SCCH&N cancer report
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SCCH&N cancer report SCCH&N cancer report Presentation Transcript

  • Study of target therapy “Cetuximab” on the squamous cell carcinomas of the head and neck (SCCHN) Student ID : Student : H Date :2009 1
  • Outline  Introduction  Squamous cell carcinomas of the head and neck (SCCHN)  EGFR’s role on SCCHN  RT/CT’s influence on SCCHN  Cetuximab was used on the locally advanced SCCHN  Cetuximab was used on the first line recur/meta SCCHN  Cetuximab was used on the 2nd line recur/meta SCCHN  Conclusions 2
  •  Cancers arising in the upper aerodigestive tract, including the oral cavity, pharynx and larynx  Tumors are further classified by Histological type (Adenocarcinomas, Squamous cell carcinomas )  Brain tumors are excluded as they behave, and are treated, very differently 3
  •  Squamous cell carcinomas are derived from:  The epithelium lining the aerodigestive tract  Account for approx. 90% of primary head and neck cancers  SCCHN occur in a range of different sites resulting in:  Distinct clinical presentations and outcomes.  Are treated differently than other head and neck cancers 4
  •  Stage of tumor is determined at diagnosis  Staging helps assess prognosis and different treatment  TNM system is often used in all solid tumors:  T – size of primary tumor  N – involvement of lymph nodes  M – presence of metastases  T definitions are specific to the site of each primary tumor  N and M definitions in SCCHN are as same as for other tumors 5 American joint committee on cancer staging (AJCC),
  • Squamous cell carcinomas head& neck 6 Prof J-L Lefebvre, personal communication
  • Factors contributing to the etiology of H&N cancers researches Dep. collected the following data: Agent/factor Cancer site Agent/factor Cancer site Tobacco Oral, larynx Occupational Exposure: Alcohol Oral, larynx Textile industry Oral, pharyngeal Areca nuts Oral Printing trade Oral, pharyngeal Asbestos Larynx Wood Nasal (Larynx) Oral snuff Oral Nickel Nasal Infectious agents: Mustard gas Larynx Sulfuric acid Larynx HPV Oral HSV Oral EBV Nasopharynx Radiation Salivary gland 7 Cancer of the larynx, www.FIRSTConsult.com, Elsevier, (07.11.09).
  • ENT and Oral surgeons represent major patients source and treat trend 70% patients are diagnosed by ENT and oral surgeons Some successful experience in penetrating radiation oncologist and ENT surgeon segments Treatment strategy generally follow protocol in multidisciplinary team Radiation RT & CT oncologist ENT / Oral Patient (Surgeon) Diagnosis & surgery CT Oncologist 8 Data source: 2007 Oct 20 1st wave survey by APR
  • Cetuximab combined RT used in locally advanced H & N Ca, 9 http://www.fda.gov/ Cetuximab monotherapy used in the Recur / meta H & N after platinum failure
  • “Evidence for a role for the EGFr in the inhibition and pathogenesis of various cancers has led to the rational design and development of agents that selectively target this receptor.”* EGFr message transmission result in cancer cells---- 10 Bernier J. and Schneider D.(2006)
  • EGFr is expressed in a variety of solid tumors Colorectal Head & neck 90 – 100% cancer Lung Lung cancer 40 – 91% (NSCLC) (NSCLC) Colorectal cancer 72 – 84% Breast cancer 14 – 91% Head & Neck (SCC) Ovarian cancer 35 – 70% Renal cell cancer 50 – 90% Cunningham et al. 2004; Grandis et al.1996; Salomon et al. 1995; Walker & Dearing.1999; Folprecht et al.2004 11
  •  Cetuximab is an IgG1 MAb targeting the EGFr  Binding blocks EGFr signaling, the message transmission and inhibits proliferation, angiogenesis ,metastasis, stimulates apoptosis and differentiation  combined chemotherapy or radiation , can enhance the anti-tumor effect  Fc region may induce antibody-dependent cell- mediated cytotoxicity (ADCC) (immune response) 12 Bernier J. and Schneider D.(2006)
  • Cetuximab: IgG1-Induced Antibody-Dependent Cell Cytotoxicity (ADCC) IgG1 (cetuximab) cetuximab) Attachment Lysis of antibody-coated cell EGFR MEDIATED IgG1 MEDIATED Anti-tumour Activity ADCC IgG1 attachment surface antigen ,trigger NK identify ca.cell by antibody MAXIMIZE ANTI-TUMOUR ACTIVITY Fan Z, et al. Cancer Res.1993;53:4322-8 Res.1993;53:4322- 13
  • High EGFr expression in SCCHN is linked to lower survival and increased risk of locoregional relapse Overall survival Locoregional relapse 100 100 p=0.0006 p=0.003 75 75 EGFr>median Failed (%) Alive (%) EGFrmedian 50 50 EGFrmedian 25 25 EGFr>median n=155 n=155 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years from randomization Years from randomization inhibit EGFr pathway extened tumor progression Ang K. K, et al. 2002 14
  • Treatment modalities in SCCHN locally adv rec/met SCCHN refractory Surgery RT Alone RT + CT CT Palliation • Early disease is treated with surgery or radiotherapy alone • Locally advanced SCCHN • Radiotherapy for patients at intermediate risk • Chemoradiotherapy for high-riska disease • Recurrent and/or metastatic disease • Chemotherapy is main treatment • Combination therapies are associated with increased toxicities – eg mucositis and swallowing dysfunction aStage 15 III–IV disease, excluding T1–2 N1 and T3 N0
  • Acute adverse effects: grade 3 or higher 34% with RT alone vs 77% with CRT (p<0.001) 80 RT alone (n=231) 60 Combined RT + cisplatin (n=228) Subjects (%) 40 20 0 us ting ract kin io n ia) ic ct ia c ne i a a g i I t S c t om l og tra nem log r ph vom r G e Inf eros t eu ro na ry A to mb eso e ri a e nd p (x N ou m m He us x an sea d a Up nd la nit o uc ary n au yg Ge M N ar Ph liv Sa 16 Cooper ,J.S., et al. 2004
  • 9% 21% 10% 9% Early deaths due to treatment-related complications 6% Late deaths due to treatment-related complications 45% 15% of patient died for the SE of CT/RT not for cancer. Cause of death Time of occurrence, years median (range) Disease progression 1.5 years (0.3–8.6) Comorbidities 1.9 years (0.07–8.8) Treatment-related 0.3 years (0.03–3.4) Second primary tumors 3.5 years (1.5–10.1) Unknown 5.1 years (1.1–9.5) 17 Argiris ,A., et al. 2004
  • 18
  • BONNER Study 2006 Bonner,J .A., et al. 2006 19
  • 354:567-78, 2006 20
  • Cetuximab + RT in locally advanced SCCHN: phase III study design Stratified by  KPS (Karnofsky performance status)  Nodal involvement  Tumor stage  RT fractionationa RT (n=213) Stage III and IV non metastatic Cetuximab + RT (n=211) SCCHN R Cetuximab initial dose (400 (n=424) mg/m2) 1 week before RT Cetuximab (250 mg/m2) + RT (weeks 2–8)b • Primary endpoint: duration of locoregional control • Secondary endpoints: OS, PFS, RR, and safety 21 Bonner,J .A., et al. 2006
  • Phase III study: locoregional control 100 Cetuximab + RT p-value Locoregional control (%) RT 80 Locoregional 47% 34% <0.01 control rate 3-year 60 Cetuximab + RT (n=211) 40 20 14.9 24.4 RT (n=213) 0 0 10 20 30 40 50 60 70 Months Hazard ratio = 0.68 (95% CI: 0.52–0.89) Log-rank p=0.005 22 Bonner,J .A., et al. 2006
  • Phase III study: overall survival 100 Cetuximab + RT RT p-value 80 Survival rate 55% 45% 0.05 Overall survival (%) 3-year 60 Cetuximab + RT (n=211) 40 RT (n=213) 20 29.3 49.0 0 0 10 20 30 40 50 60 70 Months Hazard ratio = 0.74 (95% CI: 0.57–0.97) Log-rank p=0.03 23 Bonner,J .A., et al. 2006
  • RT Cetuximab Side effect (n=212) + RT p-valuea Mucositis/stomatitis 52% 56% 0.44 Dysphagia 30% 26% 0.45 Radiation dermatitis 18% 23% 0.27 Xerostomia 3% 5% 0.32 Fatigue/malaise 5% 4% 0.64 Acne-like rash 1% 17% <0.001 Infusion-related reactionsb 0% 3% 0.01 will not increase the incidence of RT side effects 24 Bonner,J .A., et al. 2006
  • First line R /M SCCHN EXTREME Study Platinum-Based Chemotherapy ± Cetuximab in Head and Neck Cancer Vermorken,J .B., et al. N Engl J Med 2008 25
  •  Randomized phase III multicenter study  Treatment: platinum (cisplatin or carboplatin) plus 5- FU, with or without cetuximab  80 sites in 17 European countries  No prior EGFr testing was required for study entry  Patients were stratified according to:  Prior chemotherapy  KPS (< 80 vs ≥ 80) 26 Vermorken,J .B., et al. 2006
  • Patients stratified according to: Group A Cetuximab 400 mg/m2 initial dose • KPS (<80 vs ≥80) then 250 mg/m2 weekly + • Prior chemotherapy (yes vs no) R EITHER carboplatin (AUC 5, d1) A Cetuximab OR cisplatin (100 mg/m2 IV, d1) N + 5-FU (1000 mg/m2/day IV, d1-4): D 3-week cycles O (6 cycles maximum) Progressive M disease or unacceptable I toxicity Z Group B E EITHER carboplatin (AUC 5, d1) D OR cisplatin (100 mg/m2 IV, d1) No treatment + 5-FU (1000 mg/m2/day IV, d1–4): 3-week cycles (6 cycles maximum) Vermorken,J .B., et al. 2006 27
  •  Primary endpoint  Overall survival time  Secondary endpoints  Duration of response  Time to progression  Response rate  Assessment of quality of life (QoL)  Safety Vermorken,J .B., et al. 200628
  • distribution of diseases are average Cetuximab + platinum / 5-FU Platinum / 5-FU (n=222) (n=220) Median age (range) 56 years (37–80) 57 years (33–78) Men / women 89% / 11% 92% / 8% Recurrence/metastasis Locoregional recurrence 54% 54% Metastasisa 46% 46% Primary metastatic disease 8% 7% aIncluding also distant metastasis and locoregional recurrence 29 Vermorken,J .B., et al. 2006
  • EXTREME: overall survival 1.0 | | || | First time R/M SCCHN over 10M in survival. 0.9 | | || 0.8 || Cetuximab + CTX | CTX only 0.7 Survival probability | 0.6 HR (95% CI): 0.797 (0.644; 0.986) 0.5 | Strat. log-rank test: 0.0362 0.4 | | | | 0.3 |||| || | | 7.4 10.1 | || |||| | || || || || months months || | | 0.2 || || | || || ||| | | | | | ||| | | | | || | | | | |||| | | || 0.1 0.0 0 3 6 9 12 15 18 21 24 Patients at risk Survival time (months) 222 184 153 118 82 57 30 15 3 220 173 127 83 65 47 19 8 1 30 Vermorken,J .B., et al. 2006
  • 1.0 | EXTREME: 0.9 | ||||| Progression-free survival (PFS) | | | ||| Cetuximab + CTX 0.8 | | | CTX only | | 0.7 || Progression free (%) | HR (95%CI): 0.538 (0.431, 0.672) | | 0.6 | | Strat. log-rank test: <0.0001 | || 0.5 | 5.6 months | 3.3 months | ||| | 0.4 | || | 0.3 | | || | 0.2 | | | | 0.1 | 0.0 0 3 6 9 12 15 Patients at risk PFS time (months) 222 138 72 29 12 7 220 103 29 8 3 1 31 Vermorken,J .B., et al. 2006
  • Cetuximab + platinum/5-FU Platinum/5-FU (n=222) (n=220) p-valuea ORR [CR + PR], % 35.6 19.5 0.0001 [95% CI] [29.3–42.3] [14.5–25.4] DCR [CR + PR + SD], % 81.1 60.0 <0.0001 [95% CI] [75.3–86.0] [53.2–66.5] Vermorken,J .B., et al. 2006 32
  • Most relevant grade 3/4 adverse events (%) 10 15 20 25 0 5 An em ia N eu t ro Th pe ro ni a m bo cy to pe n ia N au se a Vo m itin g Platinum / 5-FU (n=215) D ia rr h ea St om at itis D ys pn ea Pn eu m on Ac ia ne - li ke In ra fu sh Cetuximab + platinum / 5-FU (n=214) si on re ac tio n Vermorken,J .B., et al. 2006 33
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  • Cetuximab: summary of clinical studies in recurrent/metastatic SCCHN Type of study Disease Treatment Reference Phase I Mixed CDDP + cetuximab Shin 2001 Phase I/II/III Pt-sensitive Pt-based CT ± Burtness 2005 cetuximab Bourhis 2006 Vermorken 2007 Paclitaxel + cetuximab Hitt 2007 Phase II Pt-refractory Cetuximab alone Vermorken 2007 Platinum + cetuximab Baselga 2005 Herbst 2005 three clinical trials confirm the efficacy, refractory of patients 35 the side effects and efficacy hard to balance.
  • Grades (General Definitions) severity of side effects were divided into Grade0-5  · 0 = No adverse event or within normal limits  · 1 = Mild adverse event  · 2 = Moderate adverse event  · 3 = Severe and undesirable adverse event  · 4 = Life-threatening or disabling adverse event  · 5 = Death related to adverse event Cetuximab side effects of most below the Grade 3, side effects and survival appear positively related . 36
  • Overall survival by severity of skin rash 1.0 Grade 0 Grade 1 Grade 2/3 No. of events 27 (96%) 24 (100%) 25 (93%) 0.9 Median survival 2.2 months 5.4 months 7.1 months 0.8 [95% CI] [1.9–4.3] [2.7–6.7] [4.1–11.1] 0.7 Proportion 0.6 0.5 0.4 0.3 0.2 Grade 2/3 0.1 Grade 0 Grade 1 0 0 3 6 9 12 15 18 21 24 27 Time (months) Grade 0 28 12 6 3 1 1 Grade 1 24 16 11 5 3 1 1 Grade 2/3 27 22 15 9 7 4 1 1 1 37 balance the side effects and efficacy, SE can tolerance, handle, encouraged treat Herbst ,R.S., et al. 2005
  • Phase III study: change of QoL* as a function of time  Cetuximab + RT significantly improves locoregional control and overall survival without adversely affecting QoL, maintain quality of life. 100 Global health status / QoL score Radiotherapy 80 Radiotherapy / ERBITUX 60 40 20 0 -20 Baseline Week 4 Month 4 Month 8 Month 12 Visit 38 *Postbaseline scores for the QLQ-C30 Curran ,D., et al. 2007
  • Cetuximab ±CDDP or a variety of second-line treatments:clinical outcomes No. of TTP Treatment patients RR DCR MS (median) Cetuximab1 103 13% 46% 5.9 months 2.3 months Cetuximab + platinum2 96 10% 53% 6.2 months 2.8 months Cetuximab + CDDP3 79 10% 56% 5.2 months 2.2 months Retrospective study4 All patients 151 3% 15% 3.4 months N/A CT only 43 0% 9% 3.6 months N/A 1. Vermorken JB, et al. 2007; 2. Baselga J, et al. 2005;23:5568–557 3. Herbst RS, et al. 2005; 4. Vermorken JB, et al. 2005; 39
  • Conclusions: platinum-refractory second-line  Cetuximab is also active in second-line setting in patients with platinum-refractory SCCHN  In second-line setting Cetuximab + platinum showed similar results to Cetuximab monotherapy Vermorken JB, et al. 2007; Baselga J, et al. 2005;Herbst RS, et al. 2005; Vermorken JB, et al. 2005; 40
  • National Comprehensive Cancer Network only proposal of the target treatment on 2008 NCCN guideline Cetuximab as the most effective treatment for different stages of SCCHN, 41 either LA,RT,R/M +cisplain+5Fu and monotherapy.
  • Thanks for your attention 42