What are the current evidence based indications for chemotherapy in the MAN of HNC?
- Organ preservation of larynx (resectable stage III and IV dz, excluding T1): RT 70 Gy + high dose cisplatin
- Organ preservation of hypopharynx (resectable stage III and IV dz, excluding T1): Cisplatin + 5-FU x 3 cycles, then 70 Gy RT
- Oropharynx, resectable T3-T4 or N2-N3: RT 70 Gy + cisplatin or carboplatin + 5-FU x 3 cycles
- NP stages IIB, III, IVA, IVB: RT 70 Gy + high dose cisplatin, adjuvant cisplatin + 5-FU x 3 cycles
- Unresectable, all sites: RT 70 Gy + cisplatin
- Postop adjuvant (ECS or + margins): 70 Gy RT + high dose cisplatin
- CI to systemic chemo, stage III or IV dz: Cetuximab followed by 70 Gy RT + cetuximab
Chemotherapy effects
- Enhance effects of RT
- Shrink tumors
- Not curative
- May not reach center of tumor
What is more effective:
- Induction chemo then RT or
- Concurrent chemoRT
Concurrent chemoRT is more effective but more severe SE (mucositis, swallowing difficulties)
What are the most commonly used cytotoxic drugs used to treat recurrent or metastatic HNSCC
- Cisplatin
- Carboplatin
- Docetaxel
- Paclitaxel
- 5-FU
- MTX
- Cetuximab
Cisplatin
- Platinum-based alkylating agent
- Covalent adducts w/ DNA that block replication and transcription
- Tox: renal, GI, myelosuprression, oto, peripheral neuropathy, visual, sz’s
- HL from loss of outer hair cells via R.O.S.
Carboplatin
- Lower rates of nephro and neurotox
- Less N/V
5-FU
- Inhibits DNA synthesis by binding thymidylate synthase w/ subsequent depletion of precursor proteins for DNA synthesis
- S phase
- SE: BM suppression, GI mucositis, hyperpigmentation, dermatitis, alopecia, conjunctivitis, blepharitis, epiphora
- Synergistic w/ other chemo drugs and RT
Docetaxel
- Taxane
- Target mitosis by binding microtubules, stabilizing them and disrupting microtubule dynamics thus inhibiting spindle fnc
- Induce mitotic arrest then apoptosis
- Tox: myelosuprresion w/ neutropenia, hair loss, fluid retention
Paclitaxel
- Taxane
- Peripheral neuropathy and arthralgia
Methotrexate
- Antifolate antimetabolite
- Inhibition of dihydrofolate reductase
- Prevents nl thymidylate and purine nucleotide synthesis resulting in single and ds DNA breaks
- S phase
- Tox: myelosuppression, GI mucositis, nephrotox, hepatotox, neurotox, acute/chronic hepatic dysfnc, encephalopathy, dementia
What are biologic modifiers for HNC?
Basically all target EGFR
- Cetuximab (monoclonal Ab to EGFR)
- Panitumumab (same)
- Gefitinib (TK inhibitors (downstream of EGFR))
- Erlotinib (same)
What is the main SE of cetuximab?
Acneiform rash in 84% (a good sign for prognosis)
What are the different administration schedules of chemo?
- Induction (neoadjuvant) chemo
- Concurrent chemoRT
- Sequential (induction then concurrent)
- Adjuvant chemo
What are the general ways chemo is used in HNC?
- Organ preservation (use w/ RT)
- Locally advanced, unresectable dz
- Post-op for high risk dz (w/ RT)
- Palliation of recurrent, inoperable dz
Studies re: organ preservation of the larynx
- VA Laryngeal Cancer Study Group 1991
- 64% of advanced larynx CA pts preserved their larynx w/ chemoRT
- More chemoRT failed locally but less distantly vs surgery
- Less second primaries in the chemoRT group vs surgery
- Salvage surg predictors: T4 and Stage IV dz
- RTOG 91-11 study
- 3 arms: induction cisplatin & 5-FU then RT; concurrent cisplatin/RT; RT alone
- overall survival similar
- locoregional control better in concurrent group
- 2 yr laryngeal preservation rate better in concurrent group
- Concurrent group required less salvage TL’s
What are the recommendations for larynx preservation based on the VA study and RTOG 91-11?
- Concurrent chemoRT is standard of care for laryngeal preservation in advanced laryngeal CA
- Exception: T4 dz should get primary laryngectomy
- No organ preservation for those w/ pretreatment organ dysfnc
Organ preservation of larynx in hypopharyngeal CA
- ChemoRT is not as good at preserving larynx for hypopharyngeal CA as for laryngeal CA
- Reserved for pts w/ Stage III dz w/ low volume primary tumors
- Induction chemo followed by RT is evidence based standard of care (not concurrent chemoRT)
- Not indicated for T4 dz
What is the major risk of chemoRT with hypopharyngeal cancers?
Pharyngoesophageal strictures w/ subsequent g-tube dependence
What specific factor can help optimize treatment selection in OP CA pts?
- HPV status
- HPV-neg dz has less success w/ non-op Rx and poorer surgical salvage results
What is a CI to chemoRT w/ OP CA?
T4 dz invading the mandible bc of risk of ORN
Chemo/RT for advanced stage OP CA
- Lack of evidence comparing chemo/RT to surgery
- Chemo not beneficial for Stage I or II and for some stage III (T1 or T2 lesions and N1 dz)
- Successful salvage of OP primary site recurrence is far less likely than hypopharynx or larynx salvage (successful locoregional control w/ initial Rx is critical for survival)
HPV + tumors
- Improved survival and dz control rates vs HPV (-)
- Survival benefit INDEPENDENT of tx modality
- p/w smaller primary sites and more advanced nodal dz
- Advanced nodal stage is not negative to prognosis as long as HPV is (+)
- Increased sensitivity to RT and may not require intensive concurrent chemo regimens
NP CA
- Non-op tx is standard of care for initial tx
- Hard to get margins at the skull base
- NP CA is very radiosensitive
- Stage I and IIA – RT alone
- Stage IIB and above – concurrent chemo/RT
What are the WHO types for NP CA?
- WHO I (SCCa)
- WHO II (nonkeratinizing CA)
- WHO III (undifferentiated CA)
- I is m/c in US vs II & III m/c in world (more distant mets and more responsive to chemo/RT, a/w EBV)
