Treatments for MEN1-associated endocrine tumours: three systematic reviews and a meta-analysis.
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BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary disorder characterised by the combined occurrence of parathyroid, pancreatic, and pituitary tumours. Current treatments are based on very low-quality evidence. Our aims were to determine treatment outcomes in patients with MEN1 for: subtotal parathyroidectomy versus less than subtotal parathyroidectomy for primary hyperparathyroidism (Q1); surgery versus active surveillance for non-functioning pancreatic neuroendocrine tumours sized 2 cm or less (Q2); and dopamine agonist responses of prolactinomas in patients with MEN1 versus patients without MEN1 (Q3). METHODS: We conducted three systematic reviews and one meta-analysis. Four electronic databases (MEDLINE Ovid, Embase Ovid, The Cochrane Library, and Web of Science) were searched from Dec 1, 2001, to Feb 13, 2023, with no language restrictions. Study designs included randomised controlled trials, prospective and retrospective cohort studies, and case-controlled and case series. Adults and children with MEN1-associated tumours were included in all three systematic reviews. For each clinical question, three pairs of authors independently screened abstracts and assessed the full text for final inclusion, discordant views were resolved by senior authors. Dichotomous outcomes were calculated using risk ratios or hazard ratios for time-to-event analyses, with 95% CIs. Continuous outcomes were ascertained using mean difference with 95% CIs. Where feasible, outcomes from individual studies were analysed through meta-analysis, using a random-effects model. The systematic reviews were prospectively registered (PROSPERO reference numbers CRD42023409912, CRD42023409936, and CRD42023409949). FINDINGS: For primary hyperparathyroidism (Q1), 990 non-duplicate records were screened for title and abstract, of which 23 studies with 1073 patients were eligible for meta-analysis. These studies showed that subtotal parathyroidectomy had a significantly lower risk of persistent primary hyperparathyroidism (RR 0·32, 95% CI 0·20-0·52; I2=0%) and recurrent primary hyperparathyroidism (RR 0·78, 0·62-0·97; I2=27%), when compared with less than subtotal parathyroidectomy, although the risk of post-operative hypoparathyroidism was higher (RR 2·64, 1·63-4·29; I2=0%). For non-functioning pancreatic neuroendocrine tumours sized 2 cm and less (Q2), 1583 non-duplicate records were screened for title and abstract, of which three cohort studies were eligible for analysis. These studies showed that combined metastatic disease and mortality rates were comparable between patients in the surgery group (two [7%] of 27 to three [20%] of 15) and patients in the active surveillance group (one [3%] of 33 to four [8%] of 50]). For prolactinomas (Q3), 475 non-duplicate records were screened for title and abstract, of which ten studies with 505 patients were eligible for analysis. These studies showed that dopamine agonist treatment failure rates to normalise serum prolactin were similar between patients with MEN1 (zero of one to one [33%] of three) and patients without MEN1 (four [6%] of 68 to nine (82%) of 11), n=23 studies). GRADE certainty scores for all were low or very low. INTERPRETATION: In patients with MEN1, subtotal parathyroidectomy achieved greater reductions in persistence and recurrence of primary hyperparathyroidism than less than subtotal parathyroidectomy; for non-functioning pancreatic neuroendocrine tumours sized 2 cm or less, the few available studies suggest that active surveillance might be comparable to surgical resection; and for prolactinomas, dopamine agonist therapy appears to have comparable efficacy as in patients without MEN1. FUNDING: None.