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Combined effect of EGFR targeting with antiangiogenesis and irradiation
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Posters 93 poster COMBINED EFFECT OF EGFRTARGETING WITH ANTIANGIOGENESIS AND IRRADIATION A. Bozec ~,O. Dassonvil le ~,G. Poisson net ~, J.L Fischel 2, P. Hofman 3,G. Milano2, ICENTREANTOINELACASSAGNE~Surgery, Nice, France, 2CENTREANTOINELACASSAGNE,Oncopharmacology, Nice, France, 3CENTREHOSPITALIERUNIVERSITAIRE,HOPITALPASTEUR,Pathology, Nice, France
Purpose/Objective: Recent preclinical and clinical studies suggest beneficial effects from combining antiangiogenic drugs with radiotherapy. In addition, a survival benefit has been demonstrated in patients with head and neck tumors receiving an anti-epidermal growth factor receptor (EGFR) agent in combination with radiotherapy. To investigate the effect of combining all three approaches, we evaluated the antitumor efficacy of the antiangiogenic compound AZD2171, a highly potent, orally active, vascular endothelial growth factor (VEGF) signaling inhibitor; gefitinib, an EGFR tyrosine kinase inhibitor; and irradiation, alone and in combination. Materials/Methods: In vivo investigations were performed using a VEGF-secreting human head and neck tumor cell line, CAL33, with a high EGFRcontent (164,000 high-affinity sites per cell) established as xenografts (250 mm 3) in nude mice. AZD2171 (2.5 mglkg once daily, orally), gefitinib (50 mglkg 5 days/week, orally) and irradiation ([Rt] 6 Gy, 3 days/week), were administered alone and in combination for 2 weeks. Results: AZD2171 or gefitinib immediately slowed the growth of CAL33 tumors. Concomitant administration of both drugs produced a complete growth arrest. Irradiation slowed tumor growth after I week of treatment. Following discontinuation of treatment, animals were observed for I to S weeks. Tumor regrowth occurred immediately after the end of treatment for single drugs and drug combination; in contrast, the effect of irradiation on tumor growth was maintained for I week after cessation of treatment, followed by slowly progressive tumor regrowth. The triple combination was the most effective with immediate complete growth arrest lasting 3 weeks followed by progressive tumour regrowth. Combination ratios (CR), calculated from the mean tumor volumes (TV) of the different treatment groups at the end of the observation period (day 31 after cell injection) indicated supra-additive (CRy1) antitumor effects for AZD2171 and gefitinib in combination (CR=I.6) and both drugs administered in combination with Rt [AZD21711gefitiniblRt] (2~CR <3.S).The median time to reach a tumor volume of 1000 mm 3 was significantly increased I) for AZD2171 alone in comparison to gefitinib alone (P=O.O01) 2) for the [AZD2171 Igefitinib] combination (P=0.006) compared with either drug alone and 3) for the [AZD21711 gefitinib/Rt] combination compared with the [AZD2171/gefitinib] combination (P=0.0001) or Rt alone (P<0.0001). Conclusions: This combination of an EGFR inhibitor, an inhibitor of VEGF signaling and radiation therapy could be of clinical importance in the management of head and neck cancer patients. 94 poster GLIVEC AND CISPLATIN IN ADVANCED SALIVARY ADENOID CYSTIC CARCINOMA-A USEFUL COMBINATION N. Slevin;, K.L. Mais +,A.J. Sykes;, S.S. Banerjee2, P.A. Hulse3, B.M. Carrington 3, D. Hastings+, /CHRISTIEHOSPITAL,Clinical Oncology, Manchester, UK, 2CHRISTIEHOSPITAL,Pathology, Manchester, UK, 3CHRISTIEHOSPITAL,Radiology, Manchester, UK, 4CHRISTIEHOSPITAL,Medical Physics, Manchester, UK
Purpose/Objective: Salivary adenoidcystic carcinoma (ACC) comprises 1% of head and neck cancers. It is characterised by slow growth, tendency to local recurrence and propensity for systemic metastases. Response to cytotoxic chemotherapy is poor. 80 - 90
% ACCs express c-kit positivity such that treatment with Glivec (imatinib) is conceptually attractive. Based on ex-vivo synergy analysis we have chosen to examine the combination of Glivec and cisplatin in patients with progressive, recurrent and/or metastatic salivary ACC. Materials/Methods:This is an open, non-randomised, Gehan 2-stage phase II study (stage 119 patients, stage II depending on response rate). Pre-treatment baseline assessments included morphological imaging and FDG-PET studies. Patients received 2 months' Glivec 800mg daily followed by a combination of cisplatin (80mg/m 2 given 4-weekly) and reduced dose Glivec 400mg daily. Depending on responses and toxicity patients then continued on maintenance Glivec. 23 patients (aged 29 - 77) with advanced ACC have entered the study since February 2003. Results:Two patients progressed on Glivec alone and withdrew from the study. Of twenty assessable patients, none have progressed on Glivec plus cisplatin. The longest period with lack of progression on Glivec is 3V2 years. Response rate is currently being analysed using RECIST criteria. Responses did not seem to be related to the degree or intensity of c-kit positivity on immunohistochemistry. The Glivec/ cisplatin combination (median 5 cycles) was generally well tolerated with the main toxicities being fatigue, haematological, gastrointestinal upset, oedema and skin rash. Conclusions: Patients get a clinically useful stabilisation of disease with the combination of Glivec and cisplatin. This combination should be considered in the adjuvant setting following primary treatment with surgery and post-operative radiotherapy. 95 poster INVESTIGATION OF PREDICTIVE FACTORS OF RESPONSE IN PATIENTS WITH SQUAMOUS-CELL CARCINOMA OF THE HEAD AND NECK (SCCHN) GIVEN NEO-ADJUVANT ERLOTINIB BEFORE SURGERY; UPDATED RESULTS OF A SINGLE INSTITUTION EXPERIENCE A. BenlyazidI, F.Thomas2,J. Sarini;, M. Rives3, D. Hamelin 3,F. Courbon +, P. Rochaixs,JR Delord 2 IINSTITUTCLAUDIUSREGAUD,Head and Neck Surgery, Toulouse, France, 21NSTITUTCLAUDIUSREGAUD,Oncology, Toulouse, France, 31NST~TUTCLAUDIUSREGAUD,Radiotherapy, Toulouse, France, flNST~TUTCLAUDIUSREGAUD,Nuclear Medicine, Toulouse, France, 51NST~TUTCLAUDIUSREGAUD,Pathology, Toulouse, France
Purpose/Objective: To date, immunohistochemistry (IHC) and molecular analyses have not identified prognostic markers of response to epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors in SCCHN.The selection of patients who could benefit from such agents consequently remains a challenge. A 'pilot' clinical trial was initiated in patients (pts) with SCCHN pending first-line surgery for their disease. Materials/Methods: Erlotinib (Tarceva ®) was given at 150mg/day to pts with resectable SCCHN during the period between pan-endoscopy and surgery. Tumour response was assessed using RECIST criteria. Tumour samples were assessed by IHC for EGFR and other membrane/nuclear protein expression levels (Phospho-EGFR Tyr 1086, Phospho-Tyr, Phospho-AKT, STAT3, STATSb, Phospho-erk 1/2, p27, p21 ). Results: Thirty-five pts with resectable SCCHN were recruited: orat cavity (17 pts), oropharyngeal (7 pts), hypopharyngeal (5 pts), laryngeal (6 pts). Thirty pts received a complete course of erlotinib treatment (i.e. without close reduction/discontinuation); the main reason for early discontinuation was rash. The median duration of treatment was 21 days (14-27). Pts were clinically evaluated and their tumours assessed radiologically pre- and post-treatment. Thirty-one pts were evaluable, there were 9 good responders (30-80% decrease in tumour size), 20 with stable disease and 2 with minor progression. Toxicities were as expected: rash (grade 213 in 11 pts), diarrhoea (grade 2 in I pt). All pts underwent surgery; the incidence of post-operative complications was similar to our historical series.
Posters 93 poster COMBINED EFFECT OF EGFRTARGETING WITH ANTIANGIOGENESIS AND IRRADIATION A. Bozec ~,O. Dassonvil le ~,G. Poisson net ~, J.L Fischel 2, P. Hofman 3,G. Milano2, ICENTREANTOINELACASSAGNE~Surgery, Nice, France, 2CENTREANTOINELACASSAGNE,Oncopharmacology, Nice, France, 3CENTREHOSPITALIERUNIVERSITAIRE,HOPITALPASTEUR,Pathology, Nice, France
Purpose/Objective: Recent preclinical and clinical studies suggest beneficial effects from combining antiangiogenic drugs with radiotherapy. In addition, a survival benefit has been demonstrated in patients with head and neck tumors receiving an anti-epidermal growth factor receptor (EGFR) agent in combination with radiotherapy. To investigate the effect of combining all three approaches, we evaluated the antitumor efficacy of the antiangiogenic compound AZD2171, a highly potent, orally active, vascular endothelial growth factor (VEGF) signaling inhibitor; gefitinib, an EGFR tyrosine kinase inhibitor; and irradiation, alone and in combination. Materials/Methods: In vivo investigations were performed using a VEGF-secreting human head and neck tumor cell line, CAL33, with a high EGFRcontent (164,000 high-affinity sites per cell) established as xenografts (250 mm 3) in nude mice. AZD2171 (2.5 mglkg once daily, orally), gefitinib (50 mglkg 5 days/week, orally) and irradiation ([Rt] 6 Gy, 3 days/week), were administered alone and in combination for 2 weeks. Results: AZD2171 or gefitinib immediately slowed the growth of CAL33 tumors. Concomitant administration of both drugs produced a complete growth arrest. Irradiation slowed tumor growth after I week of treatment. Following discontinuation of treatment, animals were observed for I to S weeks. Tumor regrowth occurred immediately after the end of treatment for single drugs and drug combination; in contrast, the effect of irradiation on tumor growth was maintained for I week after cessation of treatment, followed by slowly progressive tumor regrowth. The triple combination was the most effective with immediate complete growth arrest lasting 3 weeks followed by progressive tumour regrowth. Combination ratios (CR), calculated from the mean tumor volumes (TV) of the different treatment groups at the end of the observation period (day 31 after cell injection) indicated supra-additive (CRy1) antitumor effects for AZD2171 and gefitinib in combination (CR=I.6) and both drugs administered in combination with Rt [AZD21711gefitiniblRt] (2~CR <3.S).The median time to reach a tumor volume of 1000 mm 3 was significantly increased I) for AZD2171 alone in comparison to gefitinib alone (P=O.O01) 2) for the [AZD2171 Igefitinib] combination (P=0.006) compared with either drug alone and 3) for the [AZD21711 gefitinib/Rt] combination compared with the [AZD2171/gefitinib] combination (P=0.0001) or Rt alone (P<0.0001). Conclusions: This combination of an EGFR inhibitor, an inhibitor of VEGF signaling and radiation therapy could be of clinical importance in the management of head and neck cancer patients. 94 poster GLIVEC AND CISPLATIN IN ADVANCED SALIVARY ADENOID CYSTIC CARCINOMA-A USEFUL COMBINATION N. Slevin;, K.L. Mais +,A.J. Sykes;, S.S. Banerjee2, P.A. Hulse3, B.M. Carrington 3, D. Hastings+, /CHRISTIEHOSPITAL,Clinical Oncology, Manchester, UK, 2CHRISTIEHOSPITAL,Pathology, Manchester, UK, 3CHRISTIEHOSPITAL,Radiology, Manchester, UK, 4CHRISTIEHOSPITAL,Medical Physics, Manchester, UK
Purpose/Objective: Salivary adenoidcystic carcinoma (ACC) comprises 1% of head and neck cancers. It is characterised by slow growth, tendency to local recurrence and propensity for systemic metastases. Response to cytotoxic chemotherapy is poor. 80 - 90
% ACCs express c-kit positivity such that treatment with Glivec (imatinib) is conceptually attractive. Based on ex-vivo synergy analysis we have chosen to examine the combination of Glivec and cisplatin in patients with progressive, recurrent and/or metastatic salivary ACC. Materials/Methods:This is an open, non-randomised, Gehan 2-stage phase II study (stage 119 patients, stage II depending on response rate). Pre-treatment baseline assessments included morphological imaging and FDG-PET studies. Patients received 2 months' Glivec 800mg daily followed by a combination of cisplatin (80mg/m 2 given 4-weekly) and reduced dose Glivec 400mg daily. Depending on responses and toxicity patients then continued on maintenance Glivec. 23 patients (aged 29 - 77) with advanced ACC have entered the study since February 2003. Results:Two patients progressed on Glivec alone and withdrew from the study. Of twenty assessable patients, none have progressed on Glivec plus cisplatin. The longest period with lack of progression on Glivec is 3V2 years. Response rate is currently being analysed using RECIST criteria. Responses did not seem to be related to the degree or intensity of c-kit positivity on immunohistochemistry. The Glivec/ cisplatin combination (median 5 cycles) was generally well tolerated with the main toxicities being fatigue, haematological, gastrointestinal upset, oedema and skin rash. Conclusions: Patients get a clinically useful stabilisation of disease with the combination of Glivec and cisplatin. This combination should be considered in the adjuvant setting following primary treatment with surgery and post-operative radiotherapy. 95 poster INVESTIGATION OF PREDICTIVE FACTORS OF RESPONSE IN PATIENTS WITH SQUAMOUS-CELL CARCINOMA OF THE HEAD AND NECK (SCCHN) GIVEN NEO-ADJUVANT ERLOTINIB BEFORE SURGERY; UPDATED RESULTS OF A SINGLE INSTITUTION EXPERIENCE A. BenlyazidI, F.Thomas2,J. Sarini;, M. Rives3, D. Hamelin 3,F. Courbon +, P. Rochaixs,JR Delord 2 IINSTITUTCLAUDIUSREGAUD,Head and Neck Surgery, Toulouse, France, 21NSTITUTCLAUDIUSREGAUD,Oncology, Toulouse, France, 31NST~TUTCLAUDIUSREGAUD,Radiotherapy, Toulouse, France, flNST~TUTCLAUDIUSREGAUD,Nuclear Medicine, Toulouse, France, 51NST~TUTCLAUDIUSREGAUD,Pathology, Toulouse, France
Purpose/Objective: To date, immunohistochemistry (IHC) and molecular analyses have not identified prognostic markers of response to epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors in SCCHN.The selection of patients who could benefit from such agents consequently remains a challenge. A 'pilot' clinical trial was initiated in patients (pts) with SCCHN pending first-line surgery for their disease. Materials/Methods: Erlotinib (Tarceva ®) was given at 150mg/day to pts with resectable SCCHN during the period between pan-endoscopy and surgery. Tumour response was assessed using RECIST criteria. Tumour samples were assessed by IHC for EGFR and other membrane/nuclear protein expression levels (Phospho-EGFR Tyr 1086, Phospho-Tyr, Phospho-AKT, STAT3, STATSb, Phospho-erk 1/2, p27, p21 ). Results: Thirty-five pts with resectable SCCHN were recruited: orat cavity (17 pts), oropharyngeal (7 pts), hypopharyngeal (5 pts), laryngeal (6 pts). Thirty pts received a complete course of erlotinib treatment (i.e. without close reduction/discontinuation); the main reason for early discontinuation was rash. The median duration of treatment was 21 days (14-27). Pts were clinically evaluated and their tumours assessed radiologically pre- and post-treatment. Thirty-one pts were evaluable, there were 9 good responders (30-80% decrease in tumour size), 20 with stable disease and 2 with minor progression. Toxicities were as expected: rash (grade 213 in 11 pts), diarrhoea (grade 2 in I pt). All pts underwent surgery; the incidence of post-operative complications was similar to our historical series.