Chemo, Immuno, & Oncology

What is head and neck cancer?

Illustration showing nasal cavity, nasopharynx, tongue, oropharunx, sophagus, larynx, tracheaHead and Neck Cancer is a group of cancers that includes tumors in several areas above the collar bone.

  • Oral Cancer
  • Laryngeal Cancer
  • Nasopharyngeal Cancer

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What we know  (Head and Neck Cancer Facts)

  • Head and neck cancer (HNC) is 6th most common cancer worldwide; 60,000 new cases per year in the United States
  • Human Papilloma Virus (HPV) is involved in the etiology of ~60-80% of Oropharyngeal HNC in the US
  • HPV(-)/Tobacco-related HNC AND HPV(+) HNC are distinct clinical entities.

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Risk Factors for Head and Neck Cancer

  • Tobacco Products: 
– Smoking Tobacco
– Cigarettes
– Cigars
– Pipes
– Chewing Tobacco
– Snuff
  • Ethanol Products
  • Chemicals:
– Asbestos
– Chromium
– Nickel
– Arsenic
– Formaldehyde
  • Other Factors:
– Ionizing Radiation
– Plummer-Vinson Syndrome
– Epstein-Barr Virus
– Human Papilloma Virus

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Possible Occupational Risks for Head and Neck Cancer

  • Woodworking
  • Leather Manufacturing
  • Nickel Refining
  • Textile Industry
  • Radium Dial Painting

Incidence Among 9/11 First Responders:
Approximately 10,000 cancers have been attributed to 9/11 attacks.

First responders at 9/11 were exposed to complex mix of toxins

9/11 Head & Neck Cancers

  • World Trade Center exposed workers to complex mix of toxins
  • Study recently compared incidence of head and neck cancers from 2003-2012 among 33,809 first responders.
  • Increased risk in later years of 2009-2012 with SIR going from 1.0 to 1.4.
  • Similar pattern was seen for HPV related oropharyngeal cancers.
  • Although caution was advised given small numbers (73)- it does suggest increased risk of another type of cancer in 9/11 responders.

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Warning Signs of Head and Neck Cancer

  • Hoarseness
  • Referred Otalgia
  • Persistent Sore Throat
  • Epistaxis
  • Nasal Obstruction
  • Serous Otitis Media
  • Neck Mass
  • Non-Healing Ulcer
  • Dysphagia
  • Submucosal Mass
Not all cancers present with symptoms at early stages!

Factors Delaying the Diagnosis of Head and Neck Cancers

  • Patient procrastination in seeking medical attention
  • Physician delay in diagnosis
  • Patient remains asymptomatic for a prolonged period

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Five-Year Survival Rate for Oropharyngeal Cancer

What we know now

  • Adjuvant concurrent chemotherapy and radiation remains effective tool to reduce risk of recurrence
  • Historically we used weekly Cisplatin due to less toxicity.
  • Was felt to be equal to every 3 week high dose Cisplatin

What we learned…

  • Curative-intent adjuvant chemoradiation with cisplatin at 100 mg/m2 every 3 weeks produced better locoregional control vs cisplatin at 30 mg/m2 every week in patients with locally advanced head and neck squamous cell cancer.
  • Severe adverse events were more common in the every-3-week group
  • Noninferiority trial, 300 patients with locally advanced head/neck cancer
  • Randomized between 2013 and 2017 to receive cisplatin at 30 mg/ m2 given once a week (n = 150) vs cisplatin at 100 mg/m2 given once every 3 weeks (n = 150), both administered concurrently with curative-intent radiotherapy.
  • Disease had to be locally advanced with no distant metastases with planned curative chemoradiation, either as adjuvant treatment for ≥ 1 high-risk feature (eg, extracapsular extension, close [≤ 5 mm] or positive margins, ≥ 2 positive nodes, or T4 primary disease) or for definitive adjuvant chemoradiation for unresectable disease or organ preservation.
  • The primary endpoint was locoregional control.
  • 279 patients (93%) received adjuvant chemoradiation.
  • At a median follow-up of 22 months, the estimated cumulative 2-year locoregional control rate was 73.1% in the every-3-week group vs 58.5% in the once-weekly group (absolute difference = 14.6%). The hazard ratio (HR) significantly favored the every-3-week group at 1.76 (P= .014).
  • Estimated median progression-free survival was 28.6 months vs 17.7 months (HR = 1.24, P= .21).
  • Estimated median overall survival was not reached vs 39.5 months (HR = 1.14, P= .48).
  • Adverse events of grade ≥ 3 occurred in 85% of the every-3-week group vs 72% of the once-weekly group (P= .006)
  • Most common being lymphopenia (89% vs 72%), dysphagia (39% vs 42%), and odynophagia (52% vs 41%).
  • Hospitalization for toxicity occurred in 31.1% vs 13.3% (P <.001). Feeding tube placement was required in 68% vs 66% (P= .68).
  • Among 126 patients in the every-3-week group and 116 in the once-weekly group evaluated for chronic toxicity, grade ≥ 3 toxicity occurred in 13.5% vs 10.3% (P= .55).


  • Once-every-3-week cisplatin at 100 mg/m2 resulted in superior (locoregional control), albeit with more toxicity, than did once-a-week cisplatin at 30 mg/m2 and should remain the preferred chemoradiotherapy regimen for locally advanced head and neck squamous cell cancer in the adjuvant setting.
  • Controversy
  • 30 mg/m2 is lower than standard dose of 40 mg/m2 typically used- further study is warranted.

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Why do we need immunotherapy in Head & Neck Cancer

  • In post operative setting, adding Cisplatin to radiation improves disease control and improves survival by approx. 10% compared with radiation alone
  • In metastatic/recurrent disease, systemic therapy achieves median survival of <11 mo
  • Second line therapy in fit patients is associated with median survival of <6 mo
  • Targeted therapy has been limited by high prevalence of tumor suppressor mutations
  • Agents that are active in the face of cisplatin-resistance or TS mutation are needed
  • Agents with durable effect on PFS and OS are needed
  • Cisplatin induced renal injury, ototoxicity, and increased risk for noncancer mortality.
  • Chronic sequelae of radiation effects — including hypothyroidism, swallowing dysfunction, and soft tissue necrosis.
  • Extensive surgery can be associated with neck/shoulder dysfunction, pain, dysphagia (feeding tube dependence)
  • Less toxic agents with durable effect on outcome could spare patients toxicity from cisplatin, radiation, and surgery.

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Head/Neck Cancer and Immune Tolerance

  • Inflamed phenotype with tumor infiltrating lymphocytes and transcription of interferon response genes
  • Expression of PDL1 and PDL2
  • High mutational load in both HPV negative and HPV driven cancers

The Yin and Yang of Immune Escape. Immune Surveillance - the Immune system recognizes malignant cells. Immune Escape Cancer is highly Immunosuppressive. Reduced antigen processing and presentation; - Anergic T cells; - Tumor-permissive cytokine profile

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Does Immunotherapy Work

Phase 2 Trial of Pembrolizumab After Progression Chemo, Immuno, & Oncology presentation Tumor Shrinkage - change from baseline displayed in graph, in sum of longest diameter of target lesion, % Phase 3 Trial of Nivolumab After Progression including key eligibility criteria Chemo, Immuno, & Oncology presentation

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What about adding Immunotherapy to chemotherapy?

Trial Design

  • KEYNOTE-048 was a 3-arm Phase III trial for patients with recurrent or metastatic head and neck squamous cell carcinoma not amenable to curative resection or radiation.
  • Patients were randomly assigned to pembrolizumab alone, a novel combination of pembrolizumab with a platinum agent and 5-fluorouracil, or the standard of care EXTREME regimen consisting of cis- or carboplatin, 5-fluorouracil and cetuximab.
  • Patient stratified by high tumor expression of PD-L1, p16 status and performance status.
  • Primary endpoint was overall survival and analyses were conducted in the total population and in those with elevated PD-L1 expression in the tumor and stromal cells (CPS).

Key eligibility criteria, stratification factors in pembrolizumab study design - from presentation Chemo, Immuno, & Oncology presentation Chemo, Immuno, & Oncology presentation Chemo, Immuno, & Oncology presentation Chemo, Immuno, & Oncology presentation Summary and conclusions: Pembrolizumab Monotherapy vs EXTREME Chemo, Immuno, & Oncology presentation Chemo, Immuno, & Oncology presentation Chemo, Immuno, & Oncology presentation Summary and conclusions: Pembrolizumab + Chemotherapy vs EXTREME

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Toxicities with Immunotherapy

Toxicities with Immunotherapy: Osteonecrosis from chemoradiation therapy

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Future Direction for Immunotherapy

  • In the future pembrolizumab will be incorporated into the first line of treatment for recurrent or metastatic head and neck cancer for the majority of patients.
  • The decision about when to use pembrolizumab alone and when to use a combination of pembrolizumab with chemotherapy may depend on both the level of PDL1 expression in an individual’s tumor, as well as clinical characteristics- data will help guide this.
  • Best biomarker appears to be high level PD-L1 expression, but elevated tumor mutational burden and interferon response gene signature are also promising in head and neck cancer.
  • Can we incorporate immunotherapy into frontline chemoradiation to decrease toxicity from chemotherapy.

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Final thoughts…

  • We learned about continuing to identify risk factors that may be unique to head/neck cancers while focusing on modifying patients behavior with understood risk factors (tobacco/ETOH)
  • We learned that continuing to evaluate current treatment options for optimization of therapy benefit while also working to improve side effects/toxicity from therapy.
  • We learned that immunotherapy provides a powerful new tool in the treatment of head/neck cancers and requires further study on how we can incorporate this in both late state and early stage disease.