Abstract ID: 2055690 MAPIE vs MAP in patients with a Poor Response to pre-operative chemotherapy for newly-diagnosed osteosarcoma: Results from EURAMOS-1 CTOS 2014, Berlin 17-Oct-2014 Neyssa Marina, Sigbjørn Smeland, Stefan S Bielack, Mark Bernstein, Gordana Jovic, Jane M Hook, Mark D Krailo, Trüde Butterfass-Bahloul, Thomas Kühne, Mikael Eriksson, Lisa Teot, Hans Gelderblom, Leo Kager, Kirsten Sundby Hall, Richard Gorlick, R. Lor Randall, Pancras W Hogendoorn , Gabriele Calaminus, Matthew R Sydes, Jeremy S Whelan on behalf of the EURAMOS-1 investigators Good afternoon, I want to thank the organizing committee for giving the EURAMOS group the opportunity to present the results of our trial evaluating whether altering post-operative therapy based on histological response improved outcome for patients with a poor histological response.

Design and eligibility Biopsy-proven diagnosis of resectable osteosarcoma REGISTER MAP (induction) Surgery Histological response assessment Poor Good RANDOMIZE MAP MAPIE MAPifn Registration Resectable high-grade osteosarcoma Extremity or axial Localized or metastatic Age ≤40yr No pretreatment for osteosarcoma No previous chemo for any disease No contraindication to treatment Registration & chemo ≤30day after biopsy Written informed consent This illustrates the study design, which included registration of all eligible patients following biopsy confirmation of diagnosis. The broad eligibility criteria included: resectable/high-grade osteosarcoma, age < 40 years, no prior treatment for osteosarcoma and no previous chemotherapy for any disease. No contraindications for treatment, written informed consent and the ability to begin therapy within 30 days of diagnostic biopsy.   Following registration patients received a 3 drug induction with cisplatin, doxorubicin and high-dose methotrexate followed by surgical resection of the primary tumor. Following pathological evaluation, patients with < 10% viable tumor were randomly assigned to continue MAP or to MAP plus interferon. Patients with at least 10% viable tumor were randomly assigned to continue with MAP or to MAP with the addition of IE.

Design and eligibility Biopsy-proven diagnosis of resectable osteosarcoma REGISTER MAP (induction) Surgery Histological response assessment Poor Good RANDOMIZE MAP MAPIE MAPifn Registration Resectable high-grade osteosarcoma Extremity or axial Localized or metastatic Age ≤40yr No pretreatment for osteosarcoma No previous chemo for any disease No contraindication to treatment Registration & chemo ≤30day after biopsy Written informed consent This presentation focuses on the results of the randomization for patients with at least 10% viable tumor.

Primary tumor resection Design MAP AP MM AP MM A MM A MM Induction MAP wk 12-29 Primary tumor resection Poor Response R AP MM x2 MAPIE wk 1-10 wk 11 AP MM IE M Ai M IE M AP MM IE M Ai MM wk 12-40 Eligibility for randomisation Poor histological response to induction MAP ≥10% viable tumor in resected specimen Complete resection of primary tumor No progression Recovered from prior therapy Dosing M Methotrexate 12gm/m2 A Doxorubicin 75mg/m2 P Cisplatin 120mg/m2 I Ifosfamide 14g/m2 i ifosfamide 9g/m2 E Etoposide 500mg/m2 Patients registered on trial received a three drug induction followed by surgical resection. To be eligible for the post surgical randomization on the poor responder arm, patients were required to have at least 10% viable tumor, a complete resection of the primary tumor, no evidence of disease progression and recovery from prior therapy. As is evident the MAPIE patients had a longer duration of therapy.

Event-free survival (EFS) Outcome measures Primary Event-free survival (EFS) Local recurrence Progression of existing metastases New metastatic disease Secondary malignancy Death Secondary include Overall survival (OS) Short & long-term toxicity Quality of life The primary outcome measure was event free survival defined as local recurrence, progression of metastases, new metastases, second malignancies or death. While secondary outcomes included overall survival, short and long-term toxicity and QOL.

Sample size Assumptions Targets Randomisation 3yr EFS 45% (MAP)  55% (MAPIE) Target HR = 0.75 Power 80% Type I error 0.05 Targets ≥ 378 EFS events 693 Poor Response randomizations over 5 years ~ 2000 registrations Randomisation Permuted blocks Stratification factors: data center, metastases status, site and location of tumor on bone Overall randomisation rate was 59% (1334/2260). Randomisation rate was higher in patients with good response 69% (716/1041) than in patients with poor response 58% (618/1059). Not known for 160 registered patients We made various assumptions for trial design: patients with a poor histological response treated with MAP would have a 3 year EFS or 45% and that MAPIE would improve that number to 55%. We were targeting a HR of 0.75 with 80% power and a type I error of 0.05. To complete the trial, we needed at least 378 events in poor responders and that would require registration of about 2000 patients resulting in approximately 693 randomized poor responders. Randomization was performed using permuted blocks stratified by data center, metastases, site and location of tumor on bone.  

Analyses Treatment effect estimated with 1. Hazard Ratio (HR) from adjusted Cox model Proportionality of hazards tested  Hazards not proportional 2. Restricted Mean Survival Time (RMST) RMST measures average time event-free up to a specified time point  5 years i.e. area under the curve Analysis Hazard ratio was estimated with Cox proportional-hazards model, adjusted* for stratification factors (data centre, metastases status, site and location on bone). To be a meaningful summary, hazard ratio requires proportionality of hazards of the treatment effect. Formal test has been done and the assumption about proportional hazards is violated. Therefore, HR is not a meaningful summary of the EFS difference between the arms. For that reason, difference between EFS in two arms has been estimated with restricted mean survival time (RMST). Restricted Mean Survival Time (how it works and interpretation) Choose time point t* A suitable time point t* is chosen, up to which we wish to compute RMST. There are two things to consider when choosing the best time point t*: (1) time point t* is determined so that it maximises the power for the comparison of arms (2) a meaningful time point from the clinical point of view. In EURAMOS, it was determined that best time point for the current poor responders analysis is 5 years. t* may change with longer follow-up Regarding power and choice of t* - please see additional slide at the end of the talk Interpretation of RMST The RMST is a “5-year EFS expectancy” or “expected time to the first event in 5 years after randomisation”. Interpretation of RMST difference between the arms: “MAPIE increases time to first event in 5 years after randomisation by 0.6 months (18 days), compared with MAP” How can we estimate RMST? RMST is estimated as the area under the survival curve up to 5 years ----- Meeting Notes (10/14/14 22:23) ----- We estimated the treatment effect using HR from adjusted Cox model and tested the proportionality of hazards. Since hazards were not proportional, we used a restricted mean survival time, which measures average time event-free up to a specified point. RMST compares the time to first event in both groups up to 5 years.

Rationale for releasing data now Analysis planned at ≥378 EFS events Fewer poor responders randomised (618/693) Event rate is lower than predicted Results unlikely to change in near future IDMC recommended early release and dissemination After routine review of the data (Jun-2014) Data released by the Trial Steering Committee Analysis includes 300 EFS events (median FU 4.5y) WE had planned our analysis to occur after at least 378 events. This was based on the assumption that 45% (567) of patients will be good responders and 55% poor responders. Unfortunately, in our trial 54% were good responders (716 patients) and 46% (618 patients) were poor responders) At its scheduled meeting in June 2014, the IDMC reviewed the data and concluded that the results were unlikely to change over time and recommended release of the data. Thus, our analysis for this presentation includes only 300 EFS events at a median FU of 4.5 years.

Recruitment: Apr2005 – Nov2011 Registration 2260 Confirmed Poor Responder 1059 Randomized 618 MAP 310 MAPIE 308 Recruitment: Apr2005 – Nov2011 1201 Not Poor Responder 1041 Confirmed Good Response 160 Response not reported 441 Not Randomized 208 (47%) Non-consent 102 (23%) Progression (local or distant) 51 (12%) Histology reported outside trial timelines 44 (10%) Not 2 cycles induction MAP 17 ( 4%) Other 15 ( 4%) No removal of mets/unresectable disease 4 ( 1%) Reason missing 1 (<1%) Good responder, entered PR rand (MAP) 2260 patients were registered on EURAMOS 1. 1059 of those were poor responders and 618 agreed to randomization. 310 MAP and 308 to MAPIE. As seen in the slide, the most common reason for non-randomization was lack of consent. The pie chart depicts randomizations by group.

Baseline characteristics MAP MAPIE Age at randomisation Median (IQR) (min-max) 15 4 (11-18) - 40 5 (12-17) Sex Male Female 174 136 (56%) (44%) 191 117 (62%) (38%) Site of tumor Proximal femur/humerus Other limb site Axial/Skeletal 43 253 14 (14%) (82%) ( 5%) 34 256 17 (11%) (83%) ( 6%) Primary metastases* Yes No 45 265 (15%) (86%) 32 274 (10%) (90%) Total 310 308 This table illustrates the baseline characteristics of the patients including a median age of 15 years, a slight male preponderance and about 80% of patients had localized disease. *metastases status missing for 2 patients on MAPIE arm

Postoperative chemotherapy received doses Cumulative standardised dose Median (IQR) Target MAP MAPIE Number of courses % Received target Target MAP MAPIE M methotrexate (g/m2) 96 8 A doxorubicin (mg/m2) 300 4 P cisplatin (mg/m2) 240 2 I ifosfamide 14g (g/m2) 52 3 i ifosfamide 9g 18 E etoposide 1.5 This illustrates the target doses of the various agents included in the trial.

Postoperative chemotherapy received doses Cumulative standardised dose Median (IQR) Target MAP MAPIE Number of courses % Received target Target MAP MAPIE M methotrexate (g/m2) 96 94 (80-97) 88 (68-97) 8 A doxorubicin (mg/m2) 300 296 (284-303) 299 (233-305) 4 P cisplatin (mg/m2) 240 239 (235-241) (230-244) 2 I ifosfamide 14g (g/m2) 52 n/a 41 (27-42) 3 i ifosfamide 9g 18 17 (9-18) E etoposide 1.5 (1.0-1.5) This slide shows the median received doses by treatment arm along with the interquartile ranges. MAP is depicted in blue, while MAPIE is depicted in orange.

Postoperative chemotherapy received doses Cumulative standardised dose Median (IQR) Target MAP MAPIE Number of courses % Received target Target MAP MAPIE M methotrexate (g/m2) 96 94 (80-97) 88 (68-97) 8 73% 58% A doxorubicin (mg/m2) 300 296 (284-303) 299 (233-305) 4 83% 78% P cisplatin (mg/m2) 240 239 (235-241) (230-244) 2 92% 84% I ifosfamide 14g (g/m2) 52 n/a 41 (27-42) 3 74% i ifosfamide 9g 18 17 (9-18) 64% E etoposide 1.5 (1-1.5) 75% This slide includes the percentage of targeted doses received by treatment arm. Again MAP is in blue and MAPIE is in orange. As is evident, patients in the MAPIE arm received a lower proportion of the prescribed doses of methotrexate, cisplatin and doxorubicin.

Worst postoperative toxicity Worst toxicity (includes all toxicities) Grade 3 MAP Grade 4 Grade 5 MAPIE Worst postoperative toxicity 26 (9%) 259 (86%) 1 (<1%) 20 (7%) (87%) Overall 286 / 300 (95%) 280 / 297 (94%) Fisher’s test p=0.585 Worst toxicity Grade 3 MAP Grade 4 Grade 5 MAPIE Worst non-haem* postoperative 177 (59%) 59 (20%) 1 (<1%) 172 (58%) 88 (30%) Overall 237 / 300 (79%) 261 / 297 (88%) Fisher’s test p=0.004 This illustrates the worst toxicity by arm following surgery. Though overall, there is no difference in toxicity by arm with MAP having 95% grade 3-5 toxicity and MAPIE having 94%. However, when one focuses on worst non-hematalogical toxicity, it becomes apparent that MAPIE was associated with a higher proportion of grade 4 non-hematological toxicity as compared to MAP (30% vs. 20%). *neutrophils and platelets excluded

This increased proportion of non-hematological toxicities is depicted here graphically for selected toxicities. Again MAP is blue and MAPIE is orange. As you can see, MAPIE patients had a higher number of hypophosphatemia, increased creatinine, infectious complications and typhillitis.

Secondary malignancies (SMN) MAP (310 pts) MAPIE (308 pts) Number of SMNs 2 (0.6%) Between 7 (2.3%) and 9 (2.9%) Types Acute Myeloid Leukaemia Acute Monocytic Leukaemia MDS 1 - 4 2 Additional reports under review* These are preliminary data; cleaning is ongoing. Additional 2 events reported as SMN, without any other information. In terms of second malignant neoplasms, there were 2 second malignancies reported in the 310 patients randomized to MAP. There are 7 documented second malignancies with 2 additional ones under investigation in MAPIE treated patients. The increased number of second malignancies in MAPIE treated patients is not unexpected and the proportion of patients treated with MAPIE with second malignancies ranges between 2.3% and 2.9%. Higher rate of SMNs expected with MAPIE (vs. MAP) Expected rate with MAPIE: <5% Observed SMNs with MAPIE arm: 2.3% (95%CI 0.9%-4.6%) potentially 2.9% (95%CI 1.3%-5.5%)

Event-Free Survival Reported: 300 EFS events 148 MAP, 152 MAPIE Target: 378 EFS events Main results HR=1.01 (0.80-1.26) p=0.99 Target HR=0.75 Hazards are not proportional (p=0.0001)  HR difficult to interpret 3-year EFS 54% (49%-60%) 52% (46%-58%) The 3 year EFS for MAP patients is 54% compared to 52% for MAPIE treated patients. In total, 300 EFS events have been reported so far: 148 on MAP and 152 on MAPIE arm. The figure presents EFS by allocated treatment (intention-to-treat analysis). Hazard ratio Estimate of hazard ratio is 1.01, (95%CI 0.80-1.26), p=0.99 (target HR was 0.75). We can see from the graph that curves are crossing, which is an indication of non-proportionality of hazards. Formal test for proportionality of hazards confirms that the proportionality of hazards is violated. MAP: lower event rate than predicted Expected EFS: 45% at 3yr Observed EFS: 54% at 3yr (49%-60%)

Event-Free Survival No difference RMST To 5yr 95%CI Reported: 300 EFS events 148 MAP, 152 MAPIE Target: 378 EFS events RMST To 5yr 95%CI MAP 37.5m 34.9 to 40.1 MAPIE 38.1m 35.6 to 40.5 Diff. 0.6m -3.1 to 4.4 P = 0.738 3-year EFS 54% (49%-60%) 52% (46%-58%) No difference MAPIE increases average EFS time by 0.6 months (p=0.738) ---------------Gordana’s notes --------------- RMST - interpretation of results Because hazards are not proportional, another summary of difference between the treatments has been used. Difference is expressed in terms of Restricted Mean Survival Time; RMST is an average event-free time over a 5-year period after randomisation. Time to first event is on average 37.5 month in MAP arm and 38.1 months in MAPIE arm, when time to 5 years from randomisation is considered. The difference in average times to first event is 0.6 months (18 days), in favour of MAPIE arm (time to first event is on average 18 days longer in MAPIE arm). The difference is not statistically significant, therefore we can conclude that there is not enough evidence to suggest that there is EFS difference between the two treatment arms. --------------------------- Other points: -lower event rate than predicted (expected/observed 3y EFS 45%/55%) -target/observed number of events (378/300) -consequence: need more time to reach target number of events At the end of the talk, there is an additional slide with event prediction – time to reaching the target number of EFS events MAP: lower event rate than predicted Expected EFS: 45% at 3yr Observed EFS: 54% at 3yr (49%-60%)

Overall survival Reported: 182 deaths 95 MAP 87 MAPIE Target: 378 deaths Target not reached 66% (60-71%) 68% (61%-73%) 5-year OS As illustrated here, the 5 year EFS is 66% for MAP and 68% for MAPIE with no difference between the two arms. MAP arm: lower event rate than predicted Expected 5-year OS: 45% Observed 5-year OS: 66% (61%-73%)

Conclusions Data reported earlier than planned: 300 / 378 events No evidence of advantage of MAPIE over MAP in EFS or OS Fewer patients on MAPIE received the intended dose MAPIE associated with greater toxicity MAPIE associated with higher risk of secondary malignancy In conclusion, 1. We are reporting results of this trial earlier than planned. 2. We find no evidence of an advantage of MAPIE over MAP in terms of EFS or OS 3. Fewer MAPIE patients received the intended dose 4. MAPIE was associated with greater toxicity and higher risk of second malignancies.

Acknowledgments All patients who participated in EURAMOS-1 Investigators & research staff at all 326 trial sites & data centers National co-ordinating investigators N Marina, M Bernstein, S Bielack, L Kager, Z Papai, T Kühne, J Starý, J Whelan, C Dhooge, M Capra, H Gelderblom, S Smeland, M Ericcson, O Johansson, M Tarkkanen, O Nielsen Members of the IDMC, TSC, TMG and trial advisory panels Funding bodies National Cancer Institute, USA ; European Science Foundation (ESF) under the EUROCORES Program European Clinical Trials (ECT), through contract No. ERASCT-2003-980409 of the European Commission, DG Research, FP6 (Ref No MM/NG/EMRC/0202); Fonds National de la Recherche Scientifique & Fonds voor Wetenschappelijk Onderzoek-Vlaanderen; Danish Medical Research Council; Academy of Finland; Deutsche Forschungsgemeinschaft; Deutsche Krebshilfe; Federal Ministry of Education and Research, Germany, BMBF 01KN1105; Semmelweis Foundation; Netherlands Council for Medical Research; Research Council of Norway; Scandinavian Sarcoma Group; Swiss Paediatric Oncology Group; Cancer Research UK, CRUK/05/013; UK Medical Research Council All patients who participated in EURAMOS-1 www.euramos.org

EFS in localised disease subgroup 539 patients 241 EFS events: 114 MAP, 127 MAPIE Target: 270 EFS events Results HR=1.06 (0.83-1.37), p=0.63 Target HR=0.71 Hazards are not proportional, p=0.002  HR difficult to interpret 3-year EFS 59% (53%-65%) 56% (49%-61%) EFS analysis in localised disease subgroup is a pre-planned analysis of our study and target number of events in this subgroup is 270. So far, 241 events have been reported. Note: Localised disease subgroup includes patients with no metastases or possible metastases. 3year EFS estimates, for M0 and M1, by allocated treatment EFS [95% Conf. Int.] ----------------------------------------------------------- No/poss mets MAP 0.5921 0.5290 0.6497 No/poss mets MAPIE 0.5553 0.4919 0.6139 Yes mets MAP 0.2529 0.1365 0.3870 Yes mets MAPIE 0.1753 0.0649 0.3302 M0 – includes patients with no mets or possible mets

Postoperative chemotherapy received doses Cumulative standardised dose Median (IQR) Target MAP MAPIE Number of courses % Received target Target MAP MAPIE M methotrexate (g/m2) 96 94 (80-97) 88 (68-97) 8 A doxorubicin (mg/m2) 300 296 (284-303) 299 (233-305) 4 P cisplatin (mg/m2) 240 239 (235-241) (230-244) 2 I ifosfomide 14g (g/m2) 52 n/a 41 (27-42) 3 i ifosfomide 9g 18 17 (9-18) E etoposide 1.5 (1.0-1.5) Standardised dose=total dose/BSA

Note: Grade 5 LVSD on MAPIE arm

Standardised received doses

EFS in localised disease subgroup RMST To 5yr 95%CI MAP 40.15m 37.3 to 43.0 MAPIE 40.09m 37.4 to 42.7 Diff. -0.06m -3.9 to 3.7 P > 0.999

Overall survival Main results HR=0.99 (0.74-1.32) p=0.81 Target HR=0.75 No evidence against proportionality of hazards (p=0.08) 66% (60-71%) 68% (61%-73%) 5-year OS ------------------------Gordana’s notes -------------- Current estimate of HR is 0.99, p=0.81 At the end of the talk, there is an additional slide with event prediction – time to reaching the target number of OS events MAP arm: lower event rate than predicted Expected 5-year OS: 45% Observed 5-year OS: 66% (61%-73%)

Additional slides

Box plots The adjacent values are the extreme data points within 1.5*IQR of the nearer quartile.   Outliers (outside values), defined as observations more than 1.5*(IQR) beyond the first or third quartile, are plotted individually in a box plot.

G3+ MAPIE arm only (no patients on MAP arm had G3+ confusion, hemorrhage, UEW)

Timelines & publications Poor Responders data released by TSC Poor Responders clean data available Publish Poor Responders data Follow-up continues  Jul 2014 Oct 2014 Nov 2014 Spring 2015 Summer 2015 Submit Good Responders paper Publish all-cohort data

Worst postoperative toxicity Worst toxicity (includes all toxicities) MAP Gr <3 Gr 3 Gr 4 Gr 5 MAPI MAPIE Worst postoperative toxicity 15 (5%) 26 (9%) 259 (86%) 1 (<1%) 17 (6%) 20 (7%) (87%) Worst toxicity Grade 3 MAP Grade 4 Grade 5 MAPIE Neutrophils 21 (7%) 246 (82%) (0%) 16 (5%) 251 (85%) Platelets 50 (17%) 180 (61%) 37 (13%) 210 (71%) Worst non-haem* postoperative 177 (59%) 59 (20%) 1 (<1%) 172 (58%) 88 (30%) First table includes worst G3+ toxicity (over all categories). Second table divides those toxicities into: Neutrophils Platelets Anything other toxicity, excluding neutrophils and platelets *neutrophils and platelets excluded

National coordinators Name Country COSS   L Kager Austria S Bielack Germany Z Papai Hungary T Kühne Switzerland (and COG) Jan Starý Czech Republic SSG Ole Sten Nielsen Denmark Maija Tarkkanen Finland Oskar Johansson Iceland S Smeland Norway M Eriksson Sweden EOI C Dhooge Belgium M Capra Ireland H Gelderblom Netherlands J Whelan United Kingdom COG M Bernstein Canada N Marina USA

Comparison of toxicity Any toxicity MAP MAPIE G 0, 1, 2 14 17 G 3, 4, 5 286 (95%) 280 (94%) Total 300 297 Fisher’s exact test for comparison of G3+ toxicities: p=0.585 non-haematological toxicity MAP MAPIE G 0, 1, 2 63 36 G 3, 4, 5 237 (79%) 261 (88%) Total 300 297 Fisher’s exact test for comparison of G3+ non-haematological toxicities: p=0.004

Worst postoperative toxicity details Grade MAP 3 MAPIE 4 5 Neutrophils 21 (7%) 16 (5%) 246 (82%) 251 (85%) (0%) Platelets 50 (17%) 37 (13%) 180 (61%) 210 (71%) LVSD 2 (1%) 1 (<1%) Febrile neutropenia 137 (46%) 135 11 (4%) 23 (8%) Infection documented clinically* 103 (34%) Infection (norm. ANC) 48 (23%) 57 (25%) 9 Creatinine (2%) HemorrhageGU bladder *with grade 3/4 ANC (ANC<1x109/L)

Worst postoperative toxicity details Grade MAP 3 MAPIE 4 5 Mucositis 84 (32%) 70 (27%) 6 (2%) 8 (3%) (0%) Thyphlitis 2 (1%) Hypophosp-hataemia 38 (17%) 53 (24%) 12 (5%) Unrin. Electrolyte wasting Confusion Mood alteration 9 Somnolence 1

Test for heterogeneity p=0.258

Choice of t* (for RMST)

Target is ≥ 200 EFS events on the control arm. EFS event prediction Target is ≥ 200 EFS events on the control arm. Event prediction: target is te least 200 EFS events on the control arm.

OS event prediction Target is ≥ 200 EFS events on the control arm.

CTOS Abstract notification e-mail Abstract ID: 2055690 Title: MAPIE FOR NEWLY-DIAGNOSED OSTEOSARCOMA: FIRST RESULTS FROM EURAMOS-1 FOR PATIENTS WITH A POOR RESPONSE TO PRE-OPERATIVE CHEMOTHERAPY Congratulations! Your abstract has been selected as an ORAL PRESENTATION for the CTOS 19th Annual Meeting, October 15- 18, 2014 at the InterContinental Hotel in Berlin, Germany. Your session information is as follows: Session Title: SESSION 3: MEDICAL ONCOLOGY Session Times: October 17, 2014 from 1:00 PM to 2:00 PM You are allocated 8 minutes for your presentation, followed by 2 minutes of questions in order for our program to stay on schedule. Please recognize that your audience are assembled experts in sarcoma research. You should not include introductory slides on sarcoma or specific sarcoma subtypes. Introductory slides will decrease the time you have to coherently present your data and you will be cut off by the session chairs if you run long!! Please bring your presentation on a USB compatible memory stick or similar device. A laptop in the meeting room will be used for all presentations. If you have not yet registered for the meeting or have not made your hotel reservation, you can do both by accessing the CTOS website at www.ctos.org. Please send questions regarding the program or if you are unable to present at the meeting to Barbara Rapp at ctos@ctos.org. Please note, this year the society will guest edit a special issue of Annals of Surgical Oncology. Authors presenting papers in the oral sessions will be selected to submit the full paper to the journal for this special issue, which will be entirely dedicated to CTOS program. This will be a special opportunity for authors and the society to raise awareness in the community around this disease and advertise the commitment of the society to fight it.