Hunt D.
      • Shipley W.U.
      • Kaufman D.S.
      • Uzzo R.
      • Wu C.-L.
      • et al.
      Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial.
      ,
      • Coen J.J.
      • Zhang P.
      • Saylor P.J.
      • Lee C.T.
      • Wu C.-L.
      • Parker W.
      • et al.
      Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712—A randomized phase II trial.
      ,
      • Zietman A.L.
      • Shipley W.U.
      • Kaufman D.S.
      • Zehr E.M.
      • Heney N.M.
      • Althausen A.F.
      • et al.
      A phase I/II trial of transurethral surgery combined with concurrent cisplatin, 5-fluorouracil and twice daily radiation followed by selective bladder preservation in operable patients with muscle invading bladder cancer.
      ]. Indeed, they included bi-fractionated regimens (2 fractions per day), with dose per fraction of around 1.5 Gy, and OTT of 8–9 weeks due to a split-course schedule. Zapatero et al. used the same schedule [
      • Zapatero A.
      • Martin De Vidales C.
      • Arellano R.
      • Ibañez Y.
      • Bocardo G.
      • Perez M.
      • et al.
      Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy.
      ]. In these trials total dose to the bladder ranged from 45.6 Gy to 52.3 Gy and total dose to the index tumor was 64.3–64.8 Gy. Hafeez et al. reported results of a dose-escalation regimen using pure hyperfractionated radiotherapy on the whole bladder and moderate accelerated boost on the index tumor with acceptable oncological outcomes and tolerance [
      • Hafeez S.
      • Warren-Oseni K.
      • McNair H.A.
      • Hansen V.N.
      • Jones K.
      • Tan M.
      • 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.
      ].

      Pure hypofractionated radiotherapy (without acceleration)

      Two trials report on the outcome of a bifractionated (BID) hypofractionated protracted regimen (OTT = 11.5 weeks) with split course among patients with localized operable MIBC: 3 Gy b.i.d at days 1, 3, 15, 17 on the whole pelvis followed by reevaluation, then, in case of complete response, 2.5 Gy b.i.d at days 64, 66, 78, 80, to a total dose of 44 Gy on the whole bladder. Complete response was obtained in 67 to 74%, and 3-year OS was 59% to 83% [
      • Kaufman D.S.
      • Winter K.A.
      • Shipley W.U.
      • Heney N.M.
      • Chetner M.P.
      • Souhami L.
      • et al.
      The initial results in muscle-invading bladder cancer of RTOG 95-06: Phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response.
      ,
      • Housset M.
      • Maulard C.
      • Chretien Y.
      • Dufour B.
      • Delanian S.
      • Huart J.
      • et al.
      Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study.
      ].

      Hyperfractionated accelerated radiotherapy

      The phase II EORTC 22971 trial is the only prospective trimodal therapy assessing hyperfractionated accelerated radiotherapy (2 daily fractions of 1.2 Gy up to 60 Gy on the whole bladder over 5 weeks). However, only 9 patients were enrolled and therefore, this study is not discussed here [
      • Poortmans P.M.
      • Richaud P.
      • Collette L.
      • Ho Goey S.
      • Pierart M.
      • Van Der Hulst M.
      • et al.
      Results of the phase II EORTC 22971 trial evaluating combined accelerated external radiation and chemotherapy with 5FU and cisplatin in patients with muscle invasive transitional cell carcinoma of the bladder.
      ].

      Hypofractionated accelerated radiotherapy

      Moderate hypofractionated accelerated radiotherapy has been assessed in five trimodal therapy trials (including one trial using non-chemotherapy based radiosensitizers) [
      • James N.D.
      • Hussain S.A.
      • Hall E.
      • Jenkins P.
      • Tremlett J.
      • Rawlings C.
      • et al.
      Radiotherapy with or without Chemotherapy in Muscle-Invasive Bladder Cancer.
      ,
      • Hoskin P.
      • Rojas A.
      • Bentzen S.
      • Saunders M.
      Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma.
      ,
      • Choudhury A.
      • Swindell R.
      • Logue J.P.
      • Elliott P.A.
      • Livsey J.E.
      • Wise M.
      • et al.
      Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer.
      ,
      • Thompson C.
      • Joseph N.
      • Sanderson B.
      • Logue J.
      • Wylie J.
      • Elliott T.
      • et al.
      Tolerability of concurrent chemoradiation therapy with gemcitabine (GemX), with and without prior neoadjuvant chemotherapy, in muscle invasive bladder cancer.
      ,
      • Hussain S.A.
      • Stocken D.D.
      • Peake D.R.
      • Glaholm J.G.
      • Zarkar A.
      • Wallace D.M.A.
      • et al.
      Long-term results of a phase II study of synchronous chemoradiotherapy in advanced muscle invasive bladder cancer.
      ]. Radiotherapy was delivered continuously over 4 weeks on the whole bladder to a total dose of 52.5–55 Gy. No direct comparison of hypofractionated versus conventional fractionated radiotherapy for trimodal therapy exists to date; however an individual patient-data meta-analysis of two phase III randomized trials [
      • James N.D.
      • Hussain S.A.
      • Hall E.
      • Jenkins P.
      • Tremlett J.
      • Rawlings C.
      • et al.
      Radiotherapy with or without Chemotherapy in Muscle-Invasive Bladder Cancer.
      ,
      • Hoskin P.
      • Rojas A.
      • Bentzen S.
      • Saunders M.
      Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma.
      ] was recently published comparing two schedules widely used in the UK: 64 Gy in 32 fractions and 55 Gy in 20 fractions among 782 patients. While the toxicity profile was similar between the two regimens, the hypofractionated schedule was non-inferior to a conventionally fractionated schedule in terms of invasive locoregional recurrence (ILRC) and OS, and superiority of the hypofractionated schedule was demonstrated for ILRC (adjusted HR 0.71 [95% CI 0.52–0.96]) [
      • Choudhury A.
      • Porta N.
      • Hall E.
      • Song Y.P.
      • Owen R.
      • MacKay R.
      • et al.
      Hypofractionated radiotherapy in locally advanced bladder cancer: an individual patient data meta-analysis of the BC2001 and BCON trials.
      ].

      Dose-escalated tumor boost

      Dose to the index tumor can be regarded as escalated if the equivalent dose in 2 Gy fraction (EQD2Gy) is more than 66 Gy. The rationale to propose such escalated doses refers to the pattern of recurrence following radiotherapy mostly at the original primary bladder tumor site [
      • Zietman A.
      • Grocela J.
      • Zehr E.
      • Kaufman D.
      • Young R.
      • Althausen A.
      • et al.
      Selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of Ta, T1, and Tis recurrence within the retained bladder.
      ] and to the radiation dose–response effect in urothelial bladder cancer [
      • Majewski W.
      • Maciejewski B.
      • Majewski S.
      • Suwinski R.
      • Miszczyk L.
      • Tarnawski R.
      Clinical radiobiology of stage T2–T3 bladder cancer.
      ,
      • Pos F.J.
      • Hart G.
      • Schneider C.
      • Sminia P.
      Radical radiotherapy for invasive bladder cancer: what dose and fractionation schedule to choose?.
      ].
      Several retrospective studies have reported interesting results using intensity modulated radiotherapy (IMRT) with simultaneous integrated boost, with various schedules [
      • Whalley D.
      • Caine H.
      • McCloud P.
      • Guo L.
      • Kneebone A.
      • Eade T.
      Promising results with image guided intensity modulated radiotherapy for muscle invasive bladder cancer.
      ,
      • Murthy V.
      • Gupta P.
      • Baruah K.
      • Krishnatry R.
      • Joshi A.
      • Prabhash K.
      • et al.
      Adaptive radiotherapy for carcinoma of the urinary bladder: long-term outcomes with dose escalation.
      ].
      Three trimodal therapy prospective trials have assessed high dose tumor boost delivered with image-guided adaptive radiotherapy. Following a pilot feasibility study of ten patients [
      • Murthy V.
      • Master Z.
      • Adurkar P.
      • Mallick I.
      • Mahantshetty U.
      • Bakshi G.
      • et al.
      ‘Plan of the day’ adaptive radiotherapy for bladder cancer using helical tomotherapy.
      ], Murthy et al. prospectively assessed the clinical outcome of 44 patients with localized MIBC treated with conventional fractionated radiotherapy to the whole bladder (64 Gy/2Gy) and weekly cisplatin [
      • Murthy V.
      • Masodkar R.
      • Kalyani N.
      • Mahantshetty U.
      • Bakshi G.
      • Prakash G.
      • et al.
      Clinical outcomes with dose-escalated adaptive radiation therapy for urinary bladder cancer: A prospective study.
      ]. Patients with a solitary tumor or 2 tumors in close proximity and without CIS were deemed suitable for dose-escalation using a simultaneous integrated boost to the tumor bed to a dose of 68 Gy/2.125 Gy (EQD2Gy = 68.7 Gy); 55% received the escalated dose. Adaptive radiotherapy was used (Table 1, Table 2). While OS and locoregional control rates were better among patients receiving the escalated dose, it was not statistically significant.
      Similarly, Hafeez et al. prospectively assessed trimodal therapy with image-guided adaptive radiotherapy using an high dose simultaneous integrated boost to the index tumor: 52 Gy/32 fractions to the whole bladder and 70 Gy/32 fractions to the tumor bed (EQD2Gy = 71 Gy) [
      • Hafeez S.
      • Warren-Oseni K.
      • McNair H.A.
      • Hansen V.N.
      • Jones K.
      • Tan M.
      • 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.
      ]. Eighteen out of 20 patients completed treatment to 70 Gy; 17 patients were alive and disease-free at a median follow up of 19 months, and no muscle-invasive recurrence occurred. No late grade ≥3 gastro-intestinal toxicity was observed and two patients experienced late grade ≥3 genito-urinary toxicity. Planning CT for simultaneous integrated boost irradiation in both trials was performed with comfortably full bladder protocols [
      • Murthy V.
      • Masodkar R.
      • Kalyani N.
      • Mahantshetty U.
      • Bakshi G.
      • Prakash G.
      • et al.
      Clinical outcomes with dose-escalated adaptive radiation therapy for urinary bladder cancer: A prospective study.
      ,
      • Hafeez S.
      • Warren-Oseni K.
      • McNair H.A.
      • Hansen V.N.
      • Jones K.
      • Tan M.
      • 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.
      ].
      This treatment approach is currently being assessed in a randomized phase II trial (RAIDER) comparing adaptive image guided standard dose versus escalated dose radiotherapy (NCT02447549).

      Split course versus continuous schedule

      When given as an alternative to surgery for patients unfit for surgery and/or with inoperable tumor, continuous chemoradiotherapy is routine as salvage-cystectomy is not feasible.
      When given as trimodal therapy with the aim of bladder-sparing for resectable tumors and fit patients, two strategies have been proposed. In protocols used in the RTOG trials, candidates for bladder-sparing were selected according to their early response to induction chemoradiation; only those with complete (or near complete) pathologic response could pursue with consolidation chemoradiation, while non-responder patients were referred for early cystectomy [
      • Giacalone N.J.
      • Shipley W.U.
      • Clayman R.H.
      • Niemierko A.
      • Drumm M.
      • Heney N.M.
      • et al.
      Long-term outcomes after bladder-preserving tri-modality therapy for patients with muscle-invasive bladder cancer: an updated analysis of the massachusetts general hospital experience.
      ]. This implies a gap of 3–5 weeks during the course of chemoradiotherapy (split course), between induction and consolidation chemoradiotherapy. Conversely, protocols developed at the University of Erlangen consist of an up-front full-course of chemoradiotherapy with no interruption and with early evaluation (at around 6 weeks after the end of radiotherapy), with potential salvage-cystectomy according to response [
      • Rödel C.
      • Grabenbauer G.G.
      • Kühn R.
      • Papadopoulos T.
      • Dunst J.
      • Meyer M.
      • et al.
      Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results.
      ].
      No formal comparison exists between the two approaches and concerns have been raised about increased OTT with split course due to radiobiological reasons. Overall, prospective split course trimodal therapy protocols have been designed with conventional fractionated radiotherapy [
      • Lagrange J.-L.
      • Bascoul-Mollevi C.
      • Geoffrois L.
      • Beckendorf V.
      • Ferrero J.-M.
      • Joly F.
      • et al.
      Quality of life assessment after concurrent chemoradiation for invasive bladder cancer: results of a multicenter prospective study (GETUG 97*015).
      ,
      • Coen J.J.
      • Zhang P.
      • Saylor P.J.
      • Lee C.T.
      • Wu C.-L.
      • Parker W.
      • et al.
      Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712—A randomized phase II trial.
      ,
      • Zietman A.L.
      • Shipley W.U.
      • Kaufman D.S.
      • Zehr E.M.
      • Heney N.M.
      • Althausen A.F.
      • et al.
      A phase I/II trial of transurethral surgery combined with concurrent cisplatin, 5-fluorouracil and twice daily radiation followed by selective bladder preservation in operable patients with muscle invading bladder cancer.
      ,
      • Tester W.
      • Porter A.
      • Asbell S.
      • Coughlin C.
      • Heaney J.
      • Krall J.
      • et al.
      Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12.
      ,
      • Tester W.
      • Caplan R.
      • Heaney J.
      • Venner P.
      • Whittington R.
      • Byhardt R.
      • et al.
      Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802.
      ,
      • Fellin G.
      • Graffer U.
      • Bolner A.
      • Ambrosini G.
      • Caffo O.
      • Luciani L.
      Combined chemotherapy and radiation with selective organ preservation for muscle-invasive bladder carcinoma. A single-institution phase II study.
      ,

      Arias F, Domı́nguez MA, Martı́nez E, Illarramendi JJ, Miquelez S, Pascual I, et al. Chemoradiotherapy for muscle invading bladder carcinoma. final report of a single institutional organ-sparing program. Int J Radiat Oncol 2000;47:373–8. 10.1016/S0360-3016(00)00444-2.

      ,
      • Mokarim A.
      • Uetani M.
      • Hayashi N.
      • Sakamoto I.
      • Minami K.
      • Ogawa Y.
      • et al.
      Combined intraarterial chemotherapy and radiotherapy in the treatment of Bladder carcinoma.
      ,
      • Lin C.-C.
      • Hsu C.-H.
      • Cheng J.C.
      • Huang C.-Y.
      • Tsai Y.-C.
      • Hsu F.-M.
      • et al.
      Induction cisplatin and fluorouracil-based chemotherapy followed by concurrent chemoradiation for muscle-invasive bladder cancer.
      ], pure hyperfractionated radiotherapy [
      • Hagan M.P.
      • Winter K.A.
      • Kaufman D.S.
      • Wajsman Z.
      • Zietman A.L.
      • Heney N.M.
      • et al.
      RTOG 97–06: Initial report of a Phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy.
      ,
      • Kaufman D.S.
      • Winter K.A.
      • Shipley W.U.
      • Heney N.M.
      • Wallace H.J.
      • Toonkel L.M.
      • et al.
      Phase I-II RTOG Study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy.
      ,
      • Mitin T.
      • Hunt D.
      • Shipley W.U.
      • Kaufman D.S.
      • Uzzo R.
      • Wu C.-L.
      • et al.
      Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial.
      ,
      • Coen J.J.
      • Zhang P.
      • Saylor P.J.
      • Lee C.T.
      • Wu C.-L.
      • Parker W.
      • et al.
      Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712—A randomized phase II trial.
      ,
      • Zietman A.L.
      • Shipley W.U.
      • Kaufman D.S.
      • Zehr E.M.
      • Heney N.M.
      • Althausen A.F.
      • et al.
      A phase I/II trial of transurethral surgery combined with concurrent cisplatin, 5-fluorouracil and twice daily radiation followed by selective bladder preservation in operable patients with muscle invading bladder cancer.
      ,
      • Zapatero A.
      • Martin De Vidales C.
      • Arellano R.
      • Ibañez Y.
      • Bocardo G.
      • Perez M.
      • et al.
      Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy.
      ] and pure hypofractionated radiotherapy [
      • Kaufman D.S.
      • Winter K.A.
      • Shipley W.U.
      • Heney N.M.
      • Chetner M.P.
      • Souhami L.
      • et al.
      The initial results in muscle-invading bladder cancer of RTOG 95-06: Phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response.
      ,
      • Housset M.
      • Maulard C.
      • Chretien Y.
      • Dufour B.
      • Delanian S.
      • Huart J.
      • et al.
      Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study.
      ]. In the two latter cases, split protocols consisted of two accelerated courses of chemoradiation (induction and consolidation) separated by a break. Prospective continuous trimodal therapy protocols have been designed with conventional fractionated radiotherapy [
      • James N.D.
      • Hussain S.A.
      • Hall E.
      • Jenkins P.
      • Tremlett J.
      • Rawlings C.
      • et al.
      Radiotherapy with or without Chemotherapy in Muscle-Invasive Bladder Cancer.
      ,
      • Gogna N.K.
      • Matthews J.H.L.
      • Turner S.L.
      • Mameghan H.
      • Duchesne G.M.
      • Spry N.
      • et al.
      Efficacy and tolerability of concurrent weekly low dose cisplatin during radiation treatment of localised muscle invasive bladder transitional cell carcinoma: A report of two sequential Phase II studies from the Trans Tasman Radiation Oncology Group.
      ,
      • Hoskin P.
      • Rojas A.
      • Bentzen S.
      • Saunders M.
      Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma.
      ,
      • Kragelj B.
      • Zaletel-Kragelj L.
      • Sedmak B.
      • Čufer T.
      • Červek J.
      Phase II study of radiochemotherapy with vinblastine in invasive bladder cancer.
      ,
      • Eapen L.
      • Steward D.
      • Collins J.
      • Peterson R.
      Effective bladder sparing therapy with intra-arterial cisplatin and radiotherapy for localized bladder cancer.
      ,
      • Caffo O.
      • Fellin G.
      • Graffer U.
      • Mussari S.
      • Tomio L.
      • Galligioni E.
      Gemcitabine and radiotherapy plus cisplatin after transurethral resection as conservative treatment for infiltrating bladder cancer.
      ,
      • Tunio M.A.
      • Hashmi A.
      • Qayyum A.
      • Mohsin R.
      • Zaeem A.
      Whole-pelvis or bladder-only chemoradiation for lymph node-negative invasive bladder cancer: single-institution experience.
      ,
      • Murthy V.
      • Masodkar R.
      • Kalyani N.
      • Mahantshetty U.
      • Bakshi G.
      • Prakash G.
      • et al.
      Clinical outcomes with dose-escalated adaptive radiation therapy for urinary bladder cancer: A prospective study.
      ], pure hyperfractionated radiotherapy [
      • Hafeez S.
      • Warren-Oseni K.
      • McNair H.A.
      • Hansen V.N.
      • Jones K.
      • Tan M.
      • 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.
      ] and hypofractionated accelerated radiotherapy [
      • James N.D.
      • Hussain S.A.
      • Hall E.
      • Jenkins P.
      • Tremlett J.
      • Rawlings C.
      • et al.
      Radiotherapy with or without Chemotherapy in Muscle-Invasive Bladder Cancer.
      ,
      • Hoskin P.
      • Rojas A.
      • Bentzen S.
      • Saunders M.
      Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma.
      ,
      • Choudhury A.
      • Swindell R.
      • Logue J.P.
      • Elliott P.A.
      • Livsey J.E.
      • Wise M.
      • et al.
      Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer.
      ,
      • Thompson C.
      • Joseph N.
      • Sanderson B.
      • Logue J.
      • Wylie J.
      • Elliott T.
      • et al.
      Tolerability of concurrent chemoradiation therapy with gemcitabine (GemX), with and without prior neoadjuvant chemotherapy, in muscle invasive bladder cancer.
      ,
      • Hussain S.A.
      • Stocken D.D.
      • Peake D.R.
      • Glaholm J.G.
      • Zarkar A.
      • Wallace D.M.A.
      • et al.
      Long-term results of a phase II study of synchronous chemoradiotherapy in advanced muscle invasive bladder cancer.
      ] (Table 1, Table 2).
      In a meta-analysis of trimodal therapy studies, Arcangeli et al. found that the complete response rate was significantly better in patients treated with a continuous schedule compared to split course (HR = 0.513, (95%CI 0.430–0.611)). This was confirmed as an independent prognostic factor in multivariable analysis. Consequently, salvage cystectomy was more frequent with split course (25% vs 19%), P < 0.05). However, the early reevaluation of split course should be kept in mind after induction chemoradiotherapy, so a low radiation dose level delivered may potentially lead to inappropriate, premature salvage cystectomy, while it is performed after full-course treatment in the continuous schedule. No differences were found in bladder-intact survival or 5-year OS. In subgroup analysis, 5-year OS was significantly better with a continuous course compared to split course among patients with >T2 tumor stage (HR = 0.641, 95%CI = 0.424–0.969), while there was no difference in complete response rate [
      • Arcangeli G.
      • Arcangeli S.
      • Strigari L.
      A systematic review and meta-analysis of clinical trials of bladder-sparing trimodality treatment for muscle-invasive bladder cancer (MIBC).
      ].

      Pelvic lymph nodes (PLN) irradiation

      PLN irradiation among patients with cN0 bladder cancer is an important matter of debate. The rationale to propose PLN irradiation is multiple: radical cystectomy with PLN dissection series in cN0 patients showing PLN micrometastases in around 25% [
      • Stein J.P.
      • Lieskovsky G.
      • Cote R.
      • Groshen S.
      • Feng A.-C.
      • Boyd S.
      • et al.
      Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients.
      ,
      • Goldsmith B.
      • Baumann B.C.
      • He J.
      • Tucker K.
      • Bekelman J.
      • Deville C.
      • et al.
      Occult pelvic lymph node involvement in bladder cancer: implications for definitive radiation.
      ], the important rate of pelvic recurrences following radical cystectomies and PLN dissection, and the negative impact of no or limited pelvic lymph nodes dissection on these recurrences [
      • Sargos P.
      • Baumann B.C.
      • Eapen L.
      • Christodouleas J.
      • Bahl A.
      • Murthy V.
      • et al.
      Risk factors for loco-regional recurrence after radical cystectomy of muscle-invasive bladder cancer: A systematic-review and framework for adjuvant radiotherapy.
      ].
      Most trimodal therapy trials initially incorporated PLN (either small pelvis (upper limit S1–S2 or S2–S3) or standard pelvis (upper limit L5-S1)). Dose to the pelvis ranged from 36 Gy to 55 Gy in conventional fractionated radiotherapy [
      • Lagrange J.-L.
      • Bascoul-Mollevi C.
      • Geoffrois L.
      • Beckendorf V.
      • Ferrero J.-M.
      • Joly F.
      • et al.
      Quality of life assessment after concurrent chemoradiation for invasive bladder cancer: results of a multicenter prospective study (GETUG 97*015).
      ,
      • Shipley W.U.
      • Winter K.A.
      • Kaufman D.S.
      • Lee W.R.
      • Heney N.M.
      • Tester W.R.
      • et al.
      Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89–03.
      ,
      • Coen J.J.
      • Zhang P.
      • Saylor P.J.
      • Lee C.T.
      • Wu C.-L.
      • Parker W.
      • et al.
      Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712—A randomized phase II trial.
      ,
      • Tester W.
      • Porter A.
      • Asbell S.
      • Coughlin C.
      • Heaney J.
      • Krall J.
      • et al.
      Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12.
      ,
      • Kragelj B.
      • Zaletel-Kragelj L.
      • Sedmak B.
      • Čufer T.
      • Červek J.
      Phase II study of radiochemotherapy with vinblastine in invasive bladder cancer.
      ,
      • Eapen L.
      • Steward D.
      • Collins J.
      • Peterson R.
      Effective bladder sparing therapy with intra-arterial cisplatin and radiotherapy for localized bladder cancer.
      ,
      • Tester W.
      • Caplan R.
      • Heaney J.
      • Venner P.
      • Whittington R.
      • Byhardt R.
      • et al.
      Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802.
      ,
      • Fellin G.
      • Graffer U.
      • Bolner A.
      • Ambrosini G.
      • Caffo O.
      • Luciani L.
      Combined chemotherapy and radiation with selective organ preservation for muscle-invasive bladder carcinoma. A single-institution phase II study.
      ,
      • Caffo O.
      • Fellin G.
      • Graffer U.
      • Mussari S.
      • Tomio L.
      • Galligioni E.
      Gemcitabine and radiotherapy plus cisplatin after transurethral resection as conservative treatment for infiltrating bladder cancer.
      ,

      Arias F, Domı́nguez MA, Martı́nez E, Illarramendi JJ, Miquelez S, Pascual I, et al. Chemoradiotherapy for muscle invading bladder carcinoma. final report of a single institutional organ-sparing program. Int J Radiat Oncol 2000;47:373–8. 10.1016/S0360-3016(00)00444-2.

      ,
      • Mokarim A.
      • Uetani M.
      • Hayashi N.
      • Sakamoto I.
      • Minami K.
      • Ogawa Y.
      • et al.
      Combined intraarterial chemotherapy and radiotherapy in the treatment of Bladder carcinoma.
      ,
      • Tunio M.A.
      • Hashmi A.
      • Qayyum A.
      • Mohsin R.
      • Zaeem A.
      Whole-pelvis or bladder-only chemoradiation for lymph node-negative invasive bladder cancer: single-institution experience.
      ,
      • Lin C.-C.
      • Hsu C.-H.
      • Cheng J.C.
      • Huang C.-Y.
      • Tsai Y.-C.
      • Hsu F.-M.
      • et al.
      Induction cisplatin and fluorouracil-based chemotherapy followed by concurrent chemoradiation for muscle-invasive bladder cancer.
      ,
      • Murthy V.
      • Masodkar R.
      • Kalyani N.
      • Mahantshetty U.
      • Bakshi G.
      • Prakash G.
      • et al.
      Clinical outcomes with dose-escalated adaptive radiation therapy for urinary bladder cancer: A prospective study.
      ], and was of 44.8–45.6 Gy in pure hyperfractionated radiotherapy [
      • Hagan M.P.
      • Winter K.A.
      • Kaufman D.S.
      • Wajsman Z.
      • Zietman A.L.
      • Heney N.M.
      • et al.
      RTOG 97–06: Initial report of a Phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy.
      ,
      • Kaufman D.S.
      • Winter K.A.
      • Shipley W.U.
      • Heney N.M.
      • Wallace H.J.
      • Toonkel L.M.
      • et al.
      Phase I-II RTOG Study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy.
      ,
      • Mitin T.
      • Hunt D.
      • Shipley W.U.
      • Kaufman D.S.
      • Uzzo R.
      • Wu C.-L.
      • et al.
      Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial.
      ,
      • Coen J.J.
      • Zhang P.
      • Saylor P.J.
      • Lee C.T.
      • Wu C.-L.
      • Parker W.
      • et al.
      Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712—A randomized phase II trial.
      ,
      • Zietman A.L.
      • Shipley W.U.
      • Kaufman D.S.
      • Zehr E.M.
      • Heney N.M.
      • Althausen A.F.
      • et al.
      A phase I/II trial of transurethral surgery combined with concurrent cisplatin, 5-fluorouracil and twice daily radiation followed by selective bladder preservation in operable patients with muscle invading bladder cancer.
      ]. PLNRT was not performed in trimodal therapy hypofractionated protocols (Table 1, Table 2).
      One phase III randomized controlled trial assessed the benefit of PLN radiotherapy: 230 patients with T2–T4, N0 urothelial bladder cancer were randomized between whole-pelvis (WP) and bladder-only (BO) continuous conventional fractionated chemoradiotherapy (with weekly cisplatin) following TURBT [
      • Tunio M.A.
      • Hashmi A.
      • Qayyum A.
      • Mohsin R.
      • Zaeem A.
      Whole-pelvis or bladder-only chemoradiation for lymph node-negative invasive bladder cancer: single-institution experience.
      ]. In both arms, dose to the whole bladder was 45 Gy and dose to the index tumor was 65 Gy: dose to the pelvis in the whole pelvis arm was 45 Gy. The primary endpoint was highly composite as it comprised toxicity, locoregional control, distant control, disease-free survival and OS. With a median follow-up of 5 years, there was no difference between whole pelvis and bladder only in late toxicity, loco-regional recurrence (41% vs 43%), 5-year PFS (47% vs 47%) and 5-year OS (53% vs 51%). However, it is worth mentioning that an isotropic 2-cm margin from the bladder walls was used with 3D conformal planning and that the bladder filling protocol was not specified, as such, at least the internal iliac vessels likely received a significant radiation dose even in the bladder-only group. These data are in line with the low rate of pelvic recurrence (6%) following bladder-only radiotherapy in the randomized BC2001 trial [
      • James N.D.
      • Hussain S.A.
      • Hall E.
      • Jenkins P.
      • Tremlett J.
      • Rawlings C.
      • et al.
      Radiotherapy with or without Chemotherapy in Muscle-Invasive Bladder Cancer.
      ].
      Among 315 patients with cT1-T4N0 urothelial bladder cancer undergoing radical cystectomy with PLN dissection (median number of dissected nodes of 19), Goldsmith et al. found that 26% had occult positive lymph nodes with the following subsite distribution: perivesicular 3%, obturator 17%, internal or external iliac 15%, presacral 3% and common iliac as high as 12%; the rate of lymph node involvement did not vary by clinical T-stage. The only predictor of pathologic pelvic lymph node involvement in multivariable analysis was the presence of lymphovascular invasion (LVI) on preoperative biopsy (OR 3.74, P < 0.001). It was marginally associated with occult common iliac LN involvement (OR 2.307, P = 0.056). Finally, they estimated that the percentages of patients with muscle-invasive disease and biopsy LVI, whose occult lymph nodes regions would have been fully encompassed by whole bladder CTV, small pelvic CTV and extended pelvic CTV (including common iliac nodes) were: 45%, 71% and 95%, respectively [
      • Goldsmith B.
      • Baumann B.C.
      • He J.
      • Tucker K.
      • Bekelman J.
      • Deville C.
      • et al.
      Occult pelvic lymph node involvement in bladder cancer: implications for definitive radiation.
      ].
      Lastly, the pelvic fields used in the trimodal therapy trials (Table 1) as well as contouring guidelines for adjuvant radiotherapy following radical cystectomy [
      • Baumann B.C.
      • Bosch W.R.
      • Bahl A.
      • Birtle A.J.
      • Breau R.H.
      • Challapalli A.
      • et al.
      Development and validation of consensus contouring guidelines for adjuvant radiation therapy for bladder cancer after radical cystectomy.
      ], suggest a standard upper limit in L5-S1 for PLN radiotherapy. However, the previous analysis of pattern of occult lymph node regions among MIBC [
      • Goldsmith B.
      • Baumann B.C.
      • He J.
      • Tucker K.
      • Bekelman J.
      • Deville C.
      • et al.
      Occult pelvic lymph node involvement in bladder cancer: implications for definitive radiation.
      ] could prompt to include common iliac nodes as well. In all cases, usual delineation guidelines around the vessels for PLN CTV should be followed [
      • Hall W.A.
      • Paulson E.
      • Davis B.J.
      • Spratt D.E.
      • Morgan T.M.
      • Dearnaley D.
      • et al.
      NRG oncology updated international consensus atlas on pelvic lymph node volumes for intact and postoperative prostate cancer.
      ].

      Radiotherapy delivery

      Intensity modulated radiotherapy

      While IMRT has been widely validated in prostate cancer [
      • Viani G.
      • Hamamura A.C.
      • Faustino A.C.
      Intensity modulated radiotherapy (IMRT) or conformational radiotherapy (3D-CRT) with conventional fractionation for prostate cancer: Is there any clinical difference?.
      ] and gynecological cancers [
      • Lin A.J.
      • Kidd E.
      • Dehdashti F.
      • Siegel B.A.
      • Mutic S.
      • Thaker P.H.
      • et al.
      Intensity modulated radiation therapy and image-guided adapted brachytherapy for cervix cancer.
      ], few data are available in bladder cancer. Several retrospective studies have compared IMRT versus 3D conformal radiotherapy: overall, IMRT dose delivery was associated with improvement of rectum and bowel sparing [
      • Sherry A.D.
      • Stewart A.
      • Luo G.
      • Kirschner A.N.
      Intensity-modulated radiotherapy is superior to three-dimensional conformal radiotherapy in the trimodality management of muscle-invasive bladder cancer with daily cone beam computed tomography optimization.
      ,
      • Søndergaard J.
      • Høyer M.
      • Petersen J.B.
      • Wright P.
      • Grau C.
      • Muren L.P.
      The normal tissue sparing obtained with simultaneous treatment of pelvic lymph nodes and bladder using intensity-modulated radiotherapy.
      ], translating into less toxicity [
      • Sherry A.D.
      • Stewart A.
      • Luo G.
      • Kirschner A.N.
      Intensity-modulated radiotherapy is superior to three-dimensional conformal radiotherapy in the trimodality management of muscle-invasive bladder cancer with daily cone beam computed tomography optimization.
      ,
      • Søndergaard J.
      • Holmberg M.
      • Jakobsen A.R.
      • Agerbæk M.
      • Muren L.P.
      • Høyer M.
      A comparison of morbidity following conformal versus intensity-modulated radiotherapy for urinary bladder cancer.
      ,
      • Lutkenhaus L.J.
      • van Os R.M.
      • Bel A.
      • Hulshof M.C.C.M.
      Clinical results of conformal versus intensity-modulated radiotherapy using a focal simultaneous boost for muscle-invasive bladder cancer in elderly or medically unfit patients.
      ].
      IMRT seems particularly relevant for hypofractionated schedules. In a retrospective series among elderly patients, hypofractionated IMRT (50 Gy in 20 fractions) within trimodal therapy was associated with 3-year OS and disease-specific survival of 61% and 71%, respectively, with no grade ≥3 late gastro-intestinal nor genito-urinary toxicity [
      • Turgeon G.-A.
      • Souhami L.
      • Cury F.L.
      • Faria S.L.
      • Duclos M.
      • Sturgeon J.
      • et al.
      Hypofractionated intensity modulated radiation therapy in combined modality treatment for bladder preservation in elderly patients with invasive bladder cancer.
      ]. The other advantage of IMRT over 3D CRT could be the feasibility of simultaneous concomitant boost on the bladder or on the tumor, which is particularly useful with continuous radiation schedules [
      • Whalley D.
      • Caine H.
      • McCloud P.
      • Guo L.
      • Kneebone A.
      • Eade T.
      Promising results with image guided intensity modulated radiotherapy for muscle invasive bladder cancer.
      ,
      • Murthy V.
      • Gupta P.
      • Baruah K.
      • Krishnatry R.
      • Joshi A.
      • Prabhash K.
      • et al.
      Adaptive radiotherapy for carcinoma of the urinary bladder: long-term outcomes with dose escalation.
      ].

      Image guided radiotherapy (IGRT)

      The assessment of bladder position and deformation relies on several imaging strategies [
      • Thariat J.
      • Aluwini S.
      • Pan Q.
      • Caullery M.
      • Marcy P.-Y.
      • Housset M.
      • et al.
      Image-guided radiation therapy for muscle-invasive bladder cancer.
      ]. In-room soft tissue imaging with either kilovoltage (kV) or megavoltage (MV) CBCT is the most frequent modality of IGRT enabling offline or online couch corrections. CBCT was used in several studies to define the optimal margins for planning (see section 2.3.3). While concerns about inter-observer variability of bladder boundary delineation on CBCT were suggested [
      • Weiss E.
      • Wu J.
      • Sleeman W.
      • Bryant J.
      • Mitra P.
      • Myers M.
      • et al.
      Clinical evaluation of soft tissue organ boundary visualization on cone-beam computed tomographic imaging.
      ], the technical improvement of this IGRT modality has finally supported the wide applicability of CBCT in this field [
      • Nishioka K.
      • Shimizu S.
      • Kinoshita R.
      • Inoue T.
      • Onodera S.
      • Yasuda K.
      • et al.
      Evaluation of inter-observer variability of bladder boundary delineation on cone-beam CT.
      ].
      Ultrasound imaging is a non-irradiating imaging modality to assess and to monitor the bladder volume with strong correlations with CT findings [
      • Stam M.R.
      • van Lin E.N.J.T.
      • van der Vight L.P.
      • Kaanders J.H.A.M.
      • Visser A.G.
      Bladder filling variation during radiation treatment of prostate cancer: Can the use of a bladder ultrasound scanner and biofeedback optimize bladder filling?.
      ], but with no control of bowel and rectum positions, and above all, no possibility to realign the isocenter. For these reasons, this modality is not routinely implemented for bladder radiotherapy. MR-guided radiotherapy is a promising IGRT strategy with high contract soft-tissue imaging, with availability to perform sagittal cine-MR [
      • Pollard J.M.
      • Wen Z.
      • Sadagopan R.
      • Wang J.
      • Ibbott G.S.
      The future of image-guided radiotherapy will be MR guided.
      ].

      Adaptive radiotherapy

      Adaptive radiotherapy (ART) consists in the modification of dose distribution through a library of plans or re-planning once or several times over the course of the treatment. The objectives of ART are a better target volume coverage as well as better healthy tissue-sparing.
      Several ART strategies for bladder radiotherapy can be distinguished. The modalities and benefits of the different strategies are summarized in Table 3. They have been described mainly within exclusive bladder radiotherapy (without PLN irradiation) studies.

      Offline composite replanning strategy

      This strategy uses the CBCT imaging acquired during the first week of treatment to create a new composite CTV/PTV representative of the target motions and deformations, and which will be used during the remaining fractions after re-planning [
      • Foroudi F.
      • Wong J.
      • Haworth A.
      • Baille A.
      • McAlpine J.
      • Rolfo A.
      • et al.
      Offline adaptive radiotherapy for bladder cancer using cone beam computed tomography.
      ,
      • Pos F.J.
      • Hulshof M.
      • Lebesque J.
      • Lotz H.
      • van Tienhoven G.
      • Moonen L.
      • et al.
      Adaptive radiotherapy for invasive bladder cancer: A feasibility study.
      ,

      Webster GJ, Stratford J, Rodgers J, Livsey JE, Macintosh D, Choudhury A. Comparison of adaptive radiotherapy techniques for the treatment of bladder cancer. Br J Radiol 2013;86:20120433–20120433. 10.1259/bjr.20120433.

      ]. This method takes into account mainly systematic deformations while random daily bladder changes are not well compensated.

      Plan of the day strategies

      Plan of the day (PoD) strategies are based upon the elaboration of several plans with the online selection of the optimal plan at each fraction, depending on the daily CBCT.

      Non individualized plan of the day

      Non individualized PoD strategies rely on the application of increasing population-based isotropic or anisotropic margins (generally in 5-mm increments) around the CTV from the planning CT to create several PTVs, leading to several treatment plans [
      • Murthy V.
      • Masodkar R.
      • Kalyani N.
      • Mahantshetty U.
      • Bakshi G.
      • Prakash G.
      • et al.
      Clinical outcomes with dose-escalated adaptive radiation therapy for urinary bladder cancer: A prospective study.
      ,
      • Murthy V.
      • Gupta P.
      • Baruah K.
      • Krishnatry R.
      • Joshi A.
      • Prabhash K.
      • et al.
      Adaptive radiotherapy for carcinoma of the urinary bladder: long-term outcomes with dose escalation.
      ,
      • Murthy V.
      • Master Z.
      • Adurkar P.
      • Mallick I.
      • Mahantshetty U.
      • Bakshi G.
      • et al.
      ‘Plan of the day’ adaptive radiotherapy for bladder cancer using helical tomotherapy.
      ,

      Webster GJ, Stratford J, Rodgers J, Livsey JE, Macintosh D, Choudhury A. Comparison of adaptive radiotherapy techniques for the treatment of bladder cancer. Br J Radiol 2013;86:20120433–20120433. 10.1259/bjr.20120433.

      ,
      • Burridge N.
      • Amer A.
      • Marchant T.
      • Sykes J.
      • Stratford J.
      • Henry A.
      • et al.
      Online adaptive radiotherapy of the bladder: Small bowel irradiated-volume reduction.
      ,
      • Vestergaard A.
      • Søndergaard J.
      • Petersen J.B.
      • Høyer M.
      • Muren L.P.
      A comparison of three different adaptive strategies in image-guided radiotherapy of bladder cancer.
      ,
      • Canlas R.
      • McVicar N.
      • Nakano S.
      • Sahota H.
      • Mahajan P.
      • Tyldesley S.
      Assessment of adaptive margins using a single planning computed tomography scan for bladder radiotherapy.
      ,
      • Kong V.C.
      • Taylor A.
      • Chung P.
      • Craig T.
      • Rosewall T.
      Comparison of 3 image-guided adaptive strategies for bladder locoregional radiotherapy.
      ].

      Individualized plan of the day

      Two main methods have been described to create individualized PoD libraries. The first method requires a single post void planning CT and repeat daily CBCTs (usually from the first five fractions), to generate a patient-specific library of small, medium and large PTVs [
      • Tolan S.
      • Kong V.
      • Rosewall T.
      • Craig T.
      • Bristow R.
      • Milosevic M.
      • et al.
      Patient-specific PTV margins in radiotherapy for bladder cancer – A feasibility study using cone beam CT.
      ,
      • Vestergaard A.
      • Søndergaard J.
      • Petersen J.B.
      • Høyer M.
      • Muren L.P.
      A comparison of three different adaptive strategies in image-guided radiotherapy of bladder cancer.
      ,
      • Grønborg C.
      • Vestergaard A.
      • Høyer M.
      • Söhn M.
      • Pedersen E.M.
      • Petersen J.B.
      • et al.
      Intra-fractional bladder motion and margins in adaptive radiotherapy for urinary bladder cancer.
      ,
      • Kuyumcian A.
      • Pham D.
      • Thomas J.M.
      • Law A.
      • Willis D.
      • Kron T.
      • et al.
      Adaptive radiotherapy for muscle-invasive bladder cancer: Optimisation of plan sizes.
      ,
      • Foroudi F.
      • Wong J.
      • Kron T.
      • Rolfo A.
      • Haworth A.
      • Roxby P.
      • et al.
      Online adaptive radiotherapy for muscle-invasive bladder cancer: results of a pilot study.
      ,
      • Vestergaard A.
      • Muren L.P.
      • Søndergaard J.
      • Elstrøm U.V.
      • Høyer M.
      • Petersen J.B.
      Adaptive plan selection vs. re-optimisation in radiotherapy for bladder cancer: A dose accumulation comparison.
      ,
      • Kron T.
      • Wong J.
      • Rolfo A.
      • Pham D.
      • Cramb J.
      • Foroudi F.
      Adaptive radiotherapy for bladder cancer reduces integral dose despite daily volumetric imaging.
      ,
      • Vestergaard A.
      • Muren L.P.
      • Lindberg H.
      • Jakobsen K.L.
      • Petersen J.B.B.
      • Elstrøm U.V.
      • et al.
      Normal tissue sparing in a phase II trial on daily adaptive plan selection in radiotherapy for urinary bladder cancer.
      ,
      • Vestergaard A.
      • Kallehauge J.F.
      • Petersen J.B.B.
      • Høyer M.
      • Søndergaard J.
      • Muren L.P.
      An adaptive radiotherapy planning strategy for bladder cancer using deformation vector fields.
      ,
      • Tuomikoski L.
      • Valli A.
      • Tenhunen M.
      • Muren L.
      • Vestergaard A.
      A comparison between two clinically applied plan library strategies in adaptive radiotherapy of bladder cancer.
      ,
      • Foroudi F.
      • Pham D.
      • Rolfo A.
      • Bressel M.
      • Tang C.I.
      • Tan A.
      • et al.
      The outcome of a multi-centre feasibility study of online adaptive radiotherapy for muscle-invasive bladder cancer TROG 10.01 BOLART.
      ,
      • Wright P.
      • Muren L.P.
      • Høyer M.
      • Malinen E.
      Evaluation of adaptive radiotherapy of bladder cancer by image-based tumour control probability modelling.
      ]. For example, Foroudi et al. determined the small CTV as the smallest of the six CTVs, the large CTV as the Boolean summation of all CTVs, and the medium CTV as the mean between the small and the large one, with finally a 5–7 mm uniform margin to create the corresponding PTVs [
      • Foroudi F.
      • Wong J.
      • Kron T.
      • Rolfo A.
      • Haworth A.
      • Roxby P.
      • et al.
      Online adaptive radiotherapy for muscle-invasive bladder cancer: results of a pilot study.
      ,
      • Foroudi F.
      • Pham D.
      • Rolfo A.
      • Bressel M.
      • Tang C.I.
      • Tan A.
      • et al.
      The outcome of a multi-centre feasibility study of online adaptive radiotherapy for muscle-invasive bladder cancer TROG 10.01 BOLART.
      ].
      The second method uses repeat planning CT (2 to 6) with different bladder filling conditions, from empty to full, to generate corresponding PTVs [
      • Lalondrelle S.
      • Huddart R.
      • Warren-Oseni K.
      • Hansen V.N.
      • McNair H.
      • Thomas K.
      • et al.
      Adaptive-predictive organ localization using cone-beam computed tomography for improved accuracy in external beam radiotherapy for bladder cancer.
      ,
      • Hafeez S.
      • Warren-Oseni K.
      • McNair H.A.
      • Hansen V.N.
      • Jones K.
      • Tan M.
      • 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.
      ,
      • Tuomikoski L.
      • Valli A.
      • Tenhunen M.
      • Muren L.
      • Vestergaard A.
      A comparison between two clinically applied plan library strategies in adaptive radiotherapy of bladder cancer.
      ,
      • Tuomikoski L.
      • Collan J.
      • Keyriläinen J.
      • Visapää H.
      • Saarilahti K.
      • Tenhunen M.
      Adaptive radiotherapy in muscle invasive urinary bladder cancer – An effective method to reduce the irradiated bowel volume.
      ,
      • McDonald F.
      • Lalondrelle S.
      • Taylor H.
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