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Keywords:

  • urothelial bladder cancer;
  • perioperative chemotherapy;
  • adjuvant;
  • neoadjuvant;
  • pattern of use;
  • outcome

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References

Objective

  • To review time-trends in the use of perioperative chemotherapy and its impact on oncological outcomes in patients with bladder urothelial cancer (UC) at a single tertiary institution.

Patients and Methods

  • Using electronic and paper medical records, 89 patients were identified who underwent radical cystectomy with or without perioperative chemotherapy between 2004 and 2011 at Austin Health in Melbourne, Australia.
  • Patient demographics, clinico-pathological characteristics and details of recurrence and death were assessed by retrospective chart review.
  • Survival analysis was carried out using the Kaplan Meier method, with the impact of predictors assessed using Cox proportional hazard models.

Results

  • The median (range) age of this cohort was 65 (37–84) years, and 66 (74%) patients were male. Pathologic features included 68 (76%) pure UC, 21 (24%) mixed UC and 84 (94%) high grade tumours.
  • On clinical staging, 63 (71%) patients had muscle-invasive bladder cancer (cT-stage ≥T2), of whom 11 (17%) received neoadjuvant chemotherapy, with an increasing trend in use over time.
  • Following radical cystectomy, pT-stage ≥T3 and/or node positive were identified in 35 (39%) patients, of whom 16 (46%) received adjuvant chemotherapy. In addition, five patients with stage pT2 received adjuvant chemotherapy.
  • Of the total cohort of patients, 31 (35%) suffered recurrences, and 33 died, 27 from urothelial carcinoma.
  • On multivariate analysis, after adjusting for age, pT-stage and pN-stage, perioperative chemotherapy was associated with a significantly lower risk of recurrence [relative risk (RR) 0.41, p < 0.05], but not death from cancer or all causes.

Conclusions

  • Perioperative chemotherapy, and in particular neoadjuvant chemotherapy, remains relatively under-utilised at our institution despite recent increases.
  • The significant reduction in the risk of recurrence following treatment with perioperative chemotherapy with radical cystectomy highlights the importance of multi-modality treatment in bladder UC.
  • Identifying barriers to more widespread implementation of perioperative chemotherapy is critical for enhancing outcomes in patients with bladder UC.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References

Bladder cancer is a commonly diagnosed disease in Western society. In Australia, an estimated 2217 new cases of bladder cancer were diagnosed in 2007, accounting for 2% of all malignancies [1]. About 70% of bladder cancers are superficial or non-muscle invasive and these patients are treated with transurethral resection, sometimes followed by intravesical immunotherapy or chemotherapy. Muscle-invasive bladder cancer, defined as a primary tumour invading the muscularis propria (TNM stage T2 or greater), has a high recurrence rate and metastatic potential with an estimated 5-year survival rate after cystectomy of 33–73% [2]. The high mortality rate is thought to be due to micro-metastatic disease present at the time of radical cystectomy. As a result, optimal management of muscle-invasive bladder cancer includes high quality surgery together with perioperative chemotherapy [3].

Perioperative chemotherapy entails the administration of neoadjuvant chemotherapy or adjuvant chemotherapy. The rationale for neoadjuvant chemotherapy is its potential to eradicate the primary lesion and to treat micrometastatic foci of disease before the patient is debilitated by the major surgery. Two randomized phase III studies have shown a survival advantage for neoadjuvant chemotherapy in bladder urothelial cancer. The first of these was conducted by the Southwestern Oncology Group (SWOG 8710) and demonstrated an improvement in 5-year survival for patients with clinical stage T2-T4a muscle-invasive bladder cancer treated with three cycles of neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) followed by radical cystectomy compared to radical cystectomy alone (57% vs. 43%; p = 0.06) [4]. The second study was led by the Medical Research Council (MRC) and found that three cycles of neoadjuvant CMV (cisplatin, methotrexate and vinblastine) prior to RC or primary radiotherapy significantly improved overall survival at 10 years compared to surgery or radiation alone (36% vs. 30%; p = 0.037, HR 0.84) [5]. The findings of these two studies are further supported by a meta-analysis which demonstrated a 5% improvement in overall survival with the addition of neoadjuvant cisplatin-based chemotherapy to radical cystectomy (50% vs. 45%; p = 0.016, HR 0.87) [6]. Gemcitabine and cisplatin (GC) is commonly used based on the favourable toxicity profile and efficacy data similar to MVAC, extrapolated from the metastatic setting [7]. A retrospective analysis examined the benefit of neoadjuvant GC and showed almost similar pT0 rates at cystectomy (26% with GC and 28% with MVAC) [8]. This regimen allowed for timely drug delivery with a median 91% drug delivery for cisplatin and 90% for gemcitabine.

The use of adjuvant chemotherapy in muscle-invasive bladder cancer is more controversial. Individual studies of adjuvant chemotherapy have generally been small, recruited slowly and been relatively underpowered. Three small studies published over 15 years ago demonstrated a significant improvement in progression free survival [9-11], however this did not result in enhanced overall survival in two of these studies [9, 11]. More contemporary studies have also failed to demonstrate an improvement in recurrence free survival with either GC [12] or MVAC [13]. Nevertheless, a meta-analysis performed in 2006 showed an absolute improvement in overall survival of 9% at three years [14]. Thus, although there is an absence of positive survival data from large, randomized studies, many medical oncologists will administer adjuvant cisplatin based chemotherapy for patients with perivesical tumour extension (≥pT3) or node positive disease [3].

Despite evidence supporting the use of perioperative chemotherapy in muscle-invasive bladder cancer, anecdotal experience suggests that the uptake of perioperative chemotherapy and especially neoadjuvant chemotherapy has been poor by the Australian oncology community. As a result, we examined the utilisation of perioperative chemotherapy over time in a contemporary cohort of bladder UC patients at our tertiary academic center.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References

Austin Health Uro-Oncology Service

Austin Health is a tertiary medical center in Melbourne, Australia with a multi-disciplinary Uro-Oncology service compromising of urological surgeons, medical oncologists, radiation oncologists and palliative care physicians. In 2007, members of the Uro-Oncology service began attending an institutional multidisciplinary meeting (MDM) [15].

Patient Population

We previously reported the pathological outcome from neoadjuvant chemotherapy for eight patients diagnosed with muscle-invasive bladder cancer [16]. In the present study, we extended our review to the entire cohort of patients treated with radical cystectomy with or without perioperative chemotherapy for bladder UC at Austin Health from 1st January 2004 to 31st December 2011. Patients were identified from our health information system, pharmacy and surgical database. Patients with mixed urothelial carcinoma but not those with pure non-urothelial carcinoma or de-novo metastatic disease were included. The study was approved by the Austin Health Human Research Ethics Committee.

Demographics for all patients as well as clinical and pathological stage were identified from reviewing medical and pathology records. The severity of patient comorbidities was quantified by age-adjusted Charlson Comorbidity Index (AACI) [17]. This comorbidity index was calculated at the time of diagnosis and post cystectomy. All patients started with the index of ≥1 because one point was scored for a history of bladder cancer. For the purposes of data analysis, AACI was stratified at three levels: ≤2, 3–5 and ≥6.

Staging

Clinical stage was determined from clinical examination, cystoscopic and histological findings from transurethral resection of bladder tumour and perioperative imaging according to the TNM classification (American Joint Committee for Cancer, AJCC 7th edition) [18]. Cystectomies were carried out by an open approach, using standardized techniques. Lymph-node dissection was carried out at the discretion of the treating surgeon. Pathological staging was determined from histology reports following cystectomy, according to the TNM classification. The two inoperable cases were assigned pT-stage 4, consistent with their cT-stage.

Chemotherapy

Perioperative chemotherapy was defined as systemic chemotherapy commenced within six months before or after radical cystectomy, given with neoadjuvant or adjuvant intent; i.e., excluding chemotherapy for known metastatic disease. The standard approach at our institution for neoadjuvant chemotherapy is to administer three cycles of cisplatin (70mg/m2) on day 1 and gemcitabine (1g/m2) on days 1, 8 and 15 at 4-weekly intervals. Restaging cystoscopy and computed tomography (CT) abdomen/pelvis are performed after two cycles of chemotherapy. In patients with stable or responding disease, a third cycle of chemotherapy is delivered followed by cystectomy after recovery from chemotherapy. In patients with progressive disease after two cycles of chemotherapy, systemic treatment is abandoned and cystectomy is performed. We substitute carboplatin [area under the curve (AUC) 5] in patients with a major contraindication to cisplatin. If carboplatin is used, gemcitabine is given only on days 1 and 8 at 21-days interval. MVAC and CMV are used infrequently and only reserved for very well selected and fit patients, as prophylactic use of granulocyte colony-stimulating factor is not approved for this indication in Australia.

For adjuvant chemotherapy, the choice of regimen is similar to that used in the neoadjuvant setting. We routinely administer four cycles of treatment unless the patients have received neoadjuvant chemotherapy, in which case three cycles are usually offered instead. During the study period, decisions regarding perioperative chemotherapy were individualized rather than protocol-driven. Following the introduction of the MDM, the decision-making in many cases was based on recommendations made at the MDM. In general, neoadjuvant chemotherapy was recommended for suitable patients with muscle-invasive bladder cancer (clinical stage ≥T2 or any nodal disease); whereas adjuvant chemotherapy was offered to those patients with high-risk pathological features (pathological stage ≥T3, any nodal disease).

Follow Up and Survival Data

As this was a retrospective study, follow up among patients varied. However, patients were typically followed every three to six months during the first two to three years; and six-monthly or annually thereafter. A surveillance CT was generally performed in the first two years following cystectomy. The treatment start date was considered to be the start of neoadjuvant chemotherapy or the date of cystectomy (for those who did not receive neoadjuvant chemotherapy). The last follow up was defined as the most recent visit to the Austin Health uro-oncology clinic or the patient's local general practitioner. Recurrence free survival (RFS) was defined as the time from starting treatment to the first date of recurrence of urothelial carcinoma on imaging or biopsy; patients without recurrence were censored at the last date of follow up. The date and cause of death was retrieved from the Austin Health medical records or from the death certificate. Overall survival (OS) and cancer-specific survival (CSS) were defined as the time from the start of treatment till death, and CSS similarly for those dying from urothelial carcinoma.

Statistical Analysis

Numerical data were summarised using the median & range or mean +/− standard deviation, as appropriate. Comparison across groups was carried out using the chi-squared, Fisher's exact test or Wilconxon's two-sample tests as appropriate. The association between predictors and chemotherapy utilisation was assessed using logistic regression analysis. The Kaplan Meier method was applied to analyse RFS, CSS and OS. Associations between predictors and recurrence or death were assessed using the Cox proportional hazards model. All analyses with p-value <0.05 were considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References

Clinico-Pathologic Findings

Between January 2004 and December 2011, 89 patients underwent radical cystectomy and/or perioperative chemotherapy for UC of the bladder. Patient demographics and clinico-pathological characteristics are shown in Table 1. Among the 89 patients, 66 (74%) were male and the median age was 65 year (range, 37 to 84). Pathologic features included 68 (76%) pure UC, 21 (24%) mixed UC; and 84 (94%) high grade tumours. On clinical staging, 63 (71%) patients had muscle-invasive bladder cancer (cT-stage ≥T2). Following cystectomy, stage ≥pT3 and/or node positive disease was identified in 35 (39%) patients.

Table 1. Clinical and pathology characteristics of the 89 study patients
CharacteristicsNumber (%)
  1. Abbreviations: UC: urothelial carcinoma; SqCC: squamous cell carcinoma; Adeno: adenocarcinoma; SmCC: small cell carcinoma; Sarc: sarcomatoid; Cis: carcinoma-in-situ; PC: perioperative chemotherapy; NAC: neoadjuvant chemotherapy; AC: adjuvant chemotherapy; AACI: age-adjusted Charlson comorbidity index.

Median age (range), years65 (37–84)
Sex
Male66 (74)
Smoking history
Current/Ex-smoker17/56 (82)
Never11 (12)
Unknown5 (6)
Grade
High84 (94)
Low5 (5)
Histology
Urothelial68 (76)
UC, SqCC10 (11)
UC, Adeno3 (3)
UC, SmCC3 (3)
UC, Sarc2 (2)
UC, Adeno, SqCC1 (1)
UC, SqCC, Sarc2 (2)
Clinical staging 
Cis3 (3)
cT123 (26)
cT249 (55)
cT37 (8)
cT47 (8)
cTany,N+5 (6)
Cystectomy87 (98)
Pathological staging
pT010 (11)
<pT218 (20)
pT226 (29)
pT322 (25)
pT413 (15)
pNx31 (35)
pN048 (54)
pTany,N+10 (11)
PC28 (31)
NAC7 (8)
AC17 (19)
Both4 (5)
AACI 
≤24 (5)
3–552 (58)
≥633 (37)

Perioperative Chemotherapy

Twenty-eight (31%) patients received perioperative chemotherapy (seven neoadjuvant, seventeen adjuvant, and four both neoadjuvant and adjuvant). No patients received neoadjuvant chemotherapy prior to 2007, the year when the uro-oncology MDM was introduced (Table 2). Over time, there was a significant increase noted in the rate of use of neoadjuvant (p < 0.005), but not adjuvant or overall peri-operative chemotherapy. All patients who received neoadjuvant chemotherapy and 64% of those who received adjuvant chemotherapy were discussed at the MDM (Table 2).

Table 2. Influence of multi-disciplinary meeting (MDM) on chemotherapy use
YearsCystectomycT2 (%)NAC/MDM (%)pT≥3 or N+ (%)AC/MDM (%)AC/Not MDM (%)
  1. Abbreviations: n: number of patients; MDM: multidisciplinary meeting was introduced in 2007; Not MDM: cases not discussed in multidisciplinary meeting; NAC: neoadjuvant; AC: adjuvant chemotherapy. *Two additional patients underwent neoadjuvant chemotherapy with curative intent, but the cancer progressed and was found to be unresectable.

200487 (88)04 (50)00/4 (0)
20051210 (83)09 (75)06/9 (67)
2006118 (73)05 (45)02/5 (40)
2007127 (58)1/1 (100)2 (17)0/1 (0)0/1 (0)
2008117 (64)3/4 (75)2 (18)0/00/2 (0)
2009138 (62)3/5 (60)4 (31)3/3 (100)0/1 (0)
201096 (67)0/3 (0)4 (44)3/3 (100)0/1 (0)
20111110 (91)4/6 (67)5 (45)¼ (25)1/1 (100)
Total87*63 (72)11/19 (58)35 (40)7/11 (63)9/24 (38)

On univariate analysis, cT-stage, cN-stage and age were significant predictors of neoadjuvant chemotherapy usage and patient comorbidities (AACI) trended towards statistical significance (Table 3). On multivariate analysis, only cN-stage remained a significant predictor, with a trend noted for cT-stage (p = 0.08). For adjuvant therapy, pT-stage and pN-stage both approached statistical significance on univariate analysis, but no predictors were significant on multivariate analysis (Table 3).

Table 3. Univariate and multivariate analyses of association between covariates and chemotherapy utilisation
VariablesUV RR (95% CI)p-valueMV RR (95% CI)p-value
  1. Abbreviations: UV: univariate; MV: multivariate; RR: relative risk; CI: confidence interval; AACI: age adjusted Charlson comorbidity index.

Neoadjuvant chemotherapy
cTstage2.85 (1.23 – 6.60)0.012.27 (0.89 – 5.80)0.08
cNstage29.14 (2.84 – 299.35)0.00519.52 (1.78 – 213.57)0.01
Age0.93 (0.88 – 0.99)0.03  
AACI0.28 (0.07 – 1.11)0.06  
Adjuvant chemotherapy
pTstage1.87 (0.91 – 3.81)0.08  
pNstage3.50 (0.86 – 14.23)0.08  
Age0.97 (0.92 – 1.02)0.16  
AACI1.01 (0.39 – 2.65)0.98  

Neoadjuvant Chemotherapy

Of the 63 (71%) patients who had preoperative muscle-invasive bladder cancer (≥cT2), 11 (17%) received neoadjuvant chemotherapy. As shown in table 4, patients receiving neoadjuvant chemotherapy were younger, had higher clinical T & N stage, but a comparable distribution of comorbidities. Reasons why patients did or did not receive neoadjuvant chemotherapy were not documented in most instances. Four patients received gemcitabine/cisplatin (GC), five received gemcitabine/carboplatin (GCb); one received cisplatin/methotrexate/vinblastine (CMV); and one patient initially treated with GC was switched to GCb because of acute renal failure.

Table 4. Clinical and pathological characteristics of patients with clinical stage ≥T2, N+ stratified by neoadjuvant chemotherapy (total patients, N = 63)
CharacteristicsNAC n (%)No NAC n (%)p-value
  1. Abbreviations: n: number of patients; NAC: neoadjuvant chemotherapy; AACI: age-adjusted Charlson comorbidity index; mo: months; NS: non-significant.

Number11 (17)52 (83) 
Median age (range)65 (35–71)67 (37–84)<0.02
Clinical T–stage  <0.002
cT24 (36)45 (87) 
cT3-47 (64)7 (13) 
Clinical N-stage  <0.002
N0/Nx7 (64)51 (98) 
N+4 (36)1 (2) 
AACI  NS
≤21 (9)2 (4) 
3–59 (82)30 (58) 
≥61 (9)20 (38) 
Pathological response  NS
pT01 (9)2 (4) 
Downstaged3 (27)6 (17) 
Median (range) follow-up30 (3–58) mo34 (0–108) moNS
Recurrence5 (45)20 (38)NS
Median (range) time to recurrence3 (0–10) mo9 (0–83) moNS
Cancer death5 (45.5)19 (34.6)NS
Median (range) time to cancer death9 (3–16) mo12 (0–84) moNS

Pathological findings at cystectomy following neoadjuvant chemotherapy showed that one (9%) patient (treated with GCb) achieved pathological complete response, three (27%) had their primary tumour downstaged, stable disease was observed in four (36%), while three had progressive disease, including two who were deemed inoperable. The proportion of patients who were found to be pT0 (4%) or downstaged (17%) at cystectomy without prior chemotherapy was slightly lower, although the difference was not statistically significant (Table 4)

The median (range) interval between chemotherapy completion and surgery was 41 (20 – 62) days. Five (45%) patients were unable to complete the planned treatment: one had developed metastatic disease, two had no shrinkage of the primary tumour after second cycle treatment, one proceeded to cystectomy due to perforated bladder during restaging cystoscopy and one who received CMV had acute renal failure and neutropenic sepsis. However, each patient only missed one cycle of treatment, and overall, 28 of 33 (85%) planned cycles were delivered. Two of the four patients who achieved pathological downstaging or complete response had completed the full course of three cycles of treatment.

Adjuvant Chemotherapy

Thirty-five (39%) patients had stage ≥pT3 and/or node positive disease. Of these patients, 16 (46%) received adjuvant therapy. GCb (9/16, 56%) was the most commonly administered regimen, followed by GC (5/16, 31%). One patient received GC then switched to GCb because of toxicity. One received adjuvant carboplatin and etoposide combination for mixed urothelial-small cell disease. The clinico-pathological characteristics of these patients are presented in Table 5.

Table 5. Clinical and pathological characteristics of patients with pathological stage ≥T3, N+ receiving no or any adjuvant chemotherapy (total patients, N = 35)
CharacteristicsAC n (%)No AC n (%)p value
  1. Abbreviations: n: number of patients; AC: adjuvant chemotherapy; AACI: age-adjusted Charlson comorbidity index; mo: months; NS: non-significant.

Number16 (46)19 (54) 
Median age (range)66.3 (37-76)66.5 (37-83)NS
pT-stage  NS
pT39 (56)13 (68) 
pT46 (38)5 (26) 
pN-stage  0.07
N0/Nx5/5 (62.5)8/7 (79) 
N+6 (37.5)4 (11) 
AACI  NS
≤22 (12.5)1 (5) 
3–58 (50)13 (69) 
≥66 (37.5)5 (26) 
Median (range) follow-up35 (6–92) mo13 (2–101) mo<0.05
Recurrence10 (62.5)11 (58)NS
Median (range) time to recurrence16 (2–65) mo4 (0–83) mo<0.02
Cancer death9 (69.2)8 (42)NS
Median (range) time to cancer death19 (6–65) mo6 (4–84) mo0.05

Of the 19 patients with ≥pT3 and/or node positive disease who did not receive adjuvant chemotherapy, 10 (53%) were deemed unsuitable on the grounds of post-operative complications, three (16%) developed interval metastatic disease, one (5%) developed another malignancy and two (10%) refused treatment. For the remaining three patients, no reason was documented for the lack of adjuvant treatment.

In addition to patients with ≥pT3 and/or node positive disease, five patients with pT2 disease received adjuvant chemotherapy. Of these five, two had mixed urothelial-small cell histology (and were treated with carboplatin AUC 5 and etoposide 100mg/m2), one had not undergone a lymph node dissection (pT2Nx), one had a positive prostatic urethral margin and one had a prior history of upper tract UC. The patient with a positive urethral margin also underwent urethrectomy as part of their treatment.

Of the 21 patients who received adjuvant chemotherapy, six (29%) were unable to complete the scheduled treatment, with the most common reason being chemotherapy-related toxicity. One patient with mixed urothelial-small cell disease developed metastatic disease during his second cycles of adjuvant chemotherapy. Overall, 67% of planned cycles were delivered.

Recurrence and Survival

Overall, 31 (35%) patients recurred, all except one of whom had pT2+ disease. Of the 11 patients treated with neoadjuvant chemotherapy, five (45%) recurred, at a median (range) time of 3 (0–10) months. The estimated 12-month RFS (95% CI) in this group was 55% (32–94%). Of the patients who received adjuvant chemotherapy, 10 had suffered recurrence, at a median (range) interval of 16 (2–65) months, which was longer compared to high-risk patients who did not receive adjuvant chemotherapy (Table 5). The estimated 24-month RFS (95% CI) of patients undergoing adjuvant chemotherapy [66% (48–90%)] was longer than for high-risk patients (pT stage ≥3 or N+) not receiving adjuvant chemotherapy [47% (27–80%)], although the difference did not reach statistical significance (p = 0.08).

Considering all patients with muscle-invasive disease, on univariate analysis, higher pathological T-stage and N-stage were associated with a higher recurrence risk, although only the former was statistically significant (Table 6). RFS was similar regardless of whether patients underwent perioperative chemotherapy (Figure 1A). However, after adjusting for age, pT-stage and pN-stage, the use of perioperative chemotherapy was found to significantly reduce the risk of recurrence (Table 6).

figure

Figure 1. Kaplan-Meier estimates for (A) recurrence free survival and (B) cancer-specific survival in the cohort 89 patients.

Download figure to PowerPoint

Table 6. Univariate and multivariate analyses of association between covariates and the risk of recurrence or death from cancer
 RecurrenceCancer death
UnivariateMultivariateUnivariateMultivariate
  1. Abbreviations: CI: confidence interval; RR: relative risk.

VariablesRR (95%CI)p-valueRR (95%CI)p-valueRR (95%CI)p-valueRR (95%CI)p-value
Age1.00 (0.97–1.04)0.740.98 (0.94–1.02)0.311.01 (0.98–1.05)0.431.01 (0.97–1.05)0.66
Sex0.96 (0.44–2.11)0.94  1.26 (0.53–2.96)0.6  
pT2.20 (1.47–3.30)<0.00012.83 (1.66–4.83)<0.00011.70 (1.14–2.53)<0.011.70 (1.10–2.65)<0.02
pN2.20 (0.94–5.14)0.072.25 (0.88–5.73)0.091.96 (0.79–4.88)0.151.90 (0.72–5.02)0.19
Chemotherapy1.02 (0.50–2.09)0.950.41 (0.17–0.97)<0.051.08 (0.51–2.31)0.820.74 (0.32–1.70)0.47
Year of treatment0.99 (0.83–1.18)0.89  0.92 (0.76–1.10)0.35  

At study completion, thirty-three (37%) patients had died, including 27 (30%) from urothelial carcinoma, with all but two of these deaths in patients with stage ≥T2. Among patients receiving neoadjuvant chemotherapy, there were five deaths from cancer at a median (interval) time of 9 (3–16) months, with the estimated 12-month CSS (95% CI) being 64% (41–100%). There were nine deaths from cancer among the patients receiving adjuvant chemotherapy, at a median (range) interval of 19 (6–65) months, which was longer than for high-risk patients who had not received adjuvant chemotherapy (Table 5). The estimated 24-month CSS (95% CI) for patients treated with adjuvant chemotherapy was 71% (53–94%).

Considering all patients with muscle-invasive disease, only pT-stage was associated with the risk of death from cancer on both univariate and multivariate analysis (Table 6). Cancer-specific survival (Figure 1B) and OS (data not shown) was similar between patients treated with or without perioperative chemotherapy.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References

In this single institution retrospective study, we examined the utilization over time and consequent oncological impact of perioperative chemotherapy in patients with bladder UC. We found that 17% and 46% of potentially eligible patients received neoadjuvant and adjuvant chemotherapy respectively. Importantly, despite the relatively small number of patients in this study, the use of perioperative chemotherapy significantly reduced the risk of recurrence.

A number of studies have previously shown that the majority of patients with bladder UC do not receive perioperative chemotherapy, with rates ranging between 1.2 and 19% for neoadjuvant chemotherapy, and 1.5 and 37% for adjuvant chemotherapy [19-26]. Consistent with these findings, data published from the Surveillance, Epidemiology and End Results (SEER) Medicare database in 2011 showed only 6% of 8719 patients received neoadjuvant chemotherapy [22]. Similarly, data from the National Cancer Database showed that only 6% of bladder UC patients received neoadjuvant chemotherapy in 2003. Interestingly, by 2011 this figure had risen to 13% [26]. In our study, we also saw a temporal increase in the uptake of neoadjuvant chemotherapy from 2007 onwards. This coincided with the introduction of our Uro-Oncology MDM, reflecting the utility of a multi-disciplinary approach to these patients.

There are several possible reasons for the low rates of use of perioperative chemotherapy in bladder UC including patient co-morbidities and potential treatment toxicities. Co-morbid illnesses are commonly found in bladder UC patients, reflecting the strong association with smoking and advanced age at diagnosis. A large United States study of bladder UC patients found that an AACI score >5 correlated with lower rates of adjuvant chemotherapy utilisation, despite the fact that they were more likely to have pT3+ and/or N+ disease [27]. In contrast, we found that the AACI score did not appear to impact on administration of perioperative chemotherapy, although smaller numbers may have limited the power of our study.

Among our patients, clinical stage was the main determinant for the use of neoadjuvant chemotherapy, consistent with prior reports [22]. However, it is well recognized that clinical staging is imprecise with risks of both under-staging and over-staging. Transurethral resection is susceptible to under-staging due to sampling error, and clinical examination is also often inaccurate in assigning clinical T-stage [28]. Conversely, computed tomography, especially if it is carried out after trans-urethral resection, is prone to overstaging. Nodal staging by imaging can be inaccurate, with high rates of both false positive and false negative results [29]. Positron emission tomography (PET) may provide greater accuracy [30], but funding and availability currently limit its use.

In regards to treatment toxicities from chemotherapy, the retrospective design of this study did not allow us to accurately assess this. However, patients prescribed neoadjuvant and adjuvant chemotherapy received 85% and 67%, respectively of their planned cycles, indicating that treatment was relatively well tolerated. Moreover, neoadjuvant chemotherapy did not delay cystectomy with the median time from completion of chemotherapy to surgery being less than six weeks. This is an important indicator since delays in the definitive surgical treatment are associated with worse outcomes in bladder UC patients [31].

Nevertheless, certain chemotherapy regimens for bladder UC can be associated with high rates of toxicity. The SWOG 8710 study reported grade 3 or 4 adverse event in over 50 % of patients treated with neoadjuvant MVAC. In the adjuvant setting, grade 3 or 4 toxicity rates of 20% and 15 % have been reported with PGC (paclitaxel, gemcitabine and cisplatin) and GC respectively [32]. Concerns about toxicity have perhaps led to lower rates of use of MVAC or CMV in Australia. In our study, the most commonly used perioperative chemotherapy regimens combined a platinum agent with gemcitabine. The use of such regimens may be associated with lower efficacy, with pathological complete response rates ranging from 7–26% [8, 33-35] for GC in comparison to a pathological complete response rate of 38% for MVAC in the SWOG 8710 study. In contrast, a recent retrospective study reported comparable pathological complete response rates for GC and MVAC (25% vs. 31%) and no difference in overall survival [36].

We acknowledge that this study has several limitations. Being a retrospective study we were not always able to ascertain the specific reasons why perioperative chemotherapy was not offered in particular patients. In addition, the number of patients was relatively small and thus there may have been insufficient power for some of the analysis. The duration of follow-up was shorter for some of the patients treated with chemotherapy, although this did not seem to have a confounding effect on outcomes.

In conclusion, we have found that perioperative chemotherapy remains relatively under-utilised at our center despite recent increases in the use of neoadjuvant treatment. Patients were more likely to receive perioperative chemotherapy if they had adverse clinical or pathological features, and chemotherapy appears to reduce their risk of recurrence. Improving outcomes for bladder UC patients remains a major challenge and our study highlights the need for further prospective studies to establish the optimal application of perioperative chemotherapy and simultaneously the development of strategies for increased utilisation of perioperative chemotherapy for those who may benefit from it.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References

Jim Siderov, Pharmacy Department for providing the chemotherapy database. MSL is supported by Australian National Health and Medical Research Council (NHMRC) postgraduate scholarship. IDD was supported by an NHMRC Practitioner Fellowship.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References
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