neoadjuvant chemoradiotherapy for rectal cancerneoadjuvant chemoradiotherapy for rectal cancer

1. Neoadjuvant Chemoradiotherapy for Rectal Cancer Jane S. Chawla, M.D.

3. Case 50 y/o F with h/o rectal bleeding found to have a rectal mass with biopsy + for moderately-differentiated adenocarcinoma. CT ? No rectal lesion seen; no evidence of metastatic disease TRUS ? Tumor 2.5 cm in diameter & located 8 cm from anal verge; scalloping of the peri-rectal fat; one hyperechoic LN seen ? Staged as T3N1M0

11. Neoadjuvant Radiotherapy Common regimens: Swedish-Style, Short course: 25 Gy in 5 fractions over 5 days, then immediate surgery Conventional: 40-50 Gy in 20-25 fractions over 4-5 weeks, then surgery in 3-6 weeks Regimens never compared directly Meta-analysis of 22 randomized trials ? RT + surgery v. surgery alone OS marginally better with surgery + RT v. surgery alone (62% v. 63% died, p=0.06) ?risk of local recurrence with RT compared to surgery alone (46% ? for preop & 37% ? for postop RT) Preoperative RT at doses = 30 Gy ? risk of local recurrence & death Fewer pts with preop RT died than those with surgery alone (45% versus 50%, p=0.0003) Impact of RT on sphincter preservation not clear

12. Are there benefits to Neoadjuvant chemoradiation in rectal cancer? Are rectal tumors downstaged with neoadjuvant CRT? Does neoadjuvant CRT ? rate of sphincter-sparing surgeries? Does neoadjuvant CRT ? OS or PFS? Does neoadjuvant CRT ? risk of local recurrence or distant recurrence? Is there a significant ? in toxicity with neoadjuvant CRT? How is patient compliance with neoadjuvant CRT?

16. FFCD 9203 Trial: 1� & 2� Endpoints 1� End Point: No significant difference in OS (5-yr) ? 67.9% RT v. 67.4% CRT (p=0.684) 2� End Points: No significant difference in PFS (5-yr) ? 55.5% RT v. 59.4% CRT Significant difference in local recurrence rate (5-yr) ? 16.5% RT v. 8.1% CRT (p=0.004)

20. Polish Trial: 2� Endpoints (4-year)

22. EORTC 22921: Preoperative Chemotherapy Downstages Tumors

25. EORTC 22921: ? Incidence of Local Recurrence in Chemotherapy Groups

26. EORTC 22921 Conclusions No significant difference in sphincter-sparing surgery ? 50.5% RT and 52.8% CRT Cumulative incidence of distant metastases did not differ significantly according to preop and postop treatment groups (p=0.14, 0.62) Adjuvant CT did not affect PFS or OS, but survival curves diverged after 2 & 4 years

30. German Trial: 2� Endpoints

32. Summary of Randomized Trials Are rectal tumors downstaged (pCR) with neoadjuvant CRT? FFCD 9203 Trial: YES (11.4% CRT v. 3.6% RT; p<0.0001) Polish Trial: YES (16.1% CRT v. 0.7% RT; p<0.001) EORTC 22921 Trial: YES (13.7% CRT v. 5.3%; p<0.001) German Trial: YES (8% Preop CRT v. 0% Postop CRT) Does neoadjuvant CRT ? rate of sphincter-sparing surgeries? FFCD 9203 Trial: NO Polish Trial: NO EORTC 22921 Trial: NO German Trial: NO (Preop vs Postop CRT)

33. Summary of Randomized Trials Does neoadjuvant CRT ? OS or PFS? FFCD 9203 Trial: NO - 67.4% / 59.4% (5-year) Polish Trial: NO - 66.2% / 55.6% (4-year) EORTC 22921 Trial: NO - 64.8% / 56.1% (5-year) German Trial: NO - 76% / 68% (5-year) Does neoadjuvant CRT ?risk of local recurrence // distant recurrence? FFCD 9203 Trial: YES (8.1% CRT v. 16.5% RT) // NO (36%) Polish Trial: NO (15.6% CRT v. 10.6% RT) // NO (34.6%) EORTC 22921 Trial: YES (13.7% CRT v. 5.3%) // NO (34.4% all grps) German Trial: YES (6% Preop CRT v. 13% Postop CRT) // NO (36% Pre)

34. Summary of Randomized Trials Is there an ? in grade 3-4 toxicity with neoadjuvant CRT? FFCD 9203 Trial: YES (14.9% CRT v. 2.9%; p<0.0001) Polish Trial: YES (18.2% CRT v. 3.2% RT; p<0.001) EORTC 22921 Trial: YES (Slight ? in toxicity CRT>RT) German Trial: NO (27% Preop v. 40% Postop; p=0.001) How is patient compliance with neoadjuvant CRT? FFCD 9203 Trial: 93% Neoadj CT & 78.1% Adjuvant CT Polish Trial: Not reported EORTC 22921 Trial: 82% Neoadj & Adjuvant CT 42.9% German Trial: 92% Preop CT & 53% Postop CT

38. Neoadjuvant Trials: Infusional 5-FU + Oxaliplatin + RT

39. Neoadjuvant Trials: Irinotecan-based regimens

41. Case revisited Our pt was enrolled in RTOG 0822 Trial: Neoadjuvant Capecitabine 1500 mg bid 5d/wk + weekly oxaliplatin x 5wks concurrently with RT She underwent LAR (+TME) with temporary ostomy Path ? She had an R0 resection; tumor was 1.5 cm in size; no venous invasion; 1/13 + LNs ? pT3N1 Pt is to undergo adjuvant chemotherapy with FOLFOX x 9 cycles

42. Conclusions Patients to consider for neoadjuvant chemoradiotherapy: T3-4 and/or N+ disease Low-lying rectal lesions if considering sphincter-sparing procedures TRUS best for assessing tumor depth; best imaging modality for assessing LN status controversial (TRUS v MR) TME is the preferred surgical procedure Neoadjuvant CRT compared to RT: No improvement in OS or PFS Significant tumor downstaging & ? local recurrence No ? in sphincter-sparing procedures

43. Conclusions Preoperative CRT compared to postoperative CRT: No improvement in OS or PFS Significant tumor downstaging & ? local recurrence ? improvement in sphincter-sparing procedures ? early and late toxicity Further study of other neoadjuvant regimens underway

44. NCCN Guidelines T3N0 or T1N1-2 disease Neoadjuvant chemo with CIVI 5-FU/LV +RT (Alternatives: bolus 5-FU/LV + RT or Xeloda + RT) Surgery 5-10 weeks s/p neoadjuvant treatment 6 months adjuvant chemo with 5-FU +/- LV, FOLFOX, or Capecitabine Pts downstaged to pT1-2N0M0 can be observed w/o adj treatment T4 and/or locally unresectable disease Neoadjuvant chemo with CIVI 5-FU/LV +RT (as above) Surgery if possible 5-10 weeks after neoadjuvant treatment Then adjuvant treatment as above Adjuvant chemo: 5-FU +/- LV or FOLFOX or Xeloda, then 5-FU/RT or Xeloda/RT, then 5-FU +/- LV or Xeloda or FOLFOX

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