Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx
systematic review and meta-analysis of clinical trials of bladder-sparingtrimodality treatment for muscle-invasive bladder cancer (MIBC)
Giorgio Arcangeli a, Stefano Arcangeli b, Lidia Strigari a,∗a Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome, Italy
b Department of Radiotherapy, Azienda Ospedaliera S. Camillo—Forlanini, Rome, Italy
urpose: Despite the numerous prospective and retrospective studies published during the last 2 decades aiming at testing the safety andhe efficacy of trimodality therapy (TMT) as a conservative treatment, an optimal therapeutic strategy has not yet been identified. We made
systematic overview of the 5-year outcomes from 31 trials of combined chemotherapy and radiation (CRT) after transurethral resection ofuscle-infiltrating bladder tumours (TURBT), the so-called trimodality therapy. We took into consideration the results of each trial i.e. the
ate of complete response (CR), local muscle-invasive local failure (LF), salvage cystectomy (SC), 5-year overall survival (OS) and 5-yearladder intact survival (BIS) from 3315 patients.esults: About half of the patients were treated with a preliminary induction followed by a consolidation CRT course in CR, or SC inon-CR patients (split treatment). The remaining half of the patients underwent an upfront full-dose CRT course (continuous treatment)
Please cite this article in press as: Arcangeli G, et al. A systematic review and meta-analysis of clinical trials of bladder-sparing trimodalitytreatment for muscle-invasive bladder cancer (MIBC). Crit Rev Oncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.11.007
ith SC reserved to non-CR patients. Excellent results were obtained by trimodality therapy (TMT), with 78% CR, 28% muscle infiltratingF and 21% SC in patients with MIBC. The 5-year OS and BIS rates were 56% and 42%, respectively. At univariate analysis, CR, andC rates appeared to be significantly better in the continuous than in the split treatment group. Multivariate analysis confirmed the formeregimen as a significant prognostic variables only for CR, while CP-based regimen was a significant prognostic factor for SC. The subgroupnalysis revealed a significant improvement in 5-year OS rate of continuous over split treatment in later stage tumours. No relevant benefitas observed with the addition of other drugs to cisplatin (CP) or neo-adjuvant chemotherapy (NATC) to CRT, although, in patients receivingACT, significantly better CR and OS rates were seen in the continuous than split treatment.onclusions: The results of this overview seem to indicate that TMT is able to produce excellent 5-year OS rates, no matter how it isone (continuous or split). No significant difference in 5-year OS rates could be observed between the two treatment regimens, although theontinuous may offer some advantage compared to split treatment in terms of higher CR and, likely lower SC rates. The highest benefit might
G. Arcangeli et al. / Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx
e achieved in later stage tumours, using a total radiation equivalent dose when delivered in 2 Gy/fraction (EQD2) of more than 60 Gy inombination with CP based regimes and preceded by 2–3 NACT cycles. Appropriate randomized trials should be addressed to confirm theesults of the present review.
In the last two decades several retrospective and prospec-ive trials have shown that the trimodality therapy (TMT),ased on the concurrent delivery of chemotherapy and radio-herapy after muscle-infiltrating bladder tumours (TURBT)an be a safe and effective treatment in the management ofuscle-invasive bladder cancer (MIBC). In fact, this strat-
gy has the advantage, with respect to radical cystectomy,f preserving, in most of the patients, a normally functionalladder, reserving cystectomy as a salvage option only inases with an infiltrating local failure (LF) without distantetastases. The rationale for the combination of chemother-
py and radiotherapy (CRT) is based on two main premises.irst, clinical and autopsy data have shown that micrometas-
ases may occur concurrently with MIBC, and their frequencyncreases with tumour stage [1]. Therefore, it is expected thathe addition of chemotherapy to radiotherapy may reduce therobability of distant failure by eradicating occult metastases.econd, some drugs such as fluorouracil, cisplatin, gem-itabine, paclitaxel, etc. act as radio-sensitizers, renderingancer cells more sensitive to radiation [2]. To avoid a sal-age cystectomy (SC), the immediate most important goal ofMT is that of achieving and maintaining the highest rate ofR with the lowest rate of infiltrating LF. Two main differ-nt CRT approaches have been employed following TURBT.n protocols developed at the Massachusetts General Hospi-al (MGH) and adopted in the Radiation Therapy Oncologyroup (RTOG) trials, candidates for bladder preservation
re selected according to their response to induction CRT,ith a cystoscopic assessment of response after a prelim-
nary course. In these protocols, consolidation CRT (splitreatment) is given only to completely responding patients,hereas all others undergo SC with a curative intent [3]. The
econd bladder preservation approach, mainly used in theniversity of Erlangen [4] and adopted by many European
entres, consists of the delivery of an upfront full-dose CRTourse (continuous treatment). In this case, patients with anncomplete response and continuing pelvis confined diseaset post-treatment evaluation undergo SC. These two thera-eutic approaches have been planned with a different intent:o reduce the risk of both uncontrolled loco-regional diseasend SC-associated complications, the former approach givesriority to cancer control by carrying out SC in patients withn incomplete response after induction CRT, with a minimal
Please cite this article in press as: Arcangeli G, et al. A systematic reviewtreatment for muscle-invasive bladder cancer (MIBC). Crit Rev Oncol/He
elay after low dose preoperative CRT. The aim of the contin-ous treatment schedule is that of increasing the chances ofladder preservation by giving a more intensive CRT course
eeo
dder cancer
nd more time for tumours to respond, reserving SC only foratients with an incomplete response and continuing pelvisonfined disease.
With the aim of identifying the optimal strategy for bladderparing in the treatment of MIBC, we performed a systematiceview and meta-analysis of the published trials employingMT.
. Methods and material
.1. Study selection criteria
In order to assess the different strategies of TMT of MIBC,e conducted a PubMed literature review using the preferred
eporting items for systematic reviews and meta-analysesPRISMA) literature selection process [5]. English medi-al literature from 1990 until 2013 was searched in PubMedsing the terms bladder cancer, urothelial carcinoma, com-ined chemo-radiation treatment, TMT, bladder preservation,rgan sparing. We selected all published full articles writ-en in English, prospective and retrospective studies on morehan 20 patients with non-metastatic MIBC, treated withrimodality bladder preservation therapy (i.e. TURBT, fol-owed by neoadjuvant chemotherapy and/or concomitantRT, with SC at local infiltrating failure in cases withoutistant relapses) reporting CR and 5-year OS rates. Compar-tive studies (when available) between different radiotherapyr chemotherapy strategies were also included in our analysis.ot included in our analysis were studies on patients with nonuscle-invasive cancer and/or receiving partial cystectomy,
r studies delivering radiotherapy alone, even if preceded byeoadjuvant chemotherapy. Few papers reported an exhaus-ive evaluation of all relevant endpoints, therefore for 3/26tudies we calculated the BIS rates (referred to 5 year-cancer-pecific survival) using the same percentage applied to the
year-OS rate. For the same reason, a study selection waslso made for subgroup analyses. Among trials reporting theesults of different therapeutic strategies or including non-uscle infiltrating tumours, when possible, we selected and
ncluded in our analysis only the groups of patients fittingur requirements. Studies not having a sufficient follow-upor the primary objective analysis were included only for theR evaluation. Of the individual or pooled studies variously
eported over time, we only considered the most updatedndpoint results. Therefore, some studies reporting different
and meta-analysis of clinical trials of bladder-sparing trimodalitymatol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.11.007
ndpoint results in different periods were selected more thannce.
The primary endpoint of interest was the 5-year OS rate.ther clinical outcomes were also evaluated, such as CR,
nfiltrating LF, SC, and 5-year BIS rate, classified as the ratef patients who survive with their own functioning bladder.ecause of incomplete or lack of report in most trials, anccurate analysis of distant relapse and 10-year OS rates wasot possible.
.3. Statistical methods
The linear-quadratic formula was used to express the totalose of each RT fractionation schedule in terms of equivalentose when delivered in 2 Gy/fraction (EQD2).
The EQD2 was calculated as follows:
QD2 = BED
1 + (2/ (α/β))
The BED was calculated using the following formula:
ED = D
[1 + d
(α/β)
]
here D = total dose; d = dose per fraction and α/β = 10 Gyor the tumour.
We evaluated the associations between the types of treat-ent (or the EQD2 value) and the investigated clinical
nd-points, calculating the hazard risk (HR) and 95% con-dence intervals (CIs). We also performed a stratificationnalyses by clinical T-stage and hydronephrosis. For splitreatment, being CR evaluated at the end of the inductionRT course, EQD2 was calculated based on the dose deliv-red at this time point; while for 5-year OS the EQD2 wasalculated as the sum of both induction and consolidationoses. A chi-square test was performed to compare groups.
pooled estimate of the HR was computed according to thenverse variance method. A HR > 1 favours the split course,hereas a HR < 1 favours continuous treatment. When theooled results were significant, the absolute risk differenceas calculated. For all analyses, a forest plot was generated
o display the results. Variables significantly associated withutcomes at the univariate analysis were included in the mul-ivariate analysis to identify independent prognostic factors.
significant level of p < 0.05 was chosen for univariate anal-sis and corrected for multiple comparison. We conductedll analyses with R-package.
. Results
Fig. 1 shows the flow-chart of identification and inclu-ion of trials, as recommended by PRISMA [5]. Overall
Please cite this article in press as: Arcangeli G, et al. A systematic reviewtreatment for muscle-invasive bladder cancer (MIBC). Crit Rev Oncol/He
24 references were identified and screened. One hundrednd twenty two studies were excluded because CRT wasot employed in the bladder preservation approach. Oneundred and two trials were selected and retrieved for
ull-text analysis. After discarding duplicates and papershat were updated or did not fulfil our inclusion crite-ia, the search yielded 31 articles with a total of 3315valuated patients [3,4,6–41]. The material was largelyeterogeneous with regard to tumour stage, prognostic vari-bles, treatment, outcome evaluation and reporting results.he percent of patients with locally advanced or non
esected tumours included in the trials ranged from 0%o more than 50%. Several trials in the continuous coursechedule included medically-inoperable patients. Intention-o-treat analysis was reported by most trials although,n some retrospective studies, the results were reportednly for patients completing the planned treatment. Radio-herapy total dose and fractionation varied among thetudies, ranging from 24 to 48 Gy in 8–16 fractions withypofractionation, 40 to 65 Gy in 20–32 fractions with con-entional fractionation, or 66 to 69 Gy in 44–46 fractionsith hyper-fractionation. Also concomitant chemotherapyaried among the studies, with the use of several dosechedules and drug combination (cisplatin ± other drugs,uorouracil, carboplatin, gemcitabine, mitomycin C, vin-lastine, metotrexate, paclitaxel, etc.), with or withouteoadjuvant courses. The patient characteristics of the tworeatment groups are summarized in Table 1. Details onreatment, number of patients, and outcomes are reported inable 2.
Fig. 2a shows the cumulative results from the evaluatedrials. CR was observed in 78% of patients. LF, i.e. tumoursot achieving CR plus later muscle-infiltrating recurrences,ccurred in 28% of cases. SC was necessary in 21% ofatients. At 5 years, OS and BIS rates were 56% and 42%,espectively. The CR rate appeared significantly better inatients treated with the continuous than split schedule with
HR of 0.513, (95% CI of 0.430–0.611), and an absoluteenefit of more than 11% (Fig. 2b). No significant differ-nces were observed in 5-year OS, BIS and infiltrating LF
and meta-analysis of clinical trials of bladder-sparing trimodalitymatol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.11.007
ates. Of relevance, SC rates were 19% (268/1416) vs. 25%287/1144) in the continuous and split regimen, respectivelyHR = 1.435, 95%CI = 1.188–1.732), with an absolute benefitf 6% (Fig. 2b).
Please cite this article in press as: Arcangeli G, et al. A systematic review and meta-analysis of clinical trials of bladder-sparing trimodalitytreatment for muscle-invasive bladder cancer (MIBC). Crit Rev Oncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.11.007
ARTICLE IN PRESSONCH-1907; No. of Pages 11
4 G. Arcangeli et al. / Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx
Fig. 1. Flow of identification and inclusion of trials as recommended by PRISMA [5].
Table 2Selected studies reporting the investigated clinical outcomes for bladder-sparing trimodality treatment for MIBC.
G. Arcangeli et al. / Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx 5
a
b
F e numbC uated pa
3
tsrt4ttcb
ttn
fow
ig. 2. (a) Cumulative results from all evaluated trials; in parentheses is thIs of outcomes comparing continuous vs. split treatment course in all eval
.1. Subgroup analysis
A subgroup analysis was attempted, testing the effects ofhe two treatment regimens on outcomes according to progno-tic and treatment variables. As expected, CR and 5-year OSates were in general significantly better in patients with T2han >T2 tumour stage (79% vs. 62%, p < 0.0001 and 61% vs.7%, p = 0.0001, respectively, Fig. 3a). In this latter group,he 5-year OS rate appeared significantly better in patients
Please cite this article in press as: Arcangeli G, et al. A systematic reviewtreatment for muscle-invasive bladder cancer (MIBC). Crit Rev Oncol/He
reated with the continuous rather than the split treatmentourse (HR = 0.641, 95%CI = 0.424–0.969) with an absoluteenefit of 11% (Fig. 3b).
tofi
er of patients evaluated for each outcome. (b) Forest plot of HRs and 95%tients.
CR rates resulted better also in patients without ratherhan with hydronephrosis (77% vs. 38%, p = 0.0001), whilehe difference in OS rates between these two groups resultedot significant (Fig. 4).
Fig. 5 shows CR (panel a) and OS (panel b) rates as aunction of the EQD2. While there seem to be no influencef total dose on 5-year OS rates, CR rates appear to increasehen increasing the EQD2.Data on the effect of different drug regimes are too sparse
and meta-analysis of clinical trials of bladder-sparing trimodalitymatol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.11.007
o be correctly evaluated. The addition of other drugs to CPr the use of different drugs does not seem to give a bene-t for 5-year OS and CR (data not shown). Because of the
6 G. Arcangeli et al. / Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx
a
b
F ages. (bc es.
lwtdrrr9
N
intCp(
ig. 3. (a) CR and 5-year OS rates in patients with T2 or >T2 tumour stontinuous vs. split treatment course in patients with T2 or >T2 tumour stag
imited number of patients receiving drugs other than CP,e analyzed only those patients receiving CP and CP con-
aining regimes. In both these groups, while no significantifference in survival could be detected between the twoadiation schedules, significantly higher CR and lower SCates were observed by continuous compared to split courseegime (HR = 0.411, 95%CI = 0.305–0.554 and HR = 1.487,
Please cite this article in press as: Arcangeli G, et al. A systematic reviewtreatment for muscle-invasive bladder cancer (MIBC). Crit Rev Oncol/He
5%CI = 1.161–1.903, respectively (Fig. 6).From the limited, currently available data, the use of
ACT did not appear to produce any significant benefit
tfa
) Forest plot of HRs and 95%CIs of CR and 5-year OS rates comparing
n terms of rate of OS and CR (Fig. 7a). However, whileo difference in OS was detected between the two radia-ion schedules in the absence of NACT, significantly betterR and OS HRs were observed in the continuous com-ared to the split regime when NACT was added to CRTFig. 7b).
Multivariate analysis testing the significance of treatment
and meta-analysis of clinical trials of bladder-sparing trimodalitymatol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.11.007
ype (continuous vs. split), NACT and CP-based treatmentor the various endpoints, confirmed the continuous courses an independent prognostic variable only for CR rate
Fig. 5. Diagram showing (a) CR and (b) 5-year OS rates as a function ofEQD2 in all trials of continuous and split treatment course. In the splittreatment, CR rate was plotted as a function of dose delivered by inductionCRT course, while 5-year OS rate was plotted as a function of dose deliveredbt
cMtemw
§ No significant association including continuous course, neoadjuvant orP-based treatment.
p = 0.0036), while CP containing regimes (yes/no) andACT (yes/no) were not significant at univariate analysis.or SC, only the CP-based regimen resulted a significantrognostic factor (p = 0.0219) (Table 3).
. Discussion
Bladder preservation strategies are perceived by manyrologists to result in inferior survival in comparison to rad-cal cystectomy (RC) and, therefore, RC is considered ashe “gold standard” in the treatment of MIBC. Nevertheless,any patients may be not candidates for radical surgery due to
dvanced age and/or multiple co-morbidities and need a safend effective treatment that can be an alternative to radicalystectomy. Furthermore, organ preservation and quality ofife in bladder cancer, as with other sites (breast, larynx, anus,rostate, etc.), are increasingly being requested by patients,
Please cite this article in press as: Arcangeli G, et al. A systematic reviewtreatment for muscle-invasive bladder cancer (MIBC). Crit Rev Oncol/He
roviding the complete eradication of cancer cells remainshe primary goal of the treatment. Appropriate randomizedrials would give definitive answers on the possibility of
py
y both induction and consolidation CRT courses also for patients undergoneo SC.
hoosing the most beneficial treatment for patients withIBC. In the meanwhile, a systematic review of radical cys-
ectomy vs. organ-sparing TMT trials, reporting a temporaryvaluation of the benefit of these two most important treat-ent modalities, has been just completed by our group andill be separately reported (paper submitted).
and meta-analysis of clinical trials of bladder-sparing trimodalitymatol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.11.007
The present overview shows that an average 56% ofatients with MIBC who underwent TMT survived at 5ears, with approximately 80% of them living with their own
8 G. Arcangeli et al. / Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx
F g contino
bt2dara
pccnasiv
itumsiahaomrpauSctsOf
osislst
ttCrI5fo
scpwirr
spriqMtbo
ig. 6. Forest plot of HRs and 95%CIs of CR and 5-year OS rates comparinther drugs.
ladder. These seem to be excellent results in considerationhat, with the exception of the RTOG 8903 [19] and BC001 trials [35], they are not obtained by well conducted ran-omized studies, but are results emerging from prospectivend retrospective studies conducted by individual institutionseporting the results of the routine therapeutic activity withoutny patient selection.
Bladder cancer constitutes a heterogeneous population ofatients with a variety of factors that may influence the out-omes (age, gender, co-morbidities, T-stage, hydronephrosis,ompleteness of TURBT, etc.). The comparison of outcomesot within but only across studies raises concern aboutbsence of prognostic balance between the two treatmentchedules. Furthermore, the intention-to-treat report, spec-fied only in few papers, may represent another confoundingariable.
For the aim of this study, the trials were simply groupednto two major treatment approaches, i.e. continuous and splitreatment course. Although at univariate analysis the contin-ous treatment showed better outcomes than split regime,ultivariate analysis confirmed the continuous schedule as a
ignificant variable only for CR rate. Of relevance, SC rates unfortunately not reported in all the investigated studiesnd, owing to the presence of other confounding factors, aigher number of patients is needed to reach the significancet a multivariate analysis. The higher CR and lower SC ratesbserved at the univariate analysis by continous treatment,ay be due to the fact that patients undergone split course
egimen received, by protocol, an early assessment for SC,otentially leading to some unnecessary SC avoidable by
later outcome evaluation. On the other hand, the contin-ous treatment course allows a sufficient time to excludeC in patients who either reached CR after the full CRTourse or developed distant disease progression during thereatment/follow-up. In this context, although the therapeutic
Please cite this article in press as: Arcangeli G, et al. A systematic reviewtreatment for muscle-invasive bladder cancer (MIBC). Crit Rev Oncol/He
chedule was not shown to significantly influence the 5-yearS rates, continuous treatment seems to offer some advantage
or patient quality of life in terms of bladder sparing.
ast
uous vs. split treatment course in patients treated with CP alone or CP plus
The worst results were observed in patients with stage >T2r obstructive uropathy. In these cases, however, continuouseems to be more effective than split treatment, with signif-cantly higher CR rates in both with/without hydronephrosisubgroups, and significantly better OS rates in patients withater tumour stages. In these latter, SC does not seem to beufficient to compensate for the lower CR rate observed afterhe split course.
As expected, higher CR rates were observed by increasingotal RT dose. Owing to the early evaluation after the induc-ion CRT course, when RT dose was only partially delivered,R rates resulted to be lower in the split than continuous
egimen where the evaluation was done after full RT course.nstead no effect of total dose, in general, was observed on-year OS rates, possibly because SC was able to compensateor the lower CR rate achieved by the induction CRT coursef the split treatment.
Although other drugs in combination or not with CP havehown to be very effective [21,23,32,34,36,38], no conclusionould be made whether their addition to CP or their use inlace of CP is better than using CP alone, since CP aloneas used in most trials. However, using CP either alone or
n combination with other drugs, higher CR and lower SCates were observed with the continuous rather than the splitegime.
Data on the benefit of using NACT are sparse. Althoughome trials showed improved outcomes with NACT inatients treated by radical cystectomy or RT alone, a recenteport from Cochrane Database [42] concluded that there wasnsufficient information to obtain a definitive answer to theuestion of whether NACT improves survival in patients withIBC. The RTOG 8903 randomized trial [18] concluded that
wo cycles of NACT with the methotrexate, cisplatin, and vin-lastine (MCV) regime was not shown to have an impact onutcomes with respect to CRT alone in patients with MIBC,
and meta-analysis of clinical trials of bladder-sparing trimodalitymatol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.11.007
lthough the number of patients was too small to detect smallignificant differences. The results of this overview on morehan 900 patients confirm the lack of benefit of the addition
G. Arcangeli et al. / Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx 9
a
b
F therapyc urse in
oSrs
5
lg
asiecttn
ig. 7. (a) CR and 5-year OS rates in patients receiving neoadjuvant chemoystectomy and 5-year OS rates comparing continuous vs. split treatment co
f NACT to CRT. However, by NACT addition, CR, OS andC rates were significantly improved in the continuous withespect to the split treatment. Appropriate randomized trialshould be addressed to test this suggestion.
. Conclusion
Please cite this article in press as: Arcangeli G, et al. A systematic reviewtreatment for muscle-invasive bladder cancer (MIBC). Crit Rev Oncol/He
We are aware that heterogeneity of patient population,arge variations in the combined treatments, unbalanced pro-nostic factors and non-standardized reporting of results
ioc
(NADCT+) or not (NADCT−). (b) Forest plot of HRs and 95%CIs of CR, patients receiving or not receiving NACT.
mong the trials may all introduce some biases especially inome subgroup analyses. For this reasons, the results emerg-ng from the current review cannot be taken as definitivevidence of the benefit of the continuous over split treatmentourse. Furthermore, not enough trials have been conductedo reliably compare late specific toxicity events between thewo treatment schedules. BST by TMT exhibit good resultso matter how it is done (split or continuous). However,
and meta-analysis of clinical trials of bladder-sparing trimodalitymatol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.11.007
n the absence of randomized trials or trials with specificbjectives, the results of this overview seem to indicate that,ompared to the split, the continuous regimen may offer some
dvantage, essentially in terms of higher CR and likely lowerC rates. The most important benefit of the continuous treat-ent schedule might be achieved in late stage tumours, with
r without hydronephrosis, using total radiation doses higherhan 60 Gy in combination with CP-based regimes and pre-eded by 2 or 3 NACT cycles. Appropriate randomized trialshould be addressed to confirm the results of the presenteview.
onflict of interest statement
None.
eviewers
Luis Souhami, MD: Professor of Oncology, Radiationncology, McGill University, Department of Oncology, Divi-
ion of Radiation Oncology, 1650 Cedar Avenue, Montreal,C, Canada H3G 1A4. Assistant—Teresa, Tel.: +1 514 934934x43915.
Jason A. Efstathiou, MD, PhD: Massachusetts Generalospital, Radiation Oncology, 100 Blossom Street, Cox 3,oston, MA 02114, United States.
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