ESA-RANDOMIZED CONTROLLED TRIAL Total Parathyroidectomy With Routine Thymectomy and Autotransplantation Versus Total Parathyroidectomy Alone for Secondary Hyperparathyroidism Results of a Nonconfirmatory Multicenter Prospective Randomized Controlled Pilot Trial Katja Schlosser, MD,Ã Detlef K. Bartsch, MD,y Markus K. Diener, MD,z Christoph M. Seiler, MD,z Tom Bruckner,§ Christoph Nies, MD,ô Moritz Meyer,ô Jens Neudecker,jj Peter E. Goretzki,ÃÃ Gabriel Glockzin,yy Ralf Konopke,zz and Matthias Rothmundy Conclusions: TPTXþATand TPTX seem to be safe and equally effective for Objective: This randomized controlled multicenter pilot trial was conducted the treatment of otherwise uncontrollable SHPT. TPTX seems to suppress to find robust estimates for the rates of recurrence of 2 surgical strategies for PTH more effectively and showed no recurrences after 3 years. The hypoth- secondary hyperparathyroidism (SHPT) within 36 months of follow-up. esis that TPTX is superior to TPTXþAT referring to the rate of recurrent Background: SHPT is a frequent consequence of chronic renal failure. Total SHPT has to be tested in a large-scale confirmatory trial. Nevertheless, TPTX parathyroidectomy with autotransplantation (TPTXþAT) and subtotal para- seems to be a feasible alternative therapeutic option for the surgical treatment thyroidectomy (SPTX) are the standard surgical procedures. Total parathyr- of SHPT. oidectomy alone (TPTX) might be a good alternative, as morbidity and recurrence rates are low according to small-scale retrospective studies. Keywords: autotransplantation, randomized controlled trial, secondary Methods: The trial was performed as a nonconfirmatory randomized con- hyperparathyroidism, total parathyroidectomy trolled pilot trial with 100 patients on long-term dialysis with otherwise (Ann Surg 2016;264:745–753) uncontrollable SHPT to generate data on the rate of recurrent disease within a 3-year follow-up period after TPTX or TPTXþAT. Parathyroid hormone (PTH) and calcium levels, recurrent or persistent hyperparathyroidism, arathyroidectomy (PTX) still plays an important role in the parathyroid reoperations, morbidity, and mortality were evaluated during a P treatment of secondary (renal) hyperparathyroidism (SHPT) despite recent advances in medical therapy. After introduction of 3-year follow-up. 1,2 3 Results: A total of 52 patients underwent TPTX and 48 TPTXþAT. Patient calcimimetics (eg, Cinacalcet) new phosphate binders and vita- min D analogs4–7 PTX rates decreased mainly between 2002 and characteristics, preoperative baseline data, duration of surgery (02:29 vs 8,9 02:47 hrs, P ¼ 0.17) and mean hospital stay (10 Æ 7.1 vs 8 Æ 3.7 days, P 2005, but increased again after 2006. Cinacalcet reduced PTX rates in patients on chronic maintenance dialysis, but did not seem to ¼ 0.11) did not differ significantly. Persistent SHPT developed in 1 TPTX and 10 2 TPTXþAT patients. None of the TPTX patients required delayed para- improve all-cause or cardiovascular mortality. In contrast, PTX thyroid AT to treat permanent hypoparathyroidism. Serum-calcium values proved to drastically lower PTH and calcium levels, ameliorate symptoms and showed some evidence11–14 to reduce stroke risk were similar (2.1 Æ 0.3 vs 2.1 Æ 0.2, P ¼ 0.95) whereas PTH rose by time in 15,16 the TPTXþAT group and was significantly higher at the end of follow-up and all-cause and cardiovascular mortality. when compared with the TPTX group (31.7 Æ 43.6 vs 98.2 Æ 156.8, There is still an ongoing debate on the optimal surgical P ¼ 0.02). Recurrent SHPT developed in 4 TPTXþAT and none of the treatment of SHPT. Subtotal PTX (SPTX) and total PTX with TPTX patients. autotransplantation (TPTXþAT), both with routine bilateral cervical thymectomy (bcT), are currently considered standard procedures.17– 20 Recurrence rates of both methods were described ranging between From the ÃDepartment for General, Visceral, and Vascular Surgery, Agaplesion 5% and 80% depending on the definition of recurrence and on the Evangelisches Krankenhaus Mittelhessen, Giessen, Germany; yDepartment length of follow-up.21–23 for Visceral, Thoracic, and Vascular Surgery, University Hospital of Giessen Although postoperative morbidity and mortality do not differ and Marburg, Marburg, Germany; zDepartment for General, Visceral, and 19,24,25 Transplantation Surgery, University Heidelberg, Heidelberg, Germany; §Insti- significantly between TPTXþAT and SPTX, reoperations for Institute of Medical Biometry and Informatics, University Heidelberg, Heidel- recurrent SHPT after SPTX entail more potential complications berg, Germany; ôDepartment for General and Visceral Surgery, because of the necessity of a neck re-exploration under general Marienhospital Osnabru¨ck, Osnabru¨ck, Germany; jjDepartment for General, Visceral, Vascular, and Thoracic Surgery, Universita¨tsmedizin Berlin, Charite´ anesthesia whereas after TPTXþAT patients with graft-dependent Campus Mitte, Berlin, Germany; ÃÃDepartment of Surgery, Lukaskrankenhaus recurrent disease have to undergo a resection of the autograft under Neuss, Neuss, Germany; yyDepartment of Surgery, University Medical Center local anesthesia only.26,27 Regensburg, Regensburg, Germany; and zzDepartment of Visceral, Thoracic, During the 1990s, TPTX without autotransplantation and and Vascular Surgery, Carl Gustav Carus University Hospital, Dresden, 28 Germany. without routine bcT, initially described by Ogg in 1967, was Reprints: Katja Schlosser, MD, Department of General, Visceral, and Vascular reported to be more efficient compared with the standard procedures Surgery, Agaplesion Evangelisches Krankenhaus Mittelhessen, Paul-Zipp-Str. just mentioned. Several authors described lower recurrence rates 171, 35398 Giessen, Germany. E-mail: [email protected]. (0%–4%), a comparable morbidity and potential economic benefits Disclosure: The authors declare no conflicts of interest. compared with published data on TPTXþAT. Patients were reported Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0003-4932/16/26405-0745 to neither develop uncontrollable hypocalcemia nor adynamic bone DOI: 10.1097/SLA.0000000000001875 disease.18,29–33 Annals of Surgery Volume 264, Number 5, November 2016 www.annalsofsurgery.com | 745 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Schlosser et al Annals of Surgery Volume 264, Number 5, November 2016 As all studies on TPTX were retrospective except one single an internet-based computer randomization (Randomizer for Clinical center trial,32 a prospective multicenter randomized controlled trial Trials 1.6.0, developed at the Institute for Medical Informatics, comparing TPTX with TPTXþAT seemed to be necessary to achieve Statistics and Documentation at Medical University of Graz, Austria).34 high internal and external validity and to create more evidence on the A standardized surgical approach to the parathyroids using a superiority of one or the other procedure. Kocher incision was performed in both groups.34 Intraoperative The data on both operative methods published at the time of monitoring of the recurrent laryngeal nerve was performed and planning the study led to a calculated number of patients of more than documented in all patients. 4000 in each treatment arm to be able to perform a confirmatory trial In all patients, the parathyroid glands had to be identified at to prove superiority of TPTX over TPTXþAT with regard to a lower their normal sites or known variants. Resection of all 4 (or more) recurrence rate.34 Because such a trial was unrealistic given the rarity parathyroid glands was performed. In the TPTX group transcervical of the disease, it was decided to run a nonconfirmatory multicenter thymectomy on one side was only performed, if less than 2 glands randomized controlled pilot trial on 100 patients to establish a were found on the respective side or if palpation revealed a suspi- hypothesis that could be tested thereafter. A detailed description cious nodule within the thymus. A small part of each gland had to be of the calculations is given in the previously published study pro- sent to pathology for frozen section to confirm organ diagnosis. The tocol.34 Till date no randomized controlled trial is published com- remaining parathyroid tissue had to be placed in cold sterile saline paring TPTX with one of the standard procedures. This is therefore solution for later cryopreservation.34 the first study to address this issue. In the TPTXþAT group, TPTX was supplemented by a bcT, followed by an ATof 20 1 mm3 pieces of the most normal appearing, for example, smallest, preferably nonnodular parathyroid gland in METHODS single muscle pockets of the nonshunt bearing forearm or the thigh. The primary objective of this pilot trial was to provide robust The number of glands detected, the necessity to perform a uni- data on the rates of recurrence after TPTXþAT and TPTX. Secon- or bilateral thymectomy or a thyroid resection, the duration of the dary objectives were operative complications (eg, rebleeding), post- surgical procedure and complications (rebleeding, reoperations, operative mortality and morbidity (eg, permanent recurrent nerve recurrent laryngeal nerve injury) had to be recorded.34 palsy and postoperative permanent hypoparathyroidism requiring Calcitriol and calcium supplementation was added to the delayed parathyroid autotransplantation) and other adverse events medication after surgery on a regular basis in all patients to stabilize until the end of follow-up. calcium values and