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A Review of Adaptive Radiotherapy for Bladder Cancer - Beyond the Abstract

Trimodal therapy (TMT), consisting of maximal transurethral resection of the bladder tumor (TURBT) and radiation therapy (RT) with concurrent chemotherapy is a well-established alternative to radical cystectomy, considered as the gold standard for the treatment of patients with non-metastatic muscle-invasive bladder cancer (MIBC).1 TMT offers the advantage of bladder preservation, a good toxicity profile, and has demonstrated survival outcomes that are comparable to those of radical cystectomy in a well-selected MIBC population, with 5-year overall survival ranging from 57% to 66%.2,3 However, RT for MIBC is technically challenging due to significant variations in bladder position, volume, and shape, both between each fraction (inter-fraction) and within a fraction (intra-fraction), resulting in inappropriate coverage of the target volumes, and/or increased dose to the organs at risk (OARs). These movement shifts can reach up to 2 cm, justifying the historical use of large planning target volume (PTV) margins in MIBC RT planning, often up to 2.5-3 cm, and potentially resulting in an increase in toxicity rates.4 To circumvent such a challenge, the concept of adaptive radiotherapy (ART) has been introduced. ART is the process by which a treatment plan can be individually modified for each patient, based on geometric variations of the target and OARs during treatment. With ART, target volume coverage and healthy tissue sparing could lead to better tumor control and reduced toxicity compared to the standard strategy. 


In this paper, Cabaille et al. did a thorough critical review of the literature on the use of ART in the treatment of localized MIBC. The purpose of the review was to define the different ART techniques used in clinical practice, to discuss their advantages compared to conventional RT in terms of target volume’s coverage and OAR dose, and to describe their feasibility in clinical practice.

The authors identified different strategies of ART, divided between off-line techniques and online techniques such as individualized or non-individualized “plan of the day (PoD)” and daily “re-optimization”. All the studies showed a significant benefit of ART compared to conventional RT in terms of target coverage with up to 46% reduction in planning target volume (PTV), and reduction of dose to the OARs. Intensity-modulated radiation therapy (IMRT) is identified as the treatment modality of choice. Clinical implementation of ART can however be onerous in terms of staff training, time required for planning, and technologies used for image guidance. Thus, the implementation of a training program is associated with a continual assessment to improve the radiographer-led plan selection and reduce the inter-observer variability in plan selection.

There are not many studies comparing the different techniques of ART in terms of dosimetric advantages and clinical outcomes; thus, the jury is still out as to which technique is the best. Daily re-optimization, consisting of replanning before treatment delivery based on the anatomy of the day, has been shown to be superior to PoD or standard RT in terms of target coverage and sparing of the OARs.5,6 However, the challenging logistical aspects of daily re-optimization may hinder its widespread implementation in all radiation oncology practices. Taking this into account, Cabaille et al. suggest that the PoD technique based on the a-POLO (adaptive-predictive organ localization) method, may be most suitable for clinical practice as it offers a better compromise between dosimetric efficacy and logistical implementation. In this method, a library of three plans (small, medium, large) is generated using simulation scans acquired at 0 and 30 minutes post-void, to which pre-defined anisotropic margins are added based on the patient’s bladder filling rates.

The use of hypofractionated RT (>2.5Gy/fractions) is becoming standard in the treatment of MIBC by TMT with trials showing its efficacy.7 The use of ART in hypofractionated RT delivery is very appealing because higher doses per fraction are delivered to the bladder and avoidance of any geographical misses is even more important to avoid pelvic toxicities. Using a PoD approach, McDonald et al.8 tested the implementation of ART in a cohort of 25 patients with MIBC treated with hypofractionated RT. They showed excellent plan selection concordance of 91%, coverage of the clinical target volume by the 95% isodose of 99%, and reduction in the volume of irradiated normal tissue compared to the standard approach.8 In a Phase II trial of adaptive weekly hypofractionated RT for 55 MIBC patients, Hafeez et al.9 used a PoD approach to treat the bladder with ultra-hypofractionated (36 Gy/6 weekly fractions). They reported an excellent local control rate of 92% and an acceptable toxicity profile with acute grade 3 genitourinary and gastrointestinal toxicities of 18% and 4% respectively, and late Grade ≥3 toxicity of 4.3% at 3 months.9 Recently, Huddart et al.10 randomized 65 patients with MIBC not suitable for radical RT to 36 Gy/6 fractions, either by a standard planning technique or an adaptive PoD technique. The local control rate at 3 months was 81.3% and the treatment was overall well tolerated. However, there was no statistically significant difference between the two planning groups for different patient-reported quality of life outcomes,10 suggesting that ART does not confer significant benefits in this specific patient population. The results from the Phase II RAIDER trial (NCT02447549) randomizing MIBC patients to either standard whole bladder RT, standard dose ART or dose-escalated ART, are eagerly awaited to shed more light on the clinical benefits of ART and which MIBC patient subgroups would benefit the most from it.

In conclusion, ART is the technique of choice for bladder cancer RT and specifically for definitive hypofractionated RT. The “plan of the day” approach, individualized according to the A-POLO methodology, seems to offer the best compromise between dosimetric efficacy and logistical implementation. However, the emergence of daily re-optimization, especially using MRI-Linac image-guided RT, is promising and more randomized clinical trials are anticipated to correlate dosimetric benefits with clinical efficacy and safety outcomes.

Written by: Mame Daro Faye, MD, PhD, Twitter: @MDFaye31, and Paul Sargos, MD, Twitter: @PaulSargos2

  1. Department of Radiation Oncology, McGill University, Montreal, Canada
  2. Departement de Radiotherapie, Institut Bergonié, 33076 Bordeaux Cedex

References:

  1. Kulkarni, Girish S., Peter C. Black, Srikala S. Sridhar, Anil Kapoor, Alexandre R. Zlotta, Bobby Shayegan, Ricardo A. Rendon et al. "Canadian Urological Association guideline: Muscle-invasive bladder cancer." Canadian Urological Association Journal 13, no. 8 (2019): 230.
  2. Efstathiou, Jason A., Daphna Y. Spiegel, William U. Shipley, Niall M. Heney, Donald S. Kaufman, Andrzej Niemierko, John J. Coen et al. "Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience." European urology 61, no. 4 (2012): 705-711.
  3. 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.
  4. Lotz, Heidi T., Marcel van Herk, Anja Betgen, Floris Pos, Joos V. Lebesque, and Peter Remeijer. "Reproducibility of the bladder shape and bladder shape changes during filling." Medical physics 32, no. 8 (2005): 2590-2597.
  5. Vestergaard, Anne, Ludvig Paul Muren, Jimmi Søndergaard, Ulrik Vindelev Elstrøm, Morten Høyer, and Jørgen B. Petersen. "Adaptive plan selection vs. re-optimisation in radiotherapy for bladder cancer: a dose accumulation comparison." Radiotherapy and Oncology 109, no. 3 (2013): 457-462.
  6. Kong, Vickie C., Amy Taylor, Peter Chung, Tim Craig, and Tara Rosewall. "Comparison of 3 image-guided adaptive strategies for bladder locoregional radiotherapy." Medical dosimetry 44, no. 2 (2019): 111-116.
  7. Amestoy, Frédéric, Guilhem Roubaud, Mikaël Antoine, Valérie Fonteyne, Brian C. Baumann, John Christodouleas, Morgan Roupret et al. "Review of hypo-fractionated radiotherapy for localized muscle invasive bladder cancer." Critical reviews in oncology/hematology 142 (2019): 76-85.
  8. McDonald, F., S. Lalondrelle, H. Taylor, K. Warren-Oseni, V. Khoo, H. A. McNair, V. Harris et al. "Clinical implementation of adaptive hypofractionated bladder radiotherapy for improvement in normal tissue irradiation." Clinical Oncology 25, no. 9 (2013): 549-556.
  9. Hafeez, Shaista, Fiona McDonald, Susan Lalondrelle, Helen McNair, Karole Warren-Oseni, Kelly Jones, Victoria Harris et al. "Clinical outcomes of image guided adaptive hypofractionated weekly radiation therapy for bladder cancer in patients unsuitable for radical treatment." International Journal of Radiation Oncology* Biology* Physics 98, no. 1 (2017): 115-122.
  10. Huddart, Robert, Shaista Hafeez, Rebecca Lewis, Helen McNair, Isabelle Syndikus, Ann Henry, John Staffurth et al. "Clinical outcomes of a randomised trial of adaptive plan of the day treatment in patients receiving ultra-hypofractionated weekly radiotherapy for bladder cancer." International Journal of Radiation Oncology* Biology* Physics (2020).

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