In the last decades, organ-preserving therapies have been developed as an alternative to radical therapy for organ-localized malignancies with the aim of minimizing toxicity and improving the quality of life (QoL), while maintaining similar oncologic outcomes. In urothelial carcinoma of the bladder (UCB), different organ-preserving treatments have been proposed such as partial cystectomy, radical transurethral resection (TUR), radiation therapy, or chemotherapy. Trimodal therapy (TMT) is probably the most effective bladder-sparing treatment, limiting salvage radical cystectomy to nonresponders or local invasive disease recurrence.
Recent guidelines propose TMT as an alternative option of radical cystectomy in selected patients [1–3]. Although organ-preserving therapies are well established and standards of care in several malignancies such as head and neck, prostate or breast cancers, TMT faces challenges to find its place in the armamentarium of curative treatments in UCB. It probably reflects the persistent concerns among urologists regarding its oncologic and functional outcomes compared with radical cystectomy and their reluctance to propose TMT as a reliable option to the eligible patients.
The purpose of this article was to review and discuss the issues regarding the equivalence of TMT and radical cystectomy based on the recent literature.
A nonsystematic Medline/PubMed literature search was performed with different combinations of keywords using ‘bladder cancer’, ‘bladder preservation’, ‘bladder sparing’, ‘trimodal therapy’, ‘chemotherapy’, ‘radiation therapy’ and ‘chemoradiation’. The time period included articles published between January 2000 and April 2015. Original articles, reviews and editorials in English language were selected based on their clinical relevance with particular emphasis on articles published during the last 2 years. Additional informative articles were collected by cross referencing the bibliography of previously selected articles.
Treatment rationale and protocols
UCB is considered a malignancy of entire bladder urothelium so that a complete bladder excision aims to avoid local recurrence and increase the chances for cure. In addition to a staging and prognostic role, a growing body of evidence suggests that an extended lymphadenectomy has a therapeutic role through the removal of micrometastases [4,5]. Therefore, key points of radical cystectomy are the complete removal of the bladder associated with an extended pelvic lymph node dissection.
Modern modalities of TMT try to address these oncologic concepts in UCB. After a maximal TUR, current protocols of TMT include generally initial radiation therapy of the whole bladder and pelvic lymph nodes to an initial dose of 40–45 Gy, followed by a consolidation radiation therapy of the whole bladder to 54 Gy and the tumor to a total dose of 64–65 Gy . Concurrent radiosensitizing chemotherapy is delivered using cisplatin or mitomycin C plus 5-fluorouracil. Cystoscopic assessment with biopsy of the tumor site and voided urine cytology may be performed at TMT completion (continuous course) or early after TMT induction (split course). Finally, although the whole bladder and pelvic lymph nodes receive, respectively, at least 54 Gy and 40 Gy, chemotherapy is expected to eradicate micrometastases and sensitize cancer cells to radiation.
Compared with the well established radical cystectomy, TMT protocols remain in their early stages and several issues are still a matter of discussion such as the following: first, equivalence of split and continuous protocols, second, dose and fractionation of radiation therapy in the bladder, third, radiation therapy of pelvic lymph nodes, and fourth, chemotherapy regimen. Recent studies have yielded relevant data regarding some of these issues.
To date, no randomized controlled trials have compared split and continuous courses. In a meta-analysis that included 3315 patients who almost equally received either continuous or split course, Arcangeli et al.[6▪] reported the rates of complete response, muscle-invasive local failure, salvage radical cystectomy, 5-year bladder intact survival, and overall survival (OS). In multivariable analysis, continuous course was an independent prognostic factor only for CR. Therefore, until a direct comparison by RCT is done, both approaches (continuous versus split course) may be considered equally efficient regarding the other endpoints.
Regarding schedule of radiation therapy in the bladder, the BC2001 trial compared a whole-bladder radiation therapy to a reduced high-dose volume using a tumor boost, with or without chemotherapy by mitomycin C and 5-fluorouracil . Toxicity and cancer relapse were low but significant reduction of the side-effects and noninferiority of locoregional control with the modified volume dose were not proven. Recently, Turgeon et al. reported the feasibility of TMT with hypofractionated intensity-modulated radiation therapy (IMRT) for the treatment of elderly patients with MIBC. All patients (n = 24) completed hypofractionated IMRT, and 79% of them tolerated all four cycles of chemotherapy. Acute toxicities to the treatment were relatively low and 83% of the patients had a complete response. Further studies are, however, necessary to define the optimal schedule of radiation therapy and the benefit of the new radiation therapy modalities such as IMRT and image-guided radiation therapy.
Advantages of radiation therapy of pelvic lymph nodes are still under debate. One randomized trial compared a bladder-only to a whole-pelvis concurrent chemoradiation and reported similar outcomes regarding the rates of salvage radical cystectomy, 5-year cancer-specific survival (CSS) and OS . In the BC2001 trial, the planning target volume only comprised the bladder with a margin of 1.5 cm and the nodal recurrence was less than 5% . Indeed, the use of three-dimensional conformal radiation therapy may lead to the eradication of occult lymph node metastases by delivering some dose to the pelvic nodes. Caution should, however, be advocated regarding IMRT or image-guided radiation therapy as their use may result in insufficient radiation dose to treat these nodes. Indeed, the dose necessary to treat a lymph node micrometastasis remains in this and other cancers.
Finally, promising results of different protocols have been reported to optimize cisplatin-based chemotherapy regimen such as a regional deep hyperthermia  and the use of intra-arterial approach [11,12]. For patients with impaired renal function who are ineligible for cisplatin-based chemotherapy regimens, MMC plus 5-FU is a well tolerated alternative. Other promising agents have been recently identified, such as gemcitabine and paclitaxel [13–15]. Future studies with head to head comparisons are, however, still mandatory to confirm the equivalence between all these chemotherapy regimens in the TMT setting as this is likely to be different to the perioperative and metastatic settings.
Patient selection for trimodal therapy
Radical cystectomy is the standard of care for localized (cT2N0M0) and locally advanced (cT3a–T4a, N0–NX, M0) UCB and a potential alternative for high-risk or recurrent nonmuscle-invasive bladder cancer, nonurothelial carcinomas of the bladder, and palliative cases . According to guidelines, TMT should only be proposed to highly selected patients with favorable baseline characteristics such as unifocal cT2 tumor without hydronephrosis, extensive carcinoma in situ, or infiltration of prostatic stroma . Thereby, only 10–15% of radical cystectomy patients with MIBC would be candidates for TMT . Moreover, there is a serious understaging issue in UCB. Pietzak et al., for example, reported that in cT2N0M0 patients eligible for TMT, pathological examination of primary radical cystectomy revealed occult positive lymph nodes and pT3 or pT4 tumors in 24.1 and 36.4% of cases, respectively. These patients would not only fail TMT, but some would lose the window of cure.
Even more than in the preoperative setting of radical cystectomy, collaborative efforts are mandatory to propose and validate tools to help physicians identify patients who are more likely to benefit from TMT. Nomograms based on age, clinical stage, presence of hydronephrosis, sex, or TURBT completeness have been recently proposed to predict outcomes after TMT regarding CR, CSS, and bladder intact survival [18▪▪]. An external validation of their predictive value is, however, necessary before their use in clinical routine. The integration of molecular markers could also improve their predictive accuracy: several molecular markers have already been identified as potential prognostic factors in TMT such as EGFR, HER2, MRE11, and VEGF [19–24]. Finally, new imaging modalities, especially diffusion-weight MRI, have yielded promising results in predicting UCB aggressiveness and sensitivity for TMT [25,26]. Until their validation in current practice, multidisciplinary consensus is mandatory to properly select the eligible patients for TMT.
Oncologic outcomes of trimodal therapy
Available literature on TMT includes large retrospective studies and prospective trials. In a pooled analysis of five RTOG phase II and one phase III multi-institutional randomized studies that included 468 patients treated by TMT, Mak et al.[27▪▪] recently reported 5 and 10-year OS of 57 and 37%, respectively. Overall, 80% of patients had an intact bladder, 5 years after the completion of TMT. Ploussard et al.[28▪▪] recently proposed a comprehensive and systematic review of all prospective and retrospective studies of TMT from 1980 to 2013. In the medically operable patients, mean CR rate after TMT was 73% whereas 5-year CSS and OS rates ranged from 50 to 82% and from 36 to 74%, respectively. Arcangeli et al. confirmed these findings in a recent meta-analysis: CR to TMT was observed in 78% of the patients whereas nonresponders and local muscle invasive recurrence accounted for 28% of cases. After 5 years, 56% of patients were alive and 79% of them had an intact bladder. In a recent review that included 10 265 patients treated with radical cystectomy and 3131 with TMT, median 5-year OS rates were 52 and 57%, respectively (P = 0.04), suggesting that TMT may be associated with better outcomes than radical cystectomy . This study did not, however, adjust for the stage bias/selection bias.
No randomized controlled trials have directly compared radical cystectomy and TMT approaches and few attempts have failed . In this context, any comparison of oncologic outcomes is challenging and results from previous studies should be considered with caution. The ranges in results underline the heterogeneity of the data regarding inclusion period, patient and tumor characteristics, follow-up, and protocols modalities. Such discrepancies lead to selection bias and clinico-pathologic stage discordance. Many of the patients from retrospective studies that received TMT had locally advanced disease, bad performance status, and were not fit for surgery. Conversely, inoperable patients were further excluded from prospective studies and favorable inclusion criteria lead to potential selection bias. For example, patients who should have been able to receive chemoradiation assumed a better general health status. Pietzak et al. demonstrated that among cT2N0M0 patients treated by radical cystectomy, those eligible for TMT had significantly better OS and CSS. Studies that merged these patients are limited by their inability to consider these potential confounders. The discordance between the clinical staging in TMT and the pathological staging of radical cystectomy also limits comparisons between both modalities. Understaging of the tumor with clinical assessment occurs in more than one-third of the patients and may favor radical cystectomy series regarding outcomes. Conversely, an estimated 17–30% of the cT2 tumors treated by TMT would have been downstaged to pT0/1 at the time of the surgery [28▪▪].
The limited adoption of TMT may also reflect its preferential use in centers of excellence and lead to a bias of publication that confounds any comparison with contemporary radical cystectomy series. Conversely, available population-based studies may provide survival outcomes in routine clinical practice. Initial studies from national registries reported better OS after radical cystectomy compared with bladder sparing treatments but did not discriminate, however, modern TMT from other bladder-sparing treatments [31,32]. Recent studies from the Surveillance, Epidemiology, and End Results-Medicare and the National Cancer Database, which focused on TMT, reported similar outcomes when compared with radical cystectomy [33,34]. Bekelman et al. demonstrated, however, that the methods of analysis are crucial to conclude on the equivalence of survival estimates.
A growing body of evidence exists to consider TMT as a reliable treatment option with good oncologic outcomes in selected patients. The available literature, however, pales in comparison to the radical cystectomy series regarding sample size and follow-up, whereas selection bias and staging discordance still limit any conclusions on the oncologic equivalence or difference between these treatments. The role of salvage radical cystectomy in the previously reported results of TMT should not be underestimated. Therefore, a close follow-up with multidisciplinary approach to propose a prompt salvage radical cystectomy, when necessary, is mandatory to warrant such oncologic outcomes.
Follow-up after trimodal therapy and salvage radical cystectomy
The estimated local recurrence rate after CR in TMT ranges from 24 to 43% with a median time of less than 2 years [28▪▪]. Therefore, after initial CR, patient will have to comply with a close follow-up that includes cystoscopy, cytology and CT, or MRI surveillance. Some authors advocate a tumor-site rebiopsy or resection and a bimanual examination under general anaesthesia [28▪▪].
Most patients will experience nonmuscle invasive recurrence. In the pooled analysis of the RTOG trials, the rates of local failure for nonmuscle and muscle-invasive recurrence after 5 years were 31 and 13%, respectively [27▪▪]. Patients with nonmuscle-invasive recurrence may be treated conservatively (TUR and intravesical therapies) but should be informed of a high risk of radical cystectomy and a potential risk to lose the window of cure. Indeed, several studies reported that patients with nonmuscle-invasive recurrence had similar 5-year CSS than those without recurrence but a lower rate of bladder intact survival (61% versus 35%, respectively) . Salvage radical cystectomy is the standard treatment for nonresponders and recurrent muscle-invasive tumors. Overall, 25–30% of the patients treated with TMT will ultimately require salvage radical cystectomy [28▪▪]. Mak et al.[27▪▪] reported 5 and 10-year CSS after salvage radical cystectomy were 60 and 47%, respectively.
One major concern is the feasibility of a radical cystectomy and an orthotopic neobladder reconstruction without complication. Appropriately staged patients with cT2N0 should and are often offered a nerve-sparing radical cystectomy with neobladder that results in high continence and potency rates [36,37]. Iwai et al. compared early complications after radical cystectomy in patients with or without previous induction and concurrent chemoradiation. Overall incidence of complications was similar in both groups (67 versus 57%, P = 0.18), but a higher rate of urinary anastomosis leakage complications was observed after chemoradiation (9 versus 1%, P = 0.01, respectively). Eswara et al. reported perioperative and postoperative outcomes of 91 patients treated with salvage radical cystectomy. During the procedure, difficulties in the dissection were noted and all patients received a noncontinent diversion. Major postoperative complications within 90 days after surgery occurred in 16% of patients and 90-day perioperative mortality was 2.2%. Eisenberg et al. reported early complications after cystectomy in patients previously treated with high dose pelvic radiation. Major complication (Clavien grade ≥3) rate was 32.4% but the type of diversion did not, however, affect this rate.
According to the risk of local recurrence after TMT, a close follow-up is mandatory to propose a prompt salvage radical cystectomy, when necessary. The salvage radical cystectomy appears feasible with a tolerable rate of morbidity. While most of the patients eligible for a TMT are, however, initially good candidates for continent urinary diversion, only few will receive such reconstruction at the time of salvage radical cystectomy. Therefore, patients treated with TMT should be fully informed of the risk of local recurrences and that in case of salvage radical cystectomy, they will probably no longer have the opportunity of an orthotopic diversion or a nerve-sparing approach.
Morbidity and quality of life of trimodal therapy
One of the main expectations of patients treated with TMT is a low risk of morbidity and the preservation of their QoL compared with radical cystectomy. Early complications with TMT have been reported in RCTs. Rates of acute grade 3–4 toxicities range from 10 to 36%, and mainly consist of haematologic (thrombocytopenia), gastro-intestinal, and genitourinary events [28▪▪]. Regarding late and long-term toxicities, the pooled analysis of the RTOG trials revealed a low incidence of late grade 3 or 4 genitourinary and gastro-intestinal toxicities (5.7 and 1.9%, respectively) with a median follow-up of 5.4 years .
Recently, one prospective study compared QoL in patients treated with radical cystectomy and orthotopic bladder reconstruction versus TMT and showed that, 3 months after treatment completion, patients with intact bladder had better scores regarding physical and emotional disease-related symptoms (including genitourinary symptoms and erectile function for men), and treatment side-effects (including gastro-intestinal symptoms) . Previously, in a retrospective study, Caffo et al. reported patients treated with radical cystectomy and noncontinent diversion had worse QoL than those treated with bladder-sparing treatments, mainly because of erectile dysfunction.
Zietman et al. assessed QoL and urodynamics among 32 patients treated with TMT and demonstrated that 54% had sufficient erections for vaginal penetration and only 8% were not satisfied with their sexual life. Regarding urodynamics, 75% had normal-functioning bladders and main clinical complaints were difficult flow (6%), urgencies (15%), and leakages (19%).
These studies confirm TMT is a well tolerated treatment option with a low rate of toxicities and probably a better QoL than patients treated with radical cystectomy. Again, these studies are subject to selection bias as TMT patients are selected, younger, and more fit compared with standard radical cystectomy patients. Longer follow-up from prospective studies is, however, mandatory to assess the long-term side-effects of pelvic irradiation. Future studies should also address the impact of cystoscopic surveillance, risk of local nonmuscle-invasive recurrences, and retreatments but also QoL for patients who will require salvage radical cystectomy but will not be offered a continent diversion and/or nerve-sparing radical cystectomy because of TMT.
Practice of trimodal therapy today
Radical cystectomy, the standard of care in MIBC, remains underused [31,44]. Analysis from the National Cancer Database showed that less than 6% of patients with nonmetastastic MIBC received a chemoradiation therapy without any significant variation of its use during the period of study (2004–2008) . It has been estimated that this rate reached 10% in patients with a stage II bladder cancer . Similar results were reported from the population-based Ontario Cancer Registry . Radiation therapy was used in 26% of the patients with a curative intent and only 12% of these patients received concurrent chemotherapy. Using the Surveillance, Epidemiology, and End Results-Medicare database, Bekelman et al. showed that patients who received TMT were older, more likely to be male, and to have comorbidities than those treated with radical cystectomy. In practice, TMT is often used for patients who are not candidates for radical cystectomy or who refuse radical cystectomy. This is in contrast to the prospective TMT trials that accrued in generally healthier and younger patients.
These population-based studies give us an insight into the place of TMT in the ‘real world’ practice and underline the noncompliance with guideline-recommended care: if radical cystectomy is probably underused, TMT is even more neglected and misused in patients with curable disease. Previously discussed concerns may partly explain these findings. Future prospective studies and multidisciplinary consensus should provide sufficient data in the following years to overcome last hesitations in urologic community to propose TMT in selected patients and promote its widespread use.
TMT is well tolerated, and when successful leads to satisfactory QoL. Its oncologic outcomes specifically local control rates seem not to be inferior to radical cystectomy in a highly selected patient population. Because of the lack of long-term results and randomized controlled trials, TMT should only be considered equal to radical cystectomy if multidisciplinary efforts and coordination provide proper selection of TMT-eligible patients and prompt salvage radical cystectomy is triggered when necessary. Further trials and studies are warranted to define best candidates and regimen for optimal TMT. Improvement in staging and early detection will be crucial for TMT. New indications may include patients with pT1 high grade tumors refractory to Bacille Calmette Guerin and/or patients who have pT0 after neoadjuvant chemotherapy.
R.M. is supported by the Scholarship Foundation of the Republic of Austria – OeAD and by the EUSP Scholarship – European Association of Urology.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
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