Presenting Author: J. Gerard Affiliation: Centre Antoine-Lacassagne, Nice 06189 Cedex 2, France
The current standard of care for locally advanced rectal cancer is preoperative chemoradiation followed by surgical resection via total mesorectal excision.
The EORTC 22921 (Bosset NEJM 2006) and FFCD 9203 (Gerard JCO 2006) trials established that 5-fluorouracil and radiotherapy (RT) is superior to radiotherapy alone for the pre-operative treatment of rectal cancer by increasing the pathologic complete response (pCR) and local control.
The German Rectal Cancer Study Group (Sauer NEJM 2004) showed an improvement in pCR rate and disease free survival by administering chemoradiation preoperatively versus postoperatively.
Several phase I/II trials have shown the feasibility and safety of the addition of oxaliplatin to the preoperative regimen (Gerard, Lyon R0-04, JCO 2003 and Rodel JCO 2003).
In addition, there have been trials in colorectal cancer showing that capecitabine, an oral prodrug of 5-FU, can be substituted for infusional 5-FU (Crane JCO 2004).
The ACCORD trial was designed to test three improvements to the preoperative regimen utilized in the FFCD 9203 trial:
The addition of oxaliplatin to 5-flurouracil chemotherapy.
The substitution of capecitabine for infusional 5-FU
The increase in radiotherapy dose from 45 to 50 Gy.
This reports the main clinical results of the ACCORD12 trial in rectal cancer after 3 years of follow-up.
Patients ? 80 years with a WHO performance status of 0 or 1 were eligible.
Inclusion criteria were: histologically-confirmed adenocarcinoma of rectum accessible to digital examination (the authors state this is usually low or middle rectum) staged T3 Nx M0 (or T2 Nx distal anterior rectum). Tumors had to be deemed to be resectable (i.e. a R0 or R1 resection).
All patients underwent digital rectal examination, rigid rectoscopy, and total colonoscopy. Tumor and nodal stage were evaluated with endorectal ultrasound and/or magnetic resonance imaging. The highest stage was the recorded stage.
Patients had to have no evidence of distant metastases, as assessed by computed tomography.
Patients were randomized to one of two neoadjuvant treatments with radiochemotherapy (RT-CT): Cap45 (RT 45 Gy + capecitabine) and Capox50 (RT 50 Gy + cape. and oxaliplatin).
Patients were stratified by center, sex, T stage (cT2, cT3, cT4), and distance from anal verge (? 6 v > 6 cm).
Radiation dose was either 45 or 50 Gy (the authors estimate this to increase the biologic effective dose (BED) by 15%) in 25 fractions of 1.8 or 2 Gy, respectively, five times per week, over a period of 5 weeks.
Dose was delivered via 3D-conformal radiotherapy, using a three-or four-field technique that included the mesorectal and medial rectal nodes but did not include the external and common iliac nodes.
In the group that received oxaliplatin and 50 Gy, a shrinking-fields technique was used after 44 Gy to treat the gross tumor only to 50 Gy.
The dose of oral capecitabine was 800 mg/m2 twice daily and the oxaliplatin dose was 50 mg/m2 weekly.
There was no specific recommendation for adjuvant chemotherapy.
Pathologic specimens were assessed according to the Dworak modified classification.
Primary endpoint was ypCR rate. Secondary end points were local control, survival, sphincter preservation, and toxicity.
A total of 590 patients were required for enrollment based on ? = .05 (two tailed) and ? = .15 to detect a difference of 11% in the pCR rate.
Bowel function was reported with a questionnaire and a global score (1 very poor to 7 excellent).
Between November 2005 and July 2008, 598 patients were enrolled at a total of 56 institutions (299 in Cap45 and 299 in Capox50 arms).
Median follow up was 36 months.
Patient characteristics were well-balanced between groups.
ypCR rate was 13% in the Cap45 arm and 19% in the Capox50 arm (p=0.09).
For T2 tumors, 33 vs. 47%; T3: 13 vs. 18%; T4: 7 vs. 13%.
CRM R1 resection occurred in 14% in the Cap45 arm and 9% in the Capox50 arm (p=sig).
Sphincter sparing surgery was possible in 75% in the Cap45 arm and 76% in the Capox50 arm (NS).
Local recurrence (LR) was the same in both (6% vs. 4%, NS).
On multivariate analysis, stable disease, circumferential radial margin (CRM > 2 mm) were predictors of increased LR.
Three-year disease-free survival (DFS) was 69 vs. 74% (NS).
On multivariate analysis, WHO PS 1-2, T3-4, stable disease, ypT2-3, ypN1-2, or circumferential radial margin (CRM > 1 mm) were predictors of poorer DFS.
Overall survival was the same in both arms (88% at 3 years).
Medial bowel function score was 5 [range 1-7] in the Cap45 arm and 5 [1-7] in the Capeox50 arm.
Any grade 3 toxicity occurred in 11% in the Cap45 arm and 25% in Capeox50 arm (p<0.001).
Oxaliplatin increases grade 3 toxicity (specifically diarrhea) and does not improve ypCR, DFS, LR, or OS.
50 Gy does increase the ypCR rate and CRM negative margin status.
Capecitabine appears to be a reasonable substitution for infusional 5-FU.
The authors recommend use of the Cap50 regimen consisting of 50 Gy over 5 weeks with a shrinking field after 44 Gy and capecitabine at 1600 mg/m2/day on radiation days.
These conclusions are strengthened by taking these data in conjunction with the STAR-01 trial which showed increased G3-4 toxicity due to oxaliplatin with no impact on the operative specimen.
Single-agent 5-FU (either as capecitabine or infusional) with radiotherapy to 50 Gy remains the standard of care for preoperative chemoradiation for locally advanced rectal cancer.
Oxaliplatin increases toxicity without improving ypCR, local control, or survival rates.
The dose of oxaliplatin used in this study, unlike in the standard FOLFOX regimen, was for radiosensitization only and, thus, the distant failure rate would be unaffected by the addition of oxaliplatin.
Recent publications of the STAR-01 (Aschele JCO 2011), NSABP R-04, and CAD/ARO-04 studies reinforce the use of single-agent 5-FU without the addition of oxaliplatin.
In order to improve on the FFCD 9205, the authors made 3 changes to the preoperative regimen, which makes the data challenging to interpret.
50 Gy appears to be tolerable in this study but it is difficult to establish if the increased toxicity in the Capox50 arm was due to the addition of oxaliplatin or increased dose.
The dose of capecitabine of 1600 mg/m2/day is lower than the standard preoperative capecitabine dose and therefore the control and survival numbers could be below what would have been seen with a higher dose.
This study was powered to detect an 11% difference in ypCR rate, needing fewer patients to detect this difference than if it had been powered on survival. This underscores that it is difficult to show meaningful differences without large studies.
Phase II studies investigating more specific patient populations may help identify which patients could benefit from preoperative therapy beyond 5-FU and 50 Gy of radiotherapy.
More tailored radiotherapy of rectal cancer will become increasingly available as biomarkers become validated (e.g. Her2).
The use of IMRT instead of 3D conformal radiotherapy and the treatment of smaller fields may permit even lower toxicity rates and dose escalation in particularly high-risk areas of disease or in the event that patients cannot undergo surgery.
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