Comparison of Two Neoadjuvant Chemoradiotherapy Regimens for Locally Advanced Rectal Cancer: Results of the Phase III Trial ACCORD 12/0405-Prodige 2
Publication: Journal of Clinical Oncology
Abstract
Purpose
Neoadjuvant chemoradiotherapy is considered a standard approach for T3-4 M0 rectal cancer. In this situation, we compared neoadjuvant radiotherapy plus capecitabine with dose-intensified radiotherapy plus capecitabine and oxaliplatin.
Patients and Methods
We randomly assigned patients to receive 5 weeks of treatment with radiotherapy 45 Gy/25 fractions with concurrent capecitabine 800 mg/m2 twice daily 5 days per week (Cap 45) or radiotherapy 50 Gy/25 fractions with capecitabine 800 mg/m2 twice daily 5 days per week and oxaliplatin 50 mg/m2 once weekly (Capox 50). The primary end point was complete sterilization of the operative specimen (ypCR).
Results
Five hundred ninety-eight patients were randomly assigned to receive Cap 45 (n = 299) or Capox 50 (n = 299). More preoperative grade 3 to 4 toxicity occurred in the Capox 50 group (25 v 1%; P < .001). Surgery was performed in 98% of patients in both groups. There were no differences between groups in the rate of conservative surgery (75%) or postoperative deaths at 60 days (0.3%). The ypCR rate was 13.9% with Cap 45 and 19.2% with Capox 50 (P = .09). When ypCR was combined with yp few residual cells, the rate was respectively 28.9% with Cap 45 and 39.4% with Capox 50 (P = .008). The rate of positive circumferential rectal margins (between 0 and 2 mm) was 19.3% with Cap 45 and 9.9% with Capox 50 (P = .02).
Conclusion
The benefit of oxaliplatin was not demonstrated and this drug should not be used with concurrent irradiation. Cap 50 merits investigation for T3-4 rectal cancers.
Introduction
In T3-4 M0 rectal cancers, total mesorectal excision remains the cornerstone of treatment.1 Local control rate is further improved with preoperative radiotherapy.2 European Organisation for the Research and Treatment of Cancer trial 229213 and Fédération Francophone de Cancérologie Digestive (FFCD) trial 92034 further showed that the addition of fluorouracil to radiotherapy significantly increased the pathologic complete response rate (ypCR) and local control. The German Rectal Cancer Study Group5 established preoperative chemoradiotherapy as a standard for most T3-4 rectal adenocarcinomas.
The aim of this study was to evaluate if it is possible to improve the result of the FFCD 9203 trial4 in which concurrent chemoradiotherapy achieved a ypCR after neoadjuvant treatment of 11.4%. Phase II studies have shown the feasibility of combining fluorouracil or capecitabine and oxaliplatin with a radiation dose of 50 Gy over 5 or 6 weeks.6,7 Trials in colorectal cancers have demonstrated the equivalence of infusional fluorouracil and oral capecitabine.8 Therefore, this randomized trial compared neoadjuvant radiotherapy 45 Gy plus capecitabine with radiotherapy 50 Gy plus capecitabine plus oxaliplatin in patients with resectable T3-4 M0 rectal cancer. The trial was launched in 2005 within the framework of a Partenariat de Recherche en Oncologie Digestive (Prodige) cooperation between the FFCD and Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC).
Patients and Methods
Eligibility
Patients were eligible if they presented with histologically confirmed stage T3 or resectable (surgery deemed to achieve a R0 or R1 resection) T4 rectal adenocarcinoma accessible to digital rectal examination and with no evidence of distant metastases, and were age ≤ 80 years with a WHO performance status of 0 or 1. Patients presenting with T2 tumors located in the anterior and lower rectum could also be included. Written informed consent was required for each patient. The study protocol was approved by the Nice ethical committee.
Work-Up
Before random assignment, 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 taken into consideration. Extension of the tumor in the mesorectum was measured in mm on the magnetic resonance imaging. Distant metastases were identified using thoracoabdomino-pelvic computed tomography. CBCs, liver function, creatinine, and serum carcinoembryonic antigen were also assessed. Any level was accepted if it was compatible with the chemoradiotherapy and the eligibility criteria.
Random Assignment and Treatment
Eligible patients were randomly allocated to either radiotherapy 45 Gy with concurrent capecitabine (Cap 45) or radiotherapy 50 Gy with concurrent capecitabine and oxaliplatin (Capox 50). Random assignment was performed centrally at the FNCLCC central office. Stratification was performed by center, sex, T stage (cT2, cT3, cT4), and distance from anal verge (≤ 6 v > 6 cm).
Radiotherapy consisted of 45 or 50 Gy (at least 8-MV photons) in 25 fractions of 1.8 or 2 Gy, respectively, five times per week, over a period of 5 weeks. This dose was delivered using a three-or four-field technique to a restricted posterior pelvic volume including the mesorectal and medial rectal nodes but excluding the external and common iliac nodes. In the Capox 50 group, the target volume was restricted to the gross tumor with shrinking field after a dose of 44 Gy was reached. Irradiation techniques and treatment volumes have been reported previously.4 Using the linear quadratic formula, and assuming an estimated α/β ratio of 4 Gy for the tumor, 45 Gy/25 fractions/5 weeks and 50 Gy/25 fractions/5 weeks were equivalent to 43.5 Gy and 50 Gy, respectively, with 2 Gy per fraction (15% increase in biologic equivalent dose in the 50 Gy group).9,10 A central review of the treatment planning was performed on a series of 60 patients selected at random. Oral capecitabine 800 mg/m2 twice daily was started on the first day of radiotherapy and given 5 days per week during radiotherapy in both groups. In the Capox 50 group, intravenous oxaliplatin 50 mg/m2 was given once weekly (total of five injections). All patients were seen by the surgeon before starting treatment. The type of surgery thought to be needed was not recorded at that time. Surgery was planned 6 weeks after the end of preoperative chemoradiotherapy. Total mesorectal excision was performed according to a standardized technique. The choice between abdominoperineal resection or anterior resection was left to the surgeon. Other types of surgery (Hartmann procedure, intersphincteric resection, or transanal local excision) were permissible at the discretion of the surgeon.
There was no specific recommendation for adjuvant chemotherapy. The decision was left to each institution, but the regimen had to be decided at the start of the trial and adhered to for the whole duration of the study.
Pathologic Examination
The surgeon was required to send the operative specimen for pathologic examination without opening it. The periphery of the specimen was inked and fixed for 48 hours. The rectum was cut into transverse sections according to the Quirke procedure.11 Distance between the outer part of the tumor or any metastatic nodules and the circumferential rectal margin was precisely measured in millimeters.12 R1 resection was defined as a tumor ≤ 1 mm from the circumferential rectal margin. ypCR was assessed according to the Dworak modified classification: 0 = no or very little response; 1 = partial response; 2 = major response with few residual cancer cells; 3 = complete response (ypCR) with no detectable cancer cells.13,14 Tumors with a mucoid flaque in the rectal wall without any visible cell in the mucin (and in the rest of the operative specimen) were classified as ypCR.
Follow-Up
During preoperative treatment, patients were seen every week. Patients were seen 3 months after surgery and then every 6 months for 5 years. Preoperative acute toxicity, surgical toxicity, and late toxicity were analyzed according to the National Cancer Institute Common Toxicity Criteria, version 3.0.
Statistical Analysis
All eligible patients were included in the analysis according to the intention-to-treat principle. The primary end point was ypCR. The hypothesis was to increase ypCR from 11% in the Cap 45 group to 20% in the Capox 50 group. To detect such a difference, with α = .05 (two tailed) and β = .15, 590 randomly assigned patients were required. Secondary end points were circumferential rectal margin, sphincter preservation, local control, and progression-free survival.
Comparisons between the two arms were performed using χ2 tests for categoric variable and Kruskal-Wallis tests for quantitative variables. P lower than .05 was considered to indicate statistical significance. Median follow-up was estimated with the inverse Kaplan-Meier method.
Trial Organization
The investigations and collection, management, and analysis of the data were performed by the FNCLCC with the help of FFCD research technicians. The article was written by the investigators.
Results
Between November 2005 and July 2008, 598 patients were randomly assigned through 56 institutions (Fig 1). Fourteen patients were ineligible because of protocol violations (consent withdrawal, n = 9; distant metastasis, n = 3; lost to follow-up, n = 1; previous history of cancer, n = 1). The analysis was performed on 584 eligible patients (Cap 45, n = 293; Capox 50, n = 291). At the time of analysis (March 2009), the median follow-up time was 12 months (range, 1 to 40 months).
Patient characteristics were well balanced between groups. Of 290 patients staged with magnetic resonance imaging, the circumferential rectal margin was fewer than 5 mm in close to 20% of cases (Table 1).
| Characteristic | Radiotherapy Plus Capecitabine (n = 293) | Radiotherapy Plus Capecitabine Plus Oxaliplatin (n = 291) | P | ||
|---|---|---|---|---|---|
| No. | % | No. | % | ||
| Median age, years | 63 | 61 | |||
| Range | 34-80 | 25-80 | .016 | ||
| Sex (male:female) | 1.87 | 2.06 | .56 | ||
| ECOG performance status | |||||
| 0 | 229 | 83.9 | 229 | 81.5 | |
| 1 | 43 | 15.8 | 51 | 18.1 | |
| 2 | 1 | 0.4 | 1 | 0.4 | .75 |
| Missing data | 20 | 10 | |||
| Location from anal verge, cm | |||||
| 0-6 | 204 | 69.6 | 184 | 63.2 | |
| > 6 | 89 | 30.4 | 107 | 36.8 | .10 |
| Clinical stage* | |||||
| T2 | 23 | 7.9 | 21 | 7.2 | |
| T3 | 255 | 87.0 | 254 | 87.3 | |
| T4 | 15 | 5.1 | 16 | 6.5 | .94 |
| Nodal stage* | |||||
| N0 | 85 | 29.3 | 78 | 27.0 | |
| N1-2 | 205 | 70.7 | 211 | 73.0 | .53 |
| Missing data | 3 | 2 | |||
| MRI circumferential rectal margin, mm | |||||
| ≥ 5 | 111 | 80.4 | 122 | 80.3 | |
| < 5 | 27 | 19.6 | 30 | 19.7 | .97 |
| Not classified/not done | 155 | 139 | |||
| Tumor histology | |||||
| Adenocarcinoma | 293 | 291 | |||
| Well differentiated | 114 | 45.2 | 124 | 48.1 | |
| Moderately differentiated | 129 | 51.2 | 120 | 46.5 | |
| Undifferentiated | 8 | 3.2 | 13 | 5.0 | |
| Colloid type | 1 | 0.4 | 1 | 0.4 | .60 |
| Missing data | 41 | 33 | |||
Abbreviations: ECOG, Eastern Cooperative Oncology Group; MRI, magnetic resonance imaging.
*
Stage defined with all available clinical and imaging results (ie, endorectal ultrasound, magnetic resonance imaging, computed tomography scan, rectoscopy, digital rectal examination). The highest stage was taken into consideration.
Compliance and Early Toxicities
Full-dose radiotherapy was given in 100% of patients in the Cap 45 group and in 87% of patients in Capox 50 group; in the latter group, only six patients received a dose of lower than 44 Gy. A definitive discontinuation of chemotherapy was observed in 2.8% of patients in the Cap 45 group and 8.8% of patients in the Capox 50 group. Dose modification of the chemotherapy regimen was performed in 50% of the Cap 45 group and 59% of patients in the Capox 50 group.
The overall rate of grade 3 to 4 toxicity was 10.9% with radiotherapy (45 Gy) plus capecitabine versus 25.4% with radiotherapy (50 Gy) plus capecitabine plus oxaliplatin (P < .001); this increase in grade 3 to 4 toxicity was mainly related to an increase in diarrhea (3.2 v 12.6%). Common early adverse events are presented in Table 2.
| Toxicity by Grade | Radiotherapy Plus Capecitabine (n = 293) | Radiotherapy Plus Capecitabine Plus Oxaliplatin (n = 291) | P | ||
|---|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | ||
| 3/4 | |||||
| All toxicity | 32 | 10.9 | 74 | 25.4 | < .001 |
| Diarrhea | 9 | 3.2 | 36 | 12.6 | < .001 |
| Hematologic | 11 | 3.7 | 14 | 4.8 | .53 |
| 3 | |||||
| Fatigue | 2 | 0.8 | 13 | 5.1 | .004 |
| Radiation dermatitis | 1 | 0.4 | 3 | 1.4 | .25 |
| Peripheral neuropathy | 0 | 2 | 0.8 | .18 | |
| 2 | |||||
| Peripheral neuropathy | 1 | 0.4 | 13 | 5.1 | .002 |
| Hand-foot syndrome | 2 | 0.8 | 0 | .50 | |
Surgery was performed after a median interval of 42 days in both groups, and 98.0% of patients (n = 287) in the Cap 45 group and 98.6% (n = 287) in the Capox 50 group underwent surgery.
Surgical Procedures and Toxicities
Ten patients did not undergo surgery (refusal, n = 6; complete clinical response and decision of follow-up, n = 2; clinical deterioration, n = 2). Of 574 patients who underwent surgery, three underwent laparotomy only and six underwent transanal local excision. In the remaining 565 patients, abdominoperineal resection or Hartmann procedures were performed in 71 (24.8%) and 65 patients (22.8%) in the Cap 45 group and Capox 50 group, respectively. At the end of the hospital stay, there was no difference in patients with permanent stomas (25.4 and 24.6%, respectively). The overall rates of surgical or medical complications were not significantly different between groups (Table 3). There was no difference in postoperative deaths at 60 deaths after surgery (0.3% in both groups). During surgery, distant metastases in the pelvis or abdomen were found in 4.2% of patients in the Cap 45 group and 2.8% in the Capox 50 group.
| Variable | Radiotherapy Plus Capecitabine | Radiotherapy Plus Capecitabine Plus Oxaliplatin | P | ||
|---|---|---|---|---|---|
| No. | % | No. | % | ||
| Eligible patients | 293 | 291 | |||
| Surgery performed | 287 | 98.0 | 287 | 98.6 | |
| Laparotomy only | 1 | 0.3 | 2 | 0.7 | |
| Type of surgery | |||||
| Abdominoperineal resection | 67 | 23.4 | 61 | 21.4 | |
| Hartmann | 4 | 1.4 | 4 | 1.4 | |
| Anterior resection | 195 | 67.9 | 205 | 71.9 | |
| Intersphincter resection | 17 | 5.9 | 13 | 4.6 | |
| Transanal local excision | 4 | 1.0 | 2 | 0.7 | |
| Gross incomplete R2* | 3 | 1.1 | 4 | 1.4 | |
| Permanent stoma after surgical procedure | 73 | 25.4 | 70 | 24.6 | .8 |
| Blood loss, ml | 200 | 200 | |||
| Range | 0-3,500 | 0-3,500 | |||
| Metastasis found at surgery | |||||
| Abdomino-pelvic | 12 | 4.2 | 8 | 2.8 | .4 |
| Liver | 10 | 3.5 | 6 | 2.1 | .3 |
| Second surgery for toxicity | 37 | 12.9 | 36 | 12.5 | .9 |
| Toxicity type | |||||
| Hemorrhage | 3 | 8.1 | 6 | 16.7 | |
| Pelvic infection | 11 | 29.7 | 14 | 38.9 | |
| Anastomotic fistula | 7 | 18.9 | 6 | 16.7 | |
| Occlusion | 6 | 16.2 | 4 | 11.1 | |
| Urinary | 1 | 2.7 | 0 | 0 | |
| Other | 9 | 24.3 | 6 | 16.7 | |
| Medical postoperative toxicity | 59 | 20.9 | 52 | 18.1 | |
| Toxicity type | |||||
| Infection | 11 | 18.6 | 16 | 30.8 | |
| Urinary | 15 | 25.4 | 12 | 23.1 | |
| Occlusion | 5 | 8.5 | 6 | 11.5 | |
| Pulmonary | 8 | 13.6 | 2 | 3.9 | |
| Anastomotic fistula | 5 | 8.5 | 4 | 7.7 | |
| Cardiovascular | 3 | 5.1 | 5 | 9.6 | |
| Hemorrhage | 4 | 6.8 | 2 | 3.9 | |
| Thrombophlebitis | 1 | 1.7 | 1 | 1.7 | |
| Myocardial infarction | 0 | 0 | 0 | 0 | |
| Other | 7 | 11.9 | 4 | 7.7 | |
| Median hospital stay, days | 15 | 15 | |||
| Death within 60 days | 1 | 0.3 | 1 | 0.3 | |
*
Without patients with no surgery or with laparotomy only.
Pathologic Characteristics
Details of the pathologic findings are presented in Table 4. The ypCR rate in 565 of 584 eligible patients who underwent total mesorectal excision was 13.9% in the Cap 45 group and 19.2% in Capox 50 group (P = .09). When a score of 3 (ypCR) and 2 (very few residual cancer cells) were grouped together, the pathologic tumor response rates were 28.9% and 39.4% in the Cap 45 and Capox 50 groups, respectively (P = .008). A trend toward a reduction in the rate of ypT4 was found in favor of the Capox 50 group (4.2% v 1.8%; P = .087). No significant difference was observed in the rate of ypN1-2 stage.
| Variable | Radiotherapy Plus Capecitabine | Radiotherapy Plus Capecitabine Plus Oxaliplatin | P | ||
|---|---|---|---|---|---|
| No. | % | No. | % | ||
| Operative TME specimen | 282 | 283 | |||
| Gross incomplete R2 resection | 3 | 1.1 | 4 | 1.4 | |
| Median gross tumor diameter, mm | 25 | 25 | |||
| Range | 0-190 | 0-100 | |||
| Missing data | 11 | 19 | |||
| Pathologic stage | |||||
| yp T0 | 40 | 14.2 | 55 | 19.6 | |
| yp Tis | 2 | 0.7 | 3 | 1.1 | |
| yp T1 | 16 | 5.7 | 11 | 3.9 | .088* |
| yp T2 | 93 | 33.0 | 75 | 26.7 | |
| yp T3 | 119 | 42.2 | 132 | 47.0 | |
| yp T4 | 12 | 4.3 | 5 | 1.8 | |
| Missing data | 0 | 2 | |||
| Median no. of sampled lymph nodes | 12 | 12 | |||
| Range | 1-45 | 1-40 | |||
| Pathologic stage | |||||
| yp N0 | 196 | 69.5 | 201 | 71.5 | |
| yp N1 | 65 | 23.0 | 54 | 19.2 | .59* |
| yp N2 | 21 | 7.5 | 26 | 9.3 | |
| Missing data | 0 | 2 | |||
| Inferior mesenteric positive nodes | 1 | 0.3 | 3 | 1.1 | |
| Missing data | 1 | 5 | |||
| Circumferential rectal margin | |||||
| R0 | 131 | 87.3 | 131 | 92.3 | |
| R1 (≤ 1 mm) | 19 | 12.7 | 11 | 7.7 | .17 |
| Missing data | 115 | 128 | |||
| Circumferential rectal margin | |||||
| R− | 121 | 80.7 | 128 | 90.1 | |
| R+ (≤ 2 mm) | 29 | 19.3 | 14 | 9.9 | .022 |
| Missing data | 115 | 128 | |||
| Dworak score (ITT analysis) | |||||
| 0 = no response | 57 | 19.9 | 46 | 16.0 | |
| 1 = partial response | 138 | 48.1 | 117 | 40.8 | |
| 2 = major response | 43 | 15.0 | 58 | 20.2 | |
| 3 = complete response | 40 | 13.9 | 55 | 19.2 | .09* |
| 95% CI | 10.1 to 18.5 | 14.8 to 24.2 | |||
| Undetermined | 9 | 3.1 | 11 | 3.8 | |
| Dworak score | |||||
| Undetermined/0/1 | 204 | 71.1 | 174 | 60.6 | |
| 2/3 | 83 | 28.9 | 113 | 39.4 | .008 |
Abbreviations: TME, total mesorectal excision; ITT, intention to treat.
*
P value from test ypT0 v ypT1-4, is/ypN0 v ypN1-2/Dworak 0, 1, 2 v 3.
The circumferential rectal margin was measured in 292 patients and classified as R1 (≤ 1 mm) in 19 patients in the Cap 45 group (12.7%) and 11 patients in the Capox 50 group (7.7%; P = .17). When, in an exploratory analysis, the distance between the outerpart of the tumor (or any metastatic nodules) and the inked circumferential rectal margin was taken between 0 and 2 mm, there were 29 patients with a positive circumferential rectal margin in the Cap 45 group (19.3%) and 14 in the Capox 50 group (9.9%; P = .022). In a subgroup analysis, a ypCR of 47% was observed in the Capox 50 group in T2, 18% in T3, and 13% in T4. In this group when the full dose of 50 Gy was delivered (278 patients), a 20.2% ypCR was observed. In the Cap 45 group ypCR rate was 33% in T2, 13% in T3, and 7% in T4.
Discussion
The aim of the ACCORD 12/0405 Prodige 2 trial was to improve the efficacy of the preoperative chemoradiotherapy regimen of the FFCD 9203 trial.4 It was designed to achieve two specific goals. First, to get a rapid answer to the hypothesis of the trial. It took 14 years from the start of FFCD 9203 (1992) to publication of the final results (2006). This was the reason for the choice of ypCR as the primary end point of this trial. The second goal was to design a regimen which we thought would provide a positive result with acceptable toxicity. This was why the FFCD 9203 regimen was modified in two ways: increased radiation dose9 and addition of oxaliplatin.6,7
The data presented here indicate that radiotherapy (50 Gy) plus capecitabine plus oxaliplatin has a positive effect on the rate of complete or near-complete sterilization of the operative specimen and on tumor-free circumferential rectal margin. It was also associated with a significant increase of early grade 3 to 4 toxicity (25.4%), but did not compromise surgical resectability or result in more surgical complications. The rate of postoperative deaths within 60 days was very low (0.3%). There was no improvement in conservative surgery rate (75%).
This study has obvious limitations. As the follow-up is short, no data regarding important clinical end points, such as rate of local recurrence, survival, and late toxicity are available. Analysis of these end points will be provided in the near future. The study is underpowered to reach statistical significance for the main end point, probably because the hypothesis of 11% ypCR in the control group was too low. In the FFCD 9203 trial,4 the ypCR during 1999 to 2003 period reached 13%. Further, the experimental regimen included two modifications relative to the control group, which complicated interpretation of the results. The main end point (ypCR) is not fully accepted as a surrogate end point.15 In contrast, this trial is representative of the daily practice management of rectal cancer in France as it was performed within 56 distinct institutions within a short period of time, thus preventing stage migration bias.
This trial is the first large phase III trial to report a ypCR of almost 20% in T(2)T3-4 rectal cancer. In other recent neoadjuvant phase III randomized trials, ypCR have varied between 11% to 16%.3,4,5,16 The prognostic importance of circumferential rectal margin R0 (> 1 mm) for local recurrence and survival is well established.1,2,12,17 The radiotherapy 50 Gy plus capecitabine plus oxaliplatin regimen achieved a circumferential rectal margin R0 rate of 92% which is one of the highest reported in randomized trials. Notably, when a negative circumferential rectal margin is defined as no visible tumor cells between 0 to 2 mm (and not 1 mm) from the stained external limit of the operative specimen,12 the Capox 50 regimen provided a significant increase in negative circumferential rectal margin (90% v 81% in the control group). It is possible that these results could translate, in the coming years, into benefits in terms of pelvic local control. According to the results of the Dutch trial,12 a 2-mm margin is the limit which fits best with the risk of local recurrence and is more predictive of local recurrence than ypCR.
The explanation for these trends toward increased pathologic tumor response and negative circumferential rectal margin with radiotherapy 50 Gy plus capecitabine plus oxaliplatin is questionable as this experimental Capox 50 regimen included modifications to both the radiotherapy dose and the chemotherapy regimen at the same time. Nevertheless, the recent Studio Terapia Adiuvante Retto (STAR) trial16 included 747 patients with T3-4 M0 rectal tumors and similar selection criteria to the ACCORD 12/0405 Prodige 2 trial. It compared neoadjuvant radiotherapy 50.4 Gy (1.8 Gy per fraction) with concurrent continuous infusion fluorouracil with the same regimen plus the addition of weekly oxaliplatin (60 mg/m2). This trial showed the same significant increase in grade 3 to 4 early toxicities with oxaliplatin (24%) as ACCORD 12/0405 Prodige 2, but no difference in the rate of ypCR (16%). These findings suggest that in ACCORD 12/0405 Prodige 2 the early toxicity may be mainly attributable to oxaliplatin, and the improved efficacy outcomes to radiotherapy dose intensification. Two other randomized trials also favor the influence of radiotherapy dose on ypCR.18,19 The ACCORD 12/0405 Prodige 2 and STAR trials also suggest that oxaliplatin does not appear to be a good radiosensitizer in rectal adenocarcinoma and should not be used with concurrent irradiation. This negative result is in agreement with a recent animal experiment where a human colorectal (HT29) xenograft in nude mice was treated with a combination of radiotherapy, oxaliplatin, and capecitabine. The addition of oxaliplatin to radiotherapy and capecitabine did not increase the tumor response rate.20 From the ACCORD 12/0405 Prodige 2 and STAR trials, it can also be reasonably assumed that, in the neoadjuvant setting, fluorouracil and capecitabine have equivalent effects.8
Is it possible to design an optimum neoadjuvant chemoradiotherapy regimen taking into consideration the STAR and ACCORD 12/0405 Prodige 2 trials? Radiation dose intensification improves the tumor response safely. Oxaliplatin does not add any benefit in terms of primary tumor response and it increases diarrhea. Oxaliplatin may be efficient to reduce intrabdominal metastasis as observed in the STAR and ACCORD 12/0405 Prodige 2 trials. Oxaliplatin as in colon cancer could be useful to decrease distant metastases which remain a major problem of rectal cancer.16 The equivalence of capecitabine and continuous intravenous infusions of fluorouracil now seems to be well accepted.8,21 It would appear reasonable to propose the following neoadjuvant regimen: external-beam radiotherapy into limited posterior pelvic volume (< 2 L) and shrinking field after 44 Gy, with a total dose of 50 Gy in 25 fractions (2 Gy per fraction) over 5 weeks. Capecitabine should be given concomitantly at a dose of 800 mg/m2 twice daily every radiation day. This protocol, Cap 50, differs slightly from the frequently used 50.4 Gy in 28 fractions over 38 days (5.5 weeks), which uses a longer overall treatment time with a lower biologically equivalent dose of 48 Gy.10 The differences between these two protocols are modest, but it can be expected that Cap 50 provides more cancer cells killing (higher biologically equivalent dose) and better convenience for the patient (three sessions fewer). Such a Cap 50 protocol could be appropriate for T3-4 M0 tumors. The need for chemoradiotherapy in early T3 disease remains controversial. It has been proposed that total mesorectal excision alone or short-course radiotherapy (5 × 5 Gy) could be used in these patients,1,2,17 although there is no reliable examination to individualize such early cT3 N0.22
In summary, oxaliplatin did not demonstrate benefit for the sterilization of the operative specimen but increased early toxicity. Dose-intensified radiotherapy improved pathologic response. High-dose radiotherapy (50 Gy/25 fractions) plus capecitabine (Cap 50) merits investigation for T3-4 rectal cancers.
Acknowledgment
We thank Lee Miller for reviewing the English writing and Yannick Lautrette for secretarial assistance; the teams of nurses and pharmacists; ARC of institutions, ARC of sponsor (FNCLCC) and of FFCD; and data management and the project team of FNCLCC, all of which were actively participating at each level in the achievement of this work.
See accompanying editorial on page 1623
Clinical trial information can be found for the following: CT# NCT00227747.
Authors' Disclosures of Potential Conflicts of Interest
The author(s) indicated no potential conflicts of interest.
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Appendix
The following institutions participated in the ACCORD 12/0405-Prodige 2 trial.
Investigators principal investigators who participated in the study.
Dr Aparicio, Centre hospitalier–Bichat; Dr Auby, Centre Hospitalier R. Boulin, Libourne; Dr Azzedine, Centre Hospitalier, Avignon; Pr Bécouarn, Institut Bergonié, Bordeaux; Dr Berdah, Clinique Ste Marguerite, Hyères; Dr Boige, Institut Gustave Roussy, Villejuif; Dr Bonnichon-Lamichane, Clinique Tivoli, Bordeaux; Pr Bouché, Centre Hospitalier R. Debré, Reims; Dr Charneau, Centre hospitalier, Boulogne sur Mer; Dr Clippe, Centre hospitalier, Valence; Pr Conroy, Centre Alexis Vautrin, Nancy; Dr Cvitkovic, Centre René Huguenin, St Cloud; Dr Debrigode, Centre Hospitalier Carémeau, Nimes; Dr Denis, Hôpital Pasteur, Colmar; Dr Dupuis, Clinique Victor Hugo, Le Mans; Dr Galais, Centre François Baclesse, Caen; Dr Gargot, Centre hospitalier, Blois; Dr Gasmi, Hôpital Nord, Marseille; Dr Guichard, Polyclinique Nord Aquitaine, Bordeaux; Dr Guichard, Polyclinique des 4 pavillons, Lormont; Dr Jouve, Centre Hospitalier Universitaire Le Bocage, Dijon; Dr Klein, Centre d'Oncologie St Yves, Vannes; Pr Lagrange, Hôpital Henri Mondor, Créteil; Dr Leloup, Centre Hospitalier “La Source,” Orléans; Dr Lledo, Clinique St Jean, Lyon; Pr Mahé, Centre René Gauducheau, Nantes-St Herblain; Dr Martin, Centre Bourgogne, Lille; Pr Michel, Centre hospitalier Ch. Nicolle, Rouen; Dr Mirabel, Centre Oscar Lambret, Lille; Dr Monnier, Centre Hospitalier A. Boulloche, Montbélliard; Dr Moraillon, Clinique Générale, Valence; Dr Moureau-Zabotto, Institut Paoli-Calmettes, Marseille; Dr Nguyen, Centre Hospitalier, Beauvais; Pr Nguyen, Institut Jean Godinot, Reims; Dr Noirclerc, Centre Hospitalier, Mulhouse; Dr Ollier, Centre Paul Strauss, Strasbourg; Dr Papadopoulou, Centre Hospitalier, Annecy; Pr Pezet, Centre Hospitalier Universitaire Hôtel Dieu, Clermont-Ferrand; Dr Platini, Hôpital Bon Secours, Metz; Dr Rives, Institut Claudius Regaud, Toulouse; Dr Rocher, Clinique Ste Marie, Châlon sur Saône; Paris; Dr Romestaing, Centre Hospitalier Lyon Sud, Pierre-Bénite, Pr Seitz, Centre hospitalier La Timone, Marseille; Dr Stremsdoerfer, Hôpital Pierre Oudot, Bourgoin Jallieu; Dr Simon, Centre hospitalier La Pitié Salpétrière, Paris; Dr Vié, Centre Maurice Tubiana, Caen; Dr Zawadi, Centre Hospitalier Les Oudairies, La Roche Sur Yon, France.
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© 2010 by American Society of Clinical Oncology.
History
Published online: March 01, 2010
Published in print: April 01, 2010
Authors
Author Contributions
Conception and design: Jean-Pierre Gérard, Sophie Gourgou-Bourgade
Administrative support: Christine Montoto-Grillot
Provision of study materials or patients: Jean-Pierre Gérard, David Azria, Isabelle Martel-Laffay, Christophe Hennequin, Pierre-Luc Etienne, Véronique Vendrely, Eric François, Guy de La Roche, Olivier Bouché, Xavier Mirabel, Bernard Denis, Laurent Mineur, Jean-François Berdah, Marc Andre Mahé, Yves Bécouarn, Olivier Dupuis, Gérard Lledo, Thierry Conroy
Collection and assembly of data: Sophie Gourgou-Bourgade, Christine Montoto-Grillot
Data analysis and interpretation: Jean-Pierre Gérard, Sophie Gourgou-Bourgade
Manuscript writing: Jean-Pierre Gérard, Sophie Gourgou-Bourgade, Thierry Conroy
Final approval of manuscript: Jean-Pierre Gérard
Disclosures
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Funding Information
Supported in part by Roche and Sanofi-Aventis together with a grant of the French National Program of Research Programmes hospitaliers de recherche clinique. The trial was conducted under the auspices of Institut National du Cancer.
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Comparison of Two Neoadjuvant Chemoradiotherapy Regimens for Locally Advanced Rectal Cancer: Results of the Phase III Trial ACCORD 12/0405-Prodige 2. JCO 28, 1638-1644(2010).
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Journal of Clinical Oncology 2010 28:10, 1638-1644
Journal of Clinical Oncology 2010 28:10, 1638-1644
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