Total Parathyroidectomy with Routine Thymectomy and Autotransplantation Versus Total Parathyroidectomy Alone for Secondary Hyper

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, 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, 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 vitamin 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 7.1 vs 8 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 0.3 vs 2.1 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 43.6 vs 98.2 156.8, 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 Department 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; Department 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

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 to meet the increased calcium requirement to During follow-up, the rate of persistent or recurrent SHPT, of because of bone remineralization. Dosage of calcitriol was consecu- re-explorations of the neck or the parathyroid autograft was recorded. tively reduced during follow-up but remained in almost all patients The detailed study protocol was previously published, where the on a maintenance level to prevent recurrent disease. At discharge, the selection of clinical study sites and the internet-based randomization frequency of persistent hyperparathyroidism (defined as PTH levels process was described in detail.34 above the five-fold of the upper normal value), inhospital morbidity The trial population comprised patients on long-term (>12 and the length of hospital stay were documented. Laboratory months) dialysis with SHPT (PTH tenfold above normal value) parameters and current specific medications were recorded again. either with hypercalcemia developing spontaneously or under treat- Assessment of vocal cord function had to be obtained by an inde- ment with vitamin D or with normocalcemia in coincidence with pendent ear, nose, and throat specialist. renal osteopathy. Detailed inclusion and exclusion criteria are speci- Follow-up visits were performed at 6, 12, 24, and 36 months fied in Table 1. after surgery. The patients were given a call and a written ques- Eligible patients had a pretreatment visit where they were tionnaire (medical history, current specific medication, and specific screened and informed about the TOPAR PILOT trial with study symptoms) was mailed to each patient, who was asked to complete it procedures, risks, benefits, and data management being clarified in with the help of their nephrologists. Laboratory data (total calcium detail. After receiving informed consent, baseline data (eg, age, and PTH values) were obtained by the nephrologists in charge of the duration of dialysis, current medication) and pretreatment laboratory patients. The PTH assays were not the same in all laboratories. values (total calcium in mmol/L, PTH in ng/L) were documented. However, the coefficients of variability (CVs) were comparable Patients were randomized into the treatment groups thereafter using (15%) and the upper and lower values were similar with negligible

TABLE 1. Subject Inclusion and Exclusion Criteria Inclusion Criteria Exclusion Criteria Patients on long term dialysis treatment (>12 months) Primary or tertiary hyperparathyroidism (hyperparathyroidism after kidney with SHPT transplantation) PTH 10-fold above upper normal value Familial hyperparathyroidism (MEN I, MEN II, hereditary hyperparathyroidism) Age equal or greater 18 years History of neck explorations for thyroid/parathyroid disorders Informed consent Malignant disease of the thyroid gland Bleeding disorder/coagulopathy Severe psychiatric or neurologic disease Drug- and/or alcohol-abuse Participation in another intervention-trial with interference of intervention and outcome Inability to follow the instructions given by the investigator (eg, insufficient command of language) This table summarizes the subject inclusion and exclusion criteria. It was published in a modified version within the trial protocol.34 MEN indicates multiple endocrine neoplasia; PTH, intact parathyroid hormone; SHPT secondary hyperparathyroidism.

differing lower and upper limits (eg, assays referring to ng/L ranged significance of 5% when applying a two sided t test to normal from 11–65 to 12–70, assays referring to pmol/L ranged from 1.0– distributed data. Statistical methods were used to assess the quality of 6.5 to 1.2–6.8). PTH values were displayed in ng/L. PTH values from data, homogeneity of treatment groups, endpoints, and safety of the assays referring to pmol/L were converted into ng/L by the following TPTX versus TPTXþAT technique. Statistical analysis was per- formula: PTH (pmol/L)/ 0.106 ¼ ng/L (ng/L ¼ pg/mL).35 formed on the basis of an intention to treat (ITT) population and with Persistent SHPT was assumed if PTH levels remained above respect to ITT principles. the five-fold of the upper normal value within the first 6 months after Baseline characteristics and efficacy and safety endpoints were surgery. Recurrent SHPT was defined as a rise in PTH levels above analyzed with descriptive methods. The description of continuous the five-fold of the upper normal value thereafter. The follow-up variables included the number of observations and mean standard visits were under the responsibility of the centers under supervision deviation in the trial population. The description of categorical vari- of the Study Centre of the German Surgical Society (SDGC). ables includes absolute and relative frequencies. Possible differences Figure 1 shows a flow-chart of the interventions. between groups were tested by applying t tests for continuous variables All 7 participating centers guaranteed cryopreservation of and x2 tests for categorical variables. The resulting P values are of parathyroid tissue from each patient to enable possible subsequent descriptive nature without any confirmatory value. To improve the parathyroid autotransplantation in case of postoperative persistent presentation of the observed data, graphical methods were applied. hypoparathyroidism refractory to medical treatment. All serious TOPAR PILOT was designed at the Department for Visceral, adverse events had to be reported to the principal investigator and Thoracic, and Vascular Surgery, Philipps University, Marburg in the leading ethic committee. For the safety analysis, the incidence of cooperation with the SDGC, Heidelberg and the Institute of Medical adverse and serious adverse events were analyzed. Patients could be Biometrics and Informatics at the University of Heidelberg. Quality withdrawn from the study at any time either at their own request or at assurance was done in cooperation with the Network of Coordinating the request of the principal investigator. Safety interim analyses were Centers for Clinical Trials. The trial was monitored by an independ- performed each year and the independent data and safety board ent monitor of the latter in Heidelberg, Germany. Project manage- followed the progress of the trial to control safety. ment and trial coordination was done by the SDGC (Study Center of A sample size of 100 patients was chosen out of the following the German Surgical Society). Data management and biometry were reasons: 50 patients per group had 80% power to detect a stand- done by the IMBI (Institute for Medical Biometry and Informatics) ardized difference (d ¼ (m1 m2)/sd) of about 0.57 with a level of Heidelberg, Director Meinhard Kieser. Clinical monitoring was

Enrollment: day of Patients with secondary hyperparathyroidism scheduled for surgery assessed for eligibility (n= 198) admission

Excluded (n= 98) Not meeting inclusion criteria (n=79) Declined to participate (n= 19) Other reasons (n= 0 )

Randomized (n=100)

Allocation: Day of Allocated to intervention TPTX+AT (n=48) admission Allocated to intervention TPTX (n=52) Received allocated intervention (n= 44) Received allocated intervention (n=46) Did not receive allocated intervention Did not receive allocated intervention (3 glands only resected, no parathyroid (TPTX+unilateral cervical thymectomy (n=3), autograft+ additional hemithyroidectomy on TPTX+ bilateral cervical thymectomy (n=2), 2 the suspected side) (n=4) glands resected only + bilateral cervical thymectomy (n=1)

Follow-Up Visits (day of discharge, 6, 12, 24 FIGURE 1. Flowchart of the interven- and 36 months after tions. This figure shows a detailed flow- surgery) chart of all the interventions of the Lost to follow-up (n=2) Lost to follow-up (n= 3) TOPAR PILOT trial. It was published Discontinued intervention: Discontinued intervention: in a modified version within the Withdrawal of informed consent (n=3) Withdrawal of informed consent (n=6) trial protocol.34 PTH indicates intact par- Death (n=7) Death (n=5) athyroid hormone; SHPT, secondary Discontinued intervention (give reasons) (n= ) hyperparathyroidism; TPTX, total parathyroidectomy alone, TPTXþAT, total Analysis parathyroidectomy with routine bilat- Analysed (n=36) Analysed (n=38) eral cervical thymectomy and parathy- Excluded from analysis (n=0) Excluded from analysis (n= 0) roid autotransplantation.

performed by the KKS (Coordination Centre for Clinical Trials) cervical thymectomy. One patient with only 2 glands resected who Heidelberg, Director Steffen Luntz. The trial was performed accord- also had bcT was cured without identification of more glands within ing to the Declaration of Helsinki in its current German version and the thymus. One of the 50 patients with 4 parathyroid glands resected the Good Clinical Practice criteria. Before the start of the trial the developed a mild persistent SHPT. This patient was cured by independent ethics committee of the Philipps University, Marburg, successful kidney transplantation within the follow-up period. gave a positive vote on August 21, 2006. The trial was registered Of the 48 patients in the TPTXþAT group, 41 patients had on August 22, 2006 at the International Standard Randomized four and 3 patients five glands removed. The fifth gland was found in Controlled Trial Number Registration (ISRCTN86202793). the thymic tongues in all 3 patients. In the remaining 4 patients, only three glands were resected, so that an additional hemithyroidectomy Financial Support on the suspected side and no AT was performed. Two of these 4 There was no specific funding for this trial. The Study Center patients did not develop persistent disease and were cured with PTH of the German Surgical Society (SDGC) received a grant by the levels below the lower normal value at discharge and PTH values German Federal Ministry of Education and Research [Bundesmi- within the normal range throughout the whole follow-up. The nisterium fu¨r Bildung und Forschung (BMBF); 01GH99033 and remaining 2 patients had persistent SHPT. One was scheduled for 01GH0702]. Part of this funding was used for project and data reoperation within the first year after initial surgery and cured after management, biometry, monitoring, travel expenses, and general resection of the missing gland that was found in the mediastinum. project coordination. The other one refused reoperation, was treated with calcimimetics with consecutive reduction of PTH below the five-fold of the upper RESULTS normal value within 2 years after surgery. A bcT as required by the Seven high-volume centers participated in the trial. The first study protocol was performed in 46/48 patients. In one of the 2 patient was randomized on January 24, 2007. Although we expected remaining patients, histopathology report revealed no thymic tissue to end inclusion after 18 months, it took until August 19, 2010 to and in the other one no reason for not performing a bcT was given. complete randomization of 100 patients. The duration of surgery was not significantly different between TPTX (02:29 01:01 hrs) and TPTXþAT (02:47 Patient Characteristics 0:51 hrs) groups (P ¼ 0.17). The trial population comprised 100 patients (65 male, 35 female) with a mean age of 49.2 15.6 years on long-term Perioperative Outcome Until Discharge dialysis (58.9 37 months) with SHPT. A total of 52 patients were Postoperative bleeding occurred in 3 of 52 TPTX (5.9%, randomized into the TPTX group whereas 48 were assigned to n¼51) and in 1 of 48 TPTXþAT patients (2.1%, n¼47, P ¼ TPTXþAT. Patient characteristics, including age, sex, ASA classi- 0.34), leading to reoperation in 1 patient of each group. In the TPTX fication, duration of dialysis before surgery, and the number of patient, bleeding resulted from a displaced clip and in the TPTXþAT patients on kidney transplantation waiting list were not different patient a hematoma was evacuated but no bleeding source was between the groups. Cinacalcet and/or paricalcitol intake before identified. The differences were not statistically significant. Unilat- surgery and preoperative PTH and serum calcium levels were also eral paralysis of the recurrent laryngeal nerve occurred in 6 patients not different. Preoperative patient characteristics and baseline data of of the TPTX and 2 patients of the TPTXþAT group (P ¼ 0.37), the trial population are depicted in Table 2. which was permanent in 1 TPTXþAT patient who received a laterofixation of the vocal cord affected. Mortality was nil. Mean Surgery serum calcium at the day of discharge was 2.0 0.2 mmol/L in both In 51 of the 52 TPTX patients, 4 or 5 (1 patient) parathyroid groups. Corresponding PTH values were 54.7 201.7 in the TPTX glands were identified and resected according to histopathology. and 53.4 163.3ng/L in the TPTXþAT group which was not Among those, 3 patients had a unilateral and 2 patients a bilateral significantly different.

TABLE 2. Patient Characteristics and Baseline Data Patient Characteristics and Baseline Data Total n¼100 TPTX n¼52 TPTX þ AT n¼48 Sex Male n % 65 (65.0%) 32 (61.5%) 33 (68.8%) Sex Female n % 35 (35.0%) 20 (38.5%) 15 (31.3%) Age Mean SD (n) 49.2 15.6 (100) 49.2 14.5 (52) 49.2 16.9 (48) ASA-classification ASA II n (%) 30 (30.0%) 19 (36.5%) 11 (22.9%) ASA III n (%) 69 (69.0%) 32 (61.5%) 37 (77.1%) ASA IV n (%) 1 (1.0%) 1 (1.9%) 0 (0.0%) Duration of dialysis therapy [months] Mean SD (n) 58.9 37.0 (98) 50.7 24.2 (51) 67.8 45.8 (47) Patient on kidney transplantation waiting list Yes n (%) 68 (68.0%) 36 (69.2%) 32 (66.7%) Vocal cord function normal n (%) 98 (100.0%) 51 (100.0%) 47 (100.0%) Baseline medication vitamin D Yes n (%) 55 (55.0%) 28 (53.8%) 27 (56.3%) Baseline medication Cinacalcet and/or Paricalcitol Yes n (%) 46 (46.0%) 23 (44.2%) 23 (47.9%) Baseline Calcium [mmol/L] Mean SD (n) 2.5 0.2 (98) 2.5 0.2 (51) 2.4 0.2 (47) Baseline iPTH [ng/L] Mean SD (n) 1250.0 906.9 (100) 1329.8 1048.0 (52) 1163.5 725.3 (48) This table provides detailed information about preoperative patient characteristics and baseline data of the trial population. None of the parameters was significantly different between the two groups. ASA indicates American Society of Anesthesiologists Physical Status Classification System; N, number; SD, standard deviation; TPTX, total parathyroidectomy alone, TPTXþAT, total parathyroidectomy with routine bilateral cervical thymectomy and parathyroid autotransplantation.

Mean hospital stay was not different between the TPTX and who completed the study after 3 years. None of the patients devel- the TPTXþAT group (10 7.1 vs 8 3.7 days, P ¼ 0.11). oped hypercalcemia. However, 21 of 38 patients still received low Approximately, 90.2% (46/52) patients of the TPTX group and dosages of oral calcium (1 g/day) and 31 of 38 patients had Vitamin 83.3% (40/48) patients of the TPTXþAT group were discharged D3. In all 38 TPTX patients, PTH was measurable, the lowest value with oral calcium, and 90.2% (46/52) patients of the TPTX and being 2.2 ng/L. Among them 16/38 patients had PTH levels below the 81.3% (39/48) of the TPTXþAT patients received oral Vitamin D lower limit (<11 ng/L). None of the TPTX patients required delayed supplementation. Perioperative data are summarized in Table 3. parathyroid autotransplantation for hypocalcemia. In the TPTXþAT group, serum calcium values were within Follow up the normal range in 28/35 patients who completed the study after Seventy-four patients regularly completed the study 3 years. None of the patients developed hypercalcemia; Fifteen out of (35 TPTXþATand 38 TPTX patients) 36 months after their surgery. 35 patients still received low dosages of oral calcium ((1 g/day), 31/ Throughout the follow-up period, 9 patients (6 TPTX, 3 TPTXþAT) 35 had Vitamin D 3 years post surgery. In 7/35 patients, PTH was decided to withdraw their informed consent. Five patients (3 TPTX, 2 below the lower limit (<11 ng/L). However, in all TPTXþAT TPTXþAT) were lost to follow-up. At the end of the study, 12/100 patients PTH was measurable, the lowest value being 3.8 ng/L. patients had died for several reasons, including myocardial infarc- The differences between the numbers of patients on oral calcium- tion, sepsis after kidney transplantation, ventricular fibrillation, and/or vitamin D supplementation were not statistically different depression with refusal to continue dialysis, and pancreatic cancer. between groups (P values: calcium ¼ 0.29, vitamin D ¼ 0.63). The There was no significant difference in mortality between the TPTX amount of calcium within dialysis fluids or intravenously applied (5/52) and the TPTXþAT (7/48) group (P ¼ 0.18). was not registered. Serum calcium values between TPTX and TPTXþAT groups Sixteen out of fifty-two patients of the TPTX group and 11/48 did not differ significantly in all of the follow-up visits except for the patients of the TPTXþAT group received successful kidney trans- values 24 months after surgery [2.2 0.2 mmol/L (TPTX) versus 2.1 plantation during follow-up. The difference was not statistically 0.2 mmol/L (TPTXAT) P ¼0.02, Fig. 2A]. PTH values of the different (P ¼ 0.38). TPTX patients remained lower when compared with the TPTXþAT group, although this difference was not statistically significant until 36 months after surgery (31.7 43.6 vs 98.2 156.8, P ¼ 0.02, DISCUSSION Fig. 2B). New medical treatment regimens (eg, with calcimimetics) for Recurrent SHPT developed in none of the TPTX, but in 4 of the treatment of sHPT limited the need for parathyroidectomy only the TPTXþAT patients. All 4 patients who developed recurrent for a rather short period. Thus, parathyroidectomy will remain a SHPT had their surgeries at the same trial site. In all of these, cornerstone in the treatment of SHPT with approximately 1% to 2% surgery was performed according to protocol with four glands of patients with renal HPT requiring PTX each year.36 However, removed together with the thymic tongues and a parathyroid auto- timing and the extent of surgery remain a constant matter of debate.37 transplantation to the forearm thereafter. In these, recurrent SHPT The surgical strategy in renal HPT should focus on an adequate developed in 1 patient after 12, in another after 24 and in 2 patients balance between extent of parathyroid resection, prevention of after 36 months, respectively (P ¼ 0.03). To date no localization persistent/recurrent disease, and avoidance of postoperative perma- studies were performed, as recurrent SHPT was mild to moderate nent hypoparathyroidism.37 The selection of a specific operative with none of the patients developing hypercalcemia. No patient approach will be mainly directed by the patient’s chances to receive needed reoperation until the end of the study. In the TPTX group, a kidney transplant, and the target range of PTH between 150 to serum calcium levels remained in the normal range in 25/38 patients 300 pg/mL for patients on permanent dialysis according the KDOQI

TABLE 3. Perioperative Data Variable Total (n¼100) TPTX (n¼52) TPTXþAT (n¼48) P Duration of surgery (hrs, mean SD) 02:37 00:58 02:29 01:01 02:47 00:51 0.13 Resection of 4 or more parathyroid glands 95/100 51/52 44/48 0.08 Unilateral thymectomy 3/100 3/52 0/48 Bilateral thymectomy 48/100 2/52 46/48 Unilateral recurrent laryngeal nerve palsy Transient 8/76 6/41 2/35 0.36 Permanent 1/35 ENT missing 24 11 13 Postoperative bleeding 4/100 3/52 1/48 necessitating reoperation 2/100 1/52 1/48 0.34 Persistent SHPT 3/100 1/52 2/48 0.14 scheduled for reoperation 1/3 0/1 1/2 Mean calcium at discharge (mmol/L, mean SD) 2.0 0.2 2.0 0.2 2.0 0.2 0.31 Mean PTH at discharge (ng/L, mean SD) 54.1 182.7 54.7 201.7 53.4 163.3 0.97 Patients with oral calcium supplementation at discharge 86 /100 (86%) 46/52 (90.2%) 40/48 (83.3%) 0.31 Patients with oral Vitamin D supplementation at discharge 85 /100 (85%) 46/52 (90.2%) 39/48 (81.3%) 0.20 Duration of hospital stay (days, mean SD) 9 5.8 10 7.1 8 3.7 0.11 This table provides detailed information about the procedures performed, perioperative complications, and the duration of hospital stay. Furthermore, intact PTH and calcium values and calcium and vitamin D supplementation at discharge of the trial population are displayed. ; ENT indicates ear, nose, and throat examination; N, number; PTH, parathyroid hormone; SD, standard deviation; SHPT,secondary hyperparathyroidism; TPTX, total parathyroidectomy alone; TPTXþAT, total parathyroidectomy with routine bilateral cervical thymectomy and parathyroid autotransplantation.

Calcium values over time TPTX TPTX+AT

3 p=0.77 p=0.94 p=0.37. * p=0.80 p=0.02 p=0.95. 2,5

1,5

1 Calcium (mmol/l)

0,5

0 A preop discharge 6 months 1 year 2 years 3 years

Parathyroid hormone values over time TPTX p= 0.37 2500 TPTX+AT

FIGURE 2. Calcium and PTH values over 2000 time. A, This figure shows total calcium values throughout the whole study period in the 2 groups. Albeit expected otherwise, 1500 calcium values were not significantly lower in the TPTX group. B, This figure shows intact parathyroid hormone (PTH) values PTH (ng/l) PTH 1000 throughout the whole study period in the 2 groups. PTH levels were not significantly lower in the TPTX group until 36 months * 500 p=0.12 p =0.02 after surgery when compared with the p=0.9 p=0.09 p=0.60 levels measured in the TPTXþAT group. 7 TPTX indicates total parathyroidectomy alone, TPTXþAT, total parathyroidectomy 0 with routine bilateral cervical thymectomy B preop discharge 6 months 1 year 2 years 3 years and parathyroid autotransplantation.

guidelines.38 SPTX and TPTXþATare the standard procedures since clinical relevant hypoparathyroidism was not observed. According many decades.37 However, in some, mostly underpowered retro- to our results, an autotransplantation after TPTX is obviously not spective studies, TPTX was also reported to be successful with low necessary. Ectopic parathyroid cell nests in the upper mediastinum or recurrence and hypocalcemia rates.18,31–33 Although conducted on the thymus most likely provide a sufficient parathyroid hormone a nonconfirmatory basis, this pilot trial is the first to compare the secretion. This is supported by the fact that the patients that had not outcome of one of the standard procedures (TPTXþAT) with TPTX undergone a cervical thymectomy (47 of 52 of the TPTX group) had alone in a prospective multicenter randomized controlled design to measurable PTH levels postoperatively. Also the prevalence of TPTX and provides reliable estimates on the rates of recurrent SHPT detectable intrathymic parathyroid cell nests or glands in patients of both surgical strategies. who underwent PTX for SHPT was described as up to 45%.40,41 In the current study, both surgical strategies seem to be safe It is also of note, that TPTX was able to suppress PTH more and effective for the treatment of otherwise uncontrollable SHPT. As effectively than TPTXþAT after 36 months (31.7 43.6 vs 98.2 expected, the operative time for TPTX tended to be shorter than for 156.8, P ¼ 0.02). This fact favors TPTX, as maintaining low PTH the TPTXþAT, although this was not significant (19 mins, P ¼ 0.13). levels after PTX is associated with a reduced cardiovascular The typical complications such as paralysis of the recurrent laryngeal mortality and an improvement of overall prognosis.42,43 nerve, postoperative hemorrhage, and postoperative hypocalcemia Patients with SHPT undergoing any type of PTX are poten- were not different between groups which is in line with the published tially at risk for the development of permanent hypoparathyroidism. literature.11,13,31–33,39 Postoperative serum calcium and PTH levels Parathyroid cryopreservation to enable delayed heterotopic para- were almost equal between groups, which is in accordance with the thyroid AT is therefore advocated since many years. In the current findings of former retrospective studies.11,13,31–34,39 Permanent study, none of the TPTX and TPTXþAT patients needed a delayed

parathyroid autotransplantation of cryopreserved tissue during fol- number of patients postoperatively. Though both methods influence low-up. This underscores the results of a recent large retrospective serum calcium levels, it is unlikely that these were of influence to the Japanese study on more than 2000 patients treated with TPTXþAT. 44 outcome and applied long term after surgery. Moreover, one third of None of these patients had to undergo delayed AT of cryopreserved the patients who completed the study underwent successful kidney tissue for persistent hypoparathyroidism. Thus, cryopreservation transplantation and developed no symptomatic hypocalcemia seems to be not necessary after TPTX and TPTXþAT. although they had no access to intravenous calcium applications The rates of persistent and recurrent HPT ranged between 0% thereafter. to 10% for TPTXþATand 0% to 4% after TPTX according to several Third, the results of this trial are limited by its nonconfirma- retrospective case series and cohort studies.29,31,32,37 In the current tory design. Some differences observed were significant between study, the persistence rate was comparably low in both the TPTX (1 both groups, though they have to be interpreted with caution. On the of 52, 1.9%) and the TPTXþAT (2/48, 4.1%) group. Persistence other hand, it is unlikely that a confirmatory trial with a large number seems to be mainly caused by an incomplete parathyroidectomy. In of patients will ever be performed. As all recurrences were observed 2 of the 3 patients with a persistence only 3 parathyroid glands were at one trial site, it is likely that the difference in recurrence rates identified and removed. The third patient had been assigned to the between both groups will be in fact smaller than observed in this study. TPTX group and had 4 glands resected. This patient developed a mild Despite of the fact that this trial cannot definitely answer the persistent SHPT, focusing on additional parathyroid tissue most question whether TPTX is superior or equal to TPTXþAT, it can be likely located within the non resected thymus. However, this per- concluded that TPTXþAT and TPTX seem to be safe and effective sistence was mild, not accompanied with hypercalcemia and cured for the treatment of otherwise uncontrollable SHPT and that TPTX is by successful kidney transplantation thereafter. This supports the a feasible alternative therapeutic option. results of recent systematic review of 53 publications with 501 patients on reoperations for recurrent or persistent renal HPT. ACKNOWLEDGMENTS Reoperation determined that inadequate cervical explorations The authors would like to thank all participating centers of the occurred in 34% of patients who had undergone TPTXþAT. 19 Of TOPAR trial group for their outstanding commitment and the excel- note, 1 TPTX patient in the current study was supposed to have an lent support of the trial, which are highly appreciated. This trial was incomplete resection because only 2 glands were identified and conducted within the German Surgical Research Network (CHIR- resected despite removal of both thymic tongues. This patient was Net). Participating centers are listed in alphabetical order of their cured thereafter and it has to be assumed that this patient either had location, patient recruitment numbers are listed in parentheses. 2 glands adherent to each other misinterpreted as one on both sides or Joachim. M. Mu¨ller, Jens-Carsten Ru¨ckert, Jens Neudecker, truly 2 glands only. Anne Zergiebel, Miko Schmitt, Department for General, Visceral, The recurrence rate in the current study was significantly Vascular, and Thoracic Surgery, Universita¨tsmedizin Berlin, Charite´ higher after TPTXþAT (4 of 48, 8.3%) than after TPTX (0%, P ¼ Campus Mitte, Berlin (10 patients); Hans Detlev Saeger, Ralf 0.03). However, it has to be of note that all 4 TPTXþAT patients with Konopke, Florian Ehehalt, Dorothee Sturm, Department of Visceral, recurrent SHPTwere operated in the same center. The significance of Thoracic, and Vascular Surgery, Carl Gustav Carus University the observed difference is therefore highly questionable, as potential Hospital, Dresden (1 patient), Markus W. Bu¨chler, Christoph M. bias has to be assumed. In all patients, surgery was performed Seiler, Markus K. Diener, Phillip Knebel, Barbara Maichle, Birgit according to the protocol with 4 parathyroid glands resected together Erni, Department of General, Visceral, and Transplantation Surgery, with the thymic tongues. Till date, no localization studies were University Hospital Heidelberg (32 patients); Matthias Rothmund, performed to localize the origin of recurrent SHPT, but the para- Katja Schlosser, Detlef K. Bartsch, Katja Maschuw, Department for thyroid autografts have to be assumed the most likely source of PTH Visceral, Thoracic, and Vascular Surgery, University Hospital of production. Reasons for this outcome could have been, for example, Giessen and Marburg, location Marburg (34 patients); Peter E. an inadequate selection of the tissue selected for AT and/or an Goretzki, Bernhard Lammers, Denis Wirowski (deceased), Gabriele inadequate number and/or size of transplanted tissue fragments. In Mahlberg, Department of Surgery, Lukaskrankenhaus Neuss this regard, it needs to be discussed, whether—irrespective of a very (4 patients); Christoph Nies, Moritz Meyer, Department for General detailed study protocol—a local training of the participating sur- and Visceral Surgery, Marienhospital Osnabru¨ck (17 patients); Hans geons and random controls by a supervising surgeon should have Ju¨rgen Schlitt, Ayman Agha, Gabriel Glockzin, Department of been performed to ensure the quality of the procedures even in Surgery, University Medical Center Regensburg (2 patients) and participating expert centers. None of the patients with recurrent the teams of the cooperating partners SDGC, Christoph M. Seiler, SHPT developed hypercalcemia or underwent reoperation for the Markus K. Diener, Inga Rossion, Philipp Holz; IMBI Biometry mild recurrence during the 36 months follow-up. Reducing the risk Thomas Bruckner, Data Management Christina Klose; and KKS for recurrent SHPT, however, is an important issue for the patients Sonja Wittkus, Jochen Kobert, Holger Wilden. and the healthcare system, as surgery for recurrent SHPT is associated with high costs for localization, a lower cure-rate and a higher REFERENCES morbidity when compared with intial parathyroidectomy.45 1. Wada M, Nagano N, Nemeth EF. The calcium receptor and calcimimetics. In the current study, the 3-years mortality was 12%, which was Curr Opin Nephrol Hypertens. 1999;8:429–433. not different between the TPTX (9,6%) and the TPTXþAT (14.5%) 2. Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for secondary group. 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Outcome of total 26. Patow CA, Norton JA, Brennan MF. Vocal cord paralysis and reoperative parathyroidectomy with or without autotransplantation versus sub- parathyroidectomy. A prospective study. Ann Surg. 1986;203:282–285. total parathyroidectomy has been analyzed in numerous retrospective 27. Liang Y, Sun Y, Ren L, et al. Short-term efficacy of surgical treatment of case collections and in few prospective studies. In this trial total secondary hyperparathyroidism. Eur Rev Med Pharmacol Sci. 2015;19:3904– parathyroidectomy with thymectomy and autotransplantation is 3909. compared with total parathyroidectomy alone. The authors should 28. Ogg CS. Total parathyroidectomy in treatment of secondary (renal) hyperparathyroidism. Br Med J. 1967;4:331–334. be acknowledged for their effort. 29. Shih ML, Duh QY, Hsieh CB, et al. Total parathyroidectomy without My comments and questions are as follows: First, the authors autotransplantation for secondary hyperparathyroidism. World J Surg. present their study as a multicenter prospective randomized con- 2009;33:248–254. trolled trial. To run a randomized control trial on this topic, more than 30. Puccini M, Carpi A, Cupisti A, et al. Total parathyroidectomy without 4000 patients in each treatment arm would be required. Because a autotransplantation for the treatment of secondary hyperparathyroidism trial with such a large sample size would be highly unrealistic, the associated with chronic kidney disease: clinical and laboratory long-term follow-up. Biomed Pharmacother. 2010;64:359–362. study was finally performed as a nonconfirmatory pilot trial with a 31. Coulston JE, Egan R, Willis E, et al. Total parathyroidectomy without sample size of 100 patients. The authors should be asked to give more autotransplantation for renal hyperparathyroidism. Br J Surg. 2010;97: information regarding the choice for the number of patients to be 1674–1679. included. Second, a hypothesis and a definition of primary and

secondary endpoints of the study is missing. Third, as it stands in the concerning quality of life. Did you assess it and ask the patients manuscript postoperative calcium and calcitriol was not required in about the frequency of tetanic episodes because the goal was that any of the patients following total parathyroidectomy. How have the patient would need the transplanted tissue only to avoid a these patients maintained their calcium homeostasis? Fourth, hypocalcemic tetany. Patients who underwent total parathyroidectomy and autotransplantation had a higher recurrence rate during the follow-up compared Response From K. Schlosser (Giessen, Germany): with those in whom autotransplantation was not part of the pro- We included an SF36-questionnaire into our protocol, which cedure. All patients with disease recurrence had surgery at the same the patients had to fill out at any visit during the trial. The acceptance institution. My concern is that this fact could bias the results. Finally, of the patients to fill out the questionnaires was a real problem. parathyroid tissue was secured for later cryopreservation. How many The return rate of the questionnaires was so low after 1 year that we of the patients underwent autotransplantation of their cryopreserved decided not to analyze it. tissue during the follow-up? F. Pattou (Lille, France): Response From K. Schlosser (Giessen, Germany): You found that recurrence of hyperparathyroidism was more Referring to questions 1 and 2: A sample size of 100 patients frequent in the autotransplanted patients. This situation is sometimes was chosen for the following reasons: 50% of patients per group had difficult to handle because the abnormal parathyroid hormone an 80% power to detect a standardized difference of about 0.57 with a secretion can originate alternatively in the neck, or the transplanted level of significance of 5%, when applying a two-sided t test to forearm. In that case, what is your strategy to localize and eradicate normally distributed data. The primary objective of this pilot trial the remaining parathyroid tissue, in term of preoperative imaging and was to provide better estimates of the rates of recurrence after surgical strategy? TPTXþAT and TPTX after 3 years of follow-up (defined as a rise My second question regarding thymectomy. We agree with in PTH above the 5-fold of the upper normal value). To answer this your overall conclusion, although we are routinely proposing thy- question, a pilot study seemed to be an appropriate tool. mectomy for secondary hyperparthyroidism. Indeed, more than 15% Referring to question 3: Vitamin D analogues were given to of the patients have a fifth gland, most often in the thymus. To be sure almost all patients as a prophylaxis against a regrowth of any para- that we are only leaving one site containing parathyroid tissue, we thyroid remnant. One gram calcium was given orally every day, but we prefer to always associate thymectomy, even in the exclusively do not know the total amount of calcium applied as calcium applied cervical operations. What do you think of that addition to the intravenously or together with dialysis fluids was not registered. proposal? Almost all patients from the Marburg trial site necessitated high amounts of calcium administered intravenously within the first year, Response From K. Schlosser (Giessen, Germany): referring to a high influx into the bones due to an almost always present If a patient with a parathyroid autograft develops recurrent hungry bone syndrome. Patients receiving a kidney transplant within disease, the first thing to do is to perform an abbreviated Casanova’s the first year after surgery might get a problem sustaining stable test. This is the easiest way to differentiate if the recurrence origins calcium levels. However, we did not see this problem in the 27 patients from the graft or from the neck. If PTH values drop in venous blood who received a kidney transplant within our trial. from any site except for the excluded extremity who bears the graft, Referring to question 4: We talked to the doctors in charge of one does not need to do anything else than remove the autografted the trial site where the recurrences in the TPTXþAT patients tissue. One can do it under local anesthesia and it can be done occurred. We suspect that there might have been a technical problem, repeatedly. If the Casanova test is not focusing on the graft, then a may it be the size or the amount of the fragments used for the Sesta-MIBI-scintigraphy and an ultrasound of the neck should be parathyroid autografts. We are planning to check the 4 patients with done. If this does not localize the origin of PTH production, I would recurrent SHPT, to find out if the recurrence is autograft-dependent prefer an MRI to look for additional glands within the mediastinum. or not. There was a detailed manual within the protocol about how to I completely agree with you that additional glands within the perform a parathyroid autotransplantation, but no supervisor visited thymus might be a problem. We did an examination at our institution the centers to check if the manual was followed properly. and found that in over 50% of patients where we regularly removed Referring to question 5: None of our patients needed their the thymic tongues additional parathyroid cell nests or even glands cryopreserved parathyroid tissue for a delayed autotranspantation. were found therein. However, this may also be an advantage as these tissues may provide at least some PTH, thus preventing adynamic N. Senninger (Mu¨nster, Germany): bone disease. If persistent disease occurs after TPTX without bilat- You mentioned 26 patients out of your series, bringing it back eral thymectomy one has to reoperate to remove the thymus. We did to 74%. Still, your message is clear. I have just one question not have a patient with this problem in the study.