Patient-Reported Quality of Life Outcomes in Patients Treated for Muscle-Invasive Bladder Cancer with Radiotherapy ± Chemotherapy in the BC2001 Phase III Randomised Controlled Trial - Beyond the Abstract

For many years the management of muscle-invasive bladder cancer has been dominated by radical cystoprostatectomy. Though obtaining high levels of local control this approach has a high rate of morbidity, significant perioperative mortality, and impacts on quality of life. It is also not suitable for many patients due to co-morbidities, this being a particular issue in older patients. As a result, oncologists have looked to radiotherapy based approaches as an alternative. Radiotherapy as an alternative to surgery has been hampered by concerns over efficacy, late toxicity and impact on quality of life.

The BC2001 clinical trial (CRUK01/004); ISRCTN68324339) was launched in the early 2000s to address these issues; testing if the addition of low toxicity chemotherapy could improve local control and if modifying radiation target volumes could reduce toxicity. In a landmark paper in 20121 we showed that adding chemotherapy (5FU and mitomycin C) had a significant impact on local control; almost halving invasive or nodal recurrences with no detectable impact on late toxicity. Modifying radiotherapy volume was less successful; the study suggested that this could be done without increasing local recurrence but the expected reduction in toxicity was not seen.2 These results taken together have made chemo-radiotherapy a more realistic proposition and this is reflected in increased recognition of its role in national/international clinical guidelines.

There remains a concern that radiotherapy has a significant detrimental impact on bladder function. To date, there has been limited data on Health-Related Quality of Life (HRQoL) to address this issue. What has been available has either been retrospective (often collected using non-validated questionnaires) and/or in limited patient populations.

In our recent paper,3 we report prospectively collected HRQoL using the validated FACT-BL quality of life tool in the 458 patients with muscle-invasive bladder cancer treated in the BC2001 trial. This makes it the largest prospectively collected cohort reported to date.

The study showed that after an immediate fall in quality of life at the end of treatment, scores improved and had returned to baseline (pre-treatment) levels by six months. Long-term global HRQoL scores, if anything, were above those seen at baseline. Bowel and bladder symptom scores showed similar patterns, with worsening of urinary and bowel function during treatment that improved and returned to near baseline levels after recovery of acute toxicity. Baseline erectile dysfunction was common when present initially function was largely maintained after treatment.

Importantly there was no evidence of a difference in HRQoL between patients receiving or not receiving concomitant chemotherapy (randomized comparison) nor between those treated with neoadjuvant chemotherapy or not (non-randomized comparison).

To investigate HRQoL further we undertook analysis on individual patients, classifying whether they had a clinically significant change from baseline (according to previously published criteria). This proved a rich source of information. At the end of treatment, approximately 50-60% of patients had some worsening of quality of life and around 15% reported improved HRQoL. As they recovered the number of patients who had worsening of quality of life reduced, whilst the number of patients having improved HRQoL increased. Though it is clear that some patients do have persistently reduced HRQoL after their radiotherapy, similar numbers of patients have improved quality of life. This explains why on average HRQoL scores are similar to baseline on follow up. Understanding and addressing the drivers of impairment of HRQoL in the subgroup with worsened scores will be an important area to investigate.

Overall the message is reassuring. Yes, patients can expect to have some temporary deterioration in HRQoL after radiotherapy, most likely driven by acute toxicity. However, in the longer-term (six months to five years after treatment) 70-75% have HRQoL that is the same as or better than it was before treatment. Patients can, therefore, receive concomitant chemotherapy, which we know improves outcome, with the knowledge that for most the long-term impacts of this treatment will be minimal.

Written by: Robert Huddart, MBBS, MRCP, FRCR, PhD, Clinical Academic Radiotherapy Team Lead, The Institute of Cancer Research (ICR-CTSU), Consultant in Urological Oncology, The Royal Marsden NHS Foundation Trust, Sutton, England, and Emma Hall, PhD, Reader of Oncology Trials, Deputy Director, Cancer Research UK-funded Clinical Trials and Statistics Unit, The Institute of Cancer Research (ICR-CTSU), Sutton, England.

References:

1. James, Nicholas D., Syed A. Hussain, Emma Hall, Peter Jenkins, Jean Tremlett, Christine Rawlings, Malcolm Crundwell et al. "Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer." New England Journal of Medicine 366, no. 16 (2012): 1477-1488.
2. Huddart, Robert A., Emma Hall, Syed A. Hussain, Peter Jenkins, Christine Rawlings, Jean Tremlett, Malcolm Crundwell et al. "Randomized noninferiority trial of reduced high-dose volume versus standard volume radiation therapy for muscle-invasive bladder cancer: results of the BC2001 trial (CRUK/01/004)." International Journal of Radiation Oncology* Biology* Physics 87, no. 2 (2013): 261-269.
3. Huddart, Robert A., Emma Hall, Rebecca Lewis, Nuria Porta, Malcolm Crundwell, Peter J. Jenkins, Christine Rawlings et al. "Patient-reported quality of life outcomes in patients treated for muscle-invasive bladder cancer with radiotherapy±chemotherapy in the BC2001 phase III randomised controlled trial." European Urology 77, no. 2 (2020): 260-268.

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