Methotrexate, Vinblastine, Doxorubicin, Cisplatin Research Articles

Comparative Effectiveness Analysis of Treatment Strategies for Surgically Resectable Neuroendocrine Carcinoma of the Urinary Tract

BackgroundNeoadjuvant chemotherapy (neoCTX) has been recommended as the optimal strategy in surgically resectable neuroendocrine carcinoma (NEC) of the urinary tract (NEC-URO). ObjectiveTo determine the systemic therapy regimen and timing, which are most active against NEC-URO. Design, setting, and participantsWe used our institutional historical clinical and pathological database to study 203 patients (cT2, 74%; cT3/4a, 22%; and cTx, 4%) with surgically resectable NEC-URO between November 1985 and May 2020. A total of 141 patients received neoCTX and 62 underwent initial radical surgery, 24 of whom received adjuvant CTX (adjCTX). InterventionNeoadjuvant CTX with etoposide/cisplatin (EP), an alternating doublet of ifosfamide/doxorubicin (IA) and EP, dose-dense methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), gemcitabine/cisplatin (GC), or others. Outcome measurements and statistical analysisOverall survival (OS), downstaging rate, and pathological complete response using a multivariable model adjusting for tumor- and patient-related factors. Results and limitationsDownstaging rate was significantly improved with neoCTX versus initial surgery (49.6% vs 14.5%, p < 0.0001), stage cT2N0 versus cT3/4N0 (44% vs 25%, p = 0.01), or presence of carcinoma in situ (47% vs 28%, p = 0.01). Downstaging was greatest with IA/EP (65%) versus EP (39%), MVAC/GC (27%), or others (36%, p = 0.04). After adjusting for age and Eastern Cooperative Oncology Group performance status, IA/EP was still associated with improved downstaging (odds ratio = 3.7 [1.3–10.2], p = 0.01). At a median follow-up of 59.7 mo, 5-yr OS rates for neoCTX followed by surgery, surgery alone, and surgery followed by adjCTX were 57%, 22%, and 30%, respectively. An NEC regimen (IA/EP or EP) versus a urothelial regimen (MVAC/GC or others) was associated with improved survival (145.4 vs 42.5 mo, hazard ratio = 0.49, 95% confidence interval: 0.25–0.94). ConclusionsNeoadjuvant CTX remains the standard-of-care treatment for NEC-URO with an advantage for NEC regimens over traditional urothelial regimens. IA/EP improves pathological downstaging at the time of surgery compared with EP, but is reserved for younger and higher function patients. Patient summaryIn this report, we looked at the outcomes from invasive neuroendocrine carcinoma of the urinary tract in a large US population. We found that the outcomes varied with treatment strategy. We conclude that the best outcomes are seen in patients treated with chemotherapy prior to surgery and regimens tailored to histology and tolerance.

Neoadjuvant Chemotherapy in Elderly Patients With Upper Tract Urothelial Cancer: Oncologic Outcomes From a Multicenter Study.

Although upper tract urothelial carcinoma (UTUC) is more common in the elderly, outcomes of neoadjuvant chemotherapy (NAC) in this population have never been explored. The objective of the study was to assess the impact of NAC on pathologic response and oncological outcomes stratified by age. This multicenter study included 164 patients treated with NAC and radical nephroureterectomy (RNU) for clinically non-metastatic, high-risk UTUC. The cohort was stratified into two groups according to median age. Patients received either cisplatin-based or non-cisplatin-based chemotherapies. Pathologic responses were defined as pathologic objective response (pOR; ≤ ypT1N0) and pathologic complete response (pCR; ypT0N0). Univariable and multivariable logistic and Cox regression analyses were performed to identify predictors for pathologic response and survival outcomes. The cohorts' median age was 68 years with the elderly group (> 68 years) comprising 74 patients. Neoadjuvant chemotherapy included methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) in 66 (40%), gemcitabine cisplatin (GC) in 66 (40%) and non-cisplatin chemotherapy in 32 patients (20%). Younger patients received more often MVAC (50% vs. 28%) while elderly received more GC (34% vs. 47%) or non-cisplatin chemotherapy (16% vs. 24%) (P=.02). Overall, pOR and pCR were similar across age groups (52% vs. 47%; P=.5 and 10% vs. 8%; P=.7). While GC and non-cisplatin chemotherapy showed a lower pCR of 5% and 3%, respectively, MVAC revealed a pCR of 17% (P=.03) and was independently associated with a higher pCR (OR 4.31; P=.03). Kaplan-Meier analysis showed no difference in recurrence-free and cancer-specific survival, whereas a lower rate was seen in overall survival for the elderly. Elderly patients with high-risk UTUC eligible for cisplatin-based NAC prior to RNU may benefit from this multimodal therapy equally as their younger counterparts. Cisplatin-ineligible patients undergoing non-cisplatin-based NAC appeared to have lower response rates and should be considered for immediate RNU.

Real-world treatment patterns and clinical outcomes among patients with metastatic urothelial carcinoma.

4538 Background: Knowledge of large-scale real-world treatment patterns and clinical outcomes in patients (pts) with metastatic urothelial carcinoma (mUC) is limited. We conducted this study to address the lack of knowledge and identify unmet needs in pts with mUC in real-world clinical practice. Methods: The US nationwide Flatiron Health electronic health records–derived, de-identified database, comprised of 280 oncology practices across the US, was utilized to conduct a retrospective cohort analysis of pts diagnosed with mUC between Jan 1, 2011, and Aug 31, 2020. Baseline pt characteristics were assessed descriptively, and treatment patterns were classified by cisplatin (CIS) eligibility. Kaplan–Meier methods were used to evaluate overall survival (OS) and progression-free survival (PFS). In a subgroup analysis of cisplatin-ineligible (CIS-inelig) pts, a multivariable model adjusting for baseline covariates was used to assess survival outcomes. Results: Of 8183 pts with mUC, median age was 73.0 years at diagnosis. Primary tumor sites were bladder (78.5%), upper tract (20.6%), and urethra (0.9%). Median (range) follow-up from mUC diagnosis was 9.7 (0.2-116.6) months. Of 5855 (71.6%) pts who received first-line (1L) systemic therapy, 1764 (30.1%) were CIS eligible (CIS-elig), 2293 (39.2%) were CIS-inelig, and 616 (10.5%) did not receive CIS despite qualifying ECOG PS (0–1) and renal function; CIS eligibility was unknown in 1182 (20.2%). Among all 1L pts, 4380 (74.8%) received chemotherapy and 1410 (24.1%) received immunotherapy (IO); of the IO users, 1345 (95.4%) received monotherapy. Among CIS-elig pts, CIS plus gemcitabine (GC) and methotrexate, vinblastine, doxorubicin, CIS (MVAC) accounted for 1562 (88.5%) of 1L therapy. Among CIS-inelig pts, carboplatin plus gemcitabine (GCa; 36.1%), pembrolizumab (pembro) monotherapy (18.5%), and atezolizumab (atezo) monotherapy (15.1%) were the most common 1L therapies. Across CIS eligibility groups, the most common second-line therapies included pembro, atezo, and GCa; the most common third-line therapies included atezo, pemetrexed, paclitaxel, and GCa. Median OS (95% CI) was longer in pts who received ≥ 1 line of systemic therapy (14.5 [14.0–15.2] months) than in those who did not receive therapy (6.8 [6.2–7.3] months). Median (95% CI) OS and PFS were also longer in CIS-elig pts (OS, 19.7 [18.2–21.4] months; PFS, 11.5 [10.8–12.1] months) than in CIS-inelig pts (OS, 11.4 [10.8–12.0] months; PFS, 7.0 [6.7–7.4] months), irrespective of receiving treatment. In a subgroup analysis of CIS-inelig pts, 1L IO monotherapy was associated with worse OS than 1L chemotherapy (HR, 1.26; 95% CI, 1.13–1.40, P &lt; 0.0001). Conclusions: This study of &gt; 8000 mUC pts, of whom almost 30% never received systemic therapy, demonstrates real-world treatment patterns in mUC and highlights the substantial unmet need in this population, in particular for CIS-inelig pts.

Meta-analysis of neoadjuvant chemotherapy compared to radical cystectomy alone in improving overall survival of muscle-invasive bladder cancer patients

BackgroundMost patients with muscle-invasive bladder cancer (MIBC) developed metastasis within 2 years, even after radical cystectomy (RC). The recurrence rate of MIBC was more than 50% of the cases. A meta-analysis conducted by Yin et al. showed that neoadjuvant chemotherapy (NAC) + RC improves overall survival in MIBC compared with RC only. However, a new meta-analysis by Li et al. concluded that NAC + RC was not superior to RC only in improving overall survival. The inconsistencies of these studies required further comprehensive analysis to recommend NAC use in bladder cancer treatment. Therefore, this meta-analysis aims to analyze previous studies that compare the efficacy of NAC + RC versus RC only to improve overall survival of MIBC.MethodsThe articles were searched using Pubmed with keywords “muscle-invasive bladder cancer”, “neoadjuvant chemotherapy”, “cystectomy”, and “overall survival”. The articles that were published until June 2020 were screened. The overall survival outcome was analyzed as hazard ratio (HR) and presented in a forest plot.ResultSeventeen studies were included in meta-analysis with a total sample of 13,391 patients, consist of 2890 received NAC followed by RC and 10,418 underwent RC only. Two studies used methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), two studies used gemcitabine/cisplatin (GC), one study used Cisplatin-based regimen, one study used MVAC or GC, one study used gemcitabine/carboplatin (GCarbo) or GC or MVAC, one study used Cisplatin/Gemcitabine or MVAC, one study used Cisplatin only, one study used Cisplatin-based (GC, MVAC) or non-Cisplatin-based (combined paclitaxel/gemcitabine/carboplatin), one study used GC, MVAC, Carboplatin, or Gemcitabine/Nedaplatin (GN), and five studies did not mention the regimen The overall survival in the NAC + RC only group was significantly better than the RC only group (HR 0.82 [0.71–0.95], p = 0.009).ConclusionNAC + RC is recommended to improve overall survival in MIBC patients. A further study assessing side effects and quality of life regarding NAC + RC is needed to establish a strong recommendation regarding this therapy.

Review of SWOG S1314: Lessons from a Randomized Phase II Study of Co-Expression Extrapolation (COXEN) with Neoadjuvant Chemotherapy for Localized, Muscle-Invasive Bladder Cancer.

SWOG1314 is a randomized phase II study of co-expression extrapolation (COXEN) with neoadjuvant chemotherapy for localized, muscle-invasive bladder cancer. COXEN is a biomarker approach in which predictive biomarkers are developed using in vitro data, which may then be applied directly into a clinical testing application. Two separate Gene Expression Models (GEMs), one for the Methotrexate, Vinblastine, Doxorubicin, Cisplatin (MVAC) regimen and another for gemcitabine plus cisplatin (GC) were tested in S1314. The lessons learned from the development and operationalization of the S1314 clinical trial are described in detail, which may help to inform the future trials of predictive biomarkers for urothelial carcinoma in the neoadjuvant setting. Specific areas addressed include: The need for broad support from the bladder cancer community, planning for non-evaluable subjects, defining adequate neoadjuvant treatment, defining adequate tissue collection, setting expectations in phase II clinical studies of predictive biomarkers, and maximizing the impact of the samples collected in these studies for broader biomarker development. With a large number of newly available treatments in advanced urothelial carcinoma in the last few years, more investigations of these agents in the neoadjuvant setting is anticipated. There will be a great need for the development of predictive biomarkers in conjunction with the use of these agents in the preoperative setting. Insights from S1314 may provide useful information and lessons learned in this development.

FGFR-altered, advanced urothelial carcinoma (UC) and response to chemotherapy prior to receiving erdafitinib.

4542 Background: FGFR-altered, advanced UC has predominantly a luminal 1 subtype, which is associated with lower response rates to immunotherapy and possibly also to chemotherapy. Objective response rates (ORR) for first-line cisplatin-based regimens, such as gemcitabine-cisplatin (gem/cis) and methotrexate-vinblastine-doxorubicin-cisplatin (MVAC), historically range between 45-60% and for gemcitabine-carboplatin (gem/carbo) 35-45%. However, the ORR on chemotherapy for the ~20% of patients with FGFR-altered tumors is unknown. Methods: BLC2001 (NCT02365597) is an ongoing global open-label phase 2 study of the pan-FGFR inhibitor erdafitinib in patients with locally advanced or metastatic UC with specific FGFR2/3 gene alterations. Patients who had received first-line (1L) or second-line (2L) chemotherapy for advanced UC were identified. Investigator-reported ORR (complete + partial responses) and median time to progression (TTP) on these pretreatments were analyzed. Results: Of 210 patients treated with erdafitinib in BLC2001, 191 had received prior systemic therapy including 184 and 83 patients who had received 1L and 2L chemotherapy, respectively. ORR were 29.3% (54/184; 95% CI 22.8%, 35.9%) to 1L chemotherapy and 24.1% (20/83; 95% CI 14.9%, 33.3%) to 2L chemotherapy. 1L therapy consisted of gem/cis in 94 patients, gem/carbo in 59 patients, and MVAC in 22 patients, with ORR (95% CI) of 35.1% (25.5%, 44.8%), 25.4% (14.3%, 36.5%), and 22.7% (5.2%, 40.2%), respectively. In the 2L setting, of 46 patients who had received a regimen containing a taxane (paclitaxel or docetaxel) or vinflunine, 8 patients (17.4%; 95% CI 6.4%, 28.3%) achieved an objective response. Median TTP was 7.16 mo (95% CI 6.18, 7.49) after 1L chemotherapy (7.6 mo for gem/cis, 6.3 mo for gem/carbo, and 5.3 mo for MVAC) and 4.35 mo (95% CI 3.3, 5.5) after 2L chemotherapy (3.6 mo for taxane or vinflunine). Conclusions: In this post-hoc analysis, the overall ORR to prior 1L chemotherapy was lower, but within the range expected based on historical data. Further investigation into the response to chemotherapy in FGFR alteration positive patients is warranted and may be useful for the development of 1L trials of combination therapy. Clinical trial information: NCT02365597.

Comparing clinical outcomes between patients with urothelial carcinoma who treated neoadjuvant chemotherapy by gemcitabine-cisplatin and dose-dense MVAC.

376 Background: Prospective randomized trials demonstrated efficacy of MVAC (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer (MIBC). In metastatic setting urothelial cell carcinoma (UCC), clinical trials showed no difference in oncologic outcomes between Gemcitabine-Cisplatin (GC) and MVAC, and another prospective trial proved dose-dense (dd) MVAC had significantly better overall survival (OS) and response rate then MVAC. Comparative data between GC and ddMVAC are limited in neoadjuvant setting. Methods: A retrospective analysis of patients with urothelial carcinoma (cT2-4aN0-1M0) who received NAC from January 2011 and December 2017 in Asan Medical Center was conducted. Patients who received GC were compared to patients received ddMVAC in terms of outcomes including downstaging ( &lt; ypT2 and no N upstaging), pathologic complete response (pCR, ypT0N0), disease-free survival (DFS), and overall survival (OS) and tolerability. Results: In a total of 277 patients, 176 patients received NAC with GC and 41 patients with dose-dense MVAC. The median chemotherapy cycle is 4 (IQR 3-4) cycles for GC group, 4 (IQR 3-5.5) cycles for dose-dense MVAC group. With an exception of age; GC group is associated with younger age (p = 0.002), other baseline characteristics are well balanced between groups. Downstaging rate are 50.8% in GC group, 58.1% in dose-dense MVAC group (p = 0.47). The rates of achieving ypT0 (28.7% vs 22.6%, p = 0.68), ypN0 (78.3% vs 81.5%, p = 0.39). There were no differences in overall survival (OS) at 3 year (72.2% vs 73.2%, p = 0.58), disease-free survival (DFS) at 3 years (54.9% vs 63.3%, p = 0.21) according to chemotherapy regimens. ddMVAC with prophylactic G-CSF are associated with higher incidence of febrile neutropenia (p = 0.004) than GC. NAC regimen is not independent prognostic factor for OS on multivariable analysis. Conclusions: GC regimen had no significant difference in oncologic outcomes compare to ddMVAC as NAC in UCC.

The role of adjuvant chemotherapy for pT2-4 upper urinary tract urothelial cancer: Exploratory analysis of large multi-institutional study (JCOG1110A).

374 Background: Recently, it was presented that adjuvant chemotherapy (AC) after radical nephroureterectomy (RNU) improved metastasis-free survival in pT2-4 upper urinary tract urothelial cancer (UTUC) with a median follow-up of 17.6 months (POUT study). However, the impact of AC on other outcomes remains unclear, especially for pT2 disease. Methods: The large case-series study, JCOG1110A, included 2,744 patients with non-metastatic UTUC who underwent RNU in 30 institutions in Japan between 1995 and 2009. In this analysis, patients with prior history or synchronous bladder cancer, patients who received neoadjuvant chemotherapy were excluded. Patients who received AC except for GC (gemcitabine, cisplatin) or MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) were also excluded. We extracted pT2-4 patients as study subjects from remaining patients, and identified 950 patients. The impact of AC on overall survival (OS) and extravesical recurrence-free survival (RFS) were examined by the multivariable Cox regression model in all patient and pT2, pT3-4 subgroups. Results: Of 244 pT2 and 706 pT3-4 patients with a median follow-up of 41.1 months, AC were performed in 34 (13.9%) and 183 (25.9%). In AC (+) group, high frequency of pT3-4 disease, high grade tumor, pathological node metastasis, lymphovascular invasion, and younger age were seen compared to AC (-) group. The 5-year survival of the AC (+) and AC (-) were 66.0% and 67.4% for OS, 58.0% and 57.8% for RFS, respectively. Multivariable analysis showed the improved outcome in AC (+) group on both OS and RFS in all patients (OS: HR 0.60, 95% CI 0.41-0.89, RFS: HR 0.71, 95% CI 0.51-1.00). Although AC had a great impact on OS in pT3-4 patients (HR 0.56, 95% CI 0.36-0.87), there was no clear impact on either OS or RFS in pT2 patients (OS: HR 0.81, 95% CI 0.32-2.07, RFS: HR 0.69, 95% CI 0.29-1.62). Conclusions: AC after RNU had the significant impacts on OS and RFS in pT2-4 UTUC patients. This tendency was seen strongly in pT3-4 patients, but not in only pT2 patients. The randomized trial is necessary to determine the utility of AC in UTUC patients, especially in pT2 patients. Clinical trial information: NCT01993979.

Chemotherapy regimen is associated with venous thromboembolism risk in patients with urothelial tract cancer.

To assess the association of venous thromboembolism (VTE) with different chemotherapy regimens in patients with urothelial tract cancer. We identified patients aged ≥66 years, diagnosed with urothelial tract cancer in the period 1998 to 2011 in the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database. The chemotherapy regimens analysed were gemcitabine/cisplatin (GC), methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), or gemcitabine/carboplatin (CarboG). Propensity scores for treatment regimen based on comorbidities, tumour characteristics, age, and year of diagnosis were calculated. VTE rates within 120days of chemotherapy initiation were calculated. VTE risk stratified by chemotherapy regimen was modelled using multivariable logistic regression, adjusting for treatment propensity scores and additional demographic characteristics. Overall survival stratified by VTE and chemotherapy regimen was estimated using Kaplan-Meier methods and the log-rank test. Of 5594 identified patients, a VTE occurred in 13.0%. The VTE rates within 120 days of chemotherapy initiation were 15.3% for GC, 8.7% for MVAC, and 12.0% for CarboG. On multivariable analysis, MVAC (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.39-0.94) and CarboG (OR 0.71, 95% CI: 0.59-0.85) were associated with lower VTE risk compared with GC. VTE was associated with worse overall survival (P < 0.001). Compared with GC, MVAC and CarboG were associated with a lower rate of VTE. This finding suggests that gemcitabine may add to the increased thrombosis risk from cisplatin. Additionally, patients with a VTE had worse survival outcomes than those without a VTE. Analysis of the risk of blood clots with different chemotherapy regimens in patients with urothelial tract cancer showed that GC was associated with the highest rate. We also found that blood clots were associated with worse patient outcomes.

Abstract 2723: In vivo activity of combinations of cytotoxic regimens with anti-PD1 and anti-PDL1 in various syngeneic cancer models

Abstract Immune checkpoint inhibitors (ICIs) show impressive response rate in multiple cancer types. Nivolumab and atezolizumab has already been approved by the FDA. However, a large proportion of patients do not show any benefits or will develop acquired resistance phenomenon. In order to increase long term survival, alternative strategies are focused on rationale combination of immunotherapies with well-known therapeutic agents such as chemotherapies. In this present project, we described the impact of various chemotherapies regimen in combination with anti-PD1 and anti-PDL-1 on preclinical bladder, colorectal and metastatic breast cancers models. We performed a study of PD-1 or PDL-1 blockade in combination with reference chemotherapies in four fully immunocompetent mouse models of cancer: we used the MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) regimen as standard chemotherapy in bladder cancer MBT-2 and MB49, cyclophosphamide and doxorubicin in breast cancer 4T1, and capecitabine with oxaliplatin in colorectal cancer MC38. We analyzed the in vivo antitumor response and collected tumor samples four days after first treatment administration to analyze the immune infiltrate in tumors. In vivo phenotype study reveals variable responsiveness to ICP blockade. We found strong effects of the combinations in two of the models studied: bladder cancer MB49 and colorectal cancer MC38, a lack of effect in breast cancer 4T1, and an inhibition of immune checkpoint antibody activity in MBT-2 preclinical model. Analysis using flow cytometry showed strong differences both at baseline between mice models as well as after exposure to ICIs, chemotherapy or the combination of both types of treatment. All the preclinical models studied at baseline were highly infiltrated with cells considered as « immunosuppressive », particularly MDSCs. We showed that the balance between antitumor effector cells and immunosuppressive cells could be inverted with some of the treatment combinations. As an example, in the MB49 model the most impressive modifications induced by the combination was an increase of the M1/M2 ratio. However, profound alterations of tumors microenvironment were not systematically correlated with a favorable in vivo phenotype. Indeed, we observed no benefit of the combination in the 4T1 model, although the combination profoundly modified the immune microenvironment with a strong decrease in MDSCs and a large increase in the CD4 and CD8 infiltrates. Our results suggest that modulation of immune cells infiltrate by cytotoxic agents could impact on the potency of ICIs when these are co-administered, with either an enhance or a reduced antitumor activity of the combination. However this impact appears to be model- and combination-dependent. The present investigations should help to select appropriate chemotherapies to combine with target monoclonal antibodies for clinical trials. Citation Format: Chloé Grasselly, Morgane Denis, Aurore Bourguignon, Nolan Talhi, Anne Tourette, Doriane Mathe, Laurent Serre, Lars Petter Jordheim, Charles Dumontet. In vivo activity of combinations of cytotoxic regimens with anti-PD1 and anti-PDL1 in various syngeneic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2723.

Abstract 2749: Effects of subtype specific chemotherapeutic immunomodulation in bladder cancer

Abstract In patients with bladder cancer, programmed death-ligand-1 (PD-L1) and programmed death-1 (PD-1) inhibitors have been shown to be effective in around twenty percent of patients, and there is evidence indicating that the level of immune infiltration and immune suppression within the tumor microenvironment correlates with response to these treatments. We have previously shown that there are intrinsic subtypes of bladder cancer, with the basal subtype characterized by high levels of immune infiltration, and the luminal subtype characterized by immune exclusion. Here we show that treatment with current standard of care chemotherapeutic agents has a subtype specific effect on the tumor microenvironment. Cisplatin-based chemotherapeutic treatment of luminal tumors induces a mesenchymal phenotype, immune infiltration, and a transition to a more basal-like tumor, while not altering these characteristics of the tumor microenvironment in basal tumors. Two of the most widely used standard of care chemotherapeutic regiments are Cisplatin-Gemcitabine (GemCis) and Methotrexate-Vinblastine-Doxorubicin-Cisplatin (MVAC), and we show that MVAC treatment induces significant immune infiltration within the luminal subtype while GemCis treatment does not, indicating there are treatment specific effects on the immune microenvironment. Furthermore, using mouse models of bladder cancer previously developed by our lab that accurately reflect the basal and luminal subtypes of bladder cancer, treatment with a representative chemotherapeutic regimen induced immune infiltration in the luminal mouse model while not affecting the tumor immune microenvironment in the basal mouse model. These results indicate chemotherapeutic regimens have subtype specific effects on the tumor microenvironment which could potentially be used to increase the efficacy of immune checkpoint inhibitors. Citation Format: Jordan Kardos, Lisa Bixby, Andrew Truong, Bhavani Krishnan, Kyle Stewart, Benjamin Vincent, William Kim. Effects of subtype specific chemotherapeutic immunomodulation in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2749.

Different Chemotherapy Regimens in the Management of Advanced or Metastatic Urothelial Cancer: a Bayesian Network Meta-Analysis of Randomized Controlled Trials

Background/Aims: Urothelial cancer (UC) as a chemotherapy-sensitive tumor, has achieved remarkable progresses in therapeutic paradigm, particularly in the advanced/metastatic stages. However, both clinicians and patients are confused when it comes to choosing the optimal chemotherapy. Hence, this article was aimed to conduct a comprehensive comparison of different chemotherapy regimens for advanced or metastatic UC in terms of survival benefits or adverse events. Methods: The online databases PubMed, EMBASE and Web of Science were searched systematically and comprehensively for randomized controlled trials (RCTs) up to September 15, 2017. The pooled hazard ratios (HRs) or odds ratios (ORs) with 95% credible interval (CrI) were calculated by Markov chain Monte Carlo methods. The effectiveness and safety of included regimens were conducted to provide a hierarchy by means of rank probabilities with the help of “R-3.4.0” software and the “gemtc-0.8.2” package. The surface under the cumulative ranking curve (SUCRA) was also incorporated in our analysis for ranking the corresponding chemotherapy regimens. Results: Ten different chemotherapy regimens involved in this article were predominantly of trials in a first-line setting, and eight clinical outcomes were ultimately analyzed in this study. In terms of Overall response rate (ORR), Overall survival (OS) or Progression-free survival (PFS)/Time to progression (TTP), the rank probabilities and SUCRA indicated that Paclitaxel/cisplatin/gemcitabine (PCG) was superior to gemcitabine/cisplatin (GC) or methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), the traditional first-line treatment for advanced/metastatic UC. In the case of ORR or PFS/TTP, GC+sorafenib also displayed its superiority in comparison with GC or MVAC. Despite their survival benefits, PCG or GC+sorafenib presented a relatively higher incidence of adverse events. Conclusion: Our results revealed that by adding a paclitaxel or sorafenib into the first-line GC, it could yield a better survival benefit, but also worsen adverse events for advanced/ metastatic UC. Clinically, physicians should weigh the merits of these approaches to maximize the survival benefits of eligible patients.

Neoadjuvant Chemotherapy with Gemcitabine plus Cisplatin in Patients with Locally Advanced Bladder Cancer

Background: Neoadjuvant chemotherapy with methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) is the standard of care for muscle-invasive urothelial bladder cancer. Gemcitabine plus cisplatin (GC) shows similar efficacy with less toxicity in the metastatic setting and has therefore often been used interchangeably with MVAC. We report on the efficacy and safety of neoadjuvant GC in patients with locally advanced urothelial cancer. Materials and Methods: We prospectively evaluated 87 patients in 2 centers. Their median age was 68 years. Treatment consisted of 3× GC prior to radical cystectomy. The primary endpoint was pathologic response. The secondary endpoints were safety, progression-free survival (PFS), and overall survival (OS). Results: In all, 83 patients finished chemotherapy; 80 patients were evaluable for the primary endpoint. Pathologic complete response (pCR) was achieved in 22.5% and near pCR was seen in 33.7% of the patients. The 1-year PFS rate was 79.5% among those patients achieving ≤pT2 versus 100% among those patients achieving pCR or near pCR (p = 0.041). Five-year OS was 61.8% (95% CI 67.6 to NA). GC was well tolerated. Grade 3/4 toxicities occurred in 38% of the patients. There was no grade 3/4 renal toxicity, febrile neutropenia, or death. Conclusion: Neoadjuvant GC is a well-tolerated regimen. Although the pathologic response is lower than that reported with MVAC, our data support GC as a feasible option in the absence of a prospective randomized comparison, particularly for older patients, since its toxicity is lower than that of MVAC.

Association of chemotherapy regimen with venous thromboembolic risk in patients with urothelial tract cancer.

314 Background: Cisplatin chemotherapy (CTX) is associated with increased risk of venous thromboembolism (VTE); however, other agents have also been hypothesized to increase risk. We assessed the association of VTE with different CTX regimens in urothelial tract cancer patients. Methods: We identified &gt; 66 year-old patients diagnosed with urothelial tract cancers (excluding renal pelvis) from the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database from 1998 to 2011. CTX regimens included gemcitabine/cisplatin (GC), methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), or gemcitabine/carboplatin (GCarbo). We calculated VTE rates within 120 days of CTX initiation and compared VTE by CTX regimen with multivariable logistic regression models adjusted for patient and cancer characteristics. Results: Of 5050 identified patients, VTE occurred in 13.1% (660/5050). VTE rates were 15.3% (265/1737) and highest for GC; 8.8% (23/262) and 12.2% (372/3051) of MVAC and GCarbo patients experienced VTE, respectively. Adjusted for patient demographic and cancer-specific variables, MVAC and GCarbo were associated with lower odds of VTE compared with GC (see Table). Conclusions: Compared with GC, MVAC and GCarbo are associated with a decreased rate of VTE. This finding suggests that gemcitabine may add to the increased thrombosis risk from cisplatin. Patients treated with GC should be counseled about this association. Sensitivity analyses to assess VTE risk of different CTX regimens in the perioperative setting will be presented. [Table: see text]

Neoadjuvant chemotherapy with methotrexate/vinblastine/doxorubicin/cisplatin vs. gemcitabine/cisplatin for muscle-invasive bladder cancer: a review and meta-analysis

Objective To systematically assess the efficacy of neoadjuvant chemotherapy (NAC) with methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) vs. gemcitabine/cisplatin (GC) for muscle-invasive bladder cancer (MIBC). Methods Randomized controlled trials (RCTs) or non-RCTs regrading the efficacy of NAC with MVAC vs. GC for MIBC were retrieved in Pubmed, Cochrane library, Sciverse, CNKI, VIP and Wanfang database from databases establishment to May 2016. According to the including and exclusion criterion, two reviewers independently reviewed the trials, conducted the Meta-analysis with RevMan 5.3 soft ware. Results A total of 13 non-randomized clinical controlled trials were eligible for the study including 1690 cases. The pooled results showed that MVAC group had a lower down staging rate (RR=0.77, 95%CI 0.61-0.97, P=0.03) and complete response rate (RR=0.70, 95%CI 0.53-0.93, P=0.01). Statistically significant were observed. However, there was no significant difference in disease free survival (RR=0.88, 95%CI 0.60-1.29, P=0.53). Conclusion Compared with MVAC, NAC with GC had higher down staging rate and complete response rate. Therefore, NAC with GC should be considered as a preferable option for MIBC. Key words: Muscle invasive bladder cancer; Methotrexate/vinblastine/doxorubicin/cisplatin (MVAC); Gemcitabine/cisplatin (GC); Neoadjuvant chemotherapy; Meta analysis

Neoadjuvant chemotherapy in urothelial bladder cancer: impact of regimen and variant histology.

We compared the efficacy of methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) versus gemcitabine/cisplatin in urothelial cancer and neoadjuvant chemotherapy (NACT) efficacy in variant histology (VH). Radical cystectomy patients were retrospectively compared with those who received NACT. Factors associated with survival, pathologic complete response (pCR) and downstaging (pDS) were evaluated in multivariable models. 9% of radical cystectomy patients (84/919) received NACT, with improved survival, pCR and pDS on both regimens. MVAC lead to higher pDS without an increase in pCR. On multivariable analysis, there was a nonsignificant increase in pDS with MVAC. NACT conferred similar responses in squamous and glandular differentiation VH. NACT was associated with improved survival, pCR and pDS. Furthermore, responses to NACT were not dependent on presence of VH.

The comparison of oncologic outcomes between metastatic upper tract urothelial carcinoma and urothelial carcinoma of the bladder after cisplatin-based chemotherapy

ObjectiveTo compare the oncologic outcomes and prognostic factors between metastatic upper tract urothelial carcinoma (UTUC) and UC of the bladder (UCB) after cisplatin-based chemotherapy. Materials and methodsWe retrospectively reviewed patients with metastatic UTUC and UCB after methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) or gemcitabine/cisplatin chemotherapy between 1997 and 2014 at Kaohsiung Chang Gung Memorial Hospital. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Univariate and multivariate analyses with Cox proportional hazard models were also performed to assess the effect of prognostic factors. ResultsTotally, 203 patients were enrolled into our study, including 120 patients with UTUC and 83 patients with UCB. For patients with UTUC, the median PFS was 7.3 months vs. 4.0 months (P<0.001), and the median OS was 17.0 months vs. 10.5 months (P<0.001) for MVAC and gemcitabine/cisplatin, respectively. For patients with UCB, the median PFS (P = 0.35) and OS (P = 0.06) of the 2 groups were insignificant. In multivariate analyses, number of metastatic sites was the identical prognostic factor for OS between UTUC (hazard ratio [HR] = 2.74; 95% CI: 1.63–4.62; P<0.001) and UCB (HR = 3.12; 95% CI: 1.52–6.39; P = 0.002). Presence of liver metastasis (HR = 1.84; 95% CI: 1.05–2.23; P = 0.03) and MVAC chemotherapy (HR = 0.54; 95% CI: 0.35–0.83; P<0.001) were significantly correlated to survival only for UTUC, not for UCB. ConclusionOur study suggests discordant oncologic outcomes and prognostic factors between metastatic UTUC and UCB after cisplatin-based chemotherapy. A prospective study is warranted to validate our results.

A comparison of the outcomes after neoadjuvant (NC) or adjuvant chemotherapy (AC) for muscle-invasive urothelial bladder cancer (UC): A French contemporary retrospective multicenter cohort.

325 Background: Our aim was to investigate outcome of patients (pts) treated with AC or NC for organ-confined UC, or with NC for clinical lymph node involvement (cN+). Methods: We retrospectively analyzed 482 pts treated in 22 French hospitals between 2000 and 2013 in 3 settings: 226 pts with radical cystectomy (RC) and AC (AC group), 193 cN0 (NC group), and 63 cN+ (cN+ group) pts received NC before a planned RC for cT2-T4, M0 UC. The primary outcome was overall survival (OS). Cancer-related survival (CRS) was also evaluated. Multivariate Cox proportional hazards regression was used to estimate adjusted hazard ratios with 95% confidence interval. Results: Median age was 62, 61.7, and 62.1 in AC, NC, and cN+, respectively. Median time between diagnosis and first treatment (RC or NC) was 2.1, 1.4 and 1.6 months, respectively (p&lt;0.001). In AC, stages were p≤T2 (n=46) or pT≥3 (n=180), pN0 (n=37), pN+ (n=168), or pNx (n=21). Gemcitabine-cisplatin and gemcitabine-carboplatin regimen were mainly delivered as AC in 71.2% and 21.7% of pts. In NC, all pts received methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) or dose-dense MVAC. Median number of cycles was 4 in each group. After NC, RC has been realized in 173 (90%) and 51 pts (82%) in NC and cN+, respectively. In 17 unoperated pts, concomitant chemoradiotherapy was performed. Median follow-up was 24.6 months. Respectively, 133 (59%), 61 (32%), and 22 (35%) pts have relapsed in AC, NC, and cN+; 74%, 63%, and 71% of them received chemotherapy for metastasis. Also 133 (59%), 41 (21%), and 18 (29%) pts died, mostly (90%) due to recurrence. Three-year OS and CRS rates were 54%, 68%, and 56% (p=0.02), and 37%, 53%, and 49% (p=0.038) in AC, NC, and cN+, respectively. In multivariate analysis, only AC (HR: 1.64, 95% CI 1.18-2.30, p=0.001) remained significantly associated with shortened OS. Conclusions: In this large retrospective study reporting real-life survivals, 3-year OS was longer in pts receiving NC, both in cN0 and in cN+ groups, than in pts treated with AC. Although several selection bias can be emphasized preventing us from drawing definitive conclusions, AC appeared to be associated with a poorer prognosis.

Delivery of perioperative chemotherapy for bladder cancer in routine clinical practice.

Few articles have documented regimens and timing of perioperative chemotherapy for bladder cancer in routine practice. Here, we describe practice patterns in the general population of Ontario, Canada. In this retrospective cohort study, treatment and physician billing records were linked to the Ontario Cancer Registry to describe use of neoadjuvant (NACT) and adjuvant (ACT) chemotherapy among all patients with muscle-invasive bladder cancer treated with cystectomy in Ontario 1994-2008. Time to initiation of ACT (TTAC) was measured from cystectomy. Multivariate Cox regression was used to identify factors associated with overall (OS) and cancer-specific survival (CSS). Of 2944 patients undergoing cystectomy, 4% (129/2944) and 19% (571/2944) were treated with NACT and ACT, respectively. Five-year OS was 25% [95% confidence interval (CI) 17% to 34%] for NACT, 29% (95% CI 25% to 33%) for ACT cases. Among patients with identifiable drug regimens, cisplatin was used in 82% (253/308) and carboplatin in 14% (43/308). The most common regimens were gemcitabine-cisplatin (54%, 166/308) and methotrexate, vinblastine, doxorubicin, cisplatin (MVAC) (21%, 66/308). Mean TTAC was 10 weeks; 23% of patients had TTAC >12 weeks. TTAC >12 weeks was associated with inferior OS [hazard ratio (HR) 1.28, 95% CI 1.00-1.62] and CSS (HR 1.30, 95% CI 1.00-1.69). In adjusted analyses, OS and CSS were lower among patients treated with carboplatin compared with those treated with cisplatin; OS HR 2.14 (95% CI 1.40-3.29) and CSS HR 2.06 (95% CI 1.26-3.37). Most patients in the general population receive cisplatin, and this may be associated with superior outcomes to carboplatin. Initiation of ACT beyond 12 weeks is associated with inferior survival. Patients should start ACT as soon as they are medically fit to do so.

870P - Impact of Histopathologic Variants on Survival of Patients with Metastatic Urothelial Carcinoma

ABSTRACT Aim: The aim of our study was to investigate the clinical and prognostic impact of histopathologic variants of metastatic urothelial carcinoma patients treated with systemic chemotherapy. Methods: A retrospective analysis of the in-hospital database was performed in Kaohsiung Chang Gung Memorial Hospital for the period January 1997 to December 2013. We enrolled a total of 206 patients who received systemic chemotherapy for metastatic urothelial carcinoma. Histopathologic types were categorized as pure urothelial carcinoma (PUC; n = 151) or variants of urothelial carcinoma (VUC, n = 55). We analyzed overall survival (OS) and progression-free survival (PFS) by Kaplan-Meier analysis and Cox's proportional regression models. Results: The median follow-up was 25.2 months. The most common histopathologic variants were squamous differentiation that accounted for 72% of all variants. Patients with VUC were more likely to have renal pelvis location (44% vs. 24%, p = 0.004) and chronic renal insufficiency (40% vs. 23%, p = 0.02) than those with PUC. All patients received at least one-line of chemotherapy, and the most common regimens were gemcitabine/cisplatin (GC) and methotrexate/vinblastine/doxorubicin/cisplatin (MVAC). On univariable analysis, the median OS of VUC patients were significantly better then PUC patients (16.2 vs. 11.2 months, p = 0.003). The median PFS of first-line chemotherapy were 6.2 months and 4.0 months for PUC and VUC, respectively (p = 0.004). On multivariable analysis, patients with VUC showed independently decreased OS compared with those with PUC (HR 1.54, 95% CI 1.03-2.3, p = 0.035). Conclusions: In metastatic urothelial carcinoma patients treated with chemotherapy, histopathologic variants showed a significant role in predicting worse survival than pure urothelial carcinoma. Disclosure: All authors have declared no conflicts of interest.