Update on Head and Neck Cancer Outline. Presenter Disclosure Information. Head and Neck Cancer Primary Disease Sites. Epidemiology

Transcription

1 Welcome to Master Class for Oncologists Miami, FL December 19, 2009 Session 5: 4:30 PM - 5:15 PM Head and Neck Cancer: Update on Comprehensive Management Speaker: David G. Pfister, MD Chief, Head & Neck Medical Oncology Memorial Sloan-Kettering Cancer Center Professor of Medicine Weill Medical College of Cornell University New York, NY Presenter Disclosure Information Update on Head and Neck Cancer Outline The following relationships exist related to this presentation: Dr Pfister receives clinical trial support from Sanofi-Aventis U. S., AstraZeneca LP, and Imclone. Epidemiology Clinical features Prevention Diagnostic evaluation Prognosis Off Label/Investigational Discussion In accordance with Pri-Med Institute policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. 3 4 Head and Neck Cancer Primary Disease Sites Epidemiology Oral cavity Pharynx Larynx Nasal cavity Paranasal sinuses 48,000 new cases, 11,000 deaths estimated for 2009 Median age of diagnosis: ~60 years African American > White/Hispanic/Asian Male:Female 3:1 Strongly associated with tobacco and alcohol Epstein-Barr virus risk factor for nasopharynx cancers Prior infection with human papillomavirus increasingly appreciated as a risk factor Jemal A, et al. CA Cancer J Clin. 2009;59:

2 Audience Response Question Human Papillomavirus (HPV)-Positive Head and Neck Cancer 1. A patient is found on exam to have a clinical T2N2B tonsil tumor. Biopsy of the tonsil yields a diagnosis of basaloid squamous cell cancer. The pathologist reports that in situ hybridization testing using a probe with affinity for high risk human papillomavirus (HPV) genotypes was positive. Which statement is most false regarding the relationship between HPV infection and head and neck cancer 1. HPV 16 is the viral subtype in the majority of these tumors. 2. HPV(+) tumors are associated with better survival rates. 3. Prior tobacco use appears to have no significant prognostic impact on survival outcome at five years in patients with HPV(+) tumors. 4. Tonsil cancers have a higher association with prior HPV infection than do lip cancers. HPV-16 is the viral subtype in the vast majority of patients. Half of oropharynx cancers will have HPV-16 DNA. Often occurs in non-smokers, non-drinkers Median age younger than HPV-negative patients; incidence increasing Associated with number of sexual partners and certain sexual practices Associated with a better prognosis when compared with outcomes of HPV-negative patients Prior tobacco use still affects prognosis 7 8 Fakhry C, Gillison ML. J Clin Oncol. 2006:24: Chaturvedi AK, et al. J Clin Oncol. 2008;26: Gillison ML, et al. J Clin Oncol. 2009;27:15s, abstr Head and Neck Cancer: Clinical Features Lymphatic Drainage Squamous cell cancer or variant Locoregional character M1 uncommon at presentation Medical comorbidity Second primary cancers: field cancerization ; condemned mucosa Each anatomic site has a predilection for spreading to different lymph node level: I: Oral cavity II/III/IV: Larynx/pharynx II/V: Nasopharynx V: Scalp III/IV/V: Thyroid IV/V: Below the clavicles 9 10 Premalignant Lesions Tumor Progression Model Progression of Carcinogenesis Tobacco Exposure HPV-16 Related Common Alteration Leukoplakia NORMAL PATCH Loss 17p TP53 mutation E6 incorporation P53/MDM2 inactivation FIELD Loss 9p, 3p p16 inactivation E7 incorporation P16/CDK/pRb inactivation Erythroplakia TUMOR Loss 5q Loss 18q Gain 11q13 Gain 18q Loss 11q14, 13q,gain3q, 5p, 8p, 8q, 9q, 20p, 20q 11 Smeets SJ, et al. Oncogene. 2006;25:

3 Screening/Prevention Chemoprevention United States Preventive Services Task Force: no definitive recommendations with regard to screening for head and neck cancers Direct inspection and palpation of oral cavity during dental examinations most commonly applied screening procedure Counsel regarding tobacco and alcohol use Human papillomavirus vaccine not standard practice for prevention of head and neck cancer No established proven serum or saliva screening test No proven standard chemopreventive agent Variable SPT*-Free Recurrence-Free Survival Survival Overall Survival Isotretinoin vs Placebo 1.06 ( ) 0.79 ( ) 1.03 ( ) Smoking Status Former vs Never 1.25 ( ) 1.23 ( ) 1.57 ( ) Current vs Never 1.64 ( ) 1.37 ( ) 2.51 ( ) Current vs Former 1.32 ( ) 1.12 ( ) 1.60 ( ) Hazard ratios (95% confidence intervals) *SPT=second primary tumor Khuri FR, et al. J Natl Cancer Inst. 2006;98: Evaluation and Staging Head and Neck Cancer Prognosis Clinical exam of the head and neck Endoscopy Fiberoptic flexible laryngopharyngoscopy Exam under anesthesia: laryngoscopy, esophagoscopy, bronchoscopy Biopsy Fine needle aspiration of a neck node Punch/core biopsy Excisional biopsy Computed axial tomography/magnetic resonance imaging of primary site and neck Chest imaging Positron emission tomography Tumor-Node-Metastasis system applied (7 th ed in 2010) Percentage (%) local unknown regional metastatic SEER registry Survival (yrs) Human Papillomavirus (HPV) Prognosis Approach HPV (+)ve HPV (-)ve P-value HR 95% CI Response Induction 82% 55% 0.01 Protocol 84% 57% 0.07 Survival - all sites PFS (2 yrs) 86% 53% OS (2 yrs) 95% 62% Survival - OP cancers PFS (2 yrs) 85% 50% 0.05 OS (2 yrs) 94% 58% Conclusion: HPV-positive tumors are associated with enhanced sensitivity to treatment and better outcomes. Disease Extent T 1 N 0-1 or T 2 N 0 T 2 N 1 or T 3-4 or N 2-3 Recurrent or M 1 Surgery or Surgery and/or Chemotherapy 17 Fakhry C, et al. J Natl Cancer Inst. 2008;100:

4 Surgical Therapy: General Principles Radiation Therapy Standard Fraction Dosage Oncologically adequate resection Conservation operation is not synonymous with a conservative one Comprehensive versus selective neck dissection Factors suggesting disease unresectable for cure: Massive skull base infiltration Involvement of prevertebral fascia Invasion of the cervical vertebrae or brachial plexus Encasement of the carotid artery Skin infiltration Rapid local or regional recurrence after surgery Setting Definitive Primary & gross lymph nodes Neck: low-risk nodal stations Adjuvant (4-6 weeks after surgery) Primary Neck: high-risk nodal stations Neck: low-risk nodal stations Dose* > 70 Gy > 50 Gy > 60 Gy > 60 Gy > 50 Gy *Fractions are 2.0 Gy/day NCCN Guidelines. Version , 05/27/09. OG 90-03: Altered Fraction Toxicities of Radiation Therapy # LRC DFS OS QD % 32% 46% BID % (P = 0.045) 38% (P = 0.067) 55% (P = 0.13) BID (split) % 33% 46% CB % (P = 0.05) 39% (P = 0.054) QD=daily; BID=twice daily; CB=concomitant boost radiation; LRC=locoregional control; DFS=disease-free survival; OS=overall survival 51% (P = 0.40) Mucositis/edema dysphagia feeding tube Xerostomia and loss of taste Hypothyroidism Lhermitte s syndrome Long-term induration and fibrosis Osteoradionecrosis of the jaw Cervical myelopathy Conclusion: Continuous course, altered fractionation schedules delivering higher total dose associated with improved disease control 21 Fu KK, et al. Int J Radiat Oncol Biol Phys. 2000;48: Approach Locoregionally Advanced Locoregionally Advanced Disease Extent T 1 N 0-1 or T 2 N 0 Surgery or Resectable Unresectable T 2 N 1 or T 3-4 or N 2-3 Recurrent or M 1 Surgery and/or Chemotherapy Surgery + ± Chemo ± Chemo Inoperable Comorbidity Low PS ± Chemo Customized 4

5 Audience Response Question Audience Response Question A patient is diagnosed with a squamous cell cancer of the right supraglottic larynx T3N1M0, and is interested in a primary chemoradiotherapy approach to avoid total laryngectomy. In a patient without significant medical comorbidity, what initial therapy is preferred by the National Comprehensive Cancer Network (NCCN) practice guidelines panel 1. High-dose cisplatin x 3 cycles with concurrent standard fractionation (SF) radiation therapy () 2. Induction docetaxel/cisplatin/5-fluorouracil followed by chemotherapy with concurrent SF 3. High-dose cisplatin x 2 cycles plus weekly cetuximab with concurrent accelerated 4. Weekly paclitaxel and cisplatin with concurrent SF A patient underwent surgery for a clinical T3N2bM0 left oral tongue tumor. Pathology is notable for a moderately-differentiated squamous cell cancer; a microscopically positive tongue margin; evidence of perineural spread; 2/35 lymph nodes positive for cancer, but without evidence of extracapsular nodal spread. Postoperative hemoglobin is 9.8 g/dl. In a medically fit patient, what adjuvant therapy is most supported by available data from randomized trials 1. Standard-fractionated (SF) radiation () alone with concurrent erythropoiesis stimulating agent 2. Hyperfractionated alone 3. High-dose cisplatin x 3 cycles with concurrent SF 4. Cisplatin/5-fluorouracil x 3 cycles with concurrent SF Meta-Analysis of Chemotherapy on Head and Neck Cancer (MACH-NC) Results Concurrent Chemoradiation OG Timing of Chemotherapy Risk Reduction P-value Absolute Benefit (5 yrs) Adjuvant -6% NS -2% Induction 4% NS 2% Concomitant 19% < % Total 12% < % R A N D O M I Z E non-responders Salvage laryngectomy cis FU cis FU cis cis cis non-responders responders non-responders Salvage laryngectomy cis FU Salvage laryngectomy 27 Pignon JP, et al. Lancet. 2000;355: Forastiere AA, et al. N Engl J Med. 2003;349: OG Larynx Preservation (LP) Trial Head and Neck Intergroup Arm Stomatitis* LP rate (5-yr) DFS (5-yr) OS (5-yr) 24% 65.7% 27.3% 53.5% Chemo 24% 70.5% 38.6% 59.2% * Grade 3 Chemo 43% 83.6% 39.0% 54.6% Conclusion: Concomitant chemoradiation is superior to induction chemotherapy followed by and alone for laryngeal preservation. There is no difference in overall survival between the 3 arms. *P < 0.05 OS DSS alone 23% 33% +Cisplatin 37%* 51%* Split +Cisplatin/FU 27% 41% Conclusion: with concurrent chemoradiation improves survival. Split-course radiation with multi-agent chemotherapy and the possibility of mid-course surgery did not improve outcome. 29 Forastiere AA, et al. N Engl J Med. 2003;349: J Clin Oncol. 2006;24. Abstract Adelstein DJ, et al. J Clin Oncol. 2003;21:

6 Hellenic Cooperative Oncology Group Altered Fraction +/- Chemotherapy: Overall Survival Outcomes 1 st Author N Drugs CT/ Med TTP* Med OS* 5-yr Survival* alone 6.3 mo 12.2 mo 9% + CDDP 45.2 mo 48.6 mo 52% Jeremic 130 CDDP 25% 46% (5-yr, P = ) Wendt 270 CDDP 5FU/LV 24% 48% (3-yr, P ) + Cb 17.7 mo 24.5 mo 38% *P = for TTP; P < for OS. Brizel 116 CDDP 5FU 34% 55% (3-yr, P = 0.12) 31 Conclusion: Concurrent administration of a platinum with radiation significantly improves survival. The efficacy of carboplatin with concurrent may be inferior to cisplatin. Fountzilas G, et al. Med Oncol. 2004;21: Staar 240 CARBO 5FU 39% 48% (2-yr, P = ) Note: GOEC RCT -> CT/ provided best efficacy tolerance ratio compared with Acc- +/- CT. (IJROBP 2008;72:S31) +/- Cetuximab (C) Erythropoiesis-stimulating Agents Radiation Therapy + C P-value Henke study DAHANCA study 3-yr OS 45% 55% 0.05 Median 29.3 mos 49 mos More grade ¾ skin rash and infusion reactions with cetuximab; no significant difference in mucositis between arms. RR 95%CI P-value Δ 3yr P-value LR-PFS LRC % 0.04 OS trend 0.16 DAHANCA=Danish Head and Neck Cancer Conclusion: Use of erythropoiesis-stimulating agents (ESAs) concurrently results in worse outcomes in patients undergoing radiation for the treatment of HNSCC. FDA alert: ESAs are not indicated during curativeintent therapy. 33 Bonner JA, et al. N Engl J Med. 2006;354: Henke M, et al. Lancet. 2003;362: ; J Clin Oncol (15s):6007 TAX 324: Sequential Combined Modality Therapy TPF vs PF Followed by Chemoradiotherapy TAX 324 Impact of TPF R A N D O M I Z E T P F P F Carboplatinum - AUC 1.5 Weekly Daily Radiotherapy Surgery as Needed Overall survival improved: hazard ratio 0.70 ( ), P = Response rate (RR) consistent with benefit: overall RR after chemotherapy alone, P = 0.07 More neutropenia and alopecia; overall, no evidence to suggest poorer tolerance TPF: Docetaxel 75 D1 + Cisplatin 100 D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3 35 Posner MR, et al. N Engl J Med. 2007;357: Posner MR, et al. N Engl J Med. 2007;357:

7 Taxane + PF Phase III Trials Summary of Efficacy Vermorken (2007) Hitt (2005) OUTCOMES C (n=119) PF + C (n=123) TPF + C (n=111) ICT + C (n=234) Chemo PF DPF PF PaPF Subjects Med PFS* 8.2 mo 11.0 mo 12 mo 20 mo Med OS* 14.5 mo 18.8 mo 37 mo 43 mo RR* 54% 68% 68% 80% Time To Failure ( ) ( ) ( ) Time To Progression ( ) ( ) ( ) P < 0.05 for all outcomes, except P = 0.06 for OS in Hitt study. Overall Survival ( ) ( ) ( ) Note: DPF better than PF as induction in larynx preservation setting as well. JCO 2009;27(15s): Adelstein DJ. JClinOncol. 2005;23: Vermorken JB, et al. NEnglJMed. 2007;357: Lefebvre JL, J Natl Cancer Inst. 2009;101: Methodological Issues Impact of Induction Chemotherapy (CT): Reconciling Opposing Views Interim analysis during recruitment Definition of TTF endpoint (given different durations of treatment) High (and different among treatment arms) number of patients excluded from efficacy analysis: 9 (7%) in C arm, and 77 (25%) in ICT arms Lack of intention-to-treat analysis Pro: allows time to optimize patient medical status; customization of dosing based on response to treatment; provides early treatment of distant micrometastatic disease Con: Induction CT may affect adversely compliance with subsequent concurrent CT/ or choice of CT/ regimen; adds 2-4 months to treatment Synthesis: Data from RCT are needed to resolve, but to date RCTs have had accrual issues or yielded no definitive answer Challenge: The NCCN already lists induction CT followed by based treatment as a treatment option What to Do Should induction chemotherapy now be routinely given to patients with locoregionally advanced, M0 head and neck cancer No, (concurrent CT/ remains the standard to which new approaches are compared) but Clinical scenarios in which to consider it: 1. Potential distant mets 2. Delay in radiation simulation 3. Impending local issue (eg, airway) 4. Markedly advanced disease (eg, bulky, low neck, dermal infiltration) 5. Patient selection - to accommodate delay in decision making regarding appropriate locoregional therapy; organ preservation strategy in patients with markedly advanced disease; advanced hypopharynx cancer. 42 Neck Dissection (ND) After Chemoradiotherapy Indicated for gross residual disease. Not indicated for pretreatment N1 disease that has achieved clinical complete response. For pretreatment N2-3 disease, opinions vary. When pretreatment neck disease is N2-3, some centers recommend routine ND regardless of response to chemoradiotherapy. However, others will observe if a clinical complete response on PET scan 12 weeks post therapy is achieved with chemoradiotherapy. Pellitteri PK, et al. Head Neck. 2006;28: Ong SC, et al. J Nucl Med. 2008;49:

8 Locoregionally Advanced OG 9501 / EOC Resectable Locoregionally Advanced Unresectable Resected squamous cell cancer head and neck cancer with poorrisk pathologic features 43 Surgery + ± Chemo ± Chemo Inoperable Comorbidity Low PS Customized ± Chemo 44 Cooper JS, et al. N Engl J Med. 2004;350: Cisplatin Days 1,22,43 Poor Risk Criteria OUTCOMES OG nodes ECE +Margins EOC Level IV/V (OC/OP) ECE +Margins Perineural disease Vascular emboli OG 9501 EOC LRC CT/ > CT/ > DC P = 0.46 P = 0.61 DFS/PFS CT/ > CT/ > ECE=extracapsular nodal extension; OC=oral cavity; OP=oropharynx OS P = 0.19 CT/ > 45 Cooper JS, et al. N Engl J Med. 2004;350: Cooper JS, et al. N Engl J Med. 2004;350: OG 9501/EOC Which Prognostic Risk Factors are Most Important Follow-Up Extracapsular nodal extension and +margins: significant benefit from chemoradiotherapy Trend toward benefit for stage III-IV disease, perineural invasion, vascular embolisms, and/or clinically enlarged level IV/V lymph nodes secondary to tumors in oral cavity or oropharynx No benefit in patients with 2 or more nodes but no extracapsular extension Assess for recurrence/2 nd primary/premalignant lesions 1st year: Q 1-3 mos 2nd year: Q 2-4 mos 3rd 5th year: Q 4-6 mos > 5 years: Q 6-12 mos TSH q 6-12 mos if neck irradiated Chest imaging as indicated Speech/swallowing evaluation/rehabilitation as indicated Counsel regarding tobacco and alcohol use Integrate general medical care Once felt disease-free, imaging of primary and neck not routinely indicated unless suspicious signs or symptoms 47 Bernier J, et al. Head Neck. 2005;27: NCCN Guidelines. Version , 05/27/09. 8

9 Approach Palliative Chemotherapy Disease Extent T 1 N 0-1 or T 2 N 0 T 2 N 1 or T 3-4 or N 2-3 Recurrent or M 1 Surgery or Surgery and/or Chemotherapy for recurrent disease without surgical or radiotherapy option 1 st -line therapy: Historically platinum-based doublet Overall RR 30-40% Median survival 6-9 months regardless of treatment Randomized controlled trials fail to demonstrate clear improvement in OS compared RX with single agents Active agents: cisplatin, carboplatin, 5-FU, taxanes, methotrexate, cetuximab, ifosfamide, gemcitabine (for nasopharynx cancer), and others CANCER Principles & Practice of Oncology, 8th Ed, 2008 E1395 Cisplatin/Paclitaxel vs Cisplatin/5-FU Cetuximab Cetuximab in recurrent/metastatic head and neck squamous cell cancer (SCC) disease trials Median OS CF 8.7 mos (CI 7, 12) CP 8.1 mos (CI 6, 10) Trial Phase Cancer Chemo RR PFS OS Trigo II SCC C225 13% 2.3mo 5.9mo Herbst II SCC CDDP + C225 13% 3.3mo 7.5mo Baselga II SCC CDDP + C225 10% 2.8mo 6.1mo Burtness (ECOG) III SCC CDDP + C225 CDDP 26% 10% 4.2mo* 2.7mo 9.2mo* 8.0mo * NS 51 Gibson MK, et al. J Clin Oncol. 2005;23: JCO 2005; 24: 5578, 5568 JCO 2005; 23: 3568, 8646 JCO 2004; 22: 488s EXTREME: Study Design EXTREME: Overall Survival R A N D O M I Z E N = FU 1000 mg/m 2 d1-4 with Cisplatin 100 mg/m 2 d1 or Carboplatin AUC 5 d1 6 cycles maximum 5-FU 1000 mg/m 2 d1-4 with Cisplatin 100 mg/m 2 d1 or Carboplatin AUC 5 d1 plus Cetuximab 250 mg/m 2 /week* q 3 weeks No treatment Cetuximab POD or toxicity POD or toxicity C225+Platinum+5-FU Platinum+5-FU HR P-value n = 222 n = months 7.4 months Conclusion: Addition of cetuximab to standard first-line platinum-based chemotherapy improves overall survival. *Loading dose of 400 mg/m 2 on week 1 53 Vermorken JB, et al. N EnglJMed. 2008;359: Vermorken JB, et al. N EnglJMed. 2008;359:

10 EGFR-TK Inhibitors Re-Irradiation EGFR-TKIs in metastatic disease trials: Cohen 2003 Cohen 2005 Kirby 2006 Soulieres 2004 Agent Gefitinib Gefitinib Gefitinib Erlotinib Median PFS 3.4 mo 1.8 mo Median OS 8.1 mo 5.5 mo 4.3 mo 6.0 mo 1-yr OS 29.2% 19% ~0% 20% ORR 10.6% 1.4% 8% 4.3% Note: RCT of Gefitinib vs MTX no significant OS improvement. Cohen EE, et al. J Clin Oncol. 2003;21: Cohen EE, et al. Clin Cancer Res. 2005;11: Kirby AM, et al. Br J Cancer. 2006;94: Soulieres D, et al. J Clin Oncol. 2004;22: Stewart JS, et al. J Clin Oncol. 2009;27: Feasible in full doses either alone or concurrently with chemotherapy Better survival outcomes for new primaries than for recurrent disease Evidence for improvement in PFS (but not OS) when adjuvant CT/Reirradiation is done after salvage surgery compared to observation alone Compared to chemotherapy alone: Median OS similar Selected pts have more durable responses OG 0421 comparing CT/Reirradiation versus CT alone, closed due to poor accrual JCO 2006;24(18S). Abstract Audience Response Question Audience Response Question 1. A patient is found on exam to have a clinical T2N2B tonsil tumor. Biopsy of the tonsil yields a diagnosis of basaloid squamous cell cancer. The pathologist reports that in situ hybridization testing using a probe with affinity for high risk human papillomavirus (HPV) genotypes was positive. Which statement is most false regarding the relationship between HPV infection and head and neck cancer 1. HPV 16 is the viral subtype in the majority of these tumors. 2. HPV(+) tumors are associated with better survival rates. 3. Prior tobacco use appears to have no significant prognostic impact on survival outcome at five years in patients with HPV(+) tumors. 4. Tonsil cancers have a higher association with prior HPV infection than do lip cancers. A patient is diagnosed with a squamous cell cancer of the right supraglottic larynx T3N1M0, and is interested in a primary chemoradiotherapy approach to avoid total laryngectomy. In a patient without significant medical comorbidity, what initial therapy is preferred by the National Comprehensive Cancer Network (NCCN) practice guidelines panel 1. High-dose cisplatin x 3 cycles with concurrent standard fractionation (SF) radiation therapy () 2. Induction docetaxel/cisplatin/5-fluorouracil followed by chemotherapy with concurrent SF 3. High-dose cisplatin x 2 cycles plus weekly cetuximab with concurrent accelerated 4. Weekly paclitaxel and cisplatin with concurrent SF Audience Response Question A patient underwent surgery for a clinical T3N2bM0 left oral tongue tumor. Pathology is notable for a moderately-differentiated squamous cell cancer; a microscopically positive tongue margin; evidence of perineural spread; 2/35 lymph nodes positive for cancer, but without evidence of extracapsular nodal spread. Postoperative hemoglobin is 9.8 g/dl. In a medically fit patient, what adjuvant therapy is most supported by available data from randomized trials 1. Standard-fractionated (SF) radiation () alone with concurrent erythropoiesis stimulating agent 2. Hyperfractionated alone 3. High-dose cisplatin x 3 cycles with concurrent SF 4. Cisplatin/5-fluorouracil x 3 cycles with concurrent SF Questions & Answers