Bladder/Urothelial neoadjuvant/adjuvant ciSplatin and gemcitabine

Indications:

• neoadjuvant transitional cell carcinoma (TCC) of the bladder
  • operable muscle invasive bladder cancer stage T2-T4a, eligible for radical cystectomy
  • ECOG performance status 0 to 1.

Cautions/Exclusions:

• pre existing neuropathies greater than or equal to Grade 2 
• significant hearing impairment/tinnitus.

Notes:

• The evidence supporting bladder/urothelial neoadjuvant treatment used differing schedules and doses of gemcitabine-cisplatin. The 3-week schedule has been shown to have a better compliance profile and similar dose intensity to the 4-week schedule.¹ It is the consensus of the reference committee that a 3-week schedule is more appropriate for this patient population and best reflects clinical practice.
• Neoadjuvant cisplatin and gemcitabine is considered a reasonable alternative to dose dense MVAC based on equivalence to conventional MVAC in the setting of advanced disease.

Indications:

• adjuvant treatment of predominant urothelial carcinoma histology of upper urinary tract (UTUC) following radical nephro-ureterectomy
  • either muscle invasive (pT2-pT4, Nx) or lymph node positive (pTx, N1-3) metastasis-free (M0) disease
  • ECOG performance status 0 to 1.

Cautions/Exclusions:

• pre existing neuropathies greater than or equal to Grade 2 
• significant hearing impairment/tinnitus.

Notes:

• The cisplatin infusion duration in this protocol differs from the trial protocol duration of 4 hours.²

The timing of chemotherapy when given as an adjunct to surgery has continued to provoke much debate over several years with proponents for neoadjuvant chemotherapy justifying their position on the basis of clinical trials such as SWOG 8710³ and ABC meta analysis collaboration;^{4, 5} whilst proponents for adjuvant chemotherapy criticise these trials (for slow and low accrual, lack of use of cisplatin/gemcitabine regimens), and also have a meta-analysis in support and prefer to offer adjuvant chemotherapy to high-risk patients such as T3 and T4 and/or node positive tumours. A search of the literature did not find strong evidence to support the use of neoadjuvant gemcitabine and cisplatin (GC) in the treatment of muscle invasive bladder cancer. The expert reference panel supported publication of the protocol on the basis of the information summarised below.

A meta-analysis of neoadjuvant chemotherapy in the form of platinum-based combination treatment found that there was an absolute survival advantage of approximately 5% at 5 years in muscle invasive bladder cancer (HR 0.86, 95% CI 0.77-0.95, p=0.003). However, none of the trials reviewed used gemcitabine and cisplatin and the most common regimen was methotrexate, vinblastine, doxorubicin and cisplatin (MVAC).⁶ GC has similar response rates, disease free survival (DFS) and overall survival (OS) in the metastatic setting when compared to MVAC with less grade 3/4 toxicity, especially non-haematological toxicities.⁷ Therefore GC is being used in the neoadjuvant setting as it has been extrapolated that it is likely to be as efficacious as MVAC. There is stronger evidence for neoadjuvant MVAC however, this regimen may be preferred due to its better toxicity profile without the need for growth factor support. There are no phase III randomised controlled trials looking at GC in the neoadjuvant setting in muscle invasive bladder cancer. Most of these are retrospective cohort studies, which show that pathological down-staging to pT0 was seen in 25.6% of patients and to less than pT2 in 46.5%.⁸ Pathological down-staging has been considered a surrogate marker for DFS and OS. As seen with neoadjuvant MVAC for muscle-invasive bladder cancer, of the patients who achieved pT0 at cystectomy the 5-year survival rate was 85%.³ 

The evidence supporting this protocol is provided by POUT, a phase III multicentre open-label randomised trial.² Between June 2012 and November 2017, 261 patients with either muscle invasive or lymph node positive metastasis-free upper tract urothelial carcinoma (UTUC), following radical nephro-ureterectomy, were randomised to receive four cycles of adjuvant chemotherapy every 21 days (n=132) or surveillance (n=129). Chemotherapy involved cisplatin 70 mg/m² (or carboplatin AUC 4.5-5 if GFR 30-49 mL/min) on day 1 and gemcitabine 1000 mg/m² on day 1 and 8, commenced within 90 days following surgery. Of the group randomised to chemotherapy, 76 patients were planned to receive gemcitabine-cisplatin and 50 planned to receive gemcitabine-carboplatin. The majority of patients (91%) were nodal stage N0. 

The primary endpoint was disease-free survival (DFS). Secondary endpoints included metastasis-free survival, overall survival (OS), treatment compliance, acute and late toxicity, and patient-reported quality of life.

1

Soto Parra, H., R. Cavina, F. Latteri, et al. 2002. "Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study." Ann Oncol 13(7):1080-1086.

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BACKGROUND: The cisplatin and gemcitabine (GC) regimen is usually administered as a 4- or 3-week schedule; however, the best schedule to use is still unclear. We therefore started a randomized phase II trial to compare toxicity and dose intensity (DI) between these two GC schedules. PATIENTS AND METHODS: Ninety-six patients with non-small-cell lung cancer (NSCLC) and an additional 11 patients with an advanced epithelial neoplasm [bladder (n = 5), head and neck (n = 3), cervix (n = 1), esophageal (n = 1) or unknown primary carcinoma (n = 1)] were randomized to receive cisplatin 70 mg/m(2) intravenously on day 2 plus either gemcitabine 1000 mg/m(2) on days 1, 8 and 15 of a 28-day cycle or gemcitabine 1000 mg/m(2) on days 1 and 8 of a 21-day cycle. Planned DI (PDI) for the 4-week schedule was 750 mg/m(2)/week for gemcitabine and 17.5 mg/m(2)/week for cisplatin; for the 3-week regimen PDI was 666 mg/m(2)/week and 23 mg/m(2)/week for gemcitabine and cisplatin, respectively. RESULTS: From July 1998 to March 2000, 107 patients were randomized. Grade 3/4 neutropenia was observed in 27.8% of patients in the 3-week versus 22.5% in the 4-week arm (P = 0.69), while grade 3/4 thrombocytopenia was higher in the 4-week arm (29.5% versus 5.5% of patients; P = 0.14). A total of 398 cycles of therapy were delivered. Overall, 51% of cycles were modified in dose, timing or both in the 4-week arm, and 19% in the 3-week arm. The 21-day schedule of GC leads to a similar received DI of gemcitabine and higher cisplatin DI. Both regimens had activity in NSCLC, with a response rate of 39% (38% for the 4-week arm, and 42% for the 3-week arm). CONCLUSIONS: The 3-week schedule has similar DI to the 4-week schedule. However the 3-week regimen has a better compliance profile and a comparable response rate in NSCLC, supporting the use of such a schedule.

2

Birtle, A., M. Johnson, J. Chester, et al. 2020. "Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial." Lancet 395(10232):1268-1277.

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BACKGROUND: Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs. METHODS: We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2–T4 pN0–N3 M0 or pTany N1–3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m²) or carboplatin (area under the curve [AUC]4·5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m²) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants. FINDINGS: Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0·45, 95% CI 0·30–0·68; p=0·0001) at a median follow-up of 30·3 months (IQR 18·0–47·5). 3-year event-free estimates were 71% (95% CI 61–78) and 46% (36–56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported. INTERPRETATION: Gemcitabine–platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population.

3

Grossman, H. B., R. B. Natale, C. M. Tangen, et al. 2003. "Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer." N Engl J Med 349(9):859-866. NULL

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BACKGROUND: Despite aggressive local therapy, patients with locally advanced bladder cancer are at significant risk for metastases. We evaluated the ability of neoadjuvant chemotherapy to improve the outcome in patients with locally advanced bladder cancer who were treated with radical cystectomy. METHODS: Patients were enrolled if they had muscle-invasive bladder cancer (stage T2 to T4a) and were to be treated with radical cystectomy. They were stratified according to age (less than 65 years vs. 65 years or older) and stage (superficial muscle invasion vs. more extensive disease) and were randomly assigned to radical cystectomy alone or three cycles of methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy. RESULTS: We enrolled 317 patients over an 11-year period, 10 of whom were found to be ineligible; thus, 154 were assigned to receive surgery alone and 153 to receive combination therapy. According to an intention-to-treat analysis, the median survival among patients assigned to surgery alone was 46 months, as compared with 77 months among patients assigned to combination therapy (P=0.06 by a two-sided stratified log-rank test). In both groups, improved survival was associated with the absence of residual cancer in the cystectomy specimen. Significantly more patients in the combination-therapy group had no residual disease than patients in the cystectomy group (38 percent vs. 15 percent, P <0.001). CONCLUSIONS: As compared with radical cystectomy alone, the use of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy increases the likelihood of eliminating residual cancer in the cystectomy specimen and is associated with improved survival among patients with locally advanced bladder cancer.

4

Advanced Bladder Cancer Meta-analysis, Collaboration. 2003. "Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis." Lancet 361(9373):1927-1934.

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BACKGROUND: Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease. METHODS: We analysed updated data for 2688 individual patients from ten available randomised trials. FINDINGS: Platinum-based combination chemotherapy showed a significant benefit to overall survival (combined hazard ratio [HR] 0.87 [95% CI 0.78-0.98, p=0.016]; 13% reduction in risk of death; 5% absolute benefit at 5 years [1-7]; overall survival increased from 45% to 50%). This effect was observed irrespective of the type of local treatment, and did not vary between subgroups of patients. The HR for all trials, including those using single-agent cisplatin, tended to favour neoadjuvant chemotherapy (HR=0.91, 95% CI 0.83-1.01) although this tendency was not significant (p=0.084). Although platinum based combination chemotherapy was beneficial, there was no evidence to support the use of single-agent platinum; indeed, there was a significant difference in the effect between these groups of trials (p=0.044). INTERPRETATION: This improvement in survival encourages the use of platinum-based combination chemotherapy for patients with invasive bladder cancer.

5

Advanced Bladder Cancer Meta-analysis, Collaboration. 2005. "Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration." Eur Urol 48(2);202-5.

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OBJECTIVES: To update a systematic review and meta-analysis that assesses the effect of neoadjuvant chemotherapy in the treatment of patients with invasive bladder cancer. METHODS: Following a prespecified protocol, we analysed updated individual patient data from all eligible randomised controlled trials that compared neoadjuvant chemotherapy plus local treatment with the same local treatment alone. RESULTS: Updated results are based on 11 trials, 3005 patients; comprising 98% of all patients from known eligible randomised controlled trials. We found a significant survival benefit associated with platinum-based combination chemotherapy (HR = 0.86, 95% CI 0.77-0.95, p = 0.003). This is equivalent to a 5% absolute improvement in survival at 5 years. There was also a significant disease-free survival benefit associated with platinum-based combination chemotherapy (HR = 0.78 95% CI 0.71-0.86, p < 0.0001), equivalent to a 9% absolute improvement at 5 years. CONCLUSIONS: These results provide the best available evidence in support of the use of neoadjuvant platinum-based combination chemotherapy.

6

Advanced Bladder Cancer Meta-analysis Collaboration. "Neo-adjuvant chemotherapy for invasive bladder cancer." Cochrane Database of Systematic Reviews 2004. Edited and republished 2012

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Background: Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials (RCTs) involving over 3000 patients. Objectives: To conduct a systematic review and meta-analysis of individual patient data to evaluate the effect of neoadjuvant chemotherapy on survival in patients with this invasive bladder cancer. Search methods: MEDLINE and Cancerlit searches were supplemented with information from registers and by hand searching meeting proceedings and also by discussion with relevant trialists and organisations. These have been regularly updated until June 2003.Selection criteria: Trials that aimed to randomise patients with biopsy proven invasive (i.e. clinical stage T2 to T4a) transitional cell carcinoma of the bladder to receive local definitive treatment with or without neoadjuvant chemotherapy were eligible for inclusion. Data collection and analysis: We collected, validated and re-analysed updated data on all randomised patients from all available randomised trials, including 3005 patients from 11 RCTs. For all outcomes, we obtained overall pooled hazard ratios using the fixed effects model. To explore the potential impact of trial design we pre-planned analyses that grouped trials by important aspects of their design that might influence the treatment effect. To investigate any differences in effect by pre-defined patient subgroups we used a stratified logrank analysis on the primary endpoint of survival. Main results: These results include data from one extra trial and so update those in the original publication ABC 2003. Platinum based combination chemotherapy showed a significant benefit on overall survival with a combined hazard ratio (HR) 0.86 (95% CI 0.77 to 0.95, P = 0.003); 14% reduction in the risk of death; 5% absolute benefit at 5 years (95% CI 1% to 7%); overall survival increased from 45% to 50%. This effect was observed irrespective of the type of local treatment and did not vary between subgroups of patients. The HR for all trials, including those that used single-agent cisplatin, tended to favour neoadjuvant chemotherapy (HR= 0.89, 95% CI 0.81 to 0.98, P = 0.022). Although platinum based combination chemotherapy was beneficial, there was no clear evidence to support the use of single-agent platinum, indeed there was significant difference in the effect between these groups of trials (P = 0.029).Authors' conclusions: This improvement in survival encourages the use of platinum based combination chemotherapy for patients with invasive bladder cancer. US: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005246/abstract

7

von der, Maase H., S. W. Hansen, J. T. Roberts, et al. 2000. "Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study." J.Clin Oncol. 18(17):3068-3077.

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PURPOSE: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m2 days 1, 8 and 15; cisplatin 70 mg/m2 day 2) or standard MVAC every 28 days for a maximum of six cycles. RESULTS: Four hundred five patients were randomized (GC, n = 203; MVAC, n = 202). The groups were well-balanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P = .75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the MVAC arm. More GC than MVAC patients had grade 3/4 anemia (27% v 18%, respectively), and thrombocytopenia (57% v 21%, respectively). On both arms, the RBC transfusion rate was 13 of 100 cycles and grade 3/4 hemorrhage or hematuria was 2%; the platelet transfusion rate was four patients per 100 cycles and two patients per 100 cycles on GC and MVAC, respectively. More MVAC patients, compared with GC patients, had grade 3/4 neutropenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), neutropenic sepsis (12% v 1%, respectively), and grade 3/4 mucositis (22% v 1%, respectively) and alopecia (55% v 11%, respectively). Quality of life was maintained during treatment on both arms; however, more patients on GC fared better regarding weight, performance status, and fatigue. CONCLUSION: GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC

8

Yuh, B., N. Ruel, & T. Wilson. et al. 2013. "Pooled analysis of clinical outcomes with neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer." J Urol. 189(5);1682-6.

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PURPOSE: Neoadjuvant chemotherapy for muscle invasive bladder cancer has been shown to confer a survival advantage in phase III studies. Although cisplatin and gemcitabine are often used in this setting, a comprehensive evaluation of this regimen is lacking. In this review we summarize the efficacy of neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer based on currently published studies. MATERIALS AND METHODS: A systematic literature review was conducted in April 2012 searching MEDLINE(R) databases. Articles were selected if they included patients with muscle invasive bladder cancer, evaluated the combination of cisplatin and gemcitabine as neoadjuvant treatment, and reported pathological data after cystectomy. Cisplatin and gemcitabine dosing regimens and clinical data were further summarized using weighted averages. RESULTS: Seven studies encompassing 164 patients were published between 2007 and 2012. The majority of patients (79%) received cisplatin and gemcitabine on a 21-day cycle. A weighted average of 19.2 lymph nodes was obtained at cystectomy, and 29.7% of patients were found to have pN1 disease. Pathological down staging to pT0 and less than pT2 occurred in 42 (25.6%) and 67 (46.5%) patients, respectively. CONCLUSIONS: Neoadjuvant cisplatin and gemcitabine yield appreciable pathological response rates in patients with muscle invasive bladder cancer. Since pathological response has been implicated as a potential surrogate for survival in muscle invasive bladder cancer, these data suggest that neoadjuvant cisplatin and gemcitabine may warrant further prospective assessment.

9

Herchenhorn, D., R. Dienstmann, F. A. Peixoto, et al. 2007. "Phase II trial of neoadjuvant gemcitabine and cisplatin in patients with resectable bladder carcinoma." Int Braz J Urol 33(5):630-638; discussion 638.

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OBJECTIVES: Gemcitabine and cisplatin (GC) is an active combination in the treatment of metastatic bladder cancer. We have prospectively analyzed the efficacy and tolerability of GC as neoadjuvant treatment of invasive bladder cancer. MATERIALS AND METHODS: In this single-institution phase II trial, patients with muscle-invasive transitional cell carcinoma received three cycles of gemcitabine 1200 mg/m2 on days 1 and 8 with cisplatin 75 mg/m2 on day 1 prior to surgery. Radiologic response was evaluated by computed tomography and magnetic resonance imaging. All patients were referred to surgery after chemotherapy completion. RESULTS: Between June 2002 and March 2005, 22 patients (19 males) were enrolled. Median age was 63 years. Initial stage was II (T2) in 11 and III (T3-4) in 11 patients. Median follow-up is 26 months (4-43). Partial or complete radiologic response rate was documented in 13 out of 20 assessable patients (70%). One patient was excluded due to sarcomatoid carcinoma at definitive pathologic examination. Cystectomy was performed in 15 patients and pelvic radiotherapy in four patients. Nine out of 21 patients (43%) relapsed and four (19%) died due to disease progression. Complete pathologic response was observed in four patients (26.7% of 15). Median progression-free survival was 27 months (CI 95% not reached) with median overall survival of 36 months (CI 95%: 28.7 - 43.3). Grade III/IV toxicity was infrequent, with no deaths due to chemotherapy. CONCLUSIONS: The combination of GC is effective and well-tolerated when used as neoadjuvant therapy in muscle-invasive bladder cancer. Longer follow-up is necessary to evaluate its impact on the overall survival of these patients.

10

Pal, S. K., N. H. Ruel, T. G. Wilson, et al. 2012. "Retrospective analysis of clinical outcomes with neoadjuvant cisplatin-based regimens for muscle-invasive bladder cancer." Clin Genitourin Cancer 10(4):246-250.

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BACKGROUND: The benefit of neoadjuvant methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) for muscle-invasive bladder cancer (MIBC) has been prospectively demonstrated in a phase III study. Extrapolating from comparative data in the metastatic setting, platinum doublets such as cisplatin-gemcitabine (CG) have been adopted. We sought to compare clinical outcomes in patients treated for MIBC with neoadjuvant CG and MVAC at our institution. PATIENTS AND METHODS: Patients with MIBC were identified from a prospectively maintained registry. Clinicopathologic information and clinical outcome data were obtained directly from the registry. When available, pharmacy records were reviewed to ascertain the use of growth factors and chemotherapy dose intensity (DI). Survival was compared in subgroups divided by the regimen of chemotherapy rendered (ie, CG vs. MVAC) using the Kaplan-Meier method. RESULTS: Median overall survival (OS) in the overall cohort (N = 61) was 23 months. OS was improved in patients receiving either MVAC or CG chemotherapy compared with patients receiving other chemotherapy (35.3 vs. 16.3 months; P = .055). Although the median OS associated with neoadjuvant CG numerically exceeded the survival associated with neoadjuvant MVAC (104.3 and 21.8 months, respectively), this was not statistically significant (P = .73). Pathologic downstaging predicted improved OS with both neoadjuvant CG and MVAC, and the rates of downstaging were similar with both regimens. CONCLUSIONS: Although warranting prospective validation, our data suggest that CG is a possible alternative neoadjuvant approach to traditional regimens such as MVAC for patients with MIBC.

11

Yeshchina, O., G. M. Badalato, M. S. Wosnitzer, et al. 2012. "Relative efficacy of perioperative gemcitabine and cisplatin versus methotrexate, vinblastine, adriamycin, and cisplatin in the management of locally advanced urothelial carcinoma of the bladder." Urology 79(2):384-390.

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OBJECTIVE: To compare the outcomes of patients treated in the perioperative setting with methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) versus gemcitabine and cisplatin (GC). Systemic cisplatin-based chemotherapy regimens are the mainstay of treatment for patients with advanced bladder cancer. GC has often been used interchangeably with MVAC in neoadjuvant or adjuvant settings for patients with locally advanced (cT2N0M0-cT4N2M0) bladder cancer without adequate evidence. METHODS: A total of 114 patients treated with systemic chemotherapy for Stage T2-T4N0-N2M0 urothelial cell carcinoma of the bladder were included in the present study. The survival times were estimated and compared using the Kaplan-Meier method and log-rank test, respectively. Univariate and multivariate Cox proportional hazards models were used to determine the statistical significance. RESULTS: Of the 114 patients included in the present study, 37 (32%) were treated with GC and 77 (68%) with MVAC. In the neoadjuvant group, no difference was found between the 2 chemotherapeutic regimens in terms of the pathologic complete response rate at either cystectomy or during cystoscopy (14 [31%] of 45 MVAC patients vs 4 [25%] of 16 GC patients; P=.645). On multivariate analysis, the choice of regimen was not an independent predictor of cancer-specific death (hazard ratio 1.3, 95% confidence interval 0.67-2.57; P=.421) or overall survival (hazard ratio 1.3, 95% confidence interval 0.76-2.24; P=.330). CONCLUSION: Despite the lack of data on the relative efficacy of GC versus MVAC in the neoadjuvant and adjuvant settings, these regimens have been used interchangeably. The present investigation did not find the choice of cisplatin-based regimen to be an independent predictor of survival. A trend was seen toward improved survival and a greater complete response rate in the MVAC group.

12

Scosyrev, E., E. M. Messing, E. van Wijngaarden, et al. 2012. "Neoadjuvant gemcitabine and cisplatin chemotherapy for locally advanced urothelial cancer of the bladder." Cancer 118(1):72-81.

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BACKGROUND: The purpose of this study was to investigate the effect of neoadjuvant chemotherapy with gemcitabine and cisplatin (GC) on pathologic down-staging of patients with locally advanced urothelial cancer (UC) of the bladder. METHODS: This was a retrospective cohort study of patients treated with radical cystectomy (RC) for clinical stage cT2-T4, N any, M0 bladder UC at Strong Memorial Hospital from 1999 to 2009. The primary exposure variable was use of neoadjuvant chemotherapy (GC vs none). The primary outcome was stage pT0 at RC. Secondary outcomes included other down-staging end points in the bladder (<pT1, <pT2, <pT3), nodal status, and surgical margins. Linear probability models were used to estimate the effect of neoadjuvant GC on tumor down-staging with adjustment for clinical staging variables. RESULTS: A total of 160 eligible patients were identified, of whom 25 were treated with neoadjuvant GC before RC (GC + RC) and 135 without neoadjuvant chemotherapy (RC only). Stage pT0 at cystectomy was found in 20% of patients in the GC + RC group and in 5% of patients in the RC group (adjusted risk difference [aRD] = 16%, P = .03). For other down-staging end points, the estimated treatment effect was as follows (all point estimates favoring chemotherapy): <pT1 aRD = 30% (P = .005); <pT2 aRD = 30% (P = .004); <pT3 aRD = 31% (P = .008); margins aRD = 8% (P = .41); nodes aRD = 4% (P = .74). CONCLUSIONS: Neoadjuvant GC was found to be capable of down-staging UC in the bladder; however, no effect on disease in nodes was seen in this study.

13

Kaneko, G., E. Kikuchi, K. Matsumoto, et al. 2011. "Neoadjuvant gemcitabine plus cisplatin for muscle-invasive bladder cancer." Jpn J Clin Oncol 41(7):908-914.

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OBJECTIVE: Downstaging by neoadjuvant chemotherapy improves the survival of patients with muscle-invasive bladder cancer. In salvage setting, gemcitabine plus cisplatin has demonstrated an efficacy similar to that of methotrexate, vinblastine, doxorubicin and cisplatin with less toxicity. Therefore, the application of neoadjuvant gemcitabine plus cisplatin is also being anticipated. METHODS: Twenty-two patients who received neoadjuvant gemcitabine plus cisplatin were evaluated. The rate of downstaging, chemotherapy delivery profile and toxicity data were assessed. As comparator group, nine patients who were administered with neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin were evaluated. RESULTS: A mean of 1.9 cycles of neoadjuvant gemcitabine plus cisplatin were performed. Achieved drug intensity for gemcitabine and cisplatin was 83.8 and 95.4%. Downstaging to pT0 and <pT2 was achieved in 50.0 and 63.6%. Grade 3 or 4 neutropenia, anemia, thrombocytopenia and febrile neutropenia appeared in 14.3, 2.4, 21.4 and 2.4%, respectively. Grade 3 or 4 non-hematologic toxicity was not observed. Thrombocytosis developed in 26.2%. A mean of 2.3 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin were performed. The achieved drug intensities for methotrexate, vinblastine, doxorubicin and cisplatin were 59.6, 69.8, 100 and 88.6%. In patients treated with neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin, downstaging to pT0 and <pT2 was achieved in 22.2 and 44.4%. Grade 3 or 4 neutropenia, anemia and thrombocytopenia was present in 19.1, 9.5 and 4.8%. Grade 3 nausea developed in 28.6%. CONCLUSIONS: The rate of downstaging by neoadjuvant gemcitabine plus cisplatin was comparable with that by methotrexate, vinblastine, doxorubicin and cisplatin. Gemcitabine plus cisplatin was associated with less non-hematologic toxicity than methotrexate, vinblastine, doxorubicin and cisplatin.

14

Weight, C. J., J. A. Garcia, D. E. Hansel, et al. 2009. "Lack of pathologic down-staging with neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma of the bladder: a contemporary series." Cancer 115(4):792-799.

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BACKGROUND: The postcystectomy survival benefit associated with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) neoadjuvant chemotherapy (NC) for muscle-invasive bladder cancer has been most evident in patients who achieve a pathologic complete response. The outcome of NC and open radical cystectomy (RC) was evaluated in a contemporary cohort of patients in a tertiary referral setting. METHODS: From January 2006 to November 2007, 117 patients underwent open RC at Cleveland Clinic for muscle-invasive bladder cancer, 29 (25%) of whom received NC. Patient information was obtained from a prospective database. RESULTS: Clinical stage at the time of diagnosis in the NC cohort was T2 in 23 (79%) and T3-4a in 6 (21%) patients. A total of 20 (69%) patients received the combination of gemcitabine and cisplatin (GC), 4 (14%) received MVAC, and 5 (17%) received other regimens. The median interval from the time of diagnosis of muscle-invasive bladder cancer to RC was 208 days (interquartile range, 149 days -327 days) in the NC cohort. Overall, only 2 patients (7%; 95% confidence interval [95% CI], 0 patients-17 patients) achieved a pathologic complete response, 18 (62%; 95% CI, 43 patients-81 patients) had nonorgan-confined residual cancer, and the overall median progression-free survival was 10.5 months (95% CI, 7 months -14 months). CONCLUSIONS: Few RC patients in these investigators' recent experience achieved a pathologic complete response with NC, and most experienced rapid disease progression. These poor outcomes may be related to the use of non-MVAC-based regimens or excessive delay in performing RC. In the absence of supportive data for GC in the neoadjuvant setting, MVAC remained the preferred regimen. Excessive delays in performing RC may negate the benefit of NC.

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Dash, A., J. A. th Pettus, H. W. Herr, et al. 2008. "A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience." Cancer 113(9):2471-2477.

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BACKGROUND: Neoadjuvant cisplatin-based chemotherapy improves survival in muscle-invasive urothelial cancer, with MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) considered the standard regimen. Gemcitabine plus cisplatin (GC) has similar efficacy and less toxicity than MVAC in metastatic disease, but is untested as neoadjuvant treatment. METHODS: The authors retrospectively evaluated patients with muscle-invasive urothelial carcinoma who received neoadjuvant GC before radical cystectomy between November 2000 and December 2006 at Memorial Sloan-Kettering Cancer Center. Post-therapy pathological downstaging to either residual disease at cystectomy (pT0) or no residual muscle-invasion (<pT2, ie, pT0, pTIS, pT1), chemotherapy delivery, and disease-free survival were the endpoints of interest. For comparison, similar endpoints were assessed in a historical cohort treated with neoadjuvant MVAC. RESULTS: Four cycles of neoadjuvant GC were given over 12 weeks (n=42). Thirty-nine (93%) of 42 patients received 4 cycles, with a median 91% drug delivery for cisplatin and 90% for gemcitabine. The pT0 proportion was 26% (95% confidence interval [CI], 14-42), and no residual muscle-invasive disease proportion (<pT2) was 36% (95% CI, 21-52); pT0 was achieved in 28% (95% CI, 16-42) and <pT2 in 35% (95% CI, 23-49) of 54 MVAC-treated patients. All 15 GC patients achieving <pT2 pathologic stage remained disease-free at a median follow-up of 30 months. CONCLUSIONS: Neoadjuvant GC is feasible and allows for timely drug delivery. The proportion of GC-treated patients whose primary tumors were downstaged, with prolonged disease-free survival and minimal or no residual disease, was similar to MVAC-treated patients.

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As ID 4036 Bladder/Urothelial neoadjuvant/adjuvant replaces an existing approved protocol, the individual history section is included below for consistency in documentation.