Is moderate hypofractionation accepted as a new standard of care in north america for prostate cancer patients treated with external beam radiotherapy? Survey of genitourinary expert radiation oncologists

McClelland, Shearwood; Sandler, Kiri A.; Degnin, Catherine; Chen, Yiyi; Hung, Arthur Y.; Mitin, Timur

doi:10.1590/S1677-5538.IBJU.2018.0275

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Original Article • IBJUInt. braz j urol 45 (2) • 2019 • https://doi.org/10.1590/S1677-5538.IBJU.2018.0275 copy

Is moderate hypofractionation accepted as a new standard of care in north america for prostate cancer patients treated with external beam radiotherapy? Survey of genitourinary expert radiation oncologists

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Introduction:

Several recent randomized clinical trials have evaluated hypofractionated regimens against conventionally fractionated EBRT and shown similar effectiveness with conflicting toxicity results. The current view regarding hypofractionation compared to conventional EBRT among North American genitourinary experts for management of prostate cancer has not been investigated.

Materials and Methods:

A survey was distributed to 88 practicing North American GU physicians serving on decision - making committees of cooperative group research organizations. Questions pertained to opinions regarding the default EBRT dose and fractionation for a hypothetical example of a favorable intermediate - risk prostate cancer (Gleason 3 + 4). Treatment recommendations were correlated with practice patterns using Fisher's exact test.

Results:

Forty - two respondents (48%) completed the survey. We excluded from analysis two respondents who selected radical hypofractionation with 5 – 12 fractions as a preferred treatment modality. Among the 40 analyzed respondents, 23 (57.5%) recommend conventional fractionation and 17 (42.5%) recommended moderate hypofractionation. No demographic factors were found to be associated with preference for a fractionation regimen. Support for brachytherapy as a first choice treatment modality for low - risk prostate cancer was borderline significantly associated with support for moderate hypofractionated EBRT treatment modality (p = 0.089).

Conclusions:

There is an almost equal split among North American GU expert radiation oncologists regarding the appropriateness to consider moderately hypofractionated EBRT as a new standard of care in management of patients with prostate cancer. Physicians who embrace brachytherapy may be more inclined to support moderate hypofractionated regimen for EBRT. It is unclear whether reports with longer follow-ups will impact this balance, or whether national care and reimbursement policies will drive the clinical decisions. In the day and age of patient - centered care delivery, patients should receive an objective recommendation based on available clinical evidence. The stark division among GU experts may influence the design of future clinical trials utilizing EBRT for patients with prostate cancer.

Keywords:
Prostatic Neoplasms; Dose Hypofractionation; Neoplasm Grading

Trial	Hypofractionation regimen	Follow-up duration	Location	Differences in OS or DFS	Differences in GU toxicity between modalities	Differences in GI toxicity between modalities
RTOG 0415 (⁷7. Lee WR, Dignam JJ, Amin MB, Bruner DW, Low D, Swanson GP, et al. Randomized Phase III Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk Prostate Cancer. J Clin Oncol. 2016;34:2325-32.)	2.5 Gy x 28	5 years	USA	No	No (late GU trended toward favoring C-RT: p=0.06)	Yes (late GI: p=0.002 favored C-RT)
CHHiP (⁸8. Dearnaley D, Syndikus I, Mossop H, Khoo V, Birtle A, Bloomfield D, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17:1047-60. Erratum in: Lancet Oncol. 2016;17:e321.)	3 Gy x 20; 3 Gy x 19	5 years	UK, Ireland, Switzerland, New Zealand	No	No	Yes (acutely favoring C-RT; none by week 18)
PROFIT (⁶6. Catton CN, Lukka H, Gu CS, Martin JM, Supiot S, Chung PWM, et al. Randomized Trial of a Hypofractionated Radiation Regimen for the Treatment of Localized Prostate Cancer. J Clin Oncol. 2017;35:1884-90.)	3 Gy x 20	5 years	Canada, Australia, France	No	No (acutely; late toxicity favored H-RT)	No (acutely; late toxicity favored H-RT)
HYPRO (⁹9. Incrocci L, Wortel RC, Alemayehu WG, Aluwini S, Schimmel E, Krol S, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17:1061-9. 10. Aluwini S, Pos F, Schimmel E, van Lin E, Krol S, van der Toorn PP, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): acute toxicity results from a randomised non-inferiority phase 3 trial. Lancet Oncol. 2015;16:274-83. Erratum in: Lancet Oncol. 2015;16:e105.-¹¹11. Aluwini S, Pos F, Schimmel E, Krol S, van der Toorn PP, de Jager H, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2016;17:464-74.)	3.4 Gy x 19	5 years	Netherlands	No	Yes (H-RT inferior for acute and late grade 3+ toxicity)	Yes (H-RT inferior for acute but not late grade 3+ toxicity)

Trial	GU toxicity (H-RT)	GU toxicity (C-RT)	GI toxicity (H-RT)	GI toxicity (C-RT)	Disease control (H-RT)	Disease control (C-RT)
RTOG 0415 (⁷7. Lee WR, Dignam JJ, Amin MB, Bruner DW, Low D, Swanson GP, et al. Randomized Phase III Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk Prostate Cancer. J Clin Oncol. 2016;34:2325-32.)	Early grade 2-4 GU = 147/545 Late grade 2-4 GU = 161/545	Early grade 2-4 GU = 145/534 Late grade 2-4 GU = 121/534	Early grade 2-4 GI = 58/545 Late grade 2-4 GI = 121/545	Early grade 2-4 GI = 55/534 Late grade 2-4 GI = 75/534	86.3% DFS (95% CI: 83.1-89.0)	85.3% DFS (95% CI: 81.9-88.1)
CHHiP (⁸8. Dearnaley D, Syndikus I, Mossop H, Khoo V, Birtle A, Bloomfield D, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17:1047-60. Erratum in: Lancet Oncol. 2016;17:e321.)	Early grade 2-4 GU = 46-49% Late grade 2-4 GU = 6.6-11.7%	Early grade 2-4 GU = 46% Late grade 2-4 GU = 9.1%	Early grade 2-4 GI = 38% Late grade 2-4 GI = 11.3-11.9%	Early grade 2-4 GI = 25% Late grade 2-4 GI = 13.7%	85.9-90.6% biochemical/clinical failure freedom	88.3% biochemical/clinical failure freedom
PROFIT (⁶6. Catton CN, Lukka H, Gu CS, Martin JM, Supiot S, Chung PWM, et al. Randomized Trial of a Hypofractionated Radiation Regimen for the Treatment of Localized Prostate Cancer. J Clin Oncol. 2017;35:1884-90.)	Early grade 2-4 GU = 185/608 Late grade 2-4 GU = 136/608	Early grade 2-4 GU = 183/598 Late grade 3-4 GU = 134/598	Early grade 2-4 GI = 99/608 Late grade 2-4 GI = 54/608	Early grade 2-4 GI = 62/598 Late grade 2-4 GI = 83/598	85% DFS	85% DFS
HYPRO (⁹9. Incrocci L, Wortel RC, Alemayehu WG, Aluwini S, Schimmel E, Krol S, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17:1061-9. 10. Aluwini S, Pos F, Schimmel E, van Lin E, Krol S, van der Toorn PP, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): acute toxicity results from a randomised non-inferiority phase 3 trial. Lancet Oncol. 2015;16:274-83. Erratum in: Lancet Oncol. 2015;16:e105.-¹¹11. Aluwini S, Pos F, Schimmel E, Krol S, van der Toorn PP, de Jager H, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2016;17:464-74.)	Early grade 2-4 GU = 75/410 Late grade 2-4 GU at three years = 163/395	Early grade 2-4 GU = 73/410 Late grade 3-4 GU at three years = 151/387	Early grade 2-4 GI = 42/410 Late grade 2-4 GI at three years = 86/395	Early grade 2-4 GI = 43/410 Late grade 2-4 GI at three years = 68/387	80.5% five-year RFS (95% CI: 75.7-84.4)	77.1% five-year RFS (95% CI: 71.9-81.5)

Clinical Scenario	Clinical Practice Recommendation	Conventional Fractionation (78 Gy in 2 Gy fractions, 79.2 Gy in 1.8 Gy fractions, or equivalent)	Moderate Hypofractionation (70 Gy in 2.5 Gy fractions or equivalent)	P value
Active surveillance recommendation for Gleason 6 disease	Yes	21 (91.3%)	17 (100%)	0.546
	No	2 (8.7%)	0 (0%)
Active surveillance recommendation for Gleason 3+4 disease	Yes	3 (13.0%)	4 (23.5%)	0.607
	No	20 (87.0%)	13 (76.5%)
SBRT for oligometastatic lesions	Yes	18 (78.3%)	12 (70.6%)	0.837
	No	5 (21.7%)	5 (29.4%)
Treatment of pelvic lymph nodes in localized high-risk prostate cancer	Rarely	9 (39.1%)	4 (23.5%)	0.377
	Often	14 (60.9%)	13 (76.5%)
Treatment of high-risk prostate cancer	EBRT+ADT	15 (65.2%)	7 (41.2%)	0.305
	EBRT+ADT+ brachytherapy boost	8 (34.8%)	10 (58.8%)
Believer in advanced-imaging (Novel ligand-based PET imaging)	Yes	14 (60.9%)	14 (82.4%)	0.137
	No	9 (39.1%)	2 (11.8%)
First choice for treatment of Gleason 6 disease who desires intervention	Brachytherapy	8 (34.8%)	12 (70.6%)	0.089
	EBRT	5 (21.7%)	1 (5.9%)
	No preference	10 (43.5%)	4 (23.5%)

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[1] Correspondence address: Timur Mitin, MD, PhD Department of Radiation Medicine Oregon Health & Science University 3181 SW Sam Jackson Park Rd, L337 Portland, OR, 97239-3098, U.S.A Fax: +1 503 346-0237 E-mail: mitin@ohsu.edu