scholarly journals ERCC1 19007 Polymorphism in Greek Patients with Advanced Urothelial Cancer Treated with Platinum-Based Chemotherapy: Effect of the Changing Treatment Paradigm. A Cohort Study by the Hellenic GU Cancer Group

2021 ◽  
Vol 28 (6) ◽  
pp. 4474-4484
Author(s):  
Aristotelis Bamias ◽  
Konstantinos Koutsoukos ◽  
Nikos Gavalas ◽  
Roubini Zakopoulou ◽  
Kimon Tzannis ◽  
...  
Keyword(s):  
Urothelial Cancer ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Pcr Amplification ◽  
Cancer Specific Survival ◽  
Cancer Group ◽  
Platinum Based Chemotherapy ◽  
Treatment Paradigm ◽  
Advanced Urothelial Cancer ◽  
Ercc1 Polymorphism

We previously showed that ERCC1 19007 C>T polymorphism was associated with cancer-specific survival (CSS) after platinum-based chemotherapy in patients with advanced urothelial cancer (aUC). We aimed to confirm this association in a different cohort of patients. Genotyping of the 19007C>T polymorphism was carried out by polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism (RFLP) in 98 aUC patients, treated with platinum-based chemotherapy. Median age of the patients was 68.8, 13.3% of them were female, 90.8% had ECOG PS of 0 or 1, and 48% received cisplatin-based chemotherapy. In addition to chemotherapy, 32.7% of the patients received immunotherapy, and 19.4% vinflunine. Eighty-one patients (82.7%) were carriers of the 19007T polymorphic allele: 46 (46.9%) were heterozygotes, and 35 (35.7%) were homozygotes. The ERCC1 polymorphism was not associated with CSS, progression-free (PFS), or overall (OS) survival in the total population. Nevertheless, there was a significant interaction between the prognostic significance of ERCC1 polymorphism and the use of modern immunotherapy: the T allele was associated with worse outcome in patients who received chemotherapy only, while this association was lost in patients who received both chemotherapy and immune checkpoint inhibitors. Our study suggests that novel therapies may influence the significance of ERCC1 polymorphism in patients with aUC. Its determination may be useful in the changing treatment landscape of the disease.

Conceptual Framework for Therapeutic Development Beyond Anti–PD-1/PD-L1 in Urothelial Cancer

2019 ◽  
pp. 284-300 ◽  
Author(s):  
Petros Grivas ◽  
Alexandra Drakaki ◽  
Terence W. Friedlander ◽  
Guru Sonpavde
Keyword(s):  
Clinical Trials ◽  
Immune Checkpoint ◽  
Urothelial Cancer ◽  
Checkpoint Inhibitors ◽  
Health Care Use ◽  
Molecular Medicine ◽  
Treatment Modalities ◽  
Molecular Heterogeneity ◽  
Platinum Based Chemotherapy ◽  
Advanced Urothelial Cancer

Platinum-based chemotherapy has been the standard of care in advanced urothelial cancer, but long-term outcomes have remained poor. Immune checkpoint inhibitors, with their favorable toxicity profiles and noteworthy efficacy, have steered a new era in advanced urothelial cancer, with five agents targeting the PD-1/PD-L1 pathway approved by the U.S. Food and Drug Administration (FDA). However, most patients do not achieve response, whereas immunotherapy-related adverse events may cause morbidity, increased health care use, and—rarely—mortality. Therefore, there is an urgent need for additional therapeutic modalities across the disease spectrum. A plethora of clinical trials are ongoing in various disease settings, including chemotherapy regimens, radiotherapy, antibody-drug conjugates, agents targeting additional immune checkpoint pathways, vaccine, cytokines, adoptive cell therapies, as well as targeted and anti-angiogenic agents. Two agents, enfortumab vedotin and erdafitinib, have breakthrough designation by the FDA but are not approved yet (at the time of this paper's preparation). Novel combinations with various treatment modalities and optimal sequencing of active therapies are being investigated in prospective clinical trials. Evaluation of new treatments has met with substantial challenges for many reasons, for example, molecular heterogeneity, clonal evolution, and genomic instability. In the era of precision molecular medicine, and because patients do not respond uniformly to current therapies, there is a growing need for identification and validation of biomarkers that can accurately predict treatment response and assist in patient selection. Here, we review current updates and future directions of experimental therapeutics in urothelial cancer, including examples (but not an exhaustive list) of ongoing clinical trials.

Metronomic Outpatient-Based Chemotherapy with 5′-DFUR and Low-Dose Cisplatin for Conventional Platinum-Based Chemotherapy-Resistant Advanced Urothelial Cancer

2007 ◽  
Vol 1 ◽  
pp. CMO.S304
Author(s):  
Tomohiko Hara ◽  
Satoru Yoshihiro ◽  
Hideaki Ito ◽  
Kazuhiro Nagao ◽  
Chietaka Ohmi ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Large Scale ◽  
Urothelial Cancer ◽  
Transitional Cell ◽  
Eastern Cooperative Oncology Group ◽  
Metronomic Chemotherapy ◽  
World Health ◽  
Severe Toxicity ◽  
Platinum Based Chemotherapy ◽  
Advanced Urothelial Cancer

Background Metronomic chemotherapy is aimed at lessening the adverse effects of treatment while rendering cancer cells cytostatic. The oral 5-fluorouracil prodrug “5′-DFUR” has been shown to inhibit angiogenesis and is regarded as a good candidate agent for metronomic chemotherapy. Moreover, cisplatin and 5′-DFUR have been shown to synergistic cytotoxic effects. Methods We evaluated the safety and efficacy of metronomic chemotherapy using daily oral 5′-DFUR at the dose of 600 mg/day and biweekly cisplatin infusion at the dose of 20 mg/person in 23 patients with urothelial cancer resistant to conventional platinum-based chemotherapy. Results Twenty-three patients were enrolled between August 2000 and December 2004. The median survival time after the initiation of metronomic chemotherapy was 15.2 months. The 1-year, 2-year and 3-year survival rates were 55.1%, 45.1% and 5.9%, respectively. Grade 3 fatigue was observed as severe toxicity in one patient. No cases showed nephrotoxicity and adverse effects necessitating medical intervention. Conclusions Although a large-scale prospective study would be necessary before the therapy is established as a standard, our metronomic chemotherapy regimen appears to be a potentially useful palliative treatment alternative for patients with advanced urothelial cancer resistant to conventional platinum-based chemotherapy. Abbreviations M-VAC: methotrexate, vinblastine, doxorubicin, and cisplatin; GC: gemcitabine and carboplatin; 5′-DFUR: 5′-deoxy-5-fluorouridine; 5-FU: 5-fluorouracil; CDDP: cisplatin; TCC: transitional cell carcinoma; ECOG: Eastern Cooperative Oncology Group; PS: performance status; UICC: Union International Contre le Cancer; WHO: World Health Organization; NCI-CTC: National Cancer Institute Common Toxicity Criteria; CI: confidence interval; PR: partial response; NC: no change; PD: progressive disease; TP: thymidine phosphorylase; AUC: areas under the curve.

From clinical trials to clinical use of checkpoint inhibitors for patients with metastatic urothelial cancer

Immunotherapy ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 67-77
Author(s):  
Rosa Tambaro ◽  
Marilena Di Napoli ◽  
Carmela Pisano ◽  
Sabrina Chiara Cecere ◽  
Laura Attademo ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Urothelial Cancer ◽  
Unmet Needs ◽  
Checkpoint Inhibitors ◽  
Slight Improvement ◽  
Metastatic Urothelial Cancer ◽  
Advanced Urothelial Cancer ◽  
Improvement In Survival ◽  
Cell Death Protein

Monoclonal antibodies targeting the checkpoint inhibitors (CPIs), programmed cell death protein-1 or programmed cell death ligand-1, are changing the landscape of urothelial carcinoma therapeutics. Overall, clinical studies in metastatic or advanced urothelial cancer showed that CPIs provided a slight improvement in survival and a relevant advantage in safety, compared with chemotherapy. After reviewing published and ongoing trials, the authors discuss expected answers to unmet needs, with a special attention to the research of biological markers for patients with urothelial cancer eligible for treatment with CPIs in this article.

scholarly journals Enfortumab Vedotin in urothelial cancer

2020 ◽  
Vol 12 ◽  
pp. 175628722098019
Author(s):  
Marie Alt ◽  
Carlos Stecca ◽  
Swanee Tobin ◽  
Di Maria Jiang ◽  
Srikala S. Sridhar
Keyword(s):  
Urothelial Cancer ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Antibody Drug Conjugate ◽  
Future Directions ◽  
Combination Strategies ◽  
Fda Approval ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy ◽  
Accelerated Approval

The treatment landscape for metastatic urothelial cancer (mUC) beyond first-line platinum-based chemotherapy has changed significantly over the last 5 years with the recent approvals of the immune checkpoint inhibitors (ICIs), fibroblast growth factor receptor (FGFR) inhibitors and most recently Enfortumab Vedotin (EV). EV is a novel antibody–drug conjugate (ADC), that delivers monomethyl auristatin E (MMAE), a microtubule-disrupting agent, inside cells harboring the cell surface nectin-4 receptor. In mUC, EV has shown encouraging response rates and received accelerated approval from the Food and Drug Administration (FDA) in December 2019 in the post-platinum and ICI setting. EV is generally well tolerated, with the main toxicities being neuropathy, skin rash, alopecia and fatigue. Notably EV can also be administered to patients with renal dysfunction, which is commonly a concern in this patient population. EV is now being tested in combination strategies and in earlier disease settings in urothelial cancers. In this review, we will discuss its mechanism of action, clinical trials leading to FDA approval as well as ongoing trials and future directions.

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