The Use and Benefit of Adjuvant Radiotherapy in Parathyroid Carcinoma: A National Cancer Database Analysis.

BACKGROUND: The routine use of external beam radiotherapy (EBRT) is not recommended for parathyroid carcinoma (PC). However, case series have demonstrated a potential benefit in preventing local recurrence with EBRT. We aimed to characterize the patient population treated with EBRT and identify any impact of EBRT on overall survival (OS) in parathyroid carcinoma. METHODS: Patients who underwent surgery for PC from 2004 to 2016 were identified from the National Cancer Database. Clinicopathologic variables and OS were compared between patients based on treatment with EBRT. Multivariable logistic and Cox regression models were performed with propensity scores and inverse-probability-weighting (IPW) adjustment to reduce treatment-selection bias in the OS analysis. RESULTS: A total of 885 patients met the inclusion criteria, with 126 (14.2%) undergoing EBRT. Demographics were similar between the two cohorts (EBRT vs. no EBRT). However, patients treated with EBRT had a higher frequency of regionally extensive disease, nodal metastases, and residual microscopic disease (all p < 0.05). On multivariable analysis, Black race, regional tumor extension, nodal metastasis, and treatment at an urban facility were independently associated with EBRT. The 5-year OS was 85.3% with a median follow-up of 60.8 months. EBRT was not associated with a difference in OS in crude, multivariable, or IPW models. More importantly, 10.5% of patients with completely resected localized disease (M0, N0 or Nx) underwent EBRT without a benefit in OS (p = 0.183). CONCLUSIONS: EBRT is not associated with any survival benefit in the treatment of PC. Therefore, it may be overutilized, particularly in patients with localized disease and complete surgical resection.

Parathyroid carcinoma arising from auto-transplanted parathyroid tissue after Total Parathyroidectomy in chronic kidney disease patient: a case report.

BACKGROUND: Secondary hyperparathyroidism is a common complication in patients with chronic kidney disease that requires vigilant treatment due to its high mortality rate. Pharmacologic therapy is recommended as an initial treatment; if there is no response, a total parathyroidectomy is performed. In some cases, surgery is accompanied by auto-transplantation of parathyroid tissue. CASE PRESENTATION: The patient was diagnosed with chronic kidney disease and received a kidney transplant. However, due to rejection of the transplanted kidney, medical nephrectomy was carried out and routine hemodialysis was initiated and observed. At this time, secondary hyperparathyroidism with elevated parathyroid hormone and hyperphosphatemia developed and pharmacologic treatment was applied. However, there was no response to pharmacologic treatment; therefore, total parathyroidectomy with auto-transplantation was performed. Eight years after surgery, a growing mass was observed in the transplantation site, accompanied by an elevation of parathyroid hormone. A complete resection of the mass was performed, and the patient was diagnosed with parathyroid carcinoma. Additional adjuvant radiation therapy was ordered, and the patient is being monitored. CONCLUSIONS: This is a rare but remarkable case of parathyroid carcinoma arising from auto-transplanted parathyroid tissue after total parathyroidectomy in a patient with secondary hyperparathyroidism. We suggest caution should be taken when choosing to auto- transplant parathyroid tissue and that careful postoperative observation should be performed.

Feasibility of bipolar radiofrequency ablation in patients with parathyroid adenoma: a first evaluation.

AIM: The aim of this study was to first assess the feasibility of bipolar radiofrequency ablation in patients with parathyroid adenoma. MATERIAL AND METHODS: Bipolar RFA was performed in 9 patients with primary parathyroid adenoma in one single session. Measured parameters were PTH and calcium serum levels prior to and after bRFA. Furthermore, using an NRS pain scale (1-10), the individual, subjective maximum sensation of pain was documented. RESULTS: The bRFA resulted in a highly significant (p = .003906) decrease of serum PTH levels (median 67 ng/l) in comparison to those prior to the intervention (median 199 ng/l). Regarding calcium levels, there was no statistical significance (p = .460938), with a decrease of median serum levels comparing pre- and post-bRFA values from 2.82 mmol/l to 2.66 mmol/l. The evaluation of the individual pain sensation during the procedure was assessed by the patients with a median of 5/10 on the NRS scale. In none of the 9 cases complications such as infections, persisting pain or nerve injury occurred. CONCLUSION: For the first time, it was possible to depict the successful therapy of parathyroid adenoma by means of bRFA. This work thus proves bRFA to be an effective, safe, applicable and, concerning sensation of pain, very well tolerable thermoablative technique in the treatment of parathyroid adenoma.

Postoperative local-regional radiation therapy in the treatment of parathyroid carcinoma: The MD Anderson experience of 35 years.

PURPOSE: We aimed to investigate outcomes of locoregional radiation therapy (XRT) in parathyroid carcinoma (PC) patients at a single institution over 35 years. METHODS AND MATERIALS: Retrospective review of PC patients who received postoperative locoregional XRT (1980-2015). Patients were grouped according to XRT after PC initial operation or after salvage surgery. All patients with a histopathological diagnosis of PC who had postoperative locoregional XRT at our institution were included. All patients with a histopathological diagnosis of uncertain malignancy, suggestive for malignancy, or atypical parathyroid tumors and those who had XRT outside our institution were excluded. RESULTS: Eight patients received XRT, 4 in each group, with a median follow-up of 12.5 years. The 4 patients who had XRT after initial surgery all had an oncologic operation, including ipsilateral thyroid lobectomy and central neck dissection, and all of these patients were disease-free at last follow-up. Of the 4 patients who received XRT after salvage surgery, only 1 remained disease free. There were no major complications/long-term side effects associated with XRT. CONCLUSIONS: XRT is well tolerated as postoperative locoregional treatment of patients with PC. Whether it is needed, and the timing of administering XRT, remains to be established.

I-131 for Remnant Ablation in Differentiated Thyroid Cancer After Thyroidectomy: A Meta-Analysis of Randomized Controlled Evidence.

BACKGROUND The aim of this study was to compare the success rate of various levels of I-131 activity for use in remnant ablation in low-risk differentiated thyroid cancer. MATERIAL AND METHODS We identified eligible studies in 5 electronic databases up to December 2014 and the reference lists of original studies and review articles were hand searched for additional articles on this topic. Summary relative risks with their 95% confidence intervals were calculated with a random-effects model. Heterogeneity was assessed using I2 statistics. RESULTS Fourteen randomized clinical trials met the eligibility criteria. The data suggest that the pooled successful ablation rate is 5% lower (95% CI, 1-9% lower) when using 30 mCi compared with 100 mCi (test for heterogeneity, p=0.468, I2=0.0%). In stratified analysis, ablation success rates using 30 mCi are similar to 100 mCi in Asia (SRRs=0.91; 95%CI=0.72-1.14). However, the results favor 100 mCi in Europe (SRRs=0.95; 95%CI=0.91-0.99). Ablation success rates using 30 mCi are similar to 100 mCi in patients who underwent TT/NTT (total thyroidectomy/near total thyroidectomy) (SRRs=0.96; 95%CI=0.92-1.00) and TT/STT (SRRs=0.98; 95%CI=0.73-1.31). However, the result favor 100 mCi in patients who underwent ST/HT (subtotal thyroidectomy/ hemithyroidectomy) (SRRs=0.80; 95%CI=0.65-0.99). There was no publication bias in the present meta-analysis. CONCLUSIONS High radioiodine activity is better than low activity in terms of successful ablation rate in low-risk differentiated thyroid cancer, but the advantage of high activity seems to only exist in patients who underwent hemithyroidectomy/subtotal thyroidectomy, but not lymph node involvement, preparation before ablation, and definition of successful ablation.

Parathyroid carcinoma and oxyphil parathyroid adenoma: an uncommon case of misinterpretation in clinical practice.

A 46 year-old male presented with persistently high level of serum parathyroid hormone (PTH), despite successful resection of an oxyphilic cell parathyroid adenoma of the left lower gland. Renal function and serum calcium were normal, leading to vitamin D deficiency being considered. Tc99m-sestamibi parathyroid scintigraphy showed no capitation, but a cervical ultrasound demonstrated an increase in the lower parathyroids. Surgery confirmed that the right gland was normal but the left corresponded to parathyroid carcinoma. The patient developed severe hypocalcemia, with PTH values being consistent with hypoparathyroidism for a few months. However, a progressive increase in calcium and PTH serum levels indicated recurrence of disease. Tc99m-sestamibi scintigraphy demonstrated hyperfixation in topography of the left inferior parathyroid and the patient was subjected to a third and more extensive surgery, with removal of lymph nodes and adjacent thyroid tissue. Serum calcium and PTH remained elevated, requiring loop diuretics and intravenous bisphosphonates to control hypercalcemia. Cervical radiotherapy was implemented as adjuvant therapy. After two months the patient complained of dyspnea, and a CT scan of the chest demonstrated areas of parenchymal condensation, suggestive of actinic pneumonitis. At the 2-year follow-up no major issues were evident.

Radioguided surgery of parathyroid adenomas and recurrent thyroid cancer using the "low sestamibi dose" protocol.

PURPOSE: The aim of this study was to establish the clinical efficacy of the "low sestamibi dose" (LSD) protocol to perform thyroid and parathyroid radioguided surgery in a large series of patients homogeneously studied and operated on by the same surgeon. The LSD protocol was initially developed in our center to cure primary hyperparathyroid (PHPT) patients with a high likelihood of a solitary parathyroid adenoma (PA) by minimally invasive radioguided surgery (MIRS). Since then, the same protocol has been applied to differentiated thyroid cancer (DTC) patients with 131I-negative, but sestamibi-positive, locoregional recurrent disease in order to obtain radical radioguided extirpation of tumoral lesions at reoperation. STUDY DESIGN: We reviewed the clinical charts of 453 consecutive patients referred at the surgical department at Padova University (Padova, Italy) to investigate a PHPT or a DTC recurrence: 336 patients (74.2%) met the inclusion criteria for radioguided surgery, and these patients were analyzed for the aim of this study. There were 298 patients affected by PHPT with a high likelihood of a solitary sestamibipositive PA and 38 DTC patients affected by 131I-negative, but sestamibi-positive, locoregional recurrence. All patients underwent a preoperative imaging work-up, including sestamibi scintigraphy (doubletracer subtraction scan in PHPT patients and single-tracer, wash-out scan in DTC patients) and high-resolution neck ultrasonography (US). The LSD protocol we developed consists of the intravenous injection of a very low (1 mCi) sestamibi dose in the operating theater just 10 minutes before commencing intervention for the purpose of radioguided surgery only. At variance with the traditional "high (20-25 mCi) sestamibi dose (HSD)" protocol in which imaging and radioguided surgery are obtained in the same day, in the LSD protocol, imaging and radioguided surgery are performed in different days. The LSD protocol allows some advantages over the HSD protocol: (1) more time for acquiring and interpreting preoperative imaging (planar scintigraphy, single-photon emission computed tomography [SPECT], US); (2) an accurate selection of patients to whom MIRS is offered, especially in countries where the prevalence of nodular goiter with sestamibi-avid thyroid nodules (exclusion criteria for MIRS) is relatively high, as in mid-south-European countries; (3) it facilitates the work planning in the operating theater (bilateral neck exploration requires an operating time of at least double to that of MIRS); and (4) the radiation exposure dose to operating theater personnel is very low-substantially negligible, using the LSD protocol: This aspect assumes great importance in countries where radioproteximetric rules are stringent, as in Europe. RESULTS: PHPT patients. MIRS was successfully performed by a 1.5-2-cm skin incision in 287 of 298 PHPT patients (96.3%) in whom such an approach was scheduled on the basis of preoperative imaging, including 41 of 57 patients (71.9%) who had previously received thyroid or unsuccessful parathyroid surgery in another center. No case of major intraoperative complication was recorded. No case of persistent or recurrent PHPT was observed during postsurgical follow-up. DTC patients. A total of 79 metastatic lesions were intraoperatively detected by the gamma probe and successfully removed (68 of them had been correctly visualized at preoperative sestamibi scintigraphy). During subsequent follow-up, 18 patients (72%) were considered disease-free, whereas 7 had persistent disease (increased serum thyroglobulin levels). The radiation exposure dose to the surgeon using the LSD protocol was 1.2 uSi/hour, that is, 20-30-fold lower than that delivered with the HSD protocol used for PHPT patients and with the 131I protocol used for DTC patients with recurrence. CONCLUSIONS: On the basis of our data, it can be concluded that the LSD protocol is a safe and effective protocol to perform in both MIRS in PHPT patients and radioguided reoperation in DTC patients with 131I-negative recurrence. Furthermore, from a radioproteximetric point of view, in comparison with other radioguided protocols used for the same purposes, the LSD protocol minimizes the radiation-exposure dose to the surgeon and operating theater personnel.

Parathyroid carcinoma: is there a role for adjuvant radiation therapy?

BACKGROUND: The authors proposed to determine risk factors associated with postoperative progression of parathyroid carcinoma within the neck (locoregional) and to assess the efficacy of postoperative adjuvant radiation therapy in preventing disease progression within the neck. METHODS: A retrospective review of patients with pathologically confirmed parathyroid carcinoma who underwent surgical resection was performed. Risk factors identified on univariate analysis were applied in a proportional hazards analysis to identify significant independent predictors of locoregional disease progression and cause-specific survival after surgical resection. Fifty-seven patients were treated with surgery alone (no adjuvant radiation therapy [RT]) and were determined to have sufficient follow-up and pathologically confirmed features to be included in the current analysis. Four patients were treated with surgery and adjuvant RT. Four patients received RT to the neck and mediastinum for unresectable locoregional disease progression. Patients were followed for a median of 75.6 months (range, 8.4-358 months). RESULTS: Twenty-five patients (44%) developed locoregional disease progression at a median of 27.1 months after surgery (range, 6.2-138.3 months). The univariate analysis revealed that surgical margin status and the institution at which the initial surgery was performed were predictive of locoregional progression-free survival. The institution at which the initial surgery was performed was found to be an independent predictor of cause-specific survival. Of the four patients treated with surgery and adjuvant RT, all were alive and without disease at the time of last follow-up. All four patients who received RT for locoregional disease progression after initial surgery achieved locoregional disease control. CONCLUSIONS: Patients with parathyroid carcinoma are reported to have a significant risk of locoregional disease progression after surgery alone. The results of the current study demonstrated that the risk of postoperative disease progression can be predicted by surgical margin status and the institution at which the initial surgery is performed. Patients treated with surgery and postoperative RT may have a lower risk of locoregional disease progression and improved cause-specific survival. RT can be used to provide locoregional control of recurrent disease.

Positive effect of radiotherapy and surgery on hormonally active pulmonary metastases of primary parathyroid carcinoma.

OBJECTIVE: Parathyroid carcinoma is a rare cause of primary hyperparathyroidism. Surgery is the primary treatment in recurrent or metastatic disease. Radiotherapy has been used as an adjuvant to control subclinical local disease but is otherwise considered ineffective. DESIGN: We report on a patient with parathyroid carcinoma with hypercalcaemia and pulmonary metastases, treated with pamidronate and radiotherapy and later with surgery. METHODS: The treatment was evaluated using serial analysis of serum parathyroid hormone (PTH) and calcium, clinical evaluation and chest radiographs. RESULTS: Intravenous pamidronate alone had limited effect on hypercalcaemia. Following irradiation of the pulmonary lesions (34 Gy in ten fractions), serum levels of calcium and PTH decreased and pamidronate could be discontinued. The patient's general condition improved parallel to a radiological response. At clinical relapse 18 months following radiotherapy, the pulmonary metastases were resected and serum PTH was normalised. CONCLUSIONS: The results indicate that parathyroid carcinoma can be radiosensitive. Thus radiotherapy may be an alternative to palliate symptoms of hypercalcaemia in patients not suited for surgery.

Radiobiological considerations in the design of fractionation strategies for intensity-modulated radiation therapy of head and neck cancers.

PURPOSE: The dose distributions of intensity-modulated radiotherapy (IMRT) treatment plans can be shown to be significantly superior in terms of higher conformality if designed to simultaneously deliver high dose to the primary disease and lower dose to the subclinical disease or electively treated regions. We use the term "simultaneous integrated boost" (SIB) to define such a treatment. The purpose of this paper is to develop suitable fractionation strategies based on radiobiological principles for clinical trials and routine use of IMRT of head and neck (HN) cancers. The fractionation strategies are intended to allow escalation of tumor dose while adequately sparing normal tissues outside the target volume and considering the tolerances of normal tissues embedded within the primary target volume. METHODS AND MATERIALS: IMRT fractionation regimens are specified in terms of "normalized total dose" (NTD), i.e., the biologically equivalent dose given in 2 Gy/fx. A linear-quadratic isoeffect formula is applied to convert NTDs into "nominal" prescription doses. Nominal prescription doses for a high dose to the primary disease, an intermediate dose to regional microscopic disease, and lower dose to electively treated nodes are used for optimizing IMRT plans. The resulting nominal dose distributions are converted back into NTD distributions for the evaluation of treatment plans. Similar calculations for critical normal tissues are also performed. Methods developed were applied for the intercomparison of several HN treatment regimens, including conventional regimens used currently and in the past, as well as SIB strategies. This was accomplished by comparing the biologically equivalent NTD values for the gross tumor and regional disease, and bone, muscle, and mucosa embedded in the gross tumor volume. RESULTS: (1) A schematic HN example was used to demonstrate that dose distributions for SIB IMRT are more conformal compared to dose distributions when IMRT is divided into a large-field phase and a boost phase. Both were shown to be significantly superior compared to dose distributions obtained using conventional beams for the large-field phase followed by IMRT for the boost phase. (2) The relationship between NTD and nominal dose for HN tumors was found to be quite sensitive to the choice of tumor clonogen doubling time but relatively insensitive to other parameters. (3) For late effect normal tissues embedded in the tumor volume and assumed to receive the same dose as the tumor, the biologically equivalent NTD for the SIB IMRT may be significantly higher. (4) Normal tissues outside the target volume receive lower dose due to the higher conformality of the IMRT plans. The biologically equivalent NTDs are even lower due to the lower dose per fraction in the SIB strategy. CONCLUSIONS: IMRT dose distributions are most conformal when designed to be delivered as SIB. Using isoeffect radiobiological relationships and published HN data, fractionation strategies can be designed in which the nominal dose levels to the primary, regional disease and electively treated volumes are appropriately adjusted, each receiving different dose/fx. Normal tissues outside the treated volumes are at reduced risk in such strategies since they receive lower total dose as well as lower dose/fx. However, the late effect toxicities of tissues embedded within the primary target volume and assumed to receive the same dose as the primary may pose a problem. The efficacy and safety of the proposed fractionation strategies will need to be evaluated with careful clinical trials.

Parathyroid carcinoma--the Princess Margaret Hospital experience.

PURPOSE: Carcinoma of the parathyroid gland is a rare disease representing 0.5 to 4% of patients with primary hyperparathyroidism. We reviewed our experience with this disease, with special emphasis on the role of adjuvant postoperative radiotherapy. METHODS: A retrospective review was conducted of all cases of parathyroid carcinoma referred to the Princess Margaret Hospital (PMH) from 1958-1996. Ten patients were identified. Their clinical features, management details, and treatment outcome are described. RESULTS: There were 5 men and 5 women with a mean age of 53 years. Of these, 7 patients underwent en bloc resection; among them, 4 had neck dissection or lymph node sampling. The other 3 patients underwent only limited surgery to remove the tumor. Seven patients were referred for consideration of adjuvant radiation treatment. Six patients were given adjuvant radiation therapy for microscopic residual disease. All patients tolerated the radiation treatment well, with minimal side effects. The 7 patients have been followed regularly with no evidence of recurrence and normal serum calcium. The mean follow-up for the 6 patients who had adjuvant radiotherapy was 62.3 months (range 12 to 156 months). The remaining 3 patients had metastatic disease and were referred for palliative radiotherapy. CONCLUSIONS: Our results in a small number of patients suggest local radiation therapy to the tumor bed may have eliminated the strong predilection for local recurrence of this disease, as reported by other investigators.

Hyperparathyroid crisis and posterior mediastinal parathyroid adenoma: a case for preoperative localization.

Hyperparathyroid crisis is a rare, life-threatening condition that requires prompt removal of the involved parathyroid gland(s). This report describes a patient with hyperparathyroid crisis caused by a mediastinal parathyroid adenoma, which was localized before operation and removed at the initial operation, without neck exploration. Surgical approaches to hyperparathyroid crisis and the importance of preoperative localization studies are discussed.

Parathyroid carcinoma: pointers to successful management.

Five patients with parathyroid carcinoma are reported. In the first case the clinical and histological features of malignancy at initial surgery were not recognised and recurrence of the tumour occurred within two years. Referring to previously published series this sequence appeared to be typical and underlined the likely reasons for the poor prognosis of this rare tumour. A review of the diagnostic criteria to improve early diagnosis was undertaken and a treatment protocol drawn up. It was based on a more radical surgical extirpation to include the tumour bed together with postoperative radiotherapy. Four further cases have subsequently been identified, treated according to the protocol and at 16 to 49 months' follow up, show no sign of recurrence and have a normal serum calcium.

Parathyroidectomy. Review of 338 consecutive cases for histology, location, and reoperation.

Three hundred thirty-eight consecutive parathyroidectomies for hyperparathyroidism were performed over a 22 year period. There were 53 dialysis patients (31 male and 22 female), 285 patients (165 female and 120 male) with primary hyperparathyroidism, 55 patients (19 percent) with parathyroid hyperplasia, and 230 patients with 236 parathyroid adenomas. The location of the adenomas were right upper in 57, right lower in 59, left upper in 60, and left lower in 60. Forty-three patients of the last 194 operated on had histories of childhood head and neck irradiation (21.6 percent), 34 patients (79.6 percent) had associated thyroid disease, and there were 10 with thyroid carcinomas. In the 285 patients, 54 percent had thyroid disease, and 18 had thyroid carcinomas. Twenty-three patients required reoperation for persistent or recurrent hypercalcemia, and 19 neck reexplorations and 6 mediastinotomies were performed. The identification and biopsy as indicated of all four parathyroid glands at initial neck exploration would have prevented over 70 percent of reoperations.