ASTRO 2022: Challenging Cases for Bladder Cancer: Treatment Planning and Technique

(UroToday.com) The 2022 ASTRO annual meeting featured a session on managing challenging bladder cancer cases, including a presentation by Dr. Brian Baumann discussing treatment planning and technique. Dr. Baumann notes that there are several controversies in treatment planning, as highlighted by the following:

1. Bladder only versus small pelvic fields versus extended nodal coverage?
2. Whole bladder to full dose versus whole bladder to lower dose and partial bladder boost to full dose?
3. Hypofractionation versus standard fractionation?
4. Online adaptive versus non-adaptive?

Bladder only versus small pelvic fields versus extended nodal coverage?

There is only one single institutional trial from Pakistan that has evaluated nodal radiotherapy versus bladder only radiotherapy.¹ Between March 2005 and May 2006, 230 patients were accrued and patients were randomly assigned to whole-pelvis concurrent chemoradiation (120 patients) and bladder only-concurrent chemoradiation (110 patients). With a median follow-up time of 5 years (range, 3-6), whole-pelvis concurrent chemoradiation was associated with a 5-year disease-free survival of 47.1% compared with 46.9% in patients treated with bladder only-concurrent chemoradiation (p = 0.5). The bladder preservation rates were 58.9% and 57.1% in whole-pelvis concurrent chemoradiation and bladder only-concurrent chemoradiation, respectively (p = 0.8), and the 5-year overall survival rates were 52.9% for whole-pelvis concurrent chemoradiation and 51% for bladder only-concurrent chemoradiation (p = 0.8). Dr. Baumann notes that there are several caveats to this trial: (i) single-institution, (ii) used 3-D conformal radiotherapy so it is unclear if results would apply to more conformal treatment (ie. IMRT), (iii) the Red Journal editors recently issued a “letter of concern” regarding the validity of the study results, and (iv) new data from prostate cancer support elective nodal radiotherapy (POP-RT, SPPORT trials).

Patterns of occult pelvic nodal involvement suggests a potential role for nodal radiotherapy. In a retrospective study of 315 patients with cT1-T4N0 patients after cystectomy, 81 (26%) were noted to be pN+.² Furthermore, lymphovascular invasion was the only factor associated with pN+ disease on multivariable analysis. As follows is the percentage of patients with occult pN+ disease fully encompassed in the treatment field:

Dr. Baumann notes that elective nodal or small pelvic field radiotherapy is very common in the US, with >85% of practitioners indicating that they treat some nodes based on a survey from 2017. Most radiation oncologists treat small pelvic fields to the top of S1. Importantly nodal radiotherapy fields (40 to 45 Gy) are designed to conserve small bowel for urinary diversions should be they be needed. In order to delineate the full pelvic lymph nodes, it is recommended to use the NRG GU nodal contouring atlas, treat to the bifurcation of the aorta (to include the common iliacs ~L4/L5 interspace when desired), and to use IMRT. To recap this section of his talk, Dr. Baumann highlighted the following points:

• There is no consensus on whether to treat small pelvic fields versus full pelvic nodes versus bladder only
• The SWOG/NRG 1806 trial is permissive on this question
• In his practice, Dr. Baumann generally includes the full pelvic nodes to 40-45 Gy for bulky T2 disease, T2 with lymphovascular invasion, or T3-T4 disease

With regards to tumor boost fields, Dr. Baumann notes that it is important to only boost the bladder partially to high dose (total 65 Gy), to incorporate all TURBT and radiographic information, and to simulate and treat an empty bladder. The rationale for tumor boost bladder radiotherapy comes from the BC2001 trial, which was a phase III multicenter trial of 219 patients randomized to standard whole-bladder radiation therapy or reduced high-dose volume radiation therapy that aimed to deliver full radiation dose to the tumor and 80% of maximum dose to the uninvolved bladder.³ Overall incidence of late toxicity was less than predicted, with a cumulative 2-year RTOG grade 3/4 toxicity rate of 13% (95% CI 8%, 20%) and no statistically significant differences between groups. The difference in 2-year locoregional recurrence free rate (reduced high-dose volume radiation therapy - standard whole-bladder radiation therapy) was 6.4% (95% CI -7.3%, 16.8%) under an intention to treat analysis and 2.6% (-12.8%, 14.6%) in the "per-protocol" population:

In Dr. Baumann’s practice, for patients with unifocal T2 tumors <5 cm that were completely excised and where he’s confident he can localize the tumor bed (ie. good pre-TURBT imaging, detailed cystoscopy report describing size/location, or fiducial marker placement), he will treat with partial bladder boost using generous margins. His goal is (1) reduce dose to the small bowel and (2) reduce the bladder volume receiving the full dose. With regards to delineating the tumor boost, an empty bladder is preferable for simulation and recreating the pre-TURBT GTV based on all available data. Additionally, it is important to expand by 1-2 cm to account for subclinical extension to generate tumor bed clinical target volume. When in doubt, err on the side of being more inclusive with the boost clinical tumor volume.

The rationale for hypofractionated bladder radiotherapy comes from a Lancet Oncology meta-analysis that showed improved locoregional control at 2 years with no significant difference in late toxicity for 55 Gy in 20 fractions versus standard fractionation, pooling results from BC2001 and BCON trials:⁴

This is the best available data comparing dose/fractionation schemes, however the caveats are that it was an unplanned secondary analysis, and selection bias could affect the results. Dr. Baumann’s interpretation is that hypofractionation appears to be at least as good as standard fractionation for cancer control, but not necessarily better. Additionally, perhaps there may be concerns with hypofractionated chemoradiotherapy + immunotherapy.

For population-based expansions for inter/intra fraction motion, it is important to do an empty bladder simulation, CTV to ITV expansion of 0.5-1.2 cm superior/anterior and 0.5-0.7 cm in all other directions, cropping out bone and muscle. Additionally, ITV to PTV expansion should be 0.5 cm. The rationale for online adaptive bladder radiotherapy is secondary to considerable inter-fraction and intra-fraction motion of the bladder, even when treating an empty bladder. There are several inter-fraction motion mitigation strategies:

1. Offline – composite volume method using initial CBCTs from the first few fractions to modify the ITV
2. Online – plan of the day approach; online adaptive treatment with daily replanning

The ARTIA Bladder Trial will assess hypofractionated radiotherapy with daily online adaptive treatment using a CT-based adaptive planning platform. The uninvolved whole bladder will be treated to 46 Gy in 20 fractions with simultaneous in-field boost to 55 Gy in 20 fractions to the tumor bed, or whole bladder treatment to 55 Gy. The primary endpoint will be acute grade >=3 GI/GU toxicity versus historical controls.

 Dr. Baumann’s approach is standard fractionation contouring with partial bladder boost. This includes 45 Gy to the pelvic nodes and whole bladder, 50.4 Gy to the whole bladder, 64.8 Gy to the tumor bed + at least 1 cm margin for clinical target volume, ITV expansion of 1.0-1.2 cm superior/anterior and 0.5-0.7 cm in all other directions, and PTV expansion of 0.5 cm. The crucial organ at risk during therapy is the small bowel and the dose constraint for SWOG/NRG 1806 (standard fraction) is D0.03 cc <= 57 Gy and V50 Gy < 20 cc. In his practice, Dr. Baumann will allow a few cc’s to get full dose but try and prevent full thickness small bowel loops from getting the full dose. Bowel that is likely to move can handle a higher dose than fixed bowel.

Dr. Baumann concluded his presentation discussing treatment planning and technique for challenging bladder cancer cases with the following take home messages:

• There is no clear consensus approach on elective nodal radiation, tumor boost, or hypofractionation
• Motion mitigation strategies are important

Presented by: Brian C. Baumann, MD, Washington University, St. Louis, MO

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Radiation Oncology (ASTRO) Annual Hybrid Meeting, San Antonio, TX, Sat, Oct 22 – Wed, Oct 26, 2022.

References:

1. Tunio MA, Hashmi A, Qayyum A, et al. Whole-pelvis or bladder-only chemoradiation for lymph node invasive bladder cancer: Single-institution experience. Int J Radiat Oncol Biol Phys. 2012;82(3):e457-462.
2. Goldsmith B, Baumann BC, He J, et al. Occult pelvic lymph node involvement in bladder cancer: Implications for definitive radiation. Int J Radiat Oncol Biol Phys. 2014;88(3):603-610.
3. Huddart RA, Hall E, Hussain SA, et al. Randomized noninferiority trial of reduced high-dose volume versus standard volume radiation therapy for muscle-invasive bladder cancer: Results of BC2001 trial (CRUK/01/004). Int J Radiat Oncol Biol Phys. 2013;87(2):261-269.
4. Choudhury A, Porta N, Hall E, 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(2):246-255.