Revision Neural Monitored Surgery for Recurrent Thyroid Cancer: Safety and Thyroglobulin Response

Transcription

1 The Laryngoscope VC 2015 The American Laryngological, Rhinological and Otological Society, Inc. Revision Neural Monitored Surgery for Recurrent Thyroid Cancer: Safety and Thyroglobulin Response Behzad Salari, MD; Yin Ren, MD, PhD; Dipti Kamani, MD; Gregory W. Randolph, MD, FACS, FACE Objectives/Hypothesis: To evaluate the quantitative biochemical response, recurrence rate, and rate of surgical complications for thyroid cancer revision surgery. Study Design: Retrospective review. Methods: This is a single institution analysis of a prospective database of 181 patients undergoing reoperation for local recurrent thyroid cancer by the same surgeon from 2004 to 2013 with intraoperative neural monitoring. Main outcome measures included pathologic findings, surgical complications, effect of reoperation on thyroglobulin (Tg) levels, and recurrence rate. We defined biochemical complete remission as postoperative stimulated Tg of 0.2 ng/ml or less. Results: Fourteen percent of the patients presented with permanent vocal cord palsy (VCP), and 20% of the patients presented with hypocalcemia prior to surgery. Among them, 70% of the patients underwent first revision surgery; whereas in 30% the surgery represented second or higher revision surgery, with 8% being a third or higher revision. None developed temporary or permanent VCP. Temporary hypocalcemia occurred in 9% of the patients, and permanent hypocalcemia occurred in 4.2%. The rate of cervical node recurrence was 5% at a median follow-up of 3.4 years. There were no diseasespecific deaths. Mean preoperative basal Tg was 22.3 ng/ml and mean postoperative Tg was 5.7 ng/ml, a decline of 74% (P , paired t test). Biochemical complete remission was achieved in 58% of all revision cases. Conclusion: Reoperative neural monitored surgery for recurrent thyroid cancer is a safe and effective procedure with limited morbidity in experienced hands, even in the setting of multiple prior revision surgeries and existing comorbidities such as VCP and hypocalcemia. Key Words: Revision thyroid surgery, thyroglobulin, Tg, safety, complications. Level of Evidence: 4. Laryngoscope, 126: , 2016 INTRODUCTION The incidence of papillary thyroid cancer (PTC) has been increasing over the past several decades world-wide. Following initial surgical resection, a combination of neck ultrasound and basal as well as stimulated thyroglobulin (stg) are performed at regular intervals to monitor for persistent or recurrent disease. 1 Locoregional recurrence after initial surgery ranges from 15% to 30% and can cause significant distress to the patient. However, its effect on survival is a matter of debate, particularly for low-volume disease. 2 4 Recurrent PTC usually presents in the form of regional lymph node metastases. 2,5 From the Division of Thyroid and Parathyroid Surgery, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary and Harvard Medical School (B.S., Y.R., D.K., G.W.R.); and the Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital and Harvard Medical School (G.W.R.), Boston, Massachusetts, U.S.A. Editor s Note: This Manuscript was accepted for publication October 30, The authors have no funding, financial relationships, or conflicts of interest to disclose.send correspondence to Greg Randolph, MD, FACS, FACE, Massachusetts Eye and Ear Infirmary (B.S., Y.R.) share the first authorship. Thyroid and Parathyroid Endocrine Surgery Division, Dept. of Otolaryngology, 243 Charles Street, Boston, MA gregory_randolph@meei.harvard.edu DOI: /lary The management of recurrent thyroid cancer necessitates a multidisciplinary approach. The optimal strategy to maximize efficacy and minimize morbidity can be achieved after gaining a thorough understanding of the benefits and risks of all available options. These include: observation, revision central and/or lateral compartment neck surgery, radioactive iodine therapy (RAI), external beam radiotherapy, percutaneous alcohol injection, or radiofrequency ablation. 2 4 The 2015 revised guidelines by the American Thyroid Association recommend reoperation of clinically significant (>8 mm in the central neck and >10 mm in the lateral neck) recurrent disease. 1 Reoperative thyroid bed surgery can be difficult due to the proximity of the tumor to important structures such as the recurrent laryngeal nerve (RLN), parathyroid glands, trachea, and larynx. Furthermore, the presence of scar tissue and distorted anatomy may result in a greater risk of complications, namely vocal cord paralysis (VCP) and hypocalcemia. Data are lacking regarding the efficacy of reoperation in achieving biochemical complete remission (BCR). 2,3 The present study reviews a single surgeon s experience with revision surgery in a large cohort of patients with locally persistent or recurrent thyroid cancer, which represents an update of a previously reported series with expanded data on thyroglobulin (Tg) response. 6 We evaluate the 1020

2 surgical approach, effectiveness of reoperation with curative intent, quantitative biochemical response, and rate of surgical complications. MATERIALS AND METHODS With the approval from the institutional review board, medical records of 181 consecutive patients who underwent surgery for recurrent/persistent thyroid cancer by the senior author (G.W.R.) from 2004 to July 2013 were reviewed. All patients underwent previous total thyroidectomy, with or without lymph node dissection, followed in some cases by adjuvant RAI therapy or external beam radiation. The majority of patients had PTC. Less than 5% of the patients had medullary thyroid cancer (MTC); they were included in this study because they presented analogous issues in terms of nodal reoperation and VCP risk. Thyroglobulin response was measured in PTC patients only. Disease recurrence was diagnosed by an amalgamation of clinical examination, biochemical measurement, imaging, and fine-needle aspiration (FNA) cytology. No attempt was made to differentiate recurrent from persistent disease through evaluation of the completeness of prior surgeries. Outcome measures included pathologic findings, surgical complications, effect of reoperation on Tg levels, and recurrence rate. Revision Neck Surgery All patients with recurrent PTC or MTC were evaluated for revision surgery by a multidisciplinary team, including endocrinologists and otolaryngologists. With the goal of resecting every clinically evident disease, we explored and dissected all compartments (unilateral or bilateral) that contained suspicious nodes confirmed by FNA and that met radiographic criteria and (i.e., central neck nodes 8 mm and lateral neck nodes 10 mm). 7 All patients had a preoperative ultrasound and axial computed tomography (CT) (with contrast) of the neck to develop a nodal map that guided the extent of surgery, as previously described. 8 All operations were performed by utilizing endotracheal tube-based surface electrode intraoperative neural monitoring (IONM) according to the guidelines of the International Neural Monitoring Study Group. 9 Preoperative and postoperative laryngeal examinations were performed according to the American Academy of Otolaryngology Thyroidectomy voice optimization guidelines. 10 Surgical Technique The approach to revision central neck surgery has been described in detail elsewhere. 11,12 To summarize in brief, the lateral (backdoor) approach was employed (Fig. 1). In this approach, muscle layers including the sternocleidomastoid, omohyoid, and sternohyoid muscles are mobilized in a sequential manner through tissue planes that were undisturbed from primary surgery. This enables identification of the jugular vein, common carotid artery, vagus nerve (with IONM confirmation), RLN (facilitated by neural mapping), trachea, paratracheal region, and esophagus. Once the RLN has been dissected and mobilized in a meticulous fashion, an attempt should be made to identify and preserve any remaining parathyroid glands. Surgical Complications All patients had laryngeal exams by flexible fiberoptic laryngoscopy before and after their last revision to assess for VCP. Recurrent laryngeal nerve paralysis/paresis was considered temporary if voice impairment was less than 6 months in duration, or permanent if it persisted greater than 6 months. Hypocalcemia Fig. 1. The backdoor lateral approach for revision central neck surgery. was considered transient if the duration of hypocalcemia that required calcium and/or vitamin D supplementation was less than 6 months, and permanent if it was greater than 6 months. Biochemical Measurements and Follow-up In patients with PTC, serum basal Tg (i.e., stimulated and unstimulated) prior to the last revision surgery was compared to postoperative Tg and stg, either by thyroid hormone withdrawal or with recombinant human thyroid stimulating hormone (rh-tsh). For efficacy analysis, we defined BCR as a postoperative stg of 0.2 ng/ml or less. In patients with MTC, pre- and postoperative calcitonin levels were obtained. Patient surveillance and follow-up included periodic evaluations by the endocrinologist and surgeon, including physical examination, high-resolution neck ultrasound, and intermittent biochemical assays. Suspicious lesions underwent further evaluation by CT imaging with contrast and FNA, as indicated. Statistical Analysis Statistical analysis was performed using SPSS (IBM Inc., Armonk, NY). All patients were included in the RLN/VCP neural safety analysis; whereas only patients with PTC (without anti-tg antibody or distant metastases) were included in the Tg analysis. Continuous variables were reported as means 6 standard deviation or as medians with range, and categorical variables were expressed as numbers and percentages. Paired t test was used to compare changes in preoperative and postoperative Tg and calcitonin levels. A P value of less than 0.05 was considered statistically significant. RESULTS A total of 181 patients (65 male, 116 female) underwent revision thyroid surgery, with a mean age of 47.7 years (range, ) and a mean follow-up of 3.9 years (range, ). Table I shows baseline characteristics, prior surgeries, and pathologic findings. Forty-one percent of the patients (n 5 74) had a total thyroidectomy 1021

3 TABLE I. Patients Baseline Characteristics, Prior Surgeries, and Pathologic Findings (N 5 181). Mean of age 6 SD* (year) At primary surgery (range, ) At first revision (range, ) At last revision (range, ) Diagnosis at last revision PTC 167 (92.3%) MTC 9 (4.9%) Others 5 (2.8%) Tumor stage at primary surgery* I 109 (69.0%) II 4 (2.5%) III 24 (15.2%) IV 21 (13.3%) Number of revision surgeries 1st revision 123 (68.0%) 2nd revision 44 (24.3%) 3rd revision 7 (3.9%) 4th revision 2 (1.1%) 5th revision 5 (2.8%) Complications at presentation Permanent VCP 25 (13.8%) Permanent hypocalcemia 37 (20.4%) *When information was available. MTC 5 medullary thyroid carcinoma; PTC 5 papillary thyroid cancer; SD 5 standard deviation; VCP 5 vocal cord paralysis. and some form of neck dissection (central and/or lateral) as their primary surgery. The mean age at primary surgery was 40.6 years (range, ). The mean number of revision surgeries was 1.5 (range, 1 7) per patient, with a mean age of 46.6 years at the time of the first revision. Three percent of the patients (n 5 6) underwent completion thyroidectomy with or without neck dissection. Specifically, the surgery performed in this series represented the first reoperation in 68% of the patients (n 5 123), the second revision in 24% of the patients, and the third or more revision in 7.8% of the patients. The mean time between the primary surgery and the last revision surgery was 6.8 years (range, ). Operative Finding of Revision Thyroid Surgery The average estimated blood loss was 31 ml (range, ml). In 98 surgeries involving unilateral paratracheal central neck dissection, a total of 460 lymph nodes were excised, with the median of four (range, 1 19) nodes per patient. The median number of positive nodes was two (range, 0 10), with a rate of extranodal extension of 15.3% (n 5 15). In 131 surgeries involving the lateral neck, a total of 2,128 lymph nodes were excised, with a median of 15 (range, 1 51) lymph nodes per patient. The median number of positive nodes was two (range, 0 16), with a rate of extranodal extension of 13.7% (n 5 18). Complications of Revision Thyroid Surgery A significant proportion of the cases presented with complications from prior thyroid operations that preceded our revision neck surgery. Specifically, this included permanent VCP in 13.8% of the patients (n 5 25) and hypocalcemia in 20.4% of the patients. Postoperatively, no patient developed temporary or permanent new/unexpected VCP, including those patients who underwent completion thyroidectomy. In one patient, the right RLN was sacrificed due to tumor invasion. Temporary hypocalcemia occurred in 9% of the patients (n 5 13), whereas permanent hypocalcemia occurred in 4.2% (n 5 6). Other complications included hematoma requiring drainage (1.7% of cases, n 5 3), temporary chyle leak that resolved with conservative management (1.7% of cases, n 5 3), and neck seroma requiring no treatment (2.2% of cases, n 5 4). Recurrence after Revision Surgery and Follow-up The median follow-up time was 3.4 years (range, ). The overall rate of cervical node recurrence after revision surgery was 5% (n 5 9). The rate of distal metastases after revision surgery was 4.5% (n 5 8). There were no recurrence-related deaths. Postoperatively, the majority of the patients (87.3% of cases, n 5 158) had RAI therapy, twenty-one (11.9%) had external beam radiotherapy, and two (1.1%) had chemotherapy. Thyroglobulin Response to Final Revision Surgery A total of 89 patients with both preoperative and postoperative Tg levels available were included in the analysis of Tg response. Thirty-five patients were excluded due to the presence of Tg antibodies (n 5 30), known distant metastases (n 5 6), or both. The mean preoperative basal Tg was 22.3 ng/ml (range, ). The mean stg after revision surgery was 5.7 ng/ml (range, ), representing a decline of 74% (P , paired t test). In 57.8% (n 5 67) of the cases, the postoperative stg level was undetectable (Figs. 2 and 3). 1022

4 ple behind reoperation in locoregional recurrence of PTC is achieving maximum biochemical remission while minimizing perioperative complications. Fig. 2. Percentage of undetectable Tg post-reoperation stratified based on number of revision. Rev 5 revision; Tg 5 thyroglobulin. Additional analysis was performed to determine the impact of increased number of revisions on the amount of Tg decline postoperatively. One hundred thirteen patients who underwent first revision surgery presented with mean preoperative Tg of 19.7 ng/ml (range, ) and postoperative stg of 1.5 ng/ml (range, ), representing a 92% decrease (P 5 P 0.062, paired t test). Among these, 67.6% (n 5 50) had undetectable stg. Forty-three the cases who underwent second revision surgery had mean preoperative Tg of 30.6 ng/ml (range, ) and postoperative stg of 12.0 ng/ml (range, ), a decline of 61% (P , paired t test), with 38.7% (n 5 12) having undetectable stg. Eleven patients with three or more revision surgeries had a mean preoperative Tg of 15.7 ng/ml (range, ) and postoperative stg of 19.0 ng/ml (range, ) (P , paired t test). Postoperative stg was undetectable in 55% (n 5 5) of the patients. Of note, one patient had a seventh revision surgery with preoperative Tg of 92 ng/ml and postoperative stg level of 685 ng/ ml. However, the patient developed lung metastases 1 year after the last surgery. Calcitonin Response to Final Revision Surgery A small subset of patients (n 5 8) presented with MTC and had both preoperative and postoperative calcitonin levels available. Two patients were excluded from analysis due to known distal metastasis. The mean calcitonin level was 465 pg/ml (range, ) preoperatively and 302 pg/ml (range, ) postoperatively, representing a decline of 35% (P , paired t test). DISCUSSION The majority of patients (69%) in our study who underwent revision surgery presented with stage I disease at their initial surgery, which presented in their 40s, with average recurrence occurring just short of 7 years after initial presentation. A large proportion of the cohort (nearly 30%) underwent second or higher revision surgeries. In particular, one patient presented for her seventh revision surgery. In general, the guiding princi- PTC and Biochemical Remission In the present study, the decline in mean Tg level in all revision surgeries was 77%. Overall, 58% of the patients (n 5 67) had an undetectable Tg postoperatively. Among those with undetectable postoperative Tg, 68% of the patients underwent their first revision, and 39% underwent a second or higher revision surgery. Although 55% (n 55) of the patients with three or more revisions also had an undetectable postoperative Tg level, the small number of patients limits further analysis. The efficacy of reoperative surgery for recurrent thyroid cancer can be quantified by the rate of biochemical remission (BCR), 2,3 which is defined as postoperative Tg level ranging between 0.5 ng/ml and 2 ng/ml Nevertheless, the definition of biochemical remission has changed over time with changes in Tg assays. Thyroid stimulating hormone stimulation with either thyroid hormone withdrawal or rh-tsh injection has greatly enhanced the sensitivity of Tg monitoring. 19 Furthermore, anti-tg antibodies occur in 15% to 20% of PTC patients, which interfere with serum Tg measurements. 19 In this study, assays that measured stg were used in both the pre- and postoperative setting. Patients with anti-tg antibodies were excluded from the analysis. A postoperative stg level of less than 0.2 ng/ml was defined as achieving BCR. Overall BCR rate in our series was 58%, and it was augmented to 68% with first revision surgery. This compares favorably to rates reported in the literature, ranging from 12% to 62.5%, with an average length of follow-up between 6 to 65 months Furthermore, in subset analysis, the rate of BCR decreased with increasing number of revision surgeries, a trend that has been reported elsewhere. 16,20 Complications of Reoperation In our series, 32% of the patients presented for their second or higher revision surgery, with nearly 8% Fig. 3. Mean preoperative and postoperative Tg stratified based on number of revision surgeries. Rev 5 revision; Tg 5 thyroglobulin. 1023

5 having their third or higher vision surgery. Permanent VCP and hypoparathyroidism are two major adverse events associated with revision neck surgeries. In this series, revision surgery patients represented a morbid group, with 14% and 20% presenting with VCP and hypoparathyroidism, respectively. There was no temporary or permanent postoperative VCP. The rate of transient new-onset hypocalcemia was 9% (n 5 13), whereas permanent hypocalcemia occurred in 4.2% of the cases (n 5 6). These rates compare favorably to those reported in the existing literature ,18,21 31 In the literature, the rate of permanent, unexpected VCP ranges from 0% with IONM 18,21 24 to 6.4% without IONM ,25 31 By contrast, permanent hypoparathyroidism occurred in 0% to 9.5% of the cases, 13 15,18,21 31 with temporary hypoparathyroidism being reported in up to 46.3% of such revision patients. 30 Reoperation presents a special challenge for the surgeon due to scarring and entrapment in fibrotic tissues, which significantly distort normal anatomic relationships and make RLN and parathyroid gland identification difficult. Techniques such as IONM, the identification of vagus at the initial phases of surgery, and the identification of the RLN inferiorly in the tracheoesophageal groove can help reduce the morbidity of central compartment dissections. Because of the chronic nature of recurrence in patients with PTC and the need for further surgeries, each parathyroid gland should be treated as the patient s only gland. 32 Utilizing these principles, several recent studies showed that reoperative surgery can have low complication rates. One study reported a lower rate of temporary hypocalcemia with revision central neck dissection (CND) (23.6%) compared to primary CND (41.8%). 31 Nevertheless, it is difficult to interpret postoperative complication rates and oncologic outcomes associated with reoperative thyroid surgery for several reasons. The patient population in existing retrospective studies usually is small. The surgical approach is not uniform across institutions because techniques range from targeted removal of clinically detectable disease to comprehensive neck dissections (central, lateral, or combined), with or without consistent utilization of IONM. Postoperative assessment, including determination of VCP, quantification of Tg (stimulated vs. unstimulated), assay sensitivity, and duration of follow-up all vary significantly between published studies. Older series tend to report higher cure rates due to the use of less-sensitive outcome parameters (clinical examination, radiologic evidence, I-131 uptake). Many of these patients would not have achieved BCR by contemporary criteria such as stg measurements. 18 Factors Affecting Recurrence Identifying the factors that increase the risk of recurrence can be helpful in designing a more cost-effective surveillance strategy. 33 In one study, higher preoperative Tg levels predicted failure to achieve clinical and biochemical remission, whereas lower stg was significantly associated with a higher BCR rate. 17 Other factors that can affect disease-free survival and rate of locoregional recurrence include: age, 25 postoperative stg level greater than 5 ng/ ml, 17 the presence of BRAF (V600E) mutation, 22 and a node positive ratio of greater than 30%. 34 Furthermore, patients with earlier disease relapse have poorer prognosis than those with late relapse. 35 Limitations This study demonstrates that neural monitored reoperative thyroid surgery in a large cohort of PTC patients is efficacious with robust response in Tg, while at the same time it is safe with a low complication rate. However, several limitations remain before the results can be generalized. These include the retrospective nature of the study, a mean follow-up period of less than 5 years, and incomplete previous primary/revision surgeries information. Finally, we were unable to perform detailed analysis for patients who underwent revision surgery for diagnoses other than PTC due to the small number of cases in this subset. CONCLUSION Reoperative thyroid surgery including both cervical lymphadenectomy and thyroid remnant removal with curative intent for recurrent/persistent thyroid cancer is a safe and effective procedure, with limited morbidity with neural monitoring in experienced hands, even in the setting of multiple prior revision surgeries and in the presence of preoperative morbidities such as VCP. It also is an oncologically safe procedure that can lead to undetectable stg level in 58% of PTC patients postoperatively. Acknowledgments The authors thank The John and Claire Bertucci Thyroid Research fund for supporting this research. BIBLIOGRAPHY 1. Haugen B, Alexander E, Bible K, et al. American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer The American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid doi: /thy Magarey MJ, Freeman JL. Recurrent well-differentiated thyroid carcinoma. Oral Oncol 2013;49: Urken ML, Milas M, Randolph GW, et al. A review of the management of recurrent and persistent metastatic lymph nodes in well differentiated thyroid cancer: a multifactorial decision making guide created for the thyroid cancer care collaborative. Head Neck 2015;37: doi: /hed Shaha AR. Recurrent differentiated thyroid cancer. Endocr Pract 2012;18: Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. 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