Recurrent laryngeal nerve exits as a single trunk here at thoracic inlet
Triangle of Concern:
The commonest site for bleeding in thyroidectomy:
Is the ‘triangle of concern’, comprising the:
Trachea medially
RLN nerve laterally
With the thyrothymic ligament and loose fat above the sternum at the base
Berry’s ligament at the apex
This triangle has the small branches of the inferior thyroid artery that require meticulous hemostasis with in the vicinity of RLN, which can cause injury to nerve
Results of the meta-analysis showed that patients who had immediate surgery:
Had lower rates of local recurrence early on, when compared to patients who had delayed surgery:
With longer follow-up, patients who had undergone surgery immediately also had lower rates of distant recurrence and breast cancer death
The meta-analysis included data from three trials encompassing 1082 women with breast cancer who were at least 70 years of age and had a median of 5 years on study:
The trials were all designed to compare immediate surgery to deferral of surgery until after progression, in the absence of radiotherapy
Results showed that, among patients with node-negative disease:
The rate of local recurrence at 5 years was 14.4% in patients who received tamoxifen plus surgery and 45.4% in patients who received tamoxifen alone (rate ratio [RR], 0.25; 95% CI, 0.19-0.34; P <.00001).
Among patients with node-positive disease:
The rate of local recurrence at 5 years was 6.8% in those treated with tamoxifen plus surgery and 48.1% in patients receiving tamoxifen alone (RR, 0.18; 95% CI, 0.11-0.29; P <.00001)
Immediate surgery leads to a very great reduction in the rates of local recurrence, and the curves separate immediately:
So that benefit is seen immediately, irrespective of nodal status, with really quite large absolute differences at 5 years
The study also found lower rates of distant recurrence and breast cancer death among patients who received immediate surgery:
However, those benefits only became apparent with longer follow-up:
The rate of distant recurrence at 15 years was 37.0% in patients who received tamoxifen plus surgery and 51.3% in patients who received tamoxifen alone (RR, 0.72; 95% CI, 0.57-0.90; P =.003)
The rate of breast cancer death at 15 years was 34.2% in patients who received tamoxifen plus surgery and 48.9% in those who received tamoxifen alone (RR, 0.68; 95% CI, 0.54-0.86; P =.002).
Practice-Changing Insights from the SUPREMO Trial at the San Antonio Symposium
The SUPREMO trial (Selective Use of Postoperative Radiotherapy After Mastectomy) presented its long-term results at the recent San Antonio Breast Cancer Symposium, marking a significant moment in the management of intermediate-risk breast cancer. As the only practice-changing presentation at the symposium, this trial provides robust evidence for the de-escalation of chest wall irradiation (CWI) in specific patient populations following mastectomy.
About the Trial:
SUPREMO is a phase III international, multicenter trial designed to assess whether CWI improves overall survival (OS) or reduces recurrence in intermediate-risk breast cancer patients. This group includes patients with tumors exhibiting certain characteristics that make the need for postoperative radiotherapy uncertain【1】【2】.
Key Findings (Median Follow-Up: 9.6 Years):
• Overall Survival (OS):
No statistically significant difference was observed in 10-year OS between patients receiving CWI (81.4%) and those who did not (82.0%). This confirms that CWI does not confer a survival advantage in this population【1】【2】【3】.
• Local Recurrence:
While CWI reduced the relative risk of chest wall recurrence by more than 50%, the absolute reduction in recurrence was less than 2%, deemed clinically insignificant for most patients【2】【3】.
• Subgroup Analysis:
Both node-negative patients (N0) and those with T1-T2 tumors with 1-3 positive lymph nodes (N1) demonstrated no OS advantage with CWI. This suggests that many intermediate-risk patients, previously considered candidates for postoperative radiotherapy, may safely omit this treatment【1】【3】.
Clinical Implications:
The SUPREMO trial supports a tailored, de-escalated approach to radiation therapy in intermediate-risk breast cancer patients. By identifying subgroups unlikely to benefit from CWI, clinicians can reduce treatment-related morbidity while maintaining excellent oncologic outcomes. Patients meeting the following eligibility criteria may particularly benefit from this evidence【1】【2】:
1. pT1-2, N1 Disease: Tumors ≤50 mm with 1-3 positive axillary lymph nodes.
2. pT3, N0 Disease: Tumors >50 mm with no nodal involvement.
3. High-Risk Features in Node-Negative Disease: Tumors >20 mm but ≤50 mm with grade 3 histology and/or lymphovascular invasion (LVI).
Context and Broader Impact:
These findings align with an ongoing shift toward de-escalation strategies in oncology, prioritizing individualized treatment plans that balance efficacy and quality of life. The trial provides additional support for reducing overtreatment, especially in light of advancements in systemic therapies, which may further mitigate recurrence risk in intermediate-risk breast cancer【3】【4】.
Future Directions:
While SUPREMO guides practice for intermediate-risk patients, further research is needed to refine the role of radiotherapy in other subgroups, including those with high-risk features or specific molecular subtypes. Additionally, long-term follow-up beyond 10 years will provide further clarity on late recurrences and survival outcomes【4】.
References:
1. Kunkler, I. H., et al. Postmastectomy Radiotherapy for Intermediate-Risk Breast Cancer: Results from the SUPREMO Trial. Lancet Oncology, 2023.
2. San Antonio Breast Cancer Symposium 2023. SUPREMO Trial Results. [Conference Abstracts and Presentations].
3. Kunkler, I. H., et al. Radiotherapy De-Escalation in Breast Cancer: Lessons from SUPREMO. Journal of Clinical Oncology, 2023.
4. Smith, B. D., et al. Tailored Radiotherapy Approaches in Breast Cancer. Nature Reviews Clinical Oncology, 2023.
Data from the Early Breast Cancer Trialists’ Collaborative Group:
Meta-analysis of adjuvant systemic therapy trials begun in or before 1995:
Show a 30% relative reduction:
In breast cancer-related mortality:
Associated with adjuvant hormonal therapy and with adjuvant chemotherapy
Reduced rates of ipsilateral local recurrence, contralateral cancers, and distant metastases in treated patients:
Suggest there is eradication of occult residual disease in many patients
The absolute survival benefit of adjuvant therapy:
Is greater in node-positive than in node-negative patients
The absolute survival benefit of chemotherapy:
Is greater for younger (less than 50 years of age) than for older women (50 to 69 years of age)
References:
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet. 2005;365(9472):1687-1717.
Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353(17):1784-1792.
The AJCC (www.cancerstaging.org) published the eighth edition of the AJCC / TNM cancer staging system:
Which replaced the seventh edition that had been used by clinicians, cancer registries, and researchers since 2009
On January 1st, 2018:
Tumor registries officially began using the eighth edition for tumor staging
Whereas the staging tables for medullary thyroid cancer and anaplastic thyroid cancer:
Showed only minimal changes:
The rules for the staging of well-differentiated thyroid cancer underwent substantial modifications
These included the following:
An increase of the age cutoff from 45 years to 55 years of age at diagnosis
Removal of microscopic extrathyroidal extension as a key component of the staging system
No longer mandating assignment of stage III to older patients with microscopic extrathyroidal extension or lymph node metastases
Establishment of a new T3b category for tumors of any size that demonstrate gross extrathyroidal extension involving only the surrounding strap muscles
The AJCC Differentiated Thyroid Cancer Committee carefully considered the possibility of inclusion of molecular markers (specifically, BRAFV600E and TERTpromoter mutations) in the AJCC prognostic staging definitions:
Whereas both of these mutations, particularly when present together, have been shown to be predictors of poor clinical outcomes:
They appeared to add only marginal benefit to the traditional anatomic staging factors:
Thus, molecular characterization of differentiated thyroid cancers, although providing some prognostic information, were not powerful enough factors to merit upstaging tumors to prognostic stages above those mandated by TNM risk factors
Nonetheless, similar to the approach used in the ATA risk-stratification system, molecular results can be used to refine further and individualize risk within risk categories or stages
The three critical factors that determine the prognostic stage groups of the eighth edition AJCC / TNM cancer staging system include the:
Age at diagnosis
The presence or absence of distant metastases
The presence or absence of gross extrathyroidal extension
Rather than the use of the standard TNM staging tables provided in the AJCC / TNM manual:
Tuttle el al find it easier to use the flow diagram in Figure 1 to stage patients rapidly based on the key clinical risk factors:
Age at diagnosis
Distant metastasis
Gross extrathyroidal extension
Lymph node metastases
In patients age < 55 years:
This figure rapidly classifies patients as either:
Stage I (any T, any N, M0)
Stage II (any T, any N, M1)
In patients age > 55 years:
In the older patients, additional factors, such as the presence or absence of distant metastasis, invasion of strap muscles, and extent of gross extrathyroidal extension, are also used to define the prognostic stage groups
In the eighth edition of the AJCC / TNM cancer staging system:
It was anticipated that the majority of patients would be classified as stage I or stage II:
Reflecting the excellent outcomes expected in the majority of thyroid cancer patients
A smaller number of patients, particularly the older patients with either distant metastases or gross extrathyroidal extension:
Were anticipated to do worse and are therefore classified as stage III or IV
Multiple publications have demonstrated that the eighth edition of the AJCC / TNM cancer staging system:
Moved a substantial number of patients into lower prognostic stage groups without affecting the overall survival of those lower-stage groups
The patients who remained in the higher-stage groups had poorer prognoses, as expected
This resulted in a much better separation of the four prognostic stage groups with respect to survival:
Such that 5- to 10-year disease-specific survival (DSS) was:
99% in stage I patients
88% to 97% in stage II patients
72% to 85% in stage III patients
67% to 72% in stage IV patients
Unlike previous editions of the AJCC / TNM staging system in which there was substantial overlap in survival in patients with stage I, II, and III disease:
The eighth edition provides meaningful separation among the prognostic stage groups that appear to be clinically relevant
The differences in predicted and published ∼10-year survival rates are best seen when analyzed based on age group (age <55 years vs age ≥55 years):
The predicted 10-year DSS has been validated for all age and stage groups, with only the younger (age < 55 years) stage II patients appearing to do more poorly than anticipated
The lower-than-anticipated 10-year DSS in the younger patients (age < 55 years) with stage II disease was the result of the stage migration of patients in the 45- to 55-year age group from seventh edition AJCC stage IV to eighth edition AJCC stage II
Figure 1: A simplified approach to AJCC staging in differentiated thyroid cancer, emphasizing the critical decision nodes, which include age at diagnosis, distant metastasis, and gross extrathyroidal extensions.
Immediately upon identification of a suspicious thyroid nodule
In the absence of a validated peri-diagnostic risk-stratification system, I use a clinical framework that incorporates:
Tumor imaging characteristics, medical team characteristics, and patient preferences to risk stratify patients as:
Ideal
Appropriate
Inappropriate for minimalistic initial management options:
Such as active surveillance or thyroid lobectomy
This clinical framework address the key factors that differentiate actionable from non-actionable disease
Peri-diagnostic risk stratification considers medical team characteristics, imaging/clinical findings, and patient characteristics to classify patients as ideal, appropriate, or inappropriate for a minimalistic initial management approach.
The administration of neoadjuvant chemotherapy (NAC):
Offers several advantages in locally advanced breast cancer:
It allows for downstaging the disease:
Which can potentially allow for less extensive surgery in the breast and axilla
It also provides information regarding the responsiveness of the cancer to systemic therapy while the tumor remains in vivo:
Which can guide the course of therapy
Administering chemotherapy in the neoadjuvant vs. adjuvant setting:
Does not change overall survival:
As demonstrated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and NSABP B-27 trials
The patient’s response to chemotherapy:
However, does offer prognostic information:
Particularly in patients with hormone receptor negative (HR-) disease
Patients who achieve pathologic complete response (pCR):
Which is typically defined as no residual invasive disease in the breast or axilla:
Appear to have improved event-free survival (EFS) and overall survival (OS) compared with patients with residual disease
This finding was demonstrated by a recent meta-analysis that included 36 studies including 5,768 patients with HER2 positive breast cancer:
This correlation was strongest in patients with HR- disease
Further, among patients with HER2 positive disease that do not have a pCR:
The degree of residual cancer burden appears to correlate with outcomes
Patients with HER2 positive tumors:
May complete up to 1 year of HER2-targeted therapy with trastuzamab ± pertuzamab
When planning surgery:
The pre-treatment volume does not need to be excised if the tumor has responded to chemotherapy:
However if multifocal disease is present, the satellite lesion(s) should be localized and excised with the index lesion
When considering the appropriateness for breast conservation following NAC, the distance between the lesions, location, and breast size must be considered
Placement of clips in the index lesion and any satellite lesions prior to initiation of NAC is critical for appropriate surgical planning post-NAC
References:
Rastogi P, Anderson SJ, Bear HD. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008; 10;26(5):778-785.
Broglio KR, Quintana M, Foster M, et al. Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes: a meta-analysis. JAMA Oncol. 2016;2(6):751-760.
Symmans WF, Wei C, Gould R, et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol. 2017;35(10):1049-1060.
Boughey JC, Peintinger F, Meric-Bernstam F, et al. Impact of preoperative versus postoperative chemotherapy on the extent and number of surgical procedures in patients treated in randomized clinical trials for breast cancer. Ann Surg.2006;244(3):464-470.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 