• A postmastectomy chest wall recurrence:
  • Carries a high risk of concurrent or subsequent distant disease:
    • So the first steps are:
      • Tissue confirmation with receptor reassessment (ER / PR and HER2) and systemic staging to establish whether the recurrence is truly isolated:
        • Which determines whether curative-intent multimodality therapy versus palliative systemic therapy is appropriate
• High risk of concurrent systemic disease:
  • Staging First:
    • In the ACOSOG / Alliance AFT-01 study of stage II to III patients:
      • Synchronous distant metastases were present in 27% overall at the time of locoregional recurrence:
        • 30% specifically for postmastectomy chest wall recurrence
        • 35% for nodal
        • 15% for in-breast
    • A separate cohort found distant metastases in:
      • ~32% of patients at diagnosis of locoregional recurrence
  • This justifies obtaining systemic staging and receptor status before committing to local therapy
• NCCN staging modalities — confirmed with nuance:
  • NCCN workup for recurrent disease (BINV-18) includes:
    • History / physical
    • CBC, comprehensive metabolic panel with LFTs and alkaline phosphatase
    • Imaging:
      • Chest diagnostic CT ± contrast
      • Abdomen ± pelvis CT with contrast or MRI
      • Bone scan or sodium fluoride PET / CT (category 2B):
        • With FDG-PET/CT “useful in certain circumstances” (and FES-PET/CT considered for ER-positive / lobular disease)
      • Brain and spine MRI are reserved for relevant symptoms
      • So PET/CT is positioned as an option in select circumstances rather than fully interchangeable with CT + bone scan
    • Critically, NCCN also mandates biopsy of the recurrence with re-evaluation of ER / PR and HER2:
      • Because receptor status can discordantly change between primary and recurrence
• Surgical excision to negative margins + comprehensive chest wall / nodal RT — confirmed:
  • For an isolated chest wall recurrence after mastectomy, NCCN (BINV-19) recommends:
    • Consider appropriate systemic therapy to best response if indicated, then surgical resection if feasible + consider surgical axillary staging + post-mastectomy RT (radiation-naïve patients), or repeat RT if feasible and indicated in previously irradiated patients
  • Corroborating data:
    • The DEGRO guideline calls:
      • Complete (R0) resection followed by chest wall RT with strongly advised regional nodal irradiation the standard, using 50 to 50.4 Gy ± 10 Gy boost
  • A retrospective series of isolated chest wall recurrences found chest wall plus RNI significantly improved progression-free and overall survival versus chest wall RT alone:
    • Supporting comprehensive nodal coverage
• Multidisciplinary management — confirmed:
  • NCCN explicitly emphasizes that a multidisciplinary approach is especially important in recurrence to consider all treatment options
  • Involvement of a plastic / reconstructive surgeon is appropriate when full-thickness chest wall resection and reconstruction are needed
• CALOR trial — confirmed, with updated final numbers:
  • The final analysis (median 9-year follow-up, 162 patients):
    • Confirmed a significant chemotherapy benefit for ER-negative isolated locoregional recurrence (DFS HR 0.29, 95% CI 0.13–0.67; 10-year DFS 70% vs 34%) but no benefit for ER-positive recurrence (HR 1.07, 95% CI 0.57–2.00; 10-year DFS 50% vs 59%; P-interaction = 0.013)
    • The overall survival interaction was not significant (P = 0.53)
    • This refined the earlier 2014 Lancet Oncology report:
      • Which had shown an overall DFS benefit (HR 0.59) driven by the ER-negative subgroup
• Systemic therapy:
  • Is tailored to receptor status of the recurrence, not just chemotherapy
  • All hormone receptor-positive recurrences:
    • Should receive endocrine therapy:
      • Which is standard of care and improves disease-free survival:
        • SAKK 23/82 established tamoxifen’s role
    • HER2-positive recurrences:
      • Should receive HER2-targeted therapy
      • Chemotherapy is the component that CALOR showed benefits specifically ER-negative disease:
        • Emerging data qualify the “no chemo for ER-positive” message
  • A 2025 multi-institutional retrospective cohort of 958 patients with HR-positive / HER2-negative locoregional recurrence:
    • Found adjuvant chemotherapy associated with better invasive DFS (HR 0.70), particularly for non-IBTR recurrences and recurrences during adjuvant endocrine therapy:
      • Though with a worse trend in overall survival and the caveats of retrospective design
  • Genomic assays (e.g., Oncotype DX) are being explored to identify HR-positive patients who can safely omit chemotherapy
  • The POLAR trial is evaluating palbociclib in HR-positive recurrences
  • These do not overturn CALOR but reflect evolving practice
• Reirradiation is now a more established option for previously irradiated patients:
  • Modern techniques (IMRT, proton therapy, brachytherapy, hyperthermia, ± radiosensitizers):
    • Achieve local control of ~ 60% to 75% with acceptable toxicity, with the decision factoring in prior dose, interval since prior RT, and cumulative normal-tissue toxicity
• NCCN cautions the same:
  • Truly unresectable or widespread systemic disease shifts management to palliative systemic therapy per the metastatic algorithms (BINV-21 onward) rather than curative local therapy
• References:
  • NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, Version 6.2026

What Are Thyroid Nodules?

Thyroid nodules are very common in the general population.

🔹 With modern high-resolution ultrasound, thyroid nodules are detected in up to 50–60% of adults

🔹 More than 90% are benign

🔹 Most people have no symptoms and feel completely well

👉 The key is not panic — it’s proper evaluation.

🔍 How should thyroid nodules be evaluated?

The most important first step is a high-resolution thyroid ultrasound, which allows us to:

Accurately measure and characterize nodules Assess features associated with cancer risk Use validated risk-stratification systems (ATA / TI-RADS) Decide whether a biopsy is actually necessary

🧪 A key fact for patients

Only 5–10% of thyroid nodules are cancer.

When thyroid cancer is detected early, cure rates are excellent.

👨‍⚕️ Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📌 Take-home message:

Having a thyroid nodule is common.

Having it evaluated correctly by an experienced team makes all the difference.

📚 References

Haugen BR et al. ATA Guidelines for Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid Durante C et al. Long-term surveillance of benign thyroid nodules. JAMA Gharib H et al. Fine-needle aspiration biopsy of thyroid nodules. Endocrine Practice

The modern evidence suggests that active surveillance (AS) is appropriate for carefully selected patients with low-volume, stable recurrent differentiated thyroid cancer (DTC), but progressive or biologically aggressive recurrence generally warrants intervention rather than continued observation.

The 2025 American Thyroid Association guidelines continue to support selective AS, but emphasize that documented progression is a major trigger for treatment escalation.  

What the 2025 ATA Guidelines Say

The new 2025 ATA DTC guidelines acknowledge that:

“Low-volume recurrent nodal disease can be indolent and approached through active surveillance.”  

However, the same guidelines also state that:

Some patients under AS should proceed to surgery “if there is concern for disease progression.”  

The ATA framework therefore supports:

Appropriate Candidates for Active Surveillance

• Small-volume nodal recurrence
• Stable lesions over time
• Slow thyroglobulin kinetics
• No invasion of critical structures
• High-risk reoperative field
• Elderly/comorbid patients
• Patient preference

Poor Candidates for Active Surveillance

• Progressive enlargement
• FDG-PET avid disease
• Aggressive histology
• Bulky nodal disease
• Extrathyroidal extension
• Radioiodine-refractory disease
• Threatened RLN/trachea/esophagus/carotid
• Rapid thyroglobulin doubling time

Evidence Supporting Active Surveillance

Memorial Sloan Kettering Cancer Center Experience

The strongest AS data comes from Memorial Sloan Kettering Cancer Center and the group led by Michael Tuttle.

Observational studies demonstrated that many small-volume recurrent lymph nodes:

• remain stable for years,
• enlarge very slowly,
• and never become clinically significant.

These data support avoiding unnecessary reoperative surgery in selected patients.  

The Major Argument Against Active Surveillance

The major concern is that:

Progression May Represent Aggressive Biology

Once recurrent disease demonstrates:

• serial growth,
• shortening Tg doubling time,
• PET avidity,
• extranodal extension,
• or invasion,

continued surveillance becomes harder to justify.

Progressive recurrence may lead to:

• loss of surgical planes,
• recurrent laryngeal nerve invasion,
• tracheal/esophageal invasion,
• carotid encasement,
• and loss of curative opportunity.

This is especially relevant in younger patients with long life expectancy.

Important ATA Size Thresholds

The ATA historically suggested observation may be reasonable for:

• Central compartment nodes ≤8 mm
• Lateral neck nodes ≤10 mm

provided they are stable and away from critical structures.  

But the key principle is:

Stability

Not merely size alone.

Progressive Disease Usually Pushes Toward Treatment

Most experienced thyroid cancer centers favor intervention when there is:

• Structural progression
• Multiple enlarging nodes
• Tg doubling time <1–3 years
• FDG avidity
• Aggressive molecular profile (TERT/BRAF)
• Threatened aerodigestive structures
• Symptomatic disease
• Bulky lateral neck recurrence

Modern Treatment Options Besides Surgery

When AS is no longer appropriate, management may include:

• Reoperative neck dissection
• Radiofrequency ablation (RFA)
• Ethanol ablation
• Radioactive iodine (if iodine avid)
• External beam radiation
• Systemic therapy (TKIs, targeted therapy)

depending on biology and extent of disease.

Important References

ATA Guidelines

American Thyroid Association

Ringel MD et al.
2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer.
Thyroid. 2025;35(8):841-985.  

Active Surveillance vs Surgery Review

Tufano RP, Clayman G, et al.
Management of Recurrent/Persistent Nodal Disease in Patients with Differentiated Thyroid Cancer: A Critical Review of the Risks and Benefits of Surgical Intervention Versus Active Surveillance.
Thyroid. 2015;25(1):15-27.  

ATA 2025 Summary Statements

“Low-volume recurrent nodal disease can be indolent and approached through active surveillance.”  

“Patients under active surveillance may require surgery if there is concern for disease progression.”  

Bottom Line

Active surveillance is:

✔ Evidence-based
✔ Accepted by ATA guidelines
✔ Appropriate for selected stable low-volume recurrences

Active surveillance becomes difficult to defend when disease is:

✘ Progressive
✘ FDG avid
✘ Biologically aggressive
✘ Threatening critical structures
✘ Rapidly enlarging

In progressive recurrent thyroid cancer, many experts would argue that progression itself is evidence that surveillance is failing.

• Epidemiology:
  • The tall cell subtype of papillary thyroid carcinoma (PTC-TC):
    • Accounts for approximately 3% to 5% of all PTCs
      • Its incidence has been rising:
        • Partly due to evolving diagnostic criteria
  • The WHO 5th edition (2022) defines PTC-TC as:
    • PTC with ≥ 30% tall cells:
      • Height-to-width ratio ≥ 3:1
  • Patients tend to be older:
    • Mean ~ 50 years vs. 42 for classic PTC
  • PTC-TC have higher rates of:
    • Extrathyroidal extension (~ 60%)
    • Vascular invasion (~ 15%)
    • Lymph node metastasis
    • Advanced stage at presentation
  • Recurrence rates range from:
    • 27% to 42% compared to 16% to 31% for classic PTC
  • 5-year disease-specific survival of:
    • Approximately 82% vs. 98% for all PTC
  • An important recent distinction is:
    • Between PTC-TC (without high-grade features) and high-grade differentiated thyroid carcinoma with tall cell phenotype (HGDTC-TC):
      • Defined by ≥ 5 mitoses / 2 mm² and / or tumor necrosis
        • When HGDTC-TC is excluded PTC-TC has a more indolent course (10-year disease-specific survival ~99%)
• Genetics and Molecular Features:
  • BRAF V600E mutation:
    • Present in ~ 80% to 90% of cases:
      • Drives MAPK pathway activation and suppresses sodium-iodide symporter expression:
        • Contributing to RAI refractoriness
  • TERT promoter mutations:
    • Independent predictor of recurrence:
      • More frequent in PTC-TC
  • BRAF V600E + TERT co-mutation:
    • Identifies a subset with particularly poor outcomes
• Surgical Management:
  • Type of Thyroidectomy:
    • Standard indications for total thyroidectomy apply:
      • Distant metastases
      • Extrathyroidal extension
      • Lateral or gross central neck node metastases
      • Tumor > 4 cm
      • Bilateral disease
    • For tumors 1 cm to 4 cm without these features:
      • Either total thyroidectomy or lobectomy may be considered
  • Key evidence:
    • A 2026 SEER analysis of 1,463 PTC-TC patients showed total thyroidectomy had superior cancer-specific survival vs. lobectomy:
      • 5-year CSS 97.8% vs. 90.7%, p = 0.019, independent of RAI
    • A Memorial Sloan Kettering study of T1 / T2 N0 PTC-TC:
      • Found no difference in outcomes with lobectomy alone, with 100% disease-specific survival in both groups
  • Summary:
    • For small (T1 / T2), node-negative PTC-TC without high-grade features:
      • Lobectomy may be adequate
    • Larger or higher-stage tumors:
      • Should undergo total thyroidectomy
• Central Compartment Neck Dissection:
  • Therapeutic central neck dissection:
    • Recommended for clinically involved nodes (cN1a)
  • Prophylactic central neck dissection:
    • Not routinely indicated per NCCN
  • Thorough preoperative ultrasound of central and lateral compartments is essential:
    • With FNA of suspicious lateral nodes
• Radioactive Iodine (RAI):
  • NCCN classifies tall cell histology as a “high-risk subtype”:
    • For which RAI is selectively recommended based on the combination of clinical factors
  • PTC-TC is classified in the ATA intermediate risk category
  • Key considerations:
    • BRAF V600E-driven PTC-TC downregulates the sodium-iodide symporter:
      • Making these tumors frequently RAI-refractory
    • For tumors > 2 cm:
      • RAI after total thyroidectomy improved overall survival:
        • 83.4% vs. 70.0%
    • For tumors ≤ 2 cm:
      • No survival benefit from RAI was demonstrated
    • A SEER-based propensity-matched study:
      • Found no significant CSS benefit from RAI in PTC-TC overall:
        • HR 0.54, 95% CI 0.25–1.17
    • Repeated RAI should be limited to patients demonstrating continued therapeutic response
• Follow-Up:
  • After total thyroidectomy with RAI, recommended surveillance includes:
    • Physical examination, TSH, thyroglobulin (Tg), and anti-thyroglobulin antibodies (TgAb)
    • Neck ultrasound at 6 to 12 months, then every 1 to 3 years for 5 to 8 years, then discontinue
  • Rising Tg or new TgAb:
    • Should prompt additional imaging:
      • Neck CT / MRI, chest / abdomen CT, FDG-PET, or RAI imaging
  • TSH suppression with levothyroxine:
    • Per risk stratification
  • For patients with no evidence of disease (NED) at low risk after 10 to 15 years:
    • No further thyroid cancer monitoring is indicated
• RAI-Refractory Disease:
  • For RAI-refractory progressive disease:
    • Molecular analysis for actionable alterations should be pursued:
      • BRAF V600E → dabrafenib / trametinib or vemurafenib / cobimetinib
      • RET fusions → selpercatinib or pralsetinib
      • NTRK fusions → larotrectinib or entrectinib
      • ALK fusions → targeted therapy
• References:
  • Shi X, Liu R, Basolo F, et al. Differential Clinicopathological Risk and Prognosis of Major Papillary Thyroid Cancer Variants. J Clin Endocrinol Metab. 2016.
  • Wu SS, Joshi N, Sharrett J, et al. Risk Factors Associated With Recurrence and Death in Patients With Tall Cell Papillary Thyroid Cancer. JAMA Otolaryngol Head Neck Surg. 2023.
  • Holoubek SA, MacKinney EC, Khokar AM, et al. Radioactive Iodine Does Not Improve Overall Survival for Patients With Aggressive Variants of Papillary Thyroid Carcinoma Less Than 2 Cm. Surgery. 2022.
  • Jin X, Koga S, Zhou X, Khan NZ, Baloch ZW. Clinicopathologic Characteristics of Papillary Thyroid Carcinoma, Tall Cell Subtype and Subtype With Tall Cell Features, an Institutional Experience. Hum Pathol. 2025.
  • Parvathareddy SK, Siraj AK, Qadri Z, et al. Tall Cell Variant Histology Predicts Poorer Disease-Free Survival in Papillary Thyroid Carcinoma: A Propensity-Matched Cohort Study. World J Surg. 2025.
  • Ghossein R, Katabi N, Dogan S, et al. Papillary Thyroid Carcinoma Tall Cell Subtype (PTC-TC)
    
    
    

• WHO Classification:
  • Keratinizing Squamous Cell Carcinoma (formerly WHO Type I):
    • Shows squamous differentiation with intercellular bridges and / or keratinization over most of its extent
    • More common in non-endemic areas:
      • Accounts for > 75% of NPC in the non-Asian US population (Caucasian)
    • Typically found in older adults:
      • Associated with smoking / alcohol
    • Carries the worst prognosis among the subtypes
    • Not typically associated with EBV:
      • HPV has emerged as a potential factor in this subtype
  • Non-Keratinizing Carcinoma (formerly WHO Types II and III):
    • The dominant subtype worldwide:
      • Constituting > 95% of cases in endemic regions:
        • Southern China
        • Southeast Asia
    • Strongly associated with:
      • EBV infection
    • More radiosensitive than the keratinizing subtype
    • Subdivided into:
      • Differentiated (formerly WHO Type II):
        • Cells show a maturation sequence without evident squamous differentiation on light microscopy
        • Fusiform or oval nuclei with scant cytoplasm
        • Display a stratified appearance and distinct cell margins
      • Undifferentiated (formerly WHO Type III):
        • Oval or round vesicular nuclei with prominent nucleoli, scant eosinophilic cytoplasma
        • Indistinct cell margins with a syncytial rather than pavemented appearance
        • Often called lymphoepithelioma (Schminke tumor) due to prominent admixed non-malignant lymphoid infiltrate
        • Most common subtype in endemic areas (~ 95% in southern China) and in children (~ 90%)
  • Basaloid Squamous Cell Carcinoma (added in 2005 WHO classification):
    • A rare subtype:
      • Also associated with EBV infection
    • Comprises a minimal subset of patients
• Evolution of the Classification:
  • The original 1978 WHO system:
    • Used a numerical scheme:
      • Types I, II, III
  • In 1991:
    • Types II and III were combined into a single “non-keratinizing carcinoma” category:
      • The numerical designations were dropped
  • The basaloid squamous cell carcinoma category:
    • Was added in the 2005 WHO classification
• Geographic Distribution of Subtypes:
  • North America:
    • ~25% type I, 12% type II, 63% type III
  • Southern China:
    • 2% type I, 3% type II, 95% type III
  • In the US:
    • Non-keratinizing subtypes:
      • Predominate in East / Southeast Asian populations
    • The discrepancy is explained by the racial /ethnic composition of the study populations:
      • In the US, disproportionately develop non-keratinizing (type III) NPC:
        • Which skews the overall North American numbers toward type III
      • When restricted to White / non-Asian patients, keratinizing SCC predominates
• References:
  • Chen YP, Chan ATC, Le QT, et al. Nasopharyngeal Carcinoma. Lancet. 2019.
  • KO, Mazul AL, Skillington SA, et al. The prognostic significance of race in nasopharyngeal carcinoma by histological subtype. Head Neck. 2021.
  • Alsavaf MB, Marquardt M, Abouammo MD, et al. Patient Characteristics and Treatment Outcomes of Nasopharyngeal Carcinoma in Nonendemic Regions. JAMA Netw Open. 2025.
  • Wei WI, Sham JS. Nasopharyngeal Carcinoma. Lancet. 2005.
  • Ayan I, Kaytan E, Ayan N.
    
    

• Overview:
  • The nasopharynx is the uppermost part of the pharynx:
    • A cuboidal muscular-mucosal space behind the nasal cavity and above the soft palate, anterior to the atlas (C1) and axis (C2)
  • It functions purely as a respiratory conduit:
    • Communicating anteriorly with the nasal cavity via the choanae and laterally with the middle ear via the Eustachian (pharyngotympanic) tubes
• Boundaries (walls)
  • Anterior:
    • Paired choanae (posterior nasal openings)
    • Bony margin bounded:
      • Anteroinferiorly by the horizontal plate of the palatine bone
      • Superiorly by the sphenoid body and vaginal process of the medial pterygoid plate
      • Laterally by the medial pterygoid plates
  • Roof and posterior wall:
    • Continuous, sloping surface formed by the sphenoid body and basilar (clival) occipital bone superiorly, continuing over the anterior arches of C1 and C2:
      • Mucosa adherent to the pharyngobasilar fascia
  • Lateral walls:
    • Organized around the Eustachian tube orifice
  • Floor / inferior boundary:
    • Open inferiorly, communicating with the oropharynx via the pharyngeal isthmus:
      • Upper surface of the soft palate forms the effective floor, and the isthmus closes during swallowing to prevent nasal reflux:
        • The nasopharyngeal cavity opens into the cavity of the oropharynx through the pharyngeal isthmus, which lies between the posterior border of the soft palate and the posterior pharyngeal wall:
          • This region is marked on the posterior pharyngeal wall by a fold of mucosa formed by the palatopharyngeal sphincter between the palatopharyngeus muscle and the superior pharyngeal constrictor muscle:
            • During swallowing, elevation of the soft palate and constriction of the palatopharyngeal sphincter seals off the pharyngeal isthmus, separating the nasopharynx from the oropharynx:
              • This prevents the retrograde flow of materials into the nasopharynx and nasal cavity
• Lateral wall structures:
  • Torus tubarius:
    • Prominent posterior lip of the tubal orifice:
      • Elevated by tubal cartilage
  • Salpingopalatine fold:
    • Anterior lip of the orifice
  • Torus levatorius:
    • Inferior elevation overlying the levator veli palatini
  • Salpingopharyngeal fold:
    • Mucosal fold below the torus tubarius overlying salpingopharyngeus
  • Fossa of Rosenmüller (pharyngeal recess):
    • Deep lateral mucosal depression behind the torus tubarius:
      • Its apex points toward the internal carotid artery:
        • With the foramen lacerum above:
          • Most common site of origin of nasopharyngeal carcinoma and a key surgical landmark
• Musculature:
  • Tensor veli palatini:
    • Opens the Eustachian during swallowing.
  • Levator veli palatini:
    • Elevates the soft palate:
      • Forms the torus levatorius
  • Salpingopharyngeus:
    • Runs in the salpingopharyngeal fold:
      • Mucosal fold below the torus tubarius
  • Superior constrictor:
    • Forms the muscular posterolateral wall
  • Pharyngobasilar fascia:
    • Suspends the pharynx from the skull base.
• Lymphoid tissue
  • Prominent components of Waldeyer’s ring:
    • Nasopharynx-associated lymphoid tissue
  • The nasopharyngeal tonsil (adenoids):
    • Lies on the roof / posterior wall:
      • Is prominent in children and atrophies with age:
        • Hypertrophy can obstruct nasal breathing or the Eustachian tube orifice
  • Tubal tonsils sit near the tubal orifices
• Epithelium
  • Largely respiratory (ciliated pseudostratified columnar) epithelium:
    • With areas of stratified squamous epithelium at contact / friction sites
• Neurovascular and clinical relations
  • Sensory innervation:
    • Trigeminal (V2, pharyngeal branch) and glossopharyngeal nerves
  • Deep lateral-wall structures:
    • Parapharyngeal internal carotid artery (lateral to the fossa of Rosenmüller)
    • Foramen lacerum and clivus posteriorly
    • Foramen ovale (V3) and pterygopalatine fossa contents (vidian nerve, sphenopalatine ganglion
    • V2 laterally / anteriorly:
      • These explain pathways of local spread and perineural invasion in nasopharyngeal carcinoma
• References
  • Endoscopic endonasal transpterygoid nasopharyngectomy: Anatomical considerations and technical note. Liu J, Zhao J, Wang Y, et al. Head & Neck. 2024;46(2):306-320. doi:10.1002/hed.27581.
  • Anatomy and assessment of the pediatric airway. Adewale L. Paediatric Anaesthesia. 2009;19 Suppl 1:1-8. doi:10.1111/j.1460-9592.2009.03012.x.

• RTOG-0129:
  • Was a phase 3 randomized trial (enrolled 2002 to 2005) conducted by the Radiation Therapy Oncology Group:
    • That tested whether accelerated-fractionation radiotherapy improves outcomes over standard-fractionation radiotherapy:
      • When each is given concurrently with cisplatin in locally advanced (stage III to IV) head and neck squamous-cell carcinoma
  • Its primary comparison was negative :
    • The two radiotherapy schedules produced equivalent survival:
    • But its retrospective HPV analysis became a landmark:
      • Establishing tumor HPV status as a strong independent prognostic factor in oropharyngeal cancer
• Design:
  • Population:
    • Patients with locally advanced (stage III to IV) squamous-cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx:
      • 743 randomized:
        • 738 analyzed
  • Standard-fractionation arm:
    • 70 Gy in 2 Gy fractions once daily, 5 days / week over 7 weeks (35 fractions), with cisplatin 100 mg/m² on days 1, 22, and 43 (3 cycles)
  • Accelerated-fractionation arm (concomitant boost):
    • 72 Gy over 6 weeks — 1.8 Gy / fraction to the large field, plus a second daily 1.5 Gy boost fraction during the last 12 treatment days — with cisplatin 100 mg/m² on days 1 and 22 (2 cycles)
  • Technique:
    • IMRT was not permitted:
      • Treatment used 2D / 3D conformal radiotherapy
  • Median follow-up was 4.8 years in the original report, with long-term follow-up of 7.9 years in later analyses
• Primary result (fractionation):
  • There was no significant difference between arms
  • The 3-year overall survival was 70.3% with accelerated fractionation versus 64.3% with standard fractionation (P=0.18; HR for death 0.90, 95% CI 0.72–1.13), and rates of high-grade acute and late toxicity were similar
  • This supported the conclusion that accelerated fractionation offers no efficacy advantage over conventional fractionation when combined with concurrent cisplatin
• Landmark HPV finding:
  • Among patients with oropharyngeal cancer, 63.8% (206/323) had HPV-positive tumors
  • These patients were younger, more often white, had fewer pack-years, and smaller primaries:
    • 3-year overall survival:
      • 82.4% (HPV-positive) vs 57.1% (HPV-negative); P<0.001
      • After adjustment for age, race, tumor / nodal stage, tobacco, and treatment:
        • HPV-positive status conferred a 58% reduction in risk of death (HR 0.42, 95% CI 0.27–0.66)
      • The 8-year overall survival rate was 70.9% vs 30.2% (HR 0.30, 95% CI 0.21–0.42)
• References:
  • Ang KK, Harris J, Wheeler R, et al. Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. N Engl J Med. 2010.
  • Ang KK, Harris J, Wheeler R, et al. Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. N Engl J Med. 2010.
  • Lacas B, Bourhis J, Overgaard J, et al. Role of Radiotherapy Fractionation in Head and Neck Cancers (MARCH): An Updated Meta-Analysis. Lancet Oncol. 2017.
  • De Felice F, Bonomo P, Sanguineti G, Orlandi E. Moderately accelerated intensity-modulated radiation therapy using simultaneous integrated boost: Practical reasons or evidence-based choice? A critical appraisal of literature. Head Neck. 2020.
  • Driessen CM, Janssens GO, van der Graaf WT, et al. Toxicity and efficacy of accelerated radiotherapy with concurrent weekly cisplatin for locally advanced head and neck carcinoma. Head Neck. 2016.
  • National Comprehensive Cancer Network. Head and Neck Cancers. 2026.
    Chow LQM. Head and Neck Cancer. N Engl J Med. 2020.
  • Budach V, Tinhofer I. Novel Prognostic Clinical Factors and Biomarkers for Outcome Prediction in Head and Neck Cancer: A Systematic Review. Lancet Oncol. 2019.