Molecular targeted approaches to Molecular targeted approaches to g g pp pp head and neck cancer head and neck cancer Lillian L. Siu Lillian L. Siu Department of Medical Oncology & Department of Medical Oncology & Hematology Hematology Princess Margaret Hospital, Princess Margaret Hospital, University of Toronto University of Toronto
Locally Advanced HNSCC Locally Advanced HNSCC
Locally Advanced HNSCC Locally Advanced HNSCC RT / RT +/- Surgery 2000: 2000: MACH MACH- -NC meta NC meta- -analysis analysis Concurrent 2006: 2006: MARCH meta MARCH meta- -analysis analysis ChemoRT +/- Surgery g y 2000+: 2000+: • Molecular targeting Molecular targeting o ecu a ta get o ecu a ta get g g ?? • Renewed interest in induction Renewed interest in induction chemotherapy chemotherapy • Intensity modulated radiation therapy Intensity modulated radiation therapy • Image Image- -guided radiation therapy guided radiation therapy
Concurrent Chemotherapy Concurrent Chemotherapy Concurrent Concurrent Concurrent Concurrent RT ↓ LRR LRR Compared to Compared to ↓ Distant mets ↓ Distant mets Distant mets Distant mets RT RT RT alone RT alone l l ↑ Survival Survival Standard Standard of Care of Care of Care of Care
Overall survival Overall survival MACH-NC MACH NC (63 trials, 10741 pts: 1965-1993) Meta-Analysis of Chemotherapy in Head & Neck Cancer Chemotherapy Risk p-value Absolute benefit timing timing reduction reduction at 5 years at 5 years * Adjuvant 2 % NS 1 % Neoadjuvant 5 % NS 2 % Concomitant 19 % < 0.0001 8 % Total 10 % < 0.0001 4 % * 5-year survival rate in control group : 32 % Pignon et al. Lancet 2000;355:949-55
Update: Overall survival Update: Overall survival MACH-NC MACH NC (87 trials, 16665 pts: 1965-2000) Meta-Analysis of Chemotherapy in Head & Neck Cancer Chemotherapy timing Chemotherapy timing Hazard ratio Hazard ratio Absolute benefit Absolute benefit or type or type at 5 yr at 5 yr Concomitant CT+ RT Concomitant CT+ RT 0.81 0.81 8% (Stewart’s) 8% (Stewart’s) (0.78 (0.78- -0.86) 0.86) 6.5% (Peto’s) 6.5% (Peto’s) conventional RT conventional RT 0.83 0.83 altered fractionation RT altered fractionation RT 0.73 0.73 platin monotherapy platin monotherapy platin monotherapy platin monotherapy 0.74 0 74 0.74 0 74 platin + 5 platin + 5- -FU FU 0.77 0.77 Pignon et al. IJROBP 2007;69:S112-4
Modified Fractionated Radiotherapy Modified Fractionated Radiotherapy in HNSCC in HNSCC • XRT hyperfractionation (same treatment duration, XRT hyperfractionation (same treatment duration, smaller dose per fraction) smaller dose per fraction) - - to injury on normal tissues to injury on normal tissues • XRT acceleration (shorter treatment duration, same XRT acceleration (shorter treatment duration, same fraction size) fraction size) - - to clonogenic tumor cell proliferation to clonogenic tumor cell proliferation
MARCH (15 trials, 6515 pts) MARCH (15 trials, 6515 pts) Altered Fractionation Altered Fractionation vs vs Standard Fractionation Standard Fractionation Risk Absolute benefit p Regimens reduction at 5 years Overall survival 22 % Hyperfractionation 8.2 % AFX ( ≅ Total Dose) 3 % 2 % ( � Total Dose) 6 % 1.7 % All All All group All group 3.4 % 3.4 % 8 % 8 % 0.003 0.003 Bourhis et al. Lancet 2007;368:843-54
Concurrent Chemotherapy + RT: Toxicity Concurrent Chemotherapy RT: Toxicity Concurrent Chemotherapy + RT: Toxicity Concurrent Chemotherapy RT: Toxicity Trial Trial Concurrent Arm Concurrent Arm Acute Tox Gr 3 Acute Tox Gr 3- -4 4 Late Tox Late Tox Ad l Ad l Adelstein Adelstein i i S Standard RT + Cis x 3 Standard RT + Cis x 3 S d d d RT d RT Ci Ci 3 3 42% l 42% leucopenia 42% l 42% leucopenia i i Not reported N Not reported N d d (2003) (2003) 45% mucositis 45% mucositis 52% feeding tube 52% feeding tube ↑ xerostomia Jeremic Jeremic Standard RT + daily Cis Standard RT + daily Cis 16% stomatitis 16% stomatitis xerostomia and ↑ skin and skin (2004) (2004) toxicity with toxicity with y Hyperfr. RT + daily Cis Hyperfr RT + daily Cis Hyperfr. RT + daily Cis Hyperfr RT + daily Cis 49% stomatitis 49% stomatitis 49% stomatitis 49% stomatitis hyperfr. RT hyperfr. RT Denis + Denis + Standard RT + 5FU + Standard RT + 5FU + 71% mucositis 71% mucositis Similar Similar Calais Calais Calais Calais Carbo Carbo Carbo Carbo betwween betwween betwween betwween 36% feeding tube 36% feeding tube 36% f 36% f di di t b t b (2004) (2004) arms arms Budach Budach Hyperfr. Acc. RT + 5FU Hyperfr. Acc. RT + 5FU 9% leucopenia 9% leucopenia Similar Similar + MMC + MMC + MMC + MMC between between between between (2005) (2005) (2005) (2005) 2% 2% platelets 2% platelets 2% l t l t l t l t arms arms 66% mucositis 66% mucositis Prophylactic Prophylactic feeding tube in most feeding tube in most
RTOG 0129 Ph III: RTOG 0129 Ph III: SFX + SFX + Cisplatin Cisplatin vs vs AFX AFX- -CB + CB + Cisplatin Cisplatin Standard R fractionation (SFX) St Stage III or IV III IV A + Cis (D1, 22, 43) N SCCHN SCCHN D O Accelerated M fractionation by I concomitant boost Z (AFX-CB) + Cis (D1+22) E N = 743 1º endpoint = OS
RTOG 0129: Feeding Tube RTOG 0129: Feeding Tube SFX + CDDP SFX + CDDP SFX + CDDP SFX + CDDP AFX-C + CDDP AFX AFX-C + CDDP AFX C + CDDP C + CDDP � Before therapy Before therapy 89/361 (25%) 89/361 (25%) 79/361 (22%) 79/361 (22%) � End of therapy End of therapy 247/361 (68%) 247/361 (68%) 239/357 (67%) 239/357 (67%) � At 1 year At 1 year 98/328 98/328* (30%) (30%) 88/325** (27%) 88/325** (27%) *39 (40%) and **31 (35%) had feeding tube at baseline *39 (40%) and **31 (35%) had feeding tube at baseline
Radiation +/- Radiation +/ - vs Cetuximab in vs Cetuximab in Locally Advanced HNSCC Locally Advanced HNSCC Locally Advanced HNSCC Locally Advanced HNSCC N = 424 pts Median F/U = 38 m Median F/U 38 m KFS: KFS: RT RT 90 90- -100 vs 60 100 vs 60- -80 80 R R R Stage III (32%) St Stage III (32%) St III (32%) III (32%) A Stage IV (68%) Stage IV (68%) Node: Node: N + (20%) + (20%) D D Oropharynx Oropharynx vs vs – – (80%) (80%) O Hypopharynx Hypopharynx M RT RT RT RT T stage: T stage: g Larynx Larynx Larynx Larynx I I T1- T1 -3 (72%) 3 (72%) Z + vs T4 (28%) vs T4 (28%) E Cetuximab Cetuximab RT: RT: Conc. Boost Conc. Boost Daily Daily Daily Daily BID BID Bonner et al, NEJM 2006;354:567-78
Radiation +/- Radiation +/ - Cetuximab: Overall Survival Cetuximab: Overall Survival cetuximab cetuximab Cetuximab + RT Cetuximab + RT RT Alone RT Alone Hazard Ratio Hazard Ratio Stratified Log- Stratified Log - (n = 211) (n = 211) (n = 213) (n = 213) (95% CI) (95% CI) Rank Rank P P Value Value Median overall survival, Median overall survival, 49.0 49.0 29.3 29.3 0.74 0.74 0.03 0.03 mo mo mo mo (0 57 0 97) (0 57 (0.57 (0.57-0.97) 0 97) 0.97) 3- -y survival rate, % y survival rate, % 55 55 45 45 — — 0.05 0.05 Bonner et al, NEJM 2006;354:567-78
Incidence of Selected Toxicities Incidence of Selected Toxicities Cetuximab + RT Cetuximab + RT Cetuximab + RT Cetuximab + RT RT RT RT RT % (n = 208) % (n = 208) % (n = 212) % (n = 212) All Grades All Grades Grade 3 Grade 3- -5 5 All Grades All Grades Grade 3 Grade 3- -5 Mucositis Mucositis 93 93 56 56 94 94 52 52 Dysphagia Dysphagia 65 65 26 26 63 63 30 30 Xerostomia Xerostomia 72 72 5 5 71 71 3 3 Radiation Radiation 86 86 23 23 90 90 18 18 dermatitis dermatitis dermatitis dermatitis Weight Loss Weight Loss 84 84 11 11 72 72 7 7 • Cetuximab did not exacerbate the common toxic effects associated with Cetuximab did not exacerbate the common toxic effects associated with radiotherapy of the head and neck, including mucositis, xerostomia, radiotherapy of the head and neck, including mucositis, xerostomia, dysphagia, pain, weight loss , and performance dysphagia, pain, weight loss , and performance- -status deterioration. status deterioration. Bonner et al, NEJM 2006;354:567-78
Late Radiation Toxicity by Site Late Radiation Toxicity by Site Late Radiation Toxicity by Site Late Radiation Toxicity by Site Cetuximab RT Cetuximab + RT Cetuximab + RT Cetuximab RT RT RT RT RT % (n = 208) % (n = 208) % (n = 212) % (n = 212) Any Grade Any Grade Any Grade Any Grade Salivary glands Salivary glands Salivary glands Salivary glands 65 65 65 65 56 56 56 56 Larynx Larynx 52 52 36 36 Subcutaneous Subcutaneous 49 49 49 49 45 45 45 45 tissue tissue Mucous Mucous 48 48 39 39 membranes membranes Esophagus Esophagus 44 44 35 35 Skin Skin 42 42 33 33 • Higher overall incidence of late radiation toxicities (any grade) in Higher overall incidence of late radiation toxicities (any grade) in Cetuximab + RT group Cetuximab + RT group • • Similar incidence of Grade 3 or 4 late RT toxicities between both groups Similar incidence of Grade 3 or 4 late RT toxicities between both groups Similar incidence of Grade 3 or 4 late RT toxicities between both groups Similar incidence of Grade 3 or 4 late RT toxicities between both groups ERBITUX TM Product Monograph, September 11 2008
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