1. Preoperative fluorouracil (FU)-based chemoradiation +/- weekly oxaliplatin in locally advanced rectal cancer. Pathologic response analysis of the STAR (Studio Terapia Adiuvante Retto)-01 randomized phase III trial. C. Aschele, C. Pinto, S. Cordio, G. Rosati, A. Tagliagambe, S. Artale, P. Rosetti, S. Lonardi, L. Boni, L. Cionini, on behalf of STAR Network Investigators.

2. BACKGROUND AND RATIONALE Locally-advanced rectal cancer  high rates of distant metastases (30 - 35 %)  +ve CRM in 10-30 % of “resectable” tumors Oxaliplatin  improves the efficacy of FU-based CT (colon ca.)  radiosensitizing properties (exp. models)  promising activity with pre-op RT and FU (phase I-II studies)

3. STUDY OUTLINE R RT 50.4 Gy FU 225 mg/m 2 /day PVI OXA 60 mg/m 2 weekly x 6 RT 50.4 Gy FU 225 mg/m 2 /day PVI TMETME FU/LV (bolus or CI, center choice) 6-8 wks stage center

4. MAIN INCLUSION CRITERIA  adenocarcinoma  within 12 cm from anal verge  cT3-T4 and/or cN+  resectable (no infiltration of the pelvic wall, prostate, bladder base)  cM0

5. STUDY END-POINTS  primary: overall survival - 30% RR in mortality rates (3-y S: 75 --> 82%) - 80% power - alpha error: 0.05  secondaries: pathologic complete response (pCR): - all path reports available (cut-off data 01/03/09) - 12% --> 25%; 90% power disease-free survival safety

6. STUDY POPULATION 747: randomized response/survival analyses 379 FU/RT 368 FU/OXA/RT 379353 5 never started - consent withdrawal (2) - squamous histology (1) - immediate surgery (2) 10 never started (3) consent withdrawal (2) squamous /melanoma (1 ) immediate surgery (2) only RT (2) different chemo 5 received FU alone 732: treated safety/compliance analyses

7. PATIENTS CHARACTERISTICS FU/RT FU/OXA/RT (n=379)(n=368) Age, years median6362 Sex, % males 6867 females 3233 ECOG PS, % 08788 1-21312

8. FU/RT FU/OXA/RT (n=379) (n=368) T stage, % T1-2 2 5 T37878 T42017 N +, %6467 cm from anal verge median 6 6 TRUS: 33; pelvic CT scan: 261; both 453 TUMORS CHARACTERISTICS

9. TREATMENT COMPLIANCE: OXALIPLATIN weekly courses patients, n * 1 3 2 6 326 424 560 83% > 6 233 66% * missing data=1 mean actually delivered dose intensity: 58.3 mg/mq/wk

10. patients, % FU/RT FU/OXA/RT (n=379) (n=353) FU > 5 weekly courses95 88 RT full dose +/- 10 %97 90 TREATMENT COMPLIANCE: 5-FU and RT

11. TOXICITY % of patients FU/RT FU/OXA/RT (n=379)(n=353) p grade III-IV any type824<.0001 diarrhea415<.0001 radiation dermatitis2 50.038 grade II-III neurosensory 0.5/0 36/1<.0001 Tx related deaths 0.3 (1) 0.6 (2)

12. patients, % FU/RT FU/OXA/RT (n= 379) (n= 368) Operated9696 LAR7273 APR1918 other 4 5 Median interval 52 days 53 days Deaths < 60 d 0.8 (3) 0.8 (3) SURGERY

13. patients, % FU/RTFU/OXA/RT (n= 379) (n= 368) p ypT0N016 16 0.94 (95% cl)(13-20) (13-20) pathologic CR

14. patients, % FU/RT FU/OXA/RT (n= 379) (n= 368) pT017 18 pT1-235 35 pT3-444 42 diameter, mm median (range)26 (1-100) 24 (2-80) CRM+ 6 4* PATHOLOGY (T) * p=0.13

15. patients, % FU/RT FU/OXA/RT (n= 379) (n= 368) examined median 12 11 range 0-47 0-42 pN0 70 68 pN1 17 17 pN2 8 10 PATHOLOGY (N)

16. patients, n FU/RT FU/OXA/RT (n=379) (n=368) p pM111 (3%) 2 (0.5%) 0.014 liver 61 peritoneal 41 nodes 1- cM1 5 - liver 4- liver+lung 1- Overall162 M+ at SURGERY (unplanned / exploratory)

17. SUMMARY The addition of OXA to FU-based preop CRT: -does not improve local tumor response -significantly increases toxicity (still manageable) and slightly reduces treatment compliance (but surgery OK) -is associated with a lower frequency of occult distant metastases at surgery

18. CONCLUSIONS  These data do not support the addition of OXA to pre-op FU/RT to maximize tumor shrinkage in LARC (radiosensitizing properties unconfirmed)  OXA-based regimens may not be the optimal back-bone for incorporation of new radiosentizing agents  The observation of a lower number of distant mts at surgery lends support to the study primary hypothesis (confirmation with more mature data is required)  Follow-up is ongoing to assess the impact on efficacy end-points. Stay tuned!

19. Studio Terapia Adiuvante Retto ALBA AREZZO AVIANO BERGAMO BOLOGNARAVENNA BOLZANORIMINI CAMPOSAMPIERORIONERO VULTURE CASTELLANZA LUGOROMA CATANIA MANTOVASANREMO CATANZARO MASSA CARRARASARONNO CATTOLICA MILANO HUMANITASSAVONA CUNEO MILANO NIGUARDASONDRIO FAENZA MILANO SAN PAOLOTARANTO FANOMODENA THIENE FELTREMONZA TORINO FORLI'NOVARA TRENTO GENOVAPADOVA UDINE LEGNAGOPISA VENEZIA LIVORNOPOTENZA VIGEVANO THANKS TO ALL THE PATIENTS, INVESTIGATORS and DATA-MANAGEMENT STAFF!

20. patients, n FU/RT FU/OXA/RT (n=379) (n=368) p pM111 (3%) 2 (0.5%) 0.014 liver 61 peritoneal 41 nodes 1- cM1 5 - liver 4- liver+lung 1- Overall162 M+ at SURGERY (unplanned / exploratory) low numbers potential biases but plausible (high OXA DI/rapid response in ACRC) consistent with the study 1ry hypothesis