Head and neck cancer accounts for 5-6% of all cancers, with over 90% being squamous cell carcinomas. Risk factors include tobacco, alcohol, and HPV. Treatment options include surgery, radiation therapy, chemotherapy, or combinations. While early stage cancer has a good prognosis with single modality treatment, advanced stages generally require combined modality treatment, though 5-year survival remains below 35%. New targeted therapies and improved radiation techniques have provided benefits in recent years.
R. Gaafar - Lung cancer - Guidelines and clinical case presentation (2-3 cases)
BALKAN MCO 2011 - J. Vermorken - Head and neck cancer - essential messages
1. Head and Neck Cancer – Essential Messages Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium Balkan Masterclass in Clinical Oncology, Dubrovnik, Croatia 2011, 11-15 May
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5. Evolving Systemic Therapies Alone or with Radiation Head and Neck squamous cell cancer 1960s Methotrexate (IC, CRT) 1970s Bleomycin, 5-fluorouracil, cisplatin Combination chemotherapy regimens 1980s Carboplatin Organ preservation trials start 1990s Paclitaxel, docetaxel CRT>RT 2000s Targeted therapies (MoAb) Evolving role for ICT Sequential therapy (ICT CRT)?
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8. Actuarial Life-table Estimates of Survival Chaturvedi et al, J Clin Oncol 2008; 26: 612-619 *Tumor extended directly into surrounding organs or tissues, into regional lymphnodes, or by both and treated by RT Period Two-year survival HPV-R vs. HPV-U* P-value 1973-1982 46.6 vs. 47.2% 0.71 1983-1992 56.0 vs. 49.6% <0.01 1993-2004 69.7 vs. 50.3% <0.01
12. HN Surgeon Radiation Oncologist Medical Oncologist Anesthesiologist Internist GP Radiologist Social worker Psychologist Patient Guidelines Clinical trials Biologist Pathologist Dietician Speech Therapist
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14. 63 randomized trials MACH-NC = Individual patients data base 7,307 deaths (68 %) 10,741 patients Lancet 2000;355:949-55 IGR 10.00 Meta-Analysis of Chemotherapy in Head & Neck Cancer MACH-NC
15. MACH-NC: Results - Overall Survival Chemotherapy Risk P Absolute benefit timing reduction value at 5 years Adjuvant 2% NS 1% Neoadjuvant* 5% NS 2% Concomitant 19% < 0.0001 8% Total 10% < 0.0001 4% * 15 studies with PF 5% Pignon et al, 2000 (63 trials / 10.741 patients)
16. MACH-NC Analysis: Survival Benefit of Concomitant Chemotherapy to Local Treatment a 50 concomitant trials; CRT, chemoradiation; CT, chemotherapy; RT, radiotherapy Pignon JP et al. Radiother Oncol 2009;92:4–14 Absolute survival benefit at 5 years: 6.5% (CRT) p=0.41 CRT regimen a Hazard ratio Postoperative RT 0.79 Conventional RT 0.83 Altered fractionated RT 0.73 Mono - CT 0.84 MonoPlatin 0.74 Poly - CT 0.78 5-FU + platinum 0.75 5-FU/platinum 0.83 Other CT 0.73 Pooled 0.81 (p<0.0001)
17. Acute adverse effects: Grade ≥ 3 p<0.05 ns Patients (%) p<0.01 Wendt TG, et al. J Clin Oncol 1998;16:1318–1324 0 10 20 30 40 50 60 Xerostomia Nausea/emesis Leukopenia Dermatitis Mucositis RT alone (n=140) CRT (n=130) ns, not significant CRT = CDDP + 5-FU + RT Late Toxicity Analysis of 230 patients receiving CRT in 3 studies (RTOG 91-11, 97-03, 99-14) 10% 12% 27% 13% 43% 0 10 20 30 40 50 Patients (%) Any severe late toxicity Feeding-tube dependence >2 yrs post-RT Pharyngeal dysfunction Laryngeal dysfunction Death Machtay M, et al. J Clin Oncol 2008; 26: 3582–3589
18. Enhancement of Radiation Effects Selective Targeting of Hypoxic Cells Induction of Pro-Apoptotic Mechanisms Anti- Angiogenesis Strategies Inhibition of Cox-2 Replacement of Mutated Tumor Suppressor Genes Inhibition of EGFR Several biological mechanisms that have potential to alter sensitization strategies (Choy and MacRae, 2003)
21. 5-Years Survival Update and QoL Assessment 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 10 20 30 40 50 60 70 Time (months) Probability of overall survival Bonner JA, et al. Presented at ASTRO 2008 ERBITUX + RT RT ERBITUX + RT RT 5-year survival rate 46% 36% p=0.018, HR=0.73 (0.56-0.95) 29.3 49.0 ERBITUX + RT does not adversely affect QoL, while significantly improving overall survival Curran D, et al. J Clin Oncol 2007; 25: 2191 –2197 a Post-baseline scores for the EORTC QLQ-C30 Global health status/QoL score a 100 80 60 40 20 0 RT RT + ERBITUX Baseline Week 4 Month 4 Month 8 Month 12
22. Compliance with Cetuximab or Chemotherapy when Administered with RT 1 Bonner JA, et al. N Engl J Med 2006; 354: 567 –578; 2 Huguenin P, et al. J Clin Oncol 2004; 22: 4665–4673; 3 Calais G, et al. J Natl Cancer Inst 1999; 91: 2081 – 2086; 4 Wendt TG, et al. J Clin Oncol 1998; 16: 1318 –1324 CRT arms of studies comparing CRT vs RT alone Cisplatin / 5-FU / FA 4 46% 51% 71% 90% 0 20 40 60 80 100 Carboplatin / 5-FU 3 Cisplatin 2 Cetuximab 1 Patients receiving all planned doses (%) 10 70 50 30 90 Weekly doses (median 8 doses) 2 cycles at weeks 1 and 5 3 cycles at weeks 1, 4, and 7 3 cycles at weeks 1, 3, and 6 2nd cycle 3rd cycle 3rd cycle
23. Overall Conclusion No direct comparison *level I evidence; **level II evidence; + with mono Platin therapy Chemoradiation Bioradiation ( cetuximab ) 50 trials, 9615 pts (MA)* 1 trial, 424 pts (Bonner trial)** HR of death 0.74 (0.67-0.82) + HR of death 0.74 (0.57-0.97) Main effect on local failure Modest effect on DM Only effect on local failure No effect on DM Efficacy irrespective of site and of fractionation schedule Effect may be site and RT schedule specific Significant acute toxicity which may inflict on late toxicity, in particular swallowing dysfunction Skin reaction?? Late toxicity as RT Compliance of receiving cetuximab 90% in the Bonner trial
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25. 1 st. TL 1 st. PLs 1 st. RT SCPL Laser CO² ASCO 1982 trial VA trial EORTC trial RTOG trial EORTC 1873 1903 1878 1970s 1994 1996 2003 2005 2007 CTscan MRI surgery radiotherapy laser Milestones in Larynx/Hypopharynx Management trial GORTEC
26. 1st Generation Larynx Preservation Trials Study Tumor Size Treatment No. of Survival LP Group and stage arms pts (at 2 or 5 yrs) VA 1 Larynx TL + RND + RT 332 60% (2) T1-T4, N2-3 CT RT* 68% (2) 64% EORTC 2 Hypopharynx TL + RND + RT 202 35% (5) T2-T4, N0-2b CT RT* 30% (5) 57% * non-responders S + RT 1 VALCSG, N Engl J Med 1991; 324: 1865-1690 2 Lefebvre et al, J Natl Cancer Inst 1996; 88: 890-899
27. 2nd Generation Larynx Preservation Trials Patients PF x 3 RT (n=173) Stage III or IV Glottic/supraglottic CCRT (n=172) SCC (excl. T1 and Large volume T4) RT (n=173) PF = P 100 mg/m² (d1) and F 1000 mg/m d x 5 P during CRT = 100 mg/m² d1, 22, 43 RT = 70 Gy, given in 35 fractions of 2 Gy over 7 weeks Forastiere et al, N Engl J Med 2003; 349: 2091-2098 (RTOG # 91-11) R A N D O M I Z E
28. RTOG 91-11 Phase III Trial of Larynx Preservation Forastiere. ASCO. 2006 LFS=laryngectomy-free survival LFS Overall Survival
29. Randomized Trials of ICT in LA-HNC Revisited Trial Arms Outcome CA 139-322 (2005) PF vs PPF CCR (TTP , OS*) Resectable/nonresectable CCRT (CDP) Improved with PPF EORTC 24971/TAX 323 PF vs TPF PFS (RR, OS)° Nonresectable (2007) RT Improved with TPF TAX 324 (2007) PF vs TPF OS (PFS , RR)° Resectable/nonresectable CCRT (Cb) Improved with TPF GORTEC 2000-01 PF vs TPF LP (OS, DFS) + Resectable (2009) T(P)L vs RT Improved with TPF *significant only in unresectable disease (JCO); °NEJM; + JNCI
30. SCCHN: Docetaxel in Locally-Advanced Disease Overall Survival TAX 324 30% reduction in risk of death TAX 323 27% reduction in risk of death TPF PF 50 Survival Time (months) Survival Probability (%) Survival Time (months) 0 6 12 18 24 30 36 42 48 54 60 66 72 0 10 20 30 40 60 70 80 90 100 TPF PF Survival Time (months) Survival Time (months) 0 6 12 18 24 30 36 42 48 54 60 66 72 Posner et al, NEJM 2007 Resectable/unresectable disease Vermorken et al, NEJM 2007 Unresectable disease
31. GORTEC Phase III Larynx Preservation Trial Comparing TPF and PF induction therapy for hypopharynx and larynx cancer At 3 years: LP 70.3% with TPF, 57.5% with PF (p=0.03) Pointreau Y, et al. J Natl Cancer Inst 2009; 101: 498-506
32. Eligibility criteria : Trials properly randomized Performed before 2007 R RT + induction 5-FU/cisplatin (PF) RT + induction taxane/5-FU/cisplatin Materials and Methods Blanchard et al, Radioth Oncol 2011; 98 (suppl 1), S6 (abstract)
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35. Randomized Trials of Sequential Therapy versus Concurrent Chemoradiation Only Group Regimen TPF (or PF) x 3 CRT (cisplatin) TTCC (Sp) CRT (cisplatin) TPF x 3 CRT (carboplatin) Boston (US) CRT (cisplatin) TPF x 2 THFX Chicago (US) THFX XRT (cetuximab) TPF x 3 XRT (PF) GCTCC (It) XRT (cetuximab) XRT (PF)
36. Prognostic Significance of HPV RTOG 0129, PI: K. Ang Stage III & IV SCC of : • Oral cavity • Oropharynx • Larynx • Hypopharynx Stratify : • Lx vs Non-Lx • No vs N+ • KPS 60-80 VS 90-100 R A N D O M I Z E Accrued 743 patients (by 6/’05) Collected 596 tumor specimens Excluded T1-2N1 Oropharyngeal Cancer Enrolled: 433 - Specimens: 317 Ang K et al. N Engl J Med 2010;361:24-35 2. AFX-CB: 72 Gy/42 F/6 W + CDDP: 100 mg/m 2 (d 1, 22) 1. SFX: 70 Gy/35 F/7 W + CDDP: 100 mg/m 2 (d 1, 22, 43)
38. 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 K et al. N Engl J Med 2010;361:24-35
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40. Development of Chemotherapy in R/M SCCHN 1977: cisplatin shows efficacy in 1 st -line SCCHN CABO, cisplatin, methotrexate, bleomycin, vincristine *significant Clavel et al. Ann Oncol 1994; Forastiere et al. JCO 1992; Gibson et al. JCO 2005; Grose et al. Cancer Treat Rep 1985; Vermorken et al. NEJM 2008; Wittes et al. Cancer Treat Rep 1977 N Regimen ORR (%) Median OS (months) Significant OS benefit Grose et al 1985 100 Methotrexate Cisplatin 16 8 5.0 4.5 No Forastiere et al 1992 277 Cisplatin + 5-FU Carboplatin + 5-FU Methotrexate 32* 21 10 6.6 5.0 5.6 No Clavel et al 1994 382 CABO Cisplatin + 5-FU Cisplatin 34* 31* 15 7.3 7.3 7.3 No Gibson et al 2005 218 Cisplatin + 5-FU Cisplatin + paclitaxel 27 26 8.7 8.1 No Vermorken et al 2008 442 Platinum + 5-FU Platinum + 5-FU + Cetuximab 20 36* 7.4 10.1* Yes
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42. Completed Randomized Trials in First-Line Recurrent/Metastatic SCCHN Study/Reference N Regimen RR (%) PFS (mo) OS (mo) ECOG 5397/ Burtness et al 2005 117 Cisplatin + cetuximab Cisplatin + placebo 26 a 10 4.2 2.7 9.2 8.0 EXTREME/ Vermorken et al 2008 442 PF 1 + cetuximab PF 1 36 a 20 5.6 b 3.3 10.1 c 7.4 SPECTRUM/ Vermorken et al 2010 657 PF 2 + panitumumab PF 2 36 a 25 5.8 b 4.6 11.1 9.0 PF 1 = cisplatin or carboplatin plus 5-FU; PF 2 = cisplatin plus 5-FU a, b, c : significant differences
43. Completed Randomized Trials in 2nd-Line Recurrent/Metastatic SCCHN Study/Reference N Regimen RR (%) PFS OS (mo) IMEX Stewart et al, 2009 486 Gefitinib (250 mg) Gefitinib (500 mg) Methotrexate 2.7 7.6 3.9 ND ND ND 5.6 6.0 6.7 ECOG 1302 Argiris et al, 2009 270 D + Gefitinib D + placebo 12 6 3.3 2.2 6.8 6.2 Zalute Machiels et al, 2010 286 Z + BSC (-MTX) BSC (optional MTX) 6 1 2.3* 1.9* 6.7° 5.2° BSC = best supportive care; Z = zalutumumab; MTX = methotrexate; ND = no data *HR (95% CI): 0.62 (0.47-0.83), p=0,0010; °HR (95% CI): 0.77 (0.57-1.05), p=0.0648
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Notas do Editor
M225, a murine monoclonal antibody, competitively binds to the EGFR and inhibits EGFR pathways. Clinical trials using murine monoclonal antibodies have been complicated by the development of the human antimouse antibody (HAMA) immune response. The HAMA response not only carries the risk of serious allergic reactions but also increases the clearance of the murine proteins. Thus, the clinical utility of murine monoclonal antibodies has been limited. Cetuximab is a human:murine chimeric anti-EGFR IgG monoclonal antibody that binds exclusively to the EGFR. Chimeric antibodies are composed of the variable regions of murine antibody (the regions responsible for antigen binding) and the constant region of the human Fc fragment.[1] Chimeric monoclonal antibodies have demonstrated specificity and a diminished incidence of immunologic reactions.[2,3] Cetuximab binds to the EGFR with a binding affinity that is approximately one log higher than natural ligands.[4] Cetuximab prevents binding of endogenous ligands and induces receptor internalization, which ultimately blocks the activities of the EGFR pathway. Owens RJ, Young RJ. The genetic engineering of monoclonal antibodies. J Immunol Methods 1994; 168:149–165. Shitara K, Kuwana Y, Nakamura K, et al. A mouse/human chimeric anti-(ganglioside GD3) antibody with enhanced tumor activities. Cancer Immunol Immunother . 1993; 36:373–380. LoBuglio AF, Wheeler RH, Trang J, et al. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci U S A . 1989; 86:4220–4224. Goldstein NI, Prewett M, Zuklys K, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res . 1995; 1:1311–1318.
Clavel M, et al. Ann Oncol 1994;5:521–526; Forastiere A, et al. J Clin Oncol 1992;10:1245–1251; Gibson MK, et al. J Clin Oncol 2005;23:3562–3567;Grose WE, et al. Cancer Treat Rep 1985;69:577–581; Vermorken JB, et al. N Engl J Med 2008;359:1116–1127; Wittes RE, et al. Cancer Treat Rep 1977;61359–61366.
Petrelli NJ et al. J Clin Oncol 2009;27:6052–6069; Gr é goire et al Annals of Oncology 21 (Supplement 5): v184–v186, 2010