Abstract
Background/Aim: This study aimed to analyse retrospectively the initial treatment outcomes and associated toxicities of a spot scanning proton beam therapy for prostate cancer at the Shonan-Kamakura General Hospital.
Patients and Methods: A laterally opposing single-field uniform dose of spot-scanning proton beam was used. The doses were determined to be 60 Gy in 20 fractions for low-risk prostate cancer and 63 Gy in 21 fractions for intermediate- and high-risk prostate cancers. Genitourinary (GU) and gastrointestinal (GI) toxicities were also evaluated. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Results: A total of 135 patients were treated over two years, 51 of whom underwent hydrogel spacer insertion. During the limited observation period, no patient experienced a recurrence. Grade 2 GU toxicities were observed in 17 patients, whereas grade 1 or greater GI toxicities were observed in seven patients. None of the patients in whom a hydrogel spacer was inserted experienced grade 1 or higher GI toxicity.
Conclusion: Proton beam therapy is safe for the treatment of prostate cancer. The insertion of a gold marker and hydrogel spacer led to a reduction in the rectal radiation dose and GI toxicity.
Introduction
Proton beam therapy (PBT) offers a superior dose concentration to the target owing to the Bragg Peak over photon therapy, as initially indicated by Robert Wilson (1). In Japan, prostate cancer is the most prevalent cancer among men, with an increasing incidence (2). The widespread use of the prostate-specific antigen (PSA) test has led to the early diagnosis of prostate cancer (3). PBT for prostate cancer, initiated at Harvard University, aims to safely increase the dose delivered to the prostate (4). This approach demonstrated that higher doses are more effective in controlling prostate cancer. Dose escalation and the development of new techniques have been extensively explored in photon therapy, which is more commonly used than proton therapy (5). Intensity-modulated radiotherapy (IMRT) was introduced to enhance the dose to the prostate while minimising exposures to the surrounding tissues, including the rectum and urinary bladder (6). A large-scale study of high dose PBT for prostate cancer at the Loma Linda University yielded excellent outcomes (7). Similarly positive results have been obtained in Japan, where PBT is now considered a standard treatment (8). Efforts to reduce treatment duration included a study comparing a standard dose of 74 Gy in 37 fractions with 60 Gy in 20 fractions using IMRT, concluding that shorter treatment courses achieve comparable control rates without compromising the safety or increasing treatment-related toxicities (9).
At our institution, spot-scanning PBT has been introduced, enabling precise radiation delivery to the prostate and significantly reducing the dose to adjacent organs, including the urinary bladder and rectum. This technique, combined with the use of a hydrogel spacer, is expected to further reduce the radiation dose to the rectum, particularly to the anterior wall. We initiated PBT to deliver high doses to the prostate while minimising exposure to surrounding organs, including the urinary bladder and rectum. This study aimed to analyse the initial treatment outcomes and identify the incidence of genitourinary (GU) and gastrointestinal (GI) toxicities in patients with prostate cancer treated with sophisticated PBT at the Shonan-Kamakura General Hospital.
Patients and Methods
Ethical considerations. Prior to starting proton beam therapy (PBT), we obtained approval from the ethics committee of the Shonan-Kamakura General Hospital (approval number: 2479). Written informed consent was obtained from all patients before their participation in the study.
Study design. This study included patients diagnosed with prostate cancer and treated with PBT between January 2022 and December 2023. The inclusion criteria were an EROTC performance status of 0-2, histologically confirmed adenocarcinoma, clinical tumour stages T1a-T3b based on the 8th edition of the TNM staging system, and no lymph node or distant metastases. Patients were excluded if they had a history of pelvic radiotherapy, concurrent malignancies, or significant comorbidities that might have influenced the outcomes.
A multidisciplinary committee comprising a urologist, diagnostic radiologist, radiation oncologist, medical physicist, radiation technologist, and nurse reviewed and approved each patient’s treatment plan.
The patients were categorised into low-, intermediate-, and high-risk groups according to the National Comprehensive Cancer Network (NCCN) criteria. Hormonal therapy was recommended as follows: not at all for the low-risk group, a minimum six-month course of maximal androgen blockage for the intermediate-risk group, and at least a two-year course for the high-risk group. PBT was initiated at least six months after the initiation of hormonal therapy, ensuring that the prostate was reduced and stabilised in size.
Radiotherapy planning and treatment delivery. Patients were instructed on bowel and bladder management before treatment planning, typically urinating and then waiting one hour after consuming 300 ml of water. They were immobilised in the supine position during MRI and CT scans for precise treatment planning, ensuring accurate delineation of the prostate and seminal vesicles.
The clinical target volume (CTV) for low-risk prostates included the prostate with a 1-mm posterior margin and a 3-mm margin in other directions. For the higher stages invading the seminal vesicle, the CTV included the prostate and seminal vesicles with the above margins. For other stages, CTV included the prostate and base of the seminal vesicle with similar margins. Margins were set to 3.5% of the range length plus 1 mm in the distal and proximal directions, 6 mm craniocaudally, and 5 mm dorsoventrally (10). Low-risk patients received 60 Gy in 20 fractions, while the higher patients received 63 Gy in 21 fractions, covering 95% of the CTV with the prescribed dose. The dose constraints and prescribed doses are listed in Table I.
Prescribed doses for clinical target volume (CTV) and dose constraints of the urinary bladder and rectum.
A single-gantry proton therapy system (PROBEAT-1; Hitachi Co., Ltd., Tokyo, Japan) was used for PBT. This system included two imagers on both sides of the gantry, serving as a real-time tracking system, and functioning as a cone beam CT with fine-tuning based on the position of the prostate and rectum (11). Treatment was administered using two lateral opposed single-field uniform dose techniques, which provided robust dose coverage and organ sparing compared to IMPT (12).
A transrectal ultrasound probe was inserted, with the patient in the lithotomy position. The injection needle was inserted through the perineal region under ultrasound guidance into the perirectal fat between Denonvilier’s fascia and the rectal wall. A small volume of saline (approximately 10 ml) was administered to allow hydrodissection and confirm the position of the needle within the perirectal fat. The saline syringe was changed to a syringe containing the two hydrogel precursors. The two precursors, which became hydrogel spacers after a few minutes of mixing, were inserted smoothly. The spacer creates adequate space and is absorbed and excreted by the body within one or two years (13).
Hydrogel spacer insertion was not possible for the first 15 months after initiating PBT. After preparing for hydrogel spacer insertion, the choice to insert the hydrogel spacer was based on patient preference. Six months after initiating hydrogel spacer use, we recommended spacer insertion because this method appears safe and reduces treatment-related toxicities.
Patients were monitored quarterly during the first year of treatment and biannually thereafter with adjustments based on individual follow-up schedules and convenience. GU and GI treatment-related toxicities were assessed by recording the onset and severity of the urinary and rectal toxicities. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Comparative analyses were conducted between patients with and without hydrogel spacers.
Statistical analyses. Kaplan-Meier methods were used to estimate the incidence of treatment-related toxicities over time, and logistic regression analysis was used to identify the factors associated with these toxicities. Statistical analyses were performed using SPSS software version 29 (SPSS Inc., Chicago, IL, USA).
Results
Between January 2022 and December 2023, 135 patients with localised prostate cancer underwent PBT. According to NCCN guidelines, these patients were divided into low-, intermediate-, and high-risk groups, numbered 6, 51, and 78, respectively. Hydrogel spacers were inserted in 51 patients. Patient characteristics are shown in Table II. All patients were followed-up until June 2024 for periods ranging from 6.2 months to 27.7 months. No recurrence was observed during the study period. The prescribed doses and dose constraints are listed in Table II.
Characteristics of patients and tumours with or without the insertion of the spacer.
The doses provided with and without spacer insertions were calculated. The doses provided with and without spacer insertions were calculated. No significant differences were found in CTV, median bladder maximum dose, and median bladder mean dose with or without spacer insertion. However, significant differences were observed in the median rectal maximum and rectum mean doses (Table III).
Provided doses with or without the insertion of the spacer.
Seventeen patients experienced Grade II toxicity (Table IV). Eighteen percent of the patients experienced GU toxicities across the patient population (Figure 1). Multiple regression analysis indicated that the presence of diabetes mellitus (p=0.004) and mean urinary wall dose (p=0.018) were significantly associated with GU toxicities among potential factors (Table V). Concerning GI toxicities, two, four, and one patient suffered from grade I, II, and III GI toxicities, respectively. A significant reduction in the irradiated rectal volume was observed in patients who had a hydrogel spacer inserted before PBT (Figure 2). In the multiple regression analysis, spacers were omitted as a reference category, and other categories were not significant for rectal treatment-related toxicities. Univariate regression analysis revealed that spacer use was a significant factor (Table VI). None of the patients who underwent hydrogel spacer insertion experienced GI toxicity, indicating a significant reduction in GI toxicity. No other factors were detected in the multivariate analysis. The introduction of hydrogel spacers with the insertion of gold markers effectively eliminated these side effects, as evidenced in another study (14).
Treatment-related toxicities with or without the insertion of the spacer.
Time course of genitourinary (GU) and gastrointestinal (GI) toxicities. One-year rates of GU and GI toxicity rates were 12.3% and 4.3%, respectively.
Predictive factors of genitourinary toxicities using univariate and multivariate analyses.
Treatment-related toxicities of genitourinary (GU) and gastrointestinal (GI) with or without the spacer. Insertion of the spacer decreased (B) GI toxicity but did not affect (A) GU toxicity. This demonstrates the efficacy of the spacer in selectively reducing the incidence of GI toxicities while leaving GU toxicities unaffected.
Predictive factors of gastrointestinal toxicities using univariate and multivariate analyses.
Discussion
This study presents compelling evidence for the efficacy of spot-scanning PBT in the management of prostate cancer, showing a notable absence of tumour recurrence throughout the follow-up period. The presence of diabetes mellitus and mean dose to the urinary bladder wall were identified as the primary factors associated with early phase GU toxicities. The rectal wall volume receiving >30 Gy was significantly reduced by insertion of a hydrogel spacer, resulting in the reduction of rectal toxicities.
Comparative analyses by Donavan et al. revealed differential toxicities between the investigated treatment-related toxicities using patient-reported outcomes and observed urinary toxicities. GU toxicities were more prevalent in the surgery group, whereas GI toxicities were more common in the radiotherapy group (15). To mitigate these toxicities, our protocol administered PBT with urine retention in the bladder to minimise the radiation dose to the bladder wall. In our study, the presence of diabetes mellitus and mean dose to the urinary bladder wall were identified as the primary factors associated with incidence. A large study of 280 patients with acute GU toxicities showed that bladder filling, baseline IPSS total score, nocturia, and urinary incontinence were risk factors. Of these, only bladder filling was a treatment-related factor, which appears to be related to the mean dose to the urinary bladder (16). The existence of diabetes mellitus was a risk factor for acute GU toxicities in this study, which may indicate a decreased ability to recover and an increased susceptibility to infections. In the PBT, the beams were set in a laterally opposed direction. In these patients, the irradiated volume of the upper urinary bladder decreased. Thus, the mean dose of PBT could be significantly lower than that of IMRT (17).
The inherent challenge of GI toxicity is the anatomical movements of the prostate, rectum, and urinary bladder during treatment, which can compromise the accuracy of radiation delivery to the intended target. The implementation of tumour fiducial markers has improved the accuracy of tumour localisation (18). The hydrogel spacer effectively reduces actual rectal radiation doses. After the introduction of the hydrogel spacer and gold marker, GI toxicities almost vanished, although GU toxicities did not change (19). This might be advantageous in PBT over surgery because GI toxicities are the main treatment-related toxicities of radiotherapy, including PBT.
The Surveillance Epidemiology and End Results (SEER) registry provides comprehensive patient demographic information, including age, race, income, and education levels. In the propensity scores-adjusted analysis, patients treated with IMRT were less likely to be diagnosed with gastrointestinal morbidity than those who received conformal radiotherapy (20). In a comparison of IMRT and PBT using the SEER database, PBT and IMRT were comparable in GU and GI toxicities (21). In terms of dose distributions, PBT can significantly reduce the integral dose and potentially lower the risk of second malignancies (22). This may be important for relatively young patients.
The limitations of this study include the small sample size and short follow-up duration.
Conclusion
Although extended follow-up is needed, PBT delivered at 60 Gy in 20 fractions or 63 Gy in 21 fractions is safe with precise positioning. The use of gold markers and hydrogel spacers has been instrumental in improving the positioning accuracy and reducing irradiation of the rectal volume, resulting in reduced GI toxicity. The continuous monitoring of urological side effects is vital for patient care.
Acknowledgements
None.
Footnotes
Authors’ Contributions
S.S. and K.T. conceived and designed the study; S.S., Y.H., R.U., T.M., I.M., and K.T. acquired the data; S.S., K.M., A.Y., M.Y., T.S., and K.T. analysed the data; S.S. and K.T. wrote the paper; All Authors were involved in article revision.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflicts of Interest
The Authors have no conflicts of interest directly relevant to the content of this article.
- Received December 9, 2024.
- Revision received December 19, 2024.
- Accepted December 23, 2024.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.