Radiotherapy-induced Hypothalamic-Pituitary axis dysfunction in adult Brain, head and neck and skull base tumor patients – A systematic review and Meta-Analysis

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HP-axis described", "1"], ["Demonstration that outcome of interest was not present at start of the study", "Absence of endocrine insufficiency at the start of the study described", "1"], ["Comparability"], ["Comparability of cohorts on the basis of the design or analysis:", "Endocrine insufficiency of at least 3 different axes described", "1"], ["Insufficiency in more than one axis described", "1"], ["Outcome"], ["Assessment of outcome", "Methodology of endocrine evaluation described", "1"], ["Was follow-up long enough for outcomes to occur?", "Median or mean follow-up period for at least 24 months described", "1"], ["Adequacy of follow-up of cohorts", "Complete follow up of at least 75 % of subjects per axis described", "1"]], "row_count": 13, "column_count": 3, "numeric_cells": 12, "header_rows": 1, "locator": "section[4]/table-wrap[1]#t0005"}}, {"id": "asset:table:pmid:39801827:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, 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Publications with * were excluded from the meta-analysis. Abbreviations: NSCLC: Non-small cell lung carcinoma; SCLC: small cell lung carcinoma; NPC: nasopharyngeal carcinoma; BM: brain metastasis; Gy: Gray; TD: total dose; PCI: prophylactic cranial irradiation; WBRT: whole brain radiotherapy; SRS: stereotactic radiosurgery; RT: radiotherapy; SRT: stereotactic radiotherapy; FSRT: fractionated stereotactic radiotherapy; IMRS: intensity-modulated radiosurgery; gEUD: generalized equivalent uniform dose; RBE: relative biological effectiveness; IDL: isodose line; IGF-1: insulin-like growth factor; LH: luteinizing hormone; FSH: follicle stimulating hormone; SHBG: sex hormone binding globulin; PRL: prolactin; TSH: thyroid stimulating hormone; fT4: free T4; ACTH: adrenocorticotrophic hormone; GH: growth hormone; ITT: insulin tolerance test; GST: glucose suppression test; GHRH: growth hormone releasing hormone; CV: cardio-vascular; (c)ChT: (concurrent) chemotherapy; TMZ: temozolomide; Dpit : dose to pituitary gland; Dhypo : dose to hypothalamus; Dhpa : dose to hypothalamic-pituitary axis; NA: data not available.", "structure": {"pmcid": "PMC11721507", "section_index": 4, "section_title": "Data review and analysis and risk of bias assessment", "row_count": 23, "column_count": 10}, "table": {"label": "Table 2a", "caption": "Patient characteristics, risk of bias assessment, nature and location of the primary tumor, radiation dose to tumor and/or HP AXIS, follow-up period, method of endocrine evaluation and additional treatment modalities. Publications with * were excluded from the meta-analysis. Abbreviations: NSCLC: Non-small cell lung carcinoma; SCLC: small cell lung carcinoma; NPC: nasopharyngeal carcinoma; BM: brain metastasis; Gy: Gray; TD: total dose; PCI: prophylactic cranial irradiation; WBRT: whole brain radiotherapy; SRS: stereotactic radiosurgery; RT: radiotherapy; SRT: stereotactic radiotherapy; FSRT: fractionated stereotactic radiotherapy; IMRS: intensity-modulated radiosurgery; gEUD: generalized equivalent uniform dose; RBE: relative biological effectiveness; IDL: isodose line; IGF-1: insulin-like growth factor; LH: luteinizing hormone; FSH: follicle stimulating hormone; SHBG: sex hormone binding globulin; PRL: prolactin; TSH: thyroid stimulating hormone; fT4: free T4; ACTH: adrenocorticotrophic hormone; GH: growth hormone; ITT: insulin tolerance test; GST: glucose suppression test; GHRH: growth hormone releasing hormone; CV: cardio-vascular; (c)ChT: (concurrent) chemotherapy; TMZ: temozolomide; Dpit : dose to pituitary gland; Dhypo : dose to hypothalamus; Dhpa : dose to hypothalamic-pituitary axis; NA: data not available.", "rows": [["First author, year of publication, [Ref.]", "No. of pts, age (range), gender", "Risk of bias", "Tumor characteristics", "Irradiation", "Single fraction dose", "BED HP structures", "Follow-up period", "Endocrine evaluation", "Other treatment modalities"], ["Gebauer, 2020 [55]", "26,Median 58 (36–81),16F/10 M", "6", "BM from NSCLC (n = 6), breast cancer (n = 3), SCLC (n = 2), urothelial cancer (n = 2) or PCI in SCLC (n = 12). Total pts 25.", "WBRT for BM: TD 36 or 35–37.5 Gy or 40 GY (n = 14); PCI TD 30 Gy (n = 12). Equal on HP-axis due to homogenic dose distribution", "TD 36 or 40 Gy: 2 Gy; TD 35–37.5 Gy: 2.5 Gy", "TD 36 Gy: 60 Gy; TD 40 Gy: 66.67 Gy; TD 35–37.2 Gy: 64.17–68.75 Gy", "Median 20.5 months (6–151 months).", "Early-morning measurement of IGF1, LH, FSH, Testosterone, SHBG (M), 17 beta-estradiol, PRL, TSH, fT4, cortisol, ACTH", "NA"], ["Kyriakakis, 2019 [20]*", "58,Mean 41 (30–52),26F/32 M", "7", "Astrocytoma (n = 32), Oligodendroglioma (n = 12), Glioblastoma (n = 8), Ependymoma (n = 5), Uncategorized glioma (n = 1)", "Dose to tumor 53.9 Gy +/- 5.6 Gy;Mean Dhpa 36.7 Gy +/- 15.9 Gy", "2 Gy", "Mean Dhpa 61.17 Gy", "Mean 98.4 months (36–161)", "ITT and GST (ACTH, GH). Basal serum levels LH/FSH, TSH, fT4, PRL, testosterone, estradiol", "Surgery + RT (n = 20); Chemo + RT (n = 6); Surgery + chemo + RT (n = 25)"], ["Kyriakakis, 2016 [24]", "107,Mean 40 (27–53),52F/55 M", "7", "Glioma (n = 60), Meningioma (n = 22), Medulloblastoma (n = 9), Pinealoma (n = 8), Other primary (n = 7), No histology (n = 1)", "Photons: Mean dose to tumor 54 Gy (n = 101); 30–50 Gy (n = 16), > 50 Gy (n = 83), unknown (n = 2); Protons: 74 Gy (n = 1), 77 Gy (n = 1), unknown dose (n = 2); Photons + protons (n = 1) 71 Gy, SRS (n = 1)", "NA", "NA", "Median 96 months (63–132)", "ITT and GST (ACTH, GH). Basal serum levels LH, FSH, TSH. PRL, IGF-1, fT4, testosterone, estradiol", "Surgery + RT (n = 54); Chemo + RT (n = 5); Surgery + RT + chemo (n = 34),"], ["Ratnasingam, 2015 [26]", "50,Mean 57 (44–69),19F/31 M", "8", "NPC stage I-IV", "Mean dose 66 Gy +/- 3.2 Gy facio-cervical; Mean dose 62 Gy +/- 2.9 Gy anterior neck;Minimum Dpit 40 Gy.", "2 Gy", "Minimum Dpit 80 Gy", "Median 96 months (36–252 months)", "Early-morning (fasting) baseline measurement of cortisol, fT4, TSH, PRL, LH, FSH, estradiol, testosterone, renal function. ITT on second visit", "Chemo + RT (n = 36); RT alone (n = 14);"], ["Appelman-Dijkstra, 2014 [27]", "80,Median 47 (18–89),", "6", "Brain (n = 40, 18F/22 M), NPC (n = 15, 4F/11 M), cerebral metastasis (n = 2), Meningioma (n = 14), other (n = 9)", "Cerebral mean dose 55.8 Gy +/- 4.4 Gy (46–62), NPC mean dose 63 Gy +/- 9.8 Gy (40–70), other mean dose 53 Gy +/- 7 Gy (40–69).Mean Dpit 56.3 Gy (40–70)", "NA", "NA", "Median 72 months (6–420)", "Early-morning (fasting) ITT measurement of IGF-1, GH, TSH, fT4, ACTH, cortisol, LH, FSH, estradiol, testosterone, SHBG, PRL, renal and liver function, CV parameters", "NA"], ["Huang, 2013 [19]", "98, Median 47 (17–70), 28F/70 M", "6", "NPC", "Mean Dpit 51.2 Gy (40–70 Gy)", "NA", "NA", "Median 17 months (6–51)", "Early morning measurements", "Chemo + RT (n = 92)"], ["Hauptman, 2012 [56]", "15, Median 56 (29–74), 7F/8 M", "3", "Chordomas & chondrosarcomas", "SRT 53–84 Gy (n = 10), SRS (n = 5). 1 patient SRT 67.6 Gy at 95 % IDL", "SRT 2 Gy, 1.9 Gy, 2.3 Gy. SRS single fractions of 15, 18, 20, 19, 16 Gy", "NA", "54 months", "NA", "Surgery n = 15; (100 %)"], ["Madaschi, 2011 [22]", "26, Median 39 (33–47),12F/14 M", "6", "Gliomas, meningiomas, neuroectodermal tumors. 26 RT, 6 controls", "RT dose to target volume: 59.4 Gy (50.1–60)Median Dhpa: 41.8 Gy (30.7–49.8 Gy)", "2 Gy", "Median Dhpa 69.67 Gy", "HP-axis dysfunction at median 32 months (12–111)", "GHRH + arginine test: IGF-1, ACTH and cortisol, PRL, TSH, fT4, testosterone, estradiol", "Surgery + RT (n = 15)Surgery + chemo + RT (n = 11)"], ["Löfdahl, 2012 [57]", "15, Median56 (32–66),4F/11 M", "4", "Oropharyngeal cancer (n = 13), epipharyngeal cancer (n = 2)", "Oropharyngeal: mean Dhypo 1.9 Gy (1.5–2.2 Gy), mean Dpit 2.4 Gy (1.8–3.3 Gy). Epipharyngeal: Dhypo 6.0–9.3 Gy, Dpit 33.5–46.1 Gy.", "1.7 Gy twice a day", "Oropharyngeal; mean Dhypo 2.98 Gy, mean Dpit 4.44 Gy. Epipharyngeal; Dhypo 9.40–14.57 Gy, Dpit 61.98–85.29 Gy.", "72 months (48–120)", "Early morning IGF-1, PRL, testosterone, FSH/LH, fT4, TSH, cortisol. ITT for GH", "Chemo + RT (n = 10)"], ["De Marzi, 2015 [17]", "103 adults", "5", "Chordoma and chondrosarcoma", "Mean Dpit with tox 63.5 +/- 6.8 Gy-RBE (34.0–72.8). Mean gEUD pituitary with tox 65 +/- 5 Gy.", "1.8–––2.0 Gy", "Mean Dpit 120.65–127 Gy", "Minimum 26 months", "NA", "Surgery, post-operative RT; 100 %"], ["Ipekci, 2015 [58]", "30, Mean 42 (33–51),10F/20 M", "6", "NPC", "Mean Dpit 46.2 Gy, mean Dhypo 10.3 Gy", "2 Gy", "Mean Dpit 92.40 Gy, mean Dhypo 17.17 Gy", "Single evaluation at 24.4 months (9.8–133) between RT and testing. 13 pts had second evaluation 12.9 +/- 2.4 months after first evaluation", "ITT after 8 h fasting, early-morning: cortisol, GH, ACTH, gonadotropin, testosterone, estradiol, FSH, LH, fT4, TSH, IGF-1, PRL", "Chemo + RT (n = 28)"], ["Shih, 2015 [23]*", "20, Median 37 (22–56),7F/13 M", "7", "Grade II glioma", "Proton therapy up to 54 Gy (RBE) to tumor or surgical bed. 6 pts > 30 Gy to pituitary, 14 pts < 30 Gy to pituitary", "1.8 Gy (RBE)", "TD 30 Gy = BED 57 Gy to pituitary", "Median 60 months.", "Serum levels of prolactin, IGF-1,TSH, fT4, cortisol, cortisol after cosyntropin stimulation, testosterone, LH, FSH, estradiol", "TMZ: 2/20.Surgery: Gross total res 4/20, subtotal 12/20, biopsy 4/20"], ["Tabrizi, 2019 [21]", "20, Median 37 (22–56),7F/13 M", "5", "Grade II glioma", "Proton therapy up to 54 Gy (RBE) to tumor or surgical bed. Dose range above and under 20 Gy to pituitary or hypothalamus reported", "1.8 Gy (RBE)", "NA", "Median 60 months. Deficiency after median 10.9 months (4.8–37.8)", "Serum levels of prolactin, IGF-1,TSH, fT4, cortisol, cortisol after cosyntropin stimulation, testosterone, LH, FSH, estradiol", "TMZ: 2/20. Surgery: Gross total res 4/20, subtotal 12/20, biopsy 4/20"], ["Partoune, 2021 [29]", "48, Median49 (37–61),45F/3 M", "8", "Skull base meningioma", "Median Dpit: 48.9 Gy (6.0–55.1), median Dhypo: 15.8 Gy (2.0–51.1)", "1.8 Gy", "Median Dpit: 92.91 Gy, median Dhypo: 25.28 Gy", "median 90 months (17–217)", "Early-morning after fasting: TSH, fT4, cortisol, ACTH, IGF-1, LH, FSH, PRL, estradiol, testosterone, GH (ITT)", "NA"], ["Vakilian, 2021 [18]", "36, Median58,16F/20 M", "7", "Skull base, different tumor types: NPC, chordomas, primary brain", "Median dose 54 Gy (50.4–70 Gy) to target volume.Dose threshold of 50 Gy (30 Gy mean dose) to pituitary for development of endocrinopathy.", "NA", "NA", "Median 32 months (18–85)", "IGF-1, PRL, fT4, TSH, Early-morning cortisol, ACTH, FSH/LH, testosterone, estradiol/progesterone", "19 pts with hormone deficiencies: 79 % surgery, 21 % chemo.17 pts without deficiencies (controls): 47 % surgery, 47 % chemo"], ["Jensen, 2010 [59]", "6, Median61 (48–70),5F/1 M", "3", "Cavernous sinus meningioma", "IMRS 14.7–15.7 Gy", "IMRS single fraction dose 14.7–15.7 Gy", "NA", "Median 42 months (13–78)", "Serum measurements of TSH, T4, T3, cortisol, IGF-1, GH, ACTH", "Craniotomy n = 4"], ["McDowell, 2018 [31]", "107, 86 for endocrine screening. Median 57 (32–82), 38F/69 M.", "6", "NPC", "70 Gy to target volume", "2 Gy", "NA", "> 48 months, 4 years after RT", "Early-morning, after fasting. PRL, IGF-1, LH, FSH, fT4, TSH, ACTH, cortisol, testosterone", "cChT (n = 100/107), 93 %"], ["Raymond, 2021 [28]", "52, Mean56 (42–70),42F/10 M", "7", "Skull base meningioma", "Mean dose to tumor 54.1 +/- 1.6.Mean Dhpa 47 +/- 9.4 Gy.", "1.8–––2.0 Gy", "Mean Dhpa 75.20–78.33 Gy.", "Median 84 months (60–120)", "Early-morning cortisol, ACTH, LH, FSH, estradiol, testosterone, IGF-1, GH, TSH, fT3, fT4, PRL", "18 (34.6 %) post-operative RT"], ["Minniti, 2011 [33]", "52, Median56 (34–74),35F/17 M", "5", "Skull base meningioma", "FSRT 50 Gy in 30 fractions. Pituitary fossa included in PTV = 50 Gy.", "1.7 Gy", "Pituitary fossa included in PTV = 92.50 Gy.", "Median 36 months", "Basal hormonal assessment and dynamic testing", "18 post-operative FSRT, 7 pts with pre-existing hypopituitarism"], ["Handisurya, 2019 [25]", "436, Median50 (19–83),198F/238 M", "3", "Gliomas", "54–60 Gy to target volume", "2 Gy", "NA", "> 37 months", "Serum concentrations of TSH, T3, T4, fT3, fT4, FSH, LH, testosterone, estradiol and prolactin", "100 % surgery. 100 % cChT, TMZ + adj TMZ"], ["Sharma, 2020 [32]", "27, Median 67 (47–83), 10F/17 M", "7", "Sinonasal cancer", "<= 60 Gy (n = 10), 66 Gy (n = 12), >= 68 Gy (n = 5). Mean Dpit 29.9 (15.0–68.1) Gy.", "2 Gy", "Mean Dpit 59.80 Gy.", "Median 76.8 months (19.2–133.2)", "Serum levels of LH, FSH, testosterone, estradiol, tT3, T4, PRL, IGF-1, plasma levels TSH and cortisol. 12 pts with corticotropin stimulation test", "surgery (n = 20) 74 % concomitant Cisplatin (n = 6), 22 %"], ["Contrera, 2023 [30]", "50, Mean 54 (31–81), 19F/31 M", "7", "NPC (20), sinonasal cancer (30)", "50 pts included, 76 % IMRT, 24 % IMPT. From 41 pts dosimetric data available. Median target dose 64 Gy (45–70 Gy). Normal pituitary function: mean Dpit 40.9 Gy, mean Dhypo 11.3 Gy. Abnormal pituitary function: mean Dpit 52.4 Gy, mean Dhypo 20.3 Gy", "2.06 Gy", "Normal pituitary function: mean Dpit 83.03 Gy, mean Dhypo 19.06 Gy. Abnormal pituitary function: mean Dpit 106.37 Gy, mean Dhypo 34.24 Gy", "Median 20 months (3–145)", "IGF-1, ACTH, total cortisol, fT4, T3, TSH, FSH, LH, total testosterone, estradiol", "70 % concurrent cisplatin or carboplatin (n = 35)"]], "row_count": 23, "column_count": 10, "numeric_cells": 182, "header_rows": 1, "locator": "section[4]/table-wrap[2]#t0010"}}, {"id": "asset:table:pmid:39801827:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:ecd6a15b01f2799c0947eeb1327e12a8dec163772312145dd2bb5a6d9b28f121", "bytes": 5008, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[7]/table-wrap[1]#t0015", "version": null, "note": "Pituitary insufficiency per axis and insufficiencies of multiple axes. Abbreviations: B: brain, H&N: head and neck; SB: base of skull; NPC: nasopharyngeal carcinoma; Gy: Gray; RT: radiotherapy; gEUD: generalized equivalent uniform dose; LH: luteinizing hormone; FSH: follicle stimulating hormone; TSH: thyroid stimulating hormone; ACTH: adrenocorticotrophic hormone; GH: growth hormone; Dmax : maximal dose; Dpit : dose to pituitary gland; Dhypo : dose to hypothalamus; NA: data not available.", "structure": {"pmcid": "PMC11721507", "section_index": 7, "section_title": "Systematic literature search", "row_count": 24, "column_count": 12}, "table": {"label": "Table 2b", "caption": "Pituitary insufficiency per axis and insufficiencies of multiple axes. Abbreviations: B: brain, H&N: head and neck; SB: base of skull; NPC: nasopharyngeal carcinoma; Gy: Gray; RT: radiotherapy; gEUD: generalized equivalent uniform dose; LH: luteinizing hormone; FSH: follicle stimulating hormone; TSH: thyroid stimulating hormone; ACTH: adrenocorticotrophic hormone; GH: growth hormone; Dmax : maximal dose; Dpit : dose to pituitary gland; Dhypo : dose to hypothalamus; NA: data not available.", "rows": [["First author, year of publication, [Ref.]", "Localization", "Pituitary insufficiency per axis", "Number of axes involved"], ["", "", "Any", "ACTH", "TSH", "GH", "Hyperprolactinemia", "FSH/LH", "1 axis", "2 axis", "3 axis", "≥ 4 axis"], ["Gebauer, 2020 [55]", "B", "50 % (13/26)", "4.8 % (1/21)", "5.0 % (1/20)", "8 % (2/25)", "26.9 % (7/26)", "37.5 % (9/24)", "35 %", "8 %", "8 %", "NA"], ["Kyriakakis, 2019 [20]", "B", "84.5 % (49/58)", "19.0 % (11/58)", "6.9 % (4/58)", "82.8 % (48/58)", "10.3 % (6/58)", "20.7 % (12/58)", "47 %", "NA", "NA", "38 %"], ["Kyriakakis, 2016 [24]", "B", "88.8 % (95/107)", "23.4 % (25/107)", "11.2 % (12/107)", "86.9 % (93/107)", "15.0 %", "34.6 % (37/107)", "41 %", "33 %", "10 %", "5 %"], ["Ratnasingam, 2015 [26]", "NPC", "82 % (41/50)", "40 % (20/50)", "4 % (2/50)", "78 % (39/50)", "30 % (15/50)", "22 % (11/50)", "30 %", "28 %", "18 %", "6 %"], ["Appelman-Dijkstra, 2014 [27]", "Mixed", "62 %, 47 % after 5 years, 60 % after 10 years, 89 % after 15 years", "31 % (25/80)", "14 % (11/80)", "33 % (27/80)", "21 % (17/80)", "25 % (20/80)", "NA", "NA", "NA", "NA"], ["Huang, 2013 [19]", "NPC", "54.1 % (53/98)", "1.0 % (1/98)", "33.7 % (33/98)", "NA", "11.2 % (11/98)", "20.4 % (20/98) and 0 % (0/98)", "NA", "NA", "NA", "NA"], ["Hauptman, 2011 [56]", "SB", "6.7 % (n = 1)", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA"], ["Madaschi, 2011 [22]", "B", "38 % (10/26)", "19 % (5/26)", "12 % (3/26)", "27 % (7/26)", "0 % (0/26)", "4 % (1/26)", "23 % (6/26)", "8 % (2/26)", "8 % (2/26)", "NA"], ["Löfdahl, 2012 [57]", "H&N", "NA", "NA", "normal", "normal", "NA", "NA", "NA", "NA", "NA", "NA"], ["De Marzi, 2015 [17]", "SB", "gEUD > 65 Gy. 44 % (45/103)", "NA", "gEUD 60 +/- 8 (52–71) Gy. 11 % (5/45)", "NA", "gEUD 63 +/- 9 (34–72) Gy. 29 % (13/45)", "NA", "NA", "NA", "NA", "gEUD 66 +/- 4 (59–75) Gy. 38 % (17/45)"], ["Ipekci, 2015 [58]", "NPC", "93.3 % (28/30)", "73.3 % (22/30)", "26.7 % (8/30)", "76.7 % (23/30)", "43.3 % (13/30)", "6.7 % (2/30)", "20 % (6/30)", "73.3 % (22/30)", "NA", "NA"], ["Shih, 2015 [23]", "B", "NA", "20 % (4/20)", "17 % (3/18)", "0 % (0/16)", "0 % (0/7)", "15 % (2/13)", "NA", "NA", "NA", "NA"], ["Tabrizi, 2019 [21]", "B", "42 % (5/12) at Dmax > 20 Gy, 13 % (1/8) at Dmax < 20 Gy. 30 % (6/20)", "20 % (4/20)", "17 % (3/18)", "NA", "NA", "15 % (2/13)", "NA", "NA", "NA", "NA"], ["Partoune, 2021 [29]", "SB", "Dpit < 45 Gy: 5 %, Dpit > 45 Gy: 61 %, Dhypo < 20 Gy: 28 %, Dhypo > 20 Gy 53 %. 38 % (18/46)", "Dpit < 45 Gy: 0 %, Dpit > 45 Gy: 25 %, Dhypo < 20 Gy: 7 %, Dhypo > 20 Gy: 26 %. 15 % (7/48)", "Dpit < 45 Gy: 7 %, Dpit > 45 Gy: 46 %, Dhypo < 20 Gy: 17 %, Dhypo > 20 Gy: 53 %. 32 % (12/38)", "Dpit < 45 Gy: 5 %, Dpit > 45 Gy: 56 %, Dhypo < 20 Gy: 23 %, Dhypo > 20 Gy: 53 %. 35 % (16/46)", "11 % (5/39)", "Dpit < 45 Gy: 0 %, Dpit > 45 Gy: 46 %, Dhypo < 20 Gy: 16 %, Dhypo > 20 Gy: 50 %28 % (11/39)", "9 % (4/46)", "13 % (6/46)", "4 % (2/46)", "13 % (6/46)"], ["Vakilian, 2021 [18]", "SB", "Mean Dpit < 30 Gy: 0 %; 40 Gy: 11 %; 50 Gy: 21 %; 60 + Gy: 68 %. 53 %", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA"], ["Jensen, 2010 [59]", "SB", "0 %", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA"], ["McDowell, 2018 [31]", "NPC", "NA", "Low in 3 % (3/86)", "NA", "Low in 55 % (47/86) and elevated in 3 % (3/86).", "Elevated in 15 % (13/86)", "FSH elevated in 7 % (6/86). LH elevated in 5 % (4/86)", "NA", "NA", "1 % (1/86)", "NA"], ["Raymond, 2021 [28]", "SB", "3 years: 19.2 % (10/52), 5 years 31.5 % (16/39), 10 years 60.2 % (22/26)", "3 years: 13.5 % (7/52), 5 years 15.4 % (8/37), 10 years 15.4 % (8/17)", "3 years: 5.8 % (3/52), 5 years 14.0 % (7/35), 10 years 28.0 % (10/18)", "3 years: 5.8 % (3/52), 5 years 9.8 % (5/35), 10 years 13.4 % (6/16)", "3 years: 1.9 % (1/52), 5 years 10.1 % (5/35), 10 years 18.5 % (7/17)", "3 years: 9.6 % (5/52), 5 years 17.8 % (9/37), 10 years 36.9 % (13/20)", "NA", "21 % at 10 years (11/52)", "8 % at 10 years (4/52)", "13 % at 10 years (7/52)"], ["Minniti, 2011 [33]", "SB", "19 % (10/52)", "NA", "NA", "NA", "NA", "NA", "NA", "21 % (11/52)", "NA", "NA"], ["Handisurya, 2019 [25]", "B", "NA", "NA", "10.9 % (22/202)", "NA", "30 % (25/84)", "FSH: 17 % (14/83), LH: 11 % (9/83)", "NA", "NA", "NA", "NA"], ["Sharma, 2020 [32]", "H&N", "22 % (6/27)", "4 % (1/27)", "11 % (3/27)", "15 % (4/27)", "4 % (1/27)", "15 % (4/27)", "7 % (2/27) at mean dose of 23.5 Gy", "11 % (3/27) at mean dose of 36.0 Gy", "NA", "4 % (1/27) at dose of 68.1 Gy"], ["Contrera, 2023 [30]", "NPC, SN", "46 % (23/50)", "2 % (1/50)", "8 % (4/50)", "0 % (0/50)", "30 % (15/50)", "6 % (3/50)", "34 % (17/50)", "22 % (11/50)", "4 % (2/50)", "NA"]], "row_count": 24, "column_count": 12, "numeric_cells": 154, "header_rows": 2, "locator": "section[7]/table-wrap[1]#t0015"}}], "gaps": ["asset:materials:the analysis programme that recomputes the published estimate not verified", "asset:materials:the source data behind the published result in pmid:39801827 not verified", "asset:source:pmid:39801827 not verified"]}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": "meta_analysis", "specific": "random effects", "label": "Meta-analysis / evidence synthesis", "dsl_operations": ["random_effects_pool"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["study_level_effect_estimates"], "evidence": {"score": 0.7, "band": "medium", "quote": "Literature search of the PubMed database was performed for HP dysfunction after radiotherapy in adult patients. A risk of bias assessment was performed to rate the quality of the included papers. Besides clinical and treatment variables, reported insufficiencies for adrenocorticotrophic hormone, thyroid stimulating hormone, growth hormone, prolactin and follicle stimulating hormone and luteinizing hormone and for insufficiency of any axis were extracted. The prevalence for hormonal insufficiency per axis and for multiple axes was calculated using a random effects meta-regression with a random effect at the study level."}}], "targets": [{"id": "target-1", "claim_id": "claim-1", "operation": null, "expected_value": 0.61, "unit": "prevalence", "tolerance": null, "state": "complete"}], "gaps": []}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["differential_expression", "gwas", "machine_learning", "meta_analysis", "molecular_docking", "network_analysis", "pca", "statistical_regression", "survival_analysis"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "blocked", "tier": "R4", "blocking_axis": "data", "blocked_on": "data:accession_absent", "axes": {"method": {"axis": "method", "tier": "R1", 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prevalence of 0.61 (95 % CI 0.44–0.75) for insufficiency on any axis was calculated.", "target_result": "Pooled prevalence of hypothalamic-pituitary axis dysfunction after radiotherapy for brain, head and neck and skull base tumours", "number_stated": true, "source_locator": "chars 19696-19826 of source sha256 f82a98f608a4a1c4bb9a8f9c7a9620ca126272a8524771ea928075935ecf0755"}, "recorded_at": "2026-10-31T14:40:46.300616+00:00"}, {"provider": "minimax-m3", "model": "MiniMax-M3", "prompt_version": "replication-target-v2", "prompt_hash": "3b681f4a473c06d51bafd951c198ca0dd57c271b837a2d425bb0cc90a361ba2c", "source_hash": "f82a98f608a4a1c4bb9a8f9c7a9620ca126272a8524771ea928075935ecf0755", "raw_response": "{\"parent_value\":0.61,\"unit\":\"\",\"evidence\":\"By means of random effects meta-regression, a prevalence of 0.61 (95 % CI 0.44–0.75) for insufficiency on any axis was calculated.\",\"target_result\":\"Pooled prevalence of hypothalamic-pituitary axis insufficiency on any axis was 0.61.\",\"number_stated\":true}", "reading": {"parent_value": 0.61, "unit": "", "evidence": "By means of random effects meta-regression, a prevalence of 0.61 (95 % CI 0.44–0.75) for insufficiency on any axis was calculated.", "target_result": "Pooled prevalence of hypothalamic-pituitary axis insufficiency on any axis was 0.61.", "number_stated": true, "source_locator": "chars 19696-19826 of source sha256 f82a98f608a4a1c4bb9a8f9c7a9620ca126272a8524771ea928075935ecf0755"}, "recorded_at": "2026-10-31T14:41:09.298269+00:00"}], "agreement": true, "disagreements": {"target_result": {"minimax-m3-1-flash": "Pooled prevalence of insufficiency on any hypothalamic-pituitary axis after radiotherapy: 0.61 (95% CI 0.44–0.75), equivalent to 61%.", "minimax-m3": "After adult radiotherapy for brain, head-and-neck, or skull-base tumors, the pooled prevalence of insufficiency on any hypothalamic-pituitary axis was 0.61 (95% CI 0.44–0.75; 61%). Site-specific pooled prevalences were 0.68 (95% CI 0.45–0.85) for nasopharyngeal carcinoma and other head-and-neck tumors, 0.60 (95% CI 0.28–0.85) for intracerebral tumors, and 0.50 (95% CI 0.23–0.76) for skull-base tumors.", "decisive": false}, "analysis_methods": {"minimax-m3-1-flash": ["Random-effects meta-analysis with random effects at the study level", "Logit transformation of study-level proportions", "Random-effects meta-regression with tumor site as a covariate", "Maximum-likelihood estimation for meta-regression", "Pearson correlation tests", "Newcastle-Ottawa Scale risk-of-bias assessment", "Biologically Equivalent Dose calculation"], "minimax-m3": ["Study-specific calculation of endocrine insufficiency proportions", "Logit transformation of proportions to effect sizes", "Random-effects meta-analysis with a study-level random effect", "Random-effects meta-regression with tumor site as a covariate", "Maximum likelihood estimation for meta-regression", "Newcastle-Ottawa Scale risk-of-bias assessment"], "decisive": false}, "source_claims": {"minimax-m3-1-flash": ["The meta-analysis estimated the pooled prevalence of insufficiency on any hypothalamic-pituitary axis using a random-effects model.", "The pooled prevalence of insufficiency on any axis was 0.61 (95% CI 0.44–0.75).", "The highest pooled prevalence was for NPC and other head-and-neck tumors at 0.68 (95% CI 0.45–0.85), followed by intracerebral tumors at 0.60 (95% CI 0.28–0.85) and skull-base tumors at 0.50 (95% CI 0.23–0.76).", "Study-level proportions were calculated from the number of patients with insufficiency divided by the number tested, logit-transformed, and pooled using a random-effects meta-analysis.", "A significant positive correlation was observed between insufficiency on any axis and follow-up time (Pearson R = 0.57, p = 0.015).", "No significant correlation was found between dose to the hypothalamic-pituitary region and insufficiency on any axis (Pearson R = 0.16, p = 0.535).", "The review included 22 publications and 1,462 patients, with heterogeneous prospective and retrospective cohorts.", "The effects of surgery and chemotherapy on hypothalamic-pituitary functioning were not included in the meta-analysis results.", "Generalizability was limited by cohort heterogeneity, possible selection bias, multimodal treatment, and incomplete follow-up information."], "minimax-m3": ["The random-effects meta-regression estimated a prevalence of 0.61 (95% CI 0.44–0.75) for insufficiency on any hypothalamic-pituitary axis.", "Pooled prevalence differed by tumor site: 0.68 for NPC and other head-and-neck tumors, 0.60 for intracerebral tumors, and 0.50 for skull-base tumors.", "The synthesis included 22 publications and 1,462 patients, with eligibility requiring adult age at radiotherapy and radiotherapy for brain tumors, cerebral metastases, head-and-neck malignancies, or skull-base malignancies.", "The authors used a random-effects model because of expected clinical heterogeneity and included tumor site as a meta-regression covariate.", "The effects of surgery and chemotherapy were not incorporated into the meta-analysis results, limiting attribution of endocrine insufficiency specifically to radiotherapy.", "The authors identified cohort heterogeneity, insufficient confounder data for multivariate correction, probable selection bias, and inadequate loss-to-follow-up information as limitations."], "decisive": false}, "unit": {"minimax-m3-1-flash": "prevalence", "minimax-m3": "", "decisive": false, "resolution": "One reader left the unit blank. The other named 'prevalence', and the paper carries that unit in its own text, so the source settles the difference.", "support": ["Keywords: Hypothalamic-pituitary dysfunction, Insufficiency, Endocrine, Brain, Head and neck, Skull base, Tumor, Radiotherapy, Adults, Prevalence, Hypothalamus, Pituitary gland\nINTRODUCTION\nRadiotherapy is a widely applied modality in the treatment of primary brain tumors, brain metastasis, head & neck (HN) and skull base (SB) malignancies.", "By means of the meta-analysis, reporting of the prevalence for any insufficiency, insufficiency per axis and insufficiency for multiple axes was possible.", "In this context, prevalence can be defined as the number of existing cases (patients with an insufficiency) at a specific time point (end of follow-up) within a specific population (patients tested) [16]."]}}, "agreement_basis": {"policy": "decisive_fields", "decisive_fields": ["number_stated", "parent_value", "unit", "work_type"], "advisory_fields": ["analysis_methods", "source_claims", "target_result"]}, "blinded": true}, "human_critique": {"status": "not_run", "reviewer": null, "signed_at": null, "conflict_checked": false, "commentary": null}, "stages": [{"key": "target_materials", "status": "pending", "reason": null, "evidence": null}, {"key": "independent_readings", "status": "passed", "reason": "Both readers returned the same number from the same sentence. 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