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neoadjuvant chemoradiotherapy for rectal cancerneoadjuvant chemoradiotherapy for rectal cancer

Objectives. CaseRectal Cancer StagingIndications for Neoadjuvant ChemoradiotherapyNeoadjuvant RadiotherapySurgical ApproachesEvidence to Support Neoadjuvant ApproachOther neoadjuvant chemoradiotherapy regimens under investigationConclusions. 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 diseaseTRUS ? Tumor 2.5 cm in diameter

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neoadjuvant chemoradiotherapy for rectal cancerneoadjuvant chemoradiotherapy for rectal cancer

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    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

    45. Resources Colorectal Collaborative Group. Adjuvant Radiotherapy for Rectal Cancer: A Systematic Overview of 8507 Patients from 22 Randomised Trials. Lancet. 2001; 358: 1291-1304. MERCURY Study Group. Extramural Depth of Tumor Invasion at Thin-Section MR in Patients with Rectal Cancer: Results of the MERCURY Study. Radiology. 2007; 243: 132-139. Sauer, R. Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer. NEJM. 2004; 351: 1731-1740. Bosset, J. Enhanced Tumorocidal Effect of Chemotherapy With Preoperative Radiotherapy for Rectal Cancer: Preliminary Results EORTC 22921. Journal of Clinical Oncology. 2005; 23: 5620-5627. Bosset, J.F. et al. Chemotherapy wit Preoperative Radiotherapy in Rectal Cancer. New England Journal of Medicine. 2006; 355: 1114-11123. Bujko, K. et al. Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomized trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy. Radiotherapy and Oncology. 72; 2004, 15-24. Bujko, K. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. British Journal of Surgery. 2006; 93: 1215-1223. Gerard et al. Preoperative Radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: Results of FFCD 9203. Journal of Clinical Oncology. 24; 2006:4620-4625. Glynne-Jones, R. & Harrison, M. Locally Advanced Rectal Cancer: What Is the Evidence for Induction Chemoradiation? The Oncologist. 2007; 12: 1309-1318. Kim, J.C. et al. Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2005;63: 346-53. Kwok H, Bissett IP, Hill GL. Preoperative staging of rectal cancer. Int J Colorectal Dis. 2000; 15: 920. DeVita, V et al. Cancer: Principles and practice of oncology.l www.Uptodate.com NCCN Guidelines

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