- 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
- For unresected, stage III to IVB head and neck squamous cell carcinoma (HNSCC), the preferred concurrent systemic agent with definitive RT is:
- 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
- Indication for adjuvant cisplatin-RT after surgery:
- 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
- Which randomized trials showed inferiority of RT + cetuximab vs RT + cisplatin in HPV+ OPSCC?
- 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
- Compared with PF, TPF induction in LA-HNSCC shows:
- 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
- First-line systemic therapy for recurrent / metastatic (R/M) HNSCC, PD-L1 CPS ≥ 1, symptomatic burden high:
- 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+
- In 2025, perioperative pembrolizumab for resectable LA-HNSCC is:
- 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
- Nasopharyngeal carcinoma (non-keratinizing, EBV+), first-line R/M standard in 2025 (US):
- 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
- RTOG 0522 asked whether adding cetuximab to accelerated cisplatin-RT:
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.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 