Cisplatin-based Combination Chemotherapy Research Articles

High-dose chemotherapy and peripheral blood stem cell transplantation as salvage therapy in primary mediastinal nonseminomatous germ cell tumors: The Indiana University experience.

Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes of patients who received high-dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) at Indiana University. The prospectively maintained Indiana University germ cell tumor database identified 32 patients with primary mediastinal nonseminomatous germ cell tumor who progressed after first-line cisplatin-based combination chemotherapy and received HDCT and PBSCT between 2006 and 2021. Therapy included two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. A second course was not given if the patient experienced progressive disease or prohibitive toxicity. Progression-free survival and overall survival were analyzed using the Kaplan-Meier method. Medians with 95% confidence intervals were also calculated along with 2-year probabilities. The median age at HDCT was 30 years (range, 18-61 years). With a median follow-up of 4.7 years (range, 1-14 years), the 2-year progression-free survival rate was 31% (95% confidence interval, 16%-47%), and the 2-year overall survival rate was 35% (95% confidence interval, 19%-52%). At last follow-up, nine patients (28%) remained without evidence of disease, including two platinum-refractory patients and two patients who were receiving HDCT as third-line therapy. There were three treatment-related deaths. Salvage HDCT and PBSCT is an active combination in patients who have relapsed primary mediastinal nonseminomatous germ cell tumor with curative potential and prolonged survival, including in platinum-refractory and third-line settings. The authors recommend this approach for initial salvage chemotherapy in this patient population.

Abstract IA003: Molecular subtypes and clinical benefit from neoadjuvant chemotherapy: A ten-year update

Abstract Ten years ago TCGA and two private groups reported that muscle-invasive bladder cancers (MIBCs) could be grouped into basal and luminal molecular subtypes that shared features with the corresponding subtypes of breast cancer. These and earlier studies by the group at Lund University demonstrated that molecular subtype membership was prognostic: patients whose tumors were assigned to basal/squamous subtypes had shorter survival than did patients whose tumors were assigned to the luminal subtypes, and these relationships were confirmed in subsequent studies. In addition, one of the studies included tumors from patients treated with neoadjuvant cisplatin-based combination chemotherapy (NAC), where patients whose tumors were infiltrated with smooth muscle cells and fibroblasts (the MD Anderson p53-like subtype) had the lowest response rates. Parallel comparisons of patients who either did or did not receive NAC concluded that patients with basal tumors derived the most clinical benefit in terms of disease-specific or overall survival. Thus, in addition to being prognostic, there was a suggestion that molecular subtypes might also be used to predict resistance to NAC. This work led to the design of two large collaborative projects that were designed to validate these observations and the conclusion that inactivating mutations in several DNA damage and repair (DDR) genes were also associated with response. One leveraged the S1314 Phase-2 “CoXEN” trial that was designed to prospectively validate another gene expression-based biomarker, and the other exploited pretreatment samples from the CALGB/Alliance 90601 Phase-3 trial of gemcitabine/cisplatin with or without bevacizumab in patients with advanced or metastatic disease. Comparisons of response rates as a function of molecular subtype membership in S1314 failed to validate the original link between the MD Anderson p53-like subtype and resistance, and patients with basal/squamous tumors in 90601 did not have better outcomes than did patients with luminal tumors. Thus, while the prognostic value of molecular subtype membership was confirmed, the predictive value was not. Developing biomarkers to predict response to chemotherapy remains a challenge not only for bladder cancer but also for other solid and hematopoietic malignancies. It seems likely that success will require the integration of measurements using multiple platforms, including liquid biopsies and others. The exciting results of the EV-302 clinical trial of enfortumab vedotin plus pembrolizumab have shifted the focus of biomarker work to these and other novel agents. Citation Format: David J McConkey. Molecular subtypes and clinical benefit from neoadjuvant chemotherapy: A ten-year update [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA003.

Management of urothelial cancer in patients with chronic kidney disease receiving platinum-based chemotherapy.

Despite recent advances in the management of urothelial cancer (UC), cisplatin-based combination chemotherapy regimens remain critical. However, their use can be complicated in patients with chronic kidney disease (CKD), which is not uncommon in UC patients. Based on the Galsky criteria for cisplatin ineligibility, most patients with CKD will be excluded from receiving cisplatin-based chemotherapy altogether. For patients with borderline kidney function, several strategies-such as the use of split-dose cisplatin, dose reductions,or extra hydration-may facilitate the use of cisplatin, but theseneedto be prospectively validated. This review highlights the critical need for a multidisciplinary team, including onco-nephrologists, to help manage renal complications and optimize delivery of cancer care in complex UC patients with CKD.

Evolution of Testicular Germ Cell Tumors in the Molecular Era With Histogenetic Implications.

The current WHO classification of testicular germ cell tumors is based on the pathogenesis of the tumors driven by different genomic events. The germ cell neoplasia in situ is the precursor lesion for all malignant germ cell tumors. The current understanding of pathogenesis is that the developmental and environmental factors with the erasure of parental genomic imprinting lead to the development of abnormal gonocytes that settle in the "spermatogonial Niche" in seminiferous tubules. The abnormal primordial germ cells in the seminiferous tubules give rise to pre-GCNIS cells under the influence of TPSY and OCT4 genes. The whole genome duplication events give rise to germ cell neoplasia in situ, which further acquires alterations in 12p along with NRAS and KRAS mutations to produce seminoma. A subset of seminomas acquires KIT mutation and does not differentiate further. The remaining KIT-stable seminomas differentiate to nonseminomatous GCTs after obtaining recurrent chromosomal losses, epigenetic modification, and posttranscriptional regulation by multiple genes. Nonseminomatous germ cell tumors also develop directly from differentiated germ cell neoplasia in situ. TP53 pathway with downstream drivers may give rise to somatic-type malignancies of GCT. The GCTs are remarkably sensitive to cisplatin-based combination chemotherapy; however, resistance to cisplatin develops in up to 8% of tumors and appears to be driven by TP53/MDM2 gene mutations. Serum and Plasma miRNAs show promise in diagnosing, managing, and following up on these tumors. The mechanisms underlying the development of most tumors have been elucidated; however, additional studies are required to pinpoint the events directing specific characteristics. Advances in identifying specific molecular markers have been seen recently and may be adopted as gold standards in the future.

Cisplatin-induced increase in heregulin 1 and its attenuation by the monoclonal ErbB3 antibody seribantumab in bladder cancer

Cisplatin-based combination chemotherapy is the foundation for treatment of advanced bladder cancer (BlCa), but many patients develop chemoresistance mediated by increased Akt and ERK phosphorylation. However, the mechanism by which cisplatin induces this increase has not been elucidated. Among six patient-derived xenograft (PDX) models of BlCa, we observed that the cisplatin-resistant BL0269 express high epidermal growth factor receptor, ErbB2/HER2 and ErbB3/HER3. Cisplatin treatment transiently increased phospho-ErbB3 (Y1328), phospho-ERK (T202/Y204) and phospho-Akt (S473), and analysis of radical cystectomy tissues from patients with BlCa showed correlation between ErbB3 and ERK phosphorylation, likely due to the activation of ERK via the ErbB3 pathway. In vitro analysis revealed a role for the ErbB3 ligand heregulin1-β1 (HRG1/NRG1), which is higher in chemoresistant lines compared to cisplatin-sensitive cells. Additionally, cisplatin treatment, both in PDX and cell models, increased HRG1 levels. The monoclonal antibody seribantumab, that obstructs ErbB3 ligand-binding, suppressed HRG1-induced ErbB3, Akt and ERK phosphorylation. Seribantumab also prevented tumor growth in both the chemosensitive BL0440 and chemoresistant BL0269 models. Our data demonstrate that cisplatin-associated increases in Akt and ERK phosphorylation is mediated by an elevation in HRG1, suggesting that inhibition of ErbB3 phosphorylation may be a useful therapeutic strategy in BlCa with high phospho-ErbB3 and HRG1 levels.

MP33-07 ANTI-PROGRAMMED DEATH RECEPTOR 1 PLUS ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODIES AND COMBINATION CHEMOTHERAPY FOR RELAPSED LOCALLY ADVANCED AND/OR METASTATIC PENILE SQUAMOUS CELL CARCINOMA

You have accessJournal of UrologyCME1 Apr 2023MP33-07 ANTI-PROGRAMMED DEATH RECEPTOR 1 PLUS ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODIES AND COMBINATION CHEMOTHERAPY FOR RELAPSED LOCALLY ADVANCED AND/OR METASTATIC PENILE SQUAMOUS CELL CARCINOMA Longbin Xiong, Lichao Wei, Ting Xue, Ru Yan, Tingyu Liu, Lijuan Jiang, Huali Ma, Yanxia Shi, Xin An, Yijun Zhang, Shengjie Guo, Kai Yao, Fangjian Zhou, and Hui Han Longbin XiongLongbin Xiong More articles by this author , Lichao WeiLichao Wei More articles by this author , Ting XueTing Xue More articles by this author , Ru YanRu Yan More articles by this author , Tingyu LiuTingyu Liu More articles by this author , Lijuan JiangLijuan Jiang More articles by this author , Huali MaHuali Ma More articles by this author , Yanxia ShiYanxia Shi More articles by this author , Xin AnXin An More articles by this author , Yijun ZhangYijun Zhang More articles by this author , Shengjie GuoShengjie Guo More articles by this author , Kai YaoKai Yao More articles by this author , Fangjian ZhouFangjian Zhou More articles by this author , and Hui HanHui Han More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003266.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Relapsed locally advanced and/or metastatic penile cancer has an extremely poor prognosis with a need for effective therapy. This study retrospectively estimated the efficacy and tolerability of anti-programmed death receptor-1 (PD1) plus anti-epidermal growth factor receptor (EGFR) antibodies and combination chemotherapy in relapsed locally advanced and/or metastatic penile squamous cell carcinoma. METHODS: A retrospective review of 30 relapsed locally advanced and/or metastatic (T4/N2-3/M1) penile squamous cell carcinoma received anti-PD1 plus anti-EGFR antibodies and cisplatin-based chemotherapy in Sun Yat-sen University Cancer Center from Jan 2018 to Aug 2022. Of 15 were chemotherapy-pretreated patients, and the remaining 15 were chemotherapy-naïve patients. Clinical responses were assessed using the Response Evaluation Criteria in Solid Tumours (RECIST v1.1) in 27 evaluable patients. Adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events (CTCAE v5.0). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: Partial responses were observed in 63% (17/27) patients, and 14 were chemotherapy-naïve patients. The objective response rate (ORR) was 100% (14/14) and 23% (3/13) in chemotherapy-naïve and chemotherapy-pretreated patients, respectively. Fourteen patients subsequently received consolidated surgery. Eight patients achieved pathological complete response, and six were chemotherapy-naïve patients. The median follow-up time was 11.4 (range: 2.3-36.2) months. The median PFS and OS were 15.6 (1.0-32.6) and 20.9 (10.5-30.3) months in chemotherapy-pretreated patients, respectively. However, these were not reached in overall cohort and chemotherapy-naïve patients. 2-year PFS (OS) was 53% (62%) in overall cohort, whereas 75% (79%) and 35% (47%) in chemotherapy-naïve and chemotherapy-pretreated patients, respectively. Treatment-related AEs were experienced by all patients, with 60% (18/30) experiencing a grade 3 or 4 AEs. The most common grade 3-4 treatment-related AEs were lymphopenia (40%), anemia (23%), and neutropenia (13%). CONCLUSIONS: Anti-PD1 antibody plus anti-EGFR antibody and cisplatin-based combination chemotherapy were effective, well-tolerated, and satisfying long-term survival outcome for relapsed locally advanced and/or metastatic penile squamous cell carcinoma. However, prolonged follow-up and large prospective clinical trials are needed to validate the findings on this important issue. Source of Funding: This study was supported by the National Natural Science Foundation of China (No. 81772755). © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e452 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Longbin Xiong More articles by this author Lichao Wei More articles by this author Ting Xue More articles by this author Ru Yan More articles by this author Tingyu Liu More articles by this author Lijuan Jiang More articles by this author Huali Ma More articles by this author Yanxia Shi More articles by this author Xin An More articles by this author Yijun Zhang More articles by this author Shengjie Guo More articles by this author Kai Yao More articles by this author Fangjian Zhou More articles by this author Hui Han More articles by this author Expand All Advertisement PDF downloadLoading ...

Current Status of Perioperative Therapy in Muscle-Invasive Bladder Cancer and Future Directions.

Cisplatin-based combination chemotherapy has been a standard of care in the perioperative management of muscle-invasive bladder cancer for years, but several novel therapies are under active investigation. This review aims to provide an update on recent relevant literature and a forward look at the future landscape of adjuvant and neoadjuvant therapy in muscle-invasive bladder cancer patients who opt for radical cystectomy. The recent approval of nivolumab as adjuvant therapy established a new treatment option for high-risk patients with muscle-invasive bladder cancer after radical cystectomy. Several phase II studies of chemo-immunotherapy combinations and immunotherapy alone have reported pathological complete responses in the 26-46% range, including studies in cisplatin-ineligible patients. Randomized studies of perioperative chemo-immunotherapy, immunotherapy alone, and enfortumab vedotin are ongoing. Muscle-invasive bladder cancer remains a challenging disease associated with significant morbidity and mortality; however, increasing options in systemic therapy and an increasingly personalized approach to cancer treatment suggest continued future improvements in patient care.

Primary mediastinal seminoma: Treatment and survival outcomes.

422 Background: Primary mediastinal pure seminoma is a rare entity and there is no clear consensus for optimal management. We report treatment and survival outcomes of patients with primary mediastinal seminoma evaluated at our institution. Methods: The Indiana University (IU) testicular cancer database was queried for patients with primary mediastinal seminoma. 21 patients evaluated at IU between 1994-2022 were included in this analysis. Kaplan-Meier methods were used for progression-free (PFS) and overall survival (OS) analysis. Results: Median age at diagnosis was 40.7 (range, 19.4-54.2). 18 (85.7%) patients were IGCCCG good risk and 3 (14.3%) were intermediate risk. Median pre-chemotherapy hCG was 10.3 (range, 0.6-1500). 12 (57.1%) patients had metastatic disease. Metastatic sites included mediastinal/supraclavicular lymph nodes in 9 patients (42.9%), lungs in 3 (14.3%), retroperitoneal lymph nodes in 3 (14.3%), brain in 1 (4.8%), liver in 1 (4.8%), adrenal gland in 1 (4.8%), kidney in 1 (4.8%) and bone in 1 (4.8%). First-line chemotherapy was BEPx3 in 9 (42.9%) patients, EPx4 in 4 (19.0%), BEPx4 in 3 (14.3%), BEPx3 + EPx1 in 2 (9.5%), VIPx4 in 2 (9.5%), and VIPx1 + BEPx3 in 1 (4.8%). With a median follow-up of 4.65 years from first-line chemotherapy start date, 3 (14.3%) patients progressed after first-line chemotherapy. Among patients who progressed, salvage 2nd line therapy was high-dose chemotherapy in 1 patient. 1 patient received more than 2 lines of therapy. 1 patient underwent surgical resection of residual mediastinal mass due to concern for local progression, with pathology revealing necrosis only. The 5-year progression-free survival (PFS) from first-line chemotherapy was 82.4% (95% CI 54.7-93.9). The 5-year overall survival (OS) was 94.1% (95% CI 65.0-99.1). At last follow-up, 20 (95.2%) patients had no evidence of disease, and 1 (4.8%) was dead of disease. Conclusions: Patients with primary mediastinal pure seminoma have high cure rates with risk adapted cisplatin-based combination chemotherapy. Despite residual masses, further surgical resection or radiation is not required in the vast majority of these patients and these residual masses can be safely monitored with surveillance.

The Bristol Bladder Trial: Five year outcomes in patients treated with neoadjuvant cabazitaxel and cisplatin chemotherapy for muscle invasive transitional cell carcinoma of the urinary bladder.

493 Background: Neoadjuvant cisplatin-based combination chemotherapy (NAC) improves survival in muscle invasive bladder cancer (MIBC). However, response rates and survival remain suboptimal. We sought to evaluate the efficacy of cabazitaxel with cisplatin in this patient group. These patients have now been followed for survival status for 5 years post NAC and radical cystectomy. Methods: This was a single arm (Simon 2 stage), phase 2 study. Patients with MIBC were included if fit to receive NAC and to undergo radical cystectomy. 26 evaluable patients were required to detect an objective response rate (ORR) of >35% with 80% power. ORR was defined as pathological complete response (pCR) plus partial response (pathological downstaging, ≥T2 at diagnosis to ≤T1 at cystectomy). Treatment was with cisplatin 70mg/m2 and cabazitaxel 15mg/m2 on day 1 of a 21-day cycle, for 4 cycles prior to surgery. Toxicity was recorded using CTCAE v.4.03. QoL data was assessed during and after chemotherapy using EQ-5D-5L and EORTC-QLQ-C30, BLM30 questionnaires. Patients were followed for 5 years post cystectomy for progression free survival (PFS) and overall survival (OS). Results: ORR was seen in 15 out of 26 evaluable patients, 57.7%, with 24.6% achieving pCR. 1 out of 15 patients who achieved ORR died due to disease progression in the 5 year follow up period. The median PFS and OS were not reached by the 5 year follow up time point with a 5 year survival rate of 65.4% being seen in this patient cohort. Median OS in non-responders (11 patients) was 20.5 months and 5 year survival rate for the non-responders was 36.4% compared to 93.3% for responders. Conclusions: Neoadjuvant cabazitaxel with cisplatin chemotherapy is an effective regimen with 65.4% patients alive and progression-free at 5 years. It also indicates that ORR (and not just pCR), is a good predictor of patient survival at 5 years post radical cystectomy with only 1 out of 15 patients who achieved ORR progressing and dying in this period. However, in current clinical practice, there are no validated predictive biomarkers regarding potential response to NAC. Taken together with our previously published data, cabazitaxel with cisplatin as neoadjuvant chemotherapy is a safe, well-tolerated and effective regimen and should be compared to the regimens e.g. cisplatin/gemcitabine considered as standard in this setting. Clinical trial information: NCT01616875 .

217P Characterization of immune cells in the tumor microenvironment of advanced bladder cancer

Cisplatin-based combination chemotherapy (CHT) improves survival in patients with muscle-invasive (MIBC) and metastatic urothelial cancer (mUC). Here we map the cellular landscape in MIBC and mUC and explore its associations to outcome.

Neoadjuvant Chemotherapy with Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Patients with Muscle-invasive Bladder Cancer: A Retrospective Age-stratified Analysis on Safety and Efficacy

BackgroundThe standard of care (SOC) for muscle-invasive bladder cancer (MIBC) includes cisplatin-based combination chemotherapy in the neoadjuvant setting followed by radical cystectomy. Older patients often do not receive SOC due to perceived toxicity concerns despite guideline-directed recommendations. ObjectiveTo characterize the safety and efficacy of neoadjuvant accelerated methotrexate, vinblastine, adriamycin, and cisplatin (aMVAC) in MIBC patients as a function of age. Design, setting, and participantsA retrospective analysis was conducted in 186 MIBC patients treated at Fox Chase Cancer Center between January 1, 2002 and December 31, 2018. Adults with histologically proven muscle-invasive urothelial cancer were eligible. The exclusion criteria included nonurothelial histology, lack of muscularis propria invasion, and primary upper tract or metastatic disease. InterventionNeoadjuvant chemotherapy with aMVAC. Outcome measurements and statistical analysisPatients were stratified by age (<65, 65–74, and >75 yr old). Renal function was assessed at baseline and at time points after treatment. Clinicopathologic variables were compared between age groups to determine efficacy. Results and limitationsThere were no statistically significant differences in dose reductions, treatment interruptions, time to surgery, or adverse events when patients were stratified by age in univariate and multivariate analyses. Full safety data were not available due to the retrospective nature of the study. Baseline renal function was significantly worse among older patients, and the percent decline in creatinine clearance was greater with older age. We found comparable efficacy of aMVAC regardless of age. ConclusionsAccelerated MVAC was safe and demonstrated efficacy in MIBC irrespective of age in this single-center, retrospective study. Careful selection based on clinical variables, and not age, should identify patients able to receive neoadjuvant chemotherapy. Patient summaryWe examined the feasibility of the standard cisplatin-based chemotherapy regimen given prior to surgery in patients with muscle-invasive bladder cancer. Elderly patients experienced a greater decline in kidney function with treatment but not more complications than younger patients and tolerated therapy with minimal dose changes, resulting in benefit regardless of age.

First-line salvage treatment options for germ cell tumor patients failing stage-adapted primary treatment

PurposeIn this review, we summarize and discuss contemporary treatment standards and possible selection criteria for decision making after failure of adjuvant or first-line cisplatin-based chemotherapy for primarily localized or metastatic germ cell tumors.MethodsThis work is based on a systematic literature search conducted for the elaboration of the first German clinical practice guideline to identify prospective clinical trials and retrospective comparative studies published between Jan 2010 and Feb 2021. Study end points of interest were progression-free (PFS) and overall survival (OS), relapse rate (RR), and/or safety.ResultsRelapses of clinical stage I (CS I) patients irrespective of prior adjuvant treatment after orchiectomy are treated stage adapted in accordance for primary metastatic patients. Surgical approaches for sole retroperitoneal relapses are investigated in ongoing clinical trials. The appropriate salvage chemotherapy for metastatic patients progressing or relapsing after first-line cisplatin-based chemotherapy is still a matter of controversy. Conventional cisplatin-based chemotherapy is the international guideline-endorsed standard of care, but based on retrospective data high-dose chemotherapy and subsequent autologous stem cell transplantation may offer a 10–15% survival benefit for all patients. Secondary complete surgical resection of all visible residual masses irrespective of size is paramount for treatment success.ConclusionsPatients relapsing after definite treatment of locoregional disease are to be treated by stage-adapted first-line standard therapy for metastatic disease. Patients with primary advanced/metastatic disease failing one line of cisplatin-based combination chemotherapy should be referred to GCT expert centers. Dose intensity is a matter of ongoing debate, but sequential high-dose chemotherapy seems to improve patients’ survival.

Randomized phase 2 trial of maintenance oral etoposide or observation following high-dose chemotherapy for relapsed metastatic germ cell tumor.

TPS429 Background: High-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplant (PBSCT) is effective salvage therapy in patients with relapsed germ-cell tumors (GCT). Utilizing HDCT and PBSCT in the 2nd line setting, cures can be achieved in about 60% of patients with relapsed non-seminoma. Maintenance daily oral etoposide after salvage therapy has been shown effective in inducing remissions (J Clin Oncol 1995;13:1167-9). We evaluate the efficacy and safety of maintenance daily oral etoposide after HDCT+PBSCT in patients with relapsed non-seminoma. Methods: This randomized phase II open label trial is evaluating maintenance oral etoposide after HDCT+PBSCT. Eligible patients are adults with metastatic non-seminomatous GCT who have progressive disease after first-line cisplatin-based combination chemotherapy. All patients will complete initial salvage with HDCT+PBSCT with the carboplatin/etoposide Indiana protocol x2 tandem cycles. All patients should have normal or declining tumor markers (AFP and/or hCG) at time of randomization and absence of progressive disease on imaging. Adverse events from prior therapy, including hematologic toxicity, should be recovered to grade≤2 at time of randomization. Randomization should occur within ≤16 weeks from time of the 2nd cycle of HDCT. Patients with primary mediastinal non-seminoma are eligible. Patients with relapsed pure seminoma are excluded. Patients are randomized in 1:1 ratio to receive maintenance etoposide vs. standard of care surveillance post HDCT. Randomization will be stratified by platinum refractory status defined as progression within 4 weeks of first-line chemotherapy (yes vs no). Patients randomized to treatment arm will receive oral etoposide 50mg/m2 daily for 21 consecutive days of 28 day cycles. A total of 3 cycles will be delivered. Weekly labs including CBC w differential will be checked to detect hematological toxicity. The primary objective is to compare the 12-month progression-free survival (PFS) for maintenance etoposide vs observation in patients with relapsed non-seminoma post HDCT. Secondary objectives include to assess the toxicity and tolerability of maintenance etoposide, and 12-month overall survival. Exploratory analysis of the biomarker micro-RNA371 at time of randomization and correlation with disease progression/relapse will be performed. As of September 20, 2021, 5 of the total sample (N = 64) have been enrolled and randomized. Clinical trial information: NCT04804007.

Randomized phase II trial of gemcitabine, avelumab and carboplatin versus no neoadjuvant therapy preceding surgery for cisplatin-ineligible muscle-invasive urothelial carcinoma (MIUC): SWOG GAP trial (S2011).

TPS591 Background: Neoadjuvant cisplatin-based combination chemotherapy improves survival in cisplatin-eligible patients (pts) with muscle invasive bladder cancer (MIBC). An unmet need exists in cisplatin-ineligible pts with MIUC who are offered upfront surgery. Neoadjuvant immune checkpoint inhibitors (ICIs) have been demonstrated to be safe and active although the benefit may not extend to the majority of pts. The combination of GCa and an ICI has been demonstrated to be safe and active in cisplatin-ineligible metastatic urothelial carcinoma. In the neoadjuvant setting, combination GCa and an ICI may improve outcomes across a broad group of MIUC by delivering early systemic therapy to pts with cisplatin-ineligible MIUC. We hypothesized that the combination of GCa and avelumab, a PD-L1 inhibitor, may improve pathologic complete remissions (pCR) and long-term outcomes compared to upfront surgery for MIUC (S2011, NCT04871529). Methods: This multicenter, randomized (1:1), open-label phase II trial is comparing the combination of GCa and avelumab (Arm A) as neoadjuvant therapy vs. upfront surgery (Arm B) for pts with cisplatin-ineligible MIUC including MIBC and high-risk upper tract urothelial carcinoma (UTUC). Adjuvant therapy following radical cystectomy, nephroureterectomy or ureterectomy is deferred to investigator discretion in both arms. Eligible pts include those with MIBC or high-grade UTUC with a predominant urothelial component who are cisplatin-ineligible (≥1 of: Zubrod performance status [PS] = 2, creatinine clearance [CrCl] 30 to &lt; 60 ml/min, neuropathy &gt; grade 1, hearing loss &gt; grade 1, congestive heart failure &gt; grade 2). The primary objective is pCR. The stratification factors include clinical stage (cT2N0M0 vs cT3-4aN0M0), Zubrod-PS (0-1 vs 2), CrCl (30 to &lt; 60 vs ≥ 60 ml/min). With 178 evaluable pts, the trial will have a power of 90% (using a 1-sided alpha 0.05) to detect pCR rate improvement from 15% to 35%. The secondary objectives are toxicities, resectability rates, surgical complications, event-free survival (EFS) and overall survival (OS). Correlative studies include tumor molecular profiling, blood immune studies, circulating tumor-DNA profiling and radiomics. Arm A receives gemcitabine 1000 mg/m2 IV days 1, 8 every 3 weeks x 4 cycles, carboplatin AUC 4.5 (escalated to AUC 5 from cycle 2 if tolerated in cycle 1) IV day 1 every 3 weeks x 4 cycles and avelumab 800 mg IV day 1 every 2 weeks x 6 cycles. Surgery is performed 4-8 weeks after the last neoadjuvant administration. The trial is funded by NIH/NCI grants U10CA180888, U10CA180819, U10CA180821, U10CA180820, U10CA180868, and in part by EMD Serono, as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) and Pfizer. Clinical trial information: NCT04871529.

A phase II trial evaluating the efficacy of cabozantinib in the treatment of patients with refractory germ-cell tumors (GCT).

TPS428 Background: While the majority of patients with metastatic testicular cancer are cured with first-line cisplatin-based chemotherapy, 20-30% of patients will relapse following initial treatment. Many will still be cured with second and even third-line chemotherapy options, but there remains a need for new therapeutic approaches for patients with relapsed/refractory disease. Cabozantinib is an oral tyrosine-kinase inhibitor (TKI) with multiple targets including c-MET, VEGF, RET, and AXL. Testicular GCT have low rates of somatic mutations, though have been shown to be associated with a gain of chromosome 7, a portion of which encodes c-MET. When hepatocyte growth factor (HGF) binds to its c-MET receptor, cell proliferation, migration, invasion, and apoptosis escape occurs. In addition, compared to normal testicular tissue, testicular GCT have been shown to have higher rates of VEGF expression. Based on these findings, we proposed a phase 2 trial with cabozantinib in patients with relapsed/refractory GCT. Methods: This phase II, single arm, open label trial with a Simon two-stage design is evaluating cabozantinib 60mg daily in patients with relapsed/refractory GCT. Eligible patients are adult men and women with GCT (seminoma, non-seminoma, or ovarian GCT) that have progressed after first-line cisplatin-based combination chemotherapy in addition to at least 1 salvage regimen and are considered incurable with standard therapies. Patients with primary mediastinal non-seminoma, late relapse, and treated stable brain metastases are eligible. 12 patients will be enrolled initially in the first stage of the Simon two-stage design. If at least one complete response (CR), partial response (PR), or stable disease (SD) for ≥3 months is achieved, the trial will be deemed worthy of further investigation and 9 additional patients will be enrolled. Patients will be treated daily with cabozantinib until time of progression or unacceptable toxicity. Primary outcome is clinical benefit rate (proportion of CR, PR, and SD for ≥3 months using RECIST 1.1, modified to include tumor markers, AFP and hCG). Secondary outcomes include objective response rate, progression-free survival, overall survival, and tolerability and toxicity of cabozantinib. Exploratory evaluation of MET overexpression by IHC and amplification by next generation sequencing in correlation with response will be performed. This study is currently enrolling patients. As of September 20, 2021, the prespecified goal for the Simon stage 1 has been met, and 7 of planned 21 patients have enrolled. Clinical trial information: NCT04876456.

Weekly Cisplatin vs. Triweekly Docetaxel Plus Cisplatin With Concurrent Chemoradiation in Post-Operative Treatment for Cervical Cancer With High-Risk Pathological Factors: A Randomized Controlled Phase III Trial From a Single Institution

After radical surgery, patients with high-risk factors were recommended adjuvant concurrent chemoradiation (CCRT). Cisplatin and cisplatin-based combination chemotherapy were the most common concurrent chemotherapy in previous studies. However, there are still few randomized controlled studies comparing which is better for survival. We conduct this prospective study to compare triweekly combination chemotherapy with weekly cisplatin chemoradiation in adjuvant radiation for cervical cancer patients with high-risk factors after radical surgery.Patients aged 18-70 years early-stage cervical cancer with high-risk pathological factors (adenocarcinoma/adenosquamous carcinoma, parametrial invasion, positive surgical margins, and lymph node metastasis) after radical hysterectomy were included and randomized 1:2 to the DDP group and DP group. The DDP group received chemotherapy with weekly cisplatin (40 mg/m2) of 5 cycles concurrent with radiation. The DP group received a triweekly regimen of cisplatin (75 mg/m2) plus docetaxel (75 mg/m2) of 4 cycles and the first cycle was initiated within 1-2weeks after surgery. Radiotherapy was started concurrently at the second cycle of chemotherapy in DP group. The primary end point was the rate of disease-free survival (DFS) at 5 years.A total of 268 patients were included in the analysis (91 in the DDP group, 177 in the DP group). The median follow-up period is 54 months (2-90m), and 2 cases were lost to follow-up. Baseline demographic and disease characteristics were balanced among the treatment groups. In the intention-to-treat population, 5-year DFS showed a better trend in DP group than DDP group, although there was no statistically significant difference (85.9% vs 78.0%; HR 1.64; 95% CI, 0.91-2.95, P = 0.096). There was no difference in 5-year OS, DMFS and LRFS between the groups (87.0%, 87.6% and 97.2% for DP group; 79.1%, 82.4% and 94.5% for DDP group, P = 0.127, 0.249 and 0.253, respectively). Distant metastasis was the major pattern of treatment failure and occurred in 37 patients (23 in DP group and 14 in DDP group). Lymph nodes (15/37), lung (9/37), liver (5/37), and bone (7/37) were the most common sites of metastasis. Forty-two patients died, of which 3 died from other causes (1 for cardiac, 1 for renal, and 1 for a second primary tumor). 142(80.2%) patients in DP group and 84(92.3%) patients in DDP group completed the treatment according to protocol. Toxic reactions are most common in hematology and intestinal tract. The incidence of severe acute hematological was significantly higher in the DP group than in the DDP group (47.6% vs 21.8%, P = 0.000), but there was no significant difference in severe intestinal reactions.Compared with weekly cisplatin, tri-weekly combined cisplatin plus docetaxel showed a tendency to improve survival in cervical cancer with pathological high-risk factors, but the difference was not statistically significant. Clinical trials.gov identifier NCT01999933.

Synergistic therapeutic effect of low-dose bevacizumab with cisplatin-based chemotherapy for advanced or recurrent cervical cancer.

Cisplatin-based chemotherapy (CBC) is highly efficacious for advanced cervical cancer; its efficacy can be enhanced by combining with 15 mg/kg (standard dose) bevacizumab (BEV). However, this standard dose is associated with various adverse events (AEs). Therefore, in this retrospective study, we analyzed the survival outcomes and AEs in patients with advanced or recurrent cervical cancer treated with CBC in combination with BEV 7.5 mg/kg. Registered patient data were retrieved between October 2014 and September 2019, and 64 patients with advanced or recurrent cervical cancer treated with CBC + BEV (n = 21) or CBC alone (n = 43) were analyzed. The primary endpoints were progression-free survival (PFS) and overall survival (OS); the secondary endpoints were the frequency and severity of AEs. The Cox proportional-hazards model was applied to explore prognostic factors associated with PFS and OS. The 1-, 2-, and 3-year PFS rates (95% CI) were 36.24% (22.0-50.5), 20.7% (9.8-34.2), and 17.7% (7.7-31.1) for the CBC group; and 71.4% (47.1-86.0), 51.0% (27.9-70.1), and 51.0% (27.9-70.1) for the CBC + BEV group, respectively. The 1-, 2-, and 3-year OS rates were 62.6% (46.4-75.18), 32.4% (18.8-46.9), and 23.2% (11.2-37.6) for the CBC group; and 85.7% (61.9-95.1), 66.6% (42.5-82.5), and 55.5% (27.1-76.7) for the CBC + BEV group, respectively. The CBC + BEV group presented higher PFS and OS rates, p = 0.003 and p = 0.005, respectively. Proteinuria (6 vs 9, p = 0.025) and hypertension (0 vs 10, p < 0.001) were less common, but anemia was more common in the CBC group (35 vs 11, p = 0.021). Overall, CBC + BEV significantly improved the PFS and OS compared with CBC alone. CBC + BEV also prevents severe AEs and hence is an efficacious and safe therapeutic option.

LBA30 Single-dose carboplatin followed by involved-node radiotherapy as curative treatment for seminoma stage IIA/B: Efficacy results from the international multicenter phase II trial SAKK 01/10

Standard treatment options for patients (pts) with seminoma clinical stage (CS) IIA/B are either extensive “dog-leg” para-aortic/pelvic radiotherapy (RT) or 3-4 cycles of cisplatin-based combination chemotherapy (ChT) with a 3-year progression free survival (PFS) of ≥90%, but potential acute and late toxicities. SAKK 01/10 is a trial of the Swiss Group for Clinical Cancer Research (SAKK) and the German Testicular Cancer Study Group (GTCSG) aiming at reducing therapy toxicity while preserving efficacy in CS IIA/B seminoma by combining deescalated ChT and RT.

A risk-group classification model in patients withbladder cancerunder neoadjuvant cisplatin-based combination chemotherapy.

The objective of the current research was toexplore the potential prognostic value of readily available clinical and pathologic variables in bladder cancer. The novel association foundbetween cholesterol levels and prognosis may provide the rationale for exploring novel treatments. Patients included had histologically confirmed urothelial bladder cancer and were treated with at least 3 cycles of cisplatin-based neoadjuvant chemotherapy before radical cystectomy with lymphadenectomy. A total of245 patients at low, intermediate and high risk, presentingwith0-1, 2 or 3-4 risk factors, including positive lymph nodes, Hb<12.8, NLR ≥2.7 and cholesterol levels ≥199, were included. Five-yearcancer-specific survival rate was 0.67, 0.78 and 0.94 athigh, intermediate and low risk, respectively. Total cholesterol levels at the time of cystectomy may represent a commonly assessable prognostic factor and maybeincorporated in a clinically meaningful risk-group classification model.

Single Incision Robotic Cystectomy and Hybrid Orthotopic Neobladder Reconstruction: A Step by Step Description

To describe a new technique for single incision robotic cystectomy and Studer-type ileal neobladder using the single-port (SP) da Vinci SP robotic platform. In April 2021, a 71 year-old patient underwent a single incision robotic cystectomy and orthotopic Studer-type ileal neobladder using the single-port da Vinci SP robotic platform for cT2, cN0 urothelial carcinoma of the bladder. He was not a candidate for neoadjuvant cisplatin-based combination chemotherapy and declined participation in a clinical trial. Total operative time was 554 minutes and estimated blood loss was 250 cc. He was discharged on postoperative day six without developing any Clavien complications. He underwent adjuvant chemotherapy for node-positive disease and follow-up through June 2021 was notable for the absence of any significant complications or readmissions. We provide a comprehensive discussion of the required instrumentation, a description of the technique with illustrations, and discuss the advantages and disadvantages of this technology as it pertains to cystectomy and urinary diversion. We make no claim regarding the superiority of this technique over others, only that it is technically feasible and that the approach holds promise.