Research ArticleClinical Studies
Open Access

Oral 5-aminolevulinic Acid for Patients With Localized Prostate Cancer Undergoing Low-dose-rate Brachytherapy: AMBER Trial

MAKITO MIYAKE, NOBUMICHI TANAKA, KENTA OHNISHI, YASUSHI NAKAI, SATOSHI ANAI, KAORU YAMAKI, ISAO ASAKAWA, NOBUTAKA NISHIMURA, TOMOMI FUJII, FUMIAKI ISOHASHI and KIYOHIDE FUJIMOTO
In Vivo November 2024, 38 (6) 3091-3105; DOI: https://doi.org/10.21873/invivo.13794

Abstract

Background/Aim: Radiotherapy is one of the most frequently used options for prostate cancer (PCa). However, adverse effects related to irradiation of surrounding normal organs are significant clinical concerns. Specifically, genitourinary toxicity can dramatically reduce the quality of life. This clinical trial investigated the efficacy of oral 5-aminolevulinic acid phosphate combined with sodium ferrous citrate (ALA-SFC) in patients treated with low-dose-rate brachytherapy (LDR-BT) using an iodine-125 seed source. Patients and Methods: The AMBER study was a prospective single-center trial involving patients with localized PCa who underwent LDR-BT without external-beam radiotherapy (jRCTs051190077). Fifty patients were included and instructed to take capsules of ALA-SFC twice a day (200 mg phosphate salt and 229.42 mg per day) for six months from the day of seed implantation (prescribed radiation dose of 160 Gy). Patient data were collected before implantation, during ALA-SFC treatment, and at 1, 3, 6, 9, and 12 months post-LDR-BT. The primary endpoint of this trial was urinary frequency at three months. Other patient-reported outcomes, investigator-reported adverse events, and oncological outcomes were secondary endpoints. Results: Of 50 enrolled cases (45 in the per-protocol analysis, 49 in the safety analysis), urinary frequency and its increase from baseline did not differ from 141 historical controls at any time point, including at three months post-LDR-BT. Propensity score matched analysis confirmed no time-course differences in frequency, volume, or urinary symptom scores between groups. Biochemical failure-free and metastasis-free survival also remained similar. Conclusion: Oral supplementation of ALA-SFC to LDR-BT did not alleviate radiation-induced toxicity or improve oncological outcomes.

Key Words:

The burden of cancer and treatment is reflected not only through oncological outcomes and mortality but also through impacts on functional outcomes, including patient quality of life (QoL). Prostate cancer (PCa) treatment significantly affects patients’ physical, emotional, social, sexual, and overall QoL. Radiotherapy is one of the most frequently used treatment modalities for patients with PCa. A nationwide Japanese prospective cohort study reported that thousands of patients receive low-dose-rate brachytherapy (LDR-BT) annually using an iodine-125 seed source (1). LDR-BT is a well-established treatment option for localized PCa with long-term oncological and functional outcomes accompanied by organ preservation (2). However, there are still significant clinical concerns regarding post-implantation adverse events related to the surrounding irradiated organs. Particularly, the gastrointestinal (GI) and genitourinary (GU) toxicities can lead to a dramatically deteriorated QoL (3-5). Great strides toward palliation of adverse effects have been made over a couple of decades, but significant room for improvement remains (6-8).

We previously evaluated the dual benefit of oral 5-aminolevulinic acid (ALA) in a syngeneic PCa model using MyC-CaP cells in FVB mice and concluded that radiosensitization of PCa tumor tissues and protection of normal pelvic organs from radiotherapy were obtained with this supplementation (7). ALA is ubiquitously distributed in plant and animal cells and is a precursor of chlorophyll, porphyrins, and heme proteins, which play essential roles in photosynthesis, aerobic energy metabolism, and the electron transport system (9). Besides, ALA has reportedly potential to confer a broad range of cytoprotective effects in preclinical studies (10-13). Based on promising results of the preclinical studies, an interventional clinical trial is ongoing to evaluate whether oral ALA phosphate-sodium ferrous citrate (ALA-SFC), which is widely accepted as a health supplement and food with functional properties, prevents cisplatin-induced renal injury (trial ID: UMIN000024642), Alzheimer disease (jRCTs041180135), and autism spectrum disorder (jRCTs051190017).

Here, we report the results of a prospective study that evaluated the clinical efficacy of orally administered ALA-SFC in patients with PCa undergoing LDR-BT. The endpoints included short-term toxicity such as urinary frequency, other types of complications of LDR-BT, QoL, and short-term oncological outcomes. To the best of our knowledge, this is the first study to investigate the potential benefits of oral ALA-SFC administration for patients subjected to radiotherapy.

Patients and Methods

Study design. This prospective, single-center, single-arm study, named the AMBER study, was conducted at Nara Medical University Hospital. This clinical trial was prospectively registered in the Japan Registry of Clinical Trials on December 5, 2019. The reference numbers are jRCTs051190077 and nara0013 (Certified Review Board of Nara Medical University, institution ID: CRB5180011). The URL for the trial registry record is available at https://jrct.niph.go.jp/en-latest-detail/jRCTs051190077. This clinical trial complied with the Declaration of Helsinki regarding investigation in humans. Informed consent and written consent forms of patients are mandatory before study participation.

Details of the study design, inclusion/exclusion criteria, intervention, assessment schedule, and primary/secondary endpoints were published in 2020 (14). The study protocol adhered to the recommendations of interventional Trials (SPIRIT) criteria. Patients who underwent supplementary external beam radiotherapy (EBRT) were excluded, whereas those who underwent short-term (4-6 months) neoadjuvant androgen deprivation therapy (neoADT) to decrease prostate volume and/or improve oncological outcomes were included. After the screening and registration, the patients were enrolled to a single treatment group of a fixed daily dose of oral ALA-SFC containing 200 mg of 5-aminolevulinic acid phosphate and 229.42 mg of sodium ferrous citrate (provided by SBI Pharmaceuticals Co., Ltd., Tokyo, Japan). The subjects underwent seed implantation under spinal anesthesia and were instructed to take capsules of ALA-SFC twice daily for 6 months from the day of seed implantation. The LDR-BT procedure has been reported previously (15, 16). The prescribed radiation dose was 160 Gy for monotherapy.

The data of the trial cases were compared with historical control data. The target sample size was determined as previously described in the protocol article (14). Patients who underwent seed implantation monotherapy (without EBRT, but neo-ADT was allowed) between February 2016 and February 2019 were included in the historical control group. The primary endpoint of this trial was urinary frequency at 3 months after LDR-BT. Briefly, the required sample size was determined to be at least 37 for trial cases and 109 for historical control cases to provide 80% power (β=0.20) and an a level of 0.05 (two-sided). Based on this estimate, we planned a total of 50 trial cases and 150 historical control cases for enrollment in this study.

Assessment schedule, data collection, and primary/secondary endpoints. The assessment schedule and data collection are described in a previous study (14). Patients were asked to fill out a frequency volume chart (FVC) (time and volume of voided urine) within 1 month before LDR-BT and 1, 3, 6, and 12 months after LDR-BT (three days at each point). Subjective urinary symptoms were evaluated using the International Prostate Symptom Score (IPSS), Overactive Bladder Symptoms Score (OABSS), and Expanded Prostate Cancer Index Composite (EPIC) questionnaires a day before and 1, 3, 6, and 12 months after LDR-BT.

The primary endpoints were as follows: Urinary frequency per day 3 months after LDR-BT (FVC evaluation). The secondary endpoints evaluated in this study were as follows:

  • i) Urinary frequency per day at 1, 6, and 12 months after LDR-BT (evaluated using FVC);

  • ii) Changes in lower urinary tract symptom-related questionnaires (evaluated using IPSS and OABSS);

  • iii) Changes in health-related QoL evaluated using the EPIC;

  • iv) LDR-BT-related adverse event (AE) evaluated using the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0;

  • v) Safety of oral ALA-SFC in AMBER trial cases (evaluated using CTCAE version 5.0);

  • vi) Biochemical recurrence-free survival (BCRFS);

  • vii) Metastasis-free survival (MFS).

Statistical analysis. GraphPad Prism version 10 (GraphPad Software, San Diego, CA, USA) was utilized for figure creation and statistical analyses. p<0.05 was considered statistically significant. Descriptive statistics were computed for all study variables. Comparison of the two groups, the trial cases and historical control cases, was performed using the Mann-Whitney U-test or Wilcoxon signed rank test for continuous variables, and the chi-square test or Fisher’s exact test as appropriate for categorical variables. Survival outcome was analyzed and compared with the Kaplan-Meier method and log-rank test. Biochemical failure after curative radiotherapy is defined as a prostate-specific antigen (PSA) rise of ≥2 ng/ml above the nadir (17). BCRFS was calculated from the date of surgery to the date of BCR or the date of last follow-up for those patients who did not experience BCR. MFS is considered a surrogate for overall survival in localized PCa. According to the SPARTAN clinical trial (18), MFS was defined as the time from LDR-BT to the first detection of distant metastasis on imaging or death from any cause, whichever occurred first. Survivals were estimated with Kaplan-Meier method and compared with the log-rank test.

R version 4.0.0 (R Development Core Team, Vienna, Austria) was used for propensity score matching (PSM). PSM was performed using a logistic regression model of treatment on baseline covariates considered potential confounding factors: PSA level at diagnosis, clinical T category, Gleason grade group, prostate volume at LDR-BT, and IPSS total score at LDR-BT. Patients in the trial and historical control populations were matched based on these propensity scores in a 1:1 ratio. Optimal matching with a caliper size of 0.2 of the standard deviation was used to avoid poor matching.

Results

Patient population. Figure 1 shows a flow diagram of the study. Fifty (41.7%) of 120 patients who underwent LDR-BT between December 24, 2019, and November 23, 2020, were enrolled in the trial cohort, whereas 141 (36.5%) of 386 patients who underwent LDR-BT between January 1, 2016, and January 1, 2019, were eligible as historical control cases (without EBRT, but neoADT allowed). All 50 trial patients reported taking ALA-SFC capsules on the day of seed implantation. One patient was mistakenly excluded because of an extreme overdose of ALA-SFC. Underdosing, defined as <80% of the full dose, was observed in four patients, taking 50%, 58%, 66%, and 74% of the full dose, respectively. In the trial cohort, 45 and 49 patients were included in the per-protocol analysis set (PPS) and safety analysis set (SAS), respectively.

Figure 1.
Figure 1.

Study flow diagram of the AMBER trial. This flowchart is based on the CONSORT diagram. ALA-SFC: Oral 5-aminolevulinic acid phosphate with sodium ferrous citrate; EBRT: external beam radiotherapy; LDR-BT: low-dose-rate brachytherapy.

The demographics and baseline characteristics of the 45 patients in the PPS group and 141 patients in the historical control group are shown in Table I. A higher proportion of patients with clinical stage T2c (20% vs. 5%) and Gleason group 3 (44% vs. 12%) were observed in the trial cohort than in the historical control cohort. Furthermore, a higher proportion of patients were treated with neoADT before seed implantation in the trial cohort (67% vs. 33%). Although prostate volume at diagnosis was not significantly different between the two cohorts, prostate volume at implantation was lower in the trial cohort than in the historical control cohort (average, 19.1 ml vs. 23.9 ml), mainly due to the effect of neoADT, resulting in a lower number of implanted seeds and less seed activity (MBq) in the trial cohort.

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Table I.

Patient demographics and baseline characteristics of the AMBER trial cases and historical control cases.

As a post hoc analysis, we performed PSM to adjust for patient baseline characteristics and decrease the influence of possible confounding factors between the AMBER trial cases and historical control cases. Adjustment using PSM resulted in a closely balanced distribution of the baseline covariates between the two groups (Table I).

Time-course changes of urinary symptoms after LDR-BT. The time-course changes in the urinary frequency per day, increase from baseline of urinary frequency per day, IPSS total score, and IPSS voiding subscore from baseline (BL) to 12 months after LDR-BT were plotted with connected line graphs and compared between the two unadjusted groups (Figure 2; PPS population of AMBER trial cases and historical control cases). The worst symptom scores were observed between one and three months; however, all scores decreased with time. The urinary frequency and increase from baseline did not differ at any time point, including 3 months after LDR-BT (primary endpoint; Figure 2A). Other FVC-based indices are listed in Table II. The voided urine volume per day and the average urinary volume per void were significantly different at baseline and at certain time points. The IPSS voiding, storage, and OABSS total scores were lower in the AMBER trial cases than in the historical control cases at 6 and 8 months after LDR-BT (Figure 2B; Table III). However, EPIC urinary domains did not differ between the two groups.

Figure 2.
Figure 2.

Time-course changes of urinary frequency and IPSS score in the AMBER trial cases and historical control cases (unadjusted). A) Urinary frequency per day was assessed using the frequency volume chart [forced vital capacity (FVC), time, and volume of voided urine] at baseline (BL) and 1, 3, 6, and 12 months after low-dose-rate brachytherapy (three days at each time point). Urinary frequency per day (left) and increase in urinary frequency per day from BL (right) are plotted as mean±standard deviation and compared at each time point using the Mann-Whitney U-test between AMBER trial cases and historical control cases. Urinary frequency per day at 3 months after LDR-BT was the primary endpoint, and urinary frequency per day at 1, 6, and 12 months was the secondary endpoint. The tabulated data show urinary frequency per day and increase in urinary frequency per day from BL, expressed as the median and range at each time point. n.s.: Not significant. B) IPSS total score (left) and IPSS voiding subscore (right; sum of questions 1, 3, 5, and 6) are plotted as mean±standard deviation and compared at each time point with the Mann-Whitney U-test between the AMBER trial cases and historical control cases. Data at 1, 3, 6, 9, and 12 months after LDR-BT were available for the AMBER trial case, but data at 9 months were not available for the historical control cases.

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Table II.

Time-course changes of frequency volume chart-based indexes: Unadjusted comparison between the AMBER trial cases and historical control cases before propensity score matching.

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Table III.

Time-course changes of urinary symptom scores of International prostate symptom score (IPSS) and overactive bladder symptom score (OABSS) questionnaires and urinary symptom domains of Expanded Prostate Cancer Index Composite questionnaires: Comparison between the AMBER trial cases and historical control cases.

The post hoc analysis compared time-course changes in FVC-based indices and urinary symptom questionnaires (IPSS, OABSS, and EPIC) between the two well-balanced groups. There were no significant differences in any of the evaluated scores, indices, or domains at any time point between the two adjusted groups (Figure 3; Table IV and Table V).

Figure 3.
Figure 3.

Time-course changes of urinary frequency and IPSS score in the AMBER trial cases and historical control cases (PSM-adjusted). Propensity score matching was performed to adjust for patient baseline characteristics and decrease the influence of possible confounding factors between the AMBER trial cases (35 patients) and historical control cases (35 patients). A) Urinary frequency per day was assessed using the frequency volume chart [forced vital capacity (FVC), time, and volume of voided urine] at baseline (BL) and 1, 3, 6, and 12 months after low-dose-rate brachytherapy (three days at each time point). Urinary frequency per day (left) and increase in urinary frequency per day from BL (right) are plotted as mean±standard deviation and compared at each time point using the Mann-Whitney U-test between AMBER trial cases and historical control cases. n.s.: Not significant. B) IPSS total score (left) and IPSS voiding subscore (right; sum of questions 1, 3, 5, and 6) are plotted as mean±standard deviation and compared at each time point with the Mann-Whitney U-test between the AMBER trial cases and historical control cases. Data at 1, 3, 6, 9, and 12 months after LDR-BT were available for the AMBER trial case, but data at 9 months were not available for the historical control cases.

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Table IV.

Time-course changes of frequency volume chart-based indexes: PSM-adjusted comparison between the AMBER trial cases and historical control cases.

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Table V.

Time-course changes of urinary symptom scores of International prostate symptom score (IPSS) and overactive bladder symptom score (OABSS) questionnaires and urinary symptom domains of Expanded Prostate Cancer Index Composite questionnaires: PSM-adjusted comparison between the AMBER trial cases and historical control cases.

Investigator-reported adverse events after LDR-BT. GU, GI, and skin AEs are listed and compared between the AMBER trial cases (SAS population, n=49) and historical control cases (n=141) in Table VI. No ≥Grade 3 AEs were observed in either cohort. The most common AEs were urinary frequency and urgency, which were observed in >80% of the patients. Regarding GI AEs, proctitis, rectal pain, and anal pain were observed in approximately 5%-10% of patients. There was no significant difference in the rate of AEs between the two cohorts. Although two patients (4.1%) experienced urticaria in the AMBER trial, no patient experienced photosensitivity, which is an AEs of special interest.

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Table VI.

Comparison of investigator-reported adverse events after low-dose-rate brachytherapy (LDR-BT) between the AMBER trial cases and historical control cases.

Oncological outcomes after LDR-BT. BCRFS and MFS after LDR-BT were compared between the AMBER trial cases (PPS population, n=45) and historical control cases (n=141), with median follow-up durations of 48 months (range=18-48) and 71 months (range=5-96), respectively. During follow-up, two patients in the AMBER trial and three patients in the historical control group had BCR. In addition, 4-year BCRFS rates were 95.5% in the AMBER trial cases and 99.3% in the historical control cases, whereas the 4-year MFS rates were 95.4% and 99.3%, respectively. No significant oncological benefits of oral ALA-SFC were observed in terms of BCRFS or MFS (Figure 4).

Figure 4.
Figure 4.

Biochemical failure-free survival (A) and metastasis-free survival (B) after low-dose-rate brachytherapy (LDR-BT) in the AMBER trial cases and historical control cases. HR: Hazard risk; CI: confidence interval.

Discussion

In LDR-BT for PCa, achieving an adequate local radiation dose—assessed by the dose received by 90% of the prostate gland (D90) or the biologically effective dose (BED)—leads to favorable oncological outcomes and may reduce the need for long-term androgen deprivation therapy (ADT) (19, 20). However, high D90 and/or BED are associated with persistent urinary bothersome and lower urinary symptom flare (3, 21). Physicians and patients face a clinical dilemma between therapeutic effect and adverse effects in the decision-making for localized PCa.

The goal of this prospective, single-center trial was to explore the potential benefits of using ALA-SFC in patients who underwent LDR-BT for localized PCa. We expected that oral ALA-SFC would lower the risk of AEs, especially GU toxicities, after LDR-BT and enhance the antitumor effects of radiotherapy. Supplementation of oral ALA-SFC on consecutive days for six months after LDR-BT did not mitigate urinary frequency (the primary endpoint) throughout the 12 months; however, this intervention could alleviate urinary voiding symptoms (IPSS voiding sub-score) during the 6-12 months after LDR-BT in the comparison between the two unadjusted cohorts (Figure 2B). However, there were substantial differences in patient demographics and baseline characteristics, including clinical T category, Gleason group, and prostate volume, which led to differences in post-dosimetric parameters. Thus, we performed a post hoc analysis using PSM to adjust for patient baseline characteristics and decrease the influence of possible confounding factors between the AMBER trial cases and historical control cases. Comparison between the two well-balanced cohorts showed no significant differences in any of the evaluated scores, indices, or domains at any time point between the two adjusted groups (Figure 3; Table IV and Table V).

In addition to the patient-reported outcomes (FVC, IPSS, OABSS, and EPIC questionnaires), we evaluated investigator-reported outcomes using CTCAE version 5.0 at each visit, demonstrating no significant difference in the rates of GU and GI AEs between the two cohorts. Skin toxicity is an adverse event of particular interest in humans. For photodynamic diagnosis during transurethral surgery for bladder cancer, 20 mg/kg of 5-aminolevulinic acid hydrochloride was orally administered before surgery (22). For example, a patient weighing 75 kg was prescribed 1.5 g ALA hydrochloride containing 1.17 g of ALA. As a photosensitive substance, protoporphyrin IX can accumulate in the skin layer after 5-aminolevulinic acid administration, and patients are advised to avoid strong light for at least 48 h to prevent photosensitivity. In the AMBER trial, a fixed dose of 200 mg of ALA phosphate was orally administered daily for 180 days, resulting in a total dose of 36 g of ALA phosphate. However, given that no patient experienced skin photosensitivity and only two patients (4.1%) had urticaria, 5-aminolevulinic acid showed low bioaccumulation in the human body and high tolerability even after long-term administration.

Our previous preclinical study using a syngeneic PCa model with MyC-CaP cells in FVB mice demonstrated that oral administration of ALA hydrochloride for 30 days significantly protected normal pelvic organs from radiotherapy (7). The higher dose (383 mg/kg/day of ALA hydrochloride containing 300 mg/kg/day of ALA) exerted a better radioprotective profile than the lower dose (30 mg/kg/day) in normal recta and urinary bladders. Besides, gene expression analyses in post-radiotherapy specimens found that interleukin-1a (Il1a), Il1b, Il12, chemokine (C-X-C motif) ligand 1 (Cxcl1), Cxcl3, and Nlpr3 might be involved in the radioprotective role of 5-aminolevulinic acid administration. As post-radiotherapy tissues such as urothelial and rectal cells were not tested in this clinical trial, a positive effect at the molecular level may occur with 5-aminolevulinic acid administration. Another potential benefit of ALA is an increase in the radiosensitization of malignant cells. Previous studies have shown that ALA supplementation sensitizes malignant cells, including PCa, glioma, melanoma, and colon adenocarcinoma cells, to radiotherapy via enhanced generation of protoporphyrin IX and reactive oxygen species (7, 10-13, 23). Based on this evidence, this trial included oncological outcomes, such as BCRFS and MFS, after LDR-BT as secondary endpoints, and found no significant oncological benefits from oral ALA-SFC. The limitations of this study include the limited number of events and the relatively short-term follow-up.

Another issue that needs to be addressed is the possible preventive effect of oral ALA-SFC against secondary cancers after radiotherapy for PCa. The bladder and rectum are adjacent to the prostate and are vulnerable to ionizing radiation. Accumulated data from clinical studies have suggested an elevated risk of second primary bladder and rectal cancers in patients with PCa undergoing radiotherapy (24-26). Exposure to ionizing radiation causes DNA single-stranded and double-stranded DNA breaks in normal epithelium. DNA single-strand and double-strand breaks in DNA can lead to gene mutations and subsequent malignant transformation of irradiated normal cells (27). Supplementation with oral ALA-SFC during and after radiotherapy is expected to have a cytoprotective effect on the normal epithelium, resulting in a reduced risk of radiation-induced secondary cancer. Owing to the limited follow-up duration in the AMBER trial cases [median, 48 months (range=18-48)], we could not confirm the potential preventive effect on the development of secondary cancers in this trial.

Conclusion

Oral supplementation of ALA-SFC to LDR-BT did not alleviate radiation-induced toxicity or improve oncological outcomes. A future randomized controlled trial with dose escalation of oral ALA-SFC (>200 mg/day) and evaluation of the changes in tissue-, urine-, and blood-based molecular profiles might provide patients with supplementary interventions and potentially change their standards of care.

Acknowledgements

The Authors would like to thank all members of the staff of the Clinical Research Center at Nara Medical University (iCATs) for their contribution to this trial. The Authors are grateful to Dr Takashi Inoue for special assistance with statistical analysis. The Authors would like to thank all participants for their participation in this trial.

Footnotes

  • Authors’ Contributions

    Conceptualization, M.M. and N.T.; methodology, M.M.; formal analysis, M.M. and N.N.; resources, acquisition, and data curation: M.M., K.O, Y.N., and S.A; writing—original draft preparation, M.M.; writing—review and editing, N.T. and K.F.; visualization and supervision, K.Y., I.A., and F.I.; project administration, N.T. and K.F.; funding acquisition, M.M., N.T. and K.F. All Authors have read and agreed to the published version of the manuscript. All Authors have agreed to be accountable for all aspects of the work and to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding

    The AMBER study is funded by SBI Pharmaceuticals Co., Ltd. The role of the funding body is production and provision of the intervention drug (ALA-SFC capsules).

  • Conflicts of Interest

    M.M., N.T., and K.F. have received a research grant from SBI Pharmaceuticals Co., Ltd, that produces ALA-SFC capsules and partially supported this clinical trial.

  • Received August 8, 2024.
  • Revision received August 28, 2024.
  • Accepted August 29, 2024.

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).

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Oral 5-aminolevulinic Acid for Patients With Localized Prostate Cancer Undergoing Low-dose-rate Brachytherapy: AMBER Trial
MAKITO MIYAKE, NOBUMICHI TANAKA, KENTA OHNISHI, YASUSHI NAKAI, SATOSHI ANAI, KAORU YAMAKI, ISAO ASAKAWA, NOBUTAKA NISHIMURA, TOMOMI FUJII, FUMIAKI ISOHASHI, KIYOHIDE FUJIMOTO
In Vivo Nov 2024, 38 (6) 3091-3105; DOI: 10.21873/invivo.13794
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