Ali Shamsedddine, MD Professor of Medicine Head of Hematology-Oncology Division

1. No Effect on Tumor Response with Weekly Oxaliplatin Added to Standard Preoperative 5-FU/RT in locally Advanced Rectal Cancer Ali Shamsedddine, MD Professor of Medicine Head of Hematology-Oncology Division American University of Beirut Medical Center

2. Challenges in treatment of rectal Cancer Does the increase in pCR improves survival? What kind of Preoperative chemotherapy should be used? What about distant failure? Can it be addressed by using chemotherapy?

3. Question What would be the current standard regarding the type of chemotherapy to use with preoperative radiotherapy? Bolus 5-FU Protracted 5-FU infusion 5-FU-Oxaliplatin Capecitabine Capecitabine-Oxaliplatin 5-FU-Irinotecan

4. Question What would be the current standard regarding the type of chemotherapy to use with preoperative radiotherapy? Bolus 5-FU Protracted 5-FU infusion 5-FU-Oxaliplatin Capecitabine Capecitabine-Oxaliplatin 5-FU-Irinotecan

5. Comparison of the published phase II study using capecitabine–oxaliplatin in combination with preoperative radiotherapy

6. 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.

7. 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)

8. R RT 50.4 Gy FU 225 mg/m2/day PVI FU/LV (bolus or CI, center choice) T M E 6-8 wks RT 50.4 Gy FU 225 mg/m2/day PVI OXA 60 mg/m2weekly x 6 STUDY OUTLINE • stage • center

9. 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

10. 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

11. STUDY POPULATION 747: randomized response/survival analyses 379FU/RT 368FU/OXA/RT 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: treatedsafety/compliance analyses 379 353

12. PATIENTS CHARACTERISTICS FU/RT FU/OXA/RT (n=379) (n=368) Age, yearsmedian 63 62 Sex, %males 68 67 females 32 33 ECOG PS, % 0 87 88 1-2 13 12

13. TUMORS CHARACTERISTICS FU/RT FU/OXA/RT (n=379) (n=368) T stage, %T1-2 2 5 T3 78 78 T4 20 17 N +, % 64 67 cm from anal verge median 6 6 TRUS: 33; pelvic CT scan: 261; both 453

14. TREATMENT COMPLIANCE:OXALIPLATIN weekly courses patients, n* 1 3 2 6 3 26 4 24 5 60 83% > 6 233 66% mean actually delivered dose intensity:58.3 mg/mq/wk * missing data=1

15. TREATMENT COMPLIANCE:5-FU and RT patients, % FU/RT FU/OXA/RT (n=379) (n=353) FU > 5 weekly courses 95 88 RT full dose +/- 10 % 97 90

16. TOXICITY % of patients FU/RT FU/OXA/RT (n=379) (n=353) p grade III-IV any type 8 24 <.0001 diarrhea 4 15 <.0001 radiation dermatitis 2 5 0.038 grade II-IIIneurosensory 0.5/0 36/1 <.0001 Tx related deaths 0.3 (1) 0.6 (2)

17. SURGERY patients, % FU/RT FU/OXA/RT (n= 379) (n= 368) Operated 96 96 LAR 72 73 APR 19 18 other 4 5 Median interval 52 days 53 days Deaths < 60 d 0.8 (3) 0.8 (3)

18. pathologic CR patients, % FU/RT FU/OXA/RT (n= 379) (n= 368) p ypT0N0 16 16 0.94 (95% cl) (13-20) (13-20)

19. PATHOLOGY (T) patients, % FU/RT FU/OXA/RT (n= 379) (n= 368) pT0 17 18 pT1-2 35 35 pT3-4 44 42 diameter, mmmedian (range) 26 (1-100) 24 (2-80) CRM+ 6 4* * p=0.13

20. PATHOLOGY (N) 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

21. M+ at SURGERY(unplanned / exploratory) patients, n FU/RT FU/OXA/RT (n=379) (n=368) p pM1 11 (3%) 2 (0.5%) 0.014 liver 6 1 peritoneal 4 1 nodes 1 - cM1 5 - liver 4 - liver+lung 1 - Overall 16 2

22. 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

23. 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!

24. Studio Terapia Adiuvante Retto THANKS TO ALL THE PATIENTS, INVESTIGATORS and DATA-MANAGEMENT STAFF!