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• Mechanism of Action (CDK4/6 inhibition in HR+ disease):
  • Core biology (why surgeons should care):
    • Ribociclib is a selective CDK4/6 inhibitor:
      • Blocks Cyclin D + CDK4/6 → RB phosphorylation → G1→S transition
      • At baseline, a breast cancer cell moves from G1 → S phase (DNA replication) only if a key checkpoint is passed
      • The core engine – Cyclin D + CDK4/6 = active complex:
        • This complex’s job is to turn OFF the brake (RB protein)
      • The critical step:
        • RB (retinoblastoma protein) normally acts as a brake
        • When phosphorylated → RB becomes inactive
        • This releases E2F transcription factors
        • E2F turns on genes needed for DNA synthesis (S phase)
      • 👉 So – Active CDK4/6 = cell allowed to divide
      • CDK4/6 Inhibitors:
        • Results in cell-cycle arrest in luminal (ER+) tumor cells
    • Key downstream effects:
      • Prevents proliferation of ER-driven clones
      • Enhances endocrine therapy sensitivity (synergistic with AI)
      • May reduce micrometastatic outgrowth → recurrence prevention
  • Clinical interpretation:
    • Not cytotoxic → cytostatic disease control
    • Most impactful in:
      • Luminal A/B biology
      • Late recurrence–prone disease:
        • Rationale for long-duration adjuvant use (3 years)
• NATALEE Trial Design (context for surgeons):
  • Phase III randomized control trial:
    • ~ 5100 patients 
    • Population:
      • HR+ / HER2− early breast cancer
      • Stage II to III:
        • Including selected N0 high-risk
    • Treatment:
      • Ribociclib (400 mg, 3 yrs) + AI ≥ 5 yrs
        vs AI alone
    • Broad inclusion → more “real-world” than monarchE
• 5-Year Update (ESMO 2025 / latest analyses):
  • Efficacy (key numbers):
  • iDFS HR ~0.72 → ~ 28% relative risk reduction 
  • 5-year iDFS:
    • 85.5% (ribociclib) vs 81.0% (ET alone):
      • Absolute benefit ~ 4.5% 
    • Benefit persists after stopping drug (3-year exposure):
      • Indicates true disease-modifying effect 
  • Other endpoints:
    • ↓ Distant recurrence (DDFS HR ~0.71) 
    • ↓ DRFS / RFS consistently improved 
    • OS trend positive but immature 
  • Important nuance:
    • Absolute benefit increases over time (3 → 5 yrs):
      • Supports late recurrence suppression
• Indications (current clinical positioning):
  • Regulatory / guideline-aligned use:
  • Adjuvant therapy with AI for:
    • HR+ / HER2− early breast cancer
    • Stage II to III at high risk of recurrence 
    • “High-risk” (NATALEE definition):
      • Includes:
        • Stage IIB to III or
        • Stage IIA with N+ or
        • N0 + high-risk biology (e.g., Ki-67 ≥ 20%, grade 3, genomic risk) 
• Unique positioning vs abemaciclib:
  • Broader population:
    • Includes:
      • Node-negative high-risk
      • Lower tumor burden
      • Lower starting dose → better tolerability strategy
• Practical Implications for Breast Surgeons:
  • Expands “systemic adjuvant” discussion at MDT
  • You now need to identify patients who may benefit before finalizing adjuvant plan:
    • Candidates to flag early:
    • Stage II (even N0) with:
      • High grade
      • High Ki-67
      • Genomic high risk
    • Any Stage III HR+ disease
• Impacts surgical-pathologic reporting priorities:
  • Surgeons should ensure:
    • Accurate nodal staging
    • Grade
    • Ki-67
    • Genomic assay (if used) integrated early
      • These directly influence eligibility for CDK4/6 therapy
• Reinforces importance of recurrence biology:
  • Luminal cancers:
    • Long natural history
    • Late relapse risk
    • Ribociclib addresses micrometastatic dormancy
      → shifts mindset from:
      “Local control + endocrine therapy”
      → to
      “Extended systemic control strategy”
• Treatment duration considerations:
  • Ribociclib:
    • 3 years
  • Endocrine therapy:
    • ≥ 5 years
• Implication:
  • Long-term adherence planning begins at surgical consultation
• Safety Profile (surgeon-relevant highlights):
  • Common:
    • Neutropenia (non-febrile)
    • LFT elevation
    • QT prolongation
  • No new long-term safety signals at 5 years 
  • Clinical takeaway:
    • Manageable → supports use in early-stage curative setting
• Key Takeaways for Surgical Practice:
  • Ribociclib is now a standard adjuvant option in HR+/HER2− EBC:
    • Especially stage II to III and biologically high-risk disease
  • 5-year data confirms durability:
    • Benefit persists beyond treatment window:
      • Increasing absolute benefit over time
  • Expands eligible population:
    • Includes node-negative high-risk patients
  • Multidisciplinary coordination is critical:
    • Surgeons play a role in:
      • Early identification
      • Pathologic risk stratification
      • Timely referral to medical oncology
• Bottom line (surgeon-focused):
  • Ribociclib from NATALEE represents a shift toward proactive systemic prevention of recurrence in luminal breast cancer, with durable 5-year benefit and broader eligibility than prior CDK4/6 strategies—making early risk identification at the surgical stage increasingly important

The Phase III LEAP-10 trial represents a major collaborative effort between Merck & Co. and Eisai, addressing a persistent unmet need in recurrent /metastatic head and neck squamous cell carcinoma (R/M HNSCC).

In patients with PD-L1 CPS ≥1 disease, the combination of lenvatinib + pembrolizumab demonstrated:

• Improved objective response rate (ORR)
• Prolonged progression-free survival (PFS)

However, these gains did not translate into an overall survival (OS) benefit compared with pembrolizumab monotherapy, which remains the backbone of first-line treatment.

---

Clinical Context: Why OS Remains Elusive

Despite encouraging activity, the absence of OS improvement reinforces the durability of the current standard established by KEYNOTE-048 trial, where:

• Pembrolizumab ± chemotherapy continues as standard of care
• Survival benefit is tightly linked to PD-L1 expression and patient selection

The LEAP-10 findings highlight a recurring challenge in HNSCC:

Early efficacy signals (ORR, PFS) do not reliably predict survival benefit, particularly in an immunotherapy-sensitive disease where post-progression treatments and tumor biology heavily influence OS.

---

Biologic Interpretation

The addition of lenvatinib, a multi-kinase inhibitor targeting VEGFR, FGFR, and others, likely:

• Enhances tumor microenvironment modulation
• Improves initial tumor shrinkage and disease control

However, potential limitations include:

• Lack of deep, durable immune reprogramming
• Emergence of resistance mechanisms
• Possible toxicity-related treatment discontinuation

These factors may blunt long-term survival impact despite improved early endpoints.

---

Where the Field Is Heading: EGFR and Beyond

Attention is now shifting toward next-generation EGFR-targeted strategies, with the hypothesis that:

• More precise targeting of EGFR-driven signaling
• Coupled with immune engagement mechanisms

may yield more durable survival benefits.

Key players advancing this space include:

• Dana-Farber Cancer Institute
• Genmab
• Bicara Therapeutics
• Johnson & Johnson
• Merus N.V.
• Harvard Medical School

Emerging modalities include:

• Bispecific antibodies (EGFR × immune targets)
• Antibody-drug conjugates (ADCs)
• Combination immunotherapy strategies

These approaches aim to:

• Overcome primary and acquired resistance
• Deliver more sustained immune activation
• Ultimately shift the OS curve, not just early endpoints

---

Key Takeaway for Clinical Practice

While lenvatinib + pembrolizumab shows meaningful biologic and clinical activity, it does not currently challenge pembrolizumab-based regimens as standard of care in PD-L1–positive R/M HNSCC.

The central question remains:

What therapeutic strategy will meaningfully and reproducibly improve overall survival in first-line HNSCC?

The next wave of EGFR-targeted and immune-engaging therapies may be the most promising path forward.

Maxillary Artery

• The maxillary artery supplies deep structures of the face.

• It branches from the external carotid artery just deep to the neck of the mandible.

• Structure:

  • The maxillary artery, the larger of the two terminal branches of the external carotid artery:

    • Arises behind the neck of the mandible, and is at first imbedded in the substance of the parotid gland.

  • It passes forward between the ramus of the mandible and the sphenomandibular ligament, and then runs, either superficial or deep to the lateral pterygoid muscle, to the pterygopalatine fossa.

  • It supplies the deep structures of the face.

• May be divided into:

  • Mandibular portion (first part / bony part)

  • Pterygoid portion (second part / muscular part)

  • Pterygopalatine portions (third part).

• Mandibular portion (first part / bony part):

  • The first or mandibular portion (or bony portion) passes horizontally forward, between the neck of the mandible and the sphenomandibular ligament:

    • Where it lies parallel to and a little below the auriculotemporal nerve.

    • It crosses the inferior alveolar nerve, and runs along the lower border of the lateral pterygoid muscle.

    • Branches include:

      • Deep auricular artery

      • Anterior tympanic artery

      • Middle meningeal artery

      • Inferior alveolar artery:

        • Which gives off its mylohyoid branch just prior to entering the mandibular foramen

      • Accessory meningeal artery

• Pterygoid portion (second part / muscular part):

  • The second or pterygoid portion (or muscular portion) runs obliquely forward and upward under cover of the ramus of the mandible and insertion of the temporalis muscle:

    • On the superficial (very infrequently on the deep) surface of the lateral pterygoid muscle.

    • It then passes between the two heads of origin of this muscle and enters the fossa.

  • Branches include:

    • Masseteric artery

    • Pterygoid branches

    • Deep temporal arteries:

      • Anterior and posterior

    • Buccal (buccinator) artery

• Pterygopalatine portions (third part):

  • The third or pterygopalatine portion lies in the pterygopalatine fossa in relation with the pterygopalatine ganglion.

  • This is considered the terminal branch of the maxillary artery.

  • Branches include:

    • Sphenopalatine artery:

      • Nasopalatine artery is the terminal branch of the maxillary artery

    • Descending palatine artery:

      • Greater palatine artery

      • Lesser palatine artery

    • Infraorbital artery

    • Posterior superior alveolar artery

    • Artery of pterygoid canal

    • Pharyngeal artery

    • Middle superior alveolar artery (could be a branch of the infraorbital artery)

    • Anterior superior alveolar arteries (could be a branch of the infraorbital artery)

 

 

Rodrigo Arrangoiz MS, MD, FACS a head and neck surgeon at the Braman Comprehensive Cancer Center at Mount Sinai Medical Center in Miami, Florida.

He is first author on some publications on oral cavity cancer:

• Oral Tongue Cancer: Literature Review and Current Management 

  • https://www.oatext.com/pdf/CRR-2-153.pdf

• Understand Cancer: Research and Treatment Oral Cavity Cancer: Literature Review and Current Management. 

  • https://www.researchgate.net/publication/303366031_Understand_Cancer_Research_and_Treatment_Oral_Cavity_Cancer_Literature_Review_and_Current_Management

Training:

• General surgery:

• Michigan State University:

• 2004 al 2010

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• Fox Chase Cancer Center (Filadelfia):

• 2010 al 2012

• Masters in Science (Clinical research for health professionals):

• Drexel University (Filadelfia):

• 2010 al 2012

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• IFHNOS / Memorial Sloan Kettering Cancer Center:

• 2014 al 2016

• The main trunk of the maxillary artery:
  • Is divided into three parts:
    • Which are named according to related structures along the artery’s course
  • These three parts are:
    • The mandibular division (1st part / bony part):
      • Named as such because it winds around deep to the neck of the mandible
    • The pterygoid division (2nd part / muscular part):
      • It has this name because it travels between the two heads of the lateral pterygoid muscle
    • The pterygopalatine division (3rd part):
      • This part derived its name from the pterygopalatine fossa, into which it enters
  • Conventionally, these three parts are described as the:
    • Part before-, part on-, and part beyond the lateral pterygoid muscle
    • This is also useful since out of the 15 branches of the maxillary artery:
      • The five branches from the second part (part on the lateral pterygoid muscle):
        • Are regarded as branches to soft tissues:
          • That do not course through foramina in bones
      • However, the remaining 10 branches:
        • From the first and third parts:
          • Go through foramina in bones
• Course:
  • The maxillary artery:
    • Continues as one of the terminal divisions of the external carotid artery:
      • At the level of the neck of the mandible:
        • Passing forward between the neck of the mandible and the sphenomandibular ligament
      • It continues its path by running deeply to the lower head and passes forward between the two heads of the lateral pterygoid muscle:
        • To break into its terminal branches at the pterygopalatine fossa

• Maxillary artery branches:
  • Branches of the first (mandibular) division:
    • The deep auricular artery:
      • Is the first branch of the mandibular part:
        • This branch runs upwards to enter the ear and courses superficially to the tympanic membrane, passing between the cartilage and bone
      • It supplies the external acoustic meatus of the ear and the deep surface of the tympanic membrane
      • The anterior tympanic artery:
        • Is the second branch that courses near the tympanic membrane
        • It passes deep to the membrane:
          • Through the petrotympanic fissure to the middle ear:
            • To join the circular anastomosis around the tympanic membrane
      • The middle meningeal artery:
        • Passes straight upwards through the foramen spinosum:
          • To join the two roots of the auriculotemporal nerve
        • It supplies bones of the skull (calvaria) and the dura mater
      • The inferior alveolar artery:
        • Runs inferiorly and anteriorly towards the inferior alveolar nerve:
          • To meet the nerve at the inferior alveolar (a.k.a. mandibular) foramen
        • The artery runs further anteriorly in the mandible:
          • Supplying the pulps of the mandibular teeth (with its dental branches) and the body of the mandible
        • Its other branch, the mental branch:
          • Emerges from the mental foramen and supplies the lower lip and skin of the chin 
      • The accessory meningeal artery:
        • Is the main source of blood supply to the trigeminal ganglion
        • It passes upwards through the foramen ovale to supply the dura mater of the floor of the middle fossa and of the trigeminal cave (Meckel’s cave)
  • Branches from the 2nd (pterygoid / muscular) segment:
    • All branches from the pterygoid part supply only soft tissues
    • The masseteric artery:
      • Accompanies the lingual nerve
      • It is small, and passes laterally through the mandibular notch to the deep surface of the masseter muscle
    • The pterygoid arteries:
      • Are small branches that vary in number
      • They supply the lateral pterygoid muscle and medial pterygoid muscle
    • The deep temporal arteries:
      • Course between the temporalis muscle and the pericranium
      • The main function of this branch is to:
        • Provide arterial supply to the temporalis muscle
    • The buccal (buccinator) artery:
      • Runs obliquely forward, between the medial pterygoid muscle and the insertion of the temporalis muscle, to the outer surface of the buccinator muscle
      • It mainly supplies the:
        • Buccinator muscle
      • Along its course, it forms anastomoses with branches of the facial and infraorbital arteries
  • Branches from the 3rd (pterygopalatine) segment:
    • The sphenopalatine artery:
      • Mainly supplies the nasal cavity:
        • Which is why it is also referred to as the nasopalatine artery
      • It passes through the sphenopalatine foramen and enters the nasal cavity
      • Here it gives off its posterior lateral nasal branches
      • Crossing the inferior surface of the sphenoid:
        • The sphenopalatine artery ends on the nasal septum giving off the posterior septal branches
    • The descending palatine artery:
      • Descends through the greater palatine canal:
        • With the greater and lesser palatine branches:
          • Of the pterygopalatine ganglion
        • It terminates by dividing into the greater and lesser palatine arteries:
          • That provide blood supply for the hard palate and soft palate, respectively
    • The infraorbital artery:
      • Passes forwards through the inferior orbital fissure:
        • Along the floor of the orbit and infraorbital canal:
          • To emerge with the infraorbital nerve on the face.
    • The posterior superior alveolar artery:
      • Supplies the maxillary teeth
      • It gives branches that accompany the corresponding nerves through foramina in the posterior wall of the maxilla
    • The middle superior alveolar artery:
      • Is most often a branch of the infraorbital artery
      • It arises within the infraorbital canal:
        • Where it descends to supply the maxillary sinus and plexus at the level of the canine tooth
    • The pharyngeal artery:
      • Supplies structures such as the pharynx and roof of the nose
    • The anterior superior alveolar artery:
      • Is branch of the infraorbital artery. 
    • The artery of the pterygoid canal:
      • Runs into the pterygoid canal:
        • It passes backwards along the pterygoid canal with the corresponding nerve
      • It supplies the upper part of the pharynx, and sends a small division into the tympanic cavity to anastomose with the tympanic arteries
        
        
        
        

The proximity or direct extension of a primary tumor of the oral cavity to the mandible requires appropriate radiological studies to establish the presence and extent of bone involvement:

• Although the absence of radiographic findings does not rule out bone invasion:

  • Bone destruction as seen on the radiograph confirms tumor invasion

• Radionuclide bone scans:
  • Often are positive before the radiographic appearance of bone destruction:
    • But they seldom provide accurate information regarding the extent of bone invasion
  • Bone scans also may be positive in non-neoplastic conditions:
    • Such as inflammatory lesions
• Plain radiographs of the mandible in the antero-posterior and oblique views:
  • Are not satisfactory as a routine screening test to establish or rule out bone destruction
• A panoramic view of the mandible (an orthopantomogram):
  • Is helpful to assess the general architecture of the mandible in relation to the dento-alveolar structures and invasion by the tumor (Figure)

• However, for technical reasons:

  • The midline of the mandible near the symphysis is not adequately evaluated by a panoramic view

  • In addition, early invasion of the lingual cortex of the mandible is not seen on a panoramic view

  • Occlusal films of the body of the mandible and intraoral dental films:

    • Often are most accurate in demonstrating early invasion by a tumor

      
      
• CT scans of the mandible:
  • Generally are not optimal for routine screening:
    • But may be considered in certain circumstances:
      • Such as primary tumors of the mandible and lesions where soft tissue extension from tumors involving the ascending ramus of the mandible is suspected (Figure)

Three-dimensional reconstructions of CT images provide an excellent overview of the mandible or maxilla from any desired angle

• A computerized tomogram of the oral cavity and neck:
  • Is the standard initial radiographic study for assessment of locoregional extent of the tumor
  • It allows comprehensive evaluation of neck nodes and also the relationship of the primary tumor to adjoining bone:
    • Especially in situations such as primary tumors of the mandible and lesions where soft-tissue extension from tumors involving the ascending ramus of the mandible is suspected

• Three-dimensional reconstructions of the mandible of a patient with an ossifying fibroma of the body of the mandible on the left-hand side causing expansion and involving the lingual cortex are shown in the Figures

  
  

 

 

• A three-dimensional CT scan and a one-to-one reproduction of the CT scan:

  • Are of great value to the surgeon for mandible reconstruction with a microvascular free flap

• Big Picture:
  • AJCC 8th Edition (2017):
    • Introduced Depth of Invasion (DOI) as a major determinant of T stage in oral cavity squamous cell carcinoma (OCSCC)
  • AJCC 9th Edition (2024 / 2025 update):
    • Retains DOI as a core component of T staging, with refinements and clarifications, not a paradigm shift

• Key Concepts Introduced:
  • DOI ≠ tumor thickness
  • DOI measured from basement membrane of adjacent normal mucosa
  • DOI strongly correlates with:
    • Nodal metastasis
    • Survival
• AJCC 9th Edition (What Changed?):
  • DOI Thresholds: UNCHANGED
    • The 5 mm and 10 mm cutoffs remain identical
    • DOI continues to upstage tumors independent of surface dimensions
    • This is critical:
      • No numeric change in DOI staging thresholds
  • Clarification of Measurement Technique:
    • The 9th edition places stronger emphasis on standardization and reproducibility:
      • Clearer distinction between:
        • Exophytic tumors (avoid overestimation)
        • Ulcerated lesions (reconstruct mucosal surface)
      • Addresses interobserver variability among pathologists
      • Reinforces:
        • Measurement from reconstructed basement membrane line
  • Integration With Other Risk Factors:
    • While DOI remains central, AJCC 9 emphasizes its interpretation within a broader biologic context:
      • DOI alone is not sufficient for prognosis
      • Must be integrated with:
        • Perineural invasion (PNI)
        • Lymphovascular invasion (LVI)
        • Worst pattern of invasion (WPOI) (not formally in AJCC but increasingly relevant)
        • Nodal disease / ENE
• This reflects modern understanding:
  • Tumor biology > single metric
• Clinical vs Pathologic DOI:
  • Reinforces distinction:
    • cDOI (imaging / clinical) vs pDOI (pathologic gold standard)
  • Encourages better use of:
    • MRI / ultrasound for preoperative planning
• What Did NOT Change
  • DOI is still:
    • A T-category modifier, not a standalone staging variable
    • Only used in oral cavity cancers (not oropharynx, etc)
    • No change to:
      • T1 / T2 / T3 definitions based on DOI
      • Surgical decision-making thresholds (though clinical use continues evolving)
• Practical Clinical Impact (2025 Reality):
  • Surgical Oncology Perspective:
    • DOI continues to guide:
      • Elective neck dissection:
        • DOI ≥ 3 mm to 4 mm → strong consideration
      • Margin planning
      • Adjuvant therapy discussions
  • Research / Modern Trends:
    • DOI is increasingly being:
      • Combined with molecular markers
      • Supplemented by AI-based histologic risk models
      • Some argue DOI may eventually be:
        • Refined or replaced by composite risk scores

Byers RM, Weber RS, Andrews T, McGill D, Kare R, Wolf P. Frequency and therapeutic implications of “skip metastases” in the neck from squamous carcinoma of the oral tongue. Head Neck. 1997 Jan;19(1):14-9. doi: 10.1002/(sici)1097-0347(199701)19:1<14::aid-hed3>3.0.co;2-y. PMID: 9030939.

• Background: 
  • Supraomohyoid neck dissection (Levels I, II, III):
  • Is an adequate operation for the elective treatment of the neck for patients with oral cavity cancer
• Squamous cell carcinoma of the oral tongue:
  • Metastasize to clinically negative nodes:
    • In 20% to 30% of patients:
      • These nodes usually are located in:
        • Levels I to III
• Methods:
  • The medical records of 277 previously untreated patients with squamous cell carcinoma of the oral tongue were reviewed between the years 1970 and 1990
  • All patients had a glossectomy and neck dissection as part of their initial treatment
  • Patients were evaluated as to the findings in their neck
  • The following group of patients were included:
    • Patients who had level III nodes positive, without disease in levels I and II
    • Patients with disease in level IV
    • Patients with disease in level IIB or IIIB
    • Patients who were electively dissected and whose neck did not demonstrate any pathologically involved nodes:
      • But level IV was not included in the dissection and the patient subsequently developed pathologically positive nodes in level IV
• Results: 
  • Of all patients:
    • 15.8% had either level IV metastasis as the only manifestation of disease in the neck or the level III node was the only node present without disease in level I to II
• Conclusion: 
  • The usual supraomohyoid neck dissection is inadequate for a complete pathologic evaluation of all the nodes at risk for patients with squamous carcinoma of the oral tongue
  • This may create a dilemma in determining whether postoperative radiotherapy is necessary
  • Consequently, all patients with squamous cell carcinoma of the oral tongue should have levels I to IV nodes (Extended Supraomohyoid Neck Dissection) removed:
    • If an elective neck dissection is part of their initial therapy

Here is an expanded summary of Baratz et al., “Neoadjuvant Immunotherapy and Chemoimmunotherapy Regimens in Head and Neck Cancer: A Systematic Review and Meta-Analysis,” published online in JAMA Otolaryngology–Head & Neck Surgery on March 12, 2026

• Why this paper matters:
  • Neoadjuvant immunotherapy in resectable HNSCC:
    • Has been attractive because:
      • It may treat micrometastatic disease early
      • Exploit the intact tumor-immune microenvironment before surgery
      • It may potentially improve pathologic response without delaying definitive treatment
    • What has been unclear is whether immunotherapy alone or chemoimmunotherapy is more effective
  • This meta-analysis addresses that question by pooling the available prospective data in resectable, treatment-naive HNSCC
• Objective:
  • The investigators aimed to:
    • Summarize the efficacy of neoadjuvant chemoimmunotherapy in HNSCC
    • Compare outcomes of chemoimmunotherapy vs immunotherapy alone:
      • Before definitive surgery in locoregionally advanced resectable HNSCC
• Methods:
  • This was a librarian-led systematic review and meta-analysis performed according to PRISMA methodology
  • The authors searched MEDLINE, EMBASE, Cochrane Central, Cochrane Database of Systematic Reviews, and Scopus from database inception through October 2024
  • They included prospective interventional trials in resectable, treatment-naive HNSCC that had completed accrual and reported pathologic response and / or RECIST response data
  • Two investigators independently performed study screening and extraction
  • The main outcomes were:
    • Major pathologic response (MPR)
    • Complete pathologic response (CPR)
    • Complete radiographic response (CR):
      • By RECIST 1.1
  • Secondary outcomes included:
    • 1-year overall survival
    • Toxicity
  • The pooled analysis used a binary random-effects model, with heterogeneity reported as I² 
  • Study population:
    • The meta-analysis included 23 studies with a total of 751 patients. Of these:
      • 357 patients (47%) received chemoimmunotherapy
      • 102 patients (14%) received dual-agent immunotherapy
      • 292 patients (39%) received single-agent immunotherapy 
    • The pooled cohort was predominantly male (77%) with an age range of 27 to 87 years 
• Main findings:
  • Pathologic response:
    • Strongly favored chemoimmunotherapy
  • The most important finding was:
    • The marked gradient in pathologic response across regimens:
      • Pooled MPR + CPR rates were:
        • 66% for chemoimmunotherapy 95% CI 58%-73%
        • 18% for dual-agent immunotherapy 95% CI 6%–29%
        • 6% for single-agent immunotherapy 95% CI 3%–9% 
  • This is the key take-home point:
    • Adding chemotherapy to immunotherapy:
      • Was associated with substantially higher pathologic response rates than immunotherapy alone
    • Clinically, this matters because in head and neck cancer:
      • Pathologic response has increasingly been explored as an early signal of antitumor activity and a possible surrogate for longer-term benefit:
        • Although it is not yet a fully validated surrogate for survival in this setting
        • That distinction is important when interpreting these results
    • The paper shows better tumor kill in the surgical specimen:
      • But it does not yet prove that patients live longer because of the neoadjuvant regimen:
      • That is why the authors call for phase 3 trials
  • Short-term survival looked promising across groups, but differences were not definitive:
    • Across the included studies, 1-year overall survival ranged:
      • 88% to 96% with single-agent immunotherapy
      • 88% to 96% with dual-agent immunotherapy
      • 88% to 100% with chemoimmunotherapy 
    • These ranges suggest that all three strategies can be delivered with good short-term outcomes in selected patients:
      • However, because these were mainly early-phase, non-comparative studies with heterogeneous populations and follow-up:
        • The survival data should be viewed as hypothesis-generating, not practice-defining
  • Toxicity was higher than dual immunotherapy, but not prohibitive:
    • Among studies reporting adverse events, grade 3 to 5 adverse events occurred in:
      • 29% of patients receiving single-agent immunotherapy
      • 3% with dual-agent immunotherapy
      • 17% with chemoimmunotherapy 
    • These numbers need cautious interpretation because toxicity reporting was not uniform across studies, and the denominators were limited to reporting studies rather than all pooled patients:
      • Still, the overall message is that chemoimmunotherapy increased efficacy while maintaining an acceptable:
        • Though not trivial, toxicity burden in selected surgical candidates. 
  • Authors’ conclusion:
    • The authors concluded that neoadjuvant chemoimmunotherapy:
      • Was associated with higher pathologic and radiographic response rates than immunotherapy alone in locoregionally advanced resectable HNSCC, and that these findings support the need for head-to-head phase 3 trials
• How to interpret this as a head and neck oncologic surgeon:
  • Strengths:
    • This study has several strengths:
      • It focuses specifically on resectable, treatment-naive HNSCC:
        • Which is the clinically relevant population for neoadjuvant decision-making
      • It includes only prospective interventional studies
      • It separates single-agent, dual-agent, and chemoimmunotherapy approaches rather than lumping all neoadjuvant immunotherapy together
      • It uses outcomes surgeons and multidisciplinary teams care about:
        • Pathologic response, radiographic response, survival, and toxicity
  • Important limitations:
    • The paper is very useful, but it does not settle the question of standard of care
    • The biggest limitations are:
      • Most included studies were phase 1 / 2, small, and often single-arm
      • There was likely substantial clinical heterogeneity:
        • Primary site, stage, PD-L1 status, regimen, number of cycles, and adjuvant treatment strategies
      • The outcome driving the signal is primarily pathologic response:
        • Not mature event-free survival or overall survival
      • Cross-trial comparisons may exaggerate differences:
        • Because these were not randomized head-to-head comparisons
      • Toxicity and imaging response reporting were not fully standardized
• So the paper supports promise:
  • Not final proof
• Practical clinical implications:
  • For a practicing surgeon:
    • This meta-analysis suggests that chemoimmunotherapy is currently the most active neoadjuvant immune-based strategy in resectable HNSCC:
      • At least if the endpoint is pathologic response
  • If a center is considering neoadjuvant treatment within a trial or highly selected multidisciplinary framework:
    • The data support prioritizing chemoimmunotherapy over immunotherapy alone when the goal is maximizing preoperative tumor regression
  • At the same time, these data do not mean every resectable oral cavity, larynx, or oropharynx patient:
    • Should routinely receive neoadjuvant chemoimmunotherapy outside a protocol
  • The field is moving quickly, and the editorial accompanying this paper emphasizes that these results arrive in the context of KEYNOTE-689:
    • The first phase 3 randomized study to establish perioperative immunotherapy as a standard-of-care option in locally advanced resectable HNSCC:
      • While also warning that enthusiasm should be balanced with caution as these strategies enter broader practice
• Bottom line:
  • This meta-analysis is one of the clearest pooled signals so far that in resectable locoregionally advanced HNSCC, neoadjuvant chemoimmunotherapy produces substantially higher pathologic response rates than immunotherapy alone
  • The benefit signal is strong for tumor response, short-term survival appears encouraging, and toxicity seems manageable in selected patients:
    • But the evidence base is still dominated by early-phase studies, so phase 3 randomized data remain essential before universal adoption

• The staging of primary tumors of the oral cavity:
  • As published by the AJCC and UICC is widely accepted
• In its most recent revision (eighth edition of the AJCC Staging Manual):
  • Depth of invasion (DOI):
    • Is added to the surface dimensions and local extent of the tumor:
      • As the required parameters for primary tumor staging in the oral cavity

• Accurate assessment of DOI by clinical examination is not possible:
  • However, the staging system stratifies DOI by 5 mm increments, and thus clinical estimates of DOI can be categorized into:
    • Thin (less than 5 mm)
    • Thick (5 to 10 mm)
    • Very thick (greater than 10 mm)
      • By palpation to assign clinical T stage

• The stage distribution of patients with squamous cell carcinoma of the oral cavity at the Memorial Sloan Kettering Cancer Center in New York is shown in the graph:

• The most important histologic feature of the primary tumor:
  • That affects selection of treatment and eventual prognosis:
    • Is its depth of invasion (DOI)
• Thin and superficially invasive lesions:
  • Have a lower risk of regional lymph node metastasis
  • Are highly curable
  • Offer an excellent prognosis
• Thicker lesions that deeply infiltrate the underlying soft tissues:
  • Have a significantly increased incidence of regional lymph node metastasis and an adverse impact on prognosis
• The risk of lymph node metastasis and survival rates in relation to the DOI of the primary lesion for T1 and T2 squamous carcinomas of the oral tongue and floor of mouth are shown in Figure:
  • Although it would be ideal to know the exact DOI of the lesion before surgical intervention, having that information before surgical excision and histopathologic examination of the primary tumor is not possible
• In general, however, estimate of DOI by assessing thickness of the lesion as appreciated by palpation:
  • Is a reasonably good indicator of deeply invasive lesions versus superficial lesions:
    • To estimate the extent of soft tissue and / or bone resection for the primary lesion and to decide on the need for elective dissection of the regional lymph nodes at risk in a clinically negative neck

• Several retrospective studies have identified DOI of the primary tumor:
  • As an important determinant of prognosis:
    • Thus DOI is now included in T staging of primary tumors of the oral cavity