Chemo, Immuno, & Oncology

What is head and neck cancer?

Chemo, Immuno, & Oncology presentationHead and Neck Cancer is a group of cancers that includes tumors in several areas above the collar bone.

  • Oral Cancer
  • Laryngeal Cancer
  • Nasopharyngeal Cancer

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.

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
  • 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.

    Chemo, Immuno, & Oncology presentation

    9/11 Head & Neck Cancers

    • World Trade Center exposed workers to complex mix of toxins
    • Study recently compared incidence of head/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.

    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

    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).

    Conclusion:

    • 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.

    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.

    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
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    Does Immunotherapy Work

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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).

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    Toxicities with Immunotherapy

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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.

    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.