Patient
VAR-HNSCC-BIOMARK · Algorithm: ALGO-HNSCC-RM-1L
Etiological driver
Etiological driver · etiologically_driven archetype
Head and neck squamous cell carcinoma
- Tobacco (smoked + smokeless) — dominant in HPV-negative disease
- Alcohol (synergistic with tobacco)
- HPV (high-risk, mostly type 16) — defines HPV+ oropharyngeal SCC, distinct biology and better prognosis
- EBV — defines nasopharyngeal carcinoma (separate entity in many guidelines but tracked under HNSCC umbrella)
- Betel nut chewing (South / Southeast Asia)
- Fanconi anemia, dyskeratosis congenita (germline susceptibility)
Clinical significance of mutations (ESCAT)
Tumor-board context — the engine does not use these tiers to rank tracks
| Biomarker | Variant | ESCAT | Evidence | Clinical significance | Drugs | Sources |
|---|
| BIO-PDL1-CPS | (gene-level) | IA | - SRC-NCCN-HNSCC-2025
- SRC-ESMO-HNSCC-2020
Evidence cited from clinical guidelines; per-source evidence levels not yet structured. See Phase-2-of-CIViC-pivot for re-cite roadmap. | PD-L1 CPS is the primary predictive biomarker for pembrolizumab in recurrent/metastatic HNSCC (KEYNOTE-048). Two threshold-stratified eligibility bands: CPS ≥1 — pembrolizumab + platinum + 5-FU 1L (superior to EXTREME regimen in CPS≥1 population); CPS ≥20 — pembrolizumab monotherapy 1L (preferred over chemo in high-expressors; mOS 14.9 mo). Both are FDA-approved and NCCN/ESMO Category 1 recommendations. Testing by IHC 22C3. Threshold selection is performed by the algorithm layer (ALGO-HNSCC-RM-1L); this BMA entry surfaces ESCAT tier context for tumor-board discussion only. | pembrolizumab monotherapy (CPS≥20 1L per SRC-NCCN-HNSCC-2025, SRC-ESMO-HNSCC-2020)
pembrolizumab + platinum + 5-FU (CPS≥1 1L per SRC-NCCN-HNSCC-2025) | - SRC-NCCN-HNSCC-2025
- SRC-ESMO-HNSCC-2020
|
Primary current-line option
- Indication
- IND-HNSCC-RM-1L-PEMBRO-CHEMO
- Regimen
- Pembrolizumab + 5-FU + platinum (HNSCC R/M, 1L; PD-L1 CPS ≥1)
- Drugs + NSZU
- Pembrolizumab (DRUG-PEMBROLIZUMAB) 200 mg IV (or 400 mg IV q6w) · Day 1 every 3 weeks (or q6w schedule), for up to 35 cycles (~2 years) or until progression / unacceptable toxicity · IV ⚠ NSZU — not for this indication
- 5-Fluorouracil (DRUG-5-FLUOROURACIL) 1000 mg/m² IV continuous infusion days 1-4 (96-hour infusion) · Days 1-4 of 21-day cycle, for 6 cycles · IV ✓ NSZU covered
- Cisplatin (DRUG-CISPLATIN) 100 mg/m² IV day 1 (preferred when ECOG 0-1, GFR ≥60, no neuropathy / ototoxicity / heart failure) · Day 1 of 21-day cycle, for 6 cycles · IV ✓ NSZU covered
- Carboplatin (DRUG-CARBOPLATIN) AUC 5 IV day 1 (substitute for cisplatin if contraindicated — GFR <60, neuropathy, hearing loss, congestive heart failure, or ECOG 2) · Day 1 of 21-day cycle, for 6 cycles (in lieu of cisplatin) · IV ⚠ NSZU — not for this indication
- Reason
- Primary current-line option selected by ALGO-HNSCC-RM-1L at step 2.
Other current-line alternatives (2 tracks)
Same treatment line; review when biomarker, access, contraindication, or patient-context assumptions change.
- Indication
- IND-HNSCC-RM-1L-PEMBRO-MONO-CPS-HIGH
- Regimen
- Pembrolizumab monotherapy (HNSCC R/M, 1L; PD-L1 CPS ≥20)
- Drugs + NSZU
- Pembrolizumab (DRUG-PEMBROLIZUMAB) 200 mg IV q3w (or 400 mg IV q6w) · Day 1 every 3 weeks (or q6w), for up to 35 cycles (~2 years) or until progression / unacceptable toxicity · IV ⚠ NSZU — not for this indication
- Reason
- Current-line alternative presented for HCP consideration
- Indication
- IND-HNSCC-RM-1L-EXTREME
- Regimen
- EXTREME (cetuximab + cisplatin/carboplatin + 5-FU; HNSCC R/M, 1L)
- Drugs + NSZU
- Cetuximab (DRUG-CETUXIMAB) Loading 400 mg/m² IV day 1; then 250 mg/m² IV weekly · Loading dose week 1; weekly maintenance through chemotherapy and beyond as monotherapy until progression / toxicity · IV ✓ NSZU covered
- Cisplatin (DRUG-CISPLATIN) 100 mg/m² IV day 1 (preferred when ECOG 0-1, GFR ≥60, no neuropathy / ototoxicity / heart failure) · Day 1 of 21-day cycle, for up to 6 cycles · IV ✓ NSZU covered
- Carboplatin (DRUG-CARBOPLATIN) AUC 5 IV day 1 (substitute for cisplatin if contraindicated — GFR <60, neuropathy, hearing loss, congestive heart failure, or ECOG 2) · Day 1 of 21-day cycle, for up to 6 cycles (in lieu of cisplatin) · IV ⚠ NSZU — not for this indication
- 5-Fluorouracil (DRUG-5-FLUOROURACIL) 1000 mg/m² IV continuous infusion days 1-4 (96-hour infusion) · Days 1-4 of 21-day cycle, for up to 6 cycles · IV ✓ NSZU covered
- Reason
- Current-line alternative presented for HCP consideration
Red flags — PRO / CONTRA aggressive
PRO-AGGRESSIVE
Triggers that push toward the aggressive track
- Active or latent infection requiring resolution / prophylaxis before initiating cisplatin-based chemoradiation, cetuximab + RT, or pembrolizumab in HNSCC: HBsAg-positive (HBV reactivation on cytotoxic chemotherapy + checkpoint inhibitors), anti-HBc-positive (occult HBV on cetuximab — anti-EGFR class), HIV-positive (ART coordination, often comorbid in HPV-related HNSCC), or active TB.
RF-HNSCC-INFECTION-SCREENING
- Baseline organ dysfunction precluding standard cisplatin-based chemoradiation or pembrolizumab + 5-FU + cisplatin / cetuximab in head and neck squamous cell carcinoma: CrCl <60 mL/min (cisplatin contraindicated at full dose, switch to carboplatin or cetuximab), hearing loss / ototoxicity baseline (cisplatin contraindicated), LVEF <50% (5-FU cardiac risk), bilirubin >3× ULN (taxane / 5-FU metabolism), or severe peripheral neuropathy (cisplatin + taxane contraindicated).
RF-HNSCC-ORGAN-DYSFUNCTION
CONTRA-AGGRESSIVE
Hard contraindications to escalation
What NOT to do
Explicit prohibitive rules, each grounded in a regimen / supportive care / contraindication entity
Standard plan (IND-HNSCC-RM-1L-PEMBRO-CHEMO)
- Do NOT initiate immunotherapy without confirmed PD-L1 CPS testing on representative tumor tissue (biopsy preferred).
- Do NOT use cisplatin in patients with GFR <60, gr ≥2 hearing loss, gr ≥2 neuropathy, or significant CHF — switch to carboplatin AUC 5.
- Do NOT continue pembrolizumab through gr ≥3 immune-related AE without high-dose corticosteroid initiation + multidisciplinary irAE management.
Aggressive plan (IND-HNSCC-RM-1L-PEMBRO-MONO-CPS-HIGH)
- Do NOT use pembrolizumab monotherapy in CPS <20 — chemo-IO or EXTREME is preferred.
- Do NOT use pembrolizumab monotherapy as 1L in rapidly progressive / visceral-crisis disease — early progression risk before IO kinetics establish.
- Do NOT continue pembrolizumab through gr ≥3 immune-related AE without high-dose corticosteroid initiation + multidisciplinary irAE management.
Standard plan (IND-HNSCC-RM-1L-EXTREME)
- Do not prescribe EXTREME without HPV testing — HPV+ status does not change EXTREME selection in the recurrent setting, but is important for prognosis + clinician feedback.
- Do not skip baseline GFR / audiogram / neuropathy assessment before cisplatin — carboplatin is an acceptable substitute if there are any contraindications.
- Do not use cetuximab without premedication at the first infusion — anaphylaxis risk especially in SE US (alpha-gal IgE).
- Do not skip prophylactic doxycycline + emollient + sunscreen for acneiform rash — substantially reduces severity + improves adherence.
- Do not start 5-FU without discussion of DPD testing — DPD-deficient patients can have fatal toxicity.
- Do not skip monitoring of magnesium / electrolytes — cetuximab + cisplatin substantially lower Mg; replacement is mandatory.
Timeline
Treatment timeline — derived from regimen + monitoring schedule
Standard plan
Induction · Pembrolizumab + 5-FU + platinum (HNSCC R/M, 1L; PD-L1 CPS ≥1)
21-day cycles × 6 cycles of chemotherapy backbone, then pembrolizumab maintenance up to 35 cycles total (~2 years)
Aggressive plan
Induction · Pembrolizumab monotherapy (HNSCC R/M, 1L; PD-L1 CPS ≥20)
21-day cycles × Up to 35 cycles (~2 years) or until progression
Standard plan
Induction · EXTREME (cetuximab + cisplatin/carboplatin + 5-FU; HNSCC R/M, 1L)
21-day cycles × Up to 6 cycles of chemotherapy backbone; cetuximab continued weekly as monotherapy until progression or unacceptable toxicity
MDT brief
Discussion questions (1, 0 blocking)
MDT talk tree (2 steps)
| # | Owner | Topic | Action |
|---|
| 1 | hematologist | Staging / disease burden | What is the current LDH? Marker of tumor burden and transformation. |
| 2 | clinical_pharmacist | Specialist review | Chemoimmunotherapy regimen — drug-drug interactions, dose adjustments, premedication. |
Skills (recommended) — for consideration (1)
Data quality
Usable with caveats. No critical default-track gap was found, but the MDT should review the listed caveats before final sign-off.
- Biomarker coverage: 1/1 known (100%), 0 missing, 0 default-track gaps
- Unevaluated RedFlags: RF-ACTIVE-AUTOIMMUNE-DISEASE-ICI-RISK, RF-HNSCC-FRAILTY-AGE, RF-HNSCC-HIGH-RISK-BIOLOGY, RF-HNSCC-INFECTION-SCREENING, RF-HNSCC-ORGAN-DYSFUNCTION, RF-HNSCC-TRANSFORMATION-PROGRESSION, RF-OCC-FORMALDEHYDE-PREVENTION, RF-OCC-WOOD-LEATHER-DUST-PREVENTION
Technical MDT skill metadata (1/16 activated in this plan)
All registered virtual specialists. ✓ — activated for this case; ○ — not activated (available for other clinical scenarios).
| Specialist | skill_id | Version | Last reviewed | Sign-offs | Domain |
|---|
| Cellular therapy specialist (CAR-T) | cellular_therapy_specialist | v0.1.0 | 2026-04-25 | 0 | cellular_therapy |
| Clinical pharmacist | clinical_pharmacist | v0.1.0 | 2026-04-25 | 0 | clinical_pharmacy |
| Hematologist / oncohematologist | hematologist | v0.1.0 | 2026-04-25 | 0 | hematology_oncology |
| Hematopathologist (lymphoma / leukemia / myeloma) | hematopathologist | v0.1.0 | 2026-04-25 | 0 | hematopathology |
| Infectious disease / hepatology | infectious_disease_hepatology | v0.1.0 | 2026-04-25 | 0 | infectious_diseases |
| Medical oncologist (solid-tumor chemotherapist) | medical_oncologist | v0.1.0 | 2026-04-25 | 0 | solid_oncology |
| Molecular geneticist / molecular oncologist | molecular_geneticist | v0.1.0 | 2026-04-25 | 0 | molecular_oncology |
| Palliative care | palliative_care | v0.1.0 | 2026-04-25 | 0 | palliative_care |
| Pathologist (general) | pathologist | v0.1.0 | 2026-04-25 | 0 | pathology |
| Primary care / family physician | primary_care | v0.1.0 | 2026-04-25 | 0 | primary_care |
| Psycho-oncologist | psychologist | v0.1.0 | 2026-04-25 | 0 | psychosocial |
| Radiation oncologist | radiation_oncologist | v0.1.0 | 2026-04-25 | 0 | radiation_oncology |
| Radiologist | radiologist | v0.1.0 | 2026-04-25 | 0 | diagnostic_imaging |
| Social worker / case manager | social_worker_case_manager | v0.1.0 | 2026-04-25 | 0 | psychosocial |
| Surgical oncologist | surgical_oncologist | v0.1.0 | 2026-04-25 | 0 | surgical_oncology |
| Transplant specialist (BMT) | transplant_specialist | v0.1.0 | 2026-04-25 | 0 | cellular_therapy |
Sources cited
- SRC-ESMO-HNSCC-2020: Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2020)
- SRC-EXTREME-VERMORKEN-2008: Platinum-based chemotherapy plus cetuximab in head and neck cancer (2008)
- SRC-NCCN-HNSCC-2025: NCCN Clinical Practice Guidelines — Head and Neck Cancers (2025.v3)
- SRC-ONCOKB: OncoKB — Precision Oncology Knowledge Base (continuous (last verified 2026-04-25))
Experimental options (clinical trials)
Third plan track — open-enrollment trials from ClinicalTrials.gov. Render-time metadata; engine selection is not affected by this block (CHARTER §8.3). Last synced: 2026-06-27.
| NCT | Title | Phase | Status | Sponsor | UA | Signals | Eligibility (excerpt) |
|---|
| NCT05854823 | The Efficacy and Safety of De-escalated Postoperative Radiotherapy in Locally Advanced HNSCC With pCR/MPR | NA | RECRUITING | — | Small N (<50) Surrogate endpoint only Single country | |
| NCT06190782 | Local Therapy for Oligometastatic ESCC Patients Treated With PD-1 Inhibitor | PHASE3 | RECRUITING | — | Surrogate endpoint only Single country | |
| NCT06876844 | Surufatinib Combined with Envolizumab As Second-line Treatment for Recurrent/Metastatic HNSCC | PHASE2 | RECRUITING | — | Small N (<50) Surrogate endpoint only Single country | |
| NCT07055841 | Single-Arm Exploratory Study of PD-L1 Antibody Plus Neoadjuvant Chemotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma | PHASE2 | RECRUITING | — | Surrogate endpoint only Single country | |
| NCT06056336 | Perioperative Tislelizumab Plus Chemotherapy for Resectable Thoracic Oesophageal Squamous Cell Carcinoma | PHASE2 | RECRUITING | — | Surrogate endpoint only Single country | |
| NCT07152678 | Brachytherapy With Radiotherapy and Immunotherapy: Guided HDR Trial in Esophageal Squamous Cell Carcinoma | PHASE2 | RECRUITING | — | Single country | |
| NCT05791149 | Epigenetic Biomarkers in the Saliva for the Diagnosis of Squamous Cells Carcinoma of the Oral Cavity | NA | RECRUITING | — | Single country | |
| NCT07195734 | Testing the Addition of Chemotherapy or Chemo-Immunotherapy to the Usual Surgery for Advanced Head and Neck Cancer | PHASE2 | RECRUITING | — | Single country | |
| NCT06725368 | Carboplatin + Paclitaxel + Cetuximab (PCC) After Failure of Pembrolizumab +/- First-line Chemotherapy in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck | PHASE2 | RECRUITING | — | Small N (<50) Surrogate endpoint only Single country | |
| NCT07223424 | Patient Preference for Subcutaneous vs. Intravenous Immune Therapy | PHASE2 | RECRUITING | — | Single country | |
Verify recruitment status directly with the trial site. ctgov data can lag behind current UA-site status.
Option availability in Ukraine
Per-track UA registration · NSZU · cost · access pathway. Render-time metadata; engine selection does not depend on these fields (CHARTER §8.3).
| Option | UA registration | NSZU | Cost orientation | Access pathway |
|---|
| Standard plan Pembrolizumab + 5-FU + platinum (HNSCC R/M, 1L; PD-L1 CPS ≥1) (REG-PEMBRO-CHEMO-HNSCC-1L) | ✓ registered | ✓ covered | ₴-? — verify pathway | NSZU formulary |
| Aggressive plan Pembrolizumab monotherapy (HNSCC R/M, 1L; PD-L1 CPS ≥20) (REG-PEMBRO-MONO-HNSCC-1L) | ✓ registered | ✓ covered | ₴-? — verify pathway | NSZU formulary |
| Standard plan EXTREME (cetuximab + cisplatin/carboplatin + 5-FU; HNSCC R/M, 1L) (REG-EXTREME-HNSCC) | ✓ registered | ✓ covered | ₴-? — verify pathway | NSZU formulary |
| Trial · NCT05854823 The Efficacy and Safety of De-escalated Postoperative Radiotherapy in Locally Advanced HNSCC With pCR/MPR No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT06190782 Local Therapy for Oligometastatic ESCC Patients Treated With PD-1 Inhibitor No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT06876844 Surufatinib Combined with Envolizumab As Second-line Treatment for Recurrent/Metastatic HNSCC No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT07055841 Single-Arm Exploratory Study of PD-L1 Antibody Plus Neoadjuvant Chemotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT06056336 Perioperative Tislelizumab Plus Chemotherapy for Resectable Thoracic Oesophageal Squamous Cell Carcinoma No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT07152678 Brachytherapy With Radiotherapy and Immunotherapy: Guided HDR Trial in Esophageal Squamous Cell Carcinoma No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT05791149 Epigenetic Biomarkers in the Saliva for the Diagnosis of Squamous Cells Carcinoma of the Oral Cavity No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT07195734 Testing the Addition of Chemotherapy or Chemo-Immunotherapy to the Usual Surgery for Advanced Head and Neck Cancer No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT06725368 Carboplatin + Paclitaxel + Cetuximab (PCC) After Failure of Pembrolizumab +/- First-line Chemotherapy in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT07223424 Patient Preference for Subcutaneous vs. Intravenous Immune Therapy No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
Cost information is orientation. Verify with a specific pharmacy / foundation / trial site. Status updated: 2026-06-27.