Radiation Oncology/Rectum/Neoadjuvant RT

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Neoadjuvant Therapy for Rectal Cancer

Preop vs Postop RT

Recommend T3-T4 or N+ pts receive pre-op chemo/RT

• RTOG 94-01 /INT 0147 - concurrent 5-FU (closed due to poor accrual)
• NSABP R-03 - concurrent 5-FU (closed due to poor accrual, see summary below)

Chemo-RT

• MRC CR07 and NCIC C016 (1998-2005) -- preop RT 25/5 vs. selective postop chemo-RT 45/25
  • Randomized. 1350 patients, operable carcinoma of rectum, <15cm from anal verge, TME encouraged but not mandated (done in 92%). Arm 1) RT 25/5 vs. Arm 2) surgery + selective postop chemo-RT if SM+ (RT 45/25 + concurrent 5-FU and leucovorin). RT sacral promontory superiorly, 3–5 cm below the inferior tumor extent, 2–3 cm anterior to the sacral promontory, 1 cm posterior to the anterior sacrum, and 1 cm lateral to the most lateral aspect of the bony true pelvis. Primary outcome LR. In postop arm, SM+ was in 12% as trigger for postop chemo-RT vs 10% in preop group. Adjuvant chemo in 40% of preop arm and 45% of postop arm
  • 2009 PMID 19269519 -- "Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial." (Sebag-Montefiore D, Lancet. 2009 Mar 7;373(9666):811-20.) Median F/U 4 years
    • Outcome: LR preop RT 4% vs. postop RT 11% (SS), DFS 77% vs. 71% (SS), no difference in OS. By SM status: SM+ 14% vs. 21% (NS), SM- 4% vs. 9% (SS). Upper 1/3 tumors lower LRR than lower 1/3, preop RT 1% vs. 5%, postop chemo-RT 6% vs. 10%
    • Conclusion: Short-course RT more effective than selective postop chemo-RT
  • Editorial (PMID 19269501): Preop RT appears to benefit both good-prognosis and bad-prognosis tumors, so need a good way to select, and patient preference likely to play a role. Nevertheless, short preop RT is an excellent option
  • 2009; Plane of surgery PMID 19269520 -- "Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial." (Quirke P, Lancet. 2009 Mar 7;373(9666):821-8.)
    • Negative CRM and good surgical plane associated with low LR. 3-yr LR 6% vs 17% for negative vs positive resection margin. LR 4% (mesorectal plane), 7% (intramesorectal), and 13% (muscularis propria). Pts with mesorectal excision who had pre-op RT had only a 1% LR.
    • Conclusion: the plane of surgery is an important prognostic indicator for local recurrence. Short-course pre-op RT reduced the rate of LR in all groups

• German Rectal Cancer Study CAO/ARO/AIO-94 (1995-2002) -- preop chemo-RT vs. postop chemo-RT
  • Randomized. 823 patients, clinical stage T3-4 or N+, inferior margin within 16cm from anal verge. Arm 1) post-op regimen: surgery (TME) -> chemo/RT (55.8 Gy) -> 4 cycles bolus 5-FU, or 2) pre-op regimen: chemo/RT (50.4 Gy) -> surgery (TME) -> 4 cycles bolus 5-FU. In both arms, chemo was 5-FU C.I. 1000 mg/m2/d on days 1-5, weeks 1+5.
  • 2004 PMID 15496622 Full text "Preoperative versus postoperative chemoradiotherapy for rectal cancer." (Sauer R, N Engl J Med. 2004 Oct 21;351(17):1731-40.) Median F/U 3.8 years
    • Outcome: 5-year OS preop 76% vs postop 74% (NS); 5-year DFS 68% vs. 65% (NS); LR 6% vs. 13% (SS); DM 36% vs. 38% (NS). Preop downstaging: pCR 8%, 25% (vs 40%) were Stage III/LN+. TNM Stage I disease found in 18% of post-op group (vs. 25% in pre-op). Increased rate of sphincter-preserving surgery (39% vs 19%) in preoperative-treatment group among patients thought to need it preoperatively; overall rates of sphincter preservation same 69% vs 71%.
    • Toxicity: Fewer acute (27% vs 40%) and late toxicities (14% vs 24%) in preoperative-treatment group.
    • Conclusion: Preop chemo-RT improved local control and improved toxicity, but did not impact overall survival
  • Critique (and clinical reality): only 54% of adjuvant patients vs. 92% of neoadjuvant patients received full RT dose
  • 2012 PMID 22529255 -- "Preoperative Versus Postoperative Chemoradiotherapy for Locally Advanced Rectal Cancer: Results of the German CAO/ARO/AIO-94 Randomized Phase III Trial After a Median Follow-Up of 11 Years." (Sauer R, J Clin Oncol online ahead of print April 23, 2012)
    • Median f/u 134 mo. 10-yr OS preop 59.6% vs postop 59.9% (NS). Local Recurrence: 7.1% vs 10.1% (SS). DM: 29.8% vs 29.6% (NS). DFS: NS.
    • Conclusion: "There is a persisting significant improvement of pre- versus postoperative CRT on local control; however, there was no effect on overall survival. "

• NSABP R-03 (1993-1999) -- Preop vs postop chemo-RT
  • Randomized. Trial closed prematurely due to poor accrual. 267/900 expected patients. Clinical T3-T4 or N+ rectal cancer. Arm 1) Preop chemo-RT 50.4/28 + 5-FU 500 mg/m2 and leucovorin 500 mg/m2 vs Arm 2) Postop chemo-RT (same as preop). Surgery APR, LAR, or local excision; TME not mandated. Both groups adjuvant 3 cycles of 5-FU/leucovorin
  • 2009 PMID 19770376 Full text — "Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03." (Roh M et al. J Clin Oncol. 2009 Nov 1;27(31):5124-30. Epub 2009 Sep 21.)
    • Outcome: 5-year DFS was improved for pre-op over post-op (64.7% v 53.4%, SS). Nonsignificant trend in 5-year OS (74.5% v 65.6%, p=0.065). No difference in locoregional recurrence, 11% in each group. pCR in 15%. Significant reduction in N+ (67% vs. 52%, SS)
    • Toxicity: Grade 4 diarrhea preop 24% vs. postop 13%; Grade 5 toxicity 5% vs 3%
    • Conclusion: Pre-op chemoradiotherapy, compared with post-op chemoradiotherapy, significantly improved DFS and showed a trend toward improved OS

RT Alone

• Sweden (Uppsala) (1980-1985)
  • Randomized. Multicenter. 471 patients with rectal and rectosigmoid CA. Treated with 1) preop RT 25.5/5 in one week or 2) postop RT 60/30 (Modified Dukes' stage B2 or C only, equivalent to Dukes B-C, T3-T4 or N+).
    • Technique: Treated prone. Target volume was from the anus up to L4. Three field - PA + 2 angled dorsal beams.
  • 1990 PMID 2405793 (Full-text on Pubmed Central) — "Pre- or postoperative radiotherapy in rectal and rectosigmoid carcinoma. Report from a randomized multicenter trial." Pahlman L et al. Ann Surg. 1990 Feb;211(2):187-95.
    • Minimum F/U 3 years; The early results are as follows
    • LR: preop RT 12% vs. postop RT 21% (SS, p<0.02). No difference in OS
    • Toxicity: Pre-op vs Post-op RT [ Mortality-3% vs 5% (NS); Post-op perineal sepsis-33% vs 18% (SS,p<0.01)
  • 1993 PMID 8500374 — "Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects." (Frykholm GJ, Dis Colon Rectum. 1993 Jun;36(6):564-72.)
    • Minimum F/U 5 years
    • LR: preop RT 13% vs. postop RT 22% (SS). No difference in OS
    • Toxicity: SBO rate - preop RT 5% vs. postop RT 11% vs. surgery alone 6%
  • Conclusion: Preop RT better, late morbidity comparable after 5-10 year follow-up

Preop RT vs. surgery alone

• Goal is sphincter preservation
• On meta-analysis, 5-year decrease in local recurrence from 22% with surgery alone to 12% with pre-op RT
• No impact on overall survival. Rectal cancer survival was significantly better with pre-op RT (50% vs. 45%), but early mortality was significantly higher as well (8% vs. 4%), for no difference in OS

Total Mesorectal Excision

• Dutch (1996-1999)
  • Randomized. 1805 patients treated with 1) Preop RT 25/5 or 2) TME alone. If surgery-only patients had SM+ (<=1mm), mandatory post-op RT
  • 2-years; 2001 PMID 11547717 -- "Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer." (Kapiteijn E, N Engl J Med. 2001 Aug 30;345(9):638-46.)
    • 2-year OS: RT 82% vs. TME alone 82%
    • 2-year LR: RT 2.4% vs. TME alone 8.2% (SS)
    • Conclusion: Short-term preop RT reduces risk of LR with TME
  • 2003 PMID 12654443 -- "Radiotherapy does not compensate for positive resection margins in rectal cancer patients: report of a multicenter randomized trial." (Marinjen CA, Int J Radiat Oncol Biol Phys. 2003 Apr 1;55(5):1311-20.)
    • LR as a function of surgical margins:
      • Wide SM: preop RT 1% vs. 6% (SS)
      • Narrow SM: preop RT 0% vs. 15% (SS)
      • Positive SM: preop RT 9% vs. 16% (NS)
    • 120 patients in surgery-only group with SM+; 47% received post-op RT; LR: Post-op RT 17% vs. surgery only 16% (NS)
    • Conclusion: Preop RT beneficial with wide or narrow SM, but not in positive SM.
  • 5-years; 2007 PMID 17968156 -- "The TME Trial After a Median Follow-up of 6 Years: Increased Local Control But No Survival Benefit in Irradiated Patients With Resectable Rectal Carcinoma." (Peeters KC, Ann Surg. 2007 Nov;246(5):693-701.). Median F/U 6.1 years
    • Outcome: 5-year LR TME 11% vs. RT + TME 6% (SS); OS 63% vs. 64% (NS)
    • Subgroup benefit: N+, tumors 5-10 cm from anal verge, negative radial margins
    • Conclusion: Preop short-term RT improves local control; no effect on survival
  • Local Recurrence; 2010 PMID 20096534 -- "Patterns of local recurrence in rectal cancer; a study of the Dutch TME trial." (Kusters M, Eur J Surg Oncol. 2010 Jan 20. [Epub ahead of print])
    • Outcome: 5-year LR rate RT+ 5% vs RT- 11%. Most common location presacral failure (43% and 33%). RT significantly reduced anastomotic LR (from 2.7% to 0.7%)
    • Conclusion: RT reduces LR in all subsites, and is especially effective in preventing anastomotic LR after LAR
  • 12-years; 2011 PMID 21596621 -- "Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial." (van Gijn W, Lancet Oncol. 2011 Jun;12(6):575-82.)
    • 10-yr incidence of LR 5% RT+ vs 11% RT-. No difference in OS.
    • Conclusion: LR reduced by more than 50% with RT compared to TME alone.

Non-TME Surgical Technique

• Swedish Rectal Cancer Trial (1987-1990)
  • Randomized. 1168 patients, 908 curative intent (included 316 patients from Stockholm II). Treated with 1) preop RT 25/5, surgery within 1 week or 2) surgery alone. RT given as AP/PA, 3-field, or 4-field; superior border at L4
  • 1993 PMID 8242317 — "Initial report from a Swedish multicentre study examining the role of preoperative irradiation in the treatment of patients with resectable rectal carcinoma. Swedish Rectal Cancer Trial." [No authors]. Br J Surg. 1993 Oct;80(10):1333-6.
    • Postop mortality comparable (4% vs. 3%); but much higher if 2F rather than 3F or 4F technique (15% vs. 3%)
    • No difference in anastomotic dehiscence or other complications; more wound infections with RT
  • 1995 PMID 8781922 — "Local recurrence rate in a randomised multicentre trial of preoperative radiotherapy compared with operation alone in resectable rectal carcinoma. Swedish Rectal Cancer Trial." [No authors]. Eur J Surg. 1996 May;162(5):397-402.
    • Local recurrence at 2 years: RT 9% vs. surgery alone 24% (SS); significant for all Dukes stages
  • 1997 PMID 9091798 — "Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial." Pahlman L et al. [No authors listed] N Engl J Med. 1997 Apr 3;336(14):980-7.
    • Local recurrence at 5 years: RT 11% vs surgery alone 27% (SS)
    • Overall survival: RT 58% vs 48% (SS)
  • Cost-effectiveness; 2002 PMID 12377315 -- "Cost-effectiveness of preoperative radiotherapy in rectal cancer: results from the Swedish Rectal Cancer Trial." (Dahlberg M, Int J Radiat Oncol Biol Phys. 2002 Nov 1;54(3):654-60.)
    • 8 year F/U. 98/1168 randomly selected patients from main trial from single region.
    • Total costs: RT USD 35,300 vs. surgery alone USD 30,000
    • Survival benefit 21 months - cost of year saved USD 3,654. Sensitivity analysis worst case USD 15,228
  • 13-years; 2005 PMID 16110023 — "Swedish Rectal Cancer Trial: long lasting benefits from radiotherapy on survival and local recurrence rate." Folkesson J et al. J Clin Oncol. 2005 Aug 20;23(24):5644-50. Median F/U 13 years
    • Overall survival: RT 38% vs. surgery alone 30% (SS); cancer-specific 72% vs. 62% (SS)
    • Local recurrence: RT 9% vs. surgery alone 26% (SS)
  • Late toxicity; 2005 PMID 16314629 — "Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial." Birgisson H et al. J Clin Oncol. 2005 Dec 1;23(34):8697-705.
    • Side effects: RT group more likely to be admitted <6 months after treatment (mostly GI related); no difference >6 months out
    • Bowel obstruction: more common long term in RT patients
  • Late GI toxicity; 2008 PMID 17849380 -- "Late gastrointestinal disorders after rectal cancer surgery with and without preoperative radiation therapy." (Birgisson H, Br J Surg. 2008 Feb;95(2):206-13.)
    • Outcome: RT increased risk of SBO (RR 2.5), surgically managed SBO (RR 7.4). Difference seen after 7-8 years for conservatively managed SBO, after 1-2 years for surgically managed SBO. No impact of RT technique
    • Conclusion: Small bowel obstruction more common in preop RT
  • Conclusion: 8% survival benefit, 10% cancer specific benefit, 17% local recurrence benefit long term
  • Criticism: high recurrence rate in surgery-alone arm (26%)

• Stockholm 1 (1980-1987)
  • Randomized. 849 patients, 679 curative intent. Treated with 1) preop RT 25/5 vs. 2) surgery alone. Median F/U 4.4 years
  • 1995 PMID 7712435 -- "The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma. A prospective randomized trial. Stockholm Colorectal Cancer Study Group." (Cedermark B, Cancer. 1995 May 1;75(9):2269-75.). Median F/U 8.9 years
    • Curative intent: LR (SS) better with RT. Time-to-failure (SS) better with RT. No difference in DM or OS
    • Toxicity: postop mortality 8% with RT vs. 2% surgery only (SS)
  • 1990 PMID 2191763 -- "Preoperative short-term radiation therapy in operable rectal carcinoma. A prospective randomized trial. Stockholm Rectal Cancer Study Group." (No Authors, Cancer. 1990 Jul 1;66(1):49-55.)
    • RT fields to pelvis and para-aortic LN to L2. AP/PA portals permitted.
    • Curative intent: LR (SS) better with RT. Time-to-failure (SS) better with RT. No difference in DM or OS
    • Toxicity: postop mortality 8% with RT vs. 2% surgery only (SS)
  • Conclusion: preop RT better, but at high periop mortality cost. RT fields need to be adjusted, see Stockholm 2

• Stockholm 2
  • Randomized. 557 patients from 12 centers. Treated with 1) preop RT 25/5, or 2) surgery alone. RT fields to pelvis only, mandated 3F or 4F plans (no AP/PA only). Median F/U 4.2 years
  • 1996 PMID 8876883 -- "Randomized study on preoperative radiotherapy in rectal carcinoma. Stockholm Colorectal Cancer Study Group." (No Authors, Ann Surg Oncol. 1996 Sep;3(5):423-30.)
    • Outcome: LR: preop RT 10% vs. surgery only 21% (SS). Distant mets 19% vs. 26% (SS); OS improved with preop RT
  • Conclusion: Preop RT reduces LR and DM, and improves OS

• Stockholm 3
  • Randomized. 303 patients were randomized to either short-course RT (5 x 5 Gy) and surgery within 1 week (group 1), short-course RT and surgery after 4-8 weeks (group 2) or long-course RT (25 x 2 Gy) and surgery after 4-8 weeks (group 3).
  • 2010 PMID 20155787 -- "Interim analysis of the Stockholm III trial of preoperative radiotherapy regimens for rectal cancer." (Pettersson D, Br J Surg. 2010 Apr;97(4):580-7)
    • Outcome: Patients receiving short-course RT with surgery 11-17 days after the start of RT had the highest complication rate (~65% of patients).
  • Conclusion: 4-8 week delay after short-course RT decreases complication rate.

• MRC (1981-1989) PMID 8961989 -- "Randomised trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Medical Research Council Rectal Cancer Working Party." (No Authors, Lancet. 1996 Dec 14;348(9042):1605-10.)
  • Randomized. 279 patients from 20 centers. Treated with 1) surgery alone, or 2) preop RT 40/20. Minimum F/U 5 years
  • Median OS: 24 months vs. 31 months (NS). But benefit on DFS
  • LR: surgery 46% vs. preop RT 36% (SS). DM surgery 48% vs. preop RT 35%
  • Conclusion: Preop RT reduces LR, but survival equivocal

• UK Multicentre PMID 7530469 -- "Long-term results of a randomised trial of short-course low-dose adjuvant pre-operative radiotherapy for rectal cancer: reduction in local treatment failure." (Goldberg PA, Eur J Cancer. 1994;30A(11):1602-6.)
  • Randomized. 468 patients with rectal CA <=12 cm from anal verge. RT 15/3 within 2 days of surgery vs. surgery alone. Minimum F/U 5 years
  • Perioperative mortality: RT 9% vs. surgery alone 4% (SS)
  • LR: RT 17% vs. surgery alone 24% (SS)
  • No difference in OS

• Northwest Rectal Cancer Group (UK) (1982-1986) PMID 7995145 -- "Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Results of a prospective, randomized trial." (Marsh PJ, Dis Colon Rectum. 1994 Dec;37(12):1205-14.)
  • Randomized. 284 patients. Preop RT 20/4 to 10x10x10cm volume in posterior pelvic vs surgery alone. Minimum F/U 8 years
  • No difference in overall or cancer-specific survival, but survival benefit for subset considered to receive curative operation
  • LR: RT 13% vs. surgery alone 36% (SS). 10 recurrences infield, 6 recurrences out of field. DM same
  • Conclusion: Recommend to all patients who will undergo curative surgery

• Western Norway (1976-1985) PMID 2245382 -- "Low-dose preoperative radiation postpones recurrences in operable rectal cancer. Results of a randomized multicenter trial in western Norway." (Dahl O, Cancer. 1990 Dec 1;66(11):2286-94.)
  • Randomized. 309 patients. Randomized to preop RT 31.5/18 with radical surgery 2-3 weeks later, or surgery alone
  • No tumor in 5% patients. No increased morbidity or mortality at surgery
  • 5-year OS: surgery alone 57% vs. RT 57%
  • Recurrence: surgery alone 13 months vs. RT 27 months (SS); LR 21% vs. 14%
  • Conclusion: should use higher RT dose

• Sao Paulo (1978-1980) PMID 2752859 -- "A comparison of nonoperative vs. preoperative radiotherapy in rectal carcinoma. A 10-year randomized trial." (Reis Neto JA, Dis Colon Rectum. 1989 Aug;32(8):702-10.)
  • Randomized. 68 patients (26% in group 1 were Dukes C, 47% in group 2 were Dukes C). Randomized to 1) preoperative RT 40/20 + surgery within 1 week, or 2) surgery alone. Minimum F/U 8 years
  • 5-year OS: RT 80% vs. 34%
  • Local recurrence: RT 3% vs. 23%

• EORTC (1976-1981) PMID 3056288 -- "Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC)." (Gerard A, Ann Surg. 1988 Nov;208(5):606-14.)
  • Randomized. 466 patients. Treated with 1) surgery alone, or 2) preop RT 34.5/15 in 2.3 Gy/fx
  • 5-year OS: no difference (59% vs. 69%) (p=0.08)
  • 5-year LR: surgery 30% vs. 15% (SS)

• Meta-analysis, 2001 PMID 11684209 -- "Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials." (Colorectal Cancer Collaborative Group, Lancet. 2001 Oct 20;358(9290):1291-304.)
  • 22 randomized trials comparing pre- and post-op RT with surgery alone. Centrally analysed individual patient data from 14 preop (6,350 patients) and 8 postop (2,157 patients)
  • 5-year OS: marginally better with RT (62% vs. 63%, p=0.06)
  • Curative resection: not improved by RT (86% vs. 85%)
  • Annual risk of recurrence: preop RT 46% lower, postop RT 37% lower
  • Preop RT: fewer deaths from rectal CA (45% vs. 50%, SS), but more early deaths (8% vs. 4%, SS)
  • Conclusion: Preop RT reduces risk of LR and death from rectal cancer, but due to high early mortality has no impact on overall survival. Post-op RT also reduces LR.

Preop RT vs Preop Chemo-RT

• Cochrane Meta-analysis--
  • 2013 PMID 23450565 -- "Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer." (Laura De Caluwé et al.Cochrane Database Syst Rev. 2013 Feb 28;2)
    • Five trials were identified and included in the meta-analysis. From one of the included trials only preliminary data are reported.
    • Outcome:
      • Response rate: CRT significantly increased the rate of complete pathological response (OR 2.12-5.84, P < 0.00001)
      • Sphincter Preservation: did not translate into a higher sphincter preservation rate (OR 0.92-1.30, P = 0.32)
      • Post-op Morbidity: marginally affected postoperative overall morbidity (OR 0.67-1.00, P = 0.05)
      • Anastomotic leak: No differences were observed in anastomotic leak rate
      • Post-op Mortality: No differences were observed in postoperative mortality
      • Local recurrence: at five years was significantly lower in the CRT group compared to RT alone (OR 0.39-0.72, P < 0.001).
      • Survival: No statistically significant differences in DFS (OR 0.92-1.34, P = 0.27) or OS (OR 0.79-1.14,P = 0.58) at five years.
    • Toxicity: increased grade III and IV acute toxicity (OR 1.68-10, P = 0.002)
    • Conclusion: CRT results in SS improved pCR and LC but this does not translate into either improved sphincter preservation or OS/DFS benefit.

• TROG 01.04 (Trans-Tasman Radiation Oncology Group) -- RT 25/5 Short Course vs Chemo-RT 50.4/28 with C.I. 5-FU
  • Randomized. 326 pts. Staged with ultrasound or MRI as T3N0-2. Short course (SC): RT 25/5 followed by early surgery and 6 courses of adjuvant chemo. Long course (LC): 50.4/28 with 5-FU, followed by surgery in 4-6 weeks, then 4 courses of adjuvant chemotherapy.
  • 2012 PMID 23008301 -- "Randomized Trial of Short-Course Radiotherapy Versus Long-Course Chemoradiation Comparing Rates of Local Recurrence in Patients With T3 Rectal Cancer: Trans-Tasman Radiation Oncology Group Trial 01.04" (Ngan SY, J Clin Oncol. 2012 -- online before print, 9/24/12)
    • No significant differences in LR, DR, or OS. 3-yr LR: 7.5% for SC vs 4.4% for LC (NS). 5-yr distant recurrence: 27% vs 30% (NS). 5-yr OS: 74% vs 70% (NS). Late toxicity rates not different.
    • Distal tumors (< 5 cm): LR in 6 of 48 pts (SC) vs 1 of 31 (LC) (NS).
    • Conclusion: "Three-year LR rates between SC and LC were not statistically significantly different." "LC may be more effective in reducing LR for distal tumors. No differences in rates of distant recurrence, relapse-free survival, overall survival, or late toxicity were detected."

• French FFCD 9203 (1993-2003)
  • 733 pts. Resectable T3-T4, Nx. Randomized to: 1) 45 Gy RT alone vs 2) RT with concurrent bolus 5-FU (350 mg/m2) + leucovorin on days 1-5, weeks 1,5. Both groups followed by surgery and 4 cycles of adjuvant 5-FU/Leucovorin.
  • 2006 PMID 17008704 -- "Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203." (Gerard JP, J Clin Oncol. 2006 Oct 1;24(28):4620-5.)
    • 5-year OS (primary endpoint): no difference. Sphincter preservation: no difference
    • 5-year LR: CRT 8% vs. 16% RT alone (SS)
    • Grade 3+ toxicity: CRT 15% vs. 3% RT alone (SS)
    • Conclusion: chemoradiation recommended for improved local control
  • 2005 ASTRO Plenary #4 - No PMID Webcast — "Preoperative Chemoradiotherapy (CT-RT) Improves Local Control in T3-4 Rectal Cancers: Results of the FFCD 9203 Randomized Trial." Gerard J et al. IJROBP Volume 63, Supplement 1, 1 October 2005, Pages S2-S3.
    • Median f/u 69 mo. Equivalent rate of sphincter-sparing surgery, 51%. Chemo/RT led to improved pCR 11.7% vs 3.7%, 5-yr LF 8% vs 16.5%. No diff in OS.
    • Conclusion: less tumor recurrence after chemo/RT compared to RT alone

• EORTC 22921
  • Randomized. 2x2 design. 1011 patients with T3 or T4 resectable rectal CA. Treated with 1) Preop RT, 2) Preop CRT, 3) Preop RT + postop CT, or 4) Preop CRT + postop CT. RT given 45/25 to posterior pelvis. 5-FU given 350 mg/m2/day
  • 2007 PMID 17906203 -- "Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group." (Collette L, J Clin Oncol. 2007 Oct 1;25(28):4379-86.)
    • Data from 785 patients with adjuvant chemo
    • Outcome: No benefit in entire group. However, ypT0-2 benefit (SS), while ypT3-4 no benefit
    • Conclusion: Only good-prognosis patients (T0-2 on surgery) benefit from adjuvant chemo
  • 2006 PMID 16971718 -- "Chemotherapy with preoperative radiotherapy in rectal cancer." (Bosset JF, N Engl J Med. 2006 Sep 14;355(11):1114-23.)
    • 5-year OS: overall 65% (no difference among the 4 groups)
    • 5-year LR: preop RT 17% vs. CRT 9% (preop CRT 9% vs. preop RT + postop CT 10% vs. preop CRT + postop CT 8%)
    • Adherence: 82% for preop CT vs. 43% for postop CT
  • 2005 PMID 16009958, 2005 — "Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results--EORTC 22921." Bosset JF et al. J Clin Oncol. 2005 Aug 20;23(24):5620-7.
    • Tumors after preop CRT vs RT alone: smaller, lower pT, lower pN, fewer examined nodes, less LVN, increase in mucinous tumors
    • Conclusion: Significant downstaging with CRT over RT alone
  • Dose Escalation; 1993 PMID 8398268 -- "Determination of the optimal dose of 5-fluorouracil when combined with low dose D,L-leucovorin and irradiation in rectal cancer: results of three consecutive phase II studies. EORTC Radiotherapy Group." (Bosset JF, Eur J Cancer. 1993;29A(10):1406-10.)
    • Three Phase II 5-FU dose escalation trials. Locally extended rectal CA. Preop RT 45/25 + concurrent 5-FU.
    • Dose: 425 mg/m2/day + 370 mg/m2/day => 370 mg/m2/day + 370 mg/m2/day => 350 mg/m2/day + 350 mg/m2/day
    • Conclusion: 350 mg/m2/day best tolerated; used in EORTC 22921
  • Overall conclusion: chemo adds significant benefit to RT alone, regardless if it's before or after surgery

Preop Chemo-RT: Chemotherapy Regimen

Randomized studies:

+/- Oxaliplatin:

• STAR-01 -- 5-FU +/- Oxali
  • Randomized. 747 pt, T3-T4 or N+. RT 50.4 Gy. Randomized to: Arm A) C.I. 5-FU alone (225 mg/m2/d), or B) 5-FU plus oxaliplatin (60 mg/m2 weekly).
  • 2011 PMID 21606427 -- "Primary Tumor Response to Preoperative Chemoradiation With or Without Oxaliplatin in Locally Advanced Rectal Cancer: Pathologic Results of the STAR-01 Randomized Phase III Trial." (Aschele C, J Clin Oncol. 2011 May 23. [Epub ahead of print])
    • No difference in pCR rate (16% in both arms), pN+ (26% vs 29%), pT3 (46% vs 44%), or positive circumferential resection margins (7% v 4%).
    • Grade 3-4 toxicity more frequent with oxali (8% v 24%). Higher rate of completing RT (>45 Gy) in control arm: 97% vs 91%.
    • Conclusion: Adding oxaliplatin to 5-FU - RT increases toxicity without affecting tumor response.

• ACCORD 12/0405-Prodige 2 (2005-2008) -- Cap 45 vs Capox 50
  • Randomized. 598 patients, resectable T3-T4 rectal adenoca, T2 tumors in anterior/lower rectum also included. Arm 1) RT 45/25 with concurrent capecitabine 800 mg/m2 BID (Cap 45) vs Arm 2) RT 50/25 with concurrent capecitabine 800 mg/m2 BID and oxaliplatin 50 mg/m2 QW (Capox 50). RT excluded external/common illiac, in Capox 50 group boost after 44 Gy. Primary endpoing ypCR to get quick answer, as follow up to FFCD 9203
  • 2010 PMID 20194850 -- "Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2." (Gerard JP, J Clin Oncol. 2010 Apr 1;28(10):1638-44. Epub 2010 Mar 1.)
    • Outcome: ypCR Cap45 14% vs Capox 50 19% (NS). SM+ (0-2mm) 19% vs 10% (SS)
    • Toxicity: Preop G3+ Cap 45 1% vs Capox 50 25% (SS). No difference in surgery (75%) or postop deaths (0.3%).
    • Conclusion: Benefit of oxaliplatin not demonstrated. Suggest Cap 50 as the next regimen to test
  • 2012 PMID 23109696 -- "Clinical Outcome of the ACCORD 12/0405 PRODIGE 2 Randomized Trial in Rectal Cancer." (Gerard JP, J Clin Oncol -- online before print, Oct 29 2012.)
    • At 3 yrs, no sig difference in LR (Cap45 6.1% vs Capox50 4.4%), OS (87.6% vs 88.3%), or DFS (67.9% vs 72.7%).
    • On multivariate analysis, the main prognostic factor was the pCR rate
    • Conclusion: "At 3 years, no significant difference in clinical outcome was achieved with the intensified CAPOX regimen. When compared with other recent randomized trials, these results indicate that concurrent administration of oxaliplatin and RT is not recommended. "

+/- Cetuximab

• EXPERT-C Clinicaltrials - Randomized Phase II -- Preop chemo/RT and adjuvant chemo +/- Cetuximab
  • 165 pts. Operable tumors, MRI defined high risk (1 or more of following: tumors within 1 mm of mesorectal fascia, T3 tumors at or below levators, extending >= 5 mm into perirectal fat, T4 tumors, extramural venous invasion).
  • Randomized to: 1) Neoadjuvant oxali + capecitabine (CAPOX) x 4 cycles; followed by neoadjuvant chemo/RT with concurrent capecitabine; surgery / TME; adjuvant chemotherapy CAPOX x 4 cycles; or 2) same regimen plus cetuximab (given weekly during neoadj chemo and chemo/RT x 17 weeks, adjuvant x 12 weeks)
  • 2012 PMID 22473163 -- "Multicenter Randomized Phase II Clinical Trial Comparing Neoadjuvant Oxaliplatin, Capecitabine, and Preoperative Radiotherapy With or Without Cetuximab Followed by Total Mesorectal Excision in Patients With High-Risk Rectal Cancer (EXPERT-C)" (Dewdney A, J Clin Oncol. 2012 Apr 2. [Epub ahead of print])
    • 60% of tumors were KRAS or BRAF wild-type. In tumors that were wild-type, addition of cetuximab did not improve pCR: 9% (CAPOX) vs 11% (CAPOX+C); PFS not improved. Cetuximab improved RR (51 vs 71% after chemo, 75 vs 93% after RT); improved OS (HR 0.27). Increased skin toxicity and diarrhea.
    • Conclusion: "Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met."

Single-arm studies:

Capecitabine + Irinotecan:

• North Wales -- phase II
  • 110 pts. MRI staged, tumor involving or within 2mm of mesorectal fascia. RT 45 Gy / 25 f. Concurrent oral capecitabine daily, IV irinotecan weekly x 4 weeks.
  • 2011 PMID 21263095 -- "Preoperative Chemoradiotherapy Using Concurrent Capecitabine and Irinotecan in Magnetic Resonance Imaging-Defined Locally Advanced Rectal Cancer: Impact on Long-Term Clinical Outcomes." (Gollins S, J Clin Oncol. 2011 Mar 10;29(6):1042-1049.)
    • pCR 22%. 67% with T-stage downstaging, 80% with N-stage downstaging. Negative circumferential resection margin in 92%. 3-yr LRFS 96.9%, MFS 71.1%, DFS 63.5%, OS 88.2%.

Clinical stage T3 N0

• Multicenter; 2008 PMID 18202411 -- "cT3N0 rectal cancer: potential overtreatment with preoperative chemoradiotherapy is warranted." (Guillem JG, J Clin Oncol. 2008 Jan 20;26(3):368-73.)
  • Retrospective. 188 pts. Multicenter, international, 6 institutions. Purpose: Analysis of preoperatively staged cT3N0 (by EUS or MRI) pts to look at accuracy of staging lymph nodes. All pts treated with neoadjuvant chemo/RT.
  • Rate of pathologically positive lymph nodes after chemo/RT in cT3N0 pts was 22%. The true rate of positive lymph nodes may be higher, due to downstaging by chemo/RT.
  • Conclusion: Recommend that preoperative chemo/RT should remain the standard of care for T3N0 patients.

RT Dose Escalation

• Princess Margaret, 2006 (1998-2002) - PMID 16242252 — "Preoperative radiation with concurrent chemotherapy for resectable rectal cancer: Effect of dose escalation on pathologic complete response, local recurrence-free survival, disease-free survival, and overall survival." Wiltshire KL et al. Int J Radiat Oncol Biol Phys. 2006 Mar 1;64(3):709-16.
  • Review of 3 Phase II studies of preoperative chemo/RT. T2 N1-2 or T3-4 N0-2. The 3 cohorts were treated to 40 Gy/20 fx, 46 Gy/23 fx, or 50 Gy/25 fx. Continuous infusion 5-FU 7 days/wk.
  • pCR in 15%, 23%, and 33%. 2-yr LRFS 72%, 90%, 89%. DFS 62%, 84%, 78%. OS 72%, 94%, 92%.
  • Conclusion: increase in LRFS, DFS, and OS with doses 46 Gy and higher, but no difference between 46 and 50 Gy.

• RTOG 00-12, 2006 (2001-2003)
  • PMID 16446336, 2006 — "Randomized Phase II Study of Neoadjuvant Combined-Modality Chemoradiation for Distal Rectal Cancer: Radiation Therapy Oncology Group Trial 0012." Mohiuddin M et al. J Clin Oncol, Vol 24, No 4 (February 1), 2006: pp. 650-655.
  • Objectives: determine pCR rate of preoperative chemo/RT
  • Randomized Phase II. 103 pts. T3 or T4 distal rectum (<9cm from dentate line). Randomized to: 1) CVI 5-FU + HF-RT 55.2 - 60 Gy (1.2 Gy BID), or 2) CVI 5-FU + irinotecan + CF-RT 50.4-54 Gy (1.8 Gy/d).
  • Response rate similar between the two arms. pCR 28% (higher than in other studies).

• Lyon R96-02 (1996-2001) -- RT 39/13 or RT 39/13 + boost 85/3
  • Randomized. 88 patients. Low rectum tumors, T2-T3Nx, involving <2/3 circumference. Treated with 1) preop RT 39/13 or 2) same RT + endocavitary boost of 85/3
  • 2004 PMID 15197202 -- "Improved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: the lyon R96-02 randomized trial." (Gerard JP, J Clin Oncol. 2004 Jun 15;22(12):2404-9.)
    • Response: CR 2% vs. 24% boost; sterilization 34% vs. 57%. Median F/U 2.8 years
    • 2-year outcome: no difference in morbidity, LR, or OS. Significant benefit for sphincter preservation (76% vs 44%, SS) in boost group
    • Conclusion: dose escalation feasible, improved tumor response in early follow-up

Interval between neoadjuvant RT and surgery

• Lyon R90-01 (1991-1995) -- 2 week interval vs 6-8 week interval between neoadjuvant RT (39/13) and surgery
  • Randomized. 29 French centers. 201 patients with T2-T2Nx. Neoadjuvant RT 39/13, followed by Arm 1) surgery in 2 weeks vs Arm 2) surgery in 6-8 weeks. Sphincter preservation (primary endpoint) per surgeon
  • 17-years PMID 26723110 -- "Pathologic Response, When Increased by Longer Interval, Is a Marker but Not the Cause of Good Prognosis in Rectal Cancer: 17-year Follow-up of the Lyon R90-01 Randomized Trial." (Cotte E, Int J Radiat Oncol Biol Phys. 2016 Mar 1;94(3):544-53. doi: 10.1016/j.ijrobp.2015.10.061. Epub 2015 Nov 4.) Median F/U 17 years
    • Outcome: ypCR short 10% vs long 26% (SS). LR 14% vs 12% (NS). 5-year OS short 67% vs long 67%, 10-year OS 49% vs 53%, 15-year OS 40% vs 42%, 17-year OS 34% vs 34% (NS). Most recurrences (83%) within first 2 years, 96% within 5 years. Second malignancies 9.4% (4% were prostate/bladder)
    • Conclusion: Increasing interval between neoadjuvant RT and surgery did not effect survival, but it did not have a detrimental effect on local control.

• Krakow (1999 - 2006) -- 1 week interval vs 4 week interval between neoadjuvant RT (25/5) and surgery
  • Randomized. 154 patients. Stage I-III (stage II 58%, stage III 25%). Neoadjuvant RT 25/5, followed by Arm 1) surgery 7-10 days vs Arm 2) surgery in 4-5 weeks. Surgery was TME and D3-lymphadenectomy
  • 5-years; 2012 PMID 22170083 -- "Randomized clinical trial on preoperative radiotherapy 25 Gy in rectal cancer--treatment results at 5-year follow-up." (Pach R, Langenbecks Arch Surg. 2012 Jun;397(5):801-7. doi: 10.1007/s00423-011-0890-8. Epub 2011 Dec 15.)
    • Outcome: No difference between type of surgery or sphincter preservation. LR short 1% vs long 7% (NS), all recurrences 14% vs 13% (NS). 5-year OS 63% vs 73% (NS). However, if downstaging after RT, survival 90% vs 60% (SS). Longer time interval resulted in higher downstaging 44% vs 13% (SS) but no effect on sphincter-sparing surgery or R0 resection (NS).
    • Conclusion: Longer time interval after neoadjuvant RT does not improve sphincter preservation. Improved 5-year OS seen only in patients with downstaging

Induction Chemo vs Adjuvant Chemo

• Neoadjuvant chemo-RT followed by surgery, with either induction chemo strategy or adjuvant chemo strategy

• Grupo Cancer De Recto 3, Spain (2006-2007) -- Induction chemo vs adjuvant chemo, with chemo-RT -> surgery
  • Randomized, Phase II. 108 patients, locally advanced rectal cancer, <12 cm from verge, LAR disease based on high-res MRI. Treated with chemo-RT followed by surgery. Randomized to Arm 1) Induction capecitabine 2000 mg/m2 and oxaliplatin 130 mg/m2 (CAPOX) x4 cycles vs Arm 2) Adjuvant CAPOX x4 cycles. Primary endpoint pCR
  • 2010 PMID 20065174 -- "Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study." (Fernandez-Martos C, J Clin Oncol. 2010 Feb 10;28(5):859-65. Epub 2010 Jan 11.)
    • Outcome: pCR induction 13% vs adjuvant 14% (NS), no difference in downstaging, tumor regression, R0 resection.
    • Toxicity: Higher during adjuvant arm. No difference during chemo-RT.
    • Conclusion: No difference in outcomes, but less toxicity with induction chemo compared with adjuvant chemo

• Royal Marsden Hospital (abstract 163 at 2005 Gastrointestinal Cancers Symposium) - Chau I et al. - poor risk pts by MRI
  • 77 pts. MRI-staged poor risk (tumor within 1 mm of mesorectal fascia, T3 tumors at or below levators, T3c or T3d (??) at any other level, T4 tumors, or any tumor with 4 or more LN +).
  • 12 weeks neoadjuvant chemotherapy with Xeloda 1000 mg/m2 BID x 14 days q3w and oxaliplatin 130 mg/m2 q3w. At week 13, Xeloda 825 mg/m2 BID concurrent with XRT 45 Gy in 25 fractions + 9 Gy boost. TME planned at 6 weeks after chemo/RT. 12 weeks post-op Xeloda 1250 mg/m2 BID x 14 days q3w.
  • 88% response rate after chemo. 97% after chemo/RT. At surgery, 79% had primary tumor downstaged. 98% had R0 resection. 24% had pCR and in 42% only microscopic tumor foci. Median f/u 15.9 months.

Adjuvant Chemotherapy

• Warsaw; 2010 PMID 20231300 -- "Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials." (Bujko K, Ann Oncol. 2010 Mar 15. [Epub ahead of print])
  • Systematic review. 4 trials
  • Outcome: No statistically significant benefit in patients undergoing preoperative radio(chemo) therapy for adjuvant chemo found
  • Conclusion: New trials should be launched

Ongoing trials

• NSABP R-04: pre-operative chemo/RT. Xeloda vs continuous infusion 5-FU vs Xeloda/oxali vs 5-FU/oxali. T3-4N0 or T1-4N+.
• EORTC: preop RT+chemo vs preop RT alone. Then randomized to adjuvant vs no further chemo.

Prognostic Factors

• Meta-analysis; 2008 PMID 18182672 -- "What is the role for the circumferential margin in the modern treatment of rectal cancer?" (Nagtegaal ID, J Clin Oncol. 2008 Jan 10;26(2):303-12.)
  • 17,500 patients; importance of CRM. CRM predictor for local recurrence, distant mets, and overall survival
  • Conclusion: CRM involvement is one of key factors in rectal cancer treatment

• Mt. Vernon, 2005 (UK) PMID 16199310 -- "Can histopathologic assessment of circumferential margin after preoperative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for 3-year disease-free survival?" (Mawdsley S, Int J Radiat Oncol Biol Phys. 2005 Nov 1;63(3):745-52.)
  • Retrospective. 150 patients, treated with neoadjuvant CRT (5-FU/folinic acid), 6-12 weeks later excision. Median follow-up 25 months
  • Of 150, 122 patients (81%) curative resection, 98 patients (65%) negative margins R0.
  • Local recurrence: R0 10% vs. R1-R2 62%; DM: R0 29% vs. R1-R2 75%; DFS: R0 52% vs. R1-R2 9%
  • 3-year OS: R0 64% vs. R1-R2 25%
  • Conclusion: "After 5-fluorouracil-based CRT, a positive CRM (margin) predicted for a high risk of subsequent local recurrence and a 3-year disease-free survival rate of only 9%."

Side Effects

• Swedish Rectal Cancer Trial
  • 1998 PMID 9593234 -- "Preoperative irradiation affects functional results after surgery for rectal cancer: results from a randomized study." (Dahlberg M, Dis Colon Rectum. 1998 May;41(5):543-9; discussion 549-51.)
    • Patient questionnaire. 171/220 patients alive >5 years.
    • Median BM frequency: RT 20/week vs. surgery alone 10/week (SS)
    • Fecal incontinence: RT 62% vs. surgery alone 27% (SS)
    • Impaired social life: RT 30% vs. surgery alone 10% (SS)
    • Conclusion: High dose preop RT influences long-term bowel function

• Stockholm Trials
  • 2006 PMID 16532369 -- "Long-term effect of preoperative radiation therapy on anorectal function." (Pollack J, Dis Colon Rectum. 2006 Mar;49(3):345-52.)
    • Patient questionnnaire. 64 patients (21 preop RT, 43 surgery alone). Mean F/U 14 years
    • Median BM frequency: RT 20/week vs. surgery alone 10/week (SS)
    • Fecal incontinence: RT 57% vs. surgery alone 26% (SS). Significantly worse resting and squeeze pressures
    • No difference in QOL between RT and surgery alone, but significantly worse for incontinent patients
    • Conclusion: short-term RT including anal sphincters impairs permanently anorectal function

• German Rectal Cancer Study CAO/ARO/AIO (1995-2002) -- preop chemo-RT vs. postop chemo-RT
  • PMID 15496622 Full text, 2004 - "Preoperative versus postoperative chemoradiotherapy for rectal cancer." Sauer R et al. N Engl J Med. 2004 Oct 21;351(17):1731-40.
    • 823 pts. clinical stage T3-4 or N+. Randomized to 1) post-op regimen: surgery (TME) -> chemo/RT (55.8 Gy) -> 5 cycles bolus 5-FU, or 2) pre-op regimen: chemo/RT (50.4 Gy) -> surgery (TME) -> 4 cycles bolus 5-FU. In both arms, chemo was CVI 5-FU (1000 mg/m2/d) on days 1-5, weeks 1+5.
    • Sphincter-preserving surgery performed: 39% in pre-op arm, 19% in post-op arm
    • Grade 3-4 acute toxicity in 27% of pre-op arm, 40% of post-op arm (p=0.001)
    • Grade 3-4 long-term toxicity in 14% of pre-op arm, 24% of post-op arm (p=0.01)

Summary of results

Study	pCR	sphincter sparing	LR	DM	DFS	OS
No adjuvant treatment:
MRC 3	n/a	-	34%	-	-	46% 5-yr
Pre-op RT alone:
Pre-op Chemo/RT:
Adjuvant Chemo:
NSABP R-02	n/a	-	13%	-	-	-
Adjuvant RT:
MRC 3	n/a	-	21%	-	-	52% 5-yr
Adjuvant Chemo/RT:
NSABP R-02	n/a	-	8%	-	-	-