Chemo, Immuno, & Oncology
What is head and neck cancer?
Head 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
- Smoking Tobacco
- Chewing Tobacco
- Ionizing Radiation
- Plummer-Vinson Syndrome
- Epstein-Barr Virus
- Human Papilloma Virus
Possible Occupational Risks for Head and Neck Cancer
- 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.
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
- Referred otalgia
- Persistent sore throat
- Nasal obstruction
- Serous otitis media
- Neck mass
- Non-healing ulcer
- 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).
- 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.
- 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
Does Immunotherapy Work
What about adding Immunotherapy to chemotherapy?
- 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).
Toxicities with Immunotherapy
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.
- 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.