Dataset Information

A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

ABSTRACT:

Background

BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours.

Methods

RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median).

Primary endpoint

invasive loco-regional control (ILRC); secondary overall survival.

Findings

Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy.

Interpretation

Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial.

Funding

Cancer Research UK, NIHR, MRC.

SUBMITTER: Smith TAD

PROVIDER: S-EPMC10897900 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

Smith Tim A D TAD West Catharine M L CML Joseph Nuradh N Lane Brian B Irlam-Jones Joely J More Elisabet E Mistry Hitesh H Reeves Kimberley J KJ Song Yee Pei YP Reardon Mark M Hoskin Peter J PJ Hussain Syed A SA Denley Helen H Hall Emma E Porta Nuria N Huddart Robert A RA James Nick D ND Choudhury Ananya A

EBioMedicine 20240221

<h4>Background</h4>BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated ...[more]

PMID: 38387404

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Project description:BackgroundBC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer, demonstrated improvement of local control and bladder cancer-specific survival from the addition of concomitant 5-fluorouracil and mitomycin C to radiotherapy.ObjectiveTo determine the impact of treatment on the health-related quality of life (HRQoL) of BC2001 participants.Design, setting, and participants458 UK patients with T2-T4a N0 M0 transitional cell carcinoma of the bladder.InterventionPatients were randomised to the chemotherapy comparison (radiotherapy, 178, or chemoradiotherapy, 182); and/or to the radiotherapy comparison (standard, 108, or reduced high-dose volume radiotherapy, 111).Outcome measurements and statistical analysisPatients completed Functional Assessment of Cancer Therapy-Bladder (FACT-BL) questionnaires at baseline, end of treatment (EoT), and 6, 12, 24, 36, 48, and 60 months after radiotherapy. The primary endpoint was change from baseline in the bladder cancer subscale (BLCS) at 12 months.Results and limitationsData were available for 331 (92%) and 204 (93%) participants at baseline and for 192 (54%) and 114 (52%) at 12 months for the chemotherapy and radiotherapy comparisons, respectively. HRQoL declined at EoT (BLCS -5.06 [99% confidence interval: -6.12 to -4.00, p< 0.001]; overall FACT-B TOTAL score -8.22 [-10.76 to -5.68, p< 0.01]), recovering to baseline at 6 months and remaining similar to baseline subsequently. There was no significant difference between randomised groups at any time point.ConclusionsImmediately following (chemo)radiotherapy, a significant proportion of patients report declines in HRQoL, which improve to baseline after 6 months. Two-thirds of patients report stable or improved HRQoL on long-term follow-up. There is no evidence of impairment in HRQoL resulting from the addition of chemotherapy.Patient summaryQuality of life of bladder cancer patients treated with radiotherapy±chemotherapy deteriorates during treatment, but improves to at least pretreatment levels within 6 months. Addition of chemotherapy to radiotherapy does not affect patient-reported quality of life.

Project description:ObjectivesThe advanced gastric adenocarcinoma (GAC) patients (stage III/IV) with surgery may have inconsistent prognoses due to different demographic and clinicopathological factors. In this retrospective study, we developed clinical prediction models for estimating the overall survival (OS) and cancer-specific survival (CSS) in advanced GAC patients with surgery.MethodsA retrospective analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER) database. The total population from 2004 to 2015 was divided into four levels according to age, of which 179 were younger than 45 years old, 695 were 45-59 years old, 1064 were 60-74 years old, and 708 were older than 75 years old. There were 1,712 men and 934 women. Univariate and multivariate Cox regression analyses were performed to identify prognostic factors for OS and CSS. Nomograms were constructed to predict the 1-, 3-, and 5-year OS and CSS. The models' calibration and discrimination efficiency were validated. Discrimination and accuracy were evaluated using the consistency index, area under the receiver operating characteristic curve, and calibration plots; and clinical usefulness was assessed using decision curve analysis. Cross-validation was also conducted to evaluate the accuracy and stability of the models. Prognostic factors identified by Cox regression were analyzed using Kaplan-Meier survival analysis.ResultsA total of 2,646 patients were included in our OS study. Age, primary site, differentiation grade, AJCC 6th_TNM stage, chemotherapy, radiotherapy, and number of regional nodes examined were identified as prognostic factors for OS in advanced GAC patients with surgery (P < 0.05). A total of 2,369 patients were included in our CSS study. Age, primary site, differentiation grade, AJCC 6th_TNM stage, chemotherapy, radiotherapy, and number of regional nodes examined were identified as risk factors for CSS in these patients (P < 0.05). These factors were used to construct the nomogram to predict the 1-, 3-, and 5-year OS and CSS of advanced GAC patients with surgery. The consistency index and area under the receiver operating characteristic curve demonstrated that the models effectively differentiated between events and nonevents. The calibration plots for 1-, 3-, and 5-year OS and CSS probability showed good consistence between the predicted and the actual events. The decision curve analysis indicated that the nomogram had higher clinical predictive value and more significant net gain than AJCC 6th_TNM stage in predicting OS and CSS of advanced GAC patients with surgery. Cross-validation also revealed good accuracy and stability of the models.ConclusionThe developed predictive models provided available prognostic estimates for advanced GAC patients with surgery. Our findings suggested that both OS and CSS can benefit from chemotherapy or radiotherapy in these patients.

Dataset Information

A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

Background

Methods

Primary endpoint

Findings

Interpretation

Funding

Publications

A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

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