Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• 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
        

• After patients with recurrent and / or metastatic squamous cell carcinoma (SCC) of the head and neck have exhausted the options of surgery and / or radiation:
  • The likelihood of cure diminishes substantially:
    • With a median survival historically being:
      • Less than 1 year
• In this group, systemic therapy administered with palliative intent is the treatment of choice:
  • Single agent therapy can produce objective responses in:
    • 10% to 30% of patients
  • Single agents that typically are used in this setting include:
    • Cisplatin
    • Taxanes
    • Methotrexate
    • 5-FU
    • Cetuximab
    • Vinorelbine, bleomycin, ifosfamide, and pemetrexed:
      • Also have shown clinical activity against advanced head and neck cancers
• The durability of response to chemotherapy alone:
  • Generally is measured in:
    • Weeks to months, not years
• An early, randomized trial reported by Morton:
  • Provided evidence that cisplatin treatment prolonged survival:
    • By approximately 10 weeks in patients with advanced head and neck cancer:
      • Compared with best supportive care
• There are no striking efficacy differences:
  • Among cytotoxic chemotherapy agents in the recurrent disease setting:
    • Hong and colleagues:
      • Compared cisplatin versus methotrexate as palliative therapy for 44 patients with head and neck cancer that had recurred after surgery and / or radiation
      • Patients had not received prior chemotherapy
      • The median survival was approximately 6 months in both arms:
        • Although methotrexate seemed to be somewhat better tolerated
  • Similarly, in a randomized study of 100 patients with advanced inoperable head and neck cancer:
    • That compared cisplatin versus methotrexate:
      • Grose and colleagues:
        • Did not detect any significant differences in survival between the two treatment groups
• Taxanes:
  • Yielded encouraging response rates as:
    • First-line therapy for patients with recurrent disease
  • Forastiere’s group:
    • Observed a response rate of 40% among 34 patients treated with paclitaxel
  • Dreyfuss and colleagues:
    • Reported a response rate of 42% among 31 patients treated with docetaxel
  • In a randomized phase II trial that compared docetaxel versus methotrexate among 57 patients with advanced head and neck cancer:
    • No difference in overall survival was found between the two groups:
      • Although the response rate was significantly better for the docetaxel group:
        • 27% versus 15%
• Combination chemotherapy regimens:
  • Appear to be associated with:
    • Increased response rates and often with increased toxicities:
      • But generally not with increased survival
  • In 1985 Vogl reported the results of a prospective study:
    • In which 163 patients were randomly assigned to receive:
      • Methotrexate monotherapy or methotrexate plus bleomycin plus cisplatin
    • Objective responses were more frequent in the combination chemotherapy group:
      • But median survival was 5.6 months in each group
  • A three-arm randomized study of 249 patients with advanced head and neck cancer that was reported by Jacobs and colleagues:
    • Compared the cisplatin plus 5-FU doublet versus cisplatin monotherapy versus 5-FU monotherapy
    • The objective response rate and hematologic toxicities were highest with the doublet regimen:
      • But median survival was approximately 5.7 months for all groups
  • Taken together, these studies suggest that:
    • Combination chemotherapy regimens may be appropriate for patients with good performance status:
      • If objective tumor response is believed to be necessary for palliation of advanced head and neck cancer
    • No combination chemotherapy regimen appears to be superior to another in terms of survival for patients with advanced head and neck cancer:
      • A Southwest Oncology Group study reported by Forastiere randomly assigned 277 patients with advanced head and neck cancer to:
        • Treatment with cisplatin plus 5-FU, carboplatin plus 5-FU, or methotrexate monotherapy
        • In the comparison of the doublet regimens:
          • Cisplatin plus 5-FU yielded a higher response rate than did carboplatin plus 5-FU:
            • 32% versus 21%, p = .05
          • However, median survival times were similar in all three treatment groups in the study
    • Gibson reported a randomized comparison of cisplatin plus 5-FU (CF) versus cisplatin plus paclitaxel (CP) for 218 patients with advanced head and neck cancer:
      • The response rate:
        • 27% in the CF group and 26% in the CP group
      • Median survival:
        • 8.7 months in the CF group and 8.1 months in the CP group
          • The overall results did not differ significantly
• These studies highlight the inherent limitations of cytotoxic chemotherapy in the recurrent or metastatic disease setting and set the stage for the development of novel molecularly targeted therapeutic agents for head and neck cancer
• Cetuximab represents the first biologic agent to enter routine clinical practice as a palliative agent for patients with advanced head and neck cancer:
  • In a phase II study of 103 patients with recurrent and / or metastatic head and neck cancer:
    • With documented disease progression within 30 days after a minimum of two and a maximum of six platinum-based chemotherapy treatments:
      • Vermorken reported that the:
        • Response rate was 13% and the median time to progression was 70 days
        • Treatment was generally well tolerated:
          • The most common adverse event was a rash
• Cetuximab can also be combined with other cytotoxic chemotherapeutic agents to achieve therapeutic advantage for some patients with advanced HNSCC:
  • In a phase III study by Burtness for patients with recurrent or metastatic disease who had not received any prior palliative chemotherapy:
    • 117 subjects were randomly assigned to receive cisplatin plus cetuximab versus cisplatin plus placebo
    • The objective response rate was higher for cisplatin plus cetuximab:
      • 26% versus 10%, p = .03:
        • But no significant difference in survival was found between the two groups
    • The investigators noted that in the cetuximab plus cisplatin group:
      • Objective responses were more frequent in patients who experienced skin toxicity:
        • Although the number of subjects was too small to establish a statistically significant correlation between dermatologic toxicity and response
  • The EXTREME trial:
    • Randomized 442 patients with untreated recurrent or metastatic head and neck cancer to platinum (cisplatin or carboplatin) plus infusional 5-FU alone for a maximum of 6 cycles with or without cetuximab
    • Patients randomized to the experimental arm (with cetuximab) with at least stable disease:
      • Were continued on cetuximab alone after combination therapy
    • Results:
      • Objective response rate:
        • 20% versus 36%, p < .001
      • Progression-free survival:
        • 3.3 months versus 5.6 months p < .001
      • Overall survival:
        • 7.4 months versus 10.1 months, p = .04
      • All favored the experimental group
    • The lack of crossover in the study design leaves open the question of whether similar improvements in overall survival could be achieved with sequential treatment with the platinum doublet followed by cetuximab, or vice versa:
      • However, the study does further establish the platinum / 5-FU plus cetuximab as a standard first-line palliative option for patients with advanced head and neck cancer.
• One of the most exciting areas of progress for head and neck cancer research is the emergence of immunotherapeutic approaches for this disease:
  • Led by the integration of therapeutic antibodies targeting the T cell immune checkpoint PD-1 (programmed death 1) into clinical practice (Figure)
    • The activity observed with these drugs established the critical proof of principle that the immune system can be pharmacologically harnessed to produce clinically significant responses in head and neck cancer patients

• CHECKMATE-141 was a randomized phase III clinical trial:
  • Comparing the efficacy of nivolumab:
    • A monoclonal antibody directed against PD-1;
      • To investigator’s choice chemotherapy (methotrexate, docetaxel, or cetuximab) in recurrent / metastatic patients with tumor progression or recurrence:
        • Within 6 months after the last dose of platinum containing chemotherapy (Ferris et al., 2016)
  • The trial demonstrated a survival benefit with nivolumab over chemotherapy:
    • With a median overall survival of 7.5 months versus 5.1 months and a 1-year overall survival of 36% versus 16.6%, respectively.
  • The response rate with nivolumab was 13.3% versus 5.8% with  chemotherapy
• KEYNOTE-012 was a multicohort phase 1b trial:
  • Evaluating the efficacy of another PD-1–directed antibody pembrolizumab in a variety of different malignancies, including  recurrent / metastatic head and neck cancer
  • Among 60 head and neck cancer patients whose tumors expressed PD-L1 (the ligand for PD-1):
    • Pembrolizumab elicited an 18% response rate and a median overall survival of 13 months (in an intent to treat analysis) (Seiwert et al., 2016)
• Another expansion cohort  in KEYNOTE-012 enrolled 132 recurrent / metastatic head and neck cancer patients regardless of PD-L1 status:
  • Reporting an 18% response rate and median overall survival of 8 months (Chow et al., 2016)
• While KEYNOTE-012–enrolled patients who had received any number of lines of prior chemotherapy for recurrent / metastatic disease (including treatment-naïve patients):
  • KEYNOTE-055 was a single-arm phase II trial designed to evaluate pembrolizumab in patients who experienced progression of disease within 6 months of platinum and cetuximab therapy (Bauml et al., 2017):
    • The reported response rate was 16% with a median overall survival of 8 months
• Both nivolumab and pembrolizumab have been FDA-approved for the treatment of  recurrent / metastatic head and neck cancer patients with disease progression on or after progression with platinum-containing chemotherapy:
  • Establishing a new standard for second-line treatment
• After the approval of pembrolizumab in this setting, the results of a randomized, open-label phase III trial comparing the efficacy of pembrolizumab to investigator’s choice chemotherapy (methotrexate, docetaxel, or cetuximab) in platinum refractory recurrent / metastatic patients, or locally advanced  disease patients with recurrence or progression within 3 to 6 months  of definitive platinum-based therapy:
  • Were reported (KEYNOTE 040; Cohen et al., 2018):
    • For the primary endpoint of overall  survival, pembrolizumab was superior compared to standard  therapies, but the degree of benefit (hazard ratio [HR] for death 0.80 [95% CI 0.65-0.98; one-sided p = 0.0161] failed to meet  the goals pre-specified for the study [HR of 0.70 or better with  one-sided a of 0.025]:
      • The authors speculated that the 13% of standard arm patients who received immune checkpoint inhibitor therapy after trial completion could have confounded this survival analysis
    • Still, most agree that the observed improvements in survival with pembrolizumab, as well as its superior safety profile compared to standard chemotherapies, justifies its use in this setting
• More broadly speaking, the smaller margins of benefit observed for nivolumab or pembrolizumab compared to chemotherapy in unselected head and neck cancer patient populations:
  • Argues for the need to develop predictive biomarkers that will allow identification of those who are most likely to  benefit from PD-1 / PD-L1 pathway targeting

• In many scenarios, single-modality radiation therapy:
  • Is a historical standard intervention after primary surgery for stages III and IV head and neck cancer
• Intergroup study 0034 (RTOG 8503):
  • Which randomly assigned patients with resected head and neck squamous cell carcinoma to receive:
    • Postoperative radiation therapy alone or postoperative cisplatin (100 mg/m2 once every 3 weeks) plus 5-FU (1000 mg/m2/day in a continuous infusion for 120 hours every 3 weeks) followed by radiotherapy:
      • Failed to show significant differences in outcomes between the two treatment groups
  • A retrospective analysis did identify subsets of patients with high-risk features on surgical pathology:
    • The study suggested that clinical studies of postoperative concurrent chemoradiation should be conducted for patients with high-risk disease
• Bachaud and colleagues conducted a randomized trial for patients who had undergone primary surgery for head and neck cancer and had high-risk disease:
  • Defined as extracapsular spread of malignancy in resected lymph nodes (Figure)
  • Eighty-three patients were randomly assigned to receive postoperative radiotherapy alone or postoperative radiotherapy with concurrent cisplatin (50 mg administered intravenously once a week in a flat dose):
    • Overall survival and disease-free survival were significantly better:
      • In the combined modality group:
        • OS: 36% vs 13% (p < 0.01)
        • DFS: 45% vs 23% (p < 0.01)
    • The improvement in the locoregional control rate approached statistical significance in favor of the combined modality group:
      • 77% vs 59% (p = 0.08)

• Cisplatin plus radiotherapy in the postoperative setting was evaluated in the:
  • EORTC 22931 and RTOG 95–01 randomized clinical trials (Figure)

• Both studies were limited to patients who had high-risk features in the surgical pathology:
  • Although the studies differed slightly in the high-risk features that were used for eligibility:
    • In EORTC 22931:
      • High risk was defined as:
        • Positive or close surgical margins (≤ 5 mm)
        • Extra-capsular extension of nodal disease
        • Involvement of lymph nodes at level IV or V:
          • From oral cavity or oropharynx primary sites
        • Perineural disease
        • Vascular embolism
    • RTOG 95–01 defined high risk as:
      • Positive surgical margins
      • Extracapsular extension
      • Involvement of two or more lymph nodes
• In both studies:
  • Patients were randomly assigned to radiation alone or radiation plus concurrent cisplatin (100 mg/m2 on days 1, 22, and 43)
• The estimated 5-year overall survival:
  • From the EORTC 22931 trial was:
    • 53% in the combined modality group and 40% in the radiotherapy group (p < .05)
  • In the EORTC 22931 trial:
    • Progression-free survival and locoregional control:
      • Also were significantly improved in the combined modality group:
        • Improved 5-year progression-free survival:
          • 47% vs. 36%, p < 0.05
        • Lower incidence of local region relapse at 5 years:
          • 18% vs. 31%, p < 0.05
  • With a median follow-up of 45.9 months, RTOG 95–01:
    • Demonstrated significant improvements in locoregional control and disease-free survival for the cisplatin plus radiation group:
      • Improved 2-year locoregional control rate:
        • 82% vs. 72%, p < 0.05
      • Improved disease free survival:
        • Hazard ratio 0.78, p < 0.05
      • But the improvement in overall survival for this group did not reach statistical significance:
        • Hazard ratio 0.84, p 0.19
• Bernier and colleagues performed a pooled analysis to compare eligibility criteria and outcomes in the two trials:
  • When the analysis was restricted to patients with high-risk disease according to criteria that were used in both studies (positive surgical margin and / or extracapsular extension):
    • A significant improvement in overall survival:
      • Was seen for the group of patients that received concurrent cisplatin and radiation therapy (Figure)
    • As such, postoperative radiation plus concurrent administration of high-dose cisplatin:
      • Is a widely accepted standard of care for fit patients with either of these high-risk features on surgical pathology

• Bottom line: 
  • q3-weekly 100 mg / m² has strongest legacy evidence for tumor control:
    • Weekly 40 mg / m² is used in practice:
      • But superiority isn’t proven in definitive settings
• Post-operative exception: 
  • JCOG1008 (high-risk post-op):
    • Showed weekly 40 mg / m² non-inferior to q3-weekly for OS with less renal / ototoxicity
• Use on exam: 
  • If the stem is definitive CRT and asks “preferred” or “most evidence-based,”:
    • Pick q3-weekly
  • If post-op high-risk:
    • Weekly is acceptable / non-inferior
• Numbers: 
  • Many programs target ≥ 200 mg / m² cumulative regardless of schedule
• Definitive CRT (unresected locally advanced head and neck SCC (LA-HNSCC):
  • Benchmark regimen:
    • High-dose cisplatin 100 mg/m² q3 weeks ×3 during standard-fractionation RT:
      • Remains the legacy standard for tumor control and survival:
        • Based on multiple RCTs and meta-analyses:
          • Most reviews still treat this as the reference arm in trials PMC
  • Weekly 30 mg / m² vs q3-weekly 100 mg / m² (inferior control):
    • The randomized Tata Memorial Trial:
      • Noronha et al., JCO 2018:
        • n=300:
          • Mostly adjuvant CRT:
            • But often extrapolated to definitive:
              • Tested 30 mg / m² weekly vs 100 mg/m² q3-weekly
        • Two-year locoregional control was:
          • 58.5% (30 mg / m²) vs 73.1% (q3w 100 mg / m²):
            • HR for LRF 1.76 (95% CI 1.11–2.79)
        • Acute grade ≥ 3 toxicity was lower with weekly:
          • 71.6% vs 84.6%
        • OS was similar at that follow-up:
          • HR 1.14; P=.48
      • Takeaway: 
        • Weekly 30 mg / m² is inferior for LRC PubMed
• Weekly 40 mg / m²vs q3-weekly 100 mg / m² (emerging / definitive setting):
  • The ConCERT phase III trial (India; definitive CRT):
    • Reported non-inferiority of weekly 40 mg / m² to q3-weekly 100 mg / m² for LRC and OS:
      • With fewer severe AEs, fewer RT interruptions and hospitalizations in the weekly-40 mg / m² arm
    • Interim 2-yr LRC rates were:
      • ~ 61.5% (weekly 40 mg / m²) vs 57.7% (q3w 100 mg / m²):
        • Absolute difference + 3.8% within the non-inferiority margin (NI margin)
    • Full peer-reviewed primary publication is pending:
      • So most guidelines still name q3-weekly as the “preferred / most evidence-based” in definitive CRT stems The ASCO PostLippincott Journals
• Adherence and cumulative dose matter:
  • Real-world and retrospective datasets show patients on q3-weekly more often achieve ≥ 200 mg / m² cumulative cisplatin:
    • 75.6% q3-weekly vs 47.1% weekly:
      • Median cumulative 200 mg / m² vs 160 mg / m²
    • Missing several weekly cycles correlates with worse survival
    • This is one reason many programs “aim for ≥ 200 mg / m²” regardless of schedule PMCJAMA Network
• What to pick on exams: 
  • If a stem asks for the “preferred / most evidence-based” regimen for definitive CRT:
    • Choose cisplatin 100 mg / m² q3 weeks:
      • Cite weekly 40 mg / m² only if the question explicitly frames it as acceptable or references ConCERT-like criteria PMC
• Post-operative high-risk CRT (positive margin and / or ENE):
  • JCOG1008 (phase II / III, JCO 2022):
    • In resected high-risk HNSCC:
      • Weekly 40 mg / m² was non-inferior to q3-weekly 100 mg / m² for overall survival: 
        • HR 0.69 (99.1% CI 0.374–1.273) at the pre-specified interim:
          • The updated analysis maintained NI (HR 0.75; 95% CI 0.50–1.13)
      • Key toxicity deltas favored weekly dosing:
        • Grade ≥ 3 neutropenia 35% vs 49%
        • Infection 7% vs 12%
        • Renal impairment (any grade) 30% vs 40%
        • Hearing impairment (any grade) 7% vs 17%
        • Grade 4 AEs 8.2% vs 18.6%:
          • Two treatment-related deaths occurred in the weekly arm
      • Practical implication: 
        • Weekly 40 mg / m² is an evidence-based option post-op high risk patients PMC+1
• Cumulative dose “≥ 200 mg/m²”: what’s the evidence?:
  • The classic systematic review (Strojan et al., Head & Neck 2016):
    • Supports an association between ≥ 200 mg/m² and better outcomes during CRT:
      • Which has driven the common “≥ 200 mg / m²” target PubMed
  • Not all cohorts confirm a strict threshold effect:
    • Swiss multicenter series didn’t reproduce a survival break at 200 mg/m²:
      • But more patients reach ≥ 200 mg m² on q3-weekly than weekly in multiple real-world datasets
  • Nuance:
    • In HPV-positive disease:
      • Dose–outcome relationships may be flatter except in T4 / N3 subsets
  • Bottom line for boards:
    • ≥ 200 mg/m² is a reasonable target, and shortfall—especially with missed weekly cycles—tracks with worse outcomes PMCScienceDirect
• Put it all together:
  • Definitive CRT: 
    • “Cisplatin 100 mg m² q3 weeks is the preferred / most established regimen for tumor control
    • Weekly 40 mg / m² is used widely:
      • ConCERT suggests non-inferiority with better tolerability:
        • But full publication is pendin:
          • So for test stems asking ‘preferred,’ pick q3-weekly.”
    • Aim for ≥ 200 mg/m² cumulativePMCThe ASCO Post
  • Post-op high-risk: 
    • “Weekly 40 mg / m² is non-inferior to q3-weekly for OS with less renal / ototoxicity(JCOG1008)”:
      • It’s acceptable to choose weekly in these stems PMC
• Numbers to memorize:
  • Noronha 2018 (weekly 30 mg / m² vs q3w 100 mg / m²): 
    • 2-yr LRC 58.5% vs 73.1%
      • HR LRF 1.76:
        • Inferior weekly-30 mg/m²
    • Acute ≥ G3 toxicity:
      • 71.6% vs 84.6  PubMed
  • ConCERT (definitive, weekly 40 mg / m² vs q3w 100 mg / m²): 
    • 2-yr LRC ~ 61.5% vs 57.7%:
      • NI met
      • Fewer severe AEs and interruptions with weekly-40 mg/m² (interim / meeting)  Lippincott JournalsThe ASCO Post
  • JCOG1008 (post-op high-risk): 
    • OS HR 0.69 (NI) at interim
    • Renal impairment 30% vs 40% and hearing impairment 7% vs 17% (weekly vs q3w) PubMedPMC
  • Cumulative dose: 
    • Many datasets target ≥ 200 mg/m²:
      • q3-weekly more often reaches that level:
        • ~76% vs ~47%weekly:
          • Missing weekly cycles worsens outcomes PMC
• Refs: JCOG1008 (JCO 2022); Noronha 2018; guideline synopses.

• Preferred concurrent agent with definitive RT in unresected stage III–IVB HNSCC:
  • Cisplatin 100 mg / m² q3 weeks
• Why it’s right: 
  • Decades of level-1 evidence show concomitant cisplatin-RT improves:
    • OS vs RT alone (MACH-NC)
  • The q3-weekly 100 mg / m² schedule is the historical standard in definitive settings:
    • Used in the pivotal organ-preservation and superiority trials that shaped practice
• When to deviate: 
  • True cisplatin-ineligible:
    • CrCl < 50, grade ≥ 2 hearing loss / neuropathy):
      • Consider cetuximab-RT or carboplatin-based radiosensitization
• Pitfalls: 
  • Choosing cetuximab to “reduce toxicity” in HPV+ disease:
    • Worse survival vs cisplatin in RTOG-1016 / De-ESCALaTE trials.
• Numbers to quote: 
  • MACH-NC:
    • CRT vs RT:
      • HR death ~ 0.83; + 6% to 7% 5-yr OS
• MACH-NC (Radiother Oncol 2021, IPD meta-analysis)
• Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group
  • What it asked: 
    • Does adding chemo to RT improve outcomes in non-metastatic HNSCC?
  • Design: 
    • Updated individual-patient meta-analysis of 107 RCTs (n≈19,800)
  • Key results: 
    • Concurrent chemoradiation (CRT) improved OS vs RT alone:
      • HR 0.83:
        • Giving an absolute + 6.5% OS at 5 yrs and + 3.6% at 10 yrs
    • Concurrent chemoradiation (CRT) improved event-free survival:
      • HR 0.80:
        • + 5.8% at 5 yrs
    • Benefit mainly from less locoregional failure (sub-HR ~0.71)
    • No clear distant-failure reduction
    • Induction or adjuvant chemotherapy did not improve OS overall
    • Benefit attenuates with age
    • Platinum-based regimens drive most of the effect
• Reference:
  • MACH-NC (Radiother Oncol 2021); RTOG 91-11; NCCN/ASCO H&N.