Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

SOUND Trial Summary

October 12, 2025September 23, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Title:
- Axillary Surgery in Breast Cancer Patients With Negative Axillary Ultrasound: The SOUND Randomized Clinical Trial
Published:
- 2023 in JAMA Oncology
  - ClinicalTrials.gov ID: NCT02167490
Location:
- Italy, Spain, Switzerland, Chile (18 hospitals)
Study Objective:
- To evaluate whether sentinel lymph node biopsy (SLNB):
  - Can be safely omitted in women:
    - With early-stage, clinically node-negative breast cancer with negative axillary ultrasound (AUS), without compromising oncologic outcomes
Patient Population:
- Women with:
  - Unifocal invasive breast cancer:
    - Tumor ≤ 2.0 cm (cT1)
  - Clinically and ultrasound-negative axilla
  - Undergoing breast-conserving surgery
  - No neoadjuvant therapy
- Tumor types:
  - Majority were hormone receptor-positive, HER2-negative
Study Design:
- Randomized, phase 3, non-inferiority trial
- Two arms:
  - SLNB group:
    - Underwent sentinel lymph node biopsy
  - Observation group:
    - No axillary surgery
- Primary endpoint:
  - 5-year distant disease-free survival (DDFS)
- Secondary endpoints:
  - Overall survival (OS)
  - Disease-free survival (DFS)
  - Axillary recurrence
  - Quality of life

Non-inferiority was met for the primary endpoint (DDFS)
Clinical Implications:
- In women with small tumors (≤ 2 cm) and negative axillary ultrasound:
  - SLNB can be omitted without compromising distant disease-free or overall survival
- Supports a less invasive approach and aligns with the de-escalation of axillary surgery trend in breast cancer care
Leads to fewer surgical complications:
- Lymphedema, seroma, pain
Limitations:
- Results apply only to women with:
  - Negative axillary ultrasound and early-stage, low-risk tumors
- Not applicable to:
  - Mastectomy patients
  - Multifocal tumors
  - Patients receiving neoadjuvant therapy
Conclusion:
- The SOUND trial confirms that routine sentinel lymph node biopsy can be safely omitted in selected patients with early-stage breast cancer and negative axillary ultrasound:
  - Supporting a shift toward minimally invasive surgical strategies in modern breast cancer management

SENOMAC Trial in Breast Cancer

October 11, 2025October 4, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Design and who was included:
- Multicenter randomized contral trial (RCT):
  - Setting:
    - Sweden, Denmark, Germany, Greece, Italy
  - Patients:
    - cN0, cT1 to cT3 tumors with 1 to 2 SLN macrometastases:
      - BCS or mastectomy allowed
    - Extra capsular extension (ECE) and cT3 permitted
    - SENOMAC did allow patients who had SLNB before neoadjuvant systemic therapy (NAST) to be enrolled if cN0 and with ≤ 2 SLN macrometastases:
      - Randomization was recommended before starting NAST
  - Randomized SLNB only vs cALND:
    - Adjuvant therapy and radiation therapy (RT) per national guidelines
  - Size and surgery type:
    - N=2766 enrolled:
      - Per-protocol N=2540:
        
        SLNB 1335
        
        cALND 1205
      - Mastectomy ≈ 36% in each arm:
        
        SLNB 490 / 1335
        
        cALND 430 / 1205
  - Radiation usage (key to applicability):
    - RT including nodal volumes given to ~ 90% in both arms:
      - SLNB 89.9%; cALND 88.4%
    - Quality assessment (QA) check showed:
      - 99.3% concordance for breast / chest-wall fields and 96.6% for nodal targets
Endpoints and follow-up:
- Primary endpoint = OS (pending):
  - In 2020 the Data and Safety Monitoring Board (DSMB):
    - Switched the primary endpoint to overall survival (OS):
      - To declare non-inferiority on OS, the trial needs 190 deaths:
        
        At last analysis there weren’t enough events:
        
        So OS is not yet formally tested
  - They still report 5-yr OS estimates:
    - ≈ 92.9% vs 92.0%
- Reported prespecified secondary endpoint:
  - RFS; NI margin HR upper bound < 1.44
- Median follow-up:
  - 46.8 months
Results (per-protocol)
- 5-yr RFS:
  - 89.7% (SLNB) vs 88.7% (cALND):
    - HR 0.89 (95% CI 0.66–1.19) → non-inferior
- 5-yr OS:
  - 92.9% (SLNB) vs 92.0% (cALND)
- Breast cancer (BC)-specific survival:
  - 97.1% (SLNB) vs 96.6% (cALND)
- Regional recurrences were rare:
  - Axilla alone in 3 patients
  - Axilla + infraclavlavicular 2 patients
  - Supraclavicular / infraclavicualar, internal mammary nodes (IMN), parasternal 1 each (locations unknown in 4)
- Local and distant events similar between arms
- Stage migration:
  - Among primary-surgery patients,:
    - cALND upstaged more often (pN2 – 9.9%, pN3 – 3.0%) vs SLNB-only (pN2 – 0.5%):
      - Without outcome benefit
    - Additional non-SLN metastasis on cALND in 34.5% overall:
      - If 1 SLN macrometatases:
        
        31.3% had more positive nodes
      - If 2 macrometastases:
        
        51.3% had more positive nodes
Toxicity / PROs:
- At 1 year:
  - Randomized SENOMAC PRO analysis:
    - SLNB-only patients reported less arm pain / symptoms and better function than cALND
- Post-hoc (Lancet Oncol 2024):
  - Focused on abemaciclib eligibility:
    - To prevent 1 iDFS event at 5 yrs via identifying ≥ pN2-pN3 with cALND:
      - ~ 104 cALNDs would be needed:
        
        Causing severe / very severe arm dysfunction in ~ 9 / 104 at 1 year:
        
        Discourages ALND purely to find pN2-pN3 for CDK4/6 indication
Why it matters (esp. mastectomy):
- ≈ 36% mastectomy:
  - With comprehensive nodal RT common:
    - Omitting cALND preserved control and survival and minimized arm morbidity:
      - Supports SLNB-only + RNI / PMRT for 1 to 2 SLN macrometastases after mastectomy
One-liner:
- SENOMAC shows that in cN0 patients with 1 to 2 SLN macrometastases including mastectomy cases:
  - SLNB – only with planned nodal RT is non-inferior to cALND for oncologic outcomes and substantially reduces arm morbidity
Summary:
- Why this trial had what it adds:
  - Prior trials (ACOSOG Z0011, AMAROS) had power / RT-field uncertainties and underrepresented subgroups
  - SENOMAC purposely broadened eligibility (included mastectomy, ECE, T3, and men) to validate omission of cALND in a larger, more representative cohort
- Consistency with prior evidence:
  - Findings align with AMAROS and OTOASOR (no oncologic advantage to cALND; morbidity higher with ALND)
  - Ongoing / related trials (e.g., POSNOC; INSEMA’s second randomization) are noted for context
- Generalizability:
  - Age distribution mirrors real-world Nordic populations, supporting external validity
  - Inclusion of substantial mastectomy volume improves applicability beyond BCS-only settings
- RT practice in the trial:
  - Adjuvant RT followed national guidelines:
    - ~ 90% received nodal RT
  - Data entry matched actual RT plans well (good concordance):
    - Though granular nodal-level dose / field details were not yet available at reporting
- Limitations called out by authors:
  - Shorter follow-up relative to late-recurring luminal cancers
  - Very few men enrolled (n≈10), limiting sex-specific analyses
  - Trial under-enrolled vs target:
    - But event counts and narrow CIs yield precise estimates for NI
  - Higher withdrawal in the ALND arm, though unlikely to affect conclusions given size and balance
- Bottom line :
  - For cN0 cT1 to cT3 patients with 1 to 2 SLN macrometastases who receive modern systemic therapy and (typically) comprehensive nodal RT:
    - Omitting cALND maintains disease control with less arm morbidity
  - Results support replacing routine cALND with SLNB ± RNI / PMRT:
    - While acknowledging the need for longer follow-up and more granular RT-field reporting

SOUND Trial – Comprehensive Journal Club Q&A (Study Guide)

October 10, 2025September 23, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Framing the Question:
- Clinical question:
  - In women with invasive breast cancer ≤ 2 cm, clinically node-negative and axillary ultrasound (AUS) negative:
    - Is omitting axillary surgery non-inferior to sentinel lymph node biopsy (SLNB):
      - For 5-year distant disease-free survival (DDFS)? JAMA Network
- Why this matters now:
  - ACOSOG Z0011:
    - Showed no therapeutic benefit for ALND over less surgery (SLNB alone):
      - The next logical step tests whether staging itself (SLNB) can be omitted:
        
        When it won’t change adjuvant plans:
        
        Reducing morbidity without compromising oncologic safety JAMA Network
Study Design Essentials:
- Design:
  - Prospective, multicenter, phase 3 non-inferiority RCT:
    - 1:1 randomization to:
      - No axillary surgery vs SLNB
  - Primary endpoint:
    - 5-yr distant disease free survival (DDFS) (ITT)
  - Secondary:
    - Disease free survival (DFS)
    - Overal survival (OS)
    - Cumulative incidence of distant and axillary recurrences, and adjuvant treatment recommendations JAMA Network
- Setting and timeline:
  - 18 hospitals in:
    - Italy, Spain, Switzerland, and Chile
  - Enrollment Feb 2012 to Jun 2017
  - Analysis 2022 to 2023 JAMA Network
- Eligibility (PICO):
  - Women of any age
  - Tumor ≤ 2 cm
  - cN0 by exam
  - Negative AUS:
    - Suspicious nodes required cytology to exclude metastasis
  - Breast-conserving surgery (BCS) common, with radiotherapy permitted:
    - Including partial breast and IORT
  - ITT N = 1,405:
    - SLNB 708
    - Omit 697
  - Median age 60
  - Median tumor 1.1 cm
  - ~ 88% ER+ / HER2 – JAMA Network
- AUS as a triage tool:
  - Despite variable sensitivity in literature:
    - Negative AUS in the SOUND trial effectively ruled out heavy nodal burden:
      - SLNB arm had 13.7% any nodal metastasis but only 0.6% had ≥ 4 positive nodes
      - Axillary recurrence 0.4% at 5 years in both arms JAMA Network
Statistics You Should Know:
- Non-inferiority setup:
  - Primary analysis ITT:
    - NI margin 2.5% for 5-year DDFS; HR with 90% CI and one-sided NI P-value
    - Assumed 5-year DDFS ≈ 96.5%:
      - Observed outcomes were higher, increasing power to show NI if risks are truly similar JAMA Network
- Follow-up:
  - Median follow-up for disease assessment 5.7 years in both arms JAMA Network
Results (with absolute numbers):
- Primary endpoint (DDFS):
  - 5-year DDFS:
    - 97.7% (SLNB) vs 98.0% (No surgery):
      - HR 0.84, 90% CI 0.45–1.54; P for non-inferiority = 0.02:
        
        Two-arm difference not significant by log-rank (P=0.67) JAMA Network
- Secondary endpoints:
  - 5-year DFS:
    - 94.7% (SLNB) vs 93.9% (No surgery), P=0.30.
  - 5-year OS:
    - 98.2% (SLNB) vs 98.4% (No surgery), P=0.72 JAMA Network
  - Regional control (events are rare):
    - 5-year cumulative axillary recurrence = 0.4% in each arm (Gray P=0.91)
  - Locoregional relapse:
    - 1.7% (SLNB) vs 1.6% (No surgery) JAMA Network
  - Absolute event counts:
    - SLNB:
      - 13 distant metastases (1.8%), 21 deaths (3.0%).
    - No surgery:
      - 14 distant metastases (2.0%), 18 deaths (2.6%) JAMA Network
  - Adjuvant therapy impact:
    - No material differences in systemic therapy or RT use between arms:
      - Supporting that, in this AUS-negative group:
        
        Pathologic nodal information didn’t drive adjuvant decisions JAMA Network
    - Radiotherapy details:
      - All RT options allowed, including partial breast / IORT
      - Notably, 114 patients (16.3%) in the no-surgery arm received ELIOT (full-dose or boost)
      - Despite this heterogeneity:
        
        Axillary failures stayed 0.4% at 5 years in both arms JAMA Network
- How often was SLNB positive?
  - 13.7% had any nodal metastasis in the SLNB arm (micro + macro metasteses)
  - Heavy burden (≥ 4 nodes) was 0.6% JAMA Network
Interpretation and External Context:
- Plain-English bottom line:
  - For AUS-negative, ≤ 2 cm, cN0 tumors planned for BCS + RT:
    - Skipping SLNB is non-inferior for 5-yearr DDFS:
      - With no increase in axillary failures and no detectable survival trade-off – and you avoid the morbidity of axillary surgery JAMA Network
How does the SOUND trial line up with INSEMA trial (NEJM 2024/2025)?:
- INSEMA broadened to T1 to T2 ≤ 5 cm BCT patients and used invasive DFS as the primary endpoint:
  - Omission was non-inferior with lower arm morbidity – reinforcing the SLNB – omission strategy for selected cN0 BCT candidates New England Journal of Medicine+2PubMed+2
Generalizability – who are “SOUND-like” in clinic?
- Mostly small (T1 / ≤ 2 cm), HR+ / HER2 – tumors, negative AUS, upfront BCS + RT:
  - Adjuvant decisions unlikely to change with nodal micrometastatic information:
    - Authors estimate ~ 25% of all breast cancer (BC) cases may fit these criteria JAMA Network
Potential practice impact:
- With ~ 2.3 M new BC cases / year, ~ 500,000 patients globally could avoid axillary surgery:
  - Improving early arm function and reducing lymphedema risk without oncologic compromise JAMA Network
Limitations and Caveats:
- Low-risk enrichment:
  - Mostly small, ER+ / HER2- tumors:
    - Short-to-mid-term risk low:
      - Longer follow-up always helpful JAMA Network
- Adjuvant therapy analysis not powered:
  - Differences in systemic / RT nuances might be too small to detect:
    - Adjuvant-recommendation analysis was secondary JAMA Network
- Late trial registration noted:
  - Registered after enrollment began; protocol / statistical plan were peer-review-published, and authors state no interim looks occurred; still worth acknowledging JAMA Network
- Radiation heterogeneity (including IORT):
  - Permissive RT techniques (e.g., ELIOT) could theoretically influence local / axillary outcomes:
    - Nonetheless axillary failure remained 0.4% in both arms JAMA Network
- Not for neoadjuvant or mastectomy:
  - SOUND trial did not test patients planned for neoadjuvant systemic therapy or mastectomy without conventional whole-breast RT:
    - Avoid extrapolating JAMA Network
- Young HR+ / HER2- patients (Rx-PONDER context):
  - In some premenopausal HR+ / HER2- patients:
    - Nodal positivity can still influence chemo or endocrine therapy type / duration:
      - If nodal information truly changes systemic therapy:
        
        SLNB may remain reasonable JAMA Network
Apply in Clinic” Checklist (What to document):
- Who qualifies for omission (SOUND-style)?
  - Tumor ≤ 2 cm
  - cN0 on exam
  - Negative AUS (suspicion cleared by cytology)
  - Upfront BCS + RT planned
  - Adjuvant plan won’t change with nodal micro-staging
  - Document shared decision-making:
    - Cite SOUND + INSEMA JAMA Network+1]
- Who should still get SLNB?
  - Neoadjuvant candidates (different evidence base)
  - Mastectomy without standard whole-breast RT
  - Cases where nodal status alters chemotherapy / Endocrine therapy decisions:
    - Younger HR+ / HER2-
  - AUS positive / suspicious nodes not cleared by cytology JAMA Network
- How to counsel about risk:
  - Explain that with negative AUS, the chance of heavy nodal disease is very low (≥ 4 nodes 0.6% in SLNB arm), and axillary recurrence at 5 years ~ 0.4% without surgery – the same as with SLNB JAMA Network
- Quick Numbers Box:
  - ITT N=1,405 (708 SLNB; 697 No surgery):
    - Median f/u 5.7 yrs. JAMA Network
  - 5-yr DDFS:
    - 97.7% vs 98.0% (HR 0.84; 90% CI 0.45–1.54; NI P=0.02) JAMA Network
  - 5-yr DFS:
    - 94.7% vs 93.9% (P=0.30)
  - 5-yr OS: 98.2% vs 98.4% (P=0.72) JAMA Network
  - Axillary recurrence (5 yrs):
    - 0.4% vs 0.4%
  - SLN+ (any):
    - 13.7%
  - ≥ 4 nodes:
    - 0.6% JAMA Network
  - RT nuance:
    - 16.3% of omission arm received ELIOT (full-dose / boost) JAMA Network
Discussion Starters:
- Endpoint choice:
  - Was DDFS the best primary endpoint versus iDFS or regional failure:
    - SOUND chose DDFS to reflect oncologic safety independent of local RT nuances JAMA Network
- Imaging vs surgery:
  - Does negative AUS sufficiently replace pathologic staging in 2025 clinics, especially with modern systemic therapy selection? JAMA Network
- RT heterogeneity:
  - Could permissive RT (including IORT) have “rescued” regional control?
    - If so, why are axillary failures identically rare in both arms? JAMA Network
- Younger HR+ / HER2- patients:
  - Where do you draw the line for still doing SLNB given Rx-PONDER-type considerations? JAMA Network
- Global impact:
  - How would your clinic operationalize AUS-triaged omission (workflow, sonographer QA, documentation templates)? JAMA Network
- How SOUND Aligns with INSEMA (one-paragraph takeaway):
  - INSEMA (NEJM 2024/2025) randomized cN0 BCT patients (T1 to T2 ≤ 5 cm) to omission vs SLNB:
    - Invasive DFS primary outcome was non-inferior, with less arm morbidity in the omission group
  - Together with SOUND (DDFS primary, ≤ 2 cm, AUS-negative), these trials support AUS-triaged omission of SLNB in carefully selected early breast cancers planned for BCS + RT New England Journal of Medicine+2PubMed+2

In p16+ Oropharyngeal Squamous Cell Carcinoma (OPSCC) – Does any Efficacy Endpoint Favor Cetuximab-RT over Cisplatin-RT?

October 9, 2025September 19, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

In p16+ OPSCC, does any efficacy endpoint favor cetuximab-RT over cisplatin-RT?
- Best answer:
  - No
- Why:
  - Neither OS, PFS, nor LRC improved with cetuximab:
    - All favored cisplatin PubMed+1
- When to deviate:
  - Only with absolute cisplatin ineligibility PMC:
    - Discuss RT + cetuximab (Bonner) or altered-fractionation RT
- Pitfalls:
  - Extrapolating the Bonner 2006 RT + cetuximab vs RT-alone result:
    - To cisplatin-eligible patients is incorrect New England Journal of Medicine
    - Bonner:
      - 5-yr OS 45.6% with RT + cetuximab vs 36.4% RT alone:
        
        Not a comparison to cisplatin
  - Under-discussing ototoxicity / renal toxicity risks with cisplatin:
    - Document shared decision-making when deviating
- Numbers:
  - RTOG – 1016 (NI trial, Lancet 2019):
  - De-ESCALaTE HPV (Lancet 2019):

Rodrigo Arrangoiz, MD (Oncology Surgeon)

HPV Positive Oropharyngeal Squamous Cell Carcinoma (OPSCC)

October 8, 2025September 19, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

HPV Positive Oropharyngeal Squamous Cell Carcinoma (HPV⁺ OPSCC):
- Radiation therpay (RT) + cetuximab vs RT + cisplatin (why substitution fails)
Clinical rule:
- In cisplatin-eligible HPV⁺ oropharynx cancer:
  - Do not replace cisplatin with cetuximab:
    - To “de-intensify”
- Two large phase III trials showed:
  - Worse survival and control with cetuximab
- RTOG-1016 (Lancet 2019; non-inferiority trial):
  - Design:
    - RT + cetuximab vs RT + cisplatin 100 mg / m² × 2 in HPV⁺ OPSCC
    - Primary endpoint OS:
      - Non-Inferiority (NI) margin HR 1.45
  - Results (median f/u ~ 4.5 y):
    - 5-yr OS:
      - 77.9% cetuximab vs 84.6% cisplatin:
        
        HR 1.45 → non-inferior criterion failed:
        
        Inferior with cetuximab
    - PFS:
      - HR 1.72:
        
        Worse with cetuximab
    - Locoregional failure:
      - HR 2.05:
        
        Higher with cetuximab
    - Acute / late grade ≥ 3 toxicity:
      - Overall similar rates (different profiles):
        
        So efficacy — not toxicity — drives the choice PubMed+1
- De-ESCALaTE HPV (Lancet 2019; “low-risk” HPV⁺):
  - Design:
    - RT + cetuximab vs RT + cisplatin
    - Primary end point:
      - Severe toxicity
  - Efficacy (≈ 2 y):
    - OS:
      - 97.5% cisplatin vs 89.4% cetuximab:
        
        HR ~ 5.0:
        
        Significantly worse with cetuximab
    - Recurrence:
      - 6.0% cisplatin vs 16.1% cetuximab:
        
        HR ~ 3.4
    - Severe toxicity:
      - Similar overall rates
      - More sever adverse effects (SAEs) with cisplatin:
        
        But not enough to offset the clear efficacy loss with cetuximab The Lancet+2Taylor & Francis Online+2
- Reinforcing data:
  - ARTSCAN III (mixed HNSCC, HPV- subset reported):
    - Concurrent cisplatin outperformed cetuximab with RT:
      - Mature results reiterate inferior outcomes with cetuximabPMC+1
  - Guidelines:
    - NCCN and contemporary reviews state that RT + cisplatin remains standard for eligible HPV⁺ OPSCC:
      - Cetuximab – RT is reserved for:
        
        True cisplatin ineligibility:
        
        CrCl < 50 mL / min, grade ≥ 2 SNHL / neuropathy) JNCCN
How to use this at tumor board:
- Eligible for cisplatin?
  - RT + cisplatin:
    - q3-weekly 100 mg / m² × 2 to 3, or weekly in appropriate settings:
      - To achieve ≥ 200 mg/m² cumulative if feasible (De-escalation ≠ drug substitution) PubMed
  - Cisplatin-ineligible?
    - RT + cetuximab (or institutionally accepted alternatives) with explicit counseling that efficacy:
      - Is inferior to cisplatin in HPV⁺ disease:
        
        Use only because platinum cannot be given JNCCN

Step-by-Step Expansion of Leukocyte Recruitment

October 7, 2025September 17, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Tethering and Rolling (milliseconds–seconds):
- What happens:
  - Fast blood flow makes first contact fleeting:
    - Cells need “molecular Velcro” that works under shear.
  - Selectins on endothelium:
    - E-selectin:
      - Induced by TNF-α / IL-1
    - P-selectin:
      - Rapidly mobilized from Weibel–Palade bodies
      - Also on platelets
  - Ligands on leukocytes:
    - PSGL-1 and other sialyl-Lewis^x (sLe^x):
      - Decorated glycoproteins
    - L-selectin (CD62L) is on leukocytes:
      - Not endothelium:
        
        It helps secondary capture / rolling:
        
        Leukocyte–leukocyte interactions
        
        Binds Peripheral Node Addressin on High Endothelial Venules (PNAd on HEVs)
    - Mechanics:
      - “Catch bonds” let cells roll, sampling endothelium for activating cues
    - ✅ Fix to your line:
      - Rolling is mainly:
        
        E-selectin / P-selectin (endothelium) ↔ sLe^x/PSGL-1 (leukocyte)
      - L-selectin:
        
        Is leukocyte-borne:
        
        It augments rolling
      - P-selectin:
        
        Is not on neutrophils
Chemokine-Triggered Integrin Activation (“inside-out”):
- What happens:
  - Endothelial-bound chemokines (on heparan sulfates:
    - For example:
      - CXCL8 /IL-8 (neutrophils), CCL2 / MCP-1(monocytes):
        
        Bind GPCRs (CXCR1/2, CCR2…), engaging Gαi → Rap1 → talin / kindlin:
        
        To flip integrins into high-affinity and clustered states
  - Key integrins switched on:
    - β2 family:
      - LFA-1 (αLβ2; CD11a/CD18)
      - Mac-1 (αMβ2; CD11b/CD18).
    - β1 family:
      - VLA-4 (α4β1):
        
        Prominent in monocytes / lymphocytes
Firm Arrest and Adhesion Strengthening (seconds–minutes):
- Counter-receptors on endothelium:
  - ICAM-1 / ICAM-2 ↔ LFA-1 / Mac-1 (β2)
  - VCAM-1 ↔ VLA-4 (β1)
- Outside-in signaling:
  - Through engaged integrins stiffens the cytoskeleton (actin remodeling via Rho / Rac / Cdc42) and spreads the cell, locking it in place
Intraluminal Crawling:
- Arrested leukocytes crawl “upstream” under shear to junctions, mainly using Mac-1 ↔ ICAM-1:
  - This helps them find permissive exit sites
Diapedesis (Transendothelial Migration):
- Two routes:
  - Paracellular (most common):
    - Through junctions
  - Transcellular:
    - Through individual endothelial cells
- Adhesion molecules guiding the crossing:
  - PECAM-1 (CD31), JAM-A/B/C, CD99, ESAM:
    - Mostly homophilic interactions at junctions
  - Transient loosening of VE-cadherin adherens junctions (kinase signaling) opens a path
- Basement membrane and pericytes:
  - Leukocytes use integrins (e.g., α6β1, αvβ3) and proteases (MMP-2/-9, elastase) to breach matrix and pericyte sheaths, aiming for naturally “low-expression regions” of laminins / collagens
- Interstitial Chemotaxis → Focus of Infection / Injury:
  - Once in tissue, cells follow gradients of:
    - Chemokines:
      - CXCL8 (neutrophils), CCL2 (monocytes), CCL19/21 (lymphocyte homing)
    - Lipid mediators:
      - LTB4, PGE₂ (context-dependent)
    - Complement & danger cues:
      - C5a, fMLP from bacteria

Exam pearls
Sequence to memorize:
- Selectin-mediated rolling → chemokine GPCR signal → integrin activation → firm adhesion → crawling → diapedesis → chemotaxis
Inside-out vs outside-in:
- Chemokines activate (inside-out) integrins
- Integrin engagement stabilizes and signals (outside-in)
Platelets matter:
- Platelet P-selectin can recruit leukocytes to thrombi (immunothrombosis)
Tissue tropism:
- VLA-4 ↔ VCAM-1 is big for monocytes / lymphocytes
- Neutrophils lean on β2 integrins

Leukocyte recruitment. (1) Circulating leukocytes express integrins in a low-affinity conformation. (2) Exposure to activated endothelium leads to rolling, which is mediated by L-selectin and P-selectin on the neutrophil and E-selectin on the endothelium. (3) Leukocyte exposure to cytokines released by macrophages phagocytosing pathogens induces a high-affinity integrin conformation. Tight leukocyte—endothelial adhesion involves integrin engagement with counter-ligand expressed on the endothelium. (4) Subsequent exposure to chemokines leads to diapedesis, which is further mediated by the family of β1- and β2-integrins.

What is the Optimal Operative Approach for DTC RECOMMENDATION 15 from the ATA 2025 Guidelines

October 6, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

When resection is performed for patients with thyroid cancer ≤ 2 cm without gross extra-thyroidal extension (cT1) and without metastases (cN0M0):
- The initial surgical procedure should be a thyroid lobectomy:
  - Unless there are bilateral cancers or other indications to remove the contralateral lobe:
    - Strong recommendation, Moderate certainty evidence
For patients with low risk, unilateral thyroid cancer > 2 and ≤ 4 cm (cT2N0M0):
- Thyroid lobectomy may be the preferred initial surgical treatment due to significantly lower risk and side effects:
  - However, the patient and treatment team may adopt total thyroidectomy to enable RAI administration and / or enhance follow-up based on disease features, suspicious contralateral nodularity, and / or patient preferences
- When thyroid lobectomy is offered as initial treatment, counsel the patient about the possibility of conversion to total thyroidectomy or need for subsequent completion thyroidectomy if higher-risk factors emerge intraoperatively or postoper-
  atively:
  - Conditional recommendation, Low-moderate
    certainty evidence
For patients with thyroid cancer > 4 cm (cT3a), cancer of any size with gross extra-thyroidal extension (cT3b or cT4), or clinically apparent metastatic disease to lymph nodes (cN1) or distant sites (cM1):
- The initial surgical procedure should include a total thyroidectomy with gross removal of all primary tumor and node dissection unless there are contraindications to this procedure
  - Strong recommendation, Moderate
    certainty evidence

RTOG-0920 (NRG-RTOG 0920)

October 6, 2025October 5, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Who was studied?
- Population:
  - Completely resected, intermediate-risk HNSCC of:
    - Oral cavity, oropharynx, or larynx:
      - Hypopharynx excluded
  - Intermediate-risk factors included any of:
    - Pernineural invasion (PNI)
    - Lymphovascular ivasion (LVI)
    - ≥ 2 lymph nodes (LNs) (all < 6 cm) or one LN > 3 cm (no extranodal extension (ENE))
    - Close margin(s) < 5 mm or focally positive then re-resected negative
    - pT3 to pT4a primary, or T2 oral cavity with DOI > 5 mm ozarkscancerresearch.org
  - Key baseline notes:
    - Majority HPV-negative (~ 80%)
    - Oral cavity ~ 64%
    - EGFR high expression in ~ 85%(assayed for stratification, not a requirement) NRG Oncology+1
- Study design and treatment:
  - Randomization (1:1):
    - PORT alone vs PORT + cetuximab
  - PORT:
    - IMRT 60 Gy in 30 fx (66 Gy allowed) ozarkscancerresearch.org
  - Cetuximab regimen:
    - 400 mg/m² loading, then 250 mg/m² weekly x 6 during RT + 4 weekly doses post-RT (total 11) ozarkscancerresearch.org
  - Primary endpoint:
    - Overall survival (OS) in all randomized / eligible
      - Pre-specified plan to test in HPV-negative subgroup
  - Secondary endpoints:
    - Disease-free survival (DFS), toxicity, others PubMed
- Results (median follow-up ~ 7.2 years):
  - Primary endpoint (OS): Negative:
    - OS HR 0.81; one-sided p=0.075 (did not meet significance)
    - 5-yr OS:
      - 76.5% (PORT+cetuximab) vs 68.7% (PORT) NRG Oncology
  - Secondary endpoint (DFS): Positive
    - DFS HR 0.75; one-sided p=0.017
    - 5-yr DFS:
      - 71.7% (PORT+cetuximab) vs 63.6% (PORT)
        
        Benefit limited to HPV-negative population NRG Oncology+1
  - Toxicity:
    - Acute grade 3 to 4:
      - 70.3% (PORT+cetuximab) vs 39.7% (PORT); p<0.0001:
        
        Largely more mucositis / dermatitis NRG Oncology
    - Late grade 3 to 4:
      - 33.2% vs 29.0%, p=0.31 (no significant increase)
    - No grade-5 events NRG Oncology
  - Quality of life:
    - A dedicated RTOG-0920 QoL analysis was presented at ASCO 2025:
      - Aligns with the toxicity profile (no long-term penalty reported in the abstract listing). ASC Publications+1
Interpretation (how to use this):
- For HPV-negative, intermediate-risk patients who are not ideal candidates for high-dose cisplatin (remember cisplatin is reserved for high-risk ENE+ / positive-margin per RTOG 9501/EORTC 22931 era):
  - Adding cetuximab to PORT is a reasonable option to improve DFS without increasing late toxicity:
    - With trade-off of substantially higher acute toxicity
    - OS was not improved PubMed+1
    - HPV-positive:
      - No signal of benefit:
        
        Do not extrapolate a DFS advantage here. PubMed
- Sites:
  - Data are particularly representative for oral cavity primaries (largest stratum) Red Journal
Practical selection checklist (tumor board quick hits):
- Use PORT + cetuximab consideration when ALL are true:
  - HPV-negative HNSCC (oral cavity / oropharynx / larynx)
  - Intermediate-risk features as per protocol list above
  - No ENE or positive margins:
    - Those are high-risk → cisplatin-based CRT
  - Patient not a good candidate for cisplatin (comorbidities, renal / hearing issues)
  - Accepts higher acute toxicity risk and closer supportive care during RT ozarkscancerresearch.org+2PubMed+2
Key trial specs (at a glance):
- NCT00956007; Opened Nov 2009, closed Mar 2018; n=577 eligible. NRG Oncology+1
- IMRT mandatory; p16 testing required for oropharynx; EGFR IHC collected (stratification/analysis). ozarkscancerresearch.org
Citation anchors:
- Machtay M, et al. JCO 2025;43(12):1474–1487. Epub Jan 22, 2025. (Primary publication.) PubMed
- NRG Oncology press summary with HRs, 5-yr estimates, and toxicity breakdown. NRG Oncology
- Protocol (2016) schema/eligibility for exact intermediate-risk feature definitions and cetuximab dosing. ozarkscancerresearch.org
- Additional baseline composition (oral cavity %, EGFR high) from earlier abstract. Red Journal

What did the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) Actually Showed?

October 5, 2025October 5, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Takeaway:
- Concomitant chemotherapy + radiation therapy (RT):
  - Yields a statistically significant OS benefit vs RT alone:
    - HR ~ 0.83; ~ 6.5% 5-yr OS gain:
      - Driven by improved locoregional control
  - Induction alone or adjuvant alone did not improve OS
Use:
- This underpins cisplatin-CRT as the default curative standard
Refs:
- Lacas et al., MACH-NC (Radiother Oncol 2021; PMC)
What it is individual-patient data meta-analysis updating the MACH-NC database:
- To 107 RCTs / 19,805 patients:
  - Accrued 1965 to 2012
- Updated median follow-up:
  - 6.6 years
- Endpoints:
  - OS, EFS, 120-day mortality, loco-regional failure (LRF), distant failure (DF), cancer vs non-cancer deaths Groningen Research Portal+1
- Results by timing of chemotherapy:
  - Concomitant chemoradiotherapy (CRT) vs loco-regional therapy alone:
    - Overall survival:
      - HR 0.83 (95% CI 0.79–0.86):
        
        Absolute OS gain + 6.5% at 5 yr and + 3.6% at 10 yr (≈ NNT ~ 15 at 5 yr)
    - EFS:
      - HR 0.80 with + 5.8% at 5 yr
    - No increase in 120-day mortality:
      - HR 1.07, p=0.37 Groningen Research Portal
    - Patterns of failure:
      - Marked LRF reduction (sub-HR 0.71)
      - No DF effect (HR 1.04)
      - Survival benefit driven by lower cancer mortality (HR 0.79; − 9.8% at 5 yr):
        
        With no change in non-cancer deaths (HR 1.01) Groningen Research Portal
    - Regimen effects:
      - Greatest effect for platinum-containing polychemotherapy (EFS HR 0.74)
      - Smallest for non-platinum monochemotherapy (HR 0.86)
      - Benefit consistent across eras and RT modalities Groningen Research Portal
- Induction chemotherapy (before RT / CRT):
  - OS and EFS:
    - No significant benefit:
      - OS HR 0.96
      - EFS HR 0.96
    - DF decreases (HR 0.76):
      - But no LRF improvement (sub-HR 1.07)
    - Benefit attenuates with worse performance status Groningen Research Portal
- Adjuvant chemotherapy (after loco-regional therapy):
  - OS and EFS:
    - No benefit:
      - OS HR 1.02
      - EFS HR 0.98
  - Early mortality:
    - Higher 120-day mortality (HR 1.89, p=0.0003)
    - Some reduction in LRF (sub-HR 0.84) and DF(HR 0.77) without survival gain Groningen Research Portal
- Direct head-to-head concomitant vs induction (same drugs):
  - Across eight comparisons (n=1,214), concomitant is superior:
    - OS HR 0.84 (≈ + 6.2% absolute OS at 5 yr)
    - EFS HR 0.85
    - LRF HR 0.86
  - Indirect comparisons concur (interaction p<0.0001) Groningen Research Portal
- Subgroups and modifiers:
  - Age:
    - Benefit of concomitant chemotherapy decreases with increasing age:
      - Use added caution > 70 yr Groningen Research Portal
  - Performance status:
    - Poorer PS attenuates benefit:
      - Noted in induction analyses:
        
        Similar theme in concomitant Groningen Research Portal
  - HPV / smoking:
    - Not evaluable here (most trials pre-HPV era)
    - Don’t expect HPV-specific signals from MACH-NC Groningen Research Portal
- Practical takeaways:
  - For curative, non-metastatic HNSCC:
    - The only timing with proven OS benefit is concomitant chemo with RT
    - Expect ~ 6% to 7% absolute 5-yr OS gain:
      - Driven by better loco-regional control Groningen Research Portal
  - Induction doesn’t improve OS vs loco-regional therapy alone (despite fewer distant mets)
  - Adjuvant chemo doesn’t improve OS and raises early mortality risk Groningen Research Portal+1
  - Within concomitant therapy:
    - Platinum-containing regimens carry the strongest signal:
      - This underpins cisplatin-based CRT as the benchmark Groningen Research Portal
Limitations the paper notes:
- Trials span 1965 to 2012:
  - Staging, RT techniques, supportive care evolved
  - Still, no interaction by accrual period and sensitivity analyses were consistent
  - HPV data were largely unavailable. Groningen Research Portal
Citation (free full text):
- Lacas B, Carmel A, Landais C, et al. MACH-NC update—107 RCTs, 19,805 pts. Radiother Oncol. 2021;156:281-293. PMC8386522. Key effect sizes and table are in the PDF’s Table 1 and text (OS/EFS/120-day mortality/LRF/DF).

What to Monitor During Chemoradiation CRT with Cisplatin for Head and Neck Cancer?

October 5, 2025September 14, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

What to monitor (and when):
- Before starting (≤ 7 days prior):
  - BMP / eGFR + electrolytes:
    - Cr, BUN, Mg, K, Ca, Na, PO₄
  - Urinalysis if concern for renal injury
    - Why:
      - Baseline renal reserve; cisplatin causes salt wasting (especially Mg) and AKI eviQ
  - CBC with differential:
    - Why:
      - Myelosuppression risk DailyMed+1
  - Audiology (baseline audiogram):
    - Why:
      - Ototoxicity risk:
        
        Establish baseline threshold:
        
        Audiology societies and monographs recommend baseline and interval monitoring American Academy of Audiology+2audiology-web.s3.amazonaws.com+2
  - Medication review and vitals / weight.:
    - Hold / avoid nephrotoxins:
      - NSAIDs, IV contrast, aminoglycosides
    - Assess fluid status eviQ
  - Antiemetic plan (cisplatin = high emetic risk):
    - Day 1:
      - NK1RA + 5-HT3RA + dexamethasone + olanzapine
    - Continue dexamethasone ± olanzapine Days 2 to 4 American Society of Clinical Oncology+2Janet Abrahm, M.D.+2
- Each cisplatin day (same day or within 24 to 48 hour before dose):
  - BMP / eGFR + Mg / K / Ca / Na / PO₄ and CBC
    - Act:
      - Replete Mg (often 10 mmol MgSO₄ pre-hydration) and correct K / Ca before dosing
      - If eGFR ↓ or SCr ↑:
        
        Evaluate per KDIGO, hydrate, and hold / modify eviQ
  - Hydration status and urine output:
    - Act:
      - Use isotonic saline pre / post hydration:
        
        Typical total 2.5 to 3.0 L around infusion
      - Routine mannitol not required:
        
        Consider only for very high-dose eviQ
  - Symptom screen:
    - Tinnitus, hearing change, paresthesias, nausea / vomiting, cramps (hypo-Mg), mucositis, dysphagia
    - Act:
      - Audiogram if otologic symptoms
      - Neuro exam each visit American Academy of Audiology+1
- Weekly during RT (even if cisplatin is q3-weekly):
  - BMP / eGFR + Mg / K / Ca (at least weekly), CBC weekly, weight, I/Os
    - Why:
      - Catch AKI and hypomagnesemia early
      - Track cytopenias and dehydration eviQ+1
  - Audiology:
    - Repeat before each cycle (q3-weekly) or sooner if symptoms; for weekly cisplatin, obtain symptom-triggered or mid-course checks per local protocol American Academy of Audiology+1
What to do with common issues?
- Rising creatinine / suspected AKI:
  - Trigger:
    - ≥ 0.3 mg/dL increase or ≥ 1.5 × baseline (KDIGO stage 1+):
      - Hold cisplatin, hydrate (NS), replete Mg / K, stop nephrotoxins, reassess in 24 to 72 hours
  - Escalate care by stage Merck Manuals+1
- Hypomagnesemia (very common):
  - Prevention / correction:
    - Include MgSO₄ in pre-hydration (e.g., 10 mmol in 1 L NS) and replete as needed:
      - Mg protects against cisplatin nephrotoxicity eviQ+1
- Emesis despite prophylaxis
  - Action:
    - Optimize 4-drug regimen (ensure NK1RA)
    - Consider scheduled olanzapine days 2 oto 4
    - Add rescue (metoclopramide, prochlorperazine) American Society of Clinical Oncology+1
- Ototoxicity symptoms (tinnitus, high-frequency loss):
  - Action:
    - Prompt audiogram:
      - If confirmed / worsening:
        
        Discuss dose holding or regimen change (risk rises with cumulative dose) American Academy of Audiology+1
Hydration—practical template (adjust per institution):
- Pre-hydration:
  - 1 L NS over ~ 60 min with 10 mmol MgSO₄
- Cisplatin infusion:
  - 1 L NS over ~ 60 min (institutional)
- Post-hydration:
  - 1 L NS over ~ 60 min:
    - Encourage oral fluids (≥ 500 mL if tolerated)
- Mannitol / diuretics:
  - Not routine; consider case-by-case (e.g., very high-dose) eviQ
One-look table (what/why/act);
- BMP / eGFR + Mg / K / Ca / Na / PO₄ (baseline and weekly):
  - Nephrotoxicity / salt wasting → hydrate, replete Mg / K, hold if AKI eviQ
- CBC weekly:
  - Myelosuppression → delay / modify if grade ≥ 3, treat per protocol DailyMed
- Audiogram baseline ± before each cycle / PRN:
  - Ototoxicity → hold / switch if worsening American Academy of Audiology
- Antiemetics each dose:
  - Cisplatin = high emetic risk → 4-drug prophylaxis American Society of Clinical Oncology
Bottom line:
- Weekly labs (BMP / eGFR, Mg / K / Ca) + CBC
- Disciplined hydration with Mg supplementation
- Symptom-triggered audiology are the pillars that prevent missed AKI, hypomagnesemia, cytopenias, and ototoxicity during CRT with cisplatin

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