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PO-101: Podoplanin expression in oropharyngeal cancer influences staging and prognosis only in p16 negative tumors
5TH ICHNO
S45 Surgery, Nice, France 2 Centre Antoine Lacassagne, Oncopharmacology Unit, Nice, France 3 Centre Antoine Lacassagne, Pathology, Nice, France 4 Centre Jean Perrin, Pathology, Clermont-Ferrand, France Purpose/Objective: Clinical benefit has been demonstrated in patients with head and neck cancer receiving an antiepidermal growth factor receptor (EGFR) agent in combination with chemotherapy. Activation of the PI3K/AKT/mTOR signaling pathway is identified as an important mechanism implicated in resistance to EGFR inhibitors. Recent preclinical studies suggest beneficial effects from combining mTOR inhibitors with anti-EGFR drugs. The aim of this experimental study was to investigate the effects of combining the mTOR inhibitor Temsirolimus (Tem) with the anti-EGFR agent Cetuximab (Cet), and conventional chemotherapeutic drugs (Cisplatin (C) and Fluorouracil (F)) on an orthotopic model of head and neck cancer. Materials and Methods: We evaluated in vivo the antitumour efficacy of Tem, Cet and C-F, given alone and in combination. Investigations were performed using a VEGFsecreting human head and neck tumour cell line, CAL33, with a high EGFR content, injected as orthotopic xenografts into the mouth floor of nude mice. Three days after tumour cell injection, Tem (5 mg/kg, 5 days a week), Cet (2.5 mg/kg, once a week) and C-F (C: 4 mg/kg, F: 15 mg/kg, once a week)) were administered by intra-peritoneal injection alone or in combination for 12 days. Results: As compared with the control, the combination of Tem and Cet led to the highest tumor inhibition and induced an almost complete tumor growth arrest (p = 0.01). Tem significantly enhanced the impact of the Cet + C-F combination on tumor growth (p < 0.001). Tem and Cet were well tolerated as indicated by the stability of the mice weight during the treatment period. The highest inhibitory effects of treatments on cell proliferation (Ki67 labelling), MAPK (pP42/44 labelling) and PI3K/AKT/mTOR (pS6R labelling) signaling pathways were found with the association Tem-Cet. The addition of Tem+Cet to the C-F treatment significantly decreased tumor vessel formation as compared to C-F treatment alone (p = 0.002). Conclusions: The results of the present study testing the association of Tem with Cet and chemotherapy could serve as a strong preclinical basis for innovative treatments combining m-TOR/PI3K inhibition with EGFR targeting therapies for an optimal management of patients with head and neck cancer. PO-100 E6 viral protein ratio correlates with outcomes in human papillomavirus related oropharyngeal cancer A. Hong1, X. Zhang1, D. Jones1, M. Zhang1, C.S. Lee1, J.G. Lyons1, A.S. Veillard1, B. Rose1 1 The University of Sydney, Faculty of Medicine, Sydney, Australia Purpose/Objective: With the raising prevalence of human papillomavirus (HPV) positive oropharyngeal cancer (OSCC), a more refined prognostic marker for HPV positive OSCC is needed to guide treatment. The aim of this study was to identify prognostic indicators that could be used in conjunction with the existing clinicopathological approach to improve the management of HPV positive OSCC. Materials and Methods: We determined the ratio of HPV E6*I and E6*II splice variants by quantitative RT-PCR in 177 HPV positive OSCC and correlated the findings with other clinicopathological data. Results: There were significantly more events and deaths among patients whose tumors had an E6*I/*II ratio ≥1 compared with an E6*I/*II ratio of <1 (38.5% vs 20.3%, p=0.015) and (30.2% vs 14.1%, p=0.023) respectively. In the
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5th ICHNO multivariable analysis, patients with E6*I/*II ratio ≥1 OSCC were twice as likely to have an event (HR 2.02, 95% CI 1.063.85, p=0.033) and to die (HR 1.95, 95% CI 0.89-4.26, p=0.094) relative to those with E6*I/*II ratio <1 OSCC. Conclusions: The detection of HPV 16 spliced transcripts may serve to identify risk factors for poorer outcomes for HPV positive OSCC. PO-101 Podoplanin expression in oropharyngeal cancer influences staging and prognosis only in p16 negative tumors M.A. Broglie Daeppen1, M. Roessle2, S.Y. Kiessling1, A. Soltermann3, S.R. Haile4, G.F. Huber5, S.J. Stoeckli6 1 Kantonsspital St. Gallen, Otolaryngology Head and Neck Surgery, St Gallen, Switzerland 2 Cantonal Hospital Graubuenden, Institute of Pathology, Chur, Switzerland 3 University Hospital Zurich, Institute of Surgical Pathology, Zurich, Switzerland 4 Kantonsspital St. Gallen, Clinical Trials Unit, St. Gallen, Switzerland 5 University Hospital Zurich, Otolaryngology Head and Neck Surgery, Zurich, Switzerland 6 Kantonsspital St. Gallen, Otolaryngology Head and Neck Surgery, St. Gallen, Switzerland Purpose/Objective: To assess the impact of podoplanin expression on staging and clinical outcome in relation to HPV status in patients with oropharyngeal cancer (OPSCC). Materials and Methods: 174 patients were consecutively included with tissue microarray (TMA) construction and immunohistochemical analysis. Estimation of survival times and importance of clinical and immunohistochemical factors for outcome by Kaplan-Meier analysis and Cox proportional hazard models. Results: For the entire cohort, the 5yr-Overall (OS), disease specific (DSS) and disease free survival (DFS) achieved 71%, 77% and 76%, respectively. Patients with p16 positive tumors had statistically significantly better 5yr-OS (p16 positive vs p16 negative patients 81% vs 60%, p=0.001), DSS (88% vs 66%, p=0.0001) and DFS (87% vs 64%, p=0.0001) than patients with p16 negative cancer. 56/174 (32%) tumor samples were expressing podoplanin. In the entire patient cohort as well as in the p16 positive subgroup no impact of podoplanin expression on nodal stage or survival could be demonstrated. In the p16 negative subgroup podoplanin expressing tumors had a more advanced N-category compared to podoplanin non-expressing tumors and had also a statistically significant worse 5yr-OS (42% vs. 70%), DSS (47% vs. 75%), and DFS (46% vs. 73%).
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S46 were reirradiated Concomitant EGFR blockade (cetuximab) was given initially at 400 mg/m2 two days prior to re-RT and weekly (250 mg/m2) thereafter. Results: 31 patients completed Re-RT (50.4-66.6 Gy, 5 X 1.8 Gy/Week) and received cetuximab as prescribed. One patient died of anaphylactic shock, two discontinued studyparticipation on their own request. Grade 3 side effects were documented for dermatitis (25.8%,) dysphagia (12.9%), acneiform rash (22.5%), mucositis (9.6%), voice change (9.6 %) and pain (9.6%). Median overall and progression-free survival times were 10.4 and 5.2 months, respectively. Conclusions: To the best of our knowledge, we report here the largest study where safety and efficacy of re-RT and concur-rent EGFR blockade have been investi-gated. We documented significant longer median overall surviv-al if patients developed acneiform rash grade 2–3 compared to patients with-out this cetuximab-related complication (14 months vs. 6 months) and sig-nificant shorter survival times in patients who relapsed more than 120 months after finishing primary RT course. Taken together, compared to standard combined therapy (cisplatin,5-Fluorouracil and cetuximab) this therapeutic strategy did not demonstrate survival benefit. PO-103 Comparison of VEGF Expression in non malignant, premalignant lesion and squamous cell carcinoma of oral cavity M. Gupta1, N. Husain2, R. Mehrotra3 1 Christian Medical College Hospital, General Pathology, Vellore, India 2 RML Medical College & Hospital, Pathology, Lucknow, India 3 King George Medical University, Pathology, Lucknow, India
Conclusions: Podoplanin is a strong and independent prognostic factor for staging and survival in the group of patients with p16 negative but not with p16 positive OPSCC and may be considered as a cofactor in risk stratification and therapeutic decisions in patients with prognostically unfavourable p16 negative OPSCC. PO-102 Reirradiation and cetuximab in patients with recurrent, unresectable previously irradiated head and neck cancer D. Milanovic1, A.L. Grosu1, M. Henke1 1 Universitätsklinik Freiburg, Department of Radiation Oncology, Freiburg, Germany Purpose/Objective: The treatment of patients with locoregionally recurrent, unresectable and previously irradiated head and neck cancer (HNSCC) is a continuing challenge. Due to the fact that the predominant cause of death of these patients is uncontrolled local progression, it has been supposed that reirradiation (re-RT) may play important role achieving local control, but median survival achieved with this therapeutic modality is approximately 10 months. The overexpression of epidermal growth factor receptor (EGFR), which is not only responsible for progression but also for increased resistance toward RT, is one of the most important molecular biological characteristics of HNSCC. We propose that better response to re-RT will be reached in case of simultaneous EGFR inhibition with cetuximab. The purpose of this retrospective study was to investigate the feasibili-ty, toxicity, and outcome of re-RT combined with cetuximab in pa-tients with inoperable, previously irradiated recurrent HNSCC. Materials and Methods: Between June 2008 and August 2014, 34 patients with inoperable and previously irradiated HNSCC
Purpose/Objective: To compare vascular endothelial growth factor (VEGF) expression in non malignant lesion (stratified squamous epithelium overlying pyogenic granuloma), premalignant lesion (leukoplakia) and squamous cell carcinoma (SCC) of oral cavity and further to evaluate expression in relation to grade of the tumour. Materials and Methods: Immunohistochemical expression of VEGF in 90 cases of oral SCC [30 cases each of well differentiated (WD), moderately differentiated (MD) and poorly differentiated (PD) carcinoma] and 30 cases each of leukoplakia and pyogenic granuloma were evaluated. VEGF expression observed as brown intracytoplasmic staining, was counted in 500 squamous cells in all cases. On the basis of intensity and percentage positivity VEGF score and VEGF grade were calculated. The intensity of VEGF staining in individual cells was graded as negative, +, ++, +++. Number of squamous cells showing VEGF expression of varying intensity was counted and VEGF score was calculated as below Number of cells with negative VEGF expression × 0 = A Number of cells with 1(+) intensity × 1 = B Number of cells with 2(++) intensity × 2 = C Number of cells with 3(+++) intensity × 3 = D VEGF score = A+B+C+D VEGF score for individual cases was calculated and mean score was obtained for each of the 5 groups VEGF grading on the basis of the score obtained for each tumor was done in the following way: VEGF grade VEGF score Grade-0 0-50 Grade-1 51 - 500 Grade 2 501-1000 Grade 3: 1001 – 1500
S45 Surgery, Nice, France 2 Centre Antoine Lacassagne, Oncopharmacology Unit, Nice, France 3 Centre Antoine Lacassagne, Pathology, Nice, France 4 Centre Jean Perrin, Pathology, Clermont-Ferrand, France Purpose/Objective: Clinical benefit has been demonstrated in patients with head and neck cancer receiving an antiepidermal growth factor receptor (EGFR) agent in combination with chemotherapy. Activation of the PI3K/AKT/mTOR signaling pathway is identified as an important mechanism implicated in resistance to EGFR inhibitors. Recent preclinical studies suggest beneficial effects from combining mTOR inhibitors with anti-EGFR drugs. The aim of this experimental study was to investigate the effects of combining the mTOR inhibitor Temsirolimus (Tem) with the anti-EGFR agent Cetuximab (Cet), and conventional chemotherapeutic drugs (Cisplatin (C) and Fluorouracil (F)) on an orthotopic model of head and neck cancer. Materials and Methods: We evaluated in vivo the antitumour efficacy of Tem, Cet and C-F, given alone and in combination. Investigations were performed using a VEGFsecreting human head and neck tumour cell line, CAL33, with a high EGFR content, injected as orthotopic xenografts into the mouth floor of nude mice. Three days after tumour cell injection, Tem (5 mg/kg, 5 days a week), Cet (2.5 mg/kg, once a week) and C-F (C: 4 mg/kg, F: 15 mg/kg, once a week)) were administered by intra-peritoneal injection alone or in combination for 12 days. Results: As compared with the control, the combination of Tem and Cet led to the highest tumor inhibition and induced an almost complete tumor growth arrest (p = 0.01). Tem significantly enhanced the impact of the Cet + C-F combination on tumor growth (p < 0.001). Tem and Cet were well tolerated as indicated by the stability of the mice weight during the treatment period. The highest inhibitory effects of treatments on cell proliferation (Ki67 labelling), MAPK (pP42/44 labelling) and PI3K/AKT/mTOR (pS6R labelling) signaling pathways were found with the association Tem-Cet. The addition of Tem+Cet to the C-F treatment significantly decreased tumor vessel formation as compared to C-F treatment alone (p = 0.002). Conclusions: The results of the present study testing the association of Tem with Cet and chemotherapy could serve as a strong preclinical basis for innovative treatments combining m-TOR/PI3K inhibition with EGFR targeting therapies for an optimal management of patients with head and neck cancer. PO-100 E6 viral protein ratio correlates with outcomes in human papillomavirus related oropharyngeal cancer A. Hong1, X. Zhang1, D. Jones1, M. Zhang1, C.S. Lee1, J.G. Lyons1, A.S. Veillard1, B. Rose1 1 The University of Sydney, Faculty of Medicine, Sydney, Australia Purpose/Objective: With the raising prevalence of human papillomavirus (HPV) positive oropharyngeal cancer (OSCC), a more refined prognostic marker for HPV positive OSCC is needed to guide treatment. The aim of this study was to identify prognostic indicators that could be used in conjunction with the existing clinicopathological approach to improve the management of HPV positive OSCC. Materials and Methods: We determined the ratio of HPV E6*I and E6*II splice variants by quantitative RT-PCR in 177 HPV positive OSCC and correlated the findings with other clinicopathological data. Results: There were significantly more events and deaths among patients whose tumors had an E6*I/*II ratio ≥1 compared with an E6*I/*II ratio of <1 (38.5% vs 20.3%, p=0.015) and (30.2% vs 14.1%, p=0.023) respectively. In the
page 50
5th ICHNO multivariable analysis, patients with E6*I/*II ratio ≥1 OSCC were twice as likely to have an event (HR 2.02, 95% CI 1.063.85, p=0.033) and to die (HR 1.95, 95% CI 0.89-4.26, p=0.094) relative to those with E6*I/*II ratio <1 OSCC. Conclusions: The detection of HPV 16 spliced transcripts may serve to identify risk factors for poorer outcomes for HPV positive OSCC. PO-101 Podoplanin expression in oropharyngeal cancer influences staging and prognosis only in p16 negative tumors M.A. Broglie Daeppen1, M. Roessle2, S.Y. Kiessling1, A. Soltermann3, S.R. Haile4, G.F. Huber5, S.J. Stoeckli6 1 Kantonsspital St. Gallen, Otolaryngology Head and Neck Surgery, St Gallen, Switzerland 2 Cantonal Hospital Graubuenden, Institute of Pathology, Chur, Switzerland 3 University Hospital Zurich, Institute of Surgical Pathology, Zurich, Switzerland 4 Kantonsspital St. Gallen, Clinical Trials Unit, St. Gallen, Switzerland 5 University Hospital Zurich, Otolaryngology Head and Neck Surgery, Zurich, Switzerland 6 Kantonsspital St. Gallen, Otolaryngology Head and Neck Surgery, St. Gallen, Switzerland Purpose/Objective: To assess the impact of podoplanin expression on staging and clinical outcome in relation to HPV status in patients with oropharyngeal cancer (OPSCC). Materials and Methods: 174 patients were consecutively included with tissue microarray (TMA) construction and immunohistochemical analysis. Estimation of survival times and importance of clinical and immunohistochemical factors for outcome by Kaplan-Meier analysis and Cox proportional hazard models. Results: For the entire cohort, the 5yr-Overall (OS), disease specific (DSS) and disease free survival (DFS) achieved 71%, 77% and 76%, respectively. Patients with p16 positive tumors had statistically significantly better 5yr-OS (p16 positive vs p16 negative patients 81% vs 60%, p=0.001), DSS (88% vs 66%, p=0.0001) and DFS (87% vs 64%, p=0.0001) than patients with p16 negative cancer. 56/174 (32%) tumor samples were expressing podoplanin. In the entire patient cohort as well as in the p16 positive subgroup no impact of podoplanin expression on nodal stage or survival could be demonstrated. In the p16 negative subgroup podoplanin expressing tumors had a more advanced N-category compared to podoplanin non-expressing tumors and had also a statistically significant worse 5yr-OS (42% vs. 70%), DSS (47% vs. 75%), and DFS (46% vs. 73%).
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S46 were reirradiated Concomitant EGFR blockade (cetuximab) was given initially at 400 mg/m2 two days prior to re-RT and weekly (250 mg/m2) thereafter. Results: 31 patients completed Re-RT (50.4-66.6 Gy, 5 X 1.8 Gy/Week) and received cetuximab as prescribed. One patient died of anaphylactic shock, two discontinued studyparticipation on their own request. Grade 3 side effects were documented for dermatitis (25.8%,) dysphagia (12.9%), acneiform rash (22.5%), mucositis (9.6%), voice change (9.6 %) and pain (9.6%). Median overall and progression-free survival times were 10.4 and 5.2 months, respectively. Conclusions: To the best of our knowledge, we report here the largest study where safety and efficacy of re-RT and concur-rent EGFR blockade have been investi-gated. We documented significant longer median overall surviv-al if patients developed acneiform rash grade 2–3 compared to patients with-out this cetuximab-related complication (14 months vs. 6 months) and sig-nificant shorter survival times in patients who relapsed more than 120 months after finishing primary RT course. Taken together, compared to standard combined therapy (cisplatin,5-Fluorouracil and cetuximab) this therapeutic strategy did not demonstrate survival benefit. PO-103 Comparison of VEGF Expression in non malignant, premalignant lesion and squamous cell carcinoma of oral cavity M. Gupta1, N. Husain2, R. Mehrotra3 1 Christian Medical College Hospital, General Pathology, Vellore, India 2 RML Medical College & Hospital, Pathology, Lucknow, India 3 King George Medical University, Pathology, Lucknow, India
Conclusions: Podoplanin is a strong and independent prognostic factor for staging and survival in the group of patients with p16 negative but not with p16 positive OPSCC and may be considered as a cofactor in risk stratification and therapeutic decisions in patients with prognostically unfavourable p16 negative OPSCC. PO-102 Reirradiation and cetuximab in patients with recurrent, unresectable previously irradiated head and neck cancer D. Milanovic1, A.L. Grosu1, M. Henke1 1 Universitätsklinik Freiburg, Department of Radiation Oncology, Freiburg, Germany Purpose/Objective: The treatment of patients with locoregionally recurrent, unresectable and previously irradiated head and neck cancer (HNSCC) is a continuing challenge. Due to the fact that the predominant cause of death of these patients is uncontrolled local progression, it has been supposed that reirradiation (re-RT) may play important role achieving local control, but median survival achieved with this therapeutic modality is approximately 10 months. The overexpression of epidermal growth factor receptor (EGFR), which is not only responsible for progression but also for increased resistance toward RT, is one of the most important molecular biological characteristics of HNSCC. We propose that better response to re-RT will be reached in case of simultaneous EGFR inhibition with cetuximab. The purpose of this retrospective study was to investigate the feasibili-ty, toxicity, and outcome of re-RT combined with cetuximab in pa-tients with inoperable, previously irradiated recurrent HNSCC. Materials and Methods: Between June 2008 and August 2014, 34 patients with inoperable and previously irradiated HNSCC
Purpose/Objective: To compare vascular endothelial growth factor (VEGF) expression in non malignant lesion (stratified squamous epithelium overlying pyogenic granuloma), premalignant lesion (leukoplakia) and squamous cell carcinoma (SCC) of oral cavity and further to evaluate expression in relation to grade of the tumour. Materials and Methods: Immunohistochemical expression of VEGF in 90 cases of oral SCC [30 cases each of well differentiated (WD), moderately differentiated (MD) and poorly differentiated (PD) carcinoma] and 30 cases each of leukoplakia and pyogenic granuloma were evaluated. VEGF expression observed as brown intracytoplasmic staining, was counted in 500 squamous cells in all cases. On the basis of intensity and percentage positivity VEGF score and VEGF grade were calculated. The intensity of VEGF staining in individual cells was graded as negative, +, ++, +++. Number of squamous cells showing VEGF expression of varying intensity was counted and VEGF score was calculated as below Number of cells with negative VEGF expression × 0 = A Number of cells with 1(+) intensity × 1 = B Number of cells with 2(++) intensity × 2 = C Number of cells with 3(+++) intensity × 3 = D VEGF score = A+B+C+D VEGF score for individual cases was calculated and mean score was obtained for each of the 5 groups VEGF grading on the basis of the score obtained for each tumor was done in the following way: VEGF grade VEGF score Grade-0 0-50 Grade-1 51 - 500 Grade 2 501-1000 Grade 3: 1001 – 1500