Primary Endpoint Analysis of a Randomized Phase III Trial of Hypofractionated vs. Conventional Post-Prostatectomy Radiotherapy: NRG Oncology GU003

Abstract

The sole benefit of internal mammary area irradiation (IMNI) on treatment outcome is unknown. We examined whether the inclusion of IMNI in regional nodal irradiation improved outcomes in women with node-positive breast cancer. Materials/Methods: KROG 08-06 is a multicenter, prospective, randomized phase 3 trial done at 13 hospitals in South Korea. Patients with pathologically confirmed node-positive breast cancer after breast conservation surgery (BCS) or mastectomy with axillary lymph node dissection were eligible. Patients with distant metastasis or those who had neoadjuvant treatment were excluded. All patients underwent regional nodal irradiation along with breast or chest wall irradiation using 3-dimensional conformal radiotherapy with a total dose of 45−54 Gy and fractional dose of 1.8−2.0 Gy. Patients were stratified according to the type of surgery (BCS or mastectomy) and N stage (N1 or N2, N3) and randomly allocated to either IMNI or no IMNI. The primary endpoint was 7-year disease-free survival (DFS). Secondary endpoints were rates of overall survival, breast cancer-specific survival, and toxicity. Results: Between 2008 and 2013, 747 patients were enrolled, of whom 362 patients in IMNI arm and 373 patients in non-IMNI arm were analyzed. Nearly all patients underwent taxane-based adjuvant systemic treatment. At a median follow-up of 8.4 years, 127 patients had breast cancerrelated events and 89 patients died. At 7 years, the DFS rates were 81.9% in non-IMNI arm and 85.3% in IMNI arm (HR, 0.80; 95% CI, 0.57−1.14; P = .220). Subgroup analyses showed significantly improved DFS and breast cancer mortality in IMNI arm among the patients with medio-centrally located tumors. In this subgroup, the 7-year DFS rates were 81.6% without IMNI versus 91.8% with IMNI (HR, 0.42; 95% CI, 0.22−0.82; P = .010) and the 7-year breast cancer mortality rates were 10.2% versus 4.9% (HR, 0.40; 95% CI, 0.17−0.99; P = .048). There were no differences in adverse effects including cardiac toxicity and radiation pneumonitis between treatment arms. Conclusion: Including IMNI in regional nodal irradiation did not significantly improve DFS for unselected women with node-positive breast cancer. Women with medially or centrally located tumors can be considered for applying IMNI when performing regional nodal irradiation.

Moderately hypofractionated salvage radiotherapy in patients with biochemical recurrence of prostate cancer after prostatectomy: long-term results and comparative analysis of two schedules

“…The early NRG-GU003 [48] results reported similar findings. At a median follow up of 2.1 years, the two treatment regimens, the conventional of 66.6 Gy in 37 fractions and the hypofractionated of 62.5 in 25 fractions, did not differ in bFFS, nor in the EPIC scores reported at 6-12 and 24 months, respectively.…”

Quality-of-Life Outcomes and Toxicity Profile Among Patients With Localized Prostate Cancer After Radical Prostatectomy Treated With Stereotactic Body Radiation: The SCIMITAR Multicenter Phase 2 Trial

“…Potential SBRT benefits include leveraging radiobiology (with prostate cancer cells thought to experience greater death with high doses per fraction 18,19 ), increased patient convenience, greater access to care, and lower healthcare costs. [20][21][22][23] While moderately hypofractionated postprostatectomy RT has shown favorable results in several phase II studies and one phase III study, [24][25][26][27][28][29][30][31][32][33][34][35] postprostatectomy SBRT has only been evaluated in two small single-institution phase 1 studies. 36,37 Despite an acceptable toxicity profile, concerns regarding the highly deformable and mobile prostate bed clinical target volume (which is adjacent to the bladder, rectum, and vesicourethal anastomosis), have precluded further study in the phase II setting.…”

A Phase 1 Trial of Highly Conformal, Hypofractionated Postprostatectomy Radiation Therapy

“…This rate of late toxicity is higher than that expected for conventional fractionation; contemporary phase III trials such as SAKK 09/10 [25] and RTOG 0534 [29] report rates of late grade 3+ GU toxicity within the range of 5.3% to 7.9% in patients undergoing post-operative, prostate bed-directed, salvage radiotherapy. The preliminary results of a recent phase III noninferiority trial, NRG GU003, designed to compare the 2-year EPIC-26 QoL scores of a more protracted hypofractionated regimen than in our trial (62.5Gy in 25 fractions) and a conventionally fractionated regimen (66.6Gy in 37 fractions) also showed a possible signal of grade 3 adverse events in the hypofractionated arm with a 4.7% rate of grade 3 cystitis as compared to 0% in the conventionally fractionated arm [12]. The aforementioned trial by Wages et al reported a rate of late grade 3 GU toxicity of 9.4% at 24 months, but were unable to find any statistically significant dosimetric predictors of grade 2+ or grade 3+ GU toxicity on exploratory analysis [27].…”

“…Based on the observation that hypofractionated PORT appears to have a more substantial impact on late grade 3+ GU toxicity as compared to GI toxicity as well as higher rates of GU toxicity as compared to prior conventionally fractionated treatments [12,25], the risk-benefit ratio of the inclusion of various post-prostatectomy anatomic zones in the treatment volume is likely different than in conventionally fractionated radiotherapy. Current CTV recommendations have been reported to inadequately provide coverage of the area posterior to the vesicourethral anastomosis (VUA) [40] and in the posterolateral aspect of the treatment field at the anorectal interface [41].…”

“… 10 This change in the standard of care has improved convenience for patients and has decreased the financial burden of treatment. 11 Although recently presented studies of MHRT have suggested this approach compares favorably to conventional fractionation in regard to post-therapy QoL, 12 a similar shift in the standard of care toward more compressed dose schedules has not yet been widely adopted as the standard of care in the postoperative setting, due to the lack of robust data to establish comparative efficacy and toxicity of such regimens. Due to the low ⍺/β ratio of prostate cancer 13 and higher ⍺/β ratio 14 , 15 , 16 of the surrounding normal tissues, 14 hypofractionated PORT may allow for the compression of the standard postoperative dose schedule without significantly increasing rates of toxicity.…”