The Evolving Treatment Algorithm for Advanced Head & Neck Squamous Cell Cancer Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium prIME Oncology Meeting, Madrid, Spain, September 10, 2017 Head & Neck Cancer Epidemiology, Risk Factors, & Presentation • 5%-6% of all cancers (688,000 new cases in 2012; 350,000 deaths) • ≥50% are ≥60 years of age; >90% squamous type (Western world) • Risk factors: – Tobacco smoking − Poor oral health – Alcohol use − Mechanical irritation – Betel chewing − Occupational exposure – HPV − Malnutrition • Localized disease 40%, regional metastases 50%, distant metastases 10% • 2/3 locally/regionally advanced • Major threat: Local recurrence, SPT, SFT HPV, human papillomavirus; SFT, second field tumor; SPT, second primary tumor Milestones in Head & Neck Cancer Management MARCH MACH-NC 19th century Surgery 1900 1950s RT CT X-rays 1970s 1980s Laser ASCO CT scan 1982 MRI 1990s PET 2000s Targeted therapies 2010 2014 TORS IT MARCH, meta-analysis of radiotherapy in squamous cell carcinomas of head and neck; MACH-NC, meta-analysis of chemotherapy in head and neck cancer; RT, radiotherapy; CT, chemotherapy; PET, positron emission tomography; TORS, Trans-oral robotic surgery; IT, immunotherapy Modified from Jean-Louis Lefebvre (with permission) Milestones in Systemic Therapies (± RT) in Head & Neck Squamous Cell Cancer (HNSCC) 1960s Single-agent chemotherapy Methotrexate 1970s Combination chemotherapy regimens Platinum compounds 1980s Induction chemotherapy Larynx preservation 1990s Concurrent chemoradiotherapy (CCRT) standard Taxanes 2000s Induction chemotherapy revisited Targeted therapy Immunotherapy Important Recent Findings • HPV is a risk factor for OPC (a growing epidemic) • Tumor HPV single strongest predictor of survival (OPC) • EGFR is a second prognostic marker • Anti-EGFR medication is getting major attention • Expanded role of chemotherapy (CCRT, ICT) • Revival of immunology/immunotherapy • Improved irradiation techniques available (IMRT) • New imaging techniques available (PET) • Quality of life of survivors is getting more attention EGFR, epidermal growth factor receptor; ICT, Induction chemotherapy; IMRT, intensity modulated radiotherapy; OPC, oropharyngeal cancer The Prognostic Significance of HPV in OPC 100 88 Had HPVnegative tumors 178 Had HPVpositive tumors 88 Had ≤10 pack-years 90 Had >10 pack-years 23 Had ≤10 pack-years 65 Had >10 pack-years Overall Survival (%) 266 patients with oropharyngeal cancer, known tumor HPV status and known number of pack years of smoking Low risk 75 Intermediate risk 50 High risk 25 0 26 Had N0-N2a cancer 114 of 266 (42.9%) were at low risk 64 Had N2b-N3 cancer 26 Had T2-T3 tumors 76 of 266 (29.7%) were at intermediate risk 8 Had T4 tumors 73 of 266 (27.4%) were at high risk 0 1 2 3 4 5 95 44 28 46 24 8 Years Since Randomization No at Risk Low risk 114 Intermediate risk 79 High risk 73 111 70 52 106 64 43 102 54 33 The 3-year rates of overall survival were 93.0% (95% CI, 88.3 to 97.7) in the low-risk group, 70.8% (95% CI, 60.7 to 80.8) in the intermediate-risk group, and 46.2% (95% CI, 34.7 to 57.7) in the high-risk group. Ang KK, et al. N Engl J Med. 2010;363(1):24-35. Multidisciplinary Team (MDT) Meetings Head and neck surgeon Biologist, pathologist Medical oncologist Patient Speech therapist Radiologist Guidelines Radiation oncologist Anesthesiologist, internist, general practitioner Oncologic dentist Physical therapist, dietitian, social worker, psychologist, psychiatrist Clinical trials Decision Making During MDT Meetings HNSCC Patients • Disease factors (eg, site, stage, biology [HPV, EGFR], specific risk factors for locoregional or distant relapse) • Patient factors (eg, age, sex, performance status, nutritional status, comorbid chronic disease, oral health, lifestyle habits, socio-economic status) • Treatment factors (surgery, radiotherapy, chemotherapy, immunotherapy, targeted therapy) • What do patients want? Clinical Practice Guidelines for Patients With Locoregionally Advanced HNSCC Standard Options Level of evidence Grade of recommendation Surgery RT or CCRT I A Concomitant CT and RT* I A Cetuximab plus RT II B CCRT or ICT RT for organ preservation II A ICT CCRT (sequential therapy) Still under evaluation *In case of mutilating surgery and in nonresectable disease; Cisplatin dose: 100 mg/m2 x3 during CCRT Grégoire V, et al. Ann Oncol. 2010:21(Suppl 5):vI84-vI86. Methods to Reduce the Toxicity of CisplatinBased CCRT in HNSCC: Treatment Factors Better targeting of RT • CT – MRI – (PET) • IGRT New radiotherapy techniques • IMRT and SW-IMRT • Stereotactic radiotherapy • IMPT Alternatives for high-dose 3-weekly cisplatin • Other cisplatin dose or schedules • Other cytotoxics (carboplatin, taxanes, low-dose gemcitabine) • Biological agents (cetuximab) • Hypoxic modification (nimorazole) CT, computed tomography; IGRT, image-guided RT; IMPT, intensity-modulated particle therapy; MRI, magnetic resonance imaging; SW-IMRT, swallowing sparing intensity modulated RT Relapsing HNSCC: Heterogenous Group (1) • Type of relapse − Local and/or regional only − Metastatic only − Both • Type of primary therapy − Single modality (S or RT) − Combined modality (S→LT*, CCRT, BRT, ICT→LT*) • Interval between primary treatment and relapse: − Short interval (<6 months) after CCRT → poor prognosis BRT, RT + cetuximab; ICT, induction chemotherapy LT, local therapy (ie. RT, CCRT or BRT); S, surgery 100 100 80 80 Survival (%) Survival (%) Relapsing HNSCC: Heterogenous Group (2) Influence of p16 status 60 40 20 0.5 40 20 p16 positive p16 negative 0 60 1.0 1.5 2.0 p16 positive p16 negative 0 0.5 Time Since Progression (years) 57 43 51 28 41 16 40 14 38 12 48 33 100 100 80 80 60 40 20 0.5 1.0 1.5 29 20 28 16 Fakhry C, et al. J Clin Oncol. 2014;32(30):3365-3373. 22 10 21 9 31 18 20 11 20 7 13 7 1.0 1.5 2.0 40 2.0 p16 positive p16 negative 0 0.5 Time Since Progression (years) No. at risk p16 positive p16 negative 2.0 60 20 p16 positive p16 negative 0 1.5 Time Since Progression (years) No. at risk p16 positive p16 negative Survival (%) Survival (%) No. at risk p16 positive p16 negative 1.0 Time Since Progression (years) 21 9 No. at risk p16 positive p16 negative 76 56 54 30 39 17 39 12 30 10 • Standard Treatment Options in Recurrent/Metastatic-HNSCC 2017 Resectable disease − Surgery at all times if possible − Post-op RT or CCRT (if not complete)1 • Nonresectable disease − RT or CCRT (if no organ dysfunction/morbidity)1 • Recurrent/metastatic disease − First-line: EXTREME (platinum/5-FU/cetuximab)2,3 Alternatives in unfavorable patients: single agents ± cetuximab − Second-line: CheckMate-141 (nivolumab single agent)3 Pembrolizumab also approved for same indication3 − Best supportive care only (performance status 3)2,3 1. Strojan P, et al. Head Neck. 2015;37(1):134-150. 2. Grégoire V, et al. Ann Oncol. 2010:21(Suppl 5):vI84-vI86. 3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Available at: https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed August 31, 2017. Unmet Needs in Head & Neck Cancer • Customized treatment guidelines • Noninvasive diagnostic tools • Better understanding of pathways that drive head and neck cancer or drug resistance • Adjuvant treatment of intermediate/high-risk HNSCC patients • Predictive markers • Supportive care needs of long-term HNSCC survivors • More information and healthcare services to caregivers
