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Bladder Radiotherapy: Is Cinderella Ready for the Ball?

2021; Elsevier BV; Volume: 33; Issue: 6 Linguagem: Inglês

10.1016/j.clon.2021.04.001

1433-2981

Robert Huddart,

Lung Cancer Diagnosis and Treatment

The management of locally advanced muscle-invasive bladder cancer (MIBC) has been dominated by radical cysto-prostectomy. In comparison, the use of radiotherapy has been a Cinderella; little used, often neglected, outside a few isolated pockets. Bladder radiotherapy, over recent years, has made much progress. In this special issue of Clinical Oncology we pull together expertise from across the globe to examine the current status of bladder radiotherapy. This should lead us to ask: is Cinderella ready for the ball? As discussed by Lodhi et al. [[1]Lodhi T. Song Y.P. West C. Hoskin P. Choudhury A. Hypoxia and its modification in bladder cancer: current and future perspectives.Clin Oncol. 2021; 33: 376-390Abstract Full Text Full Text PDF Scopus (1) Google Scholar] and Tulpule and Ballas [[2]Tulpule V. Ballas L.K. Concomitant systemic therapy: current and future perspectives.Clin Oncol. 2021; 33: e257-e263Abstract Full Text Full Text PDF Scopus (1) Google Scholar] in this special issue, a key stimulus to the awakening of radiotherapy has been two key UK-based randomised trials that showed that radio-sensitisation with either chemotherapy (5-fluorouracil and mitomycin C) [[3]James N.D. Hussain S.A. Hall E. Jenkins P. Tremlett J. Rawlings C. et al.Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer.N Engl J Med. 2012; 366: 1477-1488Crossref PubMed Scopus (531) Google Scholar] or hypoxic modification (carbogen/nicotinamide) [[4]Hoskin P.J. Rojas A.M. Bentzen S.M. Saunders M.I. Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma.J Clin Oncol. 2010; 28: 4912-4918Crossref PubMed Scopus (190) Google Scholar] significantly improved local control and survival. These results rivalled those reported in surgical series, despite being carried out in older, less fit patients. More recently, a meta-analysis of these two trials has shown that there may be an additional benefit to using hypofractionated radiotherapy [[5]Choudhury A. Porta N. Hall E. Song Y.P. Owen R. MacKay R. et al.Hypofractionated radiotherapy in locally advanced bladder cancer: an individual patient data meta-analysis of the BC2001 and BCON trials.Lancet Oncol. 2021; 22: 246-255Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar] and could thus result in a further improvement in results if adopted. This is a seemingly counterintuitive finding and is probably due to reduced repopulation in the shorter hypofractionated regimen given the assumed high α/ß ratio of bladder cancer (unless the assumptions are wrong), but is very welcome given that this results in a shorter treatment time and reduced resource use with no cost in increased toxicity. This win–win result has been particularly welcome during the COVID-19 pandemic, with evidence of rapid implementation at least within the UK [[6]Spencer K. Jones C.M. Girdler R. Roe C. Sharpe M. Lawton S. et al.The impact of the COVID-19 pandemic on radiotherapy services in England, UK: a population-based study.Lancet Oncol. 2021; 22: 309-320Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar]. There is no doubt that bladder radiotherapy is challenging, needing precision in technique and dosing, as outlined by Fonteyne and Sargos [[7]Fonteyn V. Sargos P. What is the optimal dose, fractionation and volume for bladder radiotherapy.Clin Oncol. 2021; 33: e245-e250Abstract Full Text Full Text PDF Scopus (1) Google Scholar] in their review. Data exist of significant day to day variation in bladder size, shape and volume. In previous years this has probably led, despite the use of large clinical target volume to planning target volume margins, to high rates of marginal misses. Indeed, it is perhaps surprising, given current knowledge of these issues, that older radiotherapy techniques achieved the results that they did. The advent of daily soft-tissue imaging has been a major step forward in addressing these issues and improving treatment accuracy. In 2009, I speculated that such technical innovations could leapfrog bladder from a technical backwater into the forefront of technical developments [[8]Lalondrelle S. Huddart R. Improving radiotherapy for bladder cancer: an opportunity to integrate new technologies.Clin Oncol. 2009; 21: 380-384Abstract Full Text Full Text PDF Scopus (17) Google Scholar]. The recent delivery of randomised multicentre daily adaptive ‘plan of the day’ radiotherapy trials shows that this, at least in part, has happened. As described by Kong et al. [[9]Kong V. Hansen V.H. Hafeez S. Image-guided adaptive radiotherapy for bladder cancer.Clin Oncol. 2021; 33: 350-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar], we wait with interest to see if using this technology to undertake dose-escalated tumour boosting, as used in the recent RAIDER trial [[10]Hafeez S. Lewis R. Hall E. Huddart R. Birtle A. Choudhury A. et al.Advancing radiotherapy for bladder cancer: Randomised Phase II Trial of Adaptive Image-guided Standard or Dose-escalated Tumour Boost Radiotherapy (RAIDER).Clin Oncol. 2021; 33: e251-e256Abstract Full Text Full Text PDF Scopus (1) Google Scholar], will deliver further improvement in results. The field is unlikely to stand still, with the use of magnetic resonance-guided functional treatment and real-time magnetic resonance-guided radiotherapy being especially exciting [[11]Hunt A. Hanson I. Dunlop A. Barnes H. Bower L. Chick J. et al.Feasibility of magnetic resonance guided radiotherapy for the treatment of bladder cancer.Clin Transl Radiat Oncol. 2020; 25: 46-51Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,[12]Hunt A. Hansen V.N. Oelfke U. Nill S. Hafeez S. Adaptive radiotherapy enabled by MRI guidance.Clin Oncol. 2018; 30: 711-719Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]. The acid question is how does radiotherapy compare with radical cystectomy in the management of MIBC? This is a very difficult question to answer, with multiple selection, stage migration and other biases between series of radiotherapy and surgery patients. It is regrettable that the one recent randomised trial failed to recruit, even though the limited data showed little difference in outcomes [[13]Huddart R.A. Birtle A. Maynard L. Beresford M. Blazeby J. Donovan J. et al.Clinical and patient-reported outcomes of SPARE – a randomised feasibility study of selective bladder preservation versus radical cystectomy.BJU Int. 2017; 120: 639-650Crossref PubMed Scopus (67) Google Scholar]. Radiotherapy has much to commend it; avoidance of a major operation, retention of the native bladder and likely preservation of erectile function, although treatment delivery can lead to a decline in health-related quality of life and does require continued careful follow-up of the bladder. As reviewed by Appleyard and Nikapota [[14]Appleyard S.E. Nikapota A.D. Patient-reported outcomes and health-related quality of life following radiotherapy for bladder cancer.Clin Oncol. 2021; 33: 400-406Abstract Full Text Full Text PDF Scopus (1) Google Scholar], most bladder radiotherapy survivors maintain or improve their quality of life. The limited comparative data seem to point to this being better than after cystectomy. Due to the biases described above comparing oncological outcomes from retrospective studies, case series and population-based studies are fraught with difficulties and yield mixed results. Although some appear to favour surgery, when biases are taken into account overall data show little difference between the two modalities, which is interesting, as much of the radiotherapy data come from a pre-chemoradiotherapy/image-guided era. Indeed, one recent meta-analysis of published series of reported studies comparing ‘trimodality therapy’ and surgery suggested superior outcomes from trimodality therapy [[15]Arcangeli G. Strigari L. Arcangeli S. Radical cystectomy versus organ-sparing trimodality treatment in muscle-invasive bladder cancer: a systematic review of clinical trials.Crit Rev Oncol Hematol. 2015; 95: 387-396Crossref PubMed Scopus (76) Google Scholar]. An intriguing comparison can be made with the management of anal cancer (Table 1). As a result of a number of studies of chemoradiotherapy in the 1990s, including the ‘ACT’ trials [[16]Northover J. Glynne-Jones R. Sebag-Montefiore D. James R. Meadows H. Wan S. et al.Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I).Br J Cancer. 2010; 102: 1123-1128Crossref PubMed Scopus (244) Google Scholar], this treatment has largely replaced surgery. Chemoradiotherapy with the same chemotherapy schedule achieves similar results in bladder cancer; so this raises the question as to why has chemoradiotherapy not had the same impact in bladder cancer?Table 1Comparison of outcomes of anal and bladder cancer with chemoradiotherapyAnal cancerBladder cancerKey studyACT 1BC2001Treatment5-fluorouracil and mitomycin CRadiotherapy 60 Gy/31 fractions5-fluorouracil and mitomycin CRadiotherapy 64 Gy/32 fractionsLocoregional failure∼29%33% (any recurrence)18% (invasive recurrence)Overall survival58%50%Salvage/alternative treatmentAbdomino-perineal resection/colostomyCysto/prostatectomyIleostomyReference[[16]Northover J. Glynne-Jones R. Sebag-Montefiore D. James R. Meadows H. Wan S. et al.Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I).Br J Cancer. 2010; 102: 1123-1128Crossref PubMed Scopus (244) Google Scholar][[3]James N.D. Hussain S.A. Hall E. Jenkins P. Tremlett J. Rawlings C. et al.Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer.N Engl J Med. 2012; 366: 1477-1488Crossref PubMed Scopus (531) Google Scholar] Open table in a new tab The assumption of the primacy of radical cystectomy in the management of MIBC is entrenched within both urologists and oncologists managing bladder cancer and is frequently not questioned. But, as outlined by Costin and Makaroff [[17]Costin M. Makaroff L. Bladder preservation with radiotherapy: the patient perspective.Clin Oncol. 2021; 33: 346-349Abstract Full Text Full Text PDF Scopus (1) Google Scholar], we need to listen to our patients; recognise this is a complex decision, ensure they have the full information of the options and support them with a multidisciplinary team. In the end, if eligible for both treatments, the ultimate decision should be left to the individual, as this will probably lead to a satisfied patient. The question regarding the choice of surgery or radiotherapy could be rationally answered if we had predictive biomarkers of good or poor outcomes from surgery or radiotherapy. At one stage the use of MRE11 looked promising in this context, but it has not stood up to more detailed scrutiny [[18]Walker A.K. Karaszi K. Valentine H. Strauss V.Y. Choudhury A. McGill S. et al.MRE11 as a predictive biomarker of outcome after radiation therapy in bladder cancer.Int J Radiat Oncol Biol Phys. 2019; 104: 809-818Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. In this special issue, Solanki and colleagues [[19]Solanki A.A. Venkatesulu B.P. Efasthiou J.A. Will the use of biomarkers improve bladder cancer radiotherapy delivery?.Clin Oncol. 2021; 33: e264-e273Abstract Full Text Full Text PDF Scopus (2) Google Scholar] look critically at this issue, with the conclusion that although there are interesting avenues to explore we are not yet there and need to make progress in this area. Much focus has been on either radiotherapy (or trimodality therapy) or cystectomy. However, for a proportion of patients with locally advanced tumours, Baumann et al. [[20]Baumann B.C. Zaghloul M.S. Sargos P. Murthy V. Adjuvant and neoadjuvant radiation therapy for locally advanced bladder cancer.Clin Oncol. 2021; 33: 391-399Abstract Full Text Full Text PDF Scopus (2) Google Scholar] ask the question as to whether, on the basis of a ground-breaking Egyptian trial, the choice should be both modalities acting in tandem. This raises a serious question as to how best to select such patients. One area where there is a clear role for radiotherapy is the often-neglected area of those hard to treat elderly and/or frail patients who are not fit enough for the rigours of conventional treatment. As reviewed by Slevin and Henry [[21]Slevin F. Henry A.M. Muscle-invasive bladder cancer in the elderly patient with a focus on hypofractionated radiotherapy.Clin Oncol. 2021; 33: 369-375Abstract Full Text Full Text PDF Scopus (1) Google Scholar], their needs may be met by ultra-hypofractionated radiotherapy, especially, as suggested in the recent HYBRID trial, if combined with adaptive treatment. Overall, the future looks bright for radiotherapy. There is scope for further technical improvements with the advent of magnetic resonance-guided daily adaptive radiotherapy being particularly promising. There is promise of further refinement of hypoxia manipulation [[1]Lodhi T. Song Y.P. West C. Hoskin P. Choudhury A. Hypoxia and its modification in bladder cancer: current and future perspectives.Clin Oncol. 2021; 33: 376-390Abstract Full Text Full Text PDF Scopus (1) Google Scholar] and, as discussed by Wilkins and colleagues [[22]Wilkins A. Ost P. Sundahl N. Is there a benefit of combining immunotherapy and radiotherapy in bladder cancer?.Clin Oncol. 2021; 33: 407-414Abstract Full Text Full Text PDF Scopus (1) Google Scholar], great potential for immunotherapy to improve results. A key for this brighter future is to ensure that evidence-based improvements are translated into routine clinical practice. As discussed by Varughese [[23]Varughese M. Overcoming the chasm between evidence and routine practice for bladder cancer; just a quixotic notion?.Clin Oncol. 2021; 33: e274-e284Abstract Full Text Full Text PDF Scopus (1) Google Scholar] it remains disappointing that despite the solid evidence, even today patients are not being offered neoadjuvant chemotherapy and radiosensitiser treatment. Closing this gap has to be a priority for now. If we can achieve this, we can say Cinderella is dressed and, yes, she can go to the ball. R.A. Huddart is chief investigator of BC2001, HYBRID, RAIDER and RE-ARM clinical trials. His host institution is a member of the Elekta MR Linac consortium. R.A. Huddart acknowledges the support of the Institute of Cancer Research and Royal Marsden Foundation Trust NIHR Biomedical Research Centre .