Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• A multi-institution, prospective randomized trial:
  • From participating Cancer Care Ontario centers was performed from 1993 to 1996
• The study sought to determine whether:
  • Accelerated hypofractionated whole-breast irradiation (WBI) was as effective as conventional 5-week fractionation
• Included in the study were women who received:
  • Breast-conserving surgery (BCS) for invasive breast cancer with clear surgical margins and negative axillary nodes
• Participants were randomly assigned to receive:
  • WBI either at the standard dose of 50.0 Gy in 25 fractions over 35 days (control group), or at a dose of 42.5 Gy in 16 fractions over 22 days (hypofractionated-radiation group)
  • The control group included 612 patients and the hypofractionation group had 622 patients
• Results from this study indicated:
  • That the Canadian regimen was not inferior to the standard 5-week treatment regimen for women who received BCS for invasive breast cancer with clear surgical margins and negative axillary nodes
  • The risk of local recurrence at 10 years was:
    • 6.7% in the control group and 6.2% in the hypofractionated group
  • Cosmesis at 10 years was found to be comparable between the 2 groups:
    • With good or excellent outcomes for 71.3% of women in the control group and 69.8% in the hypofractionated-radiation group
  • There was also no difference between the 2 groups in overall survival and no increase in cardiac-related deaths was seen in the hypofractionated group
• References
  • Whelan TJ, Pignol J-P, Levine MN, Julian JA, MacKenzie R, Parpia S, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010;362(6):513-520

#Arrangoiz #BreastSurgeon #BreastCancer #SurgicalOncologist #Miami #Mexico #RadiationTherapy #Hypofractionation

• The NCIC-CTG MA.20 trial:
  • Randomized 1,832 high-risk women who were treated with breast-conserving surgery and sentinel node biopsy (SLNB) or axillary lymph node dissection (ALND) to:
    • Either WBI alone or WBI plus regional nodal irradiation (RNI)
    • Axillary lymph node dissection was required for any patients with a positive SLN
    • RNI included the:
      • Internal mammary nodes
      • Supraclavicular nodes
      • High axillary nodes
  • The trial enrolled patients with node-positive or high-risk node-negative disease
  • Eighty-five percent of patients had 1 to 3 positive nodes, 5% had more than 4 positive nodes, and 10% were node negative
  • Node-negative patients:
    • With tumors greater than or equal to 2 cm who had fewer than 10 axillary nodes removedwere considered high risk if they had at least one of the following:
      • ER negative
      • Lymphovascular invasion
      • Nuclear grade 3
  • All patients had systemic therapy.
  • With a median follow-up of 10 years:
    • The addition of RNI improved:
      • Locoregional DFS from 92.2% to 95.2% (P=0.009)
      • Distant DFS from 82.4% to 86.3% (P=0.03)
    • There was no difference in OS from 81.8% to 82.8% (P=0.38)
    • The addition of RNI to WBI was associated with:
      • An increase in grade 2 or greater pneumonitis from 0.2% to 1.2% (P=0.01) and lymphedema from 4.5% to 8.4% (P=0.001)
• Similarly, European Organisation for Research and Treatment of Cancer (EORTC) 22922:
  • Randomized 4004 women undergoing breast-conserving surgery or mastectomy and ALND for histological stage I, II, or III breast cancer to:
    • RNI (supraclavicular and internal mammary nodal irradiation) or no regional nodal irradiation
  • At a median follow-up of 10.9 years:
    • The addition of regional nodal irradiation improved DFS from 69.1% to 72.1% (P=0.04)
    •  Again, there was a non-significant trend toward improvement in OS from 80.7% to 82.3% (P=0.06 among the RNI group.
• The results of NCIC-CTG MA.20:
  • Have led many to conclude that all patients with axillary nodal metastases, regardless of tumor size or extent of nodal involvement:
    • Should receive comprehensive nodal radiation therapy (RT)
• A major conundrum in current practice is resolving the apparently contradictory findings of American College of Surgeons Oncology Group (ACOSOG) Z0011 and After Mapping of the Axilla, Radiation or Surgery? (AMAROS) with those of MA.20
  • The modest benefit in DFS with nodal RT in MA.20 may reflect differences in patient populations between the studies:
    • Patients with clinically positive nodes were excluded from ACOSOG Z0011 and AMAROS (and not MA.20)
  • In addition, fewer than 10 nodes were removed in one-third of patients in the MA.20 study and the median node count was 12, compared to a median of 17 in the ALND arms of Z0011 and AMAROS
• The benefit of nodal RT:
  • Therefore may be limited to higher risk patients with more extensive nodal disease and perhaps more limited axillary surgery
• References
• Poortmans PM, Collette S, Kirkove C, Limbergen EV, Budach V, Struikmans H, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;37(4)3:317-327.
• Pepels MJ, de Boer M, Bult P, van Dijck A, van Deurzen CH, Menke-Pluymers MB, et al. Regional recurrence in breast cancer patients with sentinel node micrometastases and isolated tumor cells. Ann Surg. 2012;255(1):116-121.
• Whelan TJ, Olivotto IA, Parulekar WR, Ackerman I, Chua BH, Nabid A, et al; MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med.2015;373(4):307-316.

• The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial:
  • Was the first study to compare:
    • A 3rd-generation aromatase inhibitor (AI), anastrozole, with tamoxifen for the adjuvant treatment of early breast cancer
• The ATAC trial:
  • As designed to compare the efficacy and safety of:
    • Anastrozole (1 mg) with tamoxifen (20 mg) as adjuvant treatment for postmenopausal women with early-stage breast cancer
  • Patients were treated every day for 5 years
  • The study was a double-blind, prospective, randomized trial:
    • With 9,366 postmenopausal women
  • A proportional hazards model was used to assess:
    • The primary endpoints of:
      • DFS
    • Secondary endpoints of:
      • Time to recurrence
      • Time to distant recurrence
      • Overall survival
      • Death with or without recurrence
  • The combination arm of anastrozole and tamoxifen:
    • Was discontinued after the initial analysis:
      • As it was found to have no efficacy or tolerability benefits over tamoxifen alone.
  • Long-term follow-up of 120 months showed:
    • Significant improvements in the anastrozole group versus the tamoxifen group for:
      • DFS, time to recurrence, and time to distant recurrence
    • In hormone receptor-positive patients:
      • These benefits were seen to increase over time
    • Recurrence rates were found to:
      • Remain lower on anastrozole after treatment was completed
    • There was little difference in overall survival:
      • Between anastrazole and tamoxifen (hazard ratio, 0.95; 95% confidence interval, 0.84–1.06; P=0.4)
    • Fractures were more frequent during the active treatment in patients receiving anastrozole:
      • But were similar between the two groups in post-treatment follow-up
    • Treatment-related serious adverse events:
      • Were less common in the anastrozole group:
        • But were also found to be similar between the two groups after treatment completion
      • Anastrozole showed a non-significant increased incidence of colorectal cancer and lung cancers, and a decreased incidence of endometrial, melanoma, and ovarian cancers:
        • However, only the decrease in endometrial cancers remained statistically significant after Bonferroni correction (P<0.001)
    • Overall, anastrozole was found to have:
      • Superior long-term efficacy and safety than tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early-stage breast cancer
      • Outcomes from the ATAC trial made anastrozole the preferred treatment for postmenopausal women with localized hormone receptor-positive breast cancer
• References
  • Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, et al. Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 2005;365(9453):60-62.
  • Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, et al; ATAC/LATTE Investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010;11(12):1135-1141.

#Arrangoiz #BreastSurgeon #CancerSurgeon #SurgicalOncologist #ATAC #EndocrineTherapy #Mexico #Miami #Teacher #Surgeon

• Published in 2003 the evaluation of combination chemotherapy for breast cancer:
  • Given by both dose dense and sequential therapy
  • The goal of the study was to evaluate the best way to administer the chemotherapy regimen:
    • Doxorubicin (A), cyclophosphamide (C) followed by paclitaxel (T)
  • The study assessed chemotherapy administration in:
    • A dose dense fashion:
      • Two weeks vs. three weeks
    • Treatment sequence:
      • Concurrent versus sequential
  • The findings of the study showed:
    • That dose density improved clinical outcomes significantly
    • Sequential chemotherapy was as effective as concurrent chemotherapy:
      • But required a longer time period of administration
• Dose-dense chemotherapy:
  • Refers to decreasing the interval between cycles of treatment without the need of increasing doses and toxicity
• Sequential therapy:
  • Refers to the administration of treatments one at a time rather than concurrently
• National Cancer Institute’s Breast Intergroup INT C9741 and CALGB 9741 trial:
  • Was a prospective, randomized trial designed to study adjuvant chemotherapy treatment regimens:
    • In women with axillary node-positive breast cancer conducted from September 1997 to March 1999
  • Doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) were chosen for this study
  • Using a 2 x 2 factorial design, patients were assigned to receive one of the following 4 regimens:
    • Sequential A then C followed by T x 4 cycles every 3 weeks
    • Dose-dense, sequential A then C then T x 4 cycles every 2 weeks with filgrastim
    • Concurrent AC x 4 cycles followed by T x 4 cycles every 3 weeks
    • Dose-dense, concurrent AC x 4 cycles followed by T x 4 cycles every 2 weeks with filgrastim

• Results showed that:
  • Dose-dense treatment improved the primary endpoints of:
    • Disease-free survival (DFS) and overall survival (OS):
      • Four-year DFS was 82% for dose-dense regimens and 75% for other groups (risk ratio, 0.74, P=0.01)
      • Three-year OS was 92% for dose-dense regimens and 90% in other groups (risk ratio, 0.69, P=0.013)
    • There was no difference in either DFS or OS:
      • Between the concurrent and sequential schedules
    • Severe neutropenia:
      • Was less common in patients who received the dose-dense regimens
    • As a result of this study:
      • Dose-dense and concurrent AC chemotherapy has become one of the standard components of breast cancer therapy
• References:
  • Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol.2003;21(8):1431-1439.
  • Orzano JA, Swain SM. Concepts and clinical trials of dose-dense chemotherapy for breast cancer. Clin Breast Cancer. 2005;6(5):402-411

• NSABP B-14:
  • Was a randomized, double-blind, placebo-controlled trial:
    • Comparing tamoxifen to placebo in women with node-negative ER positive invasive breast cancer
  • It demonstrated a statistically significant improvement in 10-year disease-free survival (DFS)with the use of 5 years of tamoxifen:
    • 69% vs. 57%, P<0.0001
  • Tamoxifen was also associated with a 37% reduction in contralateral breast cancers

• The results of B-14 raised questions about the benefit of administration of additional adjuvant hormonal therapy following completion of 5 years of tamoxifen:
  • More specifically, the administration of aromatase inhibitors after completion of tamoxifen therapy became of interest

• NSABP B-33:
  • Was developed to compare exemestane with placebo in recurrence-free postmenopausal women who completed 5 years of tamoxifen therapy
  • Accrual to this study was terminated prematurely when results of NCIC-CTG MA.17 showed:
    • A significant improvement with letrozole after 5 years of tamoxifen
    • With a median follow-up of 64 months:
      • The hazard ratios of letrozole after 5 years of tamoxifen compared to placebo after similar tamoxifen therapy were:
        • 0.52 (95% confidence interval [CI], 0.45 to 0.61; P<.001) for DFS
        • 0.51 (95% CI, 0.42 to 0.61; P<.001) for distant DFS
        • 0.61 (95% CI, 0.52 to 0.71; P<.001) for overall survival
  • The patients in NSABP B-33 were then unblinded and offered 5 years of exemestane:
    • The improvement in relapse-free survival observed in B-33 with exemestane was similar to that observed in the NCIC-CTG MA.17 trial with letrozole
  • To further examine the benefits of aromatase inhibitors as primary therapy or after 2 to 5 years of tamoxifen:
    • In women with early-stage, hormone receptor-positive breast cancer:
      • The MA.17 R trial analyzed prolonging duration of therapy to 10 years:
        • With DFS as the primary endpoint
    • The study randomized 1,918 women to placebo versus letrozole
    • After a median follow-up of 6.3 years:
      • DFS was 95% for the letrozole group and 91% for the placebo group
      • There was also an improvement in the annual incidence of contralateral breast cancer:
        • With the letrozole group at 0.21% versus 0.49% for the placebo group. 
      • These data support a new standard of care for this patient population, i.e., to improve DFS through 10-year treatment with aromatase inhibitors
• References:
  • Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001;93(9):684-690.
  • Fisher B, Jeong JH, Dignam J, Anderson S, Mamounas E, Wickerham DL, et al. Findings from recent National Surgical Adjuvant Breast and Bowel Project studies in Stage I breast cancer. J Natl Cancer Inst Monogr. 2001;93(30):62-66.
  • Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol. 2008;26(12):1965-1971.
  • Ingle JN, Tu D, Pater JL, Muss HB, Martino S, Robert NJ, et al. Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17. Ann Oncol. 2008;19(5):877-882.
  • Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012;30(7):718-721.
  • Lemieux J, Goss PE, Parulekar WR, Ingle JN, Pritchard KI, Robert NJ, et al. Patient-reported outcomes from MA.17R: a randomized trial of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer. J Clin Oncol. 2016;34(18 

#Arrangoiz #BreastCancer #BreastSurgeon #SurgicalOncologist #Tamoxifen #AromataseInhibitors #EndocrineTherapy

• Several preclinical studies have demonstrated that tamoxifen acts not only by blocking the ER pathway, but also by:
  • Modulating the production of transforming growth factor-alpha and transforming growth factor-beta
  • By increasing the levels of sex hormone-binding globulin in serum
  • By increasing natural killer cell counts
  • By decreasing insulin-like growth factor

• The NSABP protocol B-23:
  • Was developed to determine whether tamoxifen has a role in patients with ER negative cancer
  • Patients with ER negative tumors were randomized to:
    • Four cycles of adjuvant doxorubicin and cyclophosphamide (AC) or 6 cycles of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without tamoxifen
  • The results of B-23 demonstrated:
    • No significant improvement in DFS or overall survival (OS) with tamoxifen added to chemotherapy:
      • DFS: CMF, 83%; CMF plus tamoxifen, 83%; AC, 83%; AC plus tamoxifen, 82%
      • OS: CMF, 89%; CMF plus tamoxifen, 89%; AC, 90%; AC plus tamoxifen, 91%
    • Additionally, protocol B-23 confirmed the results of protocol B-15:
      • That found that four cycles of AC are equivalent to 6 cycles of CMF in terms of DFS and OS
• NSABP B-24 also demonstrated the effectiveness of tamoxifen only on ER positive ductal carcinoma in situ (DCIS), as did a study by Allred et al. on the risk reduction of a subsequent breast cancer in ER positive DCIS treated with tamoxifen
• References:
  • Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER,et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001;19(4):931-942.
  • Wapnir IL, Dignam JJ, Fisher B, Mamounas EP, Anderson SJ, Julian TB, et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103(6):478-488.
  • Allred DC, Anderson SJ, Paik S, Wickerham DL, Nagtegaal ID, Swain SM, et al. Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: a study based on NSABP protocol B-24. J Clin Oncol. 2012;30(12):1268-1273.

#Arrangoiz #BreastSurgeon #CancerSurgeon #SurgicalOncologist #BreastCancer #NSABPB23 #Tamoxifen

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and the North Central Cancer Treatment Group (NCCTG) N9831 trials

• In 2000, two landmark trials combined results:
  • That compared adjuvant chemotherapy with or without concurrent trastuzumab therapy in women with surgically removed HER2-positive breast cancer
• The NSABP B-31 trial compared:
  • Doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab given concurrently with paclitaxel (group 2). 

• The North Central Cancer Treatment Group NCCTG N9831 trial conducted a similar study that compared three regimens: 
  • Group A:
    • Doxorubicin and cyclophosphamide followed by weekly paclitaxel
  • Group B:
    • Doxorubicin and cyclophosphamide followed by weekly paclitaxel, followed by 52 weeks of trastuzumab given after paclitaxel
  • Group C:
    • The same regimen in group A, followed by 52 weeks of trastuzumab initiated concurrentlywith paclitaxel

• The studies were combined to include a joint analysis:
  • Comparing groups 1 and group A (the control group) with groups 2 and group C (the trastuzumab group)
    • Group B was excluded
• Results by 2005 reported 394 events (recurrence, second primary cancer, or death before recurrence):
  • Of these events, 133 were from the trastuzumab group and 261 were in the control group (hazard ratio, 0.48; P<0.0001)
• At 3 years, the absolute difference in DFS between the trastuzumab group and the control group was:
  • 12% and trastuzumab therapy was associated with a 33% reduction in the risk of death(P=0.015)
• The interim analyses of these trials favored trastuzumab so strongly:
  • That the trials were stopped early and patients in the other arms were offered trastuzumab
• Long-term analysis of these studies was reported in 2014:
  • At a median follow-up time of 8.4 years:
    • The addition of trastuzumab to chemotherapy led to a 37% improvement in OS and an increase in 10-year survival rate from 75.2% to 84%
    • Outcomes in DFS showed an improvement of 40% and an increase in the 10-year DFS rate from 62.2% to 73.7%
• This study showed that all subgroups of HER2-positive patients (small and large tumors, hormone receptor-positive and -negative, low and high number of positive nodes, young and old patients):
  • Benefited from the addition of the targeted anti-HER2 agent, making trastuzumab an integral drug in the treatment of HER2-positive breast cancer
• References
  • Perez EA, Romond EH, Suman VJ, Jeong J-H, Sledge G, Geyer Jr GE, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744-3752.
  • Romond E, Perez E, Bryant J, Suman VJ, Geyer Jr GE, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-1684.

#Arrangoiz #BreastSurgeon #BreastCancer #CancerSurgeon #SurgicalOncologist #Miami #Mexico #NSABPB31 #NCCTGN9831

• Biochemical Testing: Perioperative Calcium And PTH
  • The ability to predict the occurrence of transient hypoPT:
    • By subjective surgeon assessment during operation:
      • Is highly variable
  • Objective serial measurement of serum calcium levels:
    • Has traditionally been used to stratify for risk of symptomatic hypocalcemia development during the postoperative period
    • And to determine the need for oral calcium and calcitriol administration
  • After thyroidectomy:
    • The absolute value of serum calcium levels
    • As well as the trend and slope or rate of change of these values:
      • Have also been employed to predict hypoPT:
        • But this approach requires sufficient time to observe such a trend
  • In one study:
    • Serum calcium levels were measured at 6 and 12 hours after total thyroidectomy
    • Patients with a positive serum calcium slope (rise in level):
      • Were deemed safe for hospital discharge with or without calcium supplementation
    • For patients with a non-positive slope but with serum calcium levels equal or greater than 8 mg/dL:
      • Discharge with calcium supplementation was also found to be safe
  • Because trending calcium often requires sampling over a 12- to 24-hour or longer time period, and because postoperative calcium levels may be confounded by prophylactic calcium and calcitriol administration or by low preoperative vitamin D levels:
    • Many groups have examined the utility of measuring intraoperative or postoperative intact PTH levels drawn at various time points in the early post-thyroidectomy period (Table) 

• Intraoperative PTH (IOPTH) refers to:
  • Rapid processing of blood specimens drawn during or shortly after thyroid or central neck surgery to determine PTH levels that will influence surgical or postoperative management
  • At many institutions, the IOPTH assay provides a rapid, actionable result:
    • Whereas the routine intact PTH assay may not have a turnaround time that is fast enough for perioperative decision making
  • It is the normal short half-life of PTH (3–5 minutes):
    • That enables decisions based on early postoperative PTH levels
  • The timing of PTH measurements in published studies has ranged from 10 minutes to 24 hours post thyroidectomy:
    • McLeod et al:
      • Found that a low recovery room drawn postoperative PTH level (< 12 pg/mL) predicted the development of hypocalcemia:
        • With a sensitivity of 100% and a specificity of 92%
    • Sywak et al:
      • Reported that a low four-hour postoperative PTH level (3 to 10 pg/mL) had a sensitivity of 90% and a specificity of 84% for predicting post-operative hypocalcemia 
    • Asari et al:
      • Reported that an intact PTH level of less than 15 pg/mL on postoperative day 1 predicted hypoPT, with a sensitivity of 97.7% and a specificity of 82.6%
  • Thus, the earliest opportunity to predict hypoPT reliably is:
    • Through measurement of serum PTH level either at the conclusion of or immediately following surgery
  • A PTH level < 15 pg/mL:
    • Is usually predictive of impending hypocalcemia
  • IOPTH levels measured alone or combined with serum calcium level measurements:
    • May guide the decision to:
      • Discharge versus monitor patients in the hospital setting
      • To prescribe prophylactic oral calcium
      • To take more aggressive measures to prevent or treat hypocalcemia
  • Based on the available evidence, and acknowledging that reference ranges differ based on assay and institution:
    • It is the opinion of the ATA Surgical Affairs Committee:
      • That a PTH value equal or greater than 15 pg/mL measured in adults at equal or greater than 20 minutes following thyroidectomy:
        • Would obviate the need for intensive serum calcium monitoring and/or calcium supplementation
  • A postoperative PTH value of  less than 15 pg/mL:
    • Would suggest an increased risk for acute hypoPT that might prompt preemptive prescribing of oral calcium and calcitriol and/or serial serum calcium measurements until calcium stability has been confirmed
  • The ability to predict transient as opposed to permanent hypoPT following thyroidectomy is uncertain:
    • At least one study found that acute postoperative hypoPT specifically did not predict permanent hypoPT
    • Several parameters, including postoperative PTH values, decline in PTH values between preoperative and postoperative measurements, degree of decrease in magnesium levels, and whether PA was carried out:
      • Have been associated with the risk of permanent hypoPT:
        • However, the utilization of these parameters is not consistently established and requires further investigation

#Arrangoiz #ThyroidSurgeon #ParathyroidSurgeon #Hypoparathyroidism #HeadandNeckSurgeon #CancerSurgeon

• Background:
  • Graves’ disease is a common cause of hyperthyroidism that impacts quality of life
  • Treatment choices for Graves’ disease include:
    • Antithyroid drugs
    • Radioactive iodine (RAI)
    • Thyroidectomy
  • Patients are frequently treated with longterm anti-thyroid drugs or RAI:
    • With relief of biochemical hyperthyroidism as a common treatment end point
  • However, euthyroid patients with Graves’ disease:
    • May continue to have impaired quality of life
  • Validated tools that study patient-reported outcomes for benign thyroid disease identify general quality-of-life indicators and thyroid-specific symptoms
  • This study prospectively evaluated, at three intervals (preoperative, short-term postoperative, and long-term postoperative), patients with Graves’ disease undergoing thyroidectomy to assess differences in thyroid-specific symptoms, quality of life, and symptom burden over time
    • Clin Thyroidol 2022;34:17–19
• Methods:
  • Adult patients who underwent total thyroidectomy for Graves’ disease between 2015 and 2020 were administered the MD Anderson Symptom Inventory (MDASI) survey:
    • A thyroid-specific patient-reported outcomes (PRO) survey, and a core symptom score to develop a composite Total Symptom Burden Score
  • Patient factors collected included age, race/ethnicity, sex, marital status, employment status, religion, and insurance status
  • Timing of survey data was defined as presurgery (< 120 days prior to surgery), short-term postsurgery (< 30 days), and long-term postsurgery (> 30 days)
  • In addition to measuring general quality-of-life indicators, the tool assesses common hyperthyroid patient symptoms, including hoarseness, heat and cold sensitivity, palpitations, dysphagia, and diarrhea
• Results:
  • The 85 patients included in this study had:
    • A median age of 42 years
    • 83.5% were female
  • Of these patients, 38.8% were obese (BMI >30)
  • Long-term postsurgery data were collected at a median of 205 days (range, 94–548 days) following thyroidectomy
  • Nearly all patients (95.3%) had started and were still taking an antithyroid drug
  • From the overall cohort, 63.5% of patients had a normal serum free thyroxine (FT4) level prior to surgery
  • The Thyroid Symptom Score improved significantly from before surgery to after, in both the short and the long term, with the most significant improvement realized between preoperative and short-term assessments
  • Specific thyroid symptoms that improved significantly after surgery included “feeling hot,” “racing heartbeat,” “diarrhea,” and “difficulty swallowing.”
  • The quality-of-life symptoms that significantly improved at short-term assessment included “general activity,” “mood,” “relationships with other people,” “walking,” “enjoyment of life,” and “work.”
  • The Total Symptom Burden Score improved significantly within 30 days after surgery
• Conclusions:
  • In this cohort study of patients with Graves’ disease who underwent thyroidectomy, nearly all patients were treated initially with antithyroid drugs and 63.5% of the overall sample had normal serum FT4 levels before undergoing thyroid surgery
  • Patient-reported outcomes, including thyroid-specific symptoms and the Total Symptom Burden Score, improved significantly within 30 days of surgery
• This study highlights important improvements in quality of life in patients with Graves’ disease who undergo thyroidectomy
• The most significant improvement in symptoms was realized at short-term follow-up (<30 days):
  • Emphasizing the utility of thyroidectomy for treatment of Graves’ disease in patients who are seeking immediate remedy of symptoms
• By contrast, a longitudinal study of the efficacy of Graves’ disease treatment in Sweden (with only 4.6% of participants treated with thyroidectomy) found that by 6 to 10 years posttreatment, over one quarter of patients reported that they had not fully recovered
• Understanding the anticipated time course for treatment effects is critical to effective patient counseling
• Nearly two thirds of patients in this study were euthyroid at the time of initial assessment
• Although prior studies have recognized more pronounced impairments in quality of life in hyperthyroid Graves’ disease patients:
  • This research demonstrated that even patients who were euthyroid preoperatively experienced significant improvement in thyroid symptoms and quality of life
  • This finding argues for a nuanced approach to long-term management of patients with Graves’ disease beyond achieving a biochemically euthyroid state
  • Many patients with Graves’ disease request or self-refer for evaluation for thyroidectomy
  • Their thyroid-specific neck symptoms, including local symptoms of dysphagia, compression, perceived shortness of breath, and neck tightness, may be discounted, particularly if their hyperthyroidism is biochemically controlled
  • Recognizing the immediate and substantial symptom improvement after thyroidectomy should prompt consideration of thyroidectomy in initial, rather than last resort, Graves’ disease management, even in patients who are able to be rendered euthyroid with antithyroid drugs

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• Background:
  • Iatrogenic injury of the recurrent laryngeal nerve (RLN) is a serious complication during thyroid surgery
  • Reports from the literature show that the rates of RLN injury during thyroidectomy range from:
    • 0.3 to 8%
  • Generally, the complication is unilateral and transient:
    • But it can be bilateral and / or permanent
  • Anatomic variations of the RLN:
    • Can potentially compromise the safety of the nerve during surgery
  • The current gold standard is:
    • Visualization of the RLN before beginning dissection of the thyroid:
      • But an anatomically intact nerve does not substantiate a functional nerve
  • In recent years, intraoperative neuromonitoring (IONM) and continuous intraoperative nerve monitoring (CONM):
    • Have been a useful adjunct in RLN identification and are helpful in assessing RLN electrophysiologic function during surgery
  • The objective of this study was to provide a global assessment of RLN anatomic variation and to identify potential correlations between RLN anatomy and electrophysiologic responses using IONM, with the aim of minimizing the rate of RLN injury during thyroidectomy
    • Clin Thyroidol 2022;34:35–37.
• Methods:
  • This was a large multi-institutional prospective survey of patients undergoing thyroidectomy with or without central or lateral neck dissections following the standards set forth by International Neural Monitoring Study Group guidelines across 17 institutions on five continents between March 2015 and November 2017
  • A total of 1000 RLNs from 574 patients were assessed
  • All patients underwent preoperative and postoperative laryngoscopy
  • Individuals with postoperative vocal-cord paralysis and paresis (VCP) were followed using laryngoscopy for 12 months postoperatively
  • The International RLN Anatomic Classification System was used to assist in the classification of RLN anatomic variations
  • Patients with extensive lymph node metastases and cases with technical IONM failure or failure to visualize the RLN were excluded from the study
• Results:
  • Nearly one-quarter (23%) of the RLNs:
    • Deviated from their anticipated anatomical course
  • 30% of RLNs were fixed, splayed, or entrapped:
    • At the level of the capsule of the thyroid
  • Entrapment at the ligament of Berry was observed in 41% of nerves
  • Loss of signal during surgery was more likely when there was:
    • Abnormal nerve trajectory
    • Fixed, splayed or entrapped nerves
    • Cancer invasion
    • In cases that included lateral lymph node dissection
  • Although the right RLN had loss of signal more often than the left:
    • Laterality was not statistically significant (P = 0.12)
  • Using IONM loss of signal as a test of postoperative VCP:
    • The positive predictive value was 74.3%
    • The negative predictive value was 99.8%
  • Traction injury:
    • Was the most common cause of RLN injury (63%):
      • Especially at the site of the ligament of Berry
• Conclusions:
  • Anatomical variations of the RLN could not be predicted preoperatively, but nearly one quarter of RLNs followed an abnormal trajectory
  • Anatomical variations were associated with higher rates of RLN injury
  • The use of IONM was a helpful risk-minimization tool
  • Traction was the most common cause of injury, and although most VCP resolved within 1 year, the recovery rate was less than previously reported
• Intraoperative verification of functional and anatomical RLN integrity:
  • Is needed for safe thyroid surgery
• Furthermore, there is significant value in identifying anatomical RLN variants and possible risk factors in order to maximize preservation of nerve function
• This study sought to further understand anatomical RLN variants and to intraoperatively assess nerve injury and electrophysiologic responses using IONM during thyroid surgery
• Even though there are several studies in the literature that assessed anatomic RLN variation, there are very few with such a large and diverse sample size that prospectively investigated anatomical data
• This study supports findings from other studies, including traction injuries as a common cause of vocal-cord paralysis
• This work is an important addition to the literature:
  • Not only is it a large multicenter international study, but it also included intraoperative electrophysiologic responses using IONM and longterm follow-up to assess functional outcomes of VCP
  • As surgeons, we often are limited by individual or institutional experience and are not always able to pinpoint the root cause of inadvertent nerve injury
  • Such a broad study more comprehensively illustrates the startling diversity of anatomic RLN variants
  • This heterogeneity is perhaps not surprising given the anatomic variation observed in other major nerves, such as the facial nerve in parotidectomy or the nerve to the vastus lateralis in microvascular surgery
  • The rates of variation, loss of signal, and eventual recovery can help surgeons better inform patients about the underlying risks of an operation
  • The study is particularly noteworthy in its assessment of the RLN position at the ligament of Berry, reporting rates at which the nerve is fixed, splayed, or entrapped
  • This area is of high interest to surgeons, who must balance nerve preservation, nerve traction, and safe removal of the maximal amount of thyroid tissue
  • Paradoxically, cancer is not often found at this junction, yet leaving too much thyroid issue behind may lead to higher levels of thyroglobulin and the potential need for radioactive iodine
  • The study’s findings will likely increase focus on the variation observed and better enlighten surgeons about their approach to this sensitive area

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