Systemic Therapy in Head & Neck Cancer Radiation Oncology Grand Rounds Tuesday, December 3, 2013 Michelle T. Ashworth, MD Clinical Fellow, Hematology-Oncology

Epidemiology: World 560,000 cases per year 300,000 deaths per year M:F 2-4:1 300,000 deaths per year 5th most common cancer worldwide. Substantial geographic variation due to differences in risk factors. World data: from http://www.qub.ac.uk/research-centres/nicr/FileStore/PDF/AllIrelandCancerAtlas1995-2007/Filetoupload,271800,en.pdf Accessed 11/23/13 #5 cancer

Epidemiology: US 53,000 cases per year 11,500 deaths per year M:F 2-4:1 11,500 deaths per year “A Snapshot of Head and Neck Cancer,” NCI, http://www.cancer.gov/researchandfunding/snapshots/pdf/HeadandNeck-Snapshot.pdf Incidence per 100,000 from 1989 to 2009. Accessed 11/23/13 Oral cavity & oropharynx M:F 2:1 Larynx M:F 4:1

Epidemiology: US 3% of all cancers in US $3.6B per year From http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2013/index and http://www.cancer.gov/researchandfunding/snapshots/pdf/HeadandNeck-Snapshot.pdf Incidence per 100,000 from 1989 to 2009. Accessed 11/23/13. Epidemiologic transition in SCCHN from elderly males to females (with rise of tobacco use) and younger patients (with increase in HPV-related oropharyngeal cancer)

Anatomic structures Anatomic definition: cancers that arise in the head and neck region, including oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, thyroid and salivary glands. Illustration from utdol.com, accessed 11/23/13.

Nasal cavity & paranasal sinuses Sinuses: maxillary, ethmoid, frontal, sphenoid Illustration from utdol.com, accessed 11/23/13.

Oral cavity Oral cavity: lips, buccal mucosa, anterior tongue, floor of mouth, hard palate, gingiva, retromolar trigone Illustration from utdol.com, accessed 11/23/13.

Salivary glands Salivary glands – Major: parotid, submandibular, sublingual Minor: located throughout submucosa of mouth and upper aerodigestive tract, including oral cavity (especially palate), paranasal sinuses, larynx, pharynx Illustration from utdol.com, accessed 11/23/13.

Pharynx Pharynx – Nasopharynx: upper pharynx Oropharynx: tonsillar area, base of tongue, soft palate, posterior pharyngeal wall Hypopharynx: piriform sinuses, posterior surface of larynx, inferoposterior & inferolateral laryngeal walls Illustration from utdol.com, accessed 11/23/13.

Larynx Larynx = vocal cords + epiglottis Supraglottic larynx Glottic larynx: true vocal cords, anterior & posterior commissures Subglottic larynx Illustration from utdol.com, accessed 11/23/13.

Lymph nodes Illustration from utdol.com, accessed 11/24/13.

Presenting symptoms Pain Ulcer Mass Voice change Weight loss Cough Dysphagia Cough Weight loss Pain can include odynophagia, referred otalgia, any Important to monitor as patients can experience synchronous or metachronous SCC

Anatomic divisions per NCCN guidelines Lip Glottic larynx Oral cavity Supraglottic larynx Oropharynx Ethmoid sinus Staging and treatment paradigms vary by site of primary (and by tumor type). Illustration from utdol.com, accessed 11/23/13. Maxillary sinus Hypopharynx Nasopharynx Occult primary

Reference: Changes in Survival in Head and Neck Cancers in the Late 20th and Early 21st Century: A Period Analysis. Pulte D, Brenner H. The Oncologist 2010;15:994-1001 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228039/pdf/onc994.pdf Data from NCI SEER program, 2009. Note: SEER reporting data do not correlate exactly with NCCN treatment guidelines anatomical divisions.

Squamous mucosal epithelium Tissues of origin 90% SCCHN Squamous mucosal epithelium Blood vessels Glands Muscle Bone Lymph nodes Glandular structures: salivary glands, thyroid gland, parathyroid glands Cancers arising from brain, eye, ear, scalp, skin, teeth, bones, muscles generally considered separately, but tend to be treated by same multidisciplinary team (except brain, eye) Cartilage Nerves

>60% oropharyngeal cancer Risk factors #1: tobacco & alcohol HPV (16): >60% oropharyngeal cancer EBV: Nasopharyngeal cancer HIV: 2-3x RR Betel nut Occ Exp Diet Risk factors Tobacco: Associated with 70% of head and neck cancers. Dose-dependent effect, related to age of onset of use, duration, and amount, with 5-25x increased risk as compared to nonsmokers Alcohol: Dose-dependent and synergistic effect with tobacco, and may be affected by genetic susceptibility Betel nut: Synergistic with tobacco and alcohol; also associated with HCC and esophageal cancer Occupational exposures: Many, including formaldehyde, leather, paint, construction, farming, cement, asbestos, auto mechanic, wood-work, metal workers, ethanol, sulfuric acid mist Diet: Preserved meats with high nitrites and NPC RT: Long latency, low risk Genetics: Fanconi anemia “Epidemiology and Risk Factors for Head and Neck Cancer,” www.utdol.com, accessed 11/23/03. Note: 90% = SCCHN RT Agent Orange Genetics

HPV as prognostic biomarker in oropharyngeal SCCHN Chaturvedi et al 2011

Pre-malignant lesions SCCHN – Pathogenesis Field cancerization Pre-malignant lesions Stepwise progression May be reversible EGFR 90% p53 50-80% HER2 50% Pathogenesis Field cancerization: adjacent normal-appearing mucosa can contain dysplasia, CIS or invasive carcinoma; biopsy of matched dysplastic and malignant lesions can show identical or unique abnormalities. Highlights importance of evaluation for synchronous primaries, and follow-up for metachronous primaries. Premalignant lesions: leukoplakia, erythroplakia Genetic abnormalities 90%: EGFR and its ligand TGF-alpha are overexpressed → autocrine activation loop (EGFR inhibitor, cetuximab); downstream constitutive activation of Src as a mechanism of EGFR resistance is now a treatment target on clinical trials (TKI, dasatinib, in combination with cetuximab) 50-80%: p53 loss (p53 can be non-mutated but inactivated by HPV E6 viral protein) [negative prognostic and predictive biomarker] 50%: HER2 overexpression 10%: PTEN loss 6-8%: PI3KCA mutations 4-5%: HRAS → RAF → MEK → ERK and also PI3K PTEN 10% PI3KCA 6-8% HRAS 5%

Pretreatment & staging evaluation All patients: H&P, biopsy, pre-anesthesia studies Fiber-optic exam, EUA, video-strobe Dental, nutrition, speech & swallow, audiogram CT/MRI primary & neck Chest imaging Consider PET/CT for stage III-IV HPV, EBV Lip F PRN D PRN Oral cavity F, EUA PRN N, SS PRN √ c √ Oropharynx N, SS, A PRN HPV Hypopharynx F, VS PRN EUA, N, SS, A PRN Nasopharynx F D, N, SS, A PRN * c √ * EBV Glottic & supraglottic larynx EUA √ c • Ethmoid sinus D PRN ^ Maxillary sinus Occult primary~ F PRN, EUA PRN = “if clinically indicated” or “consider” EUA = exam under anesthesia with endoscopy c = with contrast * = MRI with contrast of nasopharynx, base of skull, neck to clavicles (or CT of skull base/neck); consider PET/CT for nonkeratinizing histology, endemic phenotype, N2-3, stage III-IV • = CT with thin cuts through the larynx ^ = CT/MRI skull base through thoracic inlet ~ = not lymphoma, thyroid, or melanoma HPV testing by p16 IHC or HPV DNA ISH for prognosis, clinical trials

Role of systemic therapy (ST) Adjuvant (after surgery) [early stage, adverse features discovered at time of surgery] Concurrently with RT, as a radiosensitizer Definitive-intent [later stage, adverse features apparent prior to surgery] Concurrently with RT, as a radiosensitizer, or Induction followed by concurrent chemo/RT Controversial: careful patient selection and expert management of toxicities required Possibly followed by surgery for residual or recurrent disease Palliative-intent (unresectable/metastatic) Concurrently with RT or alone; combination regimens or monotherapy Intended to control symptoms, prolong life Induction – considered more often in early-stage hypopharyngeal cancer with larynx-sparing intent

Treatment paradigms for early stage SCCHN Lip, oral cavity & oropharynx: Surgery → ST/RT → VAHNC Hypopharynx: RT or ST or ST/RT → assess for response → surgery or ST/RT Nasopharynx: RT or ST/RT +/- adjuvant ST or ST → ST/RT or ST Glottic & supraglottic larynx: RT or surgery +/- adjuvant ST or ST/RT or ST → assess for response → surgery or ST/RT Ethmoid sinus: Surgery → RT or ST/RT → observation or RT or ST/RT In general, where to start for early-stage disease: Lip: Surgery → chemo/RT → VAHNC Oral cavity: Surgery → chemo/RT → VAHNC Oropharynx: Surgery → chemo/RT → VAHNC Hypopharynx: Larynx-preservation RT or induction chemo or chemo/RT; assess for response; surgery or chemo/RT Nasopharynx: Definitive RT, or chemo/RT +/- adjuvant chemo, or induction chemo then chemo/RT, or combination chemo Glottic larynx: Larynx-preservation RT or surgery +/- adjuvant chemo/RT or chemo/RT or induction chemo; assess for response; surgery or chemo/RT Supraglottic larynx: Larynx-preservation RT or surgery +/- adjuvant chemo/RT or chemo/RT or induction chemo; assess for response; surgery or chemo/RT Ethmoid sinus: Surgery → definitive RT or chemo/RT → adjuvant RT, obs, or chemo/RT

Very advanced SCCHN “Very advanced” SCCHN of lip, oral cavity, oropharynx, hypopharynx, glottic larynx, supraglottic larynx T4b, Nany, M0 or unresectable nodal disease or, if patient is not a surgical candidate Clinical trial preferred For PS 1: ST/RT or ST → RT or ST/RT For PS 2: RT +/- ST For PS 3: RT or single- agent ST or best supportive care (BSC) If primary controlled + residual disease, follow with salvage surgery / neck dissection if possible

Systemic therapy agents Bleomycin Gemcitabine (NPC) Vinorelbine Capecitabine Targeted therapy EGFR/HER1 inhibitor cetuximab Clinical trial agents Anti-PD1 or anti-PDL1 antibody, e.g. MK-3475 Injectable oncolytic virus, e.g. TVEC Other targeted agents, e.g. dasatinib Cytotoxic chemotherapy Cisplatin or carboplatin 5-FU Docetaxel or paclitaxel Hydroxyurea Epirubicin Methotrexate Ifosfamide

Systemic therapy agents Cisplatin or Carboplatin Cetuximab Docetaxel or paclitaxel 5-FU Hydroxy-urea Epirubicin MTX Ifos Cisplatin Mechanism: DNA cross-linking inhibits DNA synthesis Limitations: Highly emetogenic, myelosuppression, renal impairment, ototoxicity, neurotoxicity (peripheral neuropathy), hypersensitivity reaction Administration: PIV, 1-2L prehydration, antiemetics Carboplatin Mechanism: DNA cross-linking, inhibits DNA synthesis Limitations: Emetogenic, myelosuppression, electrolyte abnormalities, hepatotoxicity & nephrotoxicity Administration: PIV, antiemetics Cetuximab Mechanism: EGFR and HER-1 inhibitor, mAb [EGFR is found in high levels in normal proliferating tissue; aberrant expression is associated with cell proliferation, survival, angiogenesis, invasion and metastasis; high nuclear localization (nEGFR) in epithelial cancers including SCCHN; nuclear translocation is induced by radiation, cisplatin; increased nEGFR correlates decreased OS and response rate, increased recurrence rate Limitations: Infusion reactions, rash, fatigue, GI upset including dysgeusia, electrolyte abnormalities, CNS effects (headache, insomnia, confusion) Administration: PIV, antihistamine with at least 1st dose Docetaxel Mechanism: Taxane, microtubule stabilizer, inhibits synthesis of DNA, RNA and proteins during M phase Limitations: Adjust dosing for hepatic impairment; alopecia, weakness, myelosuppression, stomatitis, CNS effects including neuropathy, GI upset, hypersensitivity reactions; drug-drug interactions Administration: PIV, premedicate with steroids x3d starting 1d prior to treatment to reduce hypersensitivity reactions and fluid retention Paclitaxel Mechanism: Taxane, microtubule stabilizer, inhibits assembly of DNA, RNA and proteins Limitations: Adjust dosing for hepatic impairment; myelosuppression, alopecia, peripheral neuropathy, hypersensitivity reactions, GI upset, mucositis; drug-drug interactions Administration: PIV, premedicate with steroids starting night before treatment + steroid and dual antihistamine blockade (H1 & H2) before infusion 5-FU Mechanism: Pyrimidine analog antimetabolite, interferes with DNA and RNA synthesis Limitations: Adjust dosing for hepatic impairment; drug-drug interactions; DPD deficiency → increased toxicity Administration: PIV or CIVI via infusion pump Hydroxyurea Mechanism: Selectively inhibits ribonucleoside diphosphate reductase, preventing creation of deoxyribonucleotides; radiosensitizes by locking cells in G1 and blocking DNA repair Limitations: Adjust dosing for renal impairment; myelosuppression, dermatologic toxicity, GI upset; increased toxicity with prior XRT or chemo Administration: PO Epirubicin Mechanism: Anthracycline; intercalates between DNA base pairs, not cell-cycle specific, triggers DNA cleavage; radiosensitizes Limitations: Adjust dosing for hepatic impairment; emetogenic, myelosuppression, alopecia, mucositis; acute or delayed cardiotoxicity Administration: PIV Methotrexate Mechanism: Folate metabolite, inhibits dihydrofolate reductase → inhibits purine and thymidine synthesis, therefore DNA synthesis and repair; S-phase specific Limitations: Adjust dosing for renal or hepatic impairment; mucositis, myelosuppression, GI upset, renal impairment, hepatotoxicity; contraindicated in ascites or effusions; AVOID concurrent NSAIDs, salicylates, PPI Administration: PIV/PO Ifosfamide Mechanism: Nitrogen mustard alkylating agent → DNA crosslinking Limitations: Adjust dosing for renal or hepatic impairment; alopecia, myelosuppression, emetogenic, metabolic acidosis, CNS toxicity including characteristic encephalopathy, renal impairment Administration: PIV; requires prehydration and coadministration with mesna for bladder protection against hemorrhagic cystitis Bleomycin Mechanism: Antibiotic that binds to DNA and promotes strand breaks Limitations: Adjust dose for renal impairment; risk of anaphylaxis requires administration of test dose; risk of pulmonary toxicity with age >70 and cumulative lifetime dose >400 mg; dermatologic toxicity, mucositis, acute febrile reaction Gemcitabine (NPC) Mechanism: Pyrimidine antimetabolite; inhibits DNA polymerase and ribonucleotide reductase, therefore inhibiting DNA synthesis in S phase Limitations: Adjust dose for hepatic impairment; myelosuppression, emetogenic, hepatotoxic, proteinuria, rash, edema, fever; rarely HUS, capillary leak syndrome, pulmonary toxicity; avoid giving concurrently with radiotherapy (within ≤7 days) Administration: IV Capecitabine Mechanism: Oral prodrug hydrolyzed to 5-FU in the liver and tissues; pyrimidine analog antimetabolite, interferes with DNA and RNA synthesis Limitations: Adjust dosing for renal impairment; myelosuppression, hand-foot syndrome (palmar-plantar erythrodysesthesia), diarrhea, hepatotoxicity, paresthesias; increased toxicity with DPD deficiency; AVOID concurrent warfarin Vinorelbine Mechanism: Vinca alkaloid that inhibits microtubule depolymerization and arrests cells at metaphase, active in M and S phase; blocks glutamic acid formation Limitations: Adjust dose for hepatic impairment; myelosuppression, hepatotoxicity, GI upset, weakness, fatigue, neuropathy, alopecia Administration: IV (fatal if given intrathecally) Bleo Gem Cape Vin

Commonly used SCCHN treatment regimens Concurrent systemic therapy as radiosensitizer Cisplatin 100 mg/m2 IV every 3 weeks, or 40 mg/m2 IV weekly Carboplatin AUC 5-6 IV every 3 weeks Cetuximab 400 mg/m2 IV week 1, then 250 mg/m2 weekly thereafter Induction “PF,” Cisplatin 100 mg/m2 IV d1 + 5-FU 1000 mg/m2 daily IV d1-5 “TPF,” taxane, platinum, 5-FU: docetaxel 75 mg/m2 + cisplatin 80 mg/m2 + 5-FU 800 mg/m2/day x96h CIVI every 3 weeks x3 Palliative-intent Single-agent or combination regimens Cisplatin 100 mg/m2 every 3 weeks aka “high dose” cisplatin AUC dosing = Calvert formula: Total dose (mg) = AUC * (GFR + 25), max 125 mL/min Regimen notes: - For concurrent administration with taxanes, administer taxane first to decrease myelotoxicity and increase efficacy - Start cetuximab 1 week prior to radiotherapy; in combination chemotherapy, complete cetuximab 1 hour prior to chemotherapy Induction Chemotherapy Controversy: Controversial in NCCN treatment guidelines; concern that residual toxicity can impair ability to deliver subsequent RT or ST/RT. Data based on cisplatin + 5FU. Consensus exists for use in hypopharyngeal cancer < T4a if pt not going to surgery. Change in pattern of failure rate noted, with less distant metastases; correlation between response to induction ST and subsequent durable response to RT. However, VA comparison trial in laryngeal cancer showed highest larynx preservation rate with concurrent ST/RT, and EORTC trial in advanced hypopharyngeal cancer showed highest larynx preservation rate with concurrent therapy, and induction ST was not superior to RT alone. Update: data based on TPF shows better ORR, PFS, OS, and larynx preservation as compared to PF. OS advantage for induction ST as compared to concurrent therapy not yet demonstrated, however (DECIDE and PARADIGM trials). Another recent Phase II study in locally advanced SCCHN (n=101) showed higher CR rate with induction ST as compared to concurrent therapy. After induction ST, use weekly (not every 3 weeks) chemo in concurrent therapy. Platinum + 5-FU + cetuximab Platinum + taxane Platinum + cetuximab Platinum + 5-FU Gemcitabine + vinorelbine (NPC)

Outcomes: Concurrent ST/RT in SCCHN Metaanalysis of chemotherapy trials in SCCHN: MACH-NC 87 trials 16,665 patients Median follow-up of 5.5 years Concurrent treatment, platinum-based Meta-analysis of chemotherapy trials in SCCHN MACH-NC 87 trials, 16,665 patients, median follow-up of 5.5 years

MACH-NC Meta-analysis of chemotherapy trials in SCCHN MACH-NC 87 trials, 16,665 patients, median follow-up of 5.5 years

MACH-NC Meta-analysis of chemotherapy trials in SCCHN MACH-NC 87 trials, 16,665 patients, median follow-up of 5.5 years

Weekly vs every 3 weeks concurrent cisplatin/RT in SCCHN Series of patients treated with cisplatin/RT: younger patients with ECOG PS 0-1 were treated with cisplatin every 3 weeks and older patients with ECOG 2 were treated with cisplatin weekly CR 50% vs 40%, p>0.05 ORR 92% vs 90%, p>0.05 G3-4 AEs 53% vs 40%, p>0.05

Concurrent cetuximab/RT in SCCHN Phase III study in advanced/ inoperable SCCHN with XRT +/- cetuximab 400 mg/m2 then 250 mg/m2 weekly showed median locoregional control 24.4 mo vs 14.9 mo and OS 49 mo vs 29.3 mo, with acneiform rash and infusion reactions in cetuximab-treated group but otherwise no difference in grade ≥3 AEs (Bonner, Ang et al N Engl J Med 2006 Feb 9;354(6):567- 78)

Concurrent cetuximab/RT in SCCHN Phase III study in recurrent/metastatic SCCHN of PF+XRT +/- cetuximab 400 mg/m2 then 250 mg/m2 weekly maintenance showed response rate 36% vs 20%, median PFS 5.6 vs 3.3 mo, and OS 10.1 mo vs 7.4 mo (Vermorken, Hitt et al N Engl J Med 2008 Sep 11;359(11):1116-27)

Subgroup Analysis

Cetuximab-related rash as predictive biomarker in SCCHN

Recurrent/metastatic SCCHN Overall survival 6-9 mo Factors correlating with good prognosis: ECOG 0-1, poorly differentiated histology, h/o response to chemotherapy Factors correlating with poor prognosis: ECOG ≥2, weight loss, recurrence after RT, current smoking, significant medical comorbidity Combination therapy regimens increase PFS but have not been shown to increase OS Treatment varies by PS, prior treatment, goals of care, and medical comorbidities Overall survival 6-9 months. Factors correlating with good prognosis: ECOG 0-1, poorly differentiated histology, h/o response to chemotherapy Factors correlating with poor prognosis: ECOG ≥2, weight loss, recurrence after RT, current smoking, significant medical comorbidity

Treatment outcomes – Combination therapy in metastatic SCCHN Cisplatin 100 mg/m2 or carboplatin AUC 5 + 5-FU 1000 mg/m2/d d1-4 +/- cetuximab every 3 weeks, up to 6 cycles, + maintenance cetuximab Limited to patients not previously treated for advanced cancer, KPS ≥ 70, largely ≤ age 65 Median PFS 5.6 mo vs 3.3 mo; median OS 10.1 mo vs 7.4 mo Patients not previously treated for advanced cancer (no prior systemic therapy), KPS ≥70

Treatment outcomes – Combination chemotherapy in recurrent/ metastatic SCCHN A Cisplatin 100 mg/m2 IV d1 + 5-FU 1000 mg/m2 IV/d d1-4 every 21d vs. B carboplatin 300 mg/m2 IV d1 + 5-FU 1000 mg/m2 IV d1-4 every 28d vs. C MTX 40 mg/m2 IV weekly ORR 32% vs. 21% vs. 10%; however, similar median OS across all 3 groups http://www.ncbi.nlm.nih.gov/pubmed/1634913

Treatment outcomes – Cetuximab in metastatic SCCHN Platinum-refractory patients ORR 13%; disease control rate 46% Median PFS 70 days; median OS 178 days Platinum refractory patients; ITT population outcomes varied somewhat by central review IRC outcomes

Future directions in SCCHN RTOG 1016 RT/cisplatin vs RT/cetuximab in HPV+ oropharyngeal cancer Stratification by stage, PS, smoking hx

Future directions – targeted therapy in SCCHN Afatinib: TKI of HER2, EGFR PII study in R/M SCCHN comparing afatanib 50 mg PO daily vs cetuximab 400 mg/m2 then 250 mg/m2 weekly showed 6/34 (18%) vs 3/40 (8%) PR, 18/34 (53%) vs 20/40 (50%) SD, 10/34 (30%) vs 17/40 (43%) with PD, and comparable safety profile (Siewert, Cohen et al J Clin Oncol 28:15s, 2010 suppl; abstr 5501) Recent FDA approval in NSCLC; multiple clinical trials in SCCHN now open http://www.ncbi.nlm.nih.gov/pubmed/23746666http://meetinglibrary.asco.org/content/93724-114 http://meetinglibrary.asco.org/content/98230-114 http://meetinglibrary.asco.org/content/50775-74

Future directions – targeted therapy in SCCHN Panitumumab: humanized mAb EGFR inhibitor PIII study in R/M SCCHN comparing panitumumab + CT to CT reported efficacy of panitumamab in pts with HPV+ vs HPV- tumors (retrospectively) and showed median OS in HPV+ PCT 11 mo vs CT 12.6 mo, and HPV- PCT 11.7 mo vs CT 8.6 mo*, i.e. improvement in OS with P only in HPV- (Vermorken et al Lancet Oncol 2013 Jul; 14(8):697-710) Open clinical trials in SCCHN Nimotuzumab: humanized mAb EGFR inhibitor PIII study in A/I SCCHN comparing nimotuzumab 200 mg weekly x 6-7 wks with or without cisplatin + XRT showed 24/25 (96%) vs. 18/25 (72%) objective response rate at 6 mo, without increased toxicity (Bhatnagur, Kumbaj et al J Clin Oncol 30, 2012 suppl; abstr e16012) Open clinical trials in SCCHN

Future directions – targeted therapy in SCCHN Combination therapy?

Future directions – immunotherapy in SCCHN Ipilimumab: mAb CTLA-4 inhibitor Experience in NSCLC: PII trial in stage IIIB/IV NSCLC comparing paclitaxel 175 mg/m2 + carboplatin AUC 6 with ipilimumab 3 mg/m2 q3 wks x4 then q12 wks showed median irPFS of 5.7, 5.5, and 4.6 mo; in phased arm, HR 0.55 in SCC vs 0.82 in NSCC. Phase III trial open in squamous NSCLC (Lynch, Reck et al J Clin Oncol 2012 Jun 10;30(17):2046-54)

Future directions – immunotherapy in SCCHN Various mAb PD-1 or PDL-1 inhibitors Evidence for PD-1:PDL-1 pathway in HPV+ SCCHN, with membranous expression of PDL-1 in tonsillar crypts (site of primary HPV infection), on tumor cells, and on tumor-associated macrophages, and high PD-1 expression on CD8+ TILs (Lyford-Pike, Pai et al Cancer Res 2013 Mar 15;73(6):1733-41) In-vitro blockade of tumor growth in oral SCC cell line with anti- PD-1 mAb (Tsushima, Azuma et al Oral Oncol 2006 Mar;42(3):268-74) Clinical trial now open T-VEC: talimogene laherparepvec, injectable oncolytic herpesvirus T-VEC is an oncolytic herpesvirus that has been modified both to replicate only in tumor cells and to elaborate granulocyte-macrophage colony stimulating factor (GM-CSF), a cytokine that enhances the generation of FcR expressing antigen presenting cells including monocytes and dendritic cells. Intratumoral expression of GM-CSF may therefore enhance tumor antigen presentation and subsequent priming of adaptive anti-tumor immune responses. Injection of T-VEC into cutaneous melanoma lesions can induce systemic immune responses with an objective response rate of 26.4% and a durable response rate of 16.3% [5]. Phase 1 testing of T-VEC also demonstrated molecular evidence of activity in head and neck cancer [6], but subsequent studies of T-VEC in SCC of the head and neck were performed in combination with platinum-based chemotherapy and radiation such that the independent contribution of T-VEC to therapeutic outcome was difficult to determine. Furthermore, the largest published study of this combination included only 17 patients [7].

Salivary gland tumors Adenoid cystic carcinoma, adenocarcinoma, mucoepidermoid carcinoma High grade (more likely to invade) vs low grade (more likely to be cured with local treatment) Epidemiology: not related to tobacco + ETOH, but prior RT may increase risk Standard of care is surgery +/- RT Systemic therapy as radiosensitizer or with palliative intent in advanced disease is often used; however, due to rarity of disease and mixed histology in trials, there is not clear evidence to support or contradict this KIT mutation noted in 80% of ACC; however, ORR of 0% in one trial of imatinib given to KIT-mutation-unknown patients with ACC Clinical trial recommended: targeted therapy, e.g. EGFR or VEGF Salivary duct carcinoma may express androgen receptors or overexpress HER2 or EGFR; responses reported to anti-androgen therapy, trial of trastuzumab ongoing

Nasopharyngeal carcinoma Nasopharynx: RT or ST/RT +/- adjuvant ST or ST → ST/RT or ST Concurrent cisplatin 100 mg/m2 IV every 3 weeks +RT, then cisplatin 80 mg/m2 + 5-FU 1000 mg/m2/d d1-4 every 4 weeks 5-year PFS 62 vs 53%, 5-year OS 68 vs 64% Single-arm study of concurrent carboplatin AUC 6 every 3 weeks then carboplatin AUC 5 + 5-FU 1000 mg/m2/d d1-4 every 4 weeks Narrowed improvement in OS attributed to increase in non-cancer deaths in treatment arm

Nasopharyngeal carcinoma Concurrent cisplatin 40 mg/m2 IV weekly + RT Narrowed improvement in OS attributed to increase in non-cancer deaths in treatment arm

Advanced nasopharyngeal carcinoma Induction with TPF: docetaxel 70 mg/m2 d1 + cisplatin 75 mg/m2 d1 + 5-FU 1000 mg/m2/d IV d1-4 x3 cycles, then RT + cisplatin 100 mg/m2 every 3 weeks 3-year PFS 75.6%, 3-year OS 86.1% Narrowed improvement in OS attributed to increase in non-cancer deaths in treatment arm

Mucosal melanoma 4% of all sinonasal malignancies Melanocytes are found in the mucosa in the sinonasal cavity in 21% of individuals Mean age of presentation 64.3 years RT improves local control; 50% will have local (vs. distant) recurrence Historically, studies have shown no difference in OS in treated with surgery vs surgery + RT or ST or all 3 5-year OS 25-42% 4% of all sinonasal malignancies Melanocytes are found in the mucosa in the sinonasal cavity in 21% of individuals Mean age of presentation 64.3 years RT improves local control; 50% have local recurrence; prior studies showed no difference in OS in treated with surgery vs surgery + RT or ST or all 3 5-year OS 25-42% http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466987/pdf/ijcep0005-0739.pdf

Mucosal melanoma 4% of all sinonasal malignancies Melanocytes are found in the mucosa in the sinonasal cavity in 21% of individuals Mean age of presentation 64.3 years RT improves local control; 50% have local recurrence; prior studies showed no difference in OS in treated with surgery vs surgery + RT or ST or all 3 5-year OS 25-42% http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466987/pdf/ijcep0005-0739.pdf

Mucosal melanoma Up to stage T4aN1: Surgery → RT Stage IVB onwards: Clinical trial preferred or RT or ST Systemic therapy in advanced disease: KIT mutation present in 30-40% of mucosal melanoma; responses reported to KIT inhibitors e.g. imatinib, and targeted therapy is available off-label or on clinical trials Imatinib: ORR 21%, median OS 46.3 weeks Ipilimumab: CR in 1/30 patients, PR 1/30, median OS 6.4 mo Anti-PD1 antibody on clinical trial: early reports of observed response Palliative-intent chemotherapy http://www.ncbi.nlm.nih.gov/pubmed/21642685

Conclusion Systemic therapy is generally used as a radiosensitizer or as palliative-intent treatment in head & neck cancer Advanced head & neck cancer has a generally poor prognosis despite systemic therapy New directions: Immunotherapy Targeted therapy Don’t forget: Prevention Early detection (screening algorithms)

Thank You Dr. Alain Algazi 5th most common cancer worldwide. Substantial geographic variation due to differences in risk factors. World data: from http://www.qub.ac.uk/research-centres/nicr/FileStore/PDF/AllIrelandCancerAtlas1995-2007/Filetoupload,271800,en.pdf Accessed 11/23/13

Indications for adjuvant ST/RT after surgery – adverse pathologic findings Lip: For ECE and/or pos margin; consider for multiple positive LNs, perineural/lymphatic/vascular invasion Oral cavity: For ECE and/or pos margin; consider for pT3 or pT4 primary, N2 or N3 inv, levels IV or V, PNI, vascular embolism Oropharynx: For ECE +/- pos margin; consider for pos margin, pT3 or pT4, N2 or N3, levels IV or V, PNI, vascular embolism Hypopharynx: For ECE and/or pos margin; consider for pT3 or pT4, N2 or N3, PNI, vascular embolism Nasopharynx: n/a Glottic larynx: For ECE +/- pos margin; consider for pos margin, pT3 or pT4, N2 or N3, PNI, vascular embolism Supraglottic larynx: For ECE and/or pos margin; consider for pT4 primary, N2 or N3, PNI, vascular embolism Ethmoid sinus: Consider for pos margins, intracranial extension