III 和 IV头颈部癌的表皮生长因子受体（EGFR）的靶向治疗【加拿大2009】

EVIDENCE BASED SERIES #5-12 RECOMMENDATIONS – page 1 Evidence-based Series #5-12: Section 1 Epidermal Growth Factor Receptor (EGFR) Targeted Therapy in Stage III and IV Head and Neck Cancer: Guideline Recommendations C. Cripps, E. Winquist, D. Stys-Norman, M. Devries, R. Gilbert, and the Head and Neck Cancer Disease Site Group A Quality Initiative of the Program in Evidence-based Care (PEBC), Cancer Care Ontario (CCO) Report Date: May 15, 2009 The full Evidence-based Series #5-12 is comprised of 3 sections and is available on the CCO website (http://www.cancercare.on.ca) PEBC Head and Neck Cancer DSG page at: http://www.cancercare.on.ca/toolbox/qualityguidelines/diseasesite/head-neck-ebs/ Section 1: Guideline Recommendations Section 2: Evidentiary Base Section 3: EBS Development Methods and External Review Process QUESTION What are the benefits associated with the use of anti-epidermal growth factor receptor (anti-EGFR) therapies in squamous cell carcinoma of the head and neck (HNSCC)? Outcomes of interest include overall and progression-free survival, quality of life (QoL), and tumour response rate and duration, as well as the toxicity associated with the use of anti- EGFR therapies. Anti-EGFR therapies of interest include cetuximab, gefitinib, lapatinib, zalutumumab, erlotinib, and panitumumab. TARGET POPULATION These recommendations apply to adult patients with locally advanced (nonmetastastic (stage III or IV) or recurrent/metastatic HNSCC. INTENDED USERS This practice guideline is intended for clinicians involved in the care of patients with head and neck cancer. EVIDENCE BASED SERIES #5-12 RECOMMENDATIONS – page 2 RECOMMENDATIONS AND KEY EVIDENCE Platinum-based chemoradiotherapy remains the current standard of care for treatment of locally advanced HNSCC. In patients with locally advanced HNSCC who are medically unsuitable for concurrent platinum-based chemotherapy and/or over the age of 70 (as concurrent chemotherapy does not improve overall survival in this patient population), the addition of cetuximab to radical radiotherapy is recommended to improve overall survival, progression free survival, and time to local recurrence. o The addition of cetuximab to radiotherapy in patients with locally advanced HNSCC increased overall survival (median 49.0 months versus [vs.] 29.3 months; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.57-0.97, p=0.03) and progression-free survival (median 17.1 months vs. 12.4 months; HR 0.70, 95% CI 0.54-0.90, p=0.006) as compared with radiotherapy alone (1). Locoregional control (median 24.4 months vs. 14.9 months; HR 0.68, 95% CI 0.52-0.89, p=0.005) and objective response rate (74% vs. 64%; odds ratio [OR] for response 0.57, 95% CI 0.36-0.90, p=0.02) were also significantly improved. o Cetuximab did not increase common adverse effects that can occur during radiotherapy (2). The most common and significant side effects (grades 3-5) of cetuximab were acneiform rash (17% vs. 1%, p<0.001), and infusion reaction (3% vs. 0%, p=0.01). Overall QoL was neither clearly improved nor worsened by the addition of cetuximab to radiotherapy. Cetuximab in combination with platinum-based combination chemotherapy is superior to chemotherapy alone in patients with recurrent/metastatic HNSCC, and is recommended to improve overall survival, progression-free survival, and response rate. o Vermorken et al (4) reported that the addition of cetuximab to chemotherapy (cisplatin or carboplatin plus 5-fluorouracil) improved overall survival (10.1 months vs. 7.4 months, p=0.04), progression-free survival (5.6 months vs. 3.3 months, p<0.001) and response rate (36% vs. 20%, p<0.001) compared to chemotherapy alone in patients with recurrent/metastatic HNSCC. o In a small randomized trial, Burtness et al (3) found that the addition of cetuximab to cisplatin improved the objective response rate (26% vs. 10%, p=0.03) but did not improve overall survival (9.2 months vs. 8.0 months, p=0.21) or progression-free survival (4.2 months vs. 2.7 months, p=0.09), although the trial was inadequately powered to assess these outcomes. o In addition to the adverse effects mentioned above, hypomagnesemia was increased in patients in patients receiving cetuximab in combination with cisplatin. The role of anti-EGFR therapies in the treatment of locally advanced HNSCC is currently under study in large randomized trials, and patients with HNSCC should continue to be offered clinical trials of novel agents aimed at improving outcomes. QUALIFYING STATEMENTS Chemoradiotherapy is the current standard of care for patients with locally advanced HNSCC and, to date, there is no evidence comparing cetuximab plus radiotherapy to chemoradiotherapy or examining whether the addition of cetuximab to chemoradiotherapy is of benefit to these patients. However, there are five ongoing trials investigating the effect of the addition of EGFR inhibitors, concurrently with, prior to, or following chemoradiotherapy, on overall survival, progression-free survival, and time to local recurrence in these patients, which should determine whether cetuximab should be added to standard of care treatment. EVIDENCE BASED SERIES #5-12 RECOMMENDATIONS – page 3 In patients with recurrent/metastatic HNSCC with progressive disease despite or who unsuitable for platinum-based chemotherapy, gefitinib at doses of 250mg daily (/d) or 500mg/d did not increase median overall survival (HR 1.22, 96% CI 0.95-1.57, p=0.12 for 250 mg/d vs. methotrexate and HR 1.12, 95% CI 0.87-1.43, p=0.39 for 500 mg/d vs. methotrexate) or objective response rate (2.7% for 250 mg/d and 7.6% for 500 mg/d vs. 3.9% for methotrexate, p>0.05) compared to weekly methotrexate (5). Gefitinib was associated with an increased incidence of tumour hemorrhage as compared with weekly methotrexate (8.9% for 250mg/d and 11.4% for 500 mg/d vs. 1.9% for methotrexate). RELATED GUIDELINES Program in Evidence-Based Care Evidence Based Series (EBS) and Practice Guidelines (PG): 5-1 PG: The Role of Neoadjuvant Chemotherapy in the Treatment of Locally Advanced Squamous Cell Carcinoma of the Head and Neck (Excluding Nasopharynx) 5-6b PG: Hyperfractionated Radiotherapy for Locally Advanced Squamous Cell Carcinoma of the Head and Neck 5-6c PG: Accelerated Radiotherapy for Locally Advanced Squamous Cell Carcinoma of the Head and Neck 5-10 EBS: The Role of Post-operative Chemoradiotherapy for Squamous Cell Carcinoma of the Head and Neck Funding The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. Disclaimer Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its application or use in any way. Contact Information For further information about this report, please contact: Dr. Ralph Gilbert, Chair, Head and Neck Cancer Disease Site Group, Princess Margaret Hospital, Toronto Phone: 416-946-2822 Fax: 416-946-2300 E-mail: ralph.gilbert@uhn.on.ca For information about the PEBC and the most current version of all reports, please visit the CCO Web site at http://www.cancercare.on.ca/ or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 EVIDENCE BASED SERIES #5-12 RECOMMENDATIONS – page 4 REFERENCES 1. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin SM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578. 2. Curran D, Giralt J, Harari PM, Ang K, Cohen RB, Kies MS, et al. Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol. 2007;25(16):2191-2197. 3. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: An Eastern Cooperative Oncology Study Group. J Clin Oncol. 2005;23(34):8646-8654. 4. Vermorken J, Mesia R, Vega V, Remenar R, Hitt A, Kawecki S, et al. Cetuximab extends survival of patients with recurrent or metastatic SCCHN when added to first line platinum based therapy – results of a randomized phase III (Extreme) study. Proc Am Soc Clin Oncol [monograph on the Internet]. 2007;25(18S):6091 Available from: http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_det ail_view&confID=47&abstractID=100002 5. Stewart JSW, Cohen EEW, Licitra L, Van Herpen CML, Khorprasert C, Soulieres D, et al. A phase III randomized parallel-group study of gefitinib (IRESSA) versus methotrexate (IMEX) in patients with recurrent squamous cell carcinoma of the head and neck [monograph on the Internet]. Proc Am Assoc Cancer Res. 2007 [cited 2007 Sep 15]. Available from: http://www.abstractsonline.com/viewer/viewAbstract.asp?CKey={911DB3AF-E3C7-46A9- 961C-C27C3CF20BEC}&MKey={E3F4019C-0A43-4514-8F66- B86DC90CD935}&AKey={728BCE9C-121B-46B9-A8EE-DC51FDFC6C15}&SKey={3BEE84D4- C8C1-4302-AD14-910D96A683C8} EVIDENCE BASED SERIES #5-12 EVIDENTIARY BASE – page 1 Evidence-based Series #5-12: Section 2 Epidermal Growth Factor Receptor (EGFR) Targeted Therapy in Stage III and IV Head and Neck Cancer: Evidentiary Base C. Cripps, E. Winquist, D. Stys-Norman, M. Devries, R. Gilbert, and the Head and Neck Cancer Disease Site Group A Quality Initiative of the Program in Evidence-based Care (PEBC), Cancer Care Ontario (CCO) Report Date: May 15, 2009 QUESTION(S) What are the benefits associated with the use of anti-epidermal growth factor receptor (anti-EGFR) therapies in locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC)? Outcomes of interest include overall and progression-free survival, quality of life (QoL), tumour response rate and duration, as well as the toxicity associated with the use of anti-EGFR therapies. Anti-EGFR therapies of interest include cetuximab, gefitinib, lapatinib, zalutumumab, erlotinib, and panitumumab. INTRODUCTION Head and neck cancer includes malignant tumours arising from a variety of sites in the upper aerodigestive tract. The most common histological type is squamous cell carcinoma, which occurs in the oral cavity, oropharynx, hypopharynx, and larynx (1). HNSCC is the sixth most common neoplasm worldwide (2). Despite the advances in therapy, the long-term survival of HNSCC patients is poor. The five-year relative survival rate, worldwide, from oral cancer is generally less than 50%. The poor five-year survival rates have remained unchanged for more than three decades (1,2). Primary surgery followed by chemoradiotherapy or primary concurrent platinum-based chemoradiotherapy are the standard treatment options for patients with locally advanced HNSCC (3). However, meta-analytic data indicates that the benefit of concurrent chemotherapy disappears over the age of 70 (4). Despite treatment advances, locoregional disease recurrence is still a major problem in treating patients with advanced disease. Local recurrences occur in about 10–30% of the cases involving advanced tumours, even with histopathologically tumour-free surgical margins after resection (5). Historically the standard treatment for recurrent/metastatic HNSCC has been platinum-based chemotherapy, although its benefits on survival and QoL are debatable (6). The epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases and is abnormally activated in epithelial cancers, including HNSCC (7,8). Over 90% of HNSCC overexpress EGFR, and higher levels of EGFR expression are EVIDENCE BASED SERIES #5-12 EVIDENTIARY BASE – page 2 associated with worse clinical outcomes (9). Radiation increases the expression of EGFR in cancer cells, and blockade of EGFR signalling sensitizes cells to the effects of radiation (10). Inhibition of EGFR signalling can be accomplished by small molecules, monoclonal antibodies directed against ligands or receptors, and immunotoxin conjugates (11). Cetuximab (ErbituxTM, C225, IMC-225; ImClone Systems, Inc.) is a monoclonal antibody that binds competitively to EGFR and blocks phosphorylation and activation of receptor- associated kinases, resulting in the inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production (7,12,13). Cetuximab was approved by Health Canada for the treatment of metastatic colorectal cancer in September 2005 (17). This drug was also granted approval by the United States Food and Drug Administration (US FDA) in March 2006 for use in combination with radiation in the treatment of patients with previously untreated locally advanced HNSCC as well as for use as monotherapy for patients with recurrent and/or metastatic HNSCC who have progressed on platinum-based therapy. (18,19). Given the interest in these agents in advanced HNSCC, the Head and Neck Cancer Disease Site Group (DSG) of Cancer Care Ontario’s Program in Evidence-based Care (PEBC) decided to systematically review the literature pertaining to this topic in order to develop evidence-based recommendations for treatment. METHODS The evidence-based series (EBS) guidelines developed by Cancer Care Ontario’s Program in Evidence-Based Care (PEBC) the methods of the Practice Guidelines Development Cycle (22). For this project, the core methodology used to develop the evidentiary base was the systematic review. Evidence was selected and reviewed by two members of the PEBC Head and Neck Cancer DSG and two methodologists. This systematic review is a convenient and up-to-date source of the best available evidence on anti-EGFR targeted therapy. The body of evidence in this review is primarily comprised of mature randomized controlled trial data. That evidence forms the basis of a clinical practice guideline developed by the Head and Neck Cancer DSG. The systematic review and companion practice guideline are intended to promote evidence-based practice in Ontario, Canada. The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Literature Search Strategy The MEDLINE (1996 through 2009 February week 1), EMBASE (1996 to 2009 week 6), and Cochrane Library databases (2008, issue 4) were systematically searched for relevant articles, using the search strategy described in Appendix 1, which includes search terms related to head and neck cancer, known EGFR inhibitors, and the following publication types and study designs: practice guidelines, systematic reviews, meta-analyses, reviews, randomized controlled trials, and controlled clinical trials. The American Society of Clinical Oncology (ASCO) (1996 to 2008) online conference proceedings were searched for reports of new or ongoing trials. The Canadian Medical Association InfoBase (http://mdm.ca/cpgsnew/cpgs/index.asp) and the National Guidelines Clearinghouse (http://www.guideline.gov/search/detailedsearch.aspx) were also searched for existing evidence-based practice guidelines. The reference lists from the relevant review articles were searched for additional trials. EVIDENCE BASED SERIES #5-12 EVIDENTIARY BASE – page 3 Inclusion Criteria: Articles were selected for inclusion in this systematic review of the evidence if they met the following criteria: They were abstracts or full reports of randomized phase II or III trials of EGFR- targeting monoclonal antibodies, either alone or in combination with radiotherapy or chemotherapy, versus a control therapy (including radiotherapy, chemotherapy, chemoradiotherapy, or best supportive care) in treatment of advanced squamous cell carcinoma of the head and neck; They reported at least one of the following outcomes: compliance, survival, time-to- progression, response duration, or response rate; or They were published reports of systematic reviews or evidence-based guidelines that addressed the guideline question. Exclusion Criteria Articles published in languages other then English were excluded because of limited translation resources. Synthesizing the Evidence Data for overall survival were not pooled due to the lack of information. RESULTS Literature Search Results A total of 74 references were identified in the electronic search and reviewed for inclusion. Of the 74, only three trials in four reports met the inclusion criteria for this guideline. In addition, the authors became aware of one randomized phase III trial (23), published in abstract form at the American Association for Cancer Research 2007 annual meeting, that was included as it otherwise met our inclusion criteria. There were four phase III trials (four published reports and one meeting abstract). The treatment arms, patient characteristics, and important quality elements of these trials are described in Table 1. One randomized controlled trial (RCT) (10) studied radiation therapy with and without cetuximab in patients with locally advanced HNSCC treated curatively. Two randomized trials (6,24) examined the role of a platinum-based chemotherapy with and without cetuximab in patients with incurable advanced and/or metastatic HNSCC. A separate publication (25) reported QoL results from this RCT. One RCT (23) compared two different doses of gefitinib to weekly methotrexate in patients with incurable advanced recurrent and/or metastatic HNSCC with disease progression despite, or unsuitable, for first-line platinum-based chemotherapy. No practice guidelines, systematic reviews, or meta-analyses were found during the course of this search. Patient Characteristics The RCTs involved three distinct patient populations: those with locally advanced (stage III-IV) HNSCC being treated for cure, those with incurable advanced recurrent and/or metastatic HNSCC being treated with first-line platinum-based chemotherapy, and those with incurable advanced recurrent and/or metastatic HNSCC who had failed or were unsuitable for first-line platinum-based chemotherapy. Performance status was measured by either the Karnofsky Performance Score (KPS) or Eastern Cooperative Oncology Group (ECOG) scales, and the median age ranged from 56 to 60 years, with an overall range of 33 to 83 years. Primary tumour sites reported were the pharynx (5-63%) and larynx (23-35%). EVIDENCE BASED SERIES #5-12 EVIDENTIARY BASE – page 4 Table 1. Phase III RCT patient characteristics and treatment regimens. Study Treatment Regimen Characteristics Primary Site (%) Pts (Total) Radiation therapy plus cetuximab in locally advanced HNSCC Bonner et al 2006 (10) A: RT+ cetuximab (ID 400mg/m2 IV; then 250mg/m2 IV w