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Safety of accelerated hypofractionated whole pelvis radiation therapy prior to high dose rate brachytherapy or stereotactic body radiation therapy prostate boost

Safety of accelerated hypofractionated whole pelvis radiation therapy prior to high dose rate... Background: To evaluate acute and late genitourinary and gastrointestinal toxicities and patient reported urinary and sexual function following accelerated, hypofractionated external beam radiotherapy to the prostate, seminal vesi‑ cles and pelvic lymph nodes and high dose rate (HDR) brachytherapy or stereotactic body radiation therapy (SBRT ) prostate boost. Methods: Patients at a single institution with NCCN intermediate‑ and high‑risk localized prostate cancer with logis‑ tical barriers to completing five weeks of whole pelvic radiotherapy ( WPRT ) were retrospectively reviewed for toxicity following accelerated, hypofractionated WPRT (41.25 Gy in 15 fractions of 2.75 Gy). Patients also received prostate boost radiotherapy with either HDR brachytherapy (1 fraction of 15 Gy) or SBRT (19 Gy in 2 fractions of 9.5 Gy). The duration of androgen deprivation therapy was at the discretion of the treating radiation oncologist. Toxicity was evaluated by NCI CTCAE v 5.0. Results: Between 2015 and 2017, 22 patients with a median age of 71 years completed accelerated, hypofrac‑ tionated WPRT. Median follow‑up from the end of radiotherapy was 32 months (range 2–57). 5%, 73%, and 23% of patients had clinical T1, T2, and T3 disease, respectively. 86% of tumors were Gleason grade 7 and 14% were Gleason grade 9. 68% and 32% of patients had NCCN intermediate‑ and high‑risk disease, respectively. 91% and 9% of patients received HDR brachytherapy and SBRT prostate boost following WPRT, respectively. Crude rates of grade 2 or higher GI and GU toxicities were 23% and 23%, respectively. 3 patients (14%) had late or persistent grade 2 toxicities of urinary frequency and 1 patient (5%) had late or persistent GI toxicity of diarrhea. No patient experienced grade 3 or higher toxicity at any time. No difference in patient ‑reported urinary or sexual function was noted at 12 months. Conclusions: Accelerated, hypofractionated whole pelvis radiotherapy was associated with acceptable GU and GI toxicities and should be further validated for those at risk for harboring occult nodal disease. Keywords: Hypofractionation, Prostate cancer, Nodal radiotherapy, Pelvic radiotherapy, HDR brachytherapy Background Elective pelvic lymph node irradiation has been sug- *Correspondence: ajchang@mednet.ucla.edu gested to improve progression-free survival in unfavora- Christina Phuong and Jason W. Chan contributed equally to this work Department of Radiation Oncology, University of California Los Angeles, ble intermediate- to high-risk prostate cancer [1–3]. A Los Angeles, USA course of conventionally-fractionated pelvic radiotherapy Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Phuong et al. Radiation Oncology (2022) 17:12 Page 2 of 7 for prostate cancer is delivered over a period of approxi- model to be equivalent to a dose of 45 Gy in 1.8 Gy frac- mately 9 weeks, which is inconvenient for elderly patients tions and using an α/β value of 3 for prostate cancer. and patients traveling long distances. With implemen- The elective pelvic nodal treatment volume included tation of the Radiation Oncology Alternative Payment the obturator, external iliac, proximal internal iliac, and Model, greater emphasis is placed on cost-effectiveness common iliac nodes up to the level corresponding to the with more abbreviated treatments to increase access to L4–L5 interspace. The presacral nodes from L5-S1 to S3 care. Furthermore, hypofractionated radiotherapy may were included. The inferior extent of the external iliac result in a greater therapeutic ratio for prostate cancer nodes was at the top of the femoral heads and the infe- resulting in greater efficacy than conventional fractiona - rior extent of the obturator lymph nodes was at the top tion as suggested by the linear quadratic model with a of the symphysis pubis. A 5–7  mm PTV margin around low α/β ratio of 1.5–3. the pelvic nodal CTV was used. 2.75  Gy per fraction With improvements in the precision of radiation deliv- was used as it was previously used to target the prostate ery, several studies have supported the use of moderate alone to 55  Gy with comparable toxicity with standard hypofractionation (240–340 cGy) directed to the prostate fractionation schemes [8]. Intensity modulated radiation with favorable toxicity profiles [4–6]. In these studies, therapy with daily image guidance was performed using the clinical target volume consisted of the prostate with both cone beam computed tomography with alignment or without the seminal vesicles and pelvic lymph nodes to bony anatomy and prostate fiducial markers. were not treated. Limited data is available evaluating the safety and efficacy of hypofractionated pelvic nodal Boost treatment to prostate and seminal vesicles radiotherapy. Radiation to the prostate and seminal vesicles was deliv- The goal of this study was to evaluate the feasibility in ered as a sequential boost treatment within 14 days after terms of clinical outcome and toxicity of a hypofraction- pelvic radiotherapy portion was completed. The insti - ated regimen with inclusion of prostate, seminal vesicles, tutional practice was to offer 15  Gy in one fraction with and pelvic lymph node irradiation for the treatment of high dose rate brachytherapy. Patients who refused or intermediate- and high-risk prostate cancer in patients were not candidates for brachytherapy were offered boost with logistical barriers to completing a course of conven- treatment with stereotactic body radiotherapy to a total tionally fractionated pelvic radiotherapy. dose of 19 Gy in 2 fractions of 9.5 Gy. For SBRT, patients were simulated with an empty rectum and empty blad- Methods der due to the limited ability of patients to maintain a Patient selection full bladder through the duration of SBRT treatment. Under approval of our institutional review board (IRB), All patients also underwent an MRI of the pelvis/pros- we performed a retrospective chart abstraction to iden- tate for accurate delineation of the prostate and urethra tify men treated with hypofractionated whole pelvic radi- for treatment planning purposes. SBRT was delivered otherapy (WPRT). All men had histologically confirmed on a Cyberknife machine with daily imaging guidance intermediate- to high-risk prostate adenocarcinoma by using prostate fiducial tracking, including orthogonal NCCN criteria (T1c-T3b N0, PSA > 10, and/or Glea- pair imaging prior to treatment delivery with matching son score ≥ 7) and greater than 15% risk of lymph node to prostate fiducials as well as orthogonal pair imaging involvement by the Roach formula [7]. Patients were during treatment delivery to account for intrafraction offered accelerated, hypofractionated WPRT if there were motion. logistical difficulties with completing five weeks of pelvic radiotherapy, such as lack of transportation or nearby Follow‑up housing. Patients were not offered accelerated, hypof - After treatment, patients were followed every 3  months ractionated WPRT if they had prior pelvic irradiation, for the initial 2  years, then every 6  months up to year 5, prostate brachytherapy, history of inflammatory bowel and annually thereafter with prostate specific antigen disease or major bowel surgery, or prior transurethral (PSA) testing. At each follow-up visit, patients com- resection of the prostate (TURP) procedure. Patients also pleted IPSS and SHIM QOL questionnaires. Toxicity was received androgen deprivation therapy (ADT) at the dis- assessed according to the Common Terminology Criteria cretion of the treating radiation oncologist. for Adverse Events (CTCAE) v5.0. Whole pelvis radiation Statistical analysis The hypofractionated dose of 41.25 Gy in 15 fractions of Descriptive analysis was performed using median and 2.75  Gy to the elective pelvic nodes, prostate, and semi- interquartile values for continuous variables. Predic- nal vesicles was selected based on the linear-quadratic tive analysis was performed using logistic regression. P huong et al. Radiation Oncology (2022) 17:12 Page 3 of 7 Comparator p-values were reported using a two-sample Table 2 Radiotherapy characteristics two-sided Mann–Whitney U test. P-values of less than Whole Pelvis IMRT 0.05 were considered to be significant. 41.25 Gy in 15 fractions 22 (100%) Boost HDR 15 Gy in one fraction 20 (91%) Results SBRT 19 Gy in two fractions 2 (9%) Patient and tumor characteristics ADT Among 22 patients, the median age was 71 (Table  1). None 1 (5%) One (5%), 16 (73%), and 5 (23%) of patients had had 4 months 19 (86%) clinical T1, T2, and T3 disease, respectively. 19 (86%) 6 months 1 (5%) of tumors were Gleason grade 7 and 3 (14%) were Glea- 12 months 1 (5%) son grade 9. According to NCCN risk stratification, 13 (59%), 7 (32%), and 2 (9%) of patients had intermedi- ate-, high-, and very high-risk disease, respectively. 21 Whole pelvis radiotherapy parameters patients (95%) patients received androgen deprivation Dose-volume characteristics of hypofractionated therapy (ADT), of whom 19 patients (86%) received a whole pelvis radiotherapy is summarized in Tables  3 total of 4 months. and 4. The median small bowel V44 Gy (54  Gy at 1.8  Gy/fx) was 0  cc (IQR 0–0.01  cc) and median small bowel V32.4  Gy (40  Gy at 1.8  Gy/fx) was 156  cc (IQR Radiotherapy characteristics 100–216  cc). The median bladder V37.8  Gy (45  Gy at All 22 patients received hypofractionated whole pelvic 1.8  Gy/fx) was 29  cc (IQR 20–49  cc) and 17% of the radiotherapy with intensity modulated radiotherapy total bladder volume (IQR 13–21%). The median rec (IMRT) to 41.25  Gy in 15 fractions over three weeks tum V37.8 Gy was 5 cc (IQR 3–9 cc) and 7% of the total (Table  2). 20 (91%) patients received high dose-rate rectal volume (IQR 4–10%). There was no correlation brachytherapy boost with 15 Gy in a single fraction via found between dosimetric parameters and grade ≥ 2 a single perineal implant procedure. 2 (9%) patients GU or GI toxicity. received stereotactic body radiation therapy (SBRT) boost to the prostate with 19  Gy in two fractions on consecutive days. Disease control and toxicity At a median follow-up of 32 months, there were no bio- chemical failures, and the median post-treatment PSA Table 1 Patient characteristics was 0.09 (range 0–1.28). The crude rates of acute grade 2 or higher GI and GU toxicities were 23% and 23% Age (Table  5). These toxicities mostly consisted of urinary Median (IQR) 71 (68–74) frequency, urgency, and diarrhea. The late or persistent T‑Stage (MRI or TRUS) grade 2 or higher GI and GU toxicity rates were 4% and 1c 1 (5%) 13%, consisting of diarrhea and urinary frequency. No 2a 12 (55%) urinary strictures were observed. There was a trend of 2b 1 (5%) worsening patient-reported IPSS (p = 0.08) and SHIM 2c 3 (14%) scores (p = 0.06) at 3-month follow-up but no signifi - 3a 5 (23%) cant difference by 12-month follow-up (Fig.  1). An ini- Gleason tial decline in SHIM scores may be attributed, in part, by 3 + 3 1 (5%) the use of androgen deprivation therapy in our patient 3 + 4 9 (41%) cohort. 4 + 3 9 (41%) 4 + 5 1 (5%) 5 + 4 2 (9%) Discussion Pre‑treatment PSA Data is limited on the use of hypofractionated radio- Median (IQR) 8.8 (5.8–9.5) therapy for elective treatment of pelvic nodes in patients NCCN risk group at increased risk of harboring occult nodal disease. Our Intermediate risk 13 (59%) study demonstrates a 3 year biochemical free survival of High risk 7 (32%) 100% with a median post-treatment PSA was 0.09 and no Very high risk 2 (9%) acute or late grade ≥ 3 GU or GI toxicity. No difference Phuong et al. Radiation Oncology (2022) 17:12 Page 4 of 7 Table 3 Whole pelvis radiotherapy dosimetric parameters Organ Parameter (Gy) Parameter (equivalent at 1.8 Gy Median volume (IQR) Median % of total per fraction) organ volume (IQR) Bowel V44 D54 Gy 0 cc (0–0.01 cc) Bowel V32.4 D40 Gy 156 cc (100–216 cc) Bladder V37.8 D45 Gy 29 cc (20–49 cc) 17% (13–21%) Rectum V37.8 D45 Gy 5 cc (3–9 cc) 7% (4–10%) Table 4 Dosimetry Patient Bowel Bowel Bladder Bladder Rectum Rectum Penile Bulb Mean Dose V44Gy (cc) V32.4 Gy (cc) V37.8 Gy (% of V37.8 Gy (cc) V37.8 Gy (%) of V37.8 Gy (cc) (Gy) total volume) total volume 1 0.67 154.82 18.94 38.56 5.52 2.6 20.35 2 0 81.14 9.81 23.43 5.57 3.33 21.2 3 0 102.89 13.12 14.84 2.32 1.84 15.8 4 0 110.89 18.58 50.07 4.56 2.81 40.94 5 0 188.28 12.41 20.41 12.08 11.07 28.86 6 0.01 98.58 12.34 15.81 2.98 1.63 9.547 7 0 253.34 20.03 34.62 13.69 15.22 38.35 8 0.24 216.46 25.29 89.23 2.19 1.64 9.76 9 0.01 318.92 23.06 57.01 6.59 5.93 20.66 10 0 162.8 13.63 47.1 3.92 2.92 15.2 11 0 114.74 19.72 21.03 16.13 12.25 22.61 12 0 220.75 27.69 84.98 10.18 5.16 19.42 13 0 250.2 20.67 23.27 7.04 4.92 6.53 14 0 137.09 6.38 10.98 4.25 2.77 13.99 15 0.03 157.55 17.15 42.92 8.12 5.74 22.51 16 0 20.51 26.24 17.92 21.57 14.71 3.81 17 0 25.59 16.6 67.46 11.22 9.33 11.06 18 0 44.09 9.5 16.86 8.18 14.25 18.00 19 0 34.18 9.73 38.04 7.28 6.29 4.51 20 0 214.57 14.92 20.1 0 0 3.30 21 0.01 164.44 13.95 23.02 5.82 6.34 11.30 22 7.64 289.5 25.42 54.37 9.18 9.31 9.09 in patient-reported urinary or sexual quality of life was of some studies and given the concern that certain sub- noted pre- and 12 months post-treatment. groups have been observed to have more toxicity with Hypofractionation may improve the therapeutic ratio hypofractionation. Datta et  al. performed a meta-analy- of EBRT in localized prostate cancer as the alpha–beta sis of ten phase III trials evaluating conventional versus ratios of nearby organs-at-risk are considered to be hypofractionated radiotherapy and found that acute GI higher than prostate cancer [9]. Moderately hypofrac- toxicity was worse with the use of ADT or full inclusion tionated radiotherapy without lymph node irradiation is of the seminal vesicles [16]. Brenner et  al. commented well-studied, both in terms of efficacy and similar toxic - that moderate hypofractionation regimens of higher BED ity profiles, compared to conventional fractionation for were associated with worse toxicity [17]. the treatment of localized prostate cancer [3, 4, 10–15]. The toxicity profile of hypofractionated radiother - Nevertheless, there remains caution in the applicabil- apy with lymph node irradiation in higher risk prostate ity of these regimens for all patients with localized pros- cancer is much less studied to date [18]. Norkus et  al. tate cancer, in part due to the relatively short follow-up reported a randomized controlled trial that tested a P huong et al. Radiation Oncology (2022) 17:12 Page 5 of 7 Table 5 Toxicities Patient GI (Grade) GU (Grade) Acute Late Acute Late 1 0 0 0 0 2 1 0 0 0 3 2 2 1 1 4 0 0 0 0 5 2 0 2 2 6 1 0 1 0 7 1 0 2 0 8 0 0 2 2 9 0 0 0 0 10 0 0 1 1 11 0 0 1 1 12 0 0 0 0 13 1 0 2 0 14 0 0 0 0 15 2 0 2 0 16 0 0 0 0 17 0 0 0 0 18 1 0 0 0 19 2 0 1 2 20 0 0 1 0 21 2 0 0 0 22 0 0 1 0 Number of 5 1 5 3 patients with Grade ≥ 2 % patients with 23 5 23 14 Grade ≥ 2 Fig. 1 Patient reported quality of life. IPSS = international prostate symptom score (IPSS); SHIM = showing sexual health inventory in men (SHIM) WPRT fractionation of 44 Gy in 2.2 Gy per fraction [19]. WPRT of 25 Gy in 5 Gy per fraction was studied in both EBRT to the prostate and seminal vesicles without pel- the SATURN and FASTR trials with discordant out- vic radiation [22]. Shahid et  al. and Tharmalingam et  al. comes as the former reported no grade 3 or higher tox- have both reported very low rates of grade 3 or higher icities while the latter reported 26% grade 3 or higher GI GI and GU toxicities in of 125 and 411 patients treated or GU toxicities at 6  months [20, 21]. The experimental with a 15  Gy single fraction HDR boost with 37.5  Gy in arm in the ongoing PRIME Trial (NCT03561961) is also 2.5 Gy per fraction of EBRT to the prostate and seminal studying a WPRT regimen of 25 Gy in 5 Gy per fraction. vesicles after roughly 5  years of follow-up [23, 24]. Fur- To our knowledge, there are no reports on the safety of thermore, a recent phase IB study combining a single moderately-fractionated whole pelvis radiotherapy in 15 Gy HDR brachytherapy boost with 5, 7, or 10 fractions localized prostate cancer with this fractionation scheme. of hypofractionated EBRT to the prostate and proximal The 22 patients in our study were observed to have seminal vesicles reported only one acute grade 3 GI and acute grade 2 GI and GU toxicities of 23% and 23%, GU toxicity but no late grade 3 GU or GI toxicities at a respectively. The late grade 2 GI and GU toxicities were median follow-up of 36 months [25]. Similarly, a phase II 4% and 13%, respectively. No grade 3 or higher acute or study evaluating LDR brachytherapy in combination with late toxicities were observed in the current study. The 25 Gy in 5 fractions of external beam radiotherapy to the low toxicity is favorable when compared to RTOG 0321, prostate and seminal vesicles similarly demonstrated low which utilized HDR brachytherapy boost conventionally rates of toxicity [26]. Altogether, the low GU and GI tox- fractionated external beam radiation, and prior stud- icity observed in the current study with hypofractionated ies of HDR brachytherapy boost with hypofractionated pelvic nodal irradiation is in line with the toxicity rates Phuong et al. Radiation Oncology (2022) 17:12 Page 6 of 7 Author details observed from published studies evaluating hypofrac- Department of Radiation Oncology, University of California San Francisco, San tionated treatment to the prostate and seminal vesicles Francisco, USA. Department of Radiation Oncology, University of California only. Los Angeles, Los Angeles, USA. UCLA Radiation Oncology, 200 Medical Plaza Suite B265, Los Angeles, CA 90024, USA. The implementation of the Radiation Oncology Alter - native Payment Model has placed greater emphasis on Received: 23 September 2021 Accepted: 23 December 2021 cost-effectiveness with more abbreviated treatments. When compared to long courses of conventionally frac- tionated EBRT, both HDR brachytherapy and hypofrac- tionated EBRT offer two cost effective treatments that References 1. Roach M, DeSilvio M, Valicenti R, Grignon D, Asbell SO, Lawton C, et al. have shown promising effectiveness with low toxicity Whole‑pelvis, “mini‑pelvis”, or prostate ‑ only external beam radiotherapy rates. This could potentially allow for greater accessibil - after neoadjuvant and concurrent hormonal therapy in patients treated ity to oncologic care and providesignificant value while in the radiation therapy oncology group 9413 trial. Int J Radiat Oncol Biol Phys. 2006;66(3):647–53. striving for cost-effective healthcare. 2. 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Hypofractionated radiotherapy for prostate cancer— sions. All authors read and approved the final manuscript. Authors’ reply. Lancet Oncol. 2016;17:e518. 11. Arcangeli G, Saracino B, Arcangeli S, Gomellini S, Petrongari MG, Sangui‑ Funding neti G, et al. Moderate hypofractionation in high‑risk, organ‑ confined This work did not receive any funding. prostate cancer: final results of a phase III randomized trial. J Clin Oncol. 2017;35(17):1891–7. Availability of data and materials 12. de Vries KC, Wortel RC, Oomen‑ de Hoop E, Heemsbergen WD, Pos FJ, The datasets used/analyzed during the current study are available from the Incrocci L. Hyprofractionated versus conventionally fractionated radiation corresponding author on reasonable request. therapy for patients with intermediate‑ or high‑risk, localized, prostate cancer: 7‑ year outcomes from the randomized, multicenter, open‑label, Declarations phase 3 HYPRO trial. Int J Radiat Oncol Biol Phys. 2020;106(1):108–15. 13. 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Long‑ term results of NRG oncology/RTOG 0321: a phase II trial of combined high dose rate brachytherapy and external beam radiation therapy for adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2020;105:57. 23. Shahid N, Loblaw A, Chung HT, Cheung P, Szumacher E, Danjoux C, et al. Long‑term toxicity and health‑related quality of life after single ‑fraction high dose rate brachytherapy boost and hypofractionated external beam radiotherapy for intermediate‑risk prostate cancer. Clin Oncol. 2017;29(7):412–20. 24. Tharmalingam H, Tsang Y, Choudhury A, Alonzi R, Wylie J, Ahmed I, et al. External beam radiation therapy (EBRT ) and high‑ dose‑rate (HDR) brachytherapy for intermediate and high‑risk prostate cancer: the impact of EBRT volume. Int J Radiat Oncol Biol Phys. 2020;106(3):525–33. 25. Den RB, Greenspan J, Doyle LA, Harrison AS, Peng C, Williams NL, et al. 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Safety of accelerated hypofractionated whole pelvis radiation therapy prior to high dose rate brachytherapy or stereotactic body radiation therapy prostate boost

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Abstract

Background: To evaluate acute and late genitourinary and gastrointestinal toxicities and patient reported urinary and sexual function following accelerated, hypofractionated external beam radiotherapy to the prostate, seminal vesi‑ cles and pelvic lymph nodes and high dose rate (HDR) brachytherapy or stereotactic body radiation therapy (SBRT ) prostate boost. Methods: Patients at a single institution with NCCN intermediate‑ and high‑risk localized prostate cancer with logis‑ tical barriers to completing five weeks of whole pelvic radiotherapy ( WPRT ) were retrospectively reviewed for toxicity following accelerated, hypofractionated WPRT (41.25 Gy in 15 fractions of 2.75 Gy). Patients also received prostate boost radiotherapy with either HDR brachytherapy (1 fraction of 15 Gy) or SBRT (19 Gy in 2 fractions of 9.5 Gy). The duration of androgen deprivation therapy was at the discretion of the treating radiation oncologist. Toxicity was evaluated by NCI CTCAE v 5.0. Results: Between 2015 and 2017, 22 patients with a median age of 71 years completed accelerated, hypofrac‑ tionated WPRT. Median follow‑up from the end of radiotherapy was 32 months (range 2–57). 5%, 73%, and 23% of patients had clinical T1, T2, and T3 disease, respectively. 86% of tumors were Gleason grade 7 and 14% were Gleason grade 9. 68% and 32% of patients had NCCN intermediate‑ and high‑risk disease, respectively. 91% and 9% of patients received HDR brachytherapy and SBRT prostate boost following WPRT, respectively. Crude rates of grade 2 or higher GI and GU toxicities were 23% and 23%, respectively. 3 patients (14%) had late or persistent grade 2 toxicities of urinary frequency and 1 patient (5%) had late or persistent GI toxicity of diarrhea. No patient experienced grade 3 or higher toxicity at any time. No difference in patient ‑reported urinary or sexual function was noted at 12 months. Conclusions: Accelerated, hypofractionated whole pelvis radiotherapy was associated with acceptable GU and GI toxicities and should be further validated for those at risk for harboring occult nodal disease. Keywords: Hypofractionation, Prostate cancer, Nodal radiotherapy, Pelvic radiotherapy, HDR brachytherapy Background Elective pelvic lymph node irradiation has been sug- *Correspondence: ajchang@mednet.ucla.edu gested to improve progression-free survival in unfavora- Christina Phuong and Jason W. Chan contributed equally to this work Department of Radiation Oncology, University of California Los Angeles, ble intermediate- to high-risk prostate cancer [1–3]. A Los Angeles, USA course of conventionally-fractionated pelvic radiotherapy Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Phuong et al. Radiation Oncology (2022) 17:12 Page 2 of 7 for prostate cancer is delivered over a period of approxi- model to be equivalent to a dose of 45 Gy in 1.8 Gy frac- mately 9 weeks, which is inconvenient for elderly patients tions and using an α/β value of 3 for prostate cancer. and patients traveling long distances. With implemen- The elective pelvic nodal treatment volume included tation of the Radiation Oncology Alternative Payment the obturator, external iliac, proximal internal iliac, and Model, greater emphasis is placed on cost-effectiveness common iliac nodes up to the level corresponding to the with more abbreviated treatments to increase access to L4–L5 interspace. The presacral nodes from L5-S1 to S3 care. Furthermore, hypofractionated radiotherapy may were included. The inferior extent of the external iliac result in a greater therapeutic ratio for prostate cancer nodes was at the top of the femoral heads and the infe- resulting in greater efficacy than conventional fractiona - rior extent of the obturator lymph nodes was at the top tion as suggested by the linear quadratic model with a of the symphysis pubis. A 5–7  mm PTV margin around low α/β ratio of 1.5–3. the pelvic nodal CTV was used. 2.75  Gy per fraction With improvements in the precision of radiation deliv- was used as it was previously used to target the prostate ery, several studies have supported the use of moderate alone to 55  Gy with comparable toxicity with standard hypofractionation (240–340 cGy) directed to the prostate fractionation schemes [8]. Intensity modulated radiation with favorable toxicity profiles [4–6]. In these studies, therapy with daily image guidance was performed using the clinical target volume consisted of the prostate with both cone beam computed tomography with alignment or without the seminal vesicles and pelvic lymph nodes to bony anatomy and prostate fiducial markers. were not treated. Limited data is available evaluating the safety and efficacy of hypofractionated pelvic nodal Boost treatment to prostate and seminal vesicles radiotherapy. Radiation to the prostate and seminal vesicles was deliv- The goal of this study was to evaluate the feasibility in ered as a sequential boost treatment within 14 days after terms of clinical outcome and toxicity of a hypofraction- pelvic radiotherapy portion was completed. The insti - ated regimen with inclusion of prostate, seminal vesicles, tutional practice was to offer 15  Gy in one fraction with and pelvic lymph node irradiation for the treatment of high dose rate brachytherapy. Patients who refused or intermediate- and high-risk prostate cancer in patients were not candidates for brachytherapy were offered boost with logistical barriers to completing a course of conven- treatment with stereotactic body radiotherapy to a total tionally fractionated pelvic radiotherapy. dose of 19 Gy in 2 fractions of 9.5 Gy. For SBRT, patients were simulated with an empty rectum and empty blad- Methods der due to the limited ability of patients to maintain a Patient selection full bladder through the duration of SBRT treatment. Under approval of our institutional review board (IRB), All patients also underwent an MRI of the pelvis/pros- we performed a retrospective chart abstraction to iden- tate for accurate delineation of the prostate and urethra tify men treated with hypofractionated whole pelvic radi- for treatment planning purposes. SBRT was delivered otherapy (WPRT). All men had histologically confirmed on a Cyberknife machine with daily imaging guidance intermediate- to high-risk prostate adenocarcinoma by using prostate fiducial tracking, including orthogonal NCCN criteria (T1c-T3b N0, PSA > 10, and/or Glea- pair imaging prior to treatment delivery with matching son score ≥ 7) and greater than 15% risk of lymph node to prostate fiducials as well as orthogonal pair imaging involvement by the Roach formula [7]. Patients were during treatment delivery to account for intrafraction offered accelerated, hypofractionated WPRT if there were motion. logistical difficulties with completing five weeks of pelvic radiotherapy, such as lack of transportation or nearby Follow‑up housing. Patients were not offered accelerated, hypof - After treatment, patients were followed every 3  months ractionated WPRT if they had prior pelvic irradiation, for the initial 2  years, then every 6  months up to year 5, prostate brachytherapy, history of inflammatory bowel and annually thereafter with prostate specific antigen disease or major bowel surgery, or prior transurethral (PSA) testing. At each follow-up visit, patients com- resection of the prostate (TURP) procedure. Patients also pleted IPSS and SHIM QOL questionnaires. Toxicity was received androgen deprivation therapy (ADT) at the dis- assessed according to the Common Terminology Criteria cretion of the treating radiation oncologist. for Adverse Events (CTCAE) v5.0. Whole pelvis radiation Statistical analysis The hypofractionated dose of 41.25 Gy in 15 fractions of Descriptive analysis was performed using median and 2.75  Gy to the elective pelvic nodes, prostate, and semi- interquartile values for continuous variables. Predic- nal vesicles was selected based on the linear-quadratic tive analysis was performed using logistic regression. P huong et al. Radiation Oncology (2022) 17:12 Page 3 of 7 Comparator p-values were reported using a two-sample Table 2 Radiotherapy characteristics two-sided Mann–Whitney U test. P-values of less than Whole Pelvis IMRT 0.05 were considered to be significant. 41.25 Gy in 15 fractions 22 (100%) Boost HDR 15 Gy in one fraction 20 (91%) Results SBRT 19 Gy in two fractions 2 (9%) Patient and tumor characteristics ADT Among 22 patients, the median age was 71 (Table  1). None 1 (5%) One (5%), 16 (73%), and 5 (23%) of patients had had 4 months 19 (86%) clinical T1, T2, and T3 disease, respectively. 19 (86%) 6 months 1 (5%) of tumors were Gleason grade 7 and 3 (14%) were Glea- 12 months 1 (5%) son grade 9. According to NCCN risk stratification, 13 (59%), 7 (32%), and 2 (9%) of patients had intermedi- ate-, high-, and very high-risk disease, respectively. 21 Whole pelvis radiotherapy parameters patients (95%) patients received androgen deprivation Dose-volume characteristics of hypofractionated therapy (ADT), of whom 19 patients (86%) received a whole pelvis radiotherapy is summarized in Tables  3 total of 4 months. and 4. The median small bowel V44 Gy (54  Gy at 1.8  Gy/fx) was 0  cc (IQR 0–0.01  cc) and median small bowel V32.4  Gy (40  Gy at 1.8  Gy/fx) was 156  cc (IQR Radiotherapy characteristics 100–216  cc). The median bladder V37.8  Gy (45  Gy at All 22 patients received hypofractionated whole pelvic 1.8  Gy/fx) was 29  cc (IQR 20–49  cc) and 17% of the radiotherapy with intensity modulated radiotherapy total bladder volume (IQR 13–21%). The median rec (IMRT) to 41.25  Gy in 15 fractions over three weeks tum V37.8 Gy was 5 cc (IQR 3–9 cc) and 7% of the total (Table  2). 20 (91%) patients received high dose-rate rectal volume (IQR 4–10%). There was no correlation brachytherapy boost with 15 Gy in a single fraction via found between dosimetric parameters and grade ≥ 2 a single perineal implant procedure. 2 (9%) patients GU or GI toxicity. received stereotactic body radiation therapy (SBRT) boost to the prostate with 19  Gy in two fractions on consecutive days. Disease control and toxicity At a median follow-up of 32 months, there were no bio- chemical failures, and the median post-treatment PSA Table 1 Patient characteristics was 0.09 (range 0–1.28). The crude rates of acute grade 2 or higher GI and GU toxicities were 23% and 23% Age (Table  5). These toxicities mostly consisted of urinary Median (IQR) 71 (68–74) frequency, urgency, and diarrhea. The late or persistent T‑Stage (MRI or TRUS) grade 2 or higher GI and GU toxicity rates were 4% and 1c 1 (5%) 13%, consisting of diarrhea and urinary frequency. No 2a 12 (55%) urinary strictures were observed. There was a trend of 2b 1 (5%) worsening patient-reported IPSS (p = 0.08) and SHIM 2c 3 (14%) scores (p = 0.06) at 3-month follow-up but no signifi - 3a 5 (23%) cant difference by 12-month follow-up (Fig.  1). An ini- Gleason tial decline in SHIM scores may be attributed, in part, by 3 + 3 1 (5%) the use of androgen deprivation therapy in our patient 3 + 4 9 (41%) cohort. 4 + 3 9 (41%) 4 + 5 1 (5%) 5 + 4 2 (9%) Discussion Pre‑treatment PSA Data is limited on the use of hypofractionated radio- Median (IQR) 8.8 (5.8–9.5) therapy for elective treatment of pelvic nodes in patients NCCN risk group at increased risk of harboring occult nodal disease. Our Intermediate risk 13 (59%) study demonstrates a 3 year biochemical free survival of High risk 7 (32%) 100% with a median post-treatment PSA was 0.09 and no Very high risk 2 (9%) acute or late grade ≥ 3 GU or GI toxicity. No difference Phuong et al. Radiation Oncology (2022) 17:12 Page 4 of 7 Table 3 Whole pelvis radiotherapy dosimetric parameters Organ Parameter (Gy) Parameter (equivalent at 1.8 Gy Median volume (IQR) Median % of total per fraction) organ volume (IQR) Bowel V44 D54 Gy 0 cc (0–0.01 cc) Bowel V32.4 D40 Gy 156 cc (100–216 cc) Bladder V37.8 D45 Gy 29 cc (20–49 cc) 17% (13–21%) Rectum V37.8 D45 Gy 5 cc (3–9 cc) 7% (4–10%) Table 4 Dosimetry Patient Bowel Bowel Bladder Bladder Rectum Rectum Penile Bulb Mean Dose V44Gy (cc) V32.4 Gy (cc) V37.8 Gy (% of V37.8 Gy (cc) V37.8 Gy (%) of V37.8 Gy (cc) (Gy) total volume) total volume 1 0.67 154.82 18.94 38.56 5.52 2.6 20.35 2 0 81.14 9.81 23.43 5.57 3.33 21.2 3 0 102.89 13.12 14.84 2.32 1.84 15.8 4 0 110.89 18.58 50.07 4.56 2.81 40.94 5 0 188.28 12.41 20.41 12.08 11.07 28.86 6 0.01 98.58 12.34 15.81 2.98 1.63 9.547 7 0 253.34 20.03 34.62 13.69 15.22 38.35 8 0.24 216.46 25.29 89.23 2.19 1.64 9.76 9 0.01 318.92 23.06 57.01 6.59 5.93 20.66 10 0 162.8 13.63 47.1 3.92 2.92 15.2 11 0 114.74 19.72 21.03 16.13 12.25 22.61 12 0 220.75 27.69 84.98 10.18 5.16 19.42 13 0 250.2 20.67 23.27 7.04 4.92 6.53 14 0 137.09 6.38 10.98 4.25 2.77 13.99 15 0.03 157.55 17.15 42.92 8.12 5.74 22.51 16 0 20.51 26.24 17.92 21.57 14.71 3.81 17 0 25.59 16.6 67.46 11.22 9.33 11.06 18 0 44.09 9.5 16.86 8.18 14.25 18.00 19 0 34.18 9.73 38.04 7.28 6.29 4.51 20 0 214.57 14.92 20.1 0 0 3.30 21 0.01 164.44 13.95 23.02 5.82 6.34 11.30 22 7.64 289.5 25.42 54.37 9.18 9.31 9.09 in patient-reported urinary or sexual quality of life was of some studies and given the concern that certain sub- noted pre- and 12 months post-treatment. groups have been observed to have more toxicity with Hypofractionation may improve the therapeutic ratio hypofractionation. Datta et  al. performed a meta-analy- of EBRT in localized prostate cancer as the alpha–beta sis of ten phase III trials evaluating conventional versus ratios of nearby organs-at-risk are considered to be hypofractionated radiotherapy and found that acute GI higher than prostate cancer [9]. Moderately hypofrac- toxicity was worse with the use of ADT or full inclusion tionated radiotherapy without lymph node irradiation is of the seminal vesicles [16]. Brenner et  al. commented well-studied, both in terms of efficacy and similar toxic - that moderate hypofractionation regimens of higher BED ity profiles, compared to conventional fractionation for were associated with worse toxicity [17]. the treatment of localized prostate cancer [3, 4, 10–15]. The toxicity profile of hypofractionated radiother - Nevertheless, there remains caution in the applicabil- apy with lymph node irradiation in higher risk prostate ity of these regimens for all patients with localized pros- cancer is much less studied to date [18]. Norkus et  al. tate cancer, in part due to the relatively short follow-up reported a randomized controlled trial that tested a P huong et al. Radiation Oncology (2022) 17:12 Page 5 of 7 Table 5 Toxicities Patient GI (Grade) GU (Grade) Acute Late Acute Late 1 0 0 0 0 2 1 0 0 0 3 2 2 1 1 4 0 0 0 0 5 2 0 2 2 6 1 0 1 0 7 1 0 2 0 8 0 0 2 2 9 0 0 0 0 10 0 0 1 1 11 0 0 1 1 12 0 0 0 0 13 1 0 2 0 14 0 0 0 0 15 2 0 2 0 16 0 0 0 0 17 0 0 0 0 18 1 0 0 0 19 2 0 1 2 20 0 0 1 0 21 2 0 0 0 22 0 0 1 0 Number of 5 1 5 3 patients with Grade ≥ 2 % patients with 23 5 23 14 Grade ≥ 2 Fig. 1 Patient reported quality of life. IPSS = international prostate symptom score (IPSS); SHIM = showing sexual health inventory in men (SHIM) WPRT fractionation of 44 Gy in 2.2 Gy per fraction [19]. WPRT of 25 Gy in 5 Gy per fraction was studied in both EBRT to the prostate and seminal vesicles without pel- the SATURN and FASTR trials with discordant out- vic radiation [22]. Shahid et  al. and Tharmalingam et  al. comes as the former reported no grade 3 or higher tox- have both reported very low rates of grade 3 or higher icities while the latter reported 26% grade 3 or higher GI GI and GU toxicities in of 125 and 411 patients treated or GU toxicities at 6  months [20, 21]. The experimental with a 15  Gy single fraction HDR boost with 37.5  Gy in arm in the ongoing PRIME Trial (NCT03561961) is also 2.5 Gy per fraction of EBRT to the prostate and seminal studying a WPRT regimen of 25 Gy in 5 Gy per fraction. vesicles after roughly 5  years of follow-up [23, 24]. Fur- To our knowledge, there are no reports on the safety of thermore, a recent phase IB study combining a single moderately-fractionated whole pelvis radiotherapy in 15 Gy HDR brachytherapy boost with 5, 7, or 10 fractions localized prostate cancer with this fractionation scheme. of hypofractionated EBRT to the prostate and proximal The 22 patients in our study were observed to have seminal vesicles reported only one acute grade 3 GI and acute grade 2 GI and GU toxicities of 23% and 23%, GU toxicity but no late grade 3 GU or GI toxicities at a respectively. The late grade 2 GI and GU toxicities were median follow-up of 36 months [25]. Similarly, a phase II 4% and 13%, respectively. No grade 3 or higher acute or study evaluating LDR brachytherapy in combination with late toxicities were observed in the current study. The 25 Gy in 5 fractions of external beam radiotherapy to the low toxicity is favorable when compared to RTOG 0321, prostate and seminal vesicles similarly demonstrated low which utilized HDR brachytherapy boost conventionally rates of toxicity [26]. Altogether, the low GU and GI tox- fractionated external beam radiation, and prior stud- icity observed in the current study with hypofractionated ies of HDR brachytherapy boost with hypofractionated pelvic nodal irradiation is in line with the toxicity rates Phuong et al. Radiation Oncology (2022) 17:12 Page 6 of 7 Author details observed from published studies evaluating hypofrac- Department of Radiation Oncology, University of California San Francisco, San tionated treatment to the prostate and seminal vesicles Francisco, USA. Department of Radiation Oncology, University of California only. Los Angeles, Los Angeles, USA. UCLA Radiation Oncology, 200 Medical Plaza Suite B265, Los Angeles, CA 90024, USA. The implementation of the Radiation Oncology Alter - native Payment Model has placed greater emphasis on Received: 23 September 2021 Accepted: 23 December 2021 cost-effectiveness with more abbreviated treatments. When compared to long courses of conventionally frac- tionated EBRT, both HDR brachytherapy and hypofrac- tionated EBRT offer two cost effective treatments that References 1. Roach M, DeSilvio M, Valicenti R, Grignon D, Asbell SO, Lawton C, et al. have shown promising effectiveness with low toxicity Whole‑pelvis, “mini‑pelvis”, or prostate ‑ only external beam radiotherapy rates. This could potentially allow for greater accessibil - after neoadjuvant and concurrent hormonal therapy in patients treated ity to oncologic care and providesignificant value while in the radiation therapy oncology group 9413 trial. Int J Radiat Oncol Biol Phys. 2006;66(3):647–53. striving for cost-effective healthcare. 2. 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Journal

Radiation Oncology – Springer Journals

Published: Jan 20, 2022

Keywords: Hypofractionation; Prostate cancer; Nodal radiotherapy; Pelvic radiotherapy; HDR brachytherapy

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