Phase II study of sunitinib as first-line treatment of urothelial cancer patients ineligible to receive cisplatin-based chemotherapy: baseline interleukin-8 and tumor contrast enhancement as potential predictive factors of activity

Bellmunt, Joaquim; González-Larriba, José-Luis; Prior, Celia; Maroto, Pablo; Carles, Joan; Castellano, Daniel; Mellado, Begoña; Gallardo, Enrique; Perez-Gracia, José Luis; Aguilar, Guadalupe; Villanueva, Xavier; Albanell, Joan; Calvo, Alfonso

doi:10.1093/annonc/mdr023

Cited by 108 publications

(55 citation statements)

References 39 publications

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“…16,17), prostate cancer (18), esophageal squamous cell carcinoma (19), soft sarcoma (20) and bone sarcoma (21), renal cell carcinoma (RCC; ref. 22), urothelial tumors (23,24), hepatocellular carcinoma (HCC; refs. 25,26), colorectal cancer (27), gastric cancer (28), pancreatic cancer (29), ovarian cancer (30), breast cancer (31), neurologic tumors (32), lymphoma (33,34), and others (5,35) are available, but its value as a cancer biomarker to predict changes in tumor burden and to monitor response to cancer treatment has been poorly explored.…”

Section: Introductionmentioning

confidence: 99%

Serum Interleukin-8 Reflects Tumor Burden and Treatment Response across Malignancies of Multiple Tissue Origins

Sanmamed

Carranza-Rua

Alfaro

et al. 2014

Clinical Cancer Research

217

158

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Purpose: Interleukin-8 (IL8) is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping protumoral vascularization and inflammation/immunity. We evaluated sequential levels of serum IL8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden.Experimental Design: IL8 levels were monitored by sandwich ELISAs in cultured tumor cells supernatants, tumor-xenografted mice serum, and in samples from 126 patients with cancer. We correlated IL8 serum levels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis.Results: IL8 concentrations correlated with the number of IL8-producing tumor cells in culture. In xenografted neoplasms, IL8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n ¼ 16), renal cell carcinoma (RCC; n ¼ 23), non-small cell lung cancer (NSCLC; n ¼ 21), or hepatocellular carcinoma (HCC; n ¼ 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n ¼ 16; RCC, n ¼ 23; HCC, n ¼ 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n ¼ 16) and immunomodulatory monoclonal antibodies (melanoma, n ¼ 8). IL8 concentrations in urine (n ¼ 18) were mainly elevated in tumors with direct contact with the urinary tract.Conclusions: IL8 levels correlate with tumor burden in preclinical models and in patients with cancer.

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Section: Introductionmentioning

confidence: 99%

Serum Interleukin-8 Reflects Tumor Burden and Treatment Response across Malignancies of Multiple Tissue Origins

Sanmamed

Carranza-Rua

Alfaro

et al. 2014

Clinical Cancer Research

217

158

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“…In the last few decades, innovative targeted agents have been evaluated in clinical trials, but have also only resulted in modest anti-tumour activity [14][15][16][17][18][19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Phase II study of dual phosphoinositol‐3‐kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma

et al. 2016

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ObjectiveTo assess, in a multicentre phase II trial, the safety and efficacy of BEZ235, an oral pan-class I phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) complex1/2 inhibitor, in locally advanced or metastatic transitional cell carcinoma (TCC) after failure of platinumbased therapy. Patients and MethodsPatients with locally advanced or metastatic TCC progressing after platinum therapy were prospectively stratified by PI3K/ Akt/mTOR pathway alterations, defined as PTEN loss and PIK3CA mutation. All patients received BEZ235 until progressive disease or unacceptable toxicity. The primary endpoint was the progression-free survival (PFS) rate at 16 weeks. This study was, however, closed prematurely because BEZ235 was withdrawn from further development. ResultsA total of 20 patients (18 without and two with PI3K/Akt/ mTOR alterations) were enrolled and received BEZ235. One partial response (5%) and two cases of stable disease (10%) were observed, all in patients without PI3K/mTOR pathway alterations. The PFS rate at 8 and 16 weeks was 15 and 10%, respectively; the median (range) PFS was 62 (38-588) days (95% confidence interval [CI] 53-110); and the median (range) overall survival was 127 (41-734) days (95% CI 58-309). Among the 90% of patients who experienced drugrelated adverse events of any grade, 50% experienced grade 3-4 adverse events, including stomatitis (15%), fatigue (5%), nausea (5%), diarrhoea (5%), renal failure (5%), cutaneous rash (5%), hepatotoxicity (5%) and hypertension (5%). ConclusionBEZ235 showed modest clinical activity and an unfavourable toxicity profile in patients with advanced and pretreated TCC; however, a minority of patients experienced a clinical benefit, suggesting that a complete blockade of the PI3K/mTOR axis could improve outcome in some specific patients. Furthermore, this study showed that molecular stratification of patients for personalized medicine before treatment is feasible.

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“…19,20 The VEGF receptor and PDGFR kinase inhibitor, sunitinib, has demonstrated single-agent activity in patients with mUC, with some patients achieving objective tumor regressions and approximately 30% to 45% demonstrating prolonged stable disease. 21,22 Combining sunitinib with gemcitabine resulted in synergistic activity in bladder cancer cell lines, and combining sunitinib with cisplatin resulted in at least additive antitumor activity in a bladder cancer xenograft model. 23,24 Based on these findings and on the safety of GC and sunitinib (GCS) combined, 25 we initiated parallel phase II trials that explored GCS as a first-line treatment for patients with mUC and as neoadjuvant therapy for MIBC.…”

Section: Introductionmentioning

confidence: 99%

Gemcitabine, Cisplatin, and Sunitinib for Metastatic Urothelial Carcinoma and as Preoperative Therapy for Muscle-Invasive Bladder Cancer

Galsky

Hahn

Powles³

et al. 2013

Clinical Genitourinary Cancer

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Phase II study of sunitinib as first-line treatment of urothelial cancer patients ineligible to receive cisplatin-based chemotherapy: baseline interleukin-8 and tumor contrast enhancement as potential predictive factors of activity

Abstract: This study highlights the potential role of the angiogenic pathway as a therapy target in urothelial cancer. Baseline IL-8 serum levels and contrast enhancement of lesions warrant further study.

Cited by 108 publications

References 39 publications

Serum Interleukin-8 Reflects Tumor Burden and Treatment Response across Malignancies of Multiple Tissue Origins

Serum Interleukin-8 Reflects Tumor Burden and Treatment Response across Malignancies of Multiple Tissue Origins

Phase II study of dual phosphoinositol‐3‐kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma

Gemcitabine, Cisplatin, and Sunitinib for Metastatic Urothelial Carcinoma and as Preoperative Therapy for Muscle-Invasive Bladder Cancer

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