{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T14:46:52Z","timestamp":1791470812540,"version":"4.3.4"},"reference-count":36,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,31]],"date-time":"2025-08-31T00:00:00Z","timestamp":1756598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Toshiba Energy Systems and Solutions Corporation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Biochemical recurrence after radiotherapy for prostate cancer is commonly defined by the Phoenix criteria (prostate-specific antigen [PSA] nadir + 2 ng\/mL). However, some patients experience PSA elevation without clinical recurrence, which is known as PSA bounce. This study aimed to evaluate PSA kinetics after scanning-method carbon ion radiotherapy (CIRT) in patients with high-risk prostate cancer (HR-PCa) and to assess the clinical validity of the Phoenix criteria. Methods: We retrospectively analyzed 171 patients with HR-PCa who underwent CIRT and 2 years of androgen deprivation therapy. Patients were classified into three groups based on post-treatment PSA kinetics: non-recurrence, pseudo-recurrence (PR; PSA &gt; 2 ng\/mL followed by spontaneous decline without salvage therapy), and recurrence (R; PSA &gt; 2 ng\/mL with salvage therapy). PSA bounce was defined as a transient PSA increase &gt; 0.4 ng\/mL followed by spontaneous decline. Kaplan\u2013Meier and receiver operating characteristic (ROC) analyses were used to evaluate biochemical relapse-free survival and determine the optimal PSA cutoff. Results: Among 171 patients, 18 (10.5%) met the Phoenix criteria (R+PR), of whom 6 (33.3%) experienced spontaneous PSA decline. The 5-year biochemical relapse-free survival rate was 90.0%. PSA bounce occurred in 33.9%. ROC analysis identified an optimal PSA cutoff of 1.91 ng\/mL (area under the curve: 0.985), whereas the positive predictive value at the 2 ng\/mL cutoff was as low as 61.1% due to the influence of PSA bounce. Conclusions: After CIRT, a PSA rise of &gt;2 ng\/mL does not always indicate HR-PCa recurrence and should be interpreted with caution to avoid overtreatment.<\/jats:p>","DOI":"10.3390\/cancers17172867","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T14:02:46Z","timestamp":1756735366000},"page":"2867","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Does PSA Nadir + 2 ng\/mL Always Indicate Biochemical Recurrence? A PSA Kinetics-Based Evaluation Following Carbon Ion Radiotherapy for Localized High-Risk Prostate Cancer"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8077-5795","authenticated-orcid":false,"given":"Satoshi","family":"Shima","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan"},{"name":"Diagnostic Radiology and Radiation Oncology, Graduate School of Medicine, Chiba University, Chiba, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5218-0806","authenticated-orcid":false,"given":"Yosuke","family":"Takakusagi","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Yokohama Sakae Kyosai Hospital, Yokohama, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Okuda","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Koge","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kio","family":"Kano","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Okada","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Tsuchida","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohei","family":"Kawashiro","sequence":"additional","affiliation":[{"name":"Medical Care Bureau, Yokohama, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2464-7453","authenticated-orcid":false,"given":"Nobutaka","family":"Mizoguchi","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisaku","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Katoh","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4606-5662","authenticated-orcid":false,"given":"Takashi","family":"Uno","sequence":"additional","affiliation":[{"name":"Diagnostic Radiology and Radiation Oncology, Graduate School of Medicine, Chiba University, Chiba, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,31]]},"reference":[{"key":"ref_1","unstructured":"Cancer Statistics (2025, July 09). Cancer Information Service, National Cancer Center, Japan (National Cancer Registry, Ministry of Health, Labour and Welfare). Available online: https:\/\/ganjoho.jp\/reg_stat\/statistics\/stat\/cancer\/20_prostate.html."},{"key":"ref_2","unstructured":"(2025, July 09). Cancer Today Globocan 2022. Available online: https:\/\/gco.iarc.who.int\/media\/globocan\/factsheets\/cancers\/27-prostate-fact-sheet.pdf."},{"key":"ref_3","unstructured":"(2025, July 09). NCCN Guidelines for Prostate Cancer. Available online: https:\/\/www.nccn.org\/guidelines\/guidelines-detail?category=1&id=1459."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1111\/j.1442-2042.2012.02961.x","article-title":"Carbon-ion radiation therapy for prostate cancer","volume":"19","author":"Ishikawa","year":"2012","journal-title":"Int. J. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ejmp.2021.08.013","article-title":"Retrospective comparison of rectal toxicity between carbon-ion radiotherapy and intensity-modulated radiation therapy based on treatment plan, normal tissue complication probability model, and clinical outcomes in prostate cancer","volume":"90","author":"Fukata","year":"2021","journal-title":"Phys. Medica"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Oike, T., Niimi, A., Okonogi, N., Murata, K., Matsumura, A., Noda, S.-E., Kobayashi, D., Iwanaga, M., Tsuchida, K., and Kanai, T. (2016). Visualization of complex DNA double-strand breaks in a tumor treated with carbon ion radiotherapy. Sci. Rep., 6.","DOI":"10.1038\/srep22275"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1667\/RR13904.1","article-title":"The major DNA repair pathway after both proton and carbon-ion radiation is NHEJ, but the HR pathway is more relevant in carbon ions","volume":"183","author":"Gerelchuluun","year":"2015","journal-title":"Radiat. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/S0094-0143(03)00057-0","article-title":"PSA markers in prostate cancer detection","volume":"30","author":"Gretzer","year":"2003","journal-title":"Urol. Clin. N. Am."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.ijrobp.2006.04.029","article-title":"Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference","volume":"65","author":"Roach","year":"2006","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/S0022-5347(05)67698-7","article-title":"Prostate specific antigen bounce after radioactive seed implantation followed by external beam radiation for prostate cancer","volume":"163","author":"Critz","year":"2000","journal-title":"J. Urol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Darwis, N.D.M., Oike, T., Kawamura, H., Kawahara, M., Kubo, N., Sato, H., Miyasaka, Y., Katoh, H., Ishikawa, H., and Matsui, H. (2020). Kinetics of prostate-specific antigen after carbon ion radiotherapy for prostate cancer. Cancers, 12.","DOI":"10.3390\/cancers12030589"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.brachy.2019.08.008","article-title":"Racial differences in the PSA bounce in predicting prostate cancer outcomes after brachytherapy: Evidence from the Department of Veterans Affairs","volume":"19","author":"Slade","year":"2020","journal-title":"Brachytherapy"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.ijrobp.2017.01.025","article-title":"Increasing fractional doses increases the probability of benign PSA bounce in patients undergoing definitive HDR brachytherapy for prostate cancer","volume":"98","author":"Hauck","year":"2017","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S205","DOI":"10.1016\/j.ijrobp.2006.07.394","article-title":"The post-treatment PSA bounce for prostate cancer patients treated with external beam RT or permanent brachytherapy alone is not biochemically or clinically significant: A multi-institutional pooled analysis of more than 7500 patients","volume":"66","author":"Horwitz","year":"2006","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.radonc.2013.08.030","article-title":"Stereotactic body radiotherapy for localized prostate cancer: Pooled analysis from a multi-institutional consortium of prospective phase II trials","volume":"109","author":"King","year":"2013","journal-title":"Radiother. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Takakusagi, Y., Oike, T., Kano, K., Anno, W., Tsuchida, K., Mizoguchi, N., Serizawa, I., Yoshida, D., Katoh, H., and Kamada, T. (2020). Prostate-specific antigen dynamics after neoadjuvant androgen-deprivation therapy and carbon ion radiotherapy for prostate cancer. PLoS ONE, 15.","DOI":"10.21203\/rs.3.rs-32254\/v1"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1001\/jama.280.11.969","article-title":"Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer","volume":"280","author":"Whittington","year":"1998","journal-title":"JAMA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s13014-020-01575-7","article-title":"Preliminary result of carbon-ion radiotherapy using the spot scanning method for prostate cancer","volume":"15","author":"Takakusagi","year":"2020","journal-title":"Radiat. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/acm2.13275","article-title":"Interfractional robustness of scanning carbon ion radiotherapy for prostate cancer: An analysis based on dose distribution from daily in-room CT images","volume":"22","author":"Tsuchida","year":"2021","journal-title":"J. Appl. Clin. Med. Phys."},{"key":"ref_20","unstructured":"Python Software Foundation (2025, August 21). Python. Available online: https:\/\/www.python.org\/."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1109\/MCSE.2007.55","article-title":"Matplotlib: A 2D graphics environment","volume":"9","author":"Hunter","year":"2007","journal-title":"Comput. Sci. Eng."},{"key":"ref_22","first-page":"2825","article-title":"Scikit-learn: Machine learning in Python","volume":"12","author":"Pedregosa","year":"2011","journal-title":"J. Mach. Learn. Res."},{"key":"ref_23","unstructured":"van der Walt, S., and Millman, J. (July, January 28). Data Structures for Statistical Computing in Python. Proceedings of the 9th Python in Science Conference, Austin, TX, USA."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/s41586-020-2649-2","article-title":"Array programming with NumPy","volume":"585","author":"Harris","year":"2020","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/s41592-019-0686-2","article-title":"SciPy 1.0: Fundamental algorithms for scientific computing in Python","volume":"17","author":"Virtanen","year":"2020","journal-title":"Nat. Methods"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1002\/pros.24059","article-title":"Impact of radiation dose on recurrence in high-risk prostate cancer patients","volume":"80","author":"Deek","year":"2020","journal-title":"Prostate"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.ijrobp.2016.11.026","article-title":"Androgen suppression combined with elective nodal and dose escalated radiation therapy (the ASCENDE-RT Trial): An analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high- and intermediate-risk prostate cancer","volume":"98","author":"Morris","year":"2017","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.ijrobp.2015.05.044","article-title":"High-dose-rate brachytherapy as monotherapy for intermediate- and high-risk prostate cancer: Clinical results for a median 8-year follow-up","volume":"94","author":"Yoshioka","year":"2016","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1016\/j.ijrobp.2020.11.007","article-title":"Proton therapy for localized prostate cancer: Long-term results from a single-center experience","volume":"109","author":"Takagi","year":"2021","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.radonc.2016.10.009","article-title":"A multi-institutional analysis of prospective studies of carbon ion radiotherapy for prostate cancer: A report from the Japan Carbon ion Radiation Oncology Study Group (J-CROS)","volume":"121","author":"Nomiya","year":"2016","journal-title":"Radiother. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1111\/cas.13402","article-title":"Cancer-specific mortality of high-risk prostate cancer after carbon-ion radiotherapy plus long-term androgen deprivation therapy","volume":"108","author":"Kasuya","year":"2017","journal-title":"Cancer Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1200\/JCO.2007.15.9699","article-title":"Risk of prostate cancer recurrence in men treated with radiation alone or in conjunction with combined or less than combined androgen suppression therapy","volume":"26","author":"Chen","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.ijrobp.2008.01.056","article-title":"Determinants of change in prostate-specific antigen over time and its association with recurrence after external beam radiation therapy for prostate cancer in five large cohorts","volume":"72","author":"Taylor","year":"2008","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"18","DOI":"10.4111\/icu.2018.59.1.18","article-title":"Factors associated with testosterone recovery after androgen deprivation therapy in patients with prostate cancer","volume":"59","author":"Nam","year":"2018","journal-title":"Investig. Clin. Urol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.radonc.2021.11.005","article-title":"Refining the definition of biochemical failure in the era of stereotactic body radiation therapy for prostate cancer: The Phoenix definition and beyond","volume":"166","author":"Ma","year":"2022","journal-title":"Radiother. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Darwis, N.D.M., Oike, T., Kubo, N., Gondhowiardjo, S.A., and Ohno, T. (2020). Characteristics of PSA bounce after radiotherapy for prostate cancer: A meta-analysis. Cancers, 12.","DOI":"10.3390\/cancers12082180"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/17\/2867\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:36:29Z","timestamp":1760034989000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/17\/2867"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,31]]},"references-count":36,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["cancers17172867"],"URL":"https:\/\/doi.org\/10.3390\/cancers17172867","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,31]]}}}