Frédéric Amestoy

Guilhem Roubaud

Mikaël Antoine

Valérie Fonteyne

Brian C Baumann

John Christodouleas

Morgan Roupret

David Azria

Thomas Zilli

Christophe Hennequin

Evanguelos Xylinas

Paul Sargos
email: p.sargos@bordeaux.unicancer.fr

Review of hypo-fractionated radiotherapy for localized muscle invasive bladder cancer

Keywords: bladder neoplasm, radiotherapy, hypofractionated, chemo-radiation

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Every year, 2.7 million patients are diagnosed or treated for a bladder cancer in the world [START_REF] Siegel | Cancer statistics[END_REF].

The incidence of bladder cancer increases with age and smoking [START_REF] Antoni | Bladder cancer incidence and mortality: a global overview and recent trends[END_REF]. Mortality rates vary across countries due to differences in risk factors, diagnostic practices and availability of treatments, but also because of variations in study methodology and quality of data collection [START_REF] Burger | Epidemiology and risk factors of urothelial bladder cancer[END_REF].

The gold standard treatment for non-metastatic muscle invasive bladder cancer is radical cystectomy with pelvic lymph node dissection. However, this approach comes with a certain degree of surgical morbidity (ranges from 30% to 60%), comprises mostly post-operative complications [START_REF] Huddart | Clinical and patient-reported outcomes of SPARE -a randomised feasibility study of selective bladder preservation versus radical cystectomy[END_REF], and peri-operative mortality rate of about 1 to 7%.

Trimodal therapy (TMT) consists of a maximal transurethral resection of the bladder, followed by a concurrent radiotherapy and chemotherapy. This bladder-sparing strategy have been considered as an acceptable alternative to radical cystectomy and, despite the promising findings of a bladder cancer definitive chemo-radiotherapy phase 3 study in terms of survival outcomes [START_REF] Poortmans | 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[END_REF], no prospective trial has been completed comparing radical cystectomy vs. organ-conserving strategies; the onco-urological community lacks of level I evidence to answer that important question. In this direction, SPARE was a multicentre randomised controlled trial comparing radical cysctectomy and selective bladder preservation in patients with muscle invasive bladder cancer staged T2-3 N0 M0, fit for both treatment strategies and receiving three cycles of neoadjuvant chemotherapy. The failure of the SPARE study to accrue patients, due to the inherent difficulties to make this kind of randomization acceptable to the patients, illustrated the challenges of achieving such a comparison [START_REF] Huddart | Clinical and patient-reported outcomes of SPARE -a randomised feasibility study of selective bladder preservation versus radical cystectomy[END_REF].

For selected patients, TMT involves external beam radiotherapy, either bi-fractionated (two times daily) [START_REF] Poortmans | 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[END_REF][START_REF] Horwich | A randomised trial of accelerated radiotherapy for localised invasive bladder cancer[END_REF] or normo-fractionated [START_REF] James | Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer[END_REF][START_REF] Krause | 15-year survival rates after transurethral resection and radiochemotherapy or radiation in bladder cancer treatment[END_REF], spread over 5 to 7 weeks. Analyzing the radiobiological rationale in the context of bladder irradiation, Maciejewski et al. [START_REF] Maciejewski | Dose fractionation and tumour repopulation in radiotherapy for bladder cancer[END_REF] suggested that an average tumour clonogen repopulation in transitional cell cancer of the bladder accelerates after a lag period of about 5-6 weeks after the start of treatment; in this direction, a dose increment of 0.36 Gy per day is required to compensate for this repopulation. It suggests that overall treatment time is an important factor in the dose fractionation and protraction of time may have a significant impact on treatment outcome. This radiobiological rationale constitutes the basis for stimulating a wider interest in an accelerated hypo-fractionated radiotherapy approach using larger dose per fraction than the conventional 1.8-2 Gy. On the other hand, estimates of α/β for bladder tumours generally indicated low fractionation sensitivity (mostly, α/β = 10 Gy), but only limited data are available, highlighting discrepancies in radiobiological analyses of bladder cancer irradiation [START_REF] Van Leeuwen | The alfa and beta of tumours: a review of parameters of the linear-quadratic model, derived from clinical radiotherapy studies[END_REF]. In addition, shorter overall treatment duration would be more convenient for the patient quality of life, which could be even more important for the typical bladder cancer population which can be frail and/or elderly. Moreover, from a cost-effectiveness perspective, a shorter regimen has the potential to decrease the cost per episode of care, relative to conventional treatments.

Could these arguments, together with the observed advances for prostate, breast or head and neck cancers [START_REF] Ko | Radiobiological rationale and clinical implications of hypofractionated radiation therapy[END_REF] in the past years, be applied to the radiotherapy of localized bladder cancer?

For bladder cancers, the hypo-fractionated radiotherapy schema has been proposed in historical clinical trials of radio-chemotherapy [START_REF] Cowan | Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose-escalated partial bladder radiotherapy[END_REF], and more recently the interest towards this approach is growing [START_REF] Huddart | 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)[END_REF][START_REF] Hafeez | Clinical outcomes of image guided adaptive hypofractionated weekly radiation therapy for bladder cancer in patients unsuitable for radical treatment[END_REF]. We aimed to perform a systematic review of the literature in order to report the current results of curative hypo-fractionated radiotherapy in non-metastatic bladder cancer in terms of oncological outcomes such as local control, overall survival (OS), Pogression-Free Survival (PFS) on one hand and on the other hand in terms of patients' tolerance.

Materials and methods

We performed a systematic review in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. We searched the Medline database for articles related to bladder neoplasm and radiotherapy published between 1990 and December 2017. Articles identified by searching references from candidate articles were also included in our analysis.

The following terms were used in the extensive search: bladder neoplasm and radiotherapy. We included published full articles concerning humans and written in English. We included articles concerning phase III or phase II studies, in a population of patients mostly presenting muscle-invasive bladder cancers (≥T2 disease), with predominant urothelial carcinoma histology, without metastases, treated by hypo-fractionated radiotherapy with a curative intent. We considered studies involving moderate hypofractionation (doses of 2.5-4 Gy per fraction) and extreme hypofractionation (5-7 Gy in 4-7 fractions), excluding stereotactic body radiation therapy. In order to ensure robust results, we excluded conference abstracts/communications, letter to editors, case reports, reviews (accepted if they integrate a meta-analysis), guidelines and article comments. In case of overlapping studies from the same team or similar centers, with the same objective, the more recent publication was selected.

Medical

Articles were excluded if they could not be accessed/retrieved, were published in a language other than English, focused on a non-urothelial histology, included mainly patients presenting with a noninvasive bladder cancer or a tumor of the higher urinary tract, reported on trials without a well-defined toxicity or oncological objective, or used approaches involving heavy ions, neo-adjuvant, adjuvant or palliative radiation treatments.

We retrieved 159 publications from PubMed. Two authors (PS and FA) independently reviewed the titles and abstracts of the 159 articles and excluded 93 based on the above-mentioned exclusion criteria. In case of uncertainty in the abstract or title, the full text was read and discussed by all co-authors to decide whether to include the article or not.

A second comprehensive analysis was carried out by reading the full text of all papers assessed for eligibility; a final consensus on 18 studies was obtained. The PRISMA flowchart is presented in figure 1.

Results

Clinical and pathological characteristics of the population in studies using hypofractionation for the treatment of localized bladder cancer

In total, five phase III trials (tables 1 and 2) and 13 phase II trials (tables 3 and 4), including 2016 treated patients with transitional cell carcinoma were retained. Median age of patients cohorts ranged from 65 years to 86 years with a favorable (0-1) ECOG PS in the phase 3 trials. Tumoral stage ranged from T1 grade3 to T4a, with no lymph node involvement on initial imaging.

Neo-adjuvant platinum-based chemotherapy was used for all patients in the SPARE trial [START_REF] Huddart | Clinical and patient-reported outcomes of SPARE -a randomised feasibility study of selective bladder preservation versus radical cystectomy[END_REF],

for 22% and 24% in the two arms of Huddart et al. study [START_REF] Huddart | 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)[END_REF] and in 32.8% of the patients in the study from James et al. [START_REF] James | Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer[END_REF]. In the study reported by Thompson et al., patients were treated with gemcitabine alone [START_REF] Thompson | Tolerability of concurrent chemoradiation therapy with gemcitabine (GemX), with and without prior neoadjuvant chemotherapy, in muscle invasive bladder cancer[END_REF].

Results for hypo-fractionated irradiation alone or in combination with systemic agents for localized bladder cancer

Exclusive radiotherapy or in combination with radio-protective agents or radiosensitizers -Exclusive radiotherapy

In three phase II [START_REF] Hafeez | Clinical outcomes of image guided adaptive hypofractionated weekly radiation therapy for bladder cancer in patients unsuitable for radical treatment[END_REF][START_REF] Scholten | Hypofractionated radiotherapy for invasive bladder cancer[END_REF][START_REF] Jose | Hypofractionated radiotherapy for patients with carcinoma the bladder[END_REF] and one phase III trials [START_REF] Cowan | Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose-escalated partial bladder radiotherapy[END_REF], patients were treated with radiotherapy alone without systemic therapy. The total dose varied from 30 to 57.5 Gy, with daily (ranging from 2.63 to 3.44 Gy), weekly (6 Gy/week) or bi-weekly (12 Gy/week) fractions.

Significant acute genito-urinary (GU) and gastro-intestinal (GI) toxicities (WHO Toxicity >2

or CTCAE v.3.0 >2 or equivalent according to other scales) ranged from 10% to 58% and from 4% to 62%, respectively. In terms of moderate-to-severe long-term toxicities (RTOG >2, WHO Toxicity>2), authors observed toxicity rates between 11% and 13%. There was no homogeneity in the scales used to evaluate tolerance. Local control rates at 2 years varied between 45% and 83% excepted in the study from Jose et al. [START_REF] Jose | Hypofractionated radiotherapy for patients with carcinoma the bladder[END_REF], whose local control was around 20%; in this study, patients were more advanced in median age (81 years [71-95]) and considered clinically unfit to receive a normo-fractionated treatment. In these studies of radiotherapy alone, OS rates varied between 45% and 58%.

-Radiotherapy in combination with radio-protective agents or radiosensitizers ARCON and radiotherapy

Hyperbaric oxygen and misonidazole act as radiosensitizers able to reduce intra-tumoral hypoxic phenomena.

Nicotinamide reduces hypo-vascularization allowing to maintain local perfusion [START_REF] Overgaard | Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors[END_REF]. Based on this rationale, this approach was studied in aero-digestive cancers [START_REF] Kaanders | ARCON: experience in 215 patients with advanced head-and-neck cancer[END_REF]. In parallel, Hoskin et al. recommended the use of ARCON (nicotinamide and carbogen) in combination with radiotherapy in phase II [START_REF] Hoskin | Accelerated radiotherapy, carbogen, and nicotinamide (ARCON) in the treatment of advanced bladder cancer: mature results of a Phase II nonrandomized study[END_REF][START_REF] Hoskin | Carbogen and nicotinamide in the treatment of bladder cancer with radical radiotherapy[END_REF][START_REF] Hoskin | Hypoxic radiosensitizers in radical radiotherapy for patients with bladder carcinoma: hyperbaric oxygen, misonidazole, and accelerated radiotherapy, carbogen, and nicotinamide[END_REF], and then phase III [START_REF] Hoskin | Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma[END_REF][START_REF] Hoskin | Carbogen and nicotinamide in locally advanced bladder cancer: early results of a phase-III randomized trial[END_REF] trials. Radiotherapy was delivered daily using a moderate hypo-fractionation schedule of 50-52.5 Gy in 20 fractions over 4 weeks [START_REF] Hoskin | Carbogen and nicotinamide in locally advanced bladder cancer: early results of a phase-III randomized trial[END_REF]. At 3 years, severe GU and GI toxicities ranged, respectively, from 32% to 39% and from 5% to 7% according to the SOMA/LENT scale. These studies showed a satisfactory local control confirmed by cystoscopy at 6 months with a trend in favor of the ARCON arm. PFS at 3 years was 54% versus 43% (p=0.06) and 5-year OS rate 50% versus 39% (p=0.04) in favor of radiotherapy associated to ARCON.

Amifostine and radiotherapy

Panteliadou et al. [START_REF] Panteliadou | Treatment of invasive bladder cancer with conformal hypofractionated accelerated radiotherapy and amifostine (HypoARC)[END_REF] used amifostine combined to radiotherapy with the aim of optimizing the tolerance of organs at risk (digestive and genito-urinary structures). Amifostine, ethanethiol 2-[(3-aminopropyl) amino]-dihydrogen phosphate (ester), is an organic thiophosphate that, in animal models, selectively protects healthy tissues but not tumors from ionizing radiations, chemotherapy agents (classical alkylating agents such as cyclophosphamide and non-classical agents such as mitomycin C) and platinum analogues that target deoxyribonucleic acid (DNA). In a cohort of 82 patients treated for bladder cancer with radiotherapy, the dose of amifostine was increased and adapted to digestive toxicity.

Fifty percent of patients received concomitant anthracycline-based chemotherapy every two weeks. Conformational radiotherapy was delivered with a technique known as "field in the field" to achieve a total dose of 51 Gy (15 x 3.4 Gy) on the bladder and 37.8 Gy on the pelvis (14 x 2.7 Gy), over 19 days. Long-term GU toxicity incidence rate was less than 2.5% with mainly incontinence, dysuria (increased urinary frequency), and a hematuria. With a median follow-up of 21 months [range, 2-63 months], complete response, 3-year local control and specific survival were 86.6%, 56% and 63%, respectively [START_REF] Hussain | Long-term results of a phase II study of synchronous chemoradiotherapy in advanced muscle invasive bladder cancer[END_REF].

Radio-chemotherapy -Mitomycin with concomitant radiotherapy

In a phase II study (n=41 patients), Hussain et al. [START_REF] Hussain | Long-term results of a phase II study of synchronous chemoradiotherapy in advanced muscle invasive bladder cancer[END_REF] evaluated TMT using Mitomycin based regimen. PFS rate at 2-years was about 76% with an OS rate at 5 years of 36% .

James et al's phase III study [START_REF] Huddart | Clinical and patient-reported outcomes of SPARE -a randomised feasibility study of selective bladder preservation versus radical cystectomy[END_REF] in which patients were randomized to receive either exclusive radiotherapy or combined radiotherapy with mitomycin C and fluorouracil, showed an improvement in the 2-year PFS rate in favor of the combination arm (67% [range, 59-74] vs 54% [range, 46-62]; p=0.03). This advantage was not reflected in OS, which increased from 35% [START_REF] Orsatti | Alternating chemo-radiotherapy in bladder cancer: a conservative approach[END_REF][START_REF] Choudhury | Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer[END_REF][START_REF] Efstathiou | Long-Term Outcomes of Selective Bladder Preservation by Combined-Modality Therapy for Invasive Bladder Cancer: The MGH Experience[END_REF][START_REF] Giacalone | 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[END_REF][START_REF] Kachnic | Bladder preservation by combined modality therapy for invasive bladder cancer[END_REF][START_REF] Kijima | Selective tetramodal bladder-preservation therapy, incorporating induction chemoradiotherapy and consolidative partial cystectomy with pelvic lymph node dissection for muscleinvasive bladder cancer: oncological and functional outcomes of 107 patients[END_REF][START_REF] Huddart | Toxicity and survival outcomes of a randomized phase 2 trial of hypofractionated bladder radiation therapy in an elderly population with or without image guided adaptive plan selection (HYBRID -CRUK/12/055)[END_REF][START_REF] Kouloulias | Evaluation of efficacy and toxicity in two different hypofractionated 3D-conformal external beam radiotherapy schedules in localised muscle invasive bladder cancer[END_REF][START_REF] Tunio | Whole-pelvis or bladder-only chemoradiation for lymph node-negative invasive bladder cancer: single-institution experience[END_REF][START_REF] Caffo | Concurrent gemcitabine and radiotherapy for the treatment of muscle-invasive bladder cancer: a pooled individual data analysis of eight phase I-II trials[END_REF][START_REF] Del | Recent advances in genitourinary tumors: A review focused on biology and systemic treatment[END_REF][39][40][41][42][43] to 48% [40-55] but did not reach significance (p=0.16). Concomitant chemotherapy scheme was mitomycin C, administered on the first day of irradiation, combined with fluorouracil from D1 to D5 and from D16 to D20.

Radiotherapy was delivered with two different schedules: 64 Gy in 32 fractions or 55 Gy in 20 fractions, with no significant difference in terms of loco-regional disease-free survival between arms (p=0.59). According to consensual and validated scales (NCI CTCAE, RTOG, LENT/SOMA), there was no difference in terms of long-term toxicity depending on the irradiation protocol. Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy alone group during the treatment (36.0% vs. 27.5%, p = 0.07) but not during follow-up (8.3% vs. 15.7%, p = 0.07).

-Gemcitabine with concomitant radiotherapy

Choudhury et al. in a phase II study [START_REF] Choudhury | Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer[END_REF], combined hypo-fractionated radiotherapy at a dose of 52.5 Gy in 20 fractions and a weekly gemcitabine-based chemotherapy regimen (100 mg/m 2 / infusion). This was one of the only trials that evaluated, in the long term, erectile function among the quality of life (QoL) criteria. When annual late toxicity scores were compared with baseline pretreatment scores, there were no significant differences from baseline measures at 2 years for sexual, bladder, or bowel function with results judged satisfactory by the authors. PFS rate at 3 years was 82% with an OS rate at 5 years of 65%.

Thompson et al. [START_REF] Thompson | Tolerability of concurrent chemoradiation therapy with gemcitabine (GemX), with and without prior neoadjuvant chemotherapy, in muscle invasive bladder cancer[END_REF] evaluated acute and long-term grade >2 or more GI and GU toxicity prospectively and compared two treatment arms: one arm combining a gemcitabine injection according to the same modalities as in the trial by Choudhury et al with radiotherapy delivering 52.5 Gy in 20 fractions over 28 days (GemX), and the second arm using neoadjuvant platinum doublet chemotherapy (NeoGemX). According to the RTOG scale, acute GU toxicity rates were similar in both arms (up to 8%) and acute GI toxicities ranged from 18% to 20%. In terms of long-term GI and GU toxicity, there was no significant difference between the two treatment arms according to the LENT/SOMA score (p=0.48 and p=0.19, respectively).

Trials using platinum salts, methotrexate and sequential radiotherapy

Orsatti et al. [START_REF] Orsatti | Alternating chemo-radiotherapy in bladder cancer: a conservative approach[END_REF] proposed in 1997 an original treatment schema that involved two radiotherapy sequences within a break of one week. A total dose of 40 or 50 Gy with fractions of 2 or 2.5 Gy was delivered. A platinum-based chemotherapy or methotrexate associated to fluoro-uracil was used. Moderate to severe acute GU and GI toxicity rates according to the WHO Toxicity scale were 18% and 17% respectively, and 6-year OS rate 42%.

Irradiation and hypo-fractionation techniques reported in the literature -Techniques

None of the trials included in our analysis proposed intensity modulated conformational radiotherapy (IMRT). The irradiation was delivered according to a three-dimensional conformal technique and a treatment on linear accelerator with multi-leaf collimator. The oldest trials [START_REF] Scholten | Hypofractionated radiotherapy for invasive bladder cancer[END_REF] used a bi-dimensional technique with large doses per fraction and spread over a short period of time (6 Gy twice per week over 18 days).

-Dose, fractionation and radio-biological substrate

In the hypo-fractionated studies, the doses per fraction were mainly comprised between 2.25 and 2.5 Gy, with a maximum of 6 Gy per fraction delivered weekly [START_REF] Jose | Hypofractionated radiotherapy for patients with carcinoma the bladder[END_REF] or every two weeks [START_REF] Scholten | Hypofractionated radiotherapy for invasive bladder cancer[END_REF]. Hafeez et al. [START_REF] Hafeez | Clinical outcomes of image guided adaptive hypofractionated weekly radiation therapy for bladder cancer in patients unsuitable for radical treatment[END_REF] proposed a weekly session of 6 Gy. According to the CTCAE v.3.0 scale, acute GU and GI grade 3 toxicity rates were 18% (10/55) and 4% (2/55) respectively, with no grade 4 events observed. At 1 year, 4.3% (1/23) of patients presented a GU or GI toxicity of grade >3.

The most common schema employed doses of 50 to 55 Gy in 20 fractions ranging from 2.25Gy/fraction to 2.75 Gy/fraction over 4 weeks [START_REF] James | Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer[END_REF][START_REF] Cowan | Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose-escalated partial bladder radiotherapy[END_REF][START_REF] Huddart | 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)[END_REF][START_REF] Hoskin | Accelerated radiotherapy, carbogen, and nicotinamide (ARCON) in the treatment of advanced bladder cancer: mature results of a Phase II nonrandomized study[END_REF][START_REF] Hussain | Long-term results of a phase II study of synchronous chemoradiotherapy in advanced muscle invasive bladder cancer[END_REF][START_REF] Choudhury | Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer[END_REF].

From a radio-biological point of Panteliadou et al. [START_REF] Panteliadou | Treatment of invasive bladder cancer with conformal hypofractionated accelerated radiotherapy and amifostine (HypoARC)[END_REF] used the formula proposed by Maciejewski et al. [START_REF] Maciejewski | Dose fractionation and tumour repopulation in radiotherapy for bladder cancer[END_REF] to calculate the total normalized total dose (NTD) in fractions of 2 Gy (NTD= D [(α/β + d)/(α/β +2)]), where 'D' was the total physical dose, 'd' the dose per fraction and α/β the specific tissue ratio. The corrected NTD, which takes into account the total treatment time, was calculated according to the following formula: NTD(T)= D [(α/β +d) /(α/β +2)] + λ(Tc-T0), where Tc is the number of days to deliver NTD following a conventional fractionation and 'λ' the daily dose estimated to compensate for a rapid tumoral repopulation.

The biological dose equivalent to 2 Gy (EQD2Gy) delivered in all studies ranged from 40 to 64 Gy and from 54 to 70.81 Gy depending on α/β ratio of 10 Gy or 3 Gy for early and lateterm toxicities, respectively.

-Radiotherapy target volumes

Clinical Target Volume (CTV) was essentially limited to empty bladder to which a systematic Planning Target Volume (PTV) margin, more or less adapted to the stage and/or to the degree of differentiation was added [1.5 -3 cm]. No study used IMRT [START_REF] Scholten | Hypofractionated radiotherapy for invasive bladder cancer[END_REF].

The partial irradiation for the bladder, limited to the macroscopic tumor volume, did not yield favorable results in terms of GU and GI toxicity in Huddart et al's non-inferiority trial [START_REF] Huddart | 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)[END_REF]. Cowan et al. in 2004 [12], in a phase III trial, compared equally different irradiation volumes (only intra vesical macroscopic tumor or whole bladder) and showed the absence of differences in GU and GI toxicities. There was also no difference in OS (p=0.81). However, they observed 7% (6/89) of local intra-bladder recurrence and/or at field margins in cases of partial irradiation, without a significant difference in the rate of complete response among the three treatment arms (p=0.6).

In case of using the hypo-fractionated approach, the concomitant prophylactic pelvic irradiation was proposed, either with a standard fractionation of 2 Gy per fraction [START_REF] Pos | Concomitant boost radiotherapy for muscle invasive bladder cancer[END_REF], or with a higher dose as in Panteliadou et al.'s trial in 2012 [START_REF] Panteliadou | Treatment of invasive bladder cancer with conformal hypofractionated accelerated radiotherapy and amifostine (HypoARC)[END_REF] which proposed 2.7 Gy per fraction.

GI and GU toxicities, acute and long-term ones, of grade ≥3 according to the RTOG scale were of 14% and 13% respectively for 2 Gy per fractions [START_REF] Pos | Concomitant boost radiotherapy for muscle invasive bladder cancer[END_REF].

-Adaptive radiotherapy

Only the trial from Hafeez et al. in 2017 [START_REF] Hafeez | Clinical outcomes of image guided adaptive hypofractionated weekly radiation therapy for bladder cancer in patients unsuitable for radical treatment[END_REF] proposed a "plan of the day" (POD) adapted to bladder filling. The irradiation was delivered according to a tridimensional mode. The selected population for the study included patients not suitable for surgery. Acute GU and GI toxicity of grade 3 was of 18% and 4%, respectively, without any grade 4 toxicity according to the CTCAE v3.0 scale. Overall long-term toxicity at 6 months and 12 months decreased to 6.5% and 4.3%, respectively.

Discussion

Conducting this systematic review, we found that the conservative approach using hypofractionated radiotherapy allows a 2-year recurrence free survival rate between 43% and 83%, a 5-year OS rate ranging from 36% to 58%.

TMT constitutes an acceptable alternative to radical surgery in terms of survival outcomes as well as tolerance for selected patients [START_REF] Horwich | A randomised trial of accelerated radiotherapy for localised invasive bladder cancer[END_REF][START_REF] James | Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer[END_REF][START_REF] Krause | 15-year survival rates after transurethral resection and radiochemotherapy or radiation in bladder cancer treatment[END_REF][START_REF] Maciejewski | Dose fractionation and tumour repopulation in radiotherapy for bladder cancer[END_REF]. In these radiotherapy studies, the population was often older than in the cystectomy series and not suitable for surgery due to comorbidities.

One of the remaining questions is that, in this conservative treatment studies, the benefit on survival of neo-adjuvant chemotherapy was not clearly established, contrary to what has been demonstrated with the radical surgery treatment [START_REF] Krause | 15-year survival rates after transurethral resection and radiochemotherapy or radiation in bladder cancer treatment[END_REF][START_REF] Efstathiou | Long-Term Outcomes of Selective Bladder Preservation by Combined-Modality Therapy for Invasive Bladder Cancer: The MGH Experience[END_REF]. Nevertheless, with a median follow up of 7.21 years, the team from Boston reported, with TMT using non-hypofractionated radiotherapy, promising updated results, revealing 5-and 10-year overall survival rates of 57% and 39%, respectively [START_REF] Giacalone | 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[END_REF]. Patients who did not respond to the conservative treatment live shorter than responders (48 vs 14 months, p=0.036) and die mostly due to cancer (HR 3.865; 95% CI, 1.562-9.562) [START_REF] Kachnic | Bladder preservation by combined modality therapy for invasive bladder cancer[END_REF]. this direction, a promising approach could be interesting to maintain bladder function in an efficient conservation way. Selective tetramodal bladdersparing therapy, comprising maximal transurethral resection of bladder tumour, induction chemoradiotherapy and consolidative partial cystectomy with pelvic lymph node dissection has been evaluated prospectively in 154 patients. With a median follow-up of 48 months, the 5-year muscle invasive relapse free survival was 97% in the 107 patients who completed the protocol with excellent bladder function [START_REF] Kijima | Selective tetramodal bladder-preservation therapy, incorporating induction chemoradiotherapy and consolidative partial cystectomy with pelvic lymph node dissection for muscleinvasive bladder cancer: oncological and functional outcomes of 107 patients[END_REF].

The hypo-fractionated schedule shows less than 12% of late grade ≥ 3 GI toxicities and between 4 to 46% grade ≥ 3 GU late toxicities. It appears difficult to analyze correctly the relevant degree of toxicity given the diversity of used scales. The long-term evaluation of sexual function remains largely under-evaluated too, except for Choudhury et al's trial [START_REF] Choudhury | Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer[END_REF].

Other than tolerance, for responder patients, the rate of functional bladder in place seems correlated with good quality of life in the long term [START_REF] Kachnic | Bladder preservation by combined modality therapy for invasive bladder cancer[END_REF]; a trial are currently ongoing to address this matter (NCT02688348). Hypo-fractionated irradiation of localized bladder tumors could lead to optimizing patients' QoL. Pleading for this hypo-fractionated irradiation, we can point out that the long-term tolerance seems to be similar to that of normo-fractionated radiotherapy series. Furthermore, it represents a medico-economic advantage [START_REF] Huddart | Toxicity and survival outcomes of a randomized phase 2 trial of hypofractionated bladder radiation therapy in an elderly population with or without image guided adaptive plan selection (HYBRID -CRUK/12/055)[END_REF] compared to two-alternative schemas previously discussed by radio-biologists [START_REF] Kouloulias | Evaluation of efficacy and toxicity in two different hypofractionated 3D-conformal external beam radiotherapy schedules in localised muscle invasive bladder cancer[END_REF]. In this regard, the hypo-fractionated model, spread over 4 to 5 weeks, remains coherent concerning tumoral repopulation. The schema the most commonly reported and supported in the literature is that of 50-55 Gy in 20 fractions over 4 weeks [START_REF] James | Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer[END_REF][START_REF] Huddart | 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)[END_REF][START_REF] Hoskin | Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma[END_REF][START_REF] Hoskin | Carbogen and nicotinamide in locally advanced bladder cancer: early results of a phase-III randomized trial[END_REF][START_REF] Hussain | Long-term results of a phase II study of synchronous chemoradiotherapy in advanced muscle invasive bladder cancer[END_REF].

Very few prospective trials have evaluated the input/contribution of IGRT : the "plan of the day" strategy in Hafeez et al's study [START_REF] Hafeez | Clinical outcomes of image guided adaptive hypofractionated weekly radiation therapy for bladder cancer in patients unsuitable for radical treatment[END_REF] presented the advantage of sparing adjacent digestive structures while covering the target volumes in an optimized manner, by adapting the irradiation volume depending on the bladder repletion after routine/daily imaging control.

None of the studies included in our review used IMRT; with the purpose of decreasing/limiting pelvic toxicity, especially GI, adaptive radiotherapy (NCT01142102, NCT01000129) and the use of modern irradiation techniques are currently being evaluated (NCT00350688). These modern strategies could have an additional asset in terms of tolerance, consolidating the possibility of using the "moderate" hypo-fractionation for patients with muscle invasive bladder cancer [START_REF] Huddart | Toxicity and survival outcomes of a randomized phase 2 trial of hypofractionated bladder radiation therapy in an elderly population with or without image guided adaptive plan selection (HYBRID -CRUK/12/055)[END_REF].

In terms of target volumes definition, partial bladder irradiation limited to the macroscopic tumor volume does not appear to reduce treatment toxicity, without any benefit in terms of local control [START_REF] Huddart | 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)[END_REF]. In addition, in the conservative approach, there is no proof on the benefit of a pelvic lymph-node irradiation [START_REF] Kouloulias | Evaluation of efficacy and toxicity in two different hypofractionated 3D-conformal external beam radiotherapy schedules in localised muscle invasive bladder cancer[END_REF]. While there is no conclusive evidence to support one target volume over another, the current weight of the literature likely support targeting only the whole bladder in most patients with N0 disease.

The use of radio-sensitizers and/or radio-protective agents also presents a clinical interest but no comparison exists between the different agents used in the literature. Moreover, in daily practice, concomitant chemotherapy appears to be easier to handle in routine clinical practice.

Both Choudhury et al. and the pooled analysis of Caffo et al. strengthens the evidence that chemoradiotherapy regimens with concurrent gemcitabine are feasible and well tolerated [START_REF] Choudhury | Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer[END_REF][START_REF] Caffo | Concurrent gemcitabine and radiotherapy for the treatment of muscle-invasive bladder cancer: a pooled individual data analysis of eight phase I-II trials[END_REF]. The recent identification of multiple distinct molecular subtypes of muscle-invasive bladder cancer (MIBC) can be integrated in a patient/tumor personnalised strategy [START_REF] Del | Recent advances in genitourinary tumors: A review focused on biology and systemic treatment[END_REF] and ongoing phase II trials combining hypofractionated radiotherapy and immunotherapy represent also a future perspective (NCT02621151, NCT03419130).

Conclusion

TMT is a valuable alternative to cystectomy in selected patients with localized muscle invasive bladder cancer, particularly suitable for elderly patients for whom bladder cancer incidence is high. The hypo-fractionated schema shows valuable oncologic outcomes and a heterogeneous gastro-intestinal tolerance in published It addresses both a limitation of time constraints, based on a radiobiological rationale and a literature supply. This hypofractionated approach must be evaluated with the use of modern radiotherapy techniques such as adaptive radiotherapy in prospective trials including tolerance and quality of life evaluations.

  Subject Heading (MeSH) phrases included: ("radiotherapy"[Subheading] OR "radiotherapy"[All Fields] OR "radiotherapy"[MeSH Terms]) AND ("urinary bladder neoplasms"[MeSH Terms] OR ("urinary"[All Fields] AND "bladder"[All Fields] AND "neoplasms"[All Fields]) OR "urinary bladder neoplasms"[All Fields]) AND ((Clinical Trial, Phase II[ptyp] OR Clinical Trial, Phase III[ptyp]) AND "humans"[MeSH Terms]).

Table 1 : Summary of phase III evaluating a hypo-fractionated radiotherapy approach: description of patients and treatmentTable 2 : Summary of phase III trials evaluating a hypo-fractionated radiotherapy approach: toxicities and results

 12

	Phase Year	Authors	Name of study	Toxicity scale	Acute GU Toxicity	Acute GI Toxicity	Late GU Toxicity	Late GI Toxicity	Sexual Toxicity	PFS at 2 y.	OS at 5 y.
					RC:70% SBP
	3 2017 Huddart & al.	SPARE	CTCAE v.3	36%.(GU& GI)Tiredness &	NR	NR	NR	NR	RC: 15,3%[5,2-40,5%] SBP: 68,9%[42,5-91,5]	NR
					nycturia
							Cumulative
	3 2013 Huddart & al.	BC2001 WBRT Vs PBRT +/-CT	RTOG/CTC	15,90%	3,60%	toxicity : 13% sexual (RTOG ) Vs 46% (20% without	NR	NR	WBRT: 61% [50-71] PBRT: 64%[52-73]	WBRT: 38% [28-47] PBRT: 44%[34-53]
							dysfunction)
				CTCAE			RTOG:
	3 2012 James & al.	CRT Vs RT	RTOG LENT	CRT: 21,3% RT: 21,4% CTCAE	CRT: 9,6% RT: 2,7% CTCAE	4,6-5,2% LENT/SOMA:	NR	NR	CRT : 67%[59-74] RT: 54%[46-62]	CRT : 48%[40-55] RT: 35%[28-43]
				SOMA			34,4-35,8%
	3 2009 Hoskin & al. RT Vs RTCON	CTC v.2 LENT SOMA	ARCON: 4-15% RT only 7-18%	25% NV & one toxic death	32-39% at 3 y.	5-7% at 3 y.	NR	ARCON + RT: 54% at 3 y. RT only:43% at 3 y.	ARCON+RT :50% RT only:39%
	3 2004 Cowan & al.	WBRT Vs PBRT(4w or 3w)	WHO toxicity	50% [45-55%]	62% [50-65]	4-18%	8-12%	NR	at 2 y.: 68%WB, 63%PB4,51%PB3 at 3 y.: 58%WB, 59%PB4, 34%PB3	58%
	Legend: GU: genito urinary; GI: gastro intestinal,NV: nausea & vomiting; RC: Radical cystectomy; SBP: selective bladder preservation; ARCON: Accelerated radiotherapy carbogen and nicotinamide;
	WBRT: whole bladder radiotherapy; PBRT: partial bladder radiotherapy; NR: not mentionned; CT: chemotherapy; RT: radiotherapy; CRT: chemoradiation; w.:week; y.:year.

Table 3 : Summary of phase II trials evaluating a hypo-fractionated radiotherapy approach: description of treatment and patients

 3

	Phase Year Authors	Name of study	n. Median age	PS	Prior treatment (NAC/TURB)	Stade T Stade N	Histology	Total dose (Gy)	Fraction (n.)	Duration	Modality of RT	Concurrent tretament
	2	2017	Thompson & al.	GemX prior NAC	78	67.5[53-78] 75.5[54-82]	0-2	resection +/-NAC	T2-T4	NR	TCC & others	52.5	20	28 d.	3D	Gem J1,J8,J15,J22
	2	2017 Hafeez & al	Adaptatif hypofrac	55	86 [68-97]	WHO 0-3 Charlson 0-5	NR	T2-T4a	N1-N3 (3) M1 (2)	TCC &others 36 [24-36]	6[4-6]	6 [4-6]w.	IGRT/plan of the day	NA
																Gem
	2	2011	Choudhury & al	CRT gemcitabine	50	67 [49-84]	WHO 0-2	resection	T2-T3	N0M0 TCC & others	52.5	20	4 w.	3D
																J1,8,15,22
	2	2010	Panteliadou & al.	HypoARC	82	75 [55-88]	WHO O-1	resection or intra vesical CT	T1-T4	N0&N1	TCC	51 & 37.8	15	19 d.	SIB 3D	Amifostine Doxorubicine (50%)
	2	2009	Hoskin & al. (OS & PFS)	Accelerated RT ARCON	105 74 [48-85]	NR	NR	T1G2-T4G2	NR	TCC & others	50-55	20	4 w.	3D	ARCON
	2	2005	Hoskin & al. Phase II Tox	Accelerated RT ARCON	105 74 [38-87]	NR	NR	T1G2-T4G2	NR	TCC & others	50-55	20	4 w.	3D	ARCON
	2	2004	Hussain & al.	CRT 5FU-MMC	41 68 [58-77]	0-2	No	T2-T4	N0/Nx M0	TCC	55	20	4 w.	3D	5FU MMC
	2	2003 Pos & al.	SIB	50	79 [72-86]	WHO 0-3	resection	T2-T4	NR	TCC	40/55Gy	20	4 w. / 27 d. [23-30]	SIB 3D
	2	1999 Jose & al. RT hypofrac 65	81 [71-95]	unfit	resection	T2-T4	N0-N3 M1	TCC &SCC	30-36Gy	5-6	5-6 w.	3D
						68[48-83]										carbogene
	2	1999 Hoskin & al. carb +/-nic 61		NR	resection	T1-T3	NR	TCC	50-55 Gy	20	4 w.	3D
						67[46-81]										Nicotinamide
				ARCON
	2	1997 Hoskin & al.	A/Carb B/Nic	30	66/69/69	NR	NR	T1 G3-T3b	NR	NR	50 52.5Gy	20	4 w.	3D	NIC/ CARB/both
				C/both
	2	1996	Scholten & al.	Hypofr 2D 123	65[37-86]	NR	NR	T2-T3	N0	TCC	36	2*6Gy /w.	18 d.	2D	no
	2	1995 Orsatti & al.	Alternating CRT	76	67[44-77]	ECOG 0-1	Resection	T1-T4	N0	NR	40 50	2*10 2*10	5 w. 5 w.	3D	5FU Cispl 5FU MTX

Legend: PS: performans statut; GemX: gemcitabine + radiation; NAC: neo adjuvant chemotherapy; TURB: transurethral resection of the bladder; MMC: mytomicin C; MTX: methotrexate; 5FU: 5 fluoro uracile; ARCON: Accelerated radiotherapy carbogen and nicotinamide; Gemcis: gemcitabine + cisplatin; TCC: transitional cell carcinoma; ADK: adenocarcinoma ; SCC: squamous cell carcinoma; WBRT: whole bladder radiotherapy; PBRT: partial bladder radiotherapy; IGRT: Image-guided radiation therapy NR: not mentionned; CT: chemotherapy; RT: radiotherapy; CRT: chemoradiation; NA: not applicable; RTCON: radiotherapy and carbogen & nicotinamide;CARB: carbogene; NIC: nicotinamide; w.:week; y.:year.

Table 4 : Summary of phase II trials evaluating a hypo-fractionated radiotherapy approach: toxicities and results Phase Year Authors Name of study Toxicity scale Acute GU Toxicity Acute GI toxicity Late GU Toxicity Late GI toxicity Sexual toxicity PFS at 2 years OS at 5 years

 4

	2	2017	Thompson & al.	GemX NAC + GemX	RTOG LENT SOMA	7% 8%	18% 20%	0% 0%	5% 0%	NR	65% [48-87] 81%[68-96]	NR
	2	2017 Hafeez & al Adaptatif hypofrac	CTCAE v3.0 Acute tox. RTOG late tox.	58%	42%	4%	4%	NR	83% [92-71]	63% ( 1y.)
					RTOG acute radiation
	2	2011	Choudhury & al	CRT gemcitabine	scoring criteria LENT-RTOG/EORTC late SOMA	NR	NR	.+0,5 (ns)	0 (ns)	.+1,5 (ns)	80%	61%
					radiation morbidity SS
	2	2010	Panteliadou M. & al	HypoARC	CTC v.2 LENT-SOMA	11% frequency 1% dysuria	1% proctitis 8% diarrhea	1% dysuria ,hematuria, incontinence	0%	NR	63%	Specific survival 63% at 3 y.
	2	2009	Hoskin & al. (OS & PFS)	Accelerated RT ARCON	NR	NR	NR	10-25% at 5 y.	3-5 % at 5y.	NR	44%	38%
	2	2005	Hoskin & al. Phase II Tox	Accelerated RT ARCON	recording mobidity 1989	41% 56%	96% 76%	25% hematuria & 16% dysuria	6%	NR	At 3y. : 43% 53%	*
	2	2004	Hussain & al.	RCT 5FU-MMC	NCI grading system	2%	10%	NR	NR	NR	76%	36%
	2	2003 Pos & al.	SIB	EORTC/RTOG	14% 10%	4%	13% 11%	2%	NR	60%	45%
	2	1999 Jose & al.	RT hypofrac	RTOG grading system	20%	4%	11%	12%	NR	21%	NR
		1999 Hoskin & al.	carb+/-nic	scoring system of Dische & al.	nycturia 5 times 5 bowel mvt	3	1	NR	55% at 2y.	65% at 2y.
				ARCON
	2	1997 Hoskin & al.	A/carb B/Nic	Dische scoring system	Fcy/d.:6•	Fcy /d.:4•	NR	NR	NR	at 6 m.: 70-90%	NR
				C/both
	2	1996	Scholten & al.	Hypofrac 2D	RTOG	0%	0%	NR	NR	NR	40%	Specific survival at 5 y. 48%[39-58]
	2	1995 Orsatti & al. Alternating CRT	WHO toxicity	18%	17%	0%	0%	NR	81%	42% at 6 y.

Legend: NAC: neo adjuvant chemotherapy; GU: genito urinary; GI: gastro intestinal, MMC: mytomicin C; 5FU: 5 fluoro uracile; ARCON: Accelerated radiotherapy carbogen and nicotinamide; NR: not mentionned; CT: chemotherapy; RT: radiotherapy; CRT: chemoradiation; RTCON: radiotherapy and carbogen & nicotinamide; w.:week; y.:year; d.: day; m.: month; mvt: movement;hypofrac: hypofractioned; Carb: carbogene; Nic: nicotinamide; GemX: gemcitabine aand radiation; SIB: simultaneous integrated boost; ns: no significant.