OC-0333: Prognostic impact of HPV and smoking in RT of oropharyngeal cancer: the MARCH-HPV project

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Conclusion Our findings strongly favor use of cisplatin in CRT treatment of locally advanced p16+ OPC. Until results of randomized trials evaluating cisplatin versus cetuximab are available, off-trial use of C225 in this population as an effort to reduce morbidity should be discouraged, especially in patients with advanced tumor and nodal stage disease. In cases where cisplatin is contraindicated, the use of carboplatin as an alternative option may reduce DF compared to C225. When C225 is used, altered fractionation radiotherapy may be beneficial for LRC. OC-0332 Impact of HPV on effect of chemotherapy in SCCHN : results of the GORTEC 2007-01 randomized trial X. Sun1, Y. Tao2, A. Auperin3, C. Sire4, L. Martin5, C. Khoury6, P. Maingon7, E. Bardet8, M. Lapeyre9, Y. Pointreau10, N. Ollivier3, A. Cornely2, O. Casiraghi11, J. Bourhis12 1 CHRU- Besançon and Hôpital du Nord Franche Comté-, radiotherapy, Montbéliard, France 2 Institut Gustave Roussy, Radiation Oncology, Villejuif, France 3 Institut Gustave Roussy, Biostatistics, Villejuif, France 4 CH de Bretagne Sud, radiotherapy, Lorient, France 5 Centre Le Conquerant, radiotherapy, Le Havre, France 6 Centre Saint Louis, radiotherapy, Toulon, France 7 Centre GF Leclerc, radiotherapy, Dijon, France 8 Centre Gauducheau, radiotherapy, Nantes, France 9 Centre Perrin, radiotherapy, Clermont, France 10 Jean Bernard centre - Victor Hugo clinic, radiotherapy, Le Mans, France 11 Institut Gustave Roussy, Pathology, Villejuif, France 12 CHUV, radiation oncology, Lausanne, Switzerland Purpose or Objective Chemo-radiotherapy (CT/RT) and cetuximab-RT (cetuxRT) were established as standard treatments in nonoperated locally advanced (LA) SCCHN. The GORTEC 200701 randomized trial was restricted to patients (pts) with no or limited nodal spread (N0-N2a and non palpable N2b). The results showed that the addition of concomitant CT with cetux-RT backbone markedly improved both PFS and LRC (Bourhis et al ASCO 2016) with no significant benefit on overall survival. The impact of p16 expression on the treatment effect of these patients was not available at the time of the first presentation. Material and Methods The 1:1 randomization between cetux-RT (arm A) and cetux-CT/RT (arm B) was done by minimization on centers, N and T stages. Cetuximab was given as a loading dose of 400 mg/m2 followed by weekly 250 mg/m2 during

RT. RT total dose was 70 Gy (2 Gy/day, 5 days/week). Concurrent CT was 3 cycles of carboplatin 70mg/m²/d + 5FU 600mg/m²/d, D1-4. About 2/3 of the patients had oropharyngeal cancers (OPC) and HPV status was determined in these patients using p16 expression as a surrogate (immunohistochemistry). Smoking status was also collected. Primary endpoint was progression free survival (PFS). Results Between Feb 2008 and Feb 2014, 406 pts were randomized with 265 (65%) OPC. The median follow-up was 4.4 years. Overall, p16 was assessed in 236 OPC (89%) patients (115 pts in arm A and 121 in arm B), and p16+ was found in 21% of each arm (24 patients in arm A and 25 arm B). 15 out the 49 (31%) p16+ patients were non-smokers, while 5/187 (3%) p16- patients were non-smokers. A significant improvement in PFS was found in p16+ compared to p16OPC (p= 0.0002). A significantly improved PFS was observed with cetux-CT/RT (arm B) compared with cetuxRT (arm A) in p16- OPC (HR: 0.63, 95% CI: 0.44 – 0.91) as well as in p16+ (HR: 0.23, 95% CI: 0.07 – 0.73), and the interaction between p16 and treatment modality was not significant (p=0.13). For loco-regional control, a similar effect was found in both p16- and p16+ OPC in favor of arm B (HR= 0.33 [95%CI 0.19 – 0.56] and 0.16 [95%CI 0.02 – 1.36] respectively; interaction test p=0.51). Conclusion The large majority of OPC patients randomized in this trial were p16- and smokers. The addition of concomitant chemotherapy to cetux-RT markedly improved PFS and LRC in patients with OPC regardless of p16 status. OC-0333 Prognostic impact of HPV and smoking in RT of oropharyngeal cancer: the MARCH-HPV project P. Lassen1, B. Lacas2, A. Trotti3, B. Zackrisson4, Q. Zhang5, J. Overgaard1, J.P. Pignon2, P. Blanchard6 1 Aarhus University Hospital, Department of Experimental Clinical Oncology, Aarhus C, Denmark 2 Gustave-Roussy Paris-Saclay University Ligue Nationale Contre le Cancer meta-analysis platform, Biostatistics and Epidemiology Department, Villejuif, France 3 Moffitt Cancer Center, Department of Radiation Oncology, Tampa- Florida, USA 4 Umeå University, Department of Radiation Sciences Oncology, Umeå, Sweden 5 NRG Oncology Statistics and Data Management Center formerly RTOG, NRG Oncology Statistics and Data Management Center formerly RTOG, Philadelphia- PA, USA 6 Gustave-Roussy Paris-Saclay University, Radiotherapy Department- INSERM-U1018-CESP, Villejuif, France Purpose or Objective HPV is a favorable prognostic factor in radiotherapy (RT) of HNSCC but whether HPV is predictive of response to altered fractionated RT remains controversial. We aimed to assess the potential prognostic and predictive impact of HPV in altered fractionated RT and moreover to evaluate the combined prognostic impact of HPV and smoking. Material and Methods The MARCH-HPV project is based on the first update of the Meta-Analysis of Radiotherapy in HNSCC (MARCH), which included 33 trials and 11833 patients. HPV status was determined according to p16 immunohistochemistry. The HPV analysis was restricted to oropharyngeal cancer (OPC) and performed using a Cox model stratified by trial and adjusted on gender, age, T-stage, N-stage, type of RT schedule, p16 (positive, negative) and smoking status (never/former, current). The potential prognostic and predictive effects of HPV-status were estimated for progression-free survival (PFS) and overall survival (OS). Moreover, the combined prognostic impact of HPV and smoking were assessed for PFS and OS. Results

S176 ESTRO 36 _______________________________________________________________________________________________ Data and tumor tissue from 815 patients enrolled in 4 trials (DAHANCA 6-7, RTOG 9003, ARTSCAN, RTOG 0129) was available for analysis: 350 (43%) HPV-neg and 465 (57%) HPV-pos. Patients with HPV-pos tumors were significantly younger (mean: 56 vs 59 years, p=0.0002), in better performance status (PS=0: 74% vs 50%, p<0.0001), had smaller tumors (T1-2: 46% versus 33%, p<0.0001) and more advanced N-stage (N+: 87% versus 76%, p<0.0001) compared with the HPV-neg subgroup. HPV-status significantly influenced prognosis and HPV-pos patients had favorable PFS (HR=0.42 [95% CI: 0.34-0.51] with a 42% absolute increase at 10 years) and OS (HR=0.40 [0.32-0.49] with a 40% absolute increase at 10 years) compared to the HPV-neg subgroup. Smoking independently influenced outcome and never/former smokers had better prognosis than current smokers with HR of 0.61 [0.50-0.75] and 0.58 [0.47-0.72] for PFS and OS, respectively. A further analysis of the impact of smoking was performed classifying smoking as former/current vs never smokers. This consequently led to the exclusion of 166 patients from the ARTSCAN trial where this information was not available. Compared to the HPV-neg smoking subgroup, HPV-pos never smokers were found to have significantly better outcomes (PFS: HR: 0.20 [0.14-0.31] and OS: HR: 0.20 [0.13-0.31]). Similar, although less pronounced, survival benefits were observed for HPV-pos smokers (PFS: HR: 0.41 [0.33-0.51] and OS: HR: 0.38 [0.30-0.47]) when compared with HPV-neg smokers. There was no significant interaction between HPV-status and fractionation effect, whatever the coding for smoking. Conclusion HPV status was not found to be predictive of outcome after altered fractionated RT in this pooled analysis of OPC. However, the strong prognostic impact of HPV was confirmed and especially HPV-pos never smoking patients have superior outcome after RT. Supported by the French Ministry of Health (PHRC) OC-0334 Prospective MR assessment of dose-response kinetics of non-target muscles in head and neck cancer A.S.R. Mohamed1, R. Davuluri1, S. Frank1, Y. Ding1, S. Lai1, J. Wang1, C. Fuller1, K. Hutcheson1 1 The University of Texas- MD Anderson Cancer Center, Radiation Oncology, Houston, USA Purpose or Objective We have recently demonstrated the role of Magnetic Resonance Imaging (MRI) in characterizing radiotherapy (RT)-induced changes in non-target swallowing related musculature in a retrospective head and neck cancer cohort treated with definitive RT. We aim to validate the longitudinal dose-response changes of normal-muscle quantitative MRI signal kinetics in a prospective and well curated institutional dataset. Material and Methods A total of 39 patients were enrolled as part of an ongoing prospective clinical trial after obtaining study specific signed consent. All patients underwent three MRI studies: pre-, mid-, and post-RT. The mean T1, T1+ contrast (T1+C), and T2-weighted signal intensities (SI) for superior pharyngeal constrictors (SPC), middle pharyngeal constrictors (MPC), intrinsic tongue muscles (ITM), geniohyoid (GH), genioglossus (GG), mylohyoid (MH), masseters, medial/lateral pterygoids, anterior/posterior digastrics (ADM, PDM), and buccinators were recorded in the three time points and delta SI changes were calculated. Trapezius muscle was segment as a control due to negligible dose received. The SI changes were correlated to RT dose to the segmented structures after deformable image registration to planning CT and dose. Results All patients were stage III-IV HPV-positive oropharyngeal cancer. Median age was 58 years (range 39-80), 35 (90%) were men, and 35 (90%) were white race. Tonsillar fossa was the area of tumor origin in 20 patients (51%) and base

of tongue in 19 (49%). Prescription dose was 70 Gy in 33 fractions. At mid-RT; significant increase in mean T1+C SI was noted in the following muscles: ADM, ITM, GHM, and MPC (p=0.005, 0.01, 0.04, and 0.002, respectively) and significant increase in mean T2 SI was noted only in MPC (p=0.0005). At post-RT; significant increase in mean T1+C SI was detected in all studied muscles (p<0.05 for all). After Bonferroni correction for multiple comparisons, all remained significant except buccinators, pterygoids, and masseter. Post-RT increase in T2 SI was detected only in pharyngeal constrictors and medial pterygoids (p<0.05) and remained significant after Bonferroni correction for pharyngeal constrictors. No significant changes in mean T1 SI was detected in all tested muscles in both time points. There were no dose-parameter relationship in all muscles with increased T1+C and T2 SIs in all studied time points. Mean dose to muscle groups with significant increase in T1+C after Bonferroni correction was significantly higher compared to other muscle groups (52.7 vs. 37.5 Gy, p<0.0001). Simultaneously, mean dose to pharyngeal constrictors that showed significant T2 increase was significantly higher compared to other muscle groups (63.2 vs. 41.2 Gy, p<0.0001). Conclusion Significant dose-dependent increase in mid-RT and postRT T1+C and T2 signal intensities is noted in non-target swallowing muscles particularly in pharyngeal constrictors due to higher beam-path dose to these muscles. Symposium: GTFRCC SP-0335 GTFRCC: where to go from here? Y. Lievens1 1 University Hospital Ghent, Department of Radiation Oncology, Gent, Belgium The Global Task Force on Radiotherapy for Cancer Control (GTFRCC) has not only highlighted the urgent need for addressing the inequity gap in access to radiotherapy globally, it has also demonstrated that judicious investment in radiotherapy infrastructure and training is both effective and cost-effective. Indeed, in addition to preventing millions of cancer deaths in the decades to come, investing in radiotherapy has also been shown to bring value for money and a positive return on investment to the societies involved. The GTFRCC has articulated five calls-to-action in order to remedy the radiotherapy shortage and to make sure that radiotherapy is included into the multidisciplinary approach to cancer care. To ascertain a global impact by 2035, the time is now to build upon the GTFRCC results. ESTRO and the stakeholders involved in the GTFRCC have decided to join forces by establishing a new collaborative group with the aim of identifying timely, effective, and achievable responses to the GTFRCC’s calls-to-action, and of positioning radiotherapy as an essential component of effective cancer care globally. It is our pleasure to launch this initiative at ESTRO 36! SP-0336 Costs and needs of radiotherapy: a regional perspective E.H. Zubizarreta - zubi1 1 IAEA, Applied Radiation Biology and Radiotherapy, Wien, Austria This analysis presents the resources needed and costs at the present time globally and by region to give full access to RT. The variables and methodology were the same used by the GTFRCC. The GTFRCC reported the resources needed and costs to reach full access to RT in 2035 by income group, but not per region (Atun R et al. Expanding global access to radiotherapy. Lancet Oncol 2015; 16(10)). The division in regions adopted by the IAEA was used: Africa (AF), North America (NA) only includes USA and