World J Urol (2006) 24:517–529 DOI 10.1007/s00345-006-0114-y
T O PI C P APER
Bladder-sparing approaches to invasive disease Jason A. Efstathiou · Anthony L. Zietman · Donald S. Kaufman · Niall M. Heney · John J. Coen · William U. Shipley
Published online: 3 November 2006 © Springer-Verlag 2006
Abstract Although immediate radical cystectomy remains the standard of care for invasive bladder cancer, a large body of international experience from single institutions and cooperative groups has accumulated, suggesting favorable results with bladder-sparing approaches in appropriately selected patients. Modern selective bladder preservation with trimodality therapy, consisting of transurethral resection of the bladder tumor, radiation, and chemotherapy, can achieve complete response rates of 60–80%, 5-year survival rates of 50–60%, and survival rates with an intact bladder of 40–45%. Although no randomized comparisons between cystectomy and trimodality therapy exist, long-term data conWrm that the 10-year overall and disease-speciWc survival rates for patients in bladder-sparing protocols are comparable to outcomes reported in contemporary cystectomy series. In addition, quality of life studies have demonstrated that the retained native bladder functions well. Thus, trimodality therapy with careful cystoscopic surveillance and with prompt cystectomy for invasive recurrences has emerged as a
J. A. Efstathiou (&) · A. L. Zietman · J. J. Coen · W. U. Shipley Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 100 Blossom Street, Cox 3, Boston, MA 02114, USA e-mail:
[email protected] D. S. Kaufman Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA N. M. Heney Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
legitimate alternative to extirpative surgery. Future work will continue to optimize the bladder-sparing regimen while limiting toxicity. Keywords Bladder cancer · Radiation therapy · Chemotherapy · Radical cystectomy · Trimodality therapy · Organ preservation
Introduction Treatment options for muscle-invasive transitional cell carcinoma (TCC) of the bladder include radical cystectomy and organ-sparing approaches. Radical cystectomy involves en bloc removal of the bladder, distal ureters, pelvic peritoneum, urethra and regional pelvic lymph nodes, along with the uterus, fallopian tubes, ovaries and anterior vaginal wall in women, and the prostate and seminal vesicles in men. Such extirpative surgery remains the gold standard and the most common treatment oVered for the management of primary muscle-invasive bladder cancer. Traditionally, it has resulted in eVective local control and is often curative, with pelvic recurrence rates between 5 and 20%, and overall 5-year survival between 40 and 60% [1–9]. Operative mortality rates range between 2 and 5%, and perioperative complications occur up to 30% of the time [7, 9–12]. Following radical cystectomy, there are several types of urinary diversions [13]. The standard diversion consists of an ileal loop draining via an abdominal stoma into an appliance acting as an external reservoir. Recent advances in surgical technique allow for continent diversions that are becoming increasingly available. These include the Kock pouch (ileum) and
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Indiana pouch (colon), which act as internal reservoirs and have nipple continence valves, requiring frequent self-catheterization through a stoma. In an orthotopic neobladder, an ileal pouch is connected to the urethra and the patient relaxes pelvic Xoor muscles and increases abdominal pressure to void more naturally. However, a continent diversion does not necessarily improve patient satisfaction over an ileal conduit [14]. Complications, such as acid–base disturbances, electrolyte abnormalities, ureteral obstruction, stomal stenosis, intestinal Wstula, ureteroileal urinary leakage, urinary tract infections, and the need for revision procedures are not uncommon. In addition to long-term problems related to urinary diversion, sexual function is often impaired following radical cystectomy. Thus, the opportunity to retain a native bladder has obvious potential advantages, as long as the chance of cure is not compromised. While cystectomy remains the most commonly oVered and used approach, there has been increasing interest in bladder preservation. The use of combinedmodality treatments to achieve organ preservation has become an important paradigm for the management of many malignancies, including cancers of the head and neck, breast, esophagus, prostate and anus, as well as extremity sarcomas. Reports of equivalent outcomes with surgery reserved for salvage has made organ-preserving therapy an attractive treatment choice for selected patients. Inspired by successes in other disease sites, eVorts were made to establish a similar treatment approach in invasive bladder cancer. Modern bladdersparing approaches combine limited surgery in conjunction with radiation therapy and chemotherapy and have produced favorable results. In appropriately selected patients, combined-modality therapy can preserve a tumor-free bladder without compromising survival.
External beam radiation therapy (EBRT) with immediate versus salvage cystectomy In the 1970s, preoperative radiation therapy in patients undergoing cystectomy was the standard of care [15, 16]. In subsequent randomized trials, preoperative radiation was shown to improve local control but not survival when compared to cystectomy alone [17–20]; thus, it fell out of favor, in part to avert pelvic radiation that could complicate urinary diversion. However, over the past 30 years, external beam radiation therapy (EBRT) has remained the most frequently utilized bladder-sparing treatment. Until recently, its role was limited to patients who were considered medically
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inoperable or who refused cystectomy, or as palliation for locally advanced, unresectable tumors. Four randomized trials have compared pre-operative EBRT (40–50 Gy) followed by immediate radical cystectomy to deWnitive EBRT (60 Gy) with cystectomy for salvage [18–21]. Three of these trials demonstrated equivalent long-term survival rates with either approach, suggesting that bladder preservation could be attempted without compromising survival. The Urologic Cooperative Group from the United Kingdom reported on 189 patients [20]. Those randomized to immediate cystectomy had 5- and 10-year overall survival rates of 39 and 19%, respectively, versus 28 and 15% in those randomized to radiation and salvage cystectomy (P = not signiWcant). The Danish National Cancer Group also failed to demonstrate a signiWcant overall 5-year survival diVerence in 183 patients (29% for cystectomy vs. 23% for radiation and salvage cystectomy) [19]. The local or pelvic failure rate was lower in patients randomized to immediate cystectomy as compared to primary radiation (7 vs. 35%); however, the incidence of metastatic disease at 5-years was similar in both groups (34 and 32%, respectively). Similarly, the National Bladder Cancer Group reported on 72 patients and found no diVerence in the 5-year overall survival or distant metastasis rate in patients undergoing immediate cystectomy (27 and 38%, respectively), as compared to primary radiation and salvage cystectomy (40 and 31%, respectively) [21]. The only trial demonstrating a statistically signiWcant 5-year survival beneWt (45 vs. 22%) associated with immediate cystectomy was from the University of Texas MD Anderson Cancer Center [18]. However, this trial of 67 patients included large T3 tumors unlikely to be adequately controlled with radiation alone. In sum, these trials set the stage for selective bladder preservation by suggesting that the deferral of cystectomy until time of local recurrence did not necessarily compromise overall survival or the incidence of metastatic disease after radiation therapy.
Single modality therapy Single modality bladder-sparing approaches generally have had unacceptably low rates of local control. Results suggest that limited bladder-sparing surgery alone, such as partial cystectomy or transurethral resection of bladder tumor (TURBT), produces poor outcomes. TURBT alone can be expected to achieve only a 20% likelihood of local disease control [22–24]. In one study, only 45 of 217 consecutive patients with
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muscle-invasive disease who underwent TURBT alone had no evidence of muscle invasion on restaging cystoscopy [22]. Somewhat better results may be achieved in carefully selected patients; for example, those with well-diVerentiated, solitary lesions invading the superWcial detrusor muscle only, without associated carcinoma in situ (CIS), a palpable mass, or hydronephrosis. In the late 1970s, it was determined that chemotherapy (i.e., cisplatin) had activity against TCC. However when given alone as monotherapy, it provided a durable local control rate of less than 20% [24]. Although EBRT monotherapy resulted in higher local control around 40% [25–30], salvage cystectomy was still required for many of these patients who did not completely respond.
Trimodality therapy and selective organ preservation Rationale and schema Given that several studies demonstrated high local and distant recurrence rates with single modality treatment and that the complete response rate to TURBT followed by chemotherapy was nearly twice that achieved by chemotherapy alone [31–33] and that combining chemotherapy and radiation further improved bladder intact disease-free survival, combined-modality treatment approaches for invasive bladder cancer have attracted the attention of investigators. The primary goal of these protocols has been to oVer maximal chance of cure while preserving bladder function. In general, they follow a common algorithm (see Fig. 1), including maximal TURBT as is safely possible followed by an induction course of concurrent chemoradiation. An assessment of early treatment response is performed, including histologic response evaluated by cystoscopy and re-biopsy. Individuals who have a complete clinical response (i.e., tumor site biopsy and urine cytology both negative) continue with bladder-sparing therapy and a consolidation course of chemoradiation (total dose 64–65 Gy). Incomplete responders are advised to have an immediate cystectomy, thus allowing for timely intervention and preserving urinary diversion options. Patients with conserved bladders are then actively followed with frequent cystoscopic surveillance, and prompt cystectomy recommended at the Wrst sign of an invasive recurrence. Such an approach allows for surgical debulking prior to radiation therapy, and it exploits the synergistic eVect of concurrent radiosensitizing chemotherapy
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TURBT
Induction radiation (~40 Gy) and concurrent chemotherapy Cystoscopic assessment of treatment response Complete response
Incomplete response
Consolidation chemotherapy and radiation (~64-65Gy) ± adjuvant chemotherapy AND long-term cystoscopic surveillance
Radical cystectomy ± adjuvant chemotherapy
Recurrent tumor
Fig. 1 Schema for bladder-sparing therapy
(e.g. cisplatin, 5-Xuorouracil (5-FU) or taxol) to enhance local tumor cell death. Aside from a coordinated and dedicated multidisciplinary team of urologic surgeons, radiation oncologists, and medical oncologists, the most important aspect of a successful bladder-sparing regimen is, of course, patient selection. The best candidates for such an approach are patients with a solitary, early stage lesion of TCC histology and absence of extensive CIS, who have undergone a complete TURBT, with no evidence of hydronephrosis, and with adequate kidney function to tolerate platinum-based chemotherapy. Single-institution experiences During the past 15–20 years, there has been an accumulation of experience from single institutions in both North America and Europe evaluating combinedmodality bladder preservation therapy as an alternative in selected patients (see Table 1). In one of the earliest prospective series from the Massachusetts General Hospital (MGH), 53 patients with muscle-invasive bladder TCC (stage T2–T4a) underwent TURBT, followed by two courses of MCV (methotrexate, cisplatin, vinblastine), and then radiation therapy (40 Gy) concurrent with single agent cisplatin [34]. Radical cystectomy was performed in 8 patients with residual disease, while consolidation chemotherapy and radiation therapy (total dose 64.8 Gy) was continued in 34 patients who had either a complete response or were unsuited for cystectomy. Alternative therapy was administered to 11 patients who could not tolerate either chemotherapy or radiation. After a median follow-up of 4 years, 24 patients (45%) were alive and free of detectable tumor, while 31 (58%) had a functioning bladder that was free of invasive tumor. Of the 28 who
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Table 1 Single-institution experiences of bladder-sparing therapy Institution
Induction therapy
No. of patients
5-year Survival (%)
5-year survival with bladder intact (%)
Complete Response (%)
MGH [35] University of Paris [36, 37] University of Erlangen [38]
TURBT, §MCV, CP (or CP/5-FU) + RT TURBT, 5-FU, CP + RT
190 120
54 63
45 N/a
64 77
TURBT, CP (or Carbo or CP/5-FU) + RT or RT alone
415
51
42
72
MGH Massachusetts General Hospital; TURBT transurethral resection of bladder tumor; MCV methotrexate, cisplatin, vinblastine; CP cisplatin; 5-FU 5-Xuorouracil; RT radiation therapy; Carbo carboplatin; N/a not available
had a complete response to initial therapy and completed consolidation therapy, 89% had a functional tumor-free bladder. The 5-year overall survival rate was 48% for all patients, 68% for those with T2 disease, and 63% for those with a complete response to initial chemoradiation. A later follow-up of this single institution series included 190 patients who were treated similarly, except that surgical candidates with less than a T0 response to initial chemoradiation, and those who could not tolerate the therapy underwent cystectomy (n = 11) [35]. The 5- and 10-year actuarial overall survival rates were 54 and 36%, respectively (stage T2 tumors 62 and 41%). The 5- and 10-year disease-speciWc survival rates were 63 and 59%, and with an intact bladder they were 46 and 45%, respectively. Similarly, in Europe, a number of groups engaged in pioneering eVorts in bladder-sparing therapy. In the University of Paris series, 54 patients with T2–T4 operable invasive bladder cancer were treated with TURBT, followed by concurrent cisplatin, 5-FU, and accelerated twice-daily radiation [36]. The Wrst 18 patients demonstrated no residual tumor on cystoscopic examination and re-biopsy, but all underwent cystectomy as planned and none had residual tumor identiWed in the surgical specimen. Subsequently, patients with a clinical complete response were selected for bladder preservation with additional chemoradiation, and radical cystectomy was reserved for patients with persistent tumor. They reported a complete response rate of 74% and a 3-year diseasefree survival rate of 62% (77% amongst complete responders). There was no diVerence in survival between the complete responders treated with further chemoradiation versus those who underwent cystectomy. In a follow-up series of 120 patients, they reported a complete response rate of 77% and a 5-year survival rate of 63% [37]. In the largest series yet reported, the University of Erlangen compiled their data on 415 patients treated with TURBT and selective bladder preservation (126
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with radiation alone and 289 with chemoradiation) over an 18-year period [38]. Eighty nine patients had T1 disease only, and the remainder had T2–T4. Chemotherapy regimens consisted of cisplatin, carboplatin, or cisplatin and 5-FU. Results were reported for all patients as a group, which somewhat obscured the results for patients treated with combination therapy. A clinical complete response was achieved in 72% of patients. The 5-year overall survival (including T1 patients) was 51%, and survival with an intact bladder was 42%. These results were very similar to those of the MGH and University of Paris. Ten-year diseasespeciWc survival was 42%, with more than 80% of survivors retaining their bladder. Chemoradiation was more eVective than radiation therapy alone in terms of complete response and survival. There was no decrement in survival for patients requiring salvage cystectomy for local failure. Contemporary cystectcomy series These single-institution experiences of modern trimodality therapy compare favorably to contemporary cystectomy series. SpeciWcally, the 10-year overall and disease-speciWc survival rates for all patients and those with T2 tumors (see Table 2) in bladder-preserving protocols are comparable to the results reported with contemporary immediate radical cystectomy. This is even despite confounding due to discordance between clinical and pathological staging. To this point, a prospective study from Sweden provided evidence that clinical staging is more likely to understage the extent of disease (i.e., penetration into the muscularis propria or beyond) [39]. Thus, there very likely is an outcome bias in favor of surgical series that beneWt from pathologic staging. In addition, cystectomy series do not typically report by intention-to-treat and often exclude patients where the procedure is abandoned due to operative Wndings such as positive nodes or unresectable disease.
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Table 2 Survival outcomes in contemporary cystectomy series as compared to the MGH bladder-sparing approach in patients with T2 tumors Institution
Treatment
No. of patients
Median follow-up (years)
Stage
5-year overall 10-year survival (%) overall s urvival (%)
10-year disease/recurrence-free survival (%)
MGH [35]
Trimodality therapy and selective salvage cystectomy Radical cystectomy
90
4.6
cT2
62
41
66
311
14
pT2
63
47
72
Radical cystectomy Radical cystectomy
323 151
3 2.6
pT2 pT2
N/a 63
N/a 38a
65 65a
University of Southern California [78] University of Ulm [9] University of Bern [8]
MGH Massachusetts General Hospital, c clinical, p pathological, N/a not available a Values extrapolated from graph
A few large single-institution surgical series have been published. The University of Southern California (USC) described outcomes on 633 patients with pathologic stage T2–T4a bladder cancer undergoing radical cystectomy. Their 5- and 10-year overall survival rates were 48 and 32%, respectively (stage T2 tumors 63 and 47%) [7]. Another series from Memorial Sloan Kettering Cancer Center, reported a 5-year overall survival rate of 36% in patients with T2–T4 tumors [6]. The University of Ulm series of 788 patients reported 5- and 10-year overall survival rates of 57.7 and 44.9%, respectively; while the University of Bern had rates of 59 and 37%, respectively. An intergroup study examining neoadjuvant chemotherapy in patients undergoing radical cystectomy reported a 5-year overall survival of 50 versus 43% in patients who underwent cystectomy without receiving chemotherapy [40]. Therefore, even contemporary cystectomy series demonstrate a high rate of disease recurrence, with survival outcomes no higher than those that have been observed with modern bladdersparing approaches in comparable patients. Of course, direct comparison is hindered by the lack of a phase III randomized trial of the two approaches.
The RTOG experience In North America, most cooperative group bladdersparing investigation has occurred within the radiation therapy oncology group (RTOG). The RTOG has studied combined modality therapy in a multi-institutional setting, enrolling nearly 500 patients with T2– T4a muscle-invasive bladder cancer who were candidates for cystectomy on 7 prospective protocols (see Table 3). Six of these protocols have been phase I–II trials of concurrent chemoradiation and one was a phase III trial that tested the eYcacy of neoadjuvant chemotherapy with MCV. The background for the initial RTOG study was set by encouraging results reported by the National Bladder Cancer Group using cisplatin as a radiosensitizer with concurrent radiation in 68 patients with invasive bladder cancer who were unsuitable for cystectomy [41] and validated by a randomized trial from the NCI of Canada [42]. RTOG 85-12 treated 42 patients who were candidates for cystectomy with induction oncedaily radiation therapy (40 Gy) and concurrent cisplatin, with cystectomy reserved for patients who
Table 3 RTOG protocols of bladder-sparing therapy (1985–2002) RTOG trial
Induction therapy
No. of patients
5-year survival (%)
Complete response (%)
85-12 [43] 88-02 [44] 89-03 [45] 95-06 [46] 97-06 [47] 99-06 [53] 02-23
TURBT, CP + RT TURBT, MCV, CP + RT TURBT, §MCV then CP + RT TURBT, 5-FU plus CP + RT TURBT, CP + BID RT, adj MCV TURBT, TAX, CP + BID RT; adj CP + GEM TURBT, TAX or 5-FU, CP + BID RT
42 91 123 34 52 84 70
52 51 49 N/a N/a N/a N/a
66a 75a 59 67 74 87 N/a
TURBT transurethral resection of bladder tumor; CP cisplatin; RT radiation therapy; MCV methotrexate, cisplatin, vinblastine; 5-FU 5-Xuorouracil; BID twice-daily; adj adjuvant; TAX paclitaxel; GEM gemcitabine; N/a not available a Urine cytology was not evaluated as a response criterion
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responded incompletely [43]. Complete responders received consolidation therapy, with an additional 24 Gy delivered with concurrent cisplatin. The approach was feasible and well-tolerated, and yielded a complete response rate of 66%, a 5-year survival of 52%, and a 5-year survival with an intact bladder of 42%. The subsequent protocol, RTOG 88-02, was based on the MGH study discussed above, and looked at the role of neoadjuvant MCV given immediately following TURBT. It entered 91 patients and reported a 75% response rate and a 51% 5-year survival rate [44]. This was followed by RTOG 89-03, a phase III trial that directly tested the contribution of two cycles of neoadjuvant MCV chemotherapy before concurrent cisplatin and once-daily radiation [45]. This study fell short of its accrual goal of 174 patients and was prematurely closed because of an unexpectedly high rate of severe leukopenia in the MCV arm, which resulted in a 67% protocol completion rate and three treatmentrelated deaths. Analysis of 123 patients showed no signiWcant diVerences between the MCV arm and the non-MCV arm in 5-year overall survival (48 and 49%, respectively), distant metastasis (33 and 39%, respectively), 5-year survival with an intact bladder (36 and 40%, respectively), or complete response after induction (61 and 55%, respectively). This study was updated after a median follow-up of 8 years, and there remained no signiWcant diVerence in these outcomes. In summary, this trial suggested that two cycles of neoadjuvant MCV did not contribute positively to the outcome. The study, however, was not suYciently powered, so valid conclusions about the usefulness of neoadjuvant chemotherapy cannot be made based on this study. In 1995, the RTOG began phase I–II protocols to evaluate accelerated radiation fractionation treatments in combination with concurrent chemotherapy on an outpatient schedule. RTOG 95-06 evaluated the regimen piloted by the University of Paris, using 5-Xuorouracil (5-FU) plus cisplatin concurrent with accelerated but hypofractionated radiation therapy delivered over 17 days [46]. The eligibility criteria for this protocol were more stringent than previous RTOG studies. Patients with tumor-associated hydronephrosis were excluded, based on Wndings that these patients had a signiWcantly lower complete response rate and a higher cystectomy rate compared with patients who did not present with hydronephrosis. Among 34 evaluable patients, 67% had a complete response on induction and an encouraging actuarial 3-year survival rate of 83% was found. However, seven patients (21%) had Grade 3–4 hematologic toxicity on this regimen. No
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patients required cystectomy for radiation toxicity, despite the hypofractionation. In 1997, the RTOG turned to twice-daily hyperfractionation and began to study the role of adjuvant chemotherapy after treatment with either bladder preservation or cystectomy. In RTOG 97-06, induction and consolidation chemoradiation included twice-daily radiation and outpatient cisplatin (30 mg/m2) given on the Wrst 3 days of each week. Radiation doses of 1.8 Gy to the pelvis and 1.6 Gy to the bladder tumor were given daily for 12 days with a 4–6 h interval between fractions during induction treatment. In the consolidation phase, 1.5 Gy fractions were given to both, twicedaily for 8 days (total dose 45.6 Gy to pelvis and bladder, 64.8 Gy to bladder tumor). After consolidation chemoradiation or cystectomy (depending on response), patients received three cycles of MCV chemotherapy. The complete response rate was 74% and only 11% of patients experienced Grade 3–4 toxicity during induction and consolidation phases [47]. However, only 45% of patients went on to receive a full three cycles of MCV, and of those who did 41% developed Grade 3 toxicity. The potential beneWt of adjuvant chemotherapy in delaying or preventing metastasis exists, as the 2-year actuarial incidence of developing metastasis in this trial was only 18% (compared to about 30% in trials without adjuvant systemic therapy). RTOG 99-06, which closed recently, included some innovative changes. Firstly, it added paclitaxel as a radiation-sensitizing agent during the induction and consolidation schedules [48, 49] along with twice-daily radiation. Secondly, the protocol used the adjuvant chemotherapy regimen of cisplatin (70 mg/m2 on Day 1) and gemcitabine (1,000 mg/m2 on days 1, 8, and 15). In the metastatic setting, this regimen had demonstrated eYcacy equal to that of MVAC with less toxicity [50–52]. Preliminary outcomes of RTOG 99-06 suggest a 73% protocol completion rate with acceptable toxicity and an impressive 87% complete response rate [53], though it must be recognized that patients with hydronephrosis (a poor prognostic indicator) were not eligible for this study. In summary, long-term outcome data from single institution and cooperative group experience suggest that combined modality therapy results in complete response rates of 60–80%, 5-year survival rates of 50–60%, and 5-year survival rates with an intact bladder of 40–45%. Although no randomized comparisons directly comparing cystectomy with combined modality therapy exist, these long-term survival rates are encouraging and similar to those reported in most cystectomy series (see Table 3).
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Ongoing RTOG studies RTOG 02-33 is an ongoing randomized phase II study that continues to address the question of the optimal concurrent chemotherapy regimen by evaluating two induction regimens in an eVort to further enhance the radiation response and improve local control. In this trial, patients are randomized to twice-daily radiation with either concurrent paclitaxel and cisplatin or concurrent 5-FU and cisplatin during the induction and consolidation phases. Adjuvantly, patients receive a triplet regimen of gemcitabine (1,000 mg/m2 on days 1 and 8), paclitaxel (50 mg/m2 on days 1 and 8), and cisplatin (35 mg/m2 on days 1 and 8). This is similar to the triplet regimen piloted by Bellmunt and co-workers [54] and as tested in a Phase III trial led by the European Organization for Research and Treatment of Cancer (EORTC) and the Southwest Oncology Group (SWOG) [55]. In addition to Wne-tuning and optimizing the combined modality regimen, the RTOG Genitourinary Translational Research Group has embarked on eVorts to better delineate the molecular biology of bladder cancer and its response to therapy. In a recent report, the clinical relevance of epidermal growth factor receptor (EGFR) and Her-2 expression as measured by immunohistochemical staining on slides from 73 patients treated on four of the RTOG bladder preservation trials (RTOG 88-02, 89-03, 95-06, and 97-06) [56] was evaluated. EGFR positivity seemed to be a favorable prognostic factor and correlated with improved overall survival (P = 0.044), disease-speciWc survival (P = 0.042), and survival with an intact bladder (P = 0.021). A trend towards decreased incidence of distant metastases was also associated with EGFR expression. On multivariate analysis, adding tumor stage, tumor grade, whether or not a visibly complete TURBT was done, and patient ages to the model, EGFR positivity remained signiWcantly associated with improved disease-speciWc survival. Her-2 overexpression correlated with reduced complete response rates to chemoradiation (50 vs. 81%, P = 0.026), which remained signiWcant on multivariate analysis. Unlike Wndings in other studies, p53 and p16 had no prognostic signiWcance [57]. Further investigation into the potential diagnostic and therapeutic implications of these Wndings is warranted and may lead to the rational development of targeted therapies. In the translational spirit, the RTOG recently opened protocol 05-24, which looks at a combination of paclitaxel and trastuzumab (Herceptin) with daily radiation therapy following TURBT for non-cystectomy candidates with muscle-invasive blad-
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der cancer. This is the Wrst example of molecular targeted therapy being added to standard treatment for bladder cancer.
Clinical predictors of outcome In addition to molecular determinants of response, a number of clinical factors may predict outcome to combined modality therapy for invasive bladder cancer. Initial clinical stage continues to be the most important predictor of overall survival. In the MGH series, 5-year overall survival and disease-speciWc survival for stage T2 was 62 and 74%, respectively, while for stage T3– T4a it was 47 and 53% [35]. Similarly, 5-year diseasespeciWc survival with an intact bladder was 57% for patients with T2 disease, and only 35% for patients with stage T3–T4a. In the University of Erlangen series, 5-year overall survival was 75% for stage T1, 56% for T2, 44% for T3, and 17% for T4 [58]. The distant metastasis rate also has been shown to be associated with tumor stage and size [59]. The presence of hydronephrosis at the time of diagnosis also impacts treatment success. In the MGH series, 27 of 190 patients had hydronephrosis initially [35], and their complete response rate was 37%, compared to 68% in patients without hydronephrosis (P = 0.002). There was a trend towards improved survival among those patients who did not have hydronephrosis. The 5-year overall and disease-speciWc survival was 48 and 53% for patients with hypdronephrosis, compared to 55 and 64% for patients without hydronephrosis. As a result, patients with hydronephrosis have since been excluded from bladder-sparing protocols. In the Erlangen series, initial response to treatment was a predictive factor for disease-speciWc survival and overall survival [38]. This has not held up in other studies, though it may be an independent predictor of successful bladder preservation (discussed further below). Not surprisingly, advanced age predicts poorer overall survival (10-year overall survival 22% if >75 years old versus 40% if 5 cm) tumors, and given the discordance between clinical and pathologic staging (i.e., clinical understaging). Another approach to dose intensiWcation has been to deliver higher doses of EBRT without signiWcantly increasing toxicity by employing techniques that spare the small bowel and rectum. Advances in radiation treatment planning, veriWcation and delivery, including IMRT, are currently being studied. Treatment precision, that takes into account organ motion and patient positioning, is particularly important. As with prostate and gynecologic malignancies, pressure from surrounding bowel and rectum as well as changes in the volume of urine within the bladder lead to considerable position variation [70, 71]. Fiducial marker placement, realtime image guidance, and adaptive radiation are being evaluated and seem promising [72, 73]. Another means of improving bladder-sparing approaches has been to further optimize concurrent chemotherapy regimens. Novel chemotherapeutic approaches include newer drug regimens and mechanisms of delivery. In a phase I trial from the University of Michigan, twice-weekly gemcitabine with concurrent radiation has been shown to be well tolerated and
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to result in high rates of complete response (91%) and bladder preservation, with 78% alive (70% with bladder intact) after a median follow-up of 40.5 months [74]. In a study from Ottawa, intra-arterial (as opposed to intravenous) delivery of cisplatin and concurrent radiation has hopes of achieving a higher concentration of cisplatin in tumors and thus enhance radiosensitization [75]. This series of 200 patients reported a durable complete response rate of 90%, tumor-free bladder preservation rate of 75%, and 5-year overall and disease-speciWc survival rates comparable to cystectomy of 50 and 60%, respectively. Patient selection and eligibility criteria also may be extended in the future. Encouraging results from Erlangen suggest that for patients with high-risk T1 bladder tumors (i.e., high-grade, multifocal, large size, or multiply recurrent), a bladder-sparing approach with chemoradiation may provide a reasonable alternative to intravesical treatment or early cystectomy [76]. Furthermore, there is evidence that combined modality therapy may be feasible and safe and oVer acceptable outcomes even in patients with poor renal reserve, hydronephrosis, and advanced disease [77].
Conclusion In selected patients with muscle-invasive bladder cancer, bladder-sparing approaches appear to provide a valid and eVective treatment alternative to radical cystectomy. Evidence from institutions in North America and Europe suggests that bladder-preserving trimodality therapy oVers a high likelihood of eradicating the primary tumor while preserving good bladder function without compromising long-term survival. The optimal regimen of combined radiation and chemotherapy continues to be investigated, as does the addition of rational molecular targeted therapy. Successful selective bladder preservation requires a cooperative eVort by an experienced multidisciplinary team of radiation oncologists, medical oncologists, and urologic surgeons and motivated patients committed to life-long cystoscopic surveillance with early referral for cystectomy in the case of residual or recurrent invasive disease.
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