Neoadjuvant Gemcitabine Research Articles

Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer

BackgroundNeoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes.MethodsIn this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle-invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine–cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine–cisplatin followed by radical cystectomy alone (comparison group). Event-free survival was one of two primary end points. Overall survival was the key secondary end point.ResultsIn total, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated event-free survival at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) in the durvalumab group and 59.8% (95% CI, 55.4 to 64.0) in the comparison group (hazard ratio for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P<0.001 by stratified log-rank test). The estimated overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group and 75.2% (95% CI, 71.3 to 78.8) in the comparison group (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P=0.01 by stratified log-rank test). Treatment-related adverse events of grade 3 or 4 in severity occurred in 40.6% of the patients in the durvalumab group and in 40.9% of those in the comparison group; treatment-related adverse events leading to death occurred in 0.6% in each group. Radical cystectomy was performed in 88.0% of the patients in the durvalumab group and in 83.2% of those in the comparison group.ConclusionsPerioperative durvalumab plus neoadjuvant chemotherapy led to significant improvements in event-free survival and overall survival as compared with neoadjuvant chemotherapy alone. (Funded by AstraZeneca; NIAGARA ClinicalTrials.gov number, NCT03732677; EudraCT number, 2018-001811-59.)

Phase II study of neoadjuvant durvalumab and tremelimumab in combination with gemcitabine and cisplatin in patients with intrahepatic cholangiocarcinoma that is borderline resectable or resectable with high risk for recurrence.

TPS4198 Background: Finding effective and tolerable neoadjuvant treatment to downstage borderline resectable intrahepatic cholangiocarcinoma (ICC) could increase the rate of R0 resections and significantly improve patient outcomes. The combination of gemcitabine, cisplatin, and durvalumab based on the TOPAZ-1 trial is now the preferred first-line regimen for advanced, unresectable biliary tract cancer (1). The objective response rate (ORR) was 26.7% for the 3-drug regimen. Gemcitabine, cisplatin, durvalumab, and tremelimumab (an anti-CTLA4 antibody) in advanced, unresectable biliary tract cancer had an objective response rate of 70% in a phase II study (2). Given this response to immunotherapy plus chemotherapy, the 4-drug combination of gemcitabine, cisplatin, durvalumab, plus tremelimumab in the neoadjuvant setting may be able to improve the conversion rate of borderline resectable ICC to resectable ICC and improve R0 resection rates. Methods: This is an open-label, single-arm, multicenter phase II safety and feasibility study of neoadjuvant gemcitabine + cisplatin + durvalumab + tremelimumab in patients with ICC that is borderline resectable or resectable with a high risk of recurrence. 24 patients will receive 3-week cycles of durvalumab 1500 mg on D1, tremelimumab 300 mg only on C1D1, gemcitabine 1000mg/m2 on D1 and D8, and cisplatin 25mg/m2 on D1 and D8. Treatment will be stopped after C4 if a patient is able to proceed with surgery, otherwise they will complete 8 cycles and be re-evaluated for surgery at that point. Key eligibility criteria include no prior systemic therapy, histologically proved ICC, ECOG 0-1, and disease that is not readily suitable for resection with curative intent based on discussion with multidisciplinary committee including a hepatobiliary surgeon. Primary endpoints are feasibility and safety with secondary endpoints of overall survival, progression free survival, ORR, R0 resection rate, and pathologic complete response. Molecular biomarkers from blood to predict outcomes and organoid development from circulating tumor cells are exploratory endpoints. The study will be carried out in 2 stages. In stage 1, 11 patients will be accrued and the study will be stopped if 2 or fewer patients undergo resection based on a null hypothesis of a resection rate after neoadjuvant treatment of about 24%. Otherwise, 17 more patients will be accrued in stage 2 (assuming 15% dropout rate to hit target of 24) and if 9 or more of the 24 patients undergo resection, we will claim the treatment is feasible. The design has a type 1 error rate of 0.1 and power 0.8. Patient follow-up will be up to 3 years. The study is currently enrolling participants. 1. Oh et al. NEJM Evid 2022. 2. Oh et al. Lancet Gastroenterol Hepatol 2022. Clinical trial information: NCT06017297 .

Abstract 4025: A phase II trial of neoadjuvant gemcitabine, cisplatin plus tislelizumab followed by concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: Clinical efficacy, safety and the biomarker analysis

Abstract Immune checkpoint inhibitors (ICIs) have been widely used in recurrent or metastatic nasopharyngeal carcinoma (NPC), but the addition of ICIs to chemoradiotherapy in locoregionally advanced (LA) NPC requires further investigation. We conducted a phase II, single-arm trial to evaluate the efficacy and safety of neoadjuvant gemcitabine, cisplatin (GP) plus tislelizumab followed by concurrent chemoradiotherapy (CCRT) in LA-NPC. All participants received 3 cycles of GP chemotherapy plus tislelizumab (200 mg) followed by 3 cycles of cisplatin-based CCRT. The primary endpoint was the clinical complete response rate (CR) after neoadjuvant chemoimmunotherapy (NAT). The secondary endpoints include pathological CR rate, progression-free survival (PFS), overall survival (OS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), etc. Pretreatment blood samples and paired (pre-/post-NAT) tissue biopsies were collected to perform full-spectrum peripheral T-cell profiling, PD-L1 and tertiary lymphoid structures (TLS) staining. Among all 63 participants, the CR rate after NAT reached 41.3% (95% CI, 28.8%-53.8%), far exceeding our hypothesized CR rate of 22%. The objective response rate (ORR) and pCR rate after NAT were 88.9% (95% CI, 80.9% to 96.9%) and 74.6% (95% CI, 62.1% to 84.7%), respectively. As of July 15th, 2023, after the median follow-up of 25 months, the 2-year PFS and OS were 98.4% and 100%. The incidence of grade 3-4 immunotherapy-related adverse events was 1.6%. The compliance of CCRT was not compromised. Patients who achieved CR had significantly more circulating CD4+ and CD8+ effector memory T cells (Tem), regulatory T cells (Treg) and follicular helper T cells (Tfh). The peripheral abundance of LAG3+ Tem and Tfh were independently predictive of NAT response. The number and maturation of TLS significantly increased after NAT in the CR group, but not in the Non-CR group. GP chemotherapy plus tislelizumab followed by CCRT was highly therapeutic and safe in treating LA-NPC, further randomized phase III studies are awaited. Citation Format: Xiao-Yun Li, Si-Yi Xie, Qiu-Yan Chen, Hai-Qiang Mai, Lin-Quan Tang. A phase II trial of neoadjuvant gemcitabine, cisplatin plus tislelizumab followed by concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: Clinical efficacy, safety and the biomarker analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4025.

Long-term outcomes of neoadjuvant gemcitabine, nab-paclitaxel, and S1 (GAS) in borderline resectable pancreatic cancer with arterial contact: Results from a phase II trial.

This study reports the long-term results of a phase II trial evaluating the clinical efficacy of neoadjuvant gemcitabine, nab-paclitaxel, and S1 (GAS) in borderline resectable pancreatic cancer with arterial contact (BRPC-A). A multicenter, single-arm, phase II trial was conducted. Patients received six cycles of GAS and patients without progressive disease were intended for R0 resection. Of the 47 patients, 45 (96%) underwent pancreatectomy. At the time of this analysis, all patients were updated with no loss to follow-up. A total of 30 patients died, while the remaining 17 patients were followed for a median of 68.1 months. The updated median overall survival (OS) was 41.0 months, with 2- and 5-year OS rates of 68.0% and 44.6%, respectively. Multivariate analysis in the preoperative model showed that a tumor diameter reduction rate ≥10% and a CA19-9 reduction rate ≥95% after neoadjuvant chemotherapy remained independently associated with favorable survival. In the postoperative multivariate model, no lymph node metastasis, no major surgical complications, and completion of adjuvant chemotherapy were independently associated with improved OS. This long-term evaluation of the neoadjuvant GAS trial demonstrated the high efficacy of the regimen, suggesting that it is a promising treatment option for patients with BRPC-A.

Comparison of 3 and 4 cycles of neoadjuvant gemcitabine and cisplatin for muscle-invasive bladder cancer: a systematic review and meta-analysis

BackgroundIn muscle-invasive bladder cancer (MIBC), neoadjuvant chemotherapy (NAC) combined with radical cystectomy (RC) is critical in reducing disease recurrence, with GC (gemcitabine and cisplatin) being one of the most commonly used NACs. Different GC schedules have been used, but the best neoadjuvant regimen is still unknown. The clinical outcomes of 3 and 4 cycles of neoadjuvant GC are compared in this systematic review and meta-analysis to determine which is best for patients with MIBC.MethodsWe searched PubMed, Embase, Web of Science, Cochrane Library, CBM, CNKI, WAN FANG DATA, and meeting abstracts to identify relevant studies up to March 2023. Studies that compared 3 and 4 cycles of neoadjuvant GC for MIBC were included. The primary outcomes were pCR, pDS, OS, and CSS. The secondary outcome was recurrence and SAEs.ResultsA total of 3 studies, with 1091 patients, were included in the final analysis. Patients that received 4 cycles of GC had a higher pCR (OR = 0.66; 95% CI, 0.50–0.87; p = 0.003) and pDS (OR = 0.63; 95% CI, 0.48–0.84; p = 0.002) than those who received 3 cycles. Regarding recurrence rate (OR = 1.23; 95% CI, 0.91–1.65; p = 0.18), there were no appreciable differences between the 3 and 4 cycles of GC. Survival parameters such as OS (HR, 1.35; 95% CI, 0.86–2.12; p = 0.19) and CSS (HR, 1.06; 95% CI, 0.82–1.38; p = 0.20) were similar. Only one trial reported on the outcomes of SAEs. And there were no statistically significant differences in thrombocytopenia, infection rate, neutropenic fever, anemia, or decreased renal function between patients. The neutropenia of patients was statistically different (OR = 0.72; 95% CI, 0.52–0.99; p = 0.04).ConclusionThe 4-cycle GC regimen was superior to the 3-cycle regimen in only the pCR and pDS results. Survival and recurrence rates were similar between the two regimens. In both treatment regimes, the toxicity profile was manageable. However, due to the inherent drawbacks of retrospective research, this should be regarded with caution.

The Efficacy of Neoadjuvant Gemcitabine and Cisplatin Chemotherapy for cT3N0M0 Upper Tract Urothelial Carcinoma: The Impact of Tumor Location.

Upper tract urothelial carcinoma (UTUC) can be divided into renal pelvis tumor (RPT) and ureteral tumor (UT) based on the tumor origin. This study aimed to evaluate the efficacy of neoadjuvant chemotherapy with gemcitabine and cisplatin (NAC-GC) in terms of the pathological outcomes and oncological prognoses in patients with UTUC. We also compared its efficacy between RPT and UT. Patients who underwent radical nephroureterectomy for clinical T (cT)3N0M0 UTUC between 1999 and 2021 were included. Patients who underwent NAC-GC and those who did not were included in the NAC-GC and non-NAC-GC groups, respectively. Based on the tumor origin, we divided patients with UTUC into RPT and UT groups. Oncological prognosis was assessed using progression-free survival (PFS) and overall survival. Of 44 patients, 20 (45.5%) and 24 (54.5%) patients were in the NAC-GC and non-NAC-GC groups, respectively. The NAC-GC group had significantly lower pathological T stage and negative lymphovascular invasion (LVI), and a better PFS (p < .05) compared to those in the non-NAC-GC group. Among patients with RPT, the NAC-GC group had significantly negative LVI and better PFS than the non-NAC-GC group (p < .05). In contrast, in patients with UT, the NAC-GC group had no significant difference in pathological outcomes, and no significant difference in oncological prognosis was observed between the NAC-GC and non-NAC-GC groups. NAC-GC improves both pathological outcomes and oncological prognosis in patients with cT3N0M0 UTUC. With regard to tumor location, RPT has better pathological outcomes and oncological prognoses than UT.

A Paradigm Shifts: Neoadjuvant Therapy for Clearly Resectable Pancreatic Cancer.

Over the past decade, neoadjuvant therapy has become the standard of care for patients with borderline resectable and locally advanced pancreatic cancer. The surgical community remains divided regarding the value of neoadjuvant therapy for patients who present with clearly resectable disease. Thus far, randomized controlled trials comparing neoadjuvant therapy with conventional upfront surgical strategies for patients with clearly resectable pancreatic cancer have been plagued by poor accrual, and are often underpowered. Nonetheless, meta-analyses of the results of these trials suggest that neoadjuvant therapy can be offered as an acceptable standard of care for patients with clearly resectable pancreatic cancer. Previous trials used neoadjuvant gemcitabine, but more recent studies have demonstrated superior survival for patients who were able to tolerate neoadjuvant FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan hydrochloride, and oxaliplatin). The increased utilization of FOLFIRINOX may be shifting the treatment paradigm in favor of neoadjuvant therapy among patients with clearly resectable disease. Randomized controlled trials assessing the value of neoadjuvant FOLFIRINOX in clearly resectable pancreatic cancer, which are expected to provide more conclusive recommendations, are still ongoing. This review outlines the rationale, considerations, and current level of evidence for the use of neoadjuvant therapy in patients with clearly resectable pancreatic cancer.

Lessons and open questions in borderline resectable pancreatic cancer

Evidence-based information for borderline resectable pancreatic ductal adenocarcinoma is scarce. In The Lancet Gastroenterology & Hepatology, Paula Ghaneh and colleagues report a four-arm, randomised phase 2 feasibility trial, which provides new exploratory data.1 Patients with borderline resectable pancreatic ductal adenocarcinoma were randomly assigned to immediate surgical resection or neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy with concomitant capecitabine.

Negative prognostic impact of sarcopenia before and after neoadjuvant chemotherapy for pancreatic cancer

ObjectivesTo elucidate the prognostic impact of sarcopenia before and after neoadjuvant chemotherapy (NAC) for pancreatic cancer (PC). MethodsWe retrospectively studied 75 consecutive PC patients who underwent neoadjuvant gemcitabine plus S-1 combination therapy followed by pancreatectomy between 2008 and 2016. According to the skeletal muscle volume index (SMI), the patients were divided into the muscle attenuation group (MAG) and normal group (NG) before or after NAC. Prognostic factors for overall survival (OS) were analyzed by Cox proportional hazards models. ResultsThe MAG showed significantly poorer OS than the NG before and after NAC. Pre-NAC, median OS was 20.0 months in the MAG versus 49.0 months in the NG (p = 0.006). Post-NAC, median OS was 21.3 months in the MAG versus 48.8 months in the NG (p = 0.014). Multivariate analysis, excluding muscle attenuation after NAC because of confounding factors and lower hazard ratio (2.08, 95% confidence interval: 1.14–3.78, p = 0.016) than that before NAC (2.14, 1.23–3.70, p = 0.007) by univariate analysis, revealed the following independent prognostic factors: muscle attenuation pre-NAC (2.25, 1.26–4.05, p = 0.007); borderline resectability (1.96, 1.04–3.69, p = 0.038); operative blood loss (2.60, 1.38–4.88, p = 0.003); and distant metastasis (3.31, 1.40–7.82, p = 0.006). ConclusionsSarcopenia before and after NAC for PC is suggested to be a poor prognostic factor, with a stronger impact before than after NAC.

Possibility of Neoadjuvant Treatment for Radiologically Judged Resectable Pancreatic Cancer.

Survival remains poor even after resection of pancreatic cancer and the postoperative recurrence rate is extremely high. Thus, neoadjuvant treatment may improve outcomes for resectable pancreatic cancer (RPC). This study evaluated the efficacy of neoadjuvant therapy for radiologically judged RPC. A prospectively maintained institutional database was reviewed to identify patients who underwent potentially curative resection of radiologically judged RPC. Patient characteristics and intermediate-term outcomes were compared between groups that received neoadjuvant treatment or upfront surgery (UFS). We identified 353 eligible patients, including 55 patients who received neoadjuvant chemoradiotherapy (CRT group), 53 patients who received neoadjuvant gemcitabine plus nab-paclitaxel (GnP group), and 245 patients who underwent UFS (UFS group). The cumulative rates of pancreatic cancer recurrence at 2 years after pancreatic surgery were 49.5% in the UFS, 48.1% in the CRT group, and 52.7% in the GnP group. The recurrence rate tended to be improved after neoadjuvant treatment, although the difference was not significant at this follow-up point. While the clinical TNM classifications were noticeably different from the final pathological findings, the clinical and pathological TNM classifications were more similar in the groups that underwent neoadjuvant treatment. Neoadjuvant treatment can help identify good surgical candidates and avoid unnecessary laparotomy. Our results also suggest that neoadjuvant therapy might help improve the preoperative diagnostic accuracy for patients with RPC.

Comparative analysis of three vs. four cycles of neoadjuvant gemcitabine and cisplatin for muscle invasive bladder cancer.

Because the optimal number of cycles of neoadjuvant gemcitabine and cisplatin chemotherapy (GC) is unclear, we aimed to compare disease response and survival outcomes of patients receiving either 3 or 4 cycles of neoadjuvant GC for muscle-invasive bladder cancer (MIBC). A total of 166 patients who were treated with neoadjuvant GC and radical cystectomy for clinical stage T2-4N0M0 were identified. Response and effectiveness of different cycle counts were assessed using downstaging (complete pathologic and partial pathologic response), cancer-specific survival (CSS), and overall survival (OS). Response and survival outcomes were examined with adjusted logistic regression and Cox regression models. Statistical significance was defined as P < 0.05. Of 166 patients who received neoadjuvant GC, 107 (64.5%) received 3 cycles and 59 (35.5%) received 4 cycles. Age, insurance, comorbidity, tumor histology (pure urothelial carcinoma, urothelial with divergent differentiation, variant histology), and tumor stage were similar between the 2 treatment groups. Rates of complete response or any downstaging were similar between groups (21.5% and 40.2% in the 3-cycle group and 20.3% and 44.1% in the 4-cycle group, respectively). While disease response was similar (OR 1.03, 95% CI 0.43-2.45), both cancer-specific survival (HR 1.69, 95% CI 0.87-3.26) and overall survival (HR:1.88, 95% CI:1.02-3.48) were more favorable among patients managed with 4 cycles of neoadjuvant chemotherapy compared to those who received 3 cycles in adjusted models. Our analysis demonstrated that survival outcomes tended to be better among patients who received 4 cycle of neoadjuvant GC compared to those treated with 3 cycles. Although potential benefits of omission of fourth cycle may include expedited time to surgery, reduced chemotherapy-associated toxicity, and lower treatment costs, continuation of treatment with a fourth cycle of neoadjuvant GC chemotherapy may benefit patients with muscle-invasive bladder cancer and further improve disease outcomes.

Gemcitabine Plus Cisplatin Versus Non-Gemcitabine and Cisplatin Regimens as Neoadjuvant Treatment for Cholangiocarcinoma Patients Prior to Liver Transplantation: An Institution Experience.

BackgroundCholangiocarcinoma management is constantly being updated in view of existing evidence in order to establish practice guidelines and consensus statements. However, the available treatment guidelines to optimize outcomes for cholangiocarcinoma patients who require liver transplantation are still controversial. This study contributing to the cholangiocarcinoma care field by investigating a new promising neoadjuvant therapy that might be help to grant the liver transplant option to the patients with cholangiocarcinoma. Here, we evaluate and compare the potential efficacy of chemotherapy combination of Gemcitabine plus Cisplatin versus non- Gemcitabine and Cisplatin regimens as a neo-adjuvant treatment for cholangiocarcinoma patients prior to liver transplantation.MethodsIn this retrospective study, patients with locally advanced, unresectable, hilar, or intrahepatic cholangiocarcinoma with no evidence of extrahepatic disease or vascular involvement were treated with either the combination of neo-adjuvant Gemcitabine plus Cisplatin with no radiation or other standard options of neo-adjuvant treatment. All patients included received chemotherapy prior to being listed for liver transplantation at a single cancer center in collaboration with the same institution’s transplant center according to an open-labeled, and centers-approved clinical management protocol. Patients were listed for liver transplantation if they had a minimum of six months of scans showing response or confirmation of disease stability. The primary endpoints were the overall survival and recurrence-free survival after liver transplantation. This report, which was censored on March 18, 2022.ResultsOut of a total of 707 liver transplant recipients were screened, 37 patients were confirmed with a diagnosis of cholangiocarcinoma and only 18 patients (11 males and 7 females) with a median age of 61.83 [interquartile range: 58.27-68.74] met inclusion criteria. Of the 18 patients enrolled, 10 received Gemcitabine/Cisplatin, while 8 patients received either Gemcitabine monotherapy or Capecitabine or FOLFIRI. Months for recurrence after transplantation was 20.1 (IRQ: 20.1-20.1) in the Gemcitabine/Cisplatin group and 9.5 (8.9-12.47) months in the non-Gemcitabine/Cisplatin group (p-value=0.18). Median months of follow-up in the Gemcitabine/Cisplatin group was 28.35 (27.1-32.23) months versus 40.12 (20.6-56.22) months in the non-Gemcitabine/Cisplatin group (p-value=0.33). In non-Gemcitabine/Cisplatin patients, overall survival was 75% (95% CI 31-93%) at both years 1 and 2; 63% (95% CI 23-86%) at years 3 to 5. In Gemcitabine/Cisplatin patients, overall survival was 100% (95% CI 100-100%) at both years 1 and 2; 75% (95% CI 13-96%) at years 3 to 5. Three non-Gemcitabine/Cisplatin patients died at 328 days, 340 days, and 896 days, respectively. One Gemcitabine/Cisplatin patient died at 885 days.ConclusionOur findings suggest improved overall survival outcomes with Gemcitabine plus Cisplatin as neo-adjuvant treatment with no concomitant radiation compared to non-Gemcitabine/Cisplatin regimens in patients with cholangiocarcinoma prior to liver transplantation.

Gemcitabine plus cisplatin versus non-gemcitabine and cisplatin regimens as neoadjuvant treatment for cholangiocarcinoma patients prior to liver transplantation.

e16202 Background: Cholangiocarcinoma (CCA)management is constantly being updated in view of existing evidence in order to establish practice guidelines and consensus statements. Here, we evaluate and compare the potential efficacy of chemotherapy combination of Gemcitabine plus Cisplatin versus non- Gemcitabine and Cisplatin regimens as a neo-adjuvant treatment for cholangiocarcinoma patients prior to liver transplantation. Methods: In this prospective study, patients with locally advanced, unresectable, hilar, or intrahepatic CCA with no evidence of extrahepatic disease or vascular involvement were treated with either the combination of neo-adjuvant Gemcitabine plus Cisplatin with no radiation or other standard options of neo-adjuvant treatment. All patients included received chemotherapy prior to being listed for liver transplantation at a single cancer center in collaboration with the same institution’s transplant center according to an open-labeled, and centers-approved clinical management protocol. Patients were listed for liver transplantation if they had a minimum of six months of scans showing response or confirmation of disease stability. This report, which was censored on November 30, 2021, was an initial prospective study of patients treated under this ongoing clinical treatment protocol. Results: Out of a total of 707 liver transplant recipients, 37 patients were confirmed with a diagnosis of CCA and only 18 patients (11 males and 7 females) with a median age of 61.83 [interquartile range (IQR): 58.27-68.74] met inclusion criteria. Of the 18 patients enrolled, 10 received Gemcitabine/Cisplatin, while 8 patients received either Gemcitabine monotherapy or Capecitabine or FOLFIRI alone or with Cetuximab. Days for recurrence after transplantation was 603 (IRQ: 603-603) in the Gemcitabine/Cisplatin group and 285 (267-374) days in the non-Gemcitabine/ Cisplatin group (p-value = 0.18). The median days of follow-up in the Gemcitabine/Cisplatin group were 753 (621-885) days versus 1050 (618-1489) days in the non-Gemcitabine/ Cisplatin group (p-value = 0.25). In the non-Gemcitabine/ Cisplatin group, overall survival was 75% (95% CI 31-93%) at both years 1 and 2; 63% (95% CI 23-86%) at both years 3 and 4. In the Gemcitabine/ Cisplatin group, overall survival was 100% (95% CI 100-100%) at both years 1 and 2; 67% (95% CI 5-95%) at both years 3 and 4. Three patients in the non-Gemcitabine/ Cisplatin group died at 328 days, 340 days, and 896 days, respectively. One patient in the Gemcitabine/ Cisplatin group died at 885 days. Conclusions: To our knowledge, this is the first report to show improved overall survival outcomes with Gemcitabine plus Cisplatin as neo-adjuvant treatment with no concomitant radiation compared to non-Gemcitabine/ Cisplatin regimens in patients with CCA prior to liver transplantation.

Biomarkers of response to neoadjuvant atezolizumab with gemcitabine and cisplatin in muscle-invasive bladder cancer.

4584 Background: We previously reported the clinical outcomes of a positive multi-center phase II trial of neoadjuvant gemcitabine (G) and cisplatin (C) plus atezolizumab (A) in patients with muscle-invasive bladder cancer (Funt, et al. JCO 2022). In this and another trial of neoadjuvant GC with pembrolizumab (Rose et al, JCO 2021), PD-L1 positivity by immunohistochemistry was not predictive of non–muscle-invasive downstaging ( &lt; pT2N0). Therefore, we investigated other pre-treatment tissue-based genomic and gene expression biomarkers of response and resistance. Methods: 36 pts had pre-treatment tissue available for genomic analysis. We performed targeted hybridization capture DNA sequencing using the CLIA-certified MSK-IMPACT platform and whole transcriptome RNA sequencing. We examined genomic and gene expression biomarkers which have been previously investigated in the context of neoadjuvant cisplatin-based chemotherapy or anti-PD-1/L1 immunotherapy for MIBC, including tumor mutation burden (TMB), a DNA damage response (DDR) 9-gene panel (NCT03609216) associated with response to neoadjuvant chemotherapy, and an 8-gene cytotoxic T cell transcriptional signature associated with response to neoadjuvant A (tGE8; Powles et al, Nature Medicine 2019). We also evaluated TGF-β pathway activation, which was associated with resistance to A in pts with metastatic BC (Mariathasan et al, Nature 2018). Putative biomarkers were assessed for correlation with &lt; pT2N0, the trial’s primary endpoint. Results: DNA was available from all 36 pts, and RNA met quality control metrics for 29 pts. TMB was significantly higher in pts with &lt; pT2N0 (median 16 mut/Mb, IQR 12-25) versus ≥ pT2N0 (median 10 mut/ Mb, IQR 8-10; p &lt; 0.01). A single patient had a TMB &gt; 200 Mut/Mb with a POLE hotspot mutation and achieved pT0N0; TMB was still significantly higher in responders after omission of this patient (p &lt; 0.01). Nine of 25 pts (36%) with &lt; pT2N0 had a deleterious DDR mutation versus 1 of 10 pts (10%) with ≥ pT2N0 (p = 0.13). While tGE8 was significantly increased in patients with &lt; pT2N0 compared to those without (p = 0.01), TGF-β pathway activation was not increased in pts with ≥ pT2N0 (p = 0.99). Conclusions: TMB and the tGE8 cytotoxic T cell transcriptional signature were associated with response to combination GC+A in muscle-invasive bladder cancer. More detailed molecular analyses will be reported. Clinical trial information: NCT02989584.

Cost-effectiveness of neoadjuvant FOLFIRINOX versus gemcitabine plus nab-paclitaxel in borderline resectable/locally advanced pancreatic cancer patients.

BackgroundThe 2020 National Comprehensive Cancer Network guidelines recommend neoadjuvant FOLFIRINOX or neoadjuvant gemcitabine plus nab‐paclitaxel (G‐nP) for borderline resectable/locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC).AimThe purpose of our study was to compare treatment outcomes, toxicity profiles, costs, and quality‐of‐life measures between these two treatments to further inform clinical decision‐making.Methods and ResultsWe developed a decision‐analytic mathematical model to compare the total cost and health outcomes of neoadjuvant FOLFIRINOX against G‐nP over 12 years. The model inputs were estimated using clinical trial data and published literature. The primary endpoint was incremental cost‐effectiveness ratios (ICERs) with a willingness‐to‐pay threshold of $100 000 per quality‐adjusted‐life‐year (QALY). Secondary endpoints included overall (OS) and progression‐free survival (PFS), total cost of care, QALYs, PDAC resection rate, and monthly treatment‐related adverse events (TRAE) costs (USD). FOLFIRINOX was the cost‐effective strategy, with an ICER of $60856.47 per QALY when compared to G‐nP. G‐nP had an ICER of $44639.71 per QALY when compared to natural history. For clinical outcomes, more patients underwent an “R0” resection with FOLFIRINOX compared to G‐nP (84.9 vs. 81.0%), but FOLFIRINOX had higher TRAE costs than G‐nP ($10905.19 vs. $4894.11). A one‐way sensitivity analysis found that the ICER of FOLFIRINOX exceeded the threshold when TRAE costs were higher or PDAC recurrence rates were lower.ConclusionOur modeling analysis suggests that FOLFIRNOX is the cost‐effective treatment compared to G‐nP for BR/LA PDAC despite having a higher cost of total care due to TRAE costs. Trial data with sufficient follow‐up are needed to confirm our findings.

Neoadjuvant gemcitabine, docetaxel, and capecitabine results in comparable surgical outcomes to modified FOLFIRINOX in patients with pancreatic ductal adenocarcinoma who also receive radiation: A single institution experience.

565 Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a minority of patients (pts) eligible for curative resection. Currently, systemic treatment options for down-staging pts with borderline resectable or locally advanced PDAC is extrapolated from the metastatic setting and modified FOLFIRINOX (FFX) +/- radiation (RT) is the most widely used regimen. Herein, we report the outcomes of combination gemcitabine, docetaxel, and capecitabine (GTX) +RT as compared to FFX +RT in the neoadjuvant (NA) setting via a single institution retrospective cohort review. Methods: We retrospectively reviewed the outcomes of pts with PDAC who underwent surgical resection at Columbia University Irving Medical Center (CUIMC) between 2011-2020. We evaluated demographics, treatment, clinical, surgical, and pathological outcomes. Statistical analysis includes Kaplan-Meier analysis and paired t-tests. Results: We reviewed 717 pts who underwent surgical resection at CUIMC of which 227 pts were confirmed to have received NA chemotherapy. Of those 227 patients, 133 pts also received RT. In total, 39 pts received GTX+RT and 42 pts received FFX+RT. Median age at diagnosis of pts who received NA GTX+RT or FFX+RT was 65 and 63 years, respectively. All pts were AJCC stage III at diagnosis and ECOG 0 or 1. There was a significantly greater percentage of pts who achieved R0 resection after GTX+RT as compared to FFX+RT, 35 (89.7%) vs 29 (69.0%), respectively (p=0.022). Significantly more pts achieved N0 lymph node status after GTX+RT as compared to FFX+RT, 29 (74.4%) vs 22 (52.4%), respectively (p=0.041). No statistically significant difference was detected in recurrence-free survival (RFS) or median overall survival (mOS) in pts who received GTX+RT and achieved R0 resection as compared to FFX+RT. See Table for summary. Conclusions: GTX appears to be a viable and active NA regimen in Stage III PDAC. In our small cohort study, more patients who received GTX+RT achieved R0 resection and N0 status as compared to FFX+RT. No difference in survival was detected but this may be due to inadequate power or choice of subsequent therapies. Larger prospective studies evaluating GTX+RT as an alternative treatment in the NA setting are warranted.[Table: see text]

V13-06 FEMALE ORGAN SPARING CYSTECTOMY AND ILEAL NEOBLADDER CREATION

You have accessJournal of UrologyBladder & Upper Tract Urothelial Oncology (V13)1 Sep 2021V13-06 FEMALE ORGAN SPARING CYSTECTOMY AND ILEAL NEOBLADDER CREATION John Pfail, John Sfakianos, and Peter Wiklund John PfailJohn Pfail More articles by this author , John SfakianosJohn Sfakianos More articles by this author , and Peter WiklundPeter Wiklund More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002100.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Female organ sparing cystectomy is feasible with satisfactory functional and oncologic outcomes with proper case selection. Presented here is a 47 year old female with cT3 bladder cancer treated previously with BCG and four cycles of neoadjuvant gemcitabine, cisplatin, and nivolumab. In the footage presented, she underwent organ sparing cystectomy with creation of an ileal neobladder. METHODS: Surgical video is displayed showing the technique for an organ sparing cystectomy with creation of ileal neobladder. Additionally, and not shown in the video, she underwent b/l extended pelvic lymph node dissection. Pre and postop patient characteristics are reviewed in the video. RESULTS: The final pathology was ypT3N2. There were 63 lymph nodes removed, of which 3 were positive. At 1.5 year follow up, this patient is sexually active with good satisfaction. She also has complete daytime and nighttime continence with 0 pad usage. Additionally, she has had no evidence of recurrence. CONCLUSIONS: Organ sparing radical cystectomy with the creation of an ileal neobladder is a feasible and well tolerated surgery which may allow females to remain sexually active with good satisfaction postoperatively. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1079-e1080 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information John Pfail More articles by this author John Sfakianos More articles by this author Peter Wiklund More articles by this author Expand All Advertisement Loading ...

MP41-20 DEFINING THE UTILITY OF MSK-ACCESS, A CELL-FREE TUMOR DNA ASSAY, IN PATIENTS TREATED WITH RADICAL CYSTECTOMY FOR MUSCLE-INVASIVE BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Invasive II (MP41)1 Sep 2021MP41-20 DEFINING THE UTILITY OF MSK-ACCESS, A CELL-FREE TUMOR DNA ASSAY, IN PATIENTS TREATED WITH RADICAL CYSTECTOMY FOR MUSCLE-INVASIVE BLADDER CANCER Andrew T. Lenis, Charles Murphy, Timothy Clinton, Manuel de Jesus Escano, Hong Truong, Peter Reisz, Aditya Bagrodia, Nicholas Silva, Priscilla Baez, Ronak Shah, Christine Iacobuzio-Donahue, Eugene Pietzak, Michael Berger, David Solit, Gopa Iyer, Timothy Donahue, and Bernard Bochner Andrew T. LenisAndrew T. Lenis More articles by this author , Charles MurphyCharles Murphy More articles by this author , Timothy ClintonTimothy Clinton More articles by this author , Manuel de Jesus EscanoManuel de Jesus Escano More articles by this author , Hong TruongHong Truong More articles by this author , Peter ReiszPeter Reisz More articles by this author , Aditya BagrodiaAditya Bagrodia More articles by this author , Nicholas SilvaNicholas Silva More articles by this author , Priscilla BaezPriscilla Baez More articles by this author , Ronak ShahRonak Shah More articles by this author , Christine Iacobuzio-DonahueChristine Iacobuzio-Donahue More articles by this author , Eugene PietzakEugene Pietzak More articles by this author , Michael BergerMichael Berger More articles by this author , David SolitDavid Solit More articles by this author , Gopa IyerGopa Iyer More articles by this author , Timothy DonahueTimothy Donahue More articles by this author , and Bernard BochnerBernard Bochner More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002062.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Circulating cell-free tumor (cf) DNA in patients with bladder cancer has clinical utility in identification of minimal residual disease and prediction of recurrence after radical cystectomy. We report our experience with cfDNA detection and correlation with recurrence using a targeted exome cfDNA assay in patients with localized muscle-invasive bladder cancer. METHODS: We prospectively identified patients with cT2-3N0M0 bladder urothelial carcinoma undergoing radical cystectomy with curative intent. Plasma samples were obtained after transurethral resection, after neoadjuvant chemotherapy (if administered), and during follow-up for up to 3 years or until disease recurrence. Samples were analyzed with MSK-ACCESS, a cfDNA platform that sequences 129 genes and generates >15,000x coverage with detection of somatic mutations down to 0.1% mutant allele frequency. Primary tumor specimens were sequenced by targeted exome sequencing (MSK-IMPACT). RESULTS: A total of 72 samples were analyzed from 16 patients. The median age was 70 (IQR: 62-78) years, 75% were male, and 50% received 4 cycles of neoadjuvant gemcitabine and cisplatin. Of 11 patients with plasma drawn before treatment, 5 (45%) had detectable cfDNA; an additional 3 patients (73%) had detectable cfDNA when leveraging sequencing data from the primary tumor. All patients with detectable cfDNA had >pT2N0. Of 5 patients without detectable cfDNA, 2 had >pT2N0 and 3 had ≤pT1N0. Of 4 patients with pre- and post-neoadjuvant chemotherapy samples, 3 had detectable cfDNA pre-chemotherapy and 2 of 3 patients had detectable cfDNA post-chemotherapy, had pT3N1 disease at cystectomy, and developed metastatic recurrences. The third patient had clearance of cfDNA after chemotherapy and was pT0N0. Mutations unique to ACCESS were detected in 26 of 69 (38%) samples with available primary tumor sequencing. CONCLUSIONS: MSK-ACCESS can detect cfDNA in ∼75% of patients with localized bladder cancer. ACCESS appears specific for muscle-invasive disease. The negative predictive value was 60%. Up to one third of samples had mutations exclusive to ACCESS which may capture additional alterations missed by primary tumor sequencing due to intra- and inter-tumoral heterogeneity. Source of Funding: This research was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers and funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e769-e769 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrew T. Lenis More articles by this author Charles Murphy More articles by this author Timothy Clinton More articles by this author Manuel de Jesus Escano More articles by this author Hong Truong More articles by this author Peter Reisz More articles by this author Aditya Bagrodia More articles by this author Nicholas Silva More articles by this author Priscilla Baez More articles by this author Ronak Shah More articles by this author Christine Iacobuzio-Donahue More articles by this author Eugene Pietzak More articles by this author Michael Berger More articles by this author David Solit More articles by this author Gopa Iyer More articles by this author Timothy Donahue More articles by this author Bernard Bochner More articles by this author Expand All Advertisement Loading ...

Efficacy and Safety of Neoadjuvant Gemcitabine Plus Nab-Paclitaxel in Borderline Resectable and Locally Advanced Pancreatic Cancer—A Systematic Review and Meta-Analysis

Simple SummaryDue to the availability of effective combination chemotherapies such as gemcitabine/nab-paclitaxel (GNP) or FOLFIRINOX, neoadjuvant treatment of borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) has been increasingly investigated in recent years. However, due to toxicity, FOLFIRINOX is only available for selected patients and data on GNP are scarce. The aim of this systematic review and meta-analysis, which is to our knowledge the first addressing this question, is to evaluate the value of GNP in patients with BRPC and LAPC. We provide a comprehensive overview on data of 21 studies, comprising 950 patients treated with neoadjuvant GNP. The pooled overall and R0 resection rates were 36% and 26%, respectively. Resection rates were higher in BRPC (49%) compared to LAPC (16%). With acceptable toxicity and a median overall survival rate ranging from 12 to 30 months, neoadjuvant GNP has considerable value in this setting, with more prospective trials being warranted.Therapy with gemcitabine and nab-paclitaxel (GNP) is the most commonly used palliative chemotherapy, but its advantage in the neoadjuvant setting remains unclear. Accordingly, our aim is to evaluate the impact of first-line neoadjuvant therapy with GNP in patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). A systematic search for published studies until August 2020 was performed. The primary endpoint included resection and R0 resection rates in the intention-to-treat population. Secondary endpoints were response rate, survival and toxicity. Among 21 studies, 950 patients who received neoadjuvant GNP were evaluated. Treatment with GNP resulted in surgical resection and R0 resection rates as follows: 49% (95% CI 30–68%) and 36% (95% CI 17–58%) for BRPC and 16% (95% CI 7–26%) and 11% (95% CI 5–19%) for LAPC, respectively. The objective response rates and the median overall survival (mOS) ranged from 0 to 67% and 12 to 30 months, respectively. Neutropenia (range 5–77%) and neuropathy (range 0–22%) were the most commonly reported grade 3 to 4 adverse events. Neoadjuvant chemotherapy with GNP can be performed safely and with valuable effects in patients with BRPC and LAPC. The utility of GNP in comparison to FOLFIRINOX in the neoadjuvant setting requires further investigation in prospective randomized trials.

Neoadjuvant chemotherapy and disease recurrence after curative-intent surgery in patients with pancreatic adenocarcinoma: A single-center retrospective review.

e18610 Background: Early stage pancreatic ductal adenocarcinoma (PDAC) account for up to 30% of newly diagnosed patients. Until recently, the mainstay of treatment remained curative-intent surgery followed by adjuvant chemotherapy. More recently, the incorporation of neoadjuvant therapy (NAT) has demonstrated clinical benefit. The two commonly used regimens are 5-Fluorouracil, Leucovorin, Oxaliplatin and Irinotecan (FOLFIRINOX), or Gemcitabine and nab-Paclitaxel. Limited data is available to differentiate outcomes between the 2 common NAT regimens. We conducted a retrospective review to assess the rates of disease recurrence and progression after neoadjuvant chemotherapy and to identify any associations that may predict early recurrence. Methods: A retrospective review was conducted of all patients diagnosed with PDAC from 2017-2019 at Allegheny General Hospital. Data analysis was completed using IBM SPSS v23. Disease recurrence or progression was assessed radiologically, and time to progression was calculated as time (months) since diagnosis to evidence of radiological progression. Results: Out of 171 patients reviewed, 56 were deemed resectable or borderline resectable and underwent curative-intent surgery and were included in the analysis. Median age was 68, and 12 (41%) were male. Majority of the patients were white (90%). 29 (52%) patients received neoadjuvant chemotherapy: 16 (55%) received FOLFIRINOX, 12 (41%) received Gemcitabine with nab-Paclitaxel, and 1 received another regimen. 9 patients out of 16 (56%) that received FOLFIRINOX progressed, and 5 out of 12 patients (42%) who received Gemcitabine with nab-Paclitaxel progressed. Patterns of progression in those that received FOLFIRINOX: 1 (11%) within 6 months, 4 (44%) between 6-12 months, and 4 (44%) after 12 months. Of those that received Gemcitabine with nab-Paclitaxel, 2 (40%) progressed within 6 months, 1 (20%) progressed between 6-12 months, and 2 (40%) progressed after 12 months. On multivariate analysis, no association was identified to predict progression. Conclusions: There was no significant difference in disease progression rates among patients that received neoadjuvant FOLFIRINOX versus Gemcitabine and nab-Paclitaxel (42% vs. 56%; p = 0.46). No predictive associations were identified in patients with disease recurrence. Study limitations include a low sample size and retrospective analysis. Further, larger scale studies are warranted to better assess the difference in rates of progression after neoadjuvant FOLFIRINOX versus Gemcitabine and nab-Paclitaxel.[Table: see text]