{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T19:51:19Z","timestamp":1766087479505,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,10,26]],"date-time":"2019-10-26T00:00:00Z","timestamp":1572048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Here, we compared the toxicity profiles of contemporary stereotactic radiosurgery (SRS), modern fractionated radiotherapy (FRT), and transsphenoidal surgery used to treat nonfunctioning pituitary macroadenomas. Methods: We included the data of patients with nonfunctioning pituitary macroadenomas. To compare treatment outcomes, the patients were categorized groups 1 (those receiving modern FRT), 2 (those receiving contemporary SRS), and 3 (those receiving transsphenoidal surgery). The multivariable Cox proportional hazards regression analysis was performed to yielded adjusted hazard ratios (aHRs) and their 95% CIs for local recurrence in groups 2 and 3 compared with group 1. Results: We included the data of 248 patients with nonfunctioning pituitary macroadenomas. The analytical results revealed no significant differences in second primary brain or head and neck cancer, hypopituitarism, or optic nerve injury between the three cohorts. The multivariable Cox proportional hazards regression analysis revealed that compared with group 1, the aHRs (95% CIs) for stroke risk in groups 2 and 3 were 0.37 (0.14\u20130.99) and 0.51 (0.31\u20130.84), respectively. Conclusion: Contemporary SRS and transsphenoidal surgery for nonfunctioning pituitary macroadenoma treatment have equivalent toxicity profiles. However, modern FRT for nonfunctioning pituitary macroadenoma treatment might considerably increase stroke risk.<\/jats:p>","DOI":"10.3390\/cancers11111658","type":"journal-article","created":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T04:44:31Z","timestamp":1572237871000},"page":"1658","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Toxicity Profiles of Fractionated Radiotherapy, Contemporary Stereotactic Radiosurgery, and Transsphenoidal Surgery in Nonfunctioning Pituitary Macroadenomas"],"prefix":"10.3390","volume":"11","author":[{"given":"Chia-Lun","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 106, Taiwan"},{"name":"Department of Hemato-Oncology, Wan Fang Hospital, Taipei Medical University, Taipei 106, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin Sheng-Po","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Wan Fang Hospital, Taipei Medical University, Taipei 106, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0178-6530","authenticated-orcid":false,"given":"Alexander T.H.","family":"Wu","sequence":"additional","affiliation":[{"name":"Ph.D. Program for Translational Medicine, Taipei Medical University, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5637-558X","authenticated-orcid":false,"given":"Szu-Yuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung 413, Taiwan"},{"name":"Division of Radiation Oncology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan 265, Taiwan"},{"name":"Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 106, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1055\/s-2002-36708","article-title":"Gonadotropinomas","volume":"20","author":"Chaidarun","year":"2002","journal-title":"Semin. Reprod. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1210\/jc.2004-0875","article-title":"Clinically silent somatotropinomas may be biochemically active","volume":"90","author":"Sakharova","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1530\/EJE-11-0216","article-title":"Clinically silent somatotroph adenomas are common","volume":"165","author":"Wade","year":"2011","journal-title":"Eur. J. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.ecl.2007.10.011","article-title":"Nonfunctioning pituitary tumors and pituitary incidentalomas","volume":"37","author":"Molitch","year":"2008","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1097\/00006123-199702000-00001","article-title":"Complications of transsphenoidal surgery: Results of a national survey, review of the literature, and personal experience","volume":"40","author":"Ciric","year":"1997","journal-title":"Neurosurgery"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1210\/jcem.82.8.4188","article-title":"Surgical management of pituitary tumors","volume":"82","author":"Wilson","year":"1997","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Hsiao, P.K., Chang, C.L., Yuan, K.S., Wu, A.T.H., and Wu, S.Y. (2019). Results of Treatment with Modern Fractionated Radiotherapy, Contemporary Stereotactic Radiosurgery, and Transsphenoidal Surgery in Nonfunctioning Pituitary Macroadenoma. J. Clin. Med., 8.","DOI":"10.3390\/jcm8040518"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/j.ijrobp.2009.10.005","article-title":"Initial experience with volumetric IMRT (RapidArc) for intracranial stereotactic radiosurgery","volume":"78","author":"Mayo","year":"2010","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.radonc.2009.08.011","article-title":"Volumetric modulated arc therapy (VMAT) vs. serial tomotherapy, step-and-shoot IMRT and 3D-conformal RT for treatment of prostate cancer","volume":"93","author":"Wolff","year":"2009","journal-title":"Radiother. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3382","DOI":"10.1120\/jacmp.v13i5.3382","article-title":"Application of AAPM TG 119 to volumetric arc therapy (VMAT)","volume":"13","author":"Mynampati","year":"2012","journal-title":"J. Appl. Clin. Med. Phys."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"207","DOI":"10.4103\/0971-6203.103606","article-title":"Homogeneity Index: An objective tool for assessment of conformal radiation treatments","volume":"37","author":"Kataria","year":"2012","journal-title":"J. Med. Phys."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/1748-717X-1-46","article-title":"CyberKnife radiosurgery in the treatment of complex skull base tumors: Analysis of treatment planning parameters","volume":"1","author":"Collins","year":"2006","journal-title":"Radiat. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"A2","DOI":"10.1227\/01.neu.0000325931.26531.45","article-title":"Novalis intensity-modulated radiosurgery: Methods for pretreatment planning","volume":"62","author":"Jensen","year":"2008","journal-title":"Neurosurgery"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1161\/01.STR.23.6.908","article-title":"Stroke after pituitary irradiation","volume":"23","author":"Bowen","year":"1992","journal-title":"Stroke"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ijrobp.2013.05.006","article-title":"Incidence, causative mechanisms, and anatomic localization of stroke in pituitary adenoma patients treated with postoperative radiation therapy versus surgery alone","volume":"87","author":"Sattler","year":"2013","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"834","DOI":"10.2169\/internalmedicine.41.834","article-title":"Cerebral hemorrhagic infarction after radiation for pituitary adenoma","volume":"41","author":"Ogaki","year":"2002","journal-title":"Intern. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.1161\/STROKEAHA.111.615203","article-title":"Ischemic stroke and transient ischemic attack after head and neck radiotherapy: A review","volume":"42","author":"Plummer","year":"2011","journal-title":"Stroke"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.canlet.2004.10.023","article-title":"Radiotherapy for oral cancer as a risk factor for second primary cancers","volume":"220","author":"Hashibe","year":"2005","journal-title":"Cancer Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s11060-014-1399-0","article-title":"Visual outcome after fractionated stereotactic radiation therapy of benign anterior skull base tumors","volume":"118","author":"Astradsson","year":"2014","journal-title":"J. Neurooncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1093\/jjco\/hyu211","article-title":"Quality assessment and improvement of nationwide cancer registration system in Taiwan: A review","volume":"45","author":"Chiang","year":"2015","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"258","DOI":"10.7326\/0003-4819-148-4-200802190-00004","article-title":"A 10-year experience with universal health insurance in Taiwan: Measuring changes in health and health disparity","volume":"148","author":"Wen","year":"2008","journal-title":"Ann. Intern. Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Shao, Y.J., Chan, T.S., Tsai, K., and Wu, S.Y. (2018). Association between proton pump inhibitors and the risk of hepatocellular carcinoma. Aliment. Pharmacol. Ther.","DOI":"10.1111\/apt.14835"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1700339","DOI":"10.1002\/advs.201700339","article-title":"Radiation-Sensitive Dendrimer-Based Drug Delivery System","volume":"5","author":"Wu","year":"2018","journal-title":"Adv. Sci. (Weinh)"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1002\/cam4.1479","article-title":"Adjuvant radiotherapy and chemotherapy improve survival in patients with pancreatic adenocarcinoma receiving surgery: Adjuvant chemotherapy alone is insufficient in the era of intensity modulation radiation therapy","volume":"7","author":"Hsieh","year":"2018","journal-title":"Cancer Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Yen, Y.C., Hsu, H.L., Chang, J.H., Lin, W.C., Chang, Y.C., Chang, C.L., Chow, J.M., Yuan, K.S., Wu, A.T.H., and Wu, S.Y. (2018). Efficacy of thoracic radiotherapy in patients with stage IIIB-IV epidermal growth factor receptor-mutant lung adenocarcinomas who received and responded to tyrosine kinase inhibitor treatment. Radiother. Oncol.","DOI":"10.1016\/j.radonc.2018.03.007"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lin, Y.K., Hsieh, M.C., Wang, W.W., Lin, Y.C., Chang, W.W., Chang, C.L., Cheng, Y.F., and Wu, S.Y. (2018). Outcomes of adjuvant treatments for resectable intrahepatic cholangiocarcinoma: Chemotherapy alone, sequential chemoradiotherapy, or concurrent chemoradiotherapy. Radiother. Oncol.","DOI":"10.1016\/j.radonc.2018.05.011"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chen, T.M., Lin, K.C., Yuan, K.S., Chang, C.L., Chow, J.M., and Wu, S.Y. (2017). Treatment of advanced nasopharyngeal cancer using low- or high-dose concurrent chemoradiotherapy with intensity-modulated radiotherapy: A propensity score-matched, nationwide, population-based cohort study. Radiother. Oncol.","DOI":"10.1016\/j.radonc.2017.12.004"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chang, C.L., Tsai, H.C., Lin, W.C., Chang, J.H., Hsu, H.L., Chow, J.M., Yuan, K.S., Wu, A.T.H., and Wu, S.Y. (2017). Dose escalation intensity-modulated radiotherapy-based concurrent chemoradiotherapy is effective for advanced-stage thoracic esophageal squamous cell carcinoma. Radiother. Oncol.","DOI":"10.1016\/j.radonc.2017.08.025"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1002\/cam4.976","article-title":"Survival prognostic factors for metachronous second primary head and neck squamous cell carcinoma","volume":"6","author":"Chen","year":"2017","journal-title":"Cancer Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3717","DOI":"10.1210\/jc.2008-0643","article-title":"Treatment and follow-up of clinically nonfunctioning pituitary macroadenomas","volume":"93","author":"Dekkers","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1002\/1097-0142(19931001)72:7<2227::AID-CNCR2820720727>3.0.CO;2-I","article-title":"Glioma arising after radiation therapy for pituitary adenoma. A report of four patients and estimation of risk","volume":"72","author":"Tsang","year":"1993","journal-title":"Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1136\/bmj.304.6838.1343","article-title":"Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma","volume":"304","author":"Brada","year":"1992","journal-title":"BMJ"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Yamanaka, R., Abe, E., Sato, T., Hayano, A., and Takashima, Y. (2017). Secondary Intracranial Tumors Following Radiotherapy for Pituitary Adenomas: A Systematic Review. Cancers, 9.","DOI":"10.3390\/cancers9080103"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1186\/1748-717X-7-225","article-title":"Fractionated stereotactic radiation therapy improves cranial neuropathies in patients with skull base meningiomas: A retrospective cohort study","volume":"7","author":"Shen","year":"2012","journal-title":"Radiat. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.ijrobp.2016.07.007","article-title":"Stroke after Radiation Therapy for Head and Neck Cancer: What Is the Risk?","volume":"96","author":"Arthurs","year":"2016","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_36","first-page":"175","article-title":"Anesthesia for the elderly","volume":"11","author":"Kanonidou","year":"2007","journal-title":"Hippokratia"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1002\/cncr.22860","article-title":"The efficacy of fractionated radiotherapy and stereotactic radiosurgery for pituitary adenomas: Long-term results of 125 consecutive patients treated in a single institution","volume":"110","author":"Kong","year":"2007","journal-title":"Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1111\/j.1532-5415.2010.02767.x","article-title":"Competing risk of death: An important consideration in studies of older adults","volume":"58","author":"Berry","year":"2010","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0167-8140(99)00020-1","article-title":"Commissioning of a micro multi-leaf collimator and planning system for stereotactic radiosurgery","volume":"50","author":"Cosgrove","year":"1999","journal-title":"Radiother. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/0360-3016(92)91022-F","article-title":"Second head and neck cancers following radiation therapy of T1 and T2 cancers of the oral cavity and oropharynx","volume":"24","author":"Fijuth","year":"1992","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1667\/RR1862.1","article-title":"Vascular damage as an underlying mechanism of cardiac and cerebral toxicity in irradiated cancer patients","volume":"174","author":"Stewart","year":"2010","journal-title":"Radiat. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1161\/CIRCRESAHA.116.308398","article-title":"Stroke Risk Factors, Genetics, and Prevention","volume":"120","author":"Boehme","year":"2017","journal-title":"Circ. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1212\/WNL.0b013e318270401d","article-title":"Age at stroke: Temporal trends in stroke incidence in a large, biracial population","volume":"79","author":"Kissela","year":"2012","journal-title":"Neurology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/0360-3016(92)90948-H","article-title":"Reemergence of apoptotic cells between fractionated doses in irradiated murine tumors","volume":"30","author":"Meyn","year":"1994","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1097\/00019052-199812000-00003","article-title":"Radiation myelopathy","volume":"11","author":"Rampling","year":"1998","journal-title":"Curr. Opin. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1667\/RR3597.1","article-title":"Late effects of radiation on the central nervous system: Role of vascular endothelial damage and glial stem cell survival","volume":"166","author":"Coderre","year":"2006","journal-title":"Radiat. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"01TR01","DOI":"10.1088\/1361-6560\/aaf26a","article-title":"The linear quadratic model: Usage, interpretation and challenges","volume":"64","author":"McMahon","year":"2018","journal-title":"Phys. Med. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"362761","DOI":"10.1155\/2013\/362761","article-title":"Radiobiology of radiosurgery for the central nervous system","volume":"2013","author":"Santacroce","year":"2013","journal-title":"Biomed. Res. Int."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/0360-3016(85)90366-9","article-title":"A review of alpha\/beta ratios for experimental tumors: Implications for clinical studies of altered fractionation","volume":"11","author":"Williams","year":"1985","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/11\/1658\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:29:36Z","timestamp":1760189376000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/11\/1658"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,26]]},"references-count":49,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["cancers11111658"],"URL":"https:\/\/doi.org\/10.3390\/cancers11111658","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2019,10,26]]}}}