Blog

• Design:
  • Phase III, 891 analyzable patients with stage III to IV HNSCC randomized to:
    • Accelerated RT + cisplatin (100 mg / m² D1 and D22) with or without cetuximab (400 mg / m² load then 250 mg / m² weekly)
  • Primary endpoint: 
    • PFS
      • The Cancer Imaging Archive (TCIA)+1
• Result (no efficacy gain, more acute toxicity):
  • 3-yr PFS: 
    • 61.2% (CRT) vs 58.9% (CRT + cetuximab), P = 0.76
  • 3-yr OS: 
    • 72.9% vs 75.8%, P = 0.32
  • LRC:
    • No difference
  • DM:
    • No difference
  • Treatment delivery: 
    • Similar cisplatin given (mean 191.1 vs 185.7 mg / m²):
      • But more RT interruptions with cetuximab (26.9% vs 15.1%). PubMed
  • Toxicity signal:
    • Higher grade 3 to 4 mucositis (33% vs 43%), skin reactions (in- and out-of-field), fatigue, anorexia, and hypokalemia with the triplet
    • Late grade ≥ 3 toxicity not increased PubMed+1
• Biomarkers / subgroups:
  • p16+ OPSCC had better outcomes overall:
    • But no benefit from adding cetuximab (no predictive effect)
  • EGFR expression:
    • Did not distinguish outcomes:
      • An age interaction noted in exploratory analysis is not practice-changing PubMed
• Exam / clinic pearl:
  • Do not “stack” an EGFR inhibitor onto standard cisplatin – CRT:
    • No improvement in OS / PFS / LRC and more acute toxicity
  • If a patient is cisplatin-ineligible:
    • Switch the partner (e.g., RT+cetuximab):
      • But don’t add cetuximab to cisplatin PubMed
• References:
  • Ang KK, et al. JCO 2014 (RTOG 0522) — primary results. PubMed
  • Caudell JJ, et al. 2022/2023 long-term update — confirms lack of benefit. PMC+1
  • ASCO Post 2014 — toxicity details summary. ascopost.com
  • RTOG 0522 protocol — regimen specifics. The Cancer Imaging Archive (TCIA)+1
• Bottom line: 
  • Adding cetuximab to cisplatin – CRT:
    • Does not help and harms tolerability:
      • Reserve cetuximab as an alternative when cisplatin cannot be given

• Where we are now (2025):
  • In carefully selected cT1 to cT2, cN0 patients with negative pre-op axillary US:
    • Omitting SLNB is non-inferior to SLNB for disease endpoints and reduces arm morbidity:
      • SOUND Trial , INSEMA Trial; endorsed in ASCO 2025
  • If SLN is positive (≤ 2 nodes) after lumpectomy + WBRT:
    • Omit ALND (ACSOG Z0011, 10-yr)
  • For micrometastases:
    • IBCSG 23-01 supports no ALND
  • AMAROS:
    • Axillary RT ≈ ALND for control with less lymphedema
  • Post-NAC cN1→cN0:
    • SLNB / TAD feasible if you remove the clipped node, use dual tracers, and retrieve ≥2–3 SLNs:
      • Lower FNR:
        • ACSOG Z1071 / SENTINA / SN-FNAC
  • Persistent cN+ → ALND
  • Radiation interfaces (2025 ASTRO-ASCO-SSO PMRT update) – Clarify when RNI / PMRT substitutes for completion ALND after positive SLN, and after NAC:
    • What de-escalation buys you:
      • Meaningfully less lymphedema and arm morbidity:
        • AMAROS 5-year lymphedema: 23% ALND vs 11% axillary RT; SLNB is lower still; omission (SOUND / INSEMA) lowest
        • INSEMA: omission vs SLNB—lower arm symptoms; 5-yr iDFS 91.9% vs 91.7% (HR 0.91; NI met). 
• Trial data:
  • Upfront surgery, cN0:
    • SOUND (JAMA Oncol 2023) – negative axillary US, tumor ≤ 2 cm
      • Design: SLNB vs no axillary surgery
      • Outcome: Non-inferior 5-yr distant DFS
      • Omission safe when nodal information won’t alter plan
      • Multinational, 18 centers (Italy / Spain / Switzerland / Chile)
    • INSEMA (NEJM 2025) – mostly BCS, cT1 to 2 cN0
      • Primary: 5-yr iDFS non-inferiority met (No axillary surgery 91.9% vs SLNB 91.7%; HR 0.91 [0.73–1.14])
      • OS ~ 98% vs 97%
      • Less arm morbidity if omitted
  • ASCO 2025 SLNB guideline update:
    • Allows omission of routine SLNB in selected stage I to II patients: ≥ 50 y, HR+ / HER2−, ≤ 2 cm, G1 to G2, negative axillary imaging, BCS + adjuvant therapy, and when nodal status won’t change systemic / RT
      • Shared decision-making emphasized
    • Limited SLN positivity (upfront):
      • ACSOG Z0011 (10-yr) – lumpectomy + WBRT, 1 to 2 positive SLN
        • 10-yr OS: 86.3% SLNB-alone vs 83.6% ALND
        • Regional failures < 1%
        • ALND not routine recommended 
      • IBCSG 23-01 (10-yr) – SLN micromets ≤ 2 mm:
        • No difference DFS; non-inferior to omit ALND
        • Axillary recurrences ~ 1.7% without cALND at 10 yrs
      • AMAROS – SLN+ randomized to ALND vs axillary RT:
        • Comparable control
        • Less lymphedema with RT (≈ 11% vs 23% at 5 yrs)
        • Consider RT instead of ALND
      • Neoadjuvant setting:
        • Z1071 / SENTINA / SN-FNAC – initially cN1→NAC→ycN0
        • FNR reduced by: clip + retrieve positive node (TAD), dual tracer, and retrieving ≥ 2 to 3 SLNs
        • If still cN+, ALND remains standard.
      • Radiation guidance (2025)
        • ASTRO-ASCO-SSO PMRT update (2025)
          Clarifies PMRT / RNI after upfront surgery and after NAC
        • Indicates when axillary RT is reasonable alternative to ALND in select SLN+ scenarios
        • Encourages moderate hypofractionation, details target volumes/boost
  • Practical algorithms (evidence-based):
    • Upfront cN0 (exam + negative axillary US):
      • Meets ASCO 2025 “omission” profile (≥ 50, HR+ / HER2−, ≤ 2 cm, G1 to G2) and BCS planned → Discuss omitting SLNB (SOUND Trial /INSEMA Trial) 
      • Not low-risk or mastectomy planned → SLNB (can later omit ALND depending on path)
    • SLNB results (upfront surgery):
      • 0 nodes+ → No further axillary surgery
      • 1 to 2 nodes+, lumpectomy + WBRT → Omit ALND (Z0011) or Axillary RT (AMAROS) if nodal coverage desired
      • Micromets (≤ 2 mm) → No ALND (IBCSG 23-01)
      • > 2 nodes+, gross ENE, no RT planned /possible, inflammatory BC, or T3 / T4 → ALND (plus consider RNI / PMRT)
    • NAC pathway:
      • Biopsy-proven cN1 → Clip positive node pre-NAC:
        • ycN0 after NAC → TAD (SLNB + clipped node removal) using dual tracer, aim ≥ 2 to 3 SLNs
        • If any positive or clip not retrieved, strong consideration for ALND (or RNI per MDT)
      • ycN+ → ALND (then RNI per PMRT guideline)
  • Numbers and pearls slide:
    • INSEMA:
      • 5-yearr iDFS 91.9% (omit) vs 91.7% (SLNB); HR 0.91 (NI met)
      • Lower arm morbidity with omission
    • SOUND:
      • Negative US + small tumors → no axillary surgery non-inferior to SLNB for distant DFS at 5 yrs
    • Z0011 (10-yr):
      • OS 86.3% SLNB-alone vs 83.6% ALND; regional recurrence < 1%
    • IBCSG 23-01 (10-yr):
      • Micromets – no ALND
      • Axillary recurrence ≈ 1.7% without cALND
    • AMAROS:
      • Lymphedema 23% ALND vs 11% axillary RT (5 yrs)
      • Similar control
    • Post-NAC accuracy:
      • TAD + dual tracer + ≥ 2 to 3 SLNs lowers FNR (vs SLNB alone)
    • ASTRO-ASCO-SSO 2025 PMRT:
      • When SLN+ and no ALND, RNI/PMRT often appropriate; specifics by burden / response 
• Review Questions:
• Can I omit SLNB in a 62-year-old, HR+ / HER2−, 1.3 cm IDC, negative axillary US, BCS?
  • Yes, option to omit per ASCO 2025 (criteria met) informed by SOUND and INSEMA; confirm that nodal information won’t change systemic / RT plan
• What if the same patient is having a mastectomy
  • Generally perform SLNB (you lose SLNB opportunity later; pathology could upstage; influences RNI / PMRT)
• Patient with 2 SLN+ undergoing lumpectomy – ALND or RT?
  • No routine ALND (Z0011)
  • Consider axillary RT (AMAROS) if you want nodal coverage with less lymphedema than ALND
• Post-NAC cN1→ycN0 – how do I minimize FNR?
  • Do TAD: clip and retrieve the index node, dual tracers, retrieve ≥ 2 to 3 SLNs
  • If clip not found or any positive nodes → ALND (or RNI per MDT)
• Which patients still truly need ALND today
  • Inflammatory BC
  • Persistent cN+ after NAC
  • > 2 SLN+ upfront
  • Gross ENE
  • When WBRT / RNI not feasible but regional control is required
• How do the new PMRT guidelines affect axillary surgery choices?
  • 2025 ASTRO-ASCO-SSO:
    • Clearer indications for RNI / PMRT after upfront surgery and after NAC
    • Can replace ALND in select SLN+ cases – coordinate with radiation oncology
      
      
      
      
       
       

• Rule of Thumb:
  • Avoid cisplatin in patients with grade ≥ 2 baseline hearing loss 
• Cisplatin:
  • Is ototoxic and can cause irreversible worsening of SNHL:
    • Risk is cumulative and dose-dependent
• Alternatives:
  • Cetuximab + Radiotherapy (RT):
    • NCCN-endorsed option for cisplatin-ineligible patients
    • Inferior to cisplatin in HPV-positive disease:
      • RTOG-1016, De-ESCALaTE trials:
        • But appropriate when platinum is contraindicated
• Carboplatin-based chemoradiation:
  • Some centers use carboplatin (AUC 1 to 2 weekly) ± 5-FU or paclitaxel with RT:
    • Evidence less robust than cisplatin:
      • But can be considered when cetuximab is unsuitable
• Practice Pearls:
  • Baseline audiogram required in all patients before starting cisplatin or alternatives
  • Avoid concurrent ototoxic drugs:
    • Loop diuretics, aminoglycosides, high-dose salicylates
  • Monitor hearing during therapy if any platinum agent is considered
• References:
  • NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers, Version 2025.
  • Ahn MJ, D’Cruz A, Vermorken JB, et al. Eligibility criteria for cisplatin in head and neck cancer: consensus recommendations. Lancet Oncol. 2016;17(8):e447–e456.
  • Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in HPV-positive oropharyngeal cancer (RTOG-1016). Lancet. 2019;393:40–50.
  • Mehanna H, et al. Radiotherapy plus cisplatin or cetuximab in low-risk HPV-positive oropharyngeal cancer (De-ESCALaTE). Lancet. 2019;393:51–60.

• When to omit SLNB (new, practice-changing):
  • ASCO now recommends not performing routine SLNB in a clearly defined low-risk subgroup if omitting nodal pathology will not change adjuvant plans:
    • Postmenopausal:
      • ≥ 50 years
    • HR-positive / HER2-negative
    • Grade 1 to 2
    • Tumor ≤ 2 cm (cT1)
    • Pre-op axillary ultrasound negative
    • Breast-conserving therapy planned
    • Team agrees systemic therapy and RT will not be altered by SLNB findings:
  • Recommendation built on SOUND and INSEMA randomized trials:
    • Observed outcomes in the RCTs:
      • Omission was non-inferior to SLNB for iDFS / distant DFS
      • Regional events were rare
      • Arm morbidity lower without surgery
  • ASCO also emphasizes:
    • Do not escalate or alter adjuvant systemic therapy or radiation just because SLNB was omitted:
      • Plan treatments as you would for this low-risk profile
• When SLNB is still appropriate:
  • Outside the narrow “omit” criteria above:
    • >2 cm
    • High-grade
    • TNBC
    • HER2+
    • Multifocality affecting RT fields
    • No reliable AUS
    • Planned mastectomy where nodal information might change PMRT
  • After neoadjuvant therapy:
    • Initially cN0 or cN1→cN0:
      • ASCO continues to support SLNB (or targeted axillary dissection when appropriate) to document response:
        • The 2025 update centers on upfront surgery, don’t generalize omission to neoadjuvant settings
• When to omit completion ALND:
  • 1 to 2 positive sentinel nodes after upfront surgery:
    • Continue to omit ALND with whole-breast RT (Z0011 / AMAROS era practice remains)
  • After mastectomy with 1 to 2 positive SNs and delivery of PMRT to chest wall + regional nodes:
    • ASCO supports omitting ALND (supported by SENOMAC data):
      • Coordinate fields with radiation oncology
• Radiation interface (2025 ASTRO / ASCO / SSO PMRT update):
  • Joint 2025 PMRT guideline clarifies when PMRT / regional nodal irradiation is indicated and explicitly supports ALND omission if PMRT is given for 1 to 2 positive SNs post-mastectomy
  • Use multidisciplinary planning to balance coverage / toxicity when nodal pathology is limited or absent
• Practical checklist for your clinic (BCT, upfront surgery):
  • AUS first:
    • If AUS negative and patient fits the low-risk profile above → discuss no SLNB
    • Document that omission won’t change systemic / RT plans
  • If AUS suspicious → needle sample:
    • Positive = manage per current standards:
      • SLNB ± targeted node or ALND / RT depending on context
      • If SLNB done and 1 to 2 SN+ → omit ALND:
        • Ensure appropriate RT fields (BCT) or PMRT (after mastectomy)
  • Neoadjuvant cases:
    • Do not translate “omit SLNB” from SOUND / INSEMA:
      • Use SLNB / TAD pathways
• Pearls and Pitfalls:
  • Selection discipline matters:
    • The non-inferiority signal depends on accurate AUS triage and truly low-risk biology
  • Don’t “compensate” with extra RT or chemotherapy solely because you omitted SLNB:
    • ASCO warns against reflex escalation
  • Documentation:
    • Note eligibility criteria, shared decision discussion, and that omission won’t impact adjuvant choices
    • Monitor the edge cases (young age, lobular histology, multifocality):
      • Trials had limited power there:
        • Consider SLNB if nodal information could change RT / systemic therapy
• Sources / key reads:
  • ASCO Guideline Update (2025) — SLNB in early breast cancer; ASCO Post summary with criteria and implementation notes. 
  • INSEMA (NEJM 2025) — Omission of axillary surgery vs SLNB; non-inferior iDFS, less morbidity. 
  • SOUND (JAMA Oncol 2023) — No axillary surgery vs SLNB in small tumors with negative AUS; non-inferior distant DFS. 
  • PMRT 2025 Joint Guideline (ASTRO/ASCO/SSO) — When to deliver PMRT and how it enables ALND omission with limited SN positivity after mastectomy. 

• General principles and chemoradiation (CRT) (1–10):
  • For unresected, stage III to IVB head and neck squamous cell carcinoma (HNSCC), the preferred concurrent systemic agent with definitive RT is:
    A. Cetuximab
    B. Carboplatin AUC2 weekly
    C. Cisplatin 100 mg/m² q3 weeks
    D. Docetaxel weekly
    E. Nivolumab
  • In concurrent CRT for non-nasopharyngeal HNSCC, which statement is most accurate regarding weekly vs every 3 weeks cisplatin?
    A. Weekly 40 mg/m² is clearly superior for OS
    B. q3-weekly 100 mg/m² has stronger historical level-1 evidence and often better locoregional control (LRC)
    C. Neither schedule reaches a cumulative 200 mg/m²
    D. Weekly is contraindicated post-op
    E. Weekly causes more nephrotoxicity
  • A 64-year-old with cT3 cN2b HPV-negative oropharyngeal SCC (OPSCC), creatinine clearance (CrCl) 42 mL / min, grade-2 neuropathy. Best radiosensitizer?
    A. High-dose cisplatin
    B. Weekly cisplatin
    C. Cetuximab
    D. Pembrolizumab
    E. Docetaxel
  • During CRT with cisplatin, which premedication strategy best reduces acute Chemotherapy-Induced Nausea and Vomiting (CINV) and dehydration risk?
    A. 5-HT3 antagonist alone
    B. NK1 antagonist + 5-HT3 + dexamethasone, plus aggressive IV hydration
    C. Dexamethasone alone
    D. Metoclopramide PRN only
    E. No antiemetics needed with weekly dosing
  • In LA-HNSCC, the MACH-NC meta-analysis primarily supports which approach?
    A. Adjuvant chemo alone after RT
    B. Induction PF improves OS
    C. Concomitant chemoradiation improves OS
    D. Cetuximab + RT equals cisplatin + RT
    E. Immunotherapy + RT improves OS
  • A 58-year-old with severe baseline sensorineural hearing loss (grade 2). Best concurrent agent with curative RT?
    A. Cisplatin
    B. Carboplatin / 5-FU
    C. Cetuximab
    D. Nivolumab
    E. Paclitaxel
  • Regarding cumulative cisplatin dose during definitive CRT, best target for oncologic efficacy:
    A. ≥ 100 mg/m²
    B. ≥ 150 mg/m²
    C. ≥ 200 mg/m²
    D. ≥ 300 mg/m²
    E. No relationship
  • Which trial established cisplatin-based CRT as superior to RT alone for organ preservation in advanced laryngeal cancer?
    A. RTOG 91-11
    B. RTOG 0522
    C. RTOG 9501
    D. De-ESCALaTE HPV
    E. EXTREME
  • For a cisplatin-ineligible patient (CrCl 45 mL / min) with cT4a cN2 oral cavity cancer refusing surgery, most guideline-concordant RT partner:
    A. Cetuximab
    B. Avelumab
    C. Pembrolizumab
    D. Bevacizumab
    E. Single-agent 5-FU
  • Which statement about adding cetuximab to cisplatin-based CRT is correct?
    A. Improves OS and PFS
    B. Improves locoregional control only
    C. Increases toxicity but improves outcomes
    D. No survival benefit vs cisplatin-CRT alone
    E. Non-inferior in HPV+ disease
• Post-operative therapy (11–18):
  • Indication for adjuvant cisplatin-RT after surgery:
    A. pT1 pN1 with clear margins, no ENE
    B. Perineural invasion only
    C. Margin < 1 mm or ENE+
    D. LVSI only
    E. pN1 HPV+ without risk factors
  • In the post-operative high-risk setting, weekly cisplatin 40 mg/m² vs 100 mg/m² q3 weeks:
    A. Weekly proven inferior
    B. Weekly shown non-inferior for OS with less nephro / ototoxicity
    C. Weekly superior for DFS and OS
    D. q3-weekly contraindicated > 70 yrs
    E. Weekly increases febrile neutropenia
  • A 59-year-old with positive deep margin and ENE+. Best adjuvant plan:
    A. RT alone
    B. Cisplatin-RT
    C. Cetuximab-RT
    D. Carboplatin-RT
    E. Observation
  • Post-operative patient develops grade-3 acute kidney injury (AKI) after first cisplatin 100 mg/m². Best modification:
    A. Continue full-dose
    B. Switch to weekly cisplatin
    C. Stop systemic therapy; RT alone
    D. Substitute cetuximab with RT
    E. Reduce to cisplatin 50 mg/m² q3 weeks
  • In post-operative intermediate-risk factors (PNI, LVI, pT3), recommended systemic therapy:
    A. Mandatory cisplatin
    B. Strong evidence for chemo benefit
    C. Consider clinical trial; RT alone standard
    D. Pembrolizumab adjuvant standard
    E. TPEx
  • Absolute cisplatin contraindication:
    A. Age 75 alone
    B. Tinnitus grade 1
    C. ECOG 1
    D. CrCl < 50 mL / min or grade ≥ 2 hearing loss / neuropathy
    E. Controlled hypertension
  • Optimal cisplatin monitoring during CRT includes:
    A. CBC weekly only
    B. CBC, BMP weekly, Mg/K/Ca, audiogram as indicated
    C. End-of-treatment labs only
    D. TSH monthly
    E. No audiograms needed
  • For a smoker with p16-negative OPSCC, gross ENE, and clear margins, adjuvant systemic partner with RT:
    A. Cisplatin
    B. Cetuximab
    C. Pembrolizumab
    D. Durvalumab
    E. Docetaxel
• HPV+ oropharynx & de-intensification (19–26):
  • Which randomized trials showed inferiority of RT + cetuximab vs RT + cisplatin in HPV+ OPSCC?
    A. EXTREME, KEYNOTE-048
    B. De-ESCALaTE HPV and RTOG 1016
    C. RTOG 0522 and TAX 324
    D. KEYNOTE-412 and JAVELIN 100
    E. CheckMate 141 and RTOG 91-11
  • For low-risk HPV+ OPSCC, standard concurrent agent with RT remains:
    A. Cetuximab
    B. Cisplatin
    C. Nivolumab
    D. Avelumab
    E. Toripalimab
  • De-intensification outside trials should:
    A. Replace cisplatin with cetuximab
    B. Reduce RT dose universally
    C. Be avoided; use standard cisplatin-CRT
    D. Use immunotherapy with RT routinely
    E. Use carboplatin-paclitaxel always
  • Which endpoint was not improved by cetuximab vs cisplatin in HPV+ trials?
    A. OS
    B. LRC
    C. PFS
    D. Toxicity profile (overall rates similar)
    E. All of the above were not improved
  • A 48-year-old HPV+ cT2 cN1 wants to avoid cisplatin. Evidence-based counseling:
    A. Cetuximab has better OS
    B. Cetuximab has similar survival with less toxicity
    C. Cisplatin has better survival; toxicity spectrum differs
    D. Immunotherapy + RT is standard
    E. Surgery is contraindicated
  • In HPV+ OPSCC, which factor modifies prognosis within p16+ disease?
    A. PD-L1 CPS only
    B. Smoking history and T/N stage
    C. KRAS status
    D. HER2 expression
    E. EBV DNA
  • In definitive CRT, a practical minimum cumulative cisplatin dose goal is:
    A. 100 mg/m²
    B. 150 mg/m²
    C. ≥ 200 mg/m²
    D. 300 mg/m²
    E. No target
• Induction chemotherapy (TPF, PF) (27–33):
  • Compared with PF, TPF induction in LA-HNSCC shows:
    A. Worse OS
    B. Similar OS
    C. Improved PFS / OS at cost of some hematologic toxicity
    D. Only QoL benefit
    E. Inferior larynx preservation
  • Role of induction today for non-NPC disease is most appropriate:
    A. Routine for all LA-HNSCC
    B. Selected bulky disease to improve distant control or for organ preservation, then CRT
    C. Replace CRT entirely
    D. Only for HPV+ disease
    E. Only with IO
  • A 56-year-old with borderline resectable hypopharynx (N3). Reasonable approach:
    A. RT alone
    B. TPF induction → response-adapted CRT
    C. Cetuximab + RT
    D. Surgery first
    E. Pembrolizumab alone
  • Which regimen was used after induction in TAX 324?
    A. RT alone
    B. Carboplatin-RT
    C. Cetuximab-RT
    D. Docetaxel-RT
    E. Pembrolizumab-RT
  • Primary benefit of TPF over PF across TAX trials:
    A. Reduced need for feeding tubes
    B. Lower neuropathy
    C. Superior survival and locoregional / distant control
    D. Less neutropenia
    E. Better hearing preservation
  • For a frail 72-year-old with poor PS, induction TPF is:
    A. Standard
    B. Typically not appropriate
    C. Preferred over CRT
    D. Required pre-op
    E. Replaced by weekly cisplatin
  • Key caution when using induction prior to CRT:
    A. Lower RT dose
    B. Cumulative cisplatin ceiling 100 mg/m²
    C. Maintain nutrition, avoid treatment breaks, and plan for timely transition to CRT
    D. Avoid PEG
    E. Avoid G-CSF ever
• Recurrent / metastatic (R/M) disease (34–46):
  • First-line systemic therapy for recurrent / metastatic (R/M) HNSCC, PD-L1 CPS ≥ 1, symptomatic burden high:
    A. Pembrolizumab monotherapy
    B. Pembrolizumab + platinum / 5-FU
    C. Cetuximab + platinum / 5-FU (EXTREME) preferred
    D. Docetaxel alone
    E. Nivolumab + ipilimumab
  • PD-L1 CPS ≥ 20, low disease burden:
    A. Pembrolizumab monotherapy is acceptable
    B. Must combine with chemotherapy
    C. Cetuximab preferred
    D. Nivolumab only after platinum
    E. Bevacizumab + chemotherapy
  • After progression ≤ 6 months post-platinum, second-line with OS benefit:
    A. Nivolumab
    B. Gefitinib
    C. Methotrexate
    D. Panitumumab
    E. Bevacizumab
  • In CPS <1:
    A. Pembrolizumab monotherapy superior to cetuximab / chemotherapy
    B. Pembrolizumab / chemotherapy offers no benefit
    C. Pembrolizumab / chemotherapy still reasonable; monotherapy less effective
    D. IO contraindicated
    E. Use RT alone
  • Which first-line regimen historically improved OS vs platinum / 5-FU alone?
    A. Cetuximab + platinum / 5-FU (EXTREME)
    B. Afatinib + 5-FU
    C. Docetaxel alone
    D. Bevacizumab + chemo
    E. Pazopanib
  • An older, fit patient prefers fewer infusions; which cetuximab-containing alternative to EXTREME is used in Europe?
    A. TPF
    B. TPEx (docetaxel / cisplatin / cetuximab)
    C. FOLFOX-cetuximab
    D. Capecitabine-cetuximab
    E. Carboplatin-paclitaxel-IO
  • For oligometastatic lung-only relapse after response to pembrolizumab-chemotherapy, which is not typical?
    A. Local ablative therapy consideration
    B. Continue IO beyond progression always
    C. Switch to cetuximab regimen
    D. Clinical trial
    E. Resection / SBRT discussion
  • A patient progressed after cetuximab + chemotherapy; PD-L1 CPS 10. Best next systemic?
    A. Pembrolizumab
    B. Nivolumab
    C. Either PD-1 inhibitor is reasonable
    D. Bevacizumab
    E. Erlotinib
  • Biomarker predicting better pembrolizumab monotherapy benefit:
    A. CPS ≥1 / ≥20
    B. EGFR amplification
    C. KRAS G12C
    D. BRAF V600E
    E. HER2 IHC 3+
  • Primary toxicity concern with PD-1 inhibitors to educate patients:
    A. Alopecia
    B. Mucositis
    C. Immune-related AEs (pneumonitis, colitis, endocrinopathies)
    D. Nephrolithiasis
    E. Ototoxicity
  • Time on pembrolizumab monotherapy with stable disease at 2 years:
    A. Must stop at 1 year
    B. Typically stop around 2 years if controlled
    C. Continue indefinitely
    D. Switch to chemotherapy
    E. Mandatory biopsy
  • For symptomatic R/M disease needing rapid tumor shrinkage and CPS ≥ 1:
    A. Pembrolizumab monotherapy
    B. Pembrolizumab + platinum / 5-FU preferred
    C. Cetuximab alone
    D. Nivolumab alone
    E. RT alone
  • After 12+ months since last platinum in R/M disease and platinum-eligible:
    A. Re-challenge with platinum doublet can be considered
    B. Platinum forever contraindicated
    C. IO mandatory first
    D. Cetuximab only
    E. Taxane only
• Perioperative immunotherapy (47–49):
  • In 2025, perioperative pembrolizumab for resectable LA-HNSCC is:
    A. Investigational only
    B. FDA-approved (CPS ≥ 1) based on KEYNOTE-689 EFS benefit
    C. Contraindicated
    D. Only for HPV+
    E. Only if ENE+
  • Perioperative pembrolizumab schedule in KEYNOTE-689:
    A. Adjuvant only
    B. Neoadjuvant + adjuvant with SOC (surgery ± cisplatin-RT)
    C. CRT only
    D. Maintenance only
    E. Replaces RT
  • For a surgical candidate with CPS 0, best statement re: KEYNOTE-689 applicability:
    A. Benefit limited to CPS ≥ 20
    B. FDA label requires CPS ≥ 1
    C. CPS testing not needed
    D. Only for oral cavity
    E. Only with ENE+
• Special sites & scenarios (50–54):
  • Nasopharyngeal carcinoma (non-keratinizing, EBV+), first-line R/M standard in 2025 (US):
    A. Gemcitabine / cisplatin ± toripalimab
    B. Paclitaxel / carboplatin
    C. Cetuximab / RT
    D. Pembrolizumab monotherapy only
    E. 5-FU / methotrexate
  • Contraindication to cisplatin most aligned with consensus:
    A. ECOG 1
    B. CrCl 55 mL/min (absolute)
    C. Grade ≥2 neuropathy or hearing loss
    D. Age >70 alone
    E. Controlled CHF class II
  • For a patient with borderline GFR ~50–55 mL/min, which is most appropriate?
    A. Force high-dose cisplatin
    B. Shared decision; consider weekly cisplatin (post-op) or non-cisplatin RT partner
    C. Always switch to IO
    D. Stop RT
    E. Use oxaliplatin
  • What does not reduce cisplatin toxicity risk during CRT?
    A. Pre / post-hydration and Mg supplementation
    B. Scheduled NK1 / 5-HT3/ dex regimen
    C. Careful ototoxic med avoidance
    D. Avoiding baseline audiogram
    E. Renal function checks
  • For severe cetuximab infusion reaction (grade 3), best action:
    A. Continue with slower rate
    B. Premedicate and retry same day
    C. Permanently discontinue cetuximab
    D. Switch to panitumumab
    E. Desensitize on-site
• Trial literacy & historical data (55–60):
  • RTOG 0522 asked whether adding cetuximab to accelerated cisplatin-RT:
    A. Improved outcomes—practice changing
    B. Showed no benefit, more toxicity / signals
    C. Was stopped early for efficacy
    D. Supported cetuximab for HPV+
    E. Supported weekly cisplatin
  • The EXTREME trial showed that:
    A. Cetuximab + platinum / 5-FU improved OS vs chemotherapy alone in 1L R/M
    B. Cetuximab monotherapy improved OS
    C. Chemotherapy alone superior
    D. IO superior to cetuximab
    E. Docetaxel added benefit
  • KEYNOTE-048 established which 1L standards?
    A. Pembrolizumab + chemotherapy (all-comers) and pembrolizumab monotherapy for CPS ≥ 1
    B. Pembrolizumab only for CPS ≥ 20
    C. IO inferior to cetuximab
    D. IO with RT standard
    E. IO contraindicated in smokers
  • CheckMate 141 demonstrated:
    A. Nivolumab improved OS vs investigator’s choice post-platinum
    B. Nivolumab inferior to docetaxel
    C. Benefit only in CPS ≥ 20
    D. No QoL advantage
    E. Only for NPC
  • KEYNOTE-412 and JAVELIN-100 teach that adding IO concurrently to CRT for unresected LA-HNSCC:
    A. Clearly improves EFS / OS
    B. Is practice-changing
    C. Has not improved primary endpoints; not standard
    D. Replaces cisplatin
    E. Is mandatory for HPV+
  • For cisplatin-ineligible, randomized NRG-HN004 signals:
    A. Durvalumab-RT replaces cetuximab-RT
    B. Cetuximab-RT remains a control standard; durvalumab-RT not recommended to replace it based on phase II data
    C. IO-RT superior to cetuximab-RT
    D. RT alone is preferred
    E. IO + RT is contraindicated
    
    Answers (with micro-rationales)
  • A. General principles & CRT (1–10)
  • C — q3-weekly cisplatin (100 mg/m²) is the historical standard radiosensitizer with the strongest level-1 evidence. The Green JournalPMC
  • B — q3-weekly has the most robust legacy data; weekly is used but has mixed evidence on LRC. ASCO PublicationsThe ASCO Post
  • C — CrCl ~40s and neuropathy → cisplatin-ineligible; cetuximab-RT is guideline-concordant. PMC
  • B — High-emetogenic risk: NK1 + 5-HT3 + dexamethasone, plus aggressive hydration. (Guideline-standard supportive care.)
  • C — MACH-NC shows survival benefit from concurrent chemo-RT. PMC
  • C — Baseline grade ≥ 2 ototoxicity is a cisplatin contraindication. PMC
  • C — Aim for cumulative cisplatin ≥ 200 mg/m² in definitive CRT. PLOS
  • A — RTOG 91-11: chemo-RT superior to RT alone for larynx preservation. PMC
  • A — When truly cisplatin-ineligible, cetuximab-RT is an accepted option. PMC
  • D — Adding cetuximab to cisplatin-CRT (RTOG 0522) did not improve outcomes.
  • B. Post-operative therapy (11–18)
  • C — Positive/close margin or ENE → adjuvant cisplatin-RT (EORTC 22931 / RTOG 9501). ResearchGatePubMed
  • B — JCOG1008: weekly 40 mg/m² non-inferior to q3-weekly in the post-op high-risk setting, with less nephro/ototoxicity. PMC
  • B — ENE+ and/or positive margin → cisplatin-RT. PubMed
  • D — After grade-3 cisplatin AKI, switch to cetuximab-RT (or RT alone) rather than continue cisplatin. (Guideline-concordant practice.)
  • C — Intermediate-risk features (e.g., PNI/LVI/T3) → RT standard; chemo benefit unproven. ASCO Publications
  • D — Absolute: CrCl < 50 mL/min or grade ≥ 2 hearing loss/neuropathy. PMC
  • B — Weekly BMP/Mg/K/Ca, CBC; audiogram as indicated. (Standard safety monitoring.)
  • A — High-risk p16-negative with ENE → adjuvant cisplatin-RT. PubMed
  • C. HPV+ oropharynx & de-intensification (19–26)
  • B — De-ESCALaTE & RTOG 1016: cetuximab-RT inferior to cisplatin-RT in HPV+. New England Journal of MedicinePubMed
  • B — Cisplatin remains the concurrent agent of choice in HPV+ disease. PubMed
  • C — Outside trials, avoid de-intensification by substituting cetuximab for cisplatin. PubMed
  • E — No efficacy endpoint favored cetuximab over cisplatin in HPV+ trials. New England Journal of MedicinePubMed
  • C — Counsel that cisplatin-RT yields better survival than cetuximab-RT in HPV+. PubMed
  • B — Smoking and T/N stage stratify prognosis within p16+ disease.
  • C — Cetuximab-RT is reasonable only when cisplatin-ineligible—not as elective de-escalation. PubMedPMC
  • C — Practical cumulative cisplatin goal ≥ 200 mg/m² (definitive). PLOS
  • D. Induction chemotherapy (TPF/PF) (27–33)
  • C — TAX 323/324: TPF improved survival/control vs PF. New England Journal of Medicine+1
  • B — Induction is selective (bulky/organ-pres) → then CRT; not routine. New England Journal of Medicine
  • B — Bulky hypopharynx (N3): TPF → response-adapted CRT is reasonable. New England Journal of Medicine
  • B — TAX 324 used carboplatin-RT after induction. PubMed
  • C — Across TAX trials: superior survival and distant control with TPF. New England Journal of Medicine
  • B — Frail/poor PS → avoid induction TPF. (Toxicity.)
  • C — Maintain nutrition, avoid breaks, and transition on time to CRT.
  • E. Recurrent/metastatic (34–46)
  • B — High burden & CPS ≥ 1: pembrolizumab + platinum/5-FU (KEYNOTE-048). PMC
  • A — Low burden & CPS ≥ 20: pembrolizumab monotherapy acceptable. PMC
  • A — Post-platinum: nivolumab improved OS (CheckMate 141). PMC
  • C — CPS < 1: pembro+chemo still reasonable; mono less effective. PMC
  • A — EXTREME: cetuximab + platinum/5-FU > chemo alone. PubMed
  • B — TPEx is a validated alternative to EXTREME with less toxicity. PubMed
  • B — “Continue IO beyond progression always” is not standard; consider local therapy/switch/trial.
  • C — After cetuximab+chemo: either PD-1 agent reasonable (class).
  • A — Higher PD-L1 CPS predicts better pembro monotherapy benefit. PMC
  • C — Counsel on immune-related AEs (pneumonitis, colitis, endocrine).
  • B — Common practice: stop PD-1 at ~2 years if controlled (per trial design). PMC
  • B — Need rapid shrinkage → pembro + platinum/5-FU. PMC
  • A — Platinum re-challenge is reasonable after >~12 months if eligible.
  • F. Perioperative immunotherapy (47–49)
  • B — FDA-approved (Jun 12, 2025) peri-op pembrolizumab for resectable LA-HNSCC, CPS ≥ 1. U.S. Food and Drug Administration
  • B — Neoadjuvant pembro → surgery → adjuvant RT ± cisplatin + pembro, then pembro maintenance (KEYNOTE-689). New England Journal of Medicine
  • B — Label requires CPS ≥ 1. U.S. Food and Drug Administration
  • G. Special sites & scenarios (50–54)
  • A — NPC 1L (US): gemcitabine/cisplatin ± toripalimab (FDA-approved). U.S. Food and Drug AdministrationFDA Access Data
  • C — Absolute cisplatin no-go: grade ≥ 2 neuropathy or hearing loss (and CrCl < 50). PMC
  • B — Borderline renal function → individualized; consider weekly (post-op) or non-cisplatin partner. PMC
  • D — Skipping baseline audiogram does not reduce risk; it’s needed.
  • C — Grade-3 cetuximab infusion reaction → permanently discontinue. (Label standard.)
  • H. Trial literacy & historical data (55–60)
  • B — RTOG 0522: adding cetuximab to cisplatin-CRT no benefit.
  • A — EXTREME improved OS vs chemo alone. PubMed
  • A — KEYNOTE-048: pembro+chemo (all-comers) and pembro mono for CPS ≥ 1. PMC
  • A — CheckMate 141: nivolumab improved OS post-platinum. PMC
  • C — Adding IO concurrently to CRT (unresected) hasn’t improved primary endpoints; not standard. U.S. Food and Drug Administration
  • B — NRG-HN004: durvalumab-RT did not replace cetuximab-RT based on phase II results. The LancetNRG Oncology

Consolidated High-Yield References (for 1–20)

• MACH-NC (meta-analysis): Lacas B, et al. Radiother Oncol. 2021;156:281–293. (Concomitant chemo-RT OS HR ~0.83; ~+6.5% 5-yr OS.)
• RTOG 91-11: Forastiere AA, et al. JCO. 2013 update—larynx preservation benefit with cisplatin-RT.
• RTOG 0522: Ang KK, et al. JCO. 2014—adding cetuximab to cisplatin-RT: no benefit.
• EORTC 22931 / RTOG 9501: Bernier J NEJM 2004; Cooper JS IJROBP 2012—adjuvant cisplatin-RT for ENE+/positive margins.
• JCOG1008 (post-op): Kiyota N, et al. JCO. 2022—weekly cisplatin non-inferior to q3w for OS, less renal/ototoxicity.
• HPV+ comparisons: Gillison ML, et al. NEJM. 2019 (RTOG 1016); Mehanna H, et al. Lancet. 2019 (De-ESCALaTE)—cetuximab-RT inferior to cisplatin-RT.
• Cisplatin eligibility: Reviews/consensus (e.g., Pruefer F. Health Sci Rep. 2023) and NCCN—CrCl <50, grade ≥2 hearing/neuropathy absolute; aim ≥200 mg/m² cumulative.
• Supportive care: ASCO/ESMO CINV guidelines; hydration & Mg protocols in cisplatin CRT.

• Key Concept:
  • Threshold: 
    • ≥ 200 mg / m² cumulative cisplatin dose during a standard 6 to 7 week course of definitive radiation:
      • Is the best-validated benchmark for improved locoregional control (LRC), disease-free survival (DFS), and overall survival (OS)

• Why It Matters:
  • Tumor Control: 
    • Falling short of ~ 200 mg / m² increases risk of locoregional failure and distant metastasis
  • Plateau Effect: 
    • Doses >240 to 300 mg /m² do not add survival benefit:
      • But raise nephrotoxicity, ototoxicity, neuropathy
• Practical Application:
  • Standard q3-weekly:
    • 100 mg / m² IV day 1, 22, 43 → planned 300 mg / m² :
      • Goal ≥ 200 mg / m² even if 3rd cycle omitted
  • Weekly regimen (most common alternative):
    • 40 mg / m² weekly × 6 to 7 → target 240 to 280 mg / m²
    • Critical pearl: 
      • At least 5 full cycles (~ 200 mg /m²) must be delivered:
        • Less than 5 cycles carries inferior outcomes in multiple series
• Key Tips:
  • Assess eligibility carefully: 
    • Baseline creatinine clearance ≥ 60 mL / min, no grade ≥ 2 hearing loss, etc.
  • Supportive care: 
    • Aggressive hydration, Mg / K replacement, antiemetics to avoid dose reductions or delays
• References:L
  • Staar S, et al. J Clin Oncol. 2001;19:861-869.
  • Pignon JP, et al. MACH-NC Collaborative Group. Radiother Oncol. 2009;92:4-14.
  • Ang KK, et al. J Clin Oncol. 2014;32:2940-2948.
  • Bauml JM, et al. J Clin Oncol. 2019;37:1987-1994.
  • NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Version 2025.

• Bottom line:
  • For definitive HNSCC chemoradiation:
    • Achieve ≥ 200 mg / m² total cisplatin:
      • Regardless of dosing schedule:
        • To maintain the survival advantage demonstrated in pooled analyses and contemporary RTOG data

• Synthesis:
  • Precursor:
    • L-arginine
  • Enzyme: 
    • Nitric oxide synthase (NOS):
      • Converts L-arginine → NO + citrulline
  • Cofactors: 
    • Oxygen, NADPH, tetrahydrobiopterin (BH4), FAD, FMN
  • NOS Isoforms:
    • eNOS (endothelial NOS):
      • Maintains vascular tone
      • Anti-thrombotic
    • nNOS (neuronal NOS):
      • Neurotransmission
      • Smooth muscle relaxation in GI tract
      • Penile erection
    • iNOS (inducible NOS):
      • Macrophages during inflammation:
        • Produces large amounts of NO:
          • For microbicidal and cytotoxic activity
• Mechanism of Action:
  • NO diffuses into adjacent vascular smooth muscle cells
  • Activates soluble guanylate cyclase (sGC):
    • Increasing cGMP:
      • cGMP activates protein kinase G (PKG):
        • Decreases intracellular Ca²⁺:
          • Vascular smooth muscle relaxation (vasodilation)
  • This process is rapid, short-lived:
    • Due to NO’s gaseous and diffusible nature
• Physiologic Roles:
  • Vasodilation: 
    • Maintains baseline vascular tone
    • Prevents hypertension
  • Anti-thrombotic: 
    • Inhibits platelet aggregation and adhesion to endothelium
  • Anti-inflammatory: 
    • Inhibits leukocyte adhesion to endothelium
  • Endothelial protection: 
    • Limits smooth muscle proliferation (anti-atherogenic)
  • Neurotransmission: 
    • nNOS-derived NO acts as a neurotransmitter:
      • Penile erection
      • GI peristalsis
  • Host defense:
    • iNOS in macrophages generates high NO levels:
      • Bactericidal and tumoricidal effects
  • Endothelium-Derived Relaxing Factor (EDRF):
    • NO was historically discovered as EDRF:
      • The key mediator of endothelium-dependent vasodilation:
        • Demonstrated that the endothelium is not passive but actively regulates vascular tone
  • Counter-Regulation: Endothelin:
    • Endothelin-1 (ET-1): 
      • Potent vasoconstrictor peptide secreted by endothelial cells:
        • Acts through ETA and ETB receptors on vascular smooth muscle:
          • ↑ Ca²⁺ influx → vasoconstriction
        • Provides balance against NO-mediated vasodilation, maintaining vascular homeostasis
• Clinical Relevance:
  • Hypertension, atherosclerosis, diabetes: 
    • Impaired endothelial NO production → endothelial dysfunction → vasoconstriction, thrombosis risk
  • Pharmacology:
    • Nitroglycerin, isosorbide dinitrate: 
      • Prodrugs → release NO → vasodilation (angina, heart failure)
    • Sildenafil (Viagra): 
      • Inhibits phosphodiesterase-5 (PDE-5) → prevents cGMP breakdown → potentiates NO-mediated vasodilation → erectile dysfunction therapy, pulmonary hypertension
  • Sepsis: 
    • Excessive NO from iNOS → systemic vasodilation → hypotension / shock
  • Asthma/COPD: 
    • Exhaled NO is a biomarker of airway inflammation

• Answer concept: 
  • Neurokinin-1 (NK1) receptor antagonist and a 5-Hydroxytryptamine-3 (5-HT3) receptor antagonist + Dexamethasone with aggressive IV hydration and Mg / K supplementation
• Why: 
  • Cisplatin is highly emetogenic:
    • Triple prophylaxis is standard
  • Hydration / Mg reduce nephrotoxicity
• Pitfalls: 
  • Under-treating weekly dose (still emetogenic)
  • Missing Mg monitoring
• Refs: ASCO / ESMO CINV guidelines; supportive care standards

• The inflammatory phase of wound healing:
  • Is the body’s immediate response to injury:
    • Typically lasts from day 0 to about day 4 to 6:
      • Depending on wound severity and systemic factors
  • Its main goal is to:
    • Control bleeding (hemostasis)
    • Prevent infection
    • Lay the groundwork for tissue repair
  • Key steps of the inflammatory phase of wound healing:
    • Hemostasis (Minutes to Hours):
      • Vasoconstriction:
        • Damaged blood vessels constrict:
          • To reduce blood loss
      • Platelet plug formation:
        • Platelets adhere to exposed collagen:
          • Secondary to the trauma / injury:
            • Aggregate, and release factors:
              • Thromboxane A2
              • ADP
      • Coagulation cascade:
        • Fibrin mesh stabilizes the platelet plug:
          • Forming a clot (fibrin clot)
      • Growth factor release:
        • Platelets release:
          • PDGF
          • TGF-β
          • VEGF
            • Which recruit inflammatory cells (PMN) and initiate angiogenesis
    • Early Inflammation (Hours to ~ 48 hours):
      • Vasodilation:
        • Mediated by histamine, prostaglandins, and nitric oxide:
          • Leading to increased permeability
      • Neutrophil infiltration:
        • First responders:
          • Peak at 24 to 48 hours
        • Function:
          • Phagocytose bacteria and debris
        • Release reactive oxygen species (ROS) and proteolytic enzymes
        • Secrete cytokines (IL-1, TNF-α):
          • To amplify the inflammatory response
    • Late Inflammation / Transition (Day 2 to 5):
      • Monocyte to macrophage transition:
        • Monocytes migrate into tissue and differentiate into macrophages
        • Continue debris clearance
        • Secrete cytokines and growth factors:
          • TGF-β, VEGF, FGF:
            • That stimulate fibroblasts and angiogenesis
        • Switch from pro-inflammatory (M1) to pro-repair (M2) phenotype
        • Lymphocytes:
          • Arrive later:
            • Help regulate macrophage activity and fibroblast proliferation
• Key Features of the Inflammatory Phase:
  • Cardinal signs:
    • Redness, heat, swelling, pain, and loss of function
  • Duration:
    • Normally resolves within 4 to 6 days:
      • Prolonged inflammation delays healing and predisposes to chronic wounds
  • Outcome:
    • Clean wound bed, bacterial control, and recruitment of cells for the proliferative phase:
      • Fibroblasts, endothelial cells, keratinocytes

• Cisplatin-ineligible patient (CrCl ~ 42, grade-2 neuropathy / hearing loss) needing radiosensitizer: 
  • Cetuximab-radiation therapy (RT)
    • Why: 
      • Renal insufficiency / neuropathy:
        • Are consensus contraindications to cisplatin
      • Cetuximab-RT:
        • Is a recognized alternative when cisplatin cannot be given
  • Caveat: 
    • Do not swap to cetuximab just to avoid toxicity in otherwise eligible HPV+ patients:
      • Worse survival vs cisplatin
  • Alternatives: 
    • Carboplatin / 5-FU-RT (center-dependent) or weekly carboplatin / taxane-RT protocols
• Refs: NCCN H&N cisplatin-ineligibility; RTOG-1016/De-ESCALaTE.
• Who is cisplatin-ineligible (and why it matters):
  • Absolute / near-absolute: 
    • CrCl < 50 mL /min
    • Baseline ≥ grade-2 hearing loss
    • Neuropathy
    • Significant frailty / comorbidity
  • 50 to 60 mL / min:
    • Often treated as relative ineligibility
  • These thresholds are repeatedly endorsed in expert consensus / position pieces PMC+1
  • Implication: 
    • If the patient cannot safely receive cisplatin (e.g., CrCl 42 and G2 neuropathy), you should not try to “dose through” it:
      • Pick a non-cisplatin radiosensitizer
• What supports cetuximab + radiation therapy (RT), when cisplatin is off the table?:
  • Bonner et al., NEJM 2006 (+ 5-yr update):
    • In LA-HNSCC, RT + cetuximab vs RT alone improved locoregional control and overall survival:
      • 5-yr OS significantly higher with cetuximab
    • Toxicity profile was different:
      • More acneiform rash / infusion reactions:
        • But no global increase in common RT-related toxicities was seen
    • Important:
      • This trial did not compare against cisplatin-RT
      • It establishes cetuximab as a valid RT partner when cisplatin cannot be given New England Journal of MedicinePubMed
  • 2024 NRG-HN004 (Lancet Oncology):
    • For cisplatin-ineligible patients:
      • Durvalumab-RT did not outperform cetuximab-RT:
        • The editorial conclusion remains that cetuximab-RT is the standard comparator in the cisplatin-ineligible populationThe Lancet
  • Bottom line: 
    • In a cisplatin-ineligible patient:
      • Cetuximab-RT is a guideline-accepted radiosensitizing regimen with randomized evidence vs RT alone and remains the standard control in contemporary trials of the ineligible population The Lancet
• Why you should not swap cisplatin to cetuximab in an eligible (especially in HPV+) patient:
  • Two large, definitive, head-to-head trials in HPV-positive oropharyngeal cancer:
    • RTOG 1016 (Gillison et al., 2019):
      • RT + cetuximab failed non-inferiority to RT + cisplatin for:
        • Overall survival:
          • OS HR 1.45, one-sided 95% upper CI 1.94
        • 5-yr OS: 
          • 77.9% (cetuximab) vs 84.6% (cisplatin)
      • No clinically meaningful reduction in overall serious toxicity with cetuximab
      • Conclusion: 
        • Cisplatin-RT is superior:
          • Do not substitute cetuximab for convenience PubMed
    • De-ESCALaTE HPV (Mehanna et al., 2019):
      • 2-yr OS: 97.5% with cisplatin vs 89.4% with cetuximab
      • PFS and recurrence outcomes also favored cisplatin
      • Toxicity not globally lower with cetuximab
      • Conclusion:
        • Cetuximab-RT leads to worse survival:
          • Should not replace cisplatin in eligible HPV+ patients The LancetScienceDirect
      • Reinforcing data: 
        • Observational / registry analyses found inferior OS with cetuximab vs cisplatin in non-operative definitive settings, aligning with the RCT signal PMC
      • Guideline posture: 
        • Major guidelines and reviews explicitly caution against elective substitution of cetuximab for cisplatin in HPV+ disease:
          • Reserve cetuximab for cisplatin-ineligible patients PMC
• What about other non-cisplatin options?
  • Carboplatin / 5-FU + RT (or carboplatin / paclitaxel + RT):
    • Used at some centers for ineligible patients:
      • But randomized data are much thinner than for cetuximab-RT
    • Consider when EGFR-mAb isn’t suitable:
      • Prior severe infusion reaction or per institutional protocols PMC