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Keywords:

  • bladder preservation;
  • chemoradiotherapy;
  • muscle-invasive bladder cancer;
  • partial cystectomy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Trimodality bladder-sparing therapy
  5. Candidate selection for bladder preservation
  6. Prognostic factors in patients treated with trimodality therapy
  7. Potential limitations of trimodality bladder-sparing therapy
  8. Partial cystectomy as primary therapy for bladder preservation
  9. PC as consolidative therapy after induction CRT: The TMDU protocol
  10. Novel approaches to further improve outcomes of bladder-sparing therapy
  11. Toxicity of CRT and QoL
  12. Conclusions
  13. Acknowledgment
  14. Conflict of interest
  15. References

Radical cystectomy plus urinary diversion, the reference standard treatment for muscle-invasive bladder cancer, associates with high complication rates and compromises quality of life as a result of long-term effects on urinary, gastrointestinal and sexual function, and changes in body image. As a society ages, the number of elderly patients unfit for radical cystectomy as a result of comorbidity will increase, and thus the demand for bladder-sparing approaches for muscle-invasive bladder cancer will also inevitably increase. Trimodality bladder-sparing approaches consisting of transurethral resection, chemotherapy and radiotherapy (Σ55–65 Gy) yield overall survival rates comparable with those of radical cystectomy series (50–70% at 5 years), while preserving the native bladder in 40–60% of muscle-invasive bladder cancer patients, contributing to an improvement in quality of life for such patients. Limitations of the trimodality therapy include (i) muscle-invasive bladder cancer recurrence in the preserved bladder, which most often arises in the original muscle-invasive bladder cancer site; (ii) potential lack of curative intervention for regional lymph nodes; and (iii) increased morbidity in the event of salvage radical cystectomy for remaining or recurrent disease as a result of high-dose pelvic irradiation. Consolidative partial cystectomy with pelvic lymph node dissection followed by induction chemoradiotherapy at lower dose (e.g. 40 Gy) is a rational strategy for overcoming such limitations by strengthening locoregional control and reducing radiation dosage. Molecular profiling of the tumor and functional imaging might play important roles in optimal patient selection for bladder preservation. Refinement of radiation techniques, intensified concurrent or adjuvant chemotherapy, and novel sensitizers, including molecular targeting agent, are also expected to improve outcomes and consequently provide more muscle-invasive bladder cancer patients with favorable quality of life.


Abbreviations & Acronyms
BIS =

bladder-intact survival

CIS =

carcinoma in situ

CR =

complete response

CRT =

chemoradiotherapy

CSS =

cancer-specific survival

FU =

fluorouracil

GasLESS =

gasless laparoendoscopic single-port surgery

GC =

gemcitabine, cisplatin

HD =

hemodialysis

IAC =

intra-arterial chemotherapy

IMRT =

intensity-modulated radiation therapy

LCRT =

low-dose chemoradiotherapy

MCV =

methotrexate, cisplatin and vinblastine

MIBC =

muscle-invasive bladder cancer

MRI =

magnetic resonance imaging

MVAC =

methotrexate, vinblastine, adriamycin and cisplatin

NA =

not available

NFκB =

nuclear factor κB

NMIBC =

non-muscle-invasive bladder cancer

OS =

overall survival

PC =

partial cystectomy

PLND =

pelvic lymph node dissection

QoL =

quality of life

RC =

radical cystectomy

RTOC =

Radiation Therapy Oncology Group

SPARE =

Selective bladder Preservation Against Radical Excision

TMDU =

Tokyo Medical and Dental University

TURBT =

transurethral resection of bladder tumors

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Trimodality bladder-sparing therapy
  5. Candidate selection for bladder preservation
  6. Prognostic factors in patients treated with trimodality therapy
  7. Potential limitations of trimodality bladder-sparing therapy
  8. Partial cystectomy as primary therapy for bladder preservation
  9. PC as consolidative therapy after induction CRT: The TMDU protocol
  10. Novel approaches to further improve outcomes of bladder-sparing therapy
  11. Toxicity of CRT and QoL
  12. Conclusions
  13. Acknowledgment
  14. Conflict of interest
  15. References

RC plus urinary diversion has long been the reference standard treatment for MIBC. Although recent progress in operative techniques and perioperative management has improved surgical outcomes, RC is still associated with complication rates of up to 30% and 2–3% perioperative mortality, depending on patient age, comorbidities and complexity of the procedure.1,2 In addition, RC and urinary diversion has long-term effects on urinary, gastrointestinal and sexual function, and changes the body image of patients who use incontinent urinary diversions. These effects significantly compromise the QoL of MIBC patients who undergo RC and urinary diversion.3 Although orthotopic neobladder procedures can minimize changes in QoL, such techniques do not provide an equivalent substitute for the native bladder. Furthermore, many MIBC patients are elderly, have multiple comorbidities and thereby are not ideal candidates for RC. Based on this background, various modalities of bladder-sparing approaches have been investigated and their benefits appreciated. Because most developed countries are now facing a rapidly increasing number of aged people, the demand for bladder-sparing strategies for the elderly is increasing worldwide.

The history of the development of bladder-sparing approaches has been described in detail in excellent reviews.4–7 Briefly, several groups, including Harvard University in the USA, the University of Paris in France and the University of Erlangen in Germany, reported that the combination of TURBT, chemotherapy and radiotherapy yielded more favorable outcomes than those provided by monotherapies or other combinations of a subset of the three modalities.8–10 Over the past two decades, trimodality therapy has been investigated in several prospective studies carried out mainly by the RTOG; 5-year OS rates ranged from 50% to 60%, which were comparable to those of RC series,11,12 and 40–45% of the patients maintained their native bladder.9,13,14 Thus, trimodality therapy is now the standard protocol for bladder-sparing treatment.

In the current review, we provide an overview of the protocols and outcomes of bladder-sparing protocols for MIBC. Then, their limitations and novel approaches are discussed, especially focusing on oncological outcomes.

Trimodality bladder-sparing therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Trimodality bladder-sparing therapy
  5. Candidate selection for bladder preservation
  6. Prognostic factors in patients treated with trimodality therapy
  7. Potential limitations of trimodality bladder-sparing therapy
  8. Partial cystectomy as primary therapy for bladder preservation
  9. PC as consolidative therapy after induction CRT: The TMDU protocol
  10. Novel approaches to further improve outcomes of bladder-sparing therapy
  11. Toxicity of CRT and QoL
  12. Conclusions
  13. Acknowledgment
  14. Conflict of interest
  15. References

In the late 1980s, pioneer centers, including Harvard University, the University of Paris and the University of Erlangen, developed trimodality protocols. Despite congruent objectives, “bladder preservation” and “adequate cancer control” protocols have distinct differences, and the algorithms of these two major approaches are shown in Figure 1. In protocols developed at Harvard University15 and the University of Paris,8 candidates for bladder preservation are selected according to their response after induction CRT; only patients who achieve CR undergo consolidative CRT for bladder preservation, whereas non-CR patients undergo RC with curative intent. In the University of Erlangen protocol,10 patients receive upfront full-dose CRT and then are evaluated for therapeutic response; non-CR patients then undergo RC. The former scheme places priority on cancer control by carrying out salvage RC with minimal delay for non-responders. A lower dose of preoperative irradiation also reduces the risk of RC-associated complications for non-CR cases after induction CRT. The latter scheme gives tumors more intensive CRT and more time to respond to such therapy, which might increase the chances of bladder preservation.

image

Figure 1. Algorithms of two major trimodality bladder-sparing protocols at (a) University of Paris/Harvard University and (b) University of Erlangen.

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Table 1 lists large (n ≥ 50) prospective series of trimodality therapy for MIBC. These studies yielded CR rates of 50–90%, 5-year OS rates of 39–74%, and 5-year BIS rates of 36–61%. In most protocols, cisplatin was given systemically as chemotherapy concurrent with radiotherapy. A previous randomized trial by the National Cancer Institute of Canada showed a significant reduction in the risk of pelvic failure by concurrent use of cisplatin with radiotherapy compared with radiotherapy alone.26 This finding was confirmed by two recent series in which CRT with concurrent cisplatin or carboplatin significantly improved CR rates22,23 and OS22 compared with radiotherapy alone. The role of neoadjuvant systemic chemotherapy was evaluated in a randomized phase III trial, RTOG 89-03; this study showed that, at least, two cycles of neoadjuvant MCV does not improve CR rate or survival.13 Regarding CRT schemes, non-separated CRT at radiation doses of 50.4–69 Gy appears to yield higher CR rates, ranging from 63% to 90%, than separated CRT schemes composed of induction CRT at doses of 24–40.3 Gy (50–81%). However, OS and bladder preservation rates are similar between the two different schemes, suggesting that both CRT schemes are equivalent in terms of cancer control.

Table 1.  Series of trimodality bladder-sparing treatment for muscle-invasive bladder cancer
Investigator (publication year)No. patientsClinical stageInduction therapyCR rate (%)Consolidative therapy5-year OS (%)5-year BIS (%)
Neoadjuvant therapyCRT regimenCRT regimenAdjuvant therapy
Housset (1993)854T2-424 Gy + cisplatin/FU7420 Gy + cisplatin/FU59 (3-year)NA
Given (1995)1693T2-42 or 3 cycles MVAC or MCV64.8 Gy + cisplatin6339NA
Tester (1996)1491T2-4a2 cycles MCV39.6 Gy + cisplatin7525.2 Gy + cisplatin62 (4-year)44 (4-year)
Kachnic (1997)9106T2-4a2 cycles MCV39.6 Gy + cisplatin6625.2 Gy + cisplatin5243
Fellin (1997)1756T2-42 cycles MCV40 Gy + cisplatin5024 Gy + cisplatin5541
Shipley (1998)13123T2-4a2 cycles MCV vs no chemotherapy39.6 Gy + cisplatin61 vs 5525.2 Gy + cisplatin49 vs 4836 vs 40
Rodel (2002)10415T1-450.4–59.4 Gy + cisplatin or carboplatin(+ FU)725042
Danesi (2004)1877T2-42 cycles MCV69 Gy + cisplatin/FU905847
Kragelj (2005)1984T1-464 Gy + vinblastine7825 (9-year)NA
Dunst (2005)2068T2-450.4–59 Gy + cisplatin or paclitaxel8745NA
Weiss (2007)21112T1-455.8–59.4 Gy + cisplatin/FU88.47461
Perdona (2008)22121T2-42 cycles MCV65 Gy + no vs cisplatin or carboplatin74.4 vs 89.760.4 vs 71.846.5 vs 53.8
Gamal El-Deen (2009)23186T2-4aNo or 2 cycles MCV/MVAC/GC55–64.8 Gy + no vs cisplatin58.3 vs 81.659.7 vs 68.4NA
Kaufman (2009)2480T2-4a40.3 Gy + cisplatin/paclitaxel81%24 Gy + cisplatin/paclitaxel4 or 6 cycles GC5647
Sabaa (2010)25104T2-3a3 cycles GC60–65 Gy + cisplatin78.854.8NA

IAC is one of the therapeutic options for MIBC and a relatively common modality in Japan.27,28 Several groups incorporated IAC into the trimodality protocol (Table 2). CRT incorporating IAC produced high CR rates of 76–93%,29–32 which could be attributed to a high drug concentration at the primary lesion, with OS and BIS equivalent to those of conventional CRT regimens. However, IAC results in a unique complication, pelvic neuropathy, with an incidence of 20–30%.29,30,33 In addition, the complexity of the procedure, which involves intervention radiologists, limits the prevalence of IAC worldwide.

Table 2.  Series of trimodality bladder-sparing treatment for muscle-invasive bladder cancer incorporating intra-arterial chemotherapy
Investigator (publication year)No. patientsClinical stageInduction CRT regimenCR rate (%)Consolidative CRT regimen5-year OS (%)5-year BIS (%)
Miyanaga (2000)2942T2-340 Gy + cisplatin/methotrexate9320 or 30 Gy proton beam63 (among 36 patients with bladder)48 (among 36 patients with bladder)
Eapen (2004)30200Ta-460 Gy + cisplatin8350NA
Hashine (2009)3194T2-4a36–60 Gy + cisplatin/pirarubicin89.466.659.7
Azuma (2010)3296T2-4N0-150.4 Gy + cisplatin 100–300 mg + HD7610 Gy76.3NA (70 patients (73%) retain bladder)

Candidate selection for bladder preservation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Trimodality bladder-sparing therapy
  5. Candidate selection for bladder preservation
  6. Prognostic factors in patients treated with trimodality therapy
  7. Potential limitations of trimodality bladder-sparing therapy
  8. Partial cystectomy as primary therapy for bladder preservation
  9. PC as consolidative therapy after induction CRT: The TMDU protocol
  10. Novel approaches to further improve outcomes of bladder-sparing therapy
  11. Toxicity of CRT and QoL
  12. Conclusions
  13. Acknowledgment
  14. Conflict of interest
  15. References

Ideal candidates for bladder preservation through trimodality therapy are patients whose tumors are completely eradicated by the induction therapy. The factors relevant to tumor response to induction therapy are classified into tumor and therapeutic parameters. The clinical tumor parameters associated with favorable response include small tumor size (<5 cm), clinical T2 staging and unifocal disease, and absence of hydronephrosis.10,34 Patients with multifocal disease and CIS are at high risk for new development of tumor after initial CR. Several groups reported molecular markers relevant to CRT sensitivity, such as apoptotic index, Ki-67 index,35 bcl-2, bax,36 Her2,37 NFκB,38 and excision repair cross-complementing group 1 gene.39 The therapeutic parameters include completeness of TURBT;10 this is most important, because urologists are able to intervene to improve the response to the induction therapy. Thus, urologists should attempt TURBT as thoroughly as is safely possible for candidate bladder preservation patients.

Recently, a potential role of functional imaging in optimal candidate selection for bladder preservation has emerged. Diffusion-weighted MRI, which quantifies the diffusion of water molecules in a non-invasive manner, is useful for not only diagnosing the presence of urothelial cancer, but also predicting pathological information, including histological grade and T stage.40–42 Intriguingly, the degree of diffusion is closely associated with CRT sensitivity in MIBC, and is useful for predicting CRT response.43 Diffusion-weighted MRI is also useful for monitoring CRT response44 and potentially for monitoring recurrence of bladder cancer in bladder-preserved patients.

Many CRT series showed a clear association between good response to the induction therapy and favorable prognosis. An early series from the University of Paris reported a 3-year CSS rate of 77% for complete responders, but just 23% for the others8. The largest series from the University of Erlangen showed 5-year metastasis-free survival rates of 79% for complete responders and 52% for the others.10 Several studies showed that the prognosis for complete responders can be favorable irrespective of subsequent consolidative therapies.8,34 Given that complete responders after induction CRT typically become bladder preservation subjects, induction CRT plays a role as a tool for selecting optimal patients for bladder preservation, as well as being an effective therapeutic modality.

Prognostic factors in patients treated with trimodality therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Trimodality bladder-sparing therapy
  5. Candidate selection for bladder preservation
  6. Prognostic factors in patients treated with trimodality therapy
  7. Potential limitations of trimodality bladder-sparing therapy
  8. Partial cystectomy as primary therapy for bladder preservation
  9. PC as consolidative therapy after induction CRT: The TMDU protocol
  10. Novel approaches to further improve outcomes of bladder-sparing therapy
  11. Toxicity of CRT and QoL
  12. Conclusions
  13. Acknowledgment
  14. Conflict of interest
  15. References

Other than CRT response, prognostic factors after trimodality therapy include completeness of TURBT, clinical T stage,10,22 lymphovascular invasion,10 serum C-reactive protein level,45 epidermal growth factor receptor expression37 and Her2/NFκB expression.38 Among patients who had undergone salvage cystectomy for clinical residual disease after induction CRT, CSS was favorable in cases of organ-confined disease (≤pT2pN0; 5-year CSS rate, 85%), but quite poor when extravesical disease was present (≥pT3 or pN+, 20%).46

Potential limitations of trimodality bladder-sparing therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Trimodality bladder-sparing therapy
  5. Candidate selection for bladder preservation
  6. Prognostic factors in patients treated with trimodality therapy
  7. Potential limitations of trimodality bladder-sparing therapy
  8. Partial cystectomy as primary therapy for bladder preservation
  9. PC as consolidative therapy after induction CRT: The TMDU protocol
  10. Novel approaches to further improve outcomes of bladder-sparing therapy
  11. Toxicity of CRT and QoL
  12. Conclusions
  13. Acknowledgment
  14. Conflict of interest
  15. References

Potential limitations of trimodality bladder-sparing therapy include (i) recurrence of bladder tumor, particularly MIBC, in the preserved bladder; (ii) potential lack of curative intervention to regional lymph nodes; (iii) increased mortality and morbidity of salvage RC as a result of previous high-dose pelvic irradiation; and (iv) the delay of RC, which might compromise prognosis in a subset of patients who finally require RC after CRT.

Intravesical bladder cancer recurrence

Intravesical tumor recurrence is a common clinical feature of bladder cancer and is observed in the bladder preserved by trimodality protocols. According to relatively large CRT series for which information is available, intravesical bladder cancer recurrence rates range from 19% to 58%.10,14,15,47–49 MIBC recurrences account for approximately one half of intravesical tumor recurrences, with an incidence of 6–28%.10,14,15,47–49 In the largest series from the University of Erlangen, which consisted of 288 bladder-preserved patients, 5-year cumulative bladder cancer recurrence and MIBC recurrence rates were 41% and 28%, respectively.10 According to follow-up studies from Harvard University and the University of Erlangen, NMIBC recurrences did not affect the OS of bladder-preserved patients, while substantially lowering BIS as a result of subsequent development of MIBC recurrences.50,51 In contrast, approximately one half of patients developing MIBC recurrences eventually died of bladder cancer despite salvage RC.10,52

Regarding intravesical tumor recurrence sites, the Harvard University series showed that two-thirds of NMIBC recurrences developed in the original MIBC sites.51 Tunio et al. reported that 39 (21%) out of 186 patients with initial CR to trimodality therapy developed MIBC recurrence, and the recurrence sites were within the original MIBC site in 27 (69%).53 Thus, more than two-thirds of recurrent bladder cancers including MIBC appear to stem from the original MIBC site. This suggests that bladder cancer cells subclinically reside in the original MIBC site, even though pathology of transurethral biopsies together with cystoscopy and radiological findings show no residual disease.

Pelvic recurrence

An upfront RC series showed an incidence of micrometastasis to pelvic lymph nodes of ≥25% for MIBC patients.12 Recent investigations suggest a therapeutic significance concerning PLND at RC for MIBC patients, even if microscopic evidence of lymph node metastasis is absent.54 Early series of trimodality therapy that included pelvic lymph nodes in radiation portals of induction CRT yielded pelvic failure rates of 8.4–13%,15,47,49 which were lower than the incidence of pelvic lymph node metastasis in the upfront RC series. In our single-institutional comparative study, the incidence of pelvic lymph node metastasis was 19% for MIBC patients undergoing upfront RC, but just 8% for those undergoing induction CRT before cystectomy.55 Thus, induction CRT seems to partially eradicate pelvic lymph node micrometastasis, but the effect is limited.

Whether radiation portal including pelvic lymph nodes at induction CRT improves locoregional control of MIBC patients was investigated in a single-institutional randomized study, in which 120 patients received induction CRT at 45 Gy to the whole pelvis and another 110 received induction CRT at 45 Gy to the bladder before boost CRT at 20 Gy to the bladder tumor site. CR rates were 93% for both protocols, and 5-year OS rates were 53% and 51%, respectively. Among the patients who achieved a CR, the incidence of pelvic lymph node recurrence was 15.8% and 17.6%, respectively.53 Thus, whole pelvis irradiation at induction CRT is unlikely to reduce pelvic recurrences compared with bladder-only irradiation. Because of the limited effect of induction CRT on pelvic lymph node micrometastasis, curative intervention to the regional lymph nodes might improve the prognosis of patients treated with a bladder-sparing approach.

Increased mortality and morbidity of salvage RC

Pelvic irradiation causes tissue vulnerability, desmoplastic reaction and ischemia that can affect the surrounding pelvic structures including ureters, the urethra, small bowel and rectum,56,57 making subsequent RC and urinary diversion more technically demanding and morbid. The risk of complications depends on the doses of radiation given. High-dose (>60 Gy) pelvic irradiation is likely to increase both mortality and morbidity of RC; in patients undergoing RC after definitive radiotherapy (>60 Gy), mortality rates range from 6% to 33%,11,58,59 higher than the rates reported in published contemporary RC series for non-irradiated subjects, which range up to 4%.60–65 Reportedly, intermediate-dose (45–55 Gy) pelvic irradiation does not significantly increase mortality, but does increase morbidity associated with stomal stenosis.57 As for low-dose pelvic irradiation, induction CRT at 40 Gy does not severely compromise subsequent RC. Of 87 patients who underwent RC after induction CRT, none experienced perioperative grade 4 (life-threatening complications) or grade 5 (death) complications according to the Clavien–Dindo classification.65 Induction CRT increased urinary anastomosis-related complications by sixfold compared with the upfront RC group, but minor complications of Clavien grade 1 or 2 account for 60%.66

Impaired prognosis by the delay of RC in a subset of patients

Another potential limitation is the delay of RC, which might impair the prognosis for a subset of patients who have not achieved CR to induction CRT. Specifically, the patients who are disadvantaged by bladder-sparing therapy would be those who have developed unresectable disease during CRT, accounting for less than 5% of MIBC patients.34 CRT-resistant tumors are generally aggressive and at high risk for developing micrometastases at the onset of treatment.67 Because it is uncertain whether upfront RC improves survival of patients with such aggressive MIBC, it would be important to predict CRT resistance pretherapeutically and consider intensive neoadjuvant systemic therapy against those with CRT-resistant MIBC in the future.

Partial cystectomy as primary therapy for bladder preservation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Trimodality bladder-sparing therapy
  5. Candidate selection for bladder preservation
  6. Prognostic factors in patients treated with trimodality therapy
  7. Potential limitations of trimodality bladder-sparing therapy
  8. Partial cystectomy as primary therapy for bladder preservation
  9. PC as consolidative therapy after induction CRT: The TMDU protocol
  10. Novel approaches to further improve outcomes of bladder-sparing therapy
  11. Toxicity of CRT and QoL
  12. Conclusions
  13. Acknowledgment
  14. Conflict of interest
  15. References

PC is a viable bladder-sparing modality that offers complete tumor resection, adequate bladder and sexual function, and accurate staging and potential eradication of micrometastasis by carrying out PLND concurrently. Because early PC series showed high tumor recurrence rates as a result of suboptimal patient selection,68 this procedure has fallen out of favor. However, two large cancer centers in the USA recently reported improved local control rates after PC in MIBC patients with stringent selection criteria. In a Memorial Sloan-Kettering Cancer Center series of 58 patients, the 5-year OS rate was 69%, and 74% were alive with intact bladder at a median follow up of 31 months. Seven (12%) and four (7%) had NMIBC and MIBC recurrences in the preserved bladder, respectively.69 In an M.D. Anderson Cancer Center experience of 37 patients, the 5-year OS and CSS rates were 67% and 87%, respectively, and 65% were alive with intact bladder after a median follow up of 55 months. The intravesical recurrence rate was 24% for NMIBC and 11% for MIBC during the follow up.70 In both institutions, candidate MIBC patients for PC were those with a solitary tumor without concomitant CIS that was amenable to resection with a sufficient surgical margin (2 cm) and without the need for ureteral reimplantation in a normally functioning bladder. Among total MIBC patients, just 3–10% were estimated to meet these criteria.69,70

In the largest contemporary PC series from China, adjuvant MVAC and subsequent radiotherapy at 45–50 Gy was given when pathology of PC specimens showed pT3–4 or pN+ disease. The 5-year CSS and BIS rates for 100 MIBC patients were 68% and 63%, respectively. NMIBC and MIBC recurrences were observed in 46% and 14% of patients, respectively.71 The oncological outcomes were comparable with those of the two series from the USA (Table 3).

Table 3.  Series of bladder-sparing treatment for muscle-invasive bladder cancer incorporating partial cystectomy
Investigator (publication year)No. patientsInduction therapySelection criteria5-year OS (%)5-year CSS (%)Alive with intact bladder (%)NMIBC recurrence (%)MIBC recurrence (%)
  • Adjuvant MVAC and radiotherapy at 45–50 Gy was given for patients with pT3–4 or pN+.

Holzbeierlein (2004)6958Solitary, no CIS69NA74 (at median follow-up of 31 months)127
Kassouf (2006)7037Solitary, no CIS678765 (at median follow-up of 55 months)2411
Zhang (2010)71100No CIS, amenable to PCNA6871 (at median follow-up of 32 months)4614
Sternberg (2003)7213MVACSolitary, responders to MVAC69NANA15 (at median follow-up of 88 months)23
Smaldone (2008)7325Radiotherapy at 25 GySolitary, no CIS7084NA8 (at median follow-up of 43 months)8
Koga (2011)7446CRT at 40 GySee Figure 29510091 (at median follow-up of 36 months)150

PC as consolidative therapy after induction CRT: The TMDU protocol

  1. Top of page
  2. Abstract
  3. Introduction
  4. Trimodality bladder-sparing therapy
  5. Candidate selection for bladder preservation
  6. Prognostic factors in patients treated with trimodality therapy
  7. Potential limitations of trimodality bladder-sparing therapy
  8. Partial cystectomy as primary therapy for bladder preservation
  9. PC as consolidative therapy after induction CRT: The TMDU protocol
  10. Novel approaches to further improve outcomes of bladder-sparing therapy
  11. Toxicity of CRT and QoL
  12. Conclusions
  13. Acknowledgment
  14. Conflict of interest
  15. References

The use of PC in CRT-based bladder-sparing strategies would help overcome the inherent limitations of the trimodality therapy aforementioned: subclinical residual disease in original MIBC sites and micrometastases in pelvic lymph nodes can be eradicated by PC with PLND. Furthermore, the total dose of pelvic irradiation can be reduced by replacing boost CRT with consolidative PC, which might lower the risk of perioperative complications at salvage RC in case of MIBC recurrence. In terms of candidate selection, induction CRT would permit more MIBC patients to meet rigorous criteria for PC. To date, a small number of groups have reported their experience with small cohorts of selected MIBC patients treated with PC as a consolidative therapy after induction systemic chemotherapy72 or low-dose radiotherapy73 (Table 3). Series of PC after induction chemotherapy alone or low-dose radiotherapy alone showed similar survival and bladder cancer recurrence rates compared with upfront PC series, suggesting that such induction therapies are no more likely to improve oncological outcomes of PC for patients selected according to stringent criteria.

A selective bladder-sparing protocol incorporating consolidative PC with PLND after induction LCRT has been carried out at TMDU since 1997.34,45,75,76 The TMDU bladder-sparing protocol is shown in Figure 2. Essentially, all patients with cT2-4aN0M0 bladder cancer enrol in the protocol, except those unfit for cisplatin administration as a result of severely impaired renal function, and thus there is little selection bias in the study cohort. Only patients who desire bladder preservation and who meet PC criteria selectively undergo PC with PLND; otherwise, RC is recommended. The PC criteria include: (i) intravesically unifocal tumors (<25% of the bladder in area, excluding the bladder neck and trigone); (ii) no involvement of the bladder neck or trigone; and (iii) no residual tumor, or only small amounts of residual NMIBC in the original MIBC site at restaging TURBT. After debulking TURBT and random biopsy, induction LCRT consisting of radiotherapy to the small pelvis at 40 Gy and two cycles of systemic administration of cisplatin (20 mg/day for 5 days) is given. Of 183 MIBC patients undergoing induction LCRT, 65 (36%) met the PC criteria and 46 (25%) actually underwent PC with PLND, which was carried out using GasLESS techniques.74,77 The conceptual outline of GasLESS PC with PLND is shown in Figure 3. Among the 183-patient cohort, the 5-year OS and CSS rates were 64% and 71%, respectively. For the 46 patients undergoing PC, the 5-year OS and CSS rates were 95% and 100%, respectively. Importantly, none of these patients developed MIBC recurrence in the preserved bladder or pelvic lymph node recurrence after a median follow up of 36 months. In contrast, MIBC recurrence was observed in three (23%) out of 13 patients who achieved CR after induction LCRT and met the PC criteria, but declined PC (non-PC group). A significant difference in intravesical MIBC recurrence-free survival was observed between the PC and non-PC groups (100% and 83% at 5 years, respectively). The 5-year CSS rate was also significantly better in the PC group than the non-PC group (100% and 79%, respectively).74 This study clearly shows two points. First, when debulking TURBT and induction LCRT are applied, the bladder can be preserved through PC with PLND in up to 40% of MIBC patients while maintaining favorable oncological outcomes. Second, PC potentially reduces the risk of intravesical MIBC recurrence among patients who have achieved CR after induction LCRT. When compared with other PC series, the induction LCRT plus PC protocol might yield more favorable survivals (Table 3). To address this, validation or randomized studies are desirable.

image

Figure 2. Algorithm of bladder-sparing protocol incorporating partial cystectomy with PLND as consolidative therapy at TMDU.

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image

Figure 3. Conceptual outline of GasLESS partial cystectomy with pelvic lymph node dissection. En bloc excision of the lower ureter and ureteroneocystostomy is carried out when the original MIBC involves the ureteral orifice. Through a coin-sized single port, a wide working space is prepared by separating the anatomical plane extraperitoneally without CO2 gas insufflation. The surgical procedure is completed at low equipment cost due mainly to the use of few disposable devices. Recently, a 3-D endoscope has been applied to GasLESS.

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Novel approaches to further improve outcomes of bladder-sparing therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Trimodality bladder-sparing therapy
  5. Candidate selection for bladder preservation
  6. Prognostic factors in patients treated with trimodality therapy
  7. Potential limitations of trimodality bladder-sparing therapy
  8. Partial cystectomy as primary therapy for bladder preservation
  9. PC as consolidative therapy after induction CRT: The TMDU protocol
  10. Novel approaches to further improve outcomes of bladder-sparing therapy
  11. Toxicity of CRT and QoL
  12. Conclusions
  13. Acknowledgment
  14. Conflict of interest
  15. References

Efforts have been made to improve the outcomes of bladder-sparing therapy. These can be roughly divided into (i) refinement of radiotherapy techniques; (ii) intensification of concomitant or adjuvant chemotherapy; and (iii) use of molecular targeting agents to potentiate CRT response.

Refinement of radiotherapy techniques

For radiotherapy against bladder cancer, a four-field technique is typically used. Novel radiation techniques aim at delivering a high radiation dose to the tumor while minimizing irradiation to surrounding tissue. Such techniques include IMRT and proton beam therapy. In a preliminary series of 16 bladder cancer patients, IMRT significantly reduced radiation doses given to normal surrounding tissue including the rectum, bowel and femoral heads compared with conformal sequential boost techniques, and no severe gastrointestinal toxicity (grade 3 or 4) was reported.78 In a proton beam therapy series from the University of Tsukuba, Japan, of the 25 patients who received conventional induction CRT at 41.4 Gy with concurrent IAC, 23 who achieved a CR underwent boost proton beam therapy at 33 Gy to the tumor site. The 5-year OS rate for the 23 patients was 61% and only one patient required salvage cystectomy (the 5-year bladder preservation rate for survivors was 96%). No grade 3 or 4 gastrointestinal or genitourinary adverse event was observed.79 According to the Erlangen series, 9% and 15% of patients treated with conventional CRT at 50.4–59.4 Gy reported grade 3 and 4 genitourinary and gastrointestinal toxicities, respectively.10 Although still preliminary, novel radiation techniques might result in better tumor targeting while reducing side-effects and improving treatment outcomes compared with conventional radiotherapy techniques.

Radiotherapy is typically given in daily fractions of 2 Gy. Altered fractionation schedules might improve therapeutic effects. Theoretically, hyperfractionation schedules offer potential advantages of an improved biological effect with better control of rapidly proliferating tumors and a reduced likelihood of developing long-term complications by reducing radiation dose per fraction. A meta-analysis of randomized trials showed an increased CR rate and better survival in bladder cancer patients treated with hyperfractionated radiotherapy when compared with those receiving once-daily fraction radiotherapy.80 Practically, hyperfractionation results in more rapid completion of induction CRT and thus a shorter interval to salvage RC for non-responders, potentially contributing to improvements in survival for such patients.

Intensification of concomitant or adjuvant chemotherapy

Other efforts made to improve therapeutic outcomes of bladder-sparing approaches include intensification of chemotherapy. As gemcitabine is a rather potent radiosensitizer, its clinical application has to be implemented carefully as a result of an increased toxicity to normal tissues. Indeed, a phase II trial of concurrent thoracic radiotherapy with weekly gemcitabine at 1000 mg/m2 in stage III non-small cell lung cancer patients was prematurely closed because of significant pulmonary and esophageal toxicities.81 For MIBC patients, several clinical trials of CRT using gemcitabine have been carried out. In phase I trials, when gemcitabine was given twice weekly concurrently with radiotherapy at 60 Gy, the maximum-tolerated dose was 27 mg/m2.82 When given once weekly adjunctively with conformal radiotherapy at 52.5 Gy, the maximum recommended dose was 100 mg/m2.83 The former study consisting of 23 evaluable patients with clinical T2 disease yielded 5-year OS and BIS rates of 76% and 62%, respectively.84 For the latter study, the CR rate was 87.5% and all eight patients were disease free at a median follow up of 19.5 months.83 According to a phase II trial from the same group using weekly gemcitabine at 100 mg/m2 with concurrent conformal radiotherapy at 52.5 Gy, the CR rate was 88% (44/50) and 5-year OS and CSS rates were 65% and 78%, respectively.85 These results encourage phase III trials.

In recent series of trimodality therapy (Table 1), systemic chemotherapy with gemcitabine and cisplatin (GC regimen), which showed equivalent efficacy and less toxicity than the MVAC regimen in metastatic bladder cancer patients,86 was combined in neoadjuvant23,25 or adjuvant settings.24 Although a meta-analysis of randomized studies showed survival benefits of cisplatin-containing systemic neoadjuvant chemotherapy before RC,87 the efficacy of neoadjuvant or adjuvant GC regimens in trimodality therapy remains unknown.

A unique bladder-sparing strategy using radiation plus intensified IAC with hemodialysis was reported from Osaka Medical College, Japan.32 The regimen consisted of conformal radiation at 60.4 Gy with balloon-occluded IAC with high-dose cisplatin (100–300 mg as a single bolus). Hemodialysis was combined through two double-lumen catheters placed in the bilateral common iliac vein to reduce IAC-related toxicities. Of 96 MIBC patients, of whom most were unfit for RC, 73 (76%) achieved CR and 70 (73%) retained their native bladder during a mean follow-up period of 3 years (Table 2). No grade 3 or greater severe toxicity was observed among the 96 patients. Despite potential selection bias, patients treated with a bladder-sparing protocol showed better OS than those undergoing upfront RC, with respective 5-year OS rates of 76.3% and 59.8%.

Combination with molecular targeting therapy

In the current era of molecular targeting therapy, molecular targeting agents are also being studied as CRT sensitizers. In a study from the RTOG, expression of Her2 and epidermal growth factor receptor was associated with CRT resistance and CSS, respectively.37 Based on these findings, the RTOG is currently carrying out a clinical trial (RTOG 05–24) incorporating trastuzumab, an inhibiting monoclonal antibody against Her2, along with paclitaxel and radiation in patients with Her2 overexpressing bladder cancer.

Very recently, our group reported that overexpression of NFκB was associated with CRT resistance along with Her2 overexpression.38 The CRT resistance rate was 89% for tumors overexpressing NFκB and/or Her2, but just 11% for those negative for both. Overexpression of NFκB and/or Her2 was identified as an independent risk factor for bladder cancer death, suggesting that targeting both NFκB and Her2 would improve CRT response and consequently the prognosis of patients with MIBC overexpressing these anti-apoptotic proteins. In preclinical models, we showed that inhibitors of molecular chaperone heat shock protein 90 (Hsp90),88 which simultaneously inhibits NFκB activation and destabilizes Her2, tumor-selectively sensitize CRT-resistant bladder cancer cells to CRT.89 Hsp90 inhibitors are now under clinical trials against various malignancies.90 These findings encourage clinical trials of Hsp90 inhibitors to overcome CRT resistance and further improve the prognosis and QoL of MIBC patients.

Toxicity of CRT and QoL

  1. Top of page
  2. Abstract
  3. Introduction
  4. Trimodality bladder-sparing therapy
  5. Candidate selection for bladder preservation
  6. Prognostic factors in patients treated with trimodality therapy
  7. Potential limitations of trimodality bladder-sparing therapy
  8. Partial cystectomy as primary therapy for bladder preservation
  9. PC as consolidative therapy after induction CRT: The TMDU protocol
  10. Novel approaches to further improve outcomes of bladder-sparing therapy
  11. Toxicity of CRT and QoL
  12. Conclusions
  13. Acknowledgment
  14. Conflict of interest
  15. References

CRT is generally well tolerated. Common acute radiation-induced adverse effects including transient cystitis and enteritis are usually managed symptomatically. The symptoms typically resolve within 2 weeks after completion of CRT. Regarding late toxicity, just 7% of patients experienced late pelvic (genitourinary and gastrointestinal) toxicity and most incidents did not persist.91 Very few patients had severe bladder toxicity requiring RC; none of the 348 patients at Harvard University and just three of 186 patients at Erlangen University required RC for bladder morbidity.10,52 Among late complications of CRT, potential risk of secondary malignancies induced by CRT is another concern. Reportedly, pelvic irradiation is associated with an increased risk of secondary leukemia92 and rectal cancer.93 Although not yet reported in MIBC patients treated with CRT-based bladder-sparing protocols, careful and long-term follow up for secondary malignancies is mandatory.

After bladder preservation through trimodality therapy, most patients maintain a good QoL with favorable bladder and sexual function. According to a QoL and urodynamic study from Harvard University, three-quarters of bladder-preserved patients retained compliant bladders with normal capacity and flow values, 85% of them reported no or only mild bladder symptoms, half the men reported normal erectile function, and only one-fifth had mild to moderate bowel symptoms.94 Cross-sectional studies of MIBC patients showed better sexual function after CRT than RC and no significant difference in bowel symptoms.95–97 Health-related QoL of bladder-preserved MIBC patients treated with CRT was not significantly different from that of NMIBC patients treated conservatively.98

In MIBC patients treated with PC after induction CRT, bladder capacity was transiently reduced to approximately 100 mL just after PC, but typically recovered to >300 mL within 6 months. A median IPSS of 33 patients treated with PC was 5, which is comparable with that of age-matched Japanese men.74

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Trimodality bladder-sparing therapy
  5. Candidate selection for bladder preservation
  6. Prognostic factors in patients treated with trimodality therapy
  7. Potential limitations of trimodality bladder-sparing therapy
  8. Partial cystectomy as primary therapy for bladder preservation
  9. PC as consolidative therapy after induction CRT: The TMDU protocol
  10. Novel approaches to further improve outcomes of bladder-sparing therapy
  11. Toxicity of CRT and QoL
  12. Conclusions
  13. Acknowledgment
  14. Conflict of interest
  15. References

Similar to the goal of RC, the primary goal of a bladder-sparing approach is complete eradication of bladder cancer cells. Although survivals of MIBC patients treated with bladder-sparing approaches are almost comparable with those of RC series, this therapeutic option has not yet become established as the standard of care for MIBC. Why is acceptance resisted? The major reason is the lack of randomized trials. The unfortunate closure of the SPARE trial made clear the difficulty of carrying out randomized trials that include disparate treatment strategies.99,100 The SPARE trial randomized MIBC patients to selective bladder preservation versus RC, and was launched in the UK in 2007. Unfortunately, just 45 patients were recruited out of >800 candidates over 30 months, and the lack of eligible patients appeared to be the fundamental reason why the proposed phase III trial was deemed infeasible. One fact of interest is that despite RC being viewed by many physicians as the “gold-standard”, many patients declined randomization because they preferred the bladder-sparing arm that provided chemotherapy and radiotherapy.99

Additional potential reasons why bladder-sparing approaches are not embraced are the inherent complexity of therapeutic protocols, and a referral issue. In many Western countries, urologists typically perform surgical therapies and carry out primary management of MIBC patients, whereas medical and radiation oncologists independently take the initiative in managing patients treated with chemotherapy and radiotherapy. Patients treated with a multidisciplinary approach need to transfer among various departments and at least three specialist physicians are involved in their care. Thus, complex patient pathways might be an obstacle to broad adoption of CRT-based bladder-sparing therapy. Also, urologists might hesitate to refer patients to other specialists, because they can treat patients using the RC “gold standard” modality, and avoid the delays in definite treatment that referrals entail. In this respect, the multidisciplinary approach would be feasible in Japan, where urologists typically play an initiative role in managing MIBC patients that also receive chemotherapy and radiotherapy.

The best way to widely spread the bladder-sparing approach is to carry out randomized trials with RC; however, it would be difficult to realize the study because of the aforementioned reasons. Alternatively, accumulating evidence derived from prospective studies in large patient cohorts with longer follow up at expertise centers and validation studies at inexperienced institutions would facilitate the prevalence of the bladder-sparing therapy.

Most developed countries around the world now face rapidly aging populations. With the aging of societies, the number of elderly MIBC patients unfit for RC because of comorbidity will increase and thus the demand for bladder-sparing approaches will also inevitably increase. To date, a number of studies have shown that a substantial proportion of MIBC patients are able to conserve their bladder without compromising survival. In the future, molecular profiling of anti-apoptotic pathways and functional imaging analyses of tumors are likely to play important roles in accurate selection of patients who should benefit most from bladder-sparing therapy. In addition, better local control, achieved by incorporating novel radiation techniques, novel sensitizers (including molecular targeting agents to potentiate CRT response) and consolidative PC with PLND, is expected to further improve outcomes of bladder-sparing approaches and consequently provide more MIBC patients with favorable QoL with their native bladder.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Trimodality bladder-sparing therapy
  5. Candidate selection for bladder preservation
  6. Prognostic factors in patients treated with trimodality therapy
  7. Potential limitations of trimodality bladder-sparing therapy
  8. Partial cystectomy as primary therapy for bladder preservation
  9. PC as consolidative therapy after induction CRT: The TMDU protocol
  10. Novel approaches to further improve outcomes of bladder-sparing therapy
  11. Toxicity of CRT and QoL
  12. Conclusions
  13. Acknowledgment
  14. Conflict of interest
  15. References
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