Response to induction chemotherapy and surgery in non-organ confined bladder cancer: A single institution experience

doi:10.1016/j.ejso.2013.01.003

European Journal of Surgical Oncology (EJSO)

Volume 39, Issue 4, April 2013, Pages 365-371

https://doi.org/10.1016/j.ejso.2013.01.003 Get rights and content

Abstract

Aim

To evaluate the outcome of patients with locally advanced muscle-invasive and/or lymph node positive bladder cancer treated with induction chemotherapy and additional surgery.

Methods

All patients who were treated with induction chemotherapy in our institution between 1990 and 2010, were retrospectively evaluated using an institutional database. Induction chemotherapy consisted of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), or a combination of gemcitabine with either cisplatin or carboplatin (GC).

Results

In total 152 patients were identified, with a mean age of 59 years (range 31–76). One hundred and seven patients (70.4%) received MVAC, 35 patients received GC (23.0%) and 10 patients received GC after initial treatment with MVAC (6.6%). Median follow-up was 68 months (range 4–187 months). Overall 125 patients (82.2%) underwent cystectomy, whereas 12 patients (7.9%) received radiotherapy. Fifteen patients had no local treatment. Median overall survival was 18 months (95%CI 15–23 months). In 37.5% of patients with complete clinical response, residual disease was found at surgery (positive predictive value, PPV 62.5%). Complete pathological response was seen in 26.3% of patients, with a 5 year overall survival (OS) estimate of 54% (39%–74%). For patients with persisting node positive disease after induction chemotherapy and surgery OS was significantly worse (p < 0.0001).

Conclusions

Complete clinical and/or pathological response to induction chemotherapy results in a significant survival benefit. The accuracy of the current clinical response evaluation after induction chemotherapy is limited. Although surgery may be important for staging and prognostic purposes, its role is unclear in node positive disease after induction chemotherapy.

Introduction

Muscle-invasive bladder cancer is a serious disease that, despite meticulous and timely therapy, consisting of bilateral pelvic lymph node dissection (PLND) and radical cystectomy, results in a poor prognosis with a reported 5-years overall survival ranging from 36% to 62%.1, 2, 3, 4 For patients presenting with lymph node (LN) metastases or locally advanced disease (T3-T4) the prognosis is even worse, with 5-years survival data ranging from 26% to 38%.3, 5 For locally advanced patients, this poor outcome is probably due to under staging of the LN status and/or occult micro-metastases at the time of first diagnosis.⁶ In clinically LN negative (cN0) patients with locally advanced disease (T3-4), LN metastases may be found in up to 34% of cases at the time of surgery.⁷

Systemic treatment with cisplatin-based combination chemotherapy has been shown to improve the outcome of patients presenting with locally advanced muscle-invasive bladder cancer, albeit at best a 6.5% increase in overall survival at 5-years follow-up.8, 9, 10, 11, 12, 13, 14 The response to neoadjuvant chemotherapy is an important predictive factor, as patients who, at the time of cystectomy, have non-muscle invasive bladder cancer (<pT2) and patients without residual bladder cancer (pT0) have a more favourable prognosis up to a 5-years survival rate of 69% versus 26% for patients with persistent muscle-invasive bladder cancer.15, 16, 17, 18, 19 Nevertheless, little is known on the prognostic impact of persisting LN metastases after induction chemotherapy.

Patients presenting at our institute with locally advanced (T3-T4) and/or LN positive bladder cancer, who were eligible for surgery have been considered for induction cisplatin-based combination chemotherapy since 1990. We analysed the outcome of all patients that were treated with this strategy in our institution over the past years.

Section snippets

Patients

All patients with locally advanced muscle-invasive bladder cancer (≥T3) and/or LN positive disease (≥N1), who were treated with at least two cycles of induction chemotherapy, and were scheduled for surgery between 1990 and 2010, were identified from an institutional bladder cancer database. These patients were all discussed in multidisciplinary meetings with representatives from the departments of urology, medical oncology, pathology, radiation oncology and radiology. All patients were included

Clinical features

In total 152 patients were retrieved from an institutional bladder cancer database of 817 patients. Mean age was 59 years (range 31–76). One hundred seventeen of these patients (77.0%) received MVAC, 22 patients (14.5%) Gem/Carbo and 13 patients (8.6%) Gem/Cis treatment primarily. Ten patients switched from MVAC to either Gem/Carbo or Gem/Cis because of toxicity or renal insufficiency. Overall a median of 4 courses of chemotherapy was administered. In 25 patients (16.4%) the chemotherapy was

Discussion

This study underlines that patients with locally advanced and node positive bladder cancer face a poor prognosis despite induction chemotherapy and consolidating therapy (median OS 18 months and 5-years OS 27.2%). Patients with a complete pathological response to induction chemotherapy (pCR) after surgery fare significantly better (median OS 74 months and 5-years OS 53.8%). Clinical and pathological response to chemotherapy and the clinical node status after chemotherapy (ycN-status) are

Conflict of interest

The authors declare that they have no conflict of interest.

References (29)

M.A. Ghoneim et al.
Radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1,026 cases
J Urol
(1997)
G. Dalbagni et al.
Cystectomy for bladder cancer: a contemporary series
J Urol
(2001)
H.W. Herr et al.
Outcome of patients with grossly node positive bladder cancer after pelvic lymph node dissection and radical cystectomy
J Urol
(2001)
R.R. de Vries et al.
Long-term survival after combined modality treatment in metastatic bladder cancer patients presenting with supra-regional tumor positive lymph nodes only
Eur J Surg Oncol
(2009)
N.B. Dhar et al.
Outcome after radical cystectomy with limited or extended pelvic lymph node dissection
J Urol
(2008)
E. Winquist et al.
Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis
J Urol
(2004)
T.A. Splinter et al.
A European Organization for Research and Treatment of Cancer–Genitourinary Group phase 2 study of chemotherapy in stage T3-4N0-XM0 transitional cell cancer of the bladder: evaluation of clinical response
J Urol
(1992)
R. Rosenblatt et al.
Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer
Eur Urol
(2012)
V. Sundararajan et al.
New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality
J Clin Epidemiol
(2004)
M.E. Charlson et al.
A new method of classifying prognostic comorbidity in longitudinal studies: development and validation
J Chronic Dis
(1987)

M.D. Galsky et al.

A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy

Lancet Oncol

(2011)

H.W. Herr

Outcome of patients who refuse cystectomy after receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer

Eur Urol

(2008)

S. Yoshida et al.

Initial experience of diffusion-weighted magnetic resonance imaging to assess therapeutic response to induction chemoradiotherapy against muscle-invasive bladder cancer

Urology

(2010)

S. Madersbacher et al.

Radical cystectomy for bladder cancer today–a homogeneous series without neoadjuvant therapy

J Clin Oncol

(2003)

Cited by (27)

Preoperative chemotherapy in clinically node positive muscle invasive bladder cancer: Radiologic variables can predict response
2021, Urologic Oncology: Seminars and Original Investigations
To evaluate pathologic downstaging after radical cystectomy and pelvic lymph node dissection for clinically lymph node positive urothelial bladder cancer and to determine optimal preoperative imaging variables in predicting pathologic nodal status.
We identified all patients with clinically lymph node positive urothelial bladder cancer who underwent radical cystectomy and extended pelvic lymph node dissection with intent to cure at our institution. Patients were stratified based on pathologic node status to determine clinical associations and survival outcomes. Pre and post-chemotherapy CT scans were reviewed to characterize lymph node size and morphology. We also sought to determine associations between post-chemotherapy radiology variables and pathologic response.
We identified 130 patients with clinically node positive bladder cancer, out of which 76 (58.5%) received induction chemotherapy. Thirty three (43.4%) had pathologic T downstaging following chemotherapy, compared to 7 (12.9%) patients who had surgery alone (P< 0.0001). A complete nodal response (pN0) occurred in 31 (40.8%) patients post-chemotherapy, while 6 (11.1%) of those who received cystectomy alone ended up being pN0 (P< 0.0001). Median overall survival and recurrence-free survival were shorter in patients with pN+ versus pN0 disease (1.9 years vs. 12.8 years, P= 0.016 and 1.2 years vs. 4.3 years, P= 0.013, respectively). Review of 29 post chemotherapy CT scans showed that patients with pathologic nodal involvement had a greater median number of enlarged nodes (3.5 vs. 1, P= 0.038) and a greater median size of largest node (8.5 mm vs. 6.0 mm, P= 0.021) on imaging compared to those with complete pN0. Each 1 mm increase in size of the largest node on post-chemotherapy CT scan increased the chance of having pN+ disease by 1.57 (95% CI 1.02–2.44, P= 0.043). Using a median node size of 8 mm as a cut-off to predict pN+ disease provided a sensitivity and specificity of 72% and 80%, respectively (c-index = 0.761, P= 0.014). The positive predictive value for this cut-off was 87% (95% CI 58%–98%) and negative predictive value was 62% (32%–85%).
Patients with clinically node positive bladder cancer may have significant pN0 after induction chemotherapy. Our data suggest a post-chemotherapy CT scan with an 8 mm nodal size cut-off may be a better predictor of pathologic nodal status than more traditional measures.
Downstaging of Muscle-Invasive Bladder Cancer Using Neoadjuvant Gemcitabine and Cisplatin or Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin as Single Regimens or as Switch Therapy Modalities
2020, Clinical Genitourinary Cancer
Consensus guidelines recommend gemcitabine and cisplatin (GC) or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) as equally preferable neoadjuvant chemotherapy before cystectomy for muscle-invasive bladder cancer. This study sought to compare the ability of GC and ddMVAC to achieve pathologic response; and to evaluate the benefit of switching regimens after 1 or 2 cycles of the other.
Patients aged ≥ 18 with muscle-invasive bladder cancer (≥ cT2) and who had received either GC or ddMVAC as neoadjuvant chemotherapy followed by cystectomy were retrospectively evaluated using the electronic medical record. Patients who received 1 or 2 cycles of one regimen followed by several cycles of the other regimen before cystectomy were classified as switch therapy patients. This study assessed the rates of pathologic complete response (pCR) and any degree of downstaging.
Among 109 patients who received GC or ddMVAC, 7 (21%) of 33 ddMVAC patients demonstrated pCR, and 19 (25%) of 76 GC patients demonstrated pCR (odds ratio, 1.24; 95% confidence interval, 0.46-3.31; P = .67). Downstaging rates were 39% for ddMVAC and 50% for GC (P = .31). Thirty-three of 36 patients aged ≥ 70 years received GC (P < .001). Four of 7 patients treated with switch therapy showed downstaging, and 2 of 7 experienced pCR.
There was no difference in pCR rates between GC and ddMVAC, and patients were most often able to receive 3 or 4 cycles of treatment. Switch therapy may be of benefit in patients whose disease has a poor initial response.
Neoadjuvant Dose Dense MVAC versus Gemcitabine and Cisplatin in Patients with cT3-4aN0M0 Bladder Cancer Treated with Radical Cystectomy
2018, Journal of Urology
Citation Excerpt :
These rates are similar to those of the cT3/T4 subgroup of patients in SWOG-8710 who received MVAC (table 4).2 Furthermore, these results appear more encouraging when considering the pPR and pCR rates observed in some published cT2-4N0M0 series of standard MVAC or GC.13–16,22,23 In our previously reported, 19 institution NAC study we observed a pCR rate of 24.4% in the MVAC arm and 15.4% in the GC arm in cT3/T4 cases.8
Level I evidence supports the usefulness of neoadjuvant cisplatin based chemotherapy for muscle invasive bladder cancer. Since dose dense MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) has mostly replaced traditional MVAC, we compared pathological response and survival rates in patients with locally advanced bladder cancer who received neoadjuvant chemotherapy with dose dense MVAC vs gemcitabine and cisplatin.
We retrospectively reviewed the records of patients with urothelial cancer who received neoadjuvant chemotherapy and underwent cystectomy at a total of 20 contributing institutions from 2000 to 2015. Patients with cT3-4aN0M0 disease were selected for this analysis. The rates of ypT0N0 and ypT1N0 or less were compared between the gemcitabine and cisplatin, and dose dense MVAC regimens. Two multivariable Cox proportional hazards regression models of overall mortality were generated using preoperative and postoperative data.
Of the patients who underwent neoadjuvant chemotherapy and radical cystectomy during the study period 319 met our inclusion criteria. A significantly lower rate of ypT0N0 was observed in the gemcitabine and cisplatin arm than in the dose dense MVAC arm (14.6% vs 28.0%, p = 0.005). The rate of ypT1N0 or less was 30.1% for gemcitabine and cisplatin compared to 41.0% for dose dense MVAC (p = 0.07). The mean Kaplan-Meier estimates of overall survival in the gemcitabine and cisplatin, and dose dense MVAC groups were 4.2 and 7.0 years, respectively (p = 0.001). On multivariable cox regression analysis based on preoperative data patients who received gemcitabine and cisplatin were at higher risk for death than patients who received dose dense MVAC (HR 2.07, 95% CI 1.25–3.42, p = 0.003). Lymph node invasion (HR 1.97, 95% CI 1.15–3.36, p = 0.01) and hydronephrosis (HR 2.18, 95% CI 1.43–3.30, p <0.001) were also associated with higher risk of death.
In our retrospective cohort of patients with locally advanced bladder cancer dose dense MVAC was associated with higher complete pathological response and improved survival rates compared to gemcitabine and cisplatin. A clinical trial is warranted to validate these hypothesis generating results to test the superiority of neoadjuvant dose dense MVAC in patients with locally advanced bladder cancer.
The Role of Surgery in Metastatic Bladder Cancer: A Systematic Review [Figure presented]
2018, European Urology
Citation Excerpt :
Since currently available imaging techniques are limited in detecting LN metastasis, LN dissection remains the most accurate form of nodal staging and response evaluation after CHT. In this review, the protocol in many studies was to evaluate the clinical response, radiologically, after every two cycles of CHT [12,13,18,35,54]. In some series, diagnosis of LN metastasis was established, in addition to imaging, by fine needle aspiration or LN dissection [12,13,18,35,36].
The role of surgery in metastatic bladder cancer (BCa) is unclear.
In this collaborative review article, we reviewed the contemporary literature on the surgical management of metastatic BCa and factors associated with outcomes to support the development of clinical guidelines as well as informed clinical decision-making.
A systematic search of English language literature using PubMed-Medline and Scopus from 1999 to 2016 was performed.
The beneficial role of consolidation surgery in metastatic BCa is still unproven. In patients with clinically evident lymph node metastasis, data suggest a survival advantage for patients undergoing postchemotherapy radical cystectomy with lymphadenectomy, especially in those with measurable response to chemotherapy (CHT). Intraoperatively identified enlarged pelvic lymph nodes should be removed. Anecdotal reports of resection of pulmonary metastasis as part of multimodal approach suggest possible improved survival in well-selected patients. Cytoreductive radical cystectomy as local treatment has also been explored in patients with metastatic disease, although its benefits remain to be assessed.
Consolidative extirpative surgery may be considered in patients with clinically evident pelvic or retroperitoneal lymph nodal metastases but only if they have had a response to CHT. Surgery for limited pulmonary metastases may also be considered in very selected cases. Best candidates are those with resectable disease who demonstrate measurable response to CHT with good performance status. In the absence of data from prospective randomized studies, each patient should be evaluated on an individual basis and decisions made together with the patient and multidisciplinary teams.
Surgical resection of metastases is technically feasible and can be safely performed. It may help improve cancer control and eventually survival in very selected patients with limited metastatic burden. In a patient who is motivated to receive chemotherapy and to undergo extirpative surgical intervention, surgery should be discussed with the patient among other consolidation therapies in the setting of multidisciplinary teams.
ERBB2 Mutations Characterize a Subgroup of Muscle-invasive Bladder Cancers with Excellent Response to Neoadjuvant Chemotherapy
2016, European Urology
A pathologic complete response to neoadjuvant chemotherapy (NAC) containing platinum is a strong prognostic determinant for patients with muscle-invasive bladder cancer (MIBC). Despite comprehensive molecular characterization of bladder cancer, associations of molecular alterations with treatment response are still largely unknown. We selected pathologic complete responders (ypT0N0; n = 38) and nonresponders (higher than ypT2; n = 33) from a cohort of high-grade MIBC patients treated with NAC. DNA was isolated from prechemotherapy tumor tissue and used for next-generation sequencing of 178 cancer-associated genes (discovery cohort) or targeted sequencing (validation cohort). We found that 9 of 38 complete responders had erb-b2 receptor tyrosine kinase 2 (ERBB2) missense mutations, whereas none of 33 nonresponders had ERBB2 mutations (p = 0.003). ERBB2 missense mutations in complete responders were mostly confirmed activating mutations. ERCC2 missense mutations, recently found associated with response to NAC, were more common in complete responders; however, this association did not reach statistical significance in our cohort. We conclude that ERBB2 missense mutations characterize a subgroup of MIBC patients with an excellent response to NAC.
In this report we looked for genetic alterations that can predict the response to neoadjuvant chemotherapy (NAC) in bladder cancer. We found that mutations in the gene ERBB2 are exclusively present in patients responding to NAC.
A Multi-Institutional Analysis of Outcomes of Patients with Clinically Node Positive Urothelial Bladder Cancer Treated with Induction Chemotherapy and Radical Cystectomy
2016, Journal of Urology
Selected patients with bladder cancer with pelvic lymphadenopathy (cN1-3) are treated with induction chemotherapy followed by radical cystectomy. However, the data on clinical outcomes in these patients are limited. In this study we assess pathological and survival outcomes in patients with cN1-3 disease treated with induction chemotherapy and radical cystectomy.
Data were collected on patients from 19 North American and European centers with cT1-4aN1-N3 urothelial carcinoma who received chemotherapy followed by radical cystectomy between 2000 and 2013. The primary end points were pathological complete (pT0N0) and partial (pT1N0 or less) response rates, with overall survival as a secondary end point. Logistic regression and Cox proportional hazard ratios were used for multivariate analysis of factors predicting these outcomes.
The total of 304 patients had clinical evidence of lymph node involvement (cN1-N3). Methotrexate/vinblastine/doxorubicin/cisplatin was used in 128 (42%), gemcitabine/cisplatin in 132 (43%) and other regimens in 44 (15%) patients. The pN0 rate was 48% (cN1—56%, cN2—39%, cN3—39%, p=0.03). The complete and partial pathological response rates for the entire cohort were 14.5% and 27%, respectively. The estimated median overall survival time for the cohort was 22 months (IQR 8.0, 54). On Cox regression analysis overall survival was associated with pN0, negative surgical margins, removal of 15 or more pelvic nodes and cisplatin therapy.
Complete pathological nodal response can be achieved in a proportion of patients with cN1-3 disease receiving induction chemotherapy. The best survival outcomes are observed in male patients on cisplatin regimens with subsequent negative radical cystectomy margins and complete nodal response (pN0) with excision of 15 or more pelvic nodes.

View all citing articles on Scopus

View full text

Response to induction chemotherapy and surgery in non-organ confined bladder cancer: A single institution experience

Abstract

Aim

Methods

Results

Conclusions

Introduction

Section snippets

Patients

Clinical features

Discussion

Conflict of interest

J Urol

J Urol

J Urol

Eur J Surg Oncol

J Urol

J Urol

J Urol

Eur Urol

J Clin Epidemiol

J Chronic Dis

Lancet Oncol

Eur Urol

Urology

Radical cystectomy for bladder cancer today–a homogeneous series without neoadjuvant therapy

J Clin Oncol