Improved 5-Factor Prognostic Classification of Patients Receiving Salvage Systemic Therapy for Advanced Urothelial Carcinoma

Abstract

Purpose Prognostic factors in patients receiving salvage systemic therapy for advanced urothelial carcinoma (UC) include performance status (PS), liver metastasis (LM), hemoglobin (Hb) and time from prior chemotherapy (TFPC). We investigated the impact of albumin and neutrophil, lymphocyte and platelet counts. Materials and methods Patient level data from 10 phase II trials were utilized. Cox proportional hazards regression was used to evaluate their association with overall survival (OS). An optimal regression model was constructed using forward stepwise selection and risk groups defined using number of adverse factors. Trial was a stratification factor. External validation was conducted in a separate dataset of 5 salvage phase II trials. Results Data for discovery was obtained from 708 patients. After adjustment for the 4 known factors, platelet ≥upper limit of normal and albumin <lower limit of normal were significant poor prognostic factors. Only the addition of albumin was externally validated. The median OS (months) was 8.9, 6.4, 4.5 for 0–1, 2, 3+ risk factors (n=207, 171, 113) in the discovery dataset (n=491), and 10.6, 10.0, 7.0 with n=73, 47, 47 in the validation dataset (n=167). The c-index improved from 0.610 to 0.639 in the discovery set and from 0.616 to 0.646 in the validation set by adding albumin. Conclusions Albumin was externally validated as a prognostic factor for OS after accounting for TFPC, Hb, PS and LM status in patients receiving salvage systemic therapy for advanced UC. The discovery of molecular prognostic factors is a priority to further enhance this new preferred 5-factor clinical prognostic model.

Population Modeling of Tumor Kinetics and Overall Survival to Identify Prognostic and Predictive Biomarkers of Efficacy for Durvalumab in Patients With Urothelial Carcinoma

“…The effects of TC and IC on OS suggests that intratumoral PD‐L1 expression is predictive not only of tumor response, but also of OS independently of tumor response, after durvalumab treatment. The effects of liver metastasis and hemoglobin and albumin levels on OS are consistent with literature reports on UC patients and supports our conclusion that the population modeling approach can accurately identify prognostic and predictive biomarkers in a multivariate framework . In a recent pooled study across multiple phase II trials in patients receiving salvage systemic therapy for advanced UC, a five‐factor prognostic model was proposed for patients receiving salvage systemic therapy for advanced UC .…”

“…Potential prognostic factors, including time since prior chemotherapy; baseline albumin, hemoglobin, and lactate dehydrogenase levels; neutrophil-to-lymphocyte (N:L) ratio; and Eastern Cooperative Oncology Group (ECOG) performance status were evaluated on tumor growth rate constant (k g ) and were chosen based on literature reports of prognostic factors affecting survival in UC patients receiving other salvage therapies. [9][10][11] Intratumor PD-L1 expression on tumor cell membrane (TC) and on tumor-infiltrating immune cells (IC) has been evaluated as a predictive biomarker for other anti-PD-1/PD-L1 therapies and was associated with efficacy in study 1108 3 ; therefore, TC and IC were evaluated as covariates on killing rate constant (k kill ) only. Smoking history was also evaluated on k kill due to its association with mutational burden.…”

SEOM Clinical Guideline for treatment of muscle-invasive and metastatic urothelial bladder cancer (2016)

“…After internal and external validation, four categories were established from the presence of none, one, two or three factors with median survival times of 14.2, 7.3, 3.8, and 1.7 months. Time from first-line chemotherapy [21] and albumin levels [22] have also proved independent prognostic significance and external validation.…”

Immunotherapy advances in uro-genital malignancies

“…Globally, the median PFS and OS estimates approximate 3 and 6 months, respectively, with a few exceptions for patients having favorable prognostic factors Sonpavde et al, 2015a). Some recommendations for patient eligibility and stratification of patients in clinical trials in the salvage setting have been proposed, and indeed improvements in the stratification of outcome in the second-line setting have been achieved as well, with enhanced prognostic grouping systems that are now available (Sonpavde et al, 2015b;Sonpavde et al, 2014).…”