Preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and Oxaliplatin versus 5-fluorouracil alone in locally advanced rectal cancer: First results of the German CAO/ARO/AIO-04 randomized phase III trial

Reporter: J. Nicholas Lukens, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2011

Presenter: Claus Roedel, MD
Presenter's Institution: German Rectal Cancer Study Group; University of Frankfurt, Frankfurt, Germany


  • The first German Rectal Cancer Study (CAO/ARO/AIO-04) established pre-operative chemoradiotherapy with infusional 5-FU given during the first and fifth weeks of RT (50.4 Gy), followed by TME and an additional 4 months of adjuvant 5-FU bolus chemotherapy, as the standard of care for locally advanced rectal cancer.
  • Benefits to preoperative vs adjuvant therapy in the German trial included higher rates of sphincter-sparing procedures, decreased acute and long term toxicity, and improved local control rates.
    • The 5-year cumulative incidence of local recurrence was 6% in the pre-operative arm.
  • However, there was no benefit in terms of overall survival with neoadjuvant vs adjuvant therapy, and this was presumed to be due to the fact that distant metastases were not adequately addressed with this regimen.
    • The cumulative incidence of distant recurrence in this study was 36% at 5 years.
  • Therefore, there was impetus to add additional agents to improve systemic control for locally advanced rectal cancer.
  • There were 2 previous studies evaluating the addition of Oxaliplatin to 5-FU in the neo-adjuvant setting: STAR-01 and ACCORD trials. Both demonstrated no significant improvement in the pathologic complete response rates, as well as increased toxicity with Oxaliplatin, and therefore poor compliance with pre-op Oxaliplatin regimens.
  • Previous Phase I and II trials had been conducted by these authors evaluating Oxaliplatin in combination with capecitabine, both during neo-adjuvant concurrent chemoradiation (CRT), and to post-operative capecitabine following TME.
    • In these studies, to help manage the acute toxicity during CRT and improve compliance, a chemotherapy gap during the 3rd week of radiation was implemented.
  • The study presented here set out to evaluate the tolerability and efficacy of the addition of Oxaliplatin to 5-FU in the neo-adjuvant treatment of locally advanced rectal cancer, by comparing the best arm of the first German Rectal Cancer Study to an arm that incorporated Oxaliplatin during pre-operative chemoRT and post-operative adjuvant 5-FU.


  • Patients with T3/4 or Node+ rectal cancer within 12 cm of the anal verge were eligible, and randomized 1:1 to:
    • The best arm of the German Rectal Cancer Study: Neo-adjuvant CRT consisting of infusional 5-FU (1 g/m2) during weeks 1 and 5 of RT to 50.4 Gy -> TME -> 4 cycles of adjuvant bolus 5-FU (500 mg/m2), or
    • RT to 50.4 Gy + infusional 5-FU (250 mg/m2) days 1-14 and 22-35 + weekly Oxaliplatin 50 mg/m2 during weeks 1,2, 4 and 5 -> TME -> modified FOLFOX regimen (4 months).
      • Note chemotherapy gap was imposed during the 3rd week of radiation in the experimental arm.
  • Patients were clinically staged with EUS + CT, and MRI was encouraged but not mandatory.
  • Primary endpoint: Disease free survival
    • Powered to detect a 7% difference in 3-year DFS, requiring 1200 patients.
  • Secondary endpoints: Toxicity and compliance, R0 resection rate, and pCR rate
  • In this presentation early secondary endpoints were presented, including acute toxicity, treatment compliance, and pathologic clinical response (pCR) rates.


  • 1265 patients were randomized, and 1237 were eligible.
  • Compliance was excellent in both arms: 99% in each arm underwent CRT, 97% underwent planned surgery, and 74% started planned adjuvant chemotherapy.
  • The groups were well-balanced. Over 90% in each arm were T3/4, and over 70% in each arm were clinically node positive.
  • Toxicity: overall Grade 3/4 toxicity rates were similar between the groups (22% for 5-FU and 23% for 5-FU/Oxaliplatin), with slightly more Grade 3/4 diarrhea in the Oxaliplatin arm (12% vs 8%).
    • Full dose RT was delivered in 94% of patients, and full dose chemoradiotherapy was delivered in 85% of patients in the Oxaliplatin arm.
  • Rates of sphincter preserving surgery were equivalent between the 2 arms (70%), with APR required in 25% of patients in each group. Post-operative complications were low in both groups.
  • This study employed strict quality assurance to ensure adequate surgery, including:
    • Pathologic confirmation of mesorectal plane in 74% of patients.
    • The majority of patients in each arm had R0 resections (92% for control, 90% for Oxaliplatin).
    • The median number of lymph nodes examined in each group was 15.
  • In terms of pathologic response rates, there was a slight increase in the proportion of ypT0 specimens in the Oxaliplatin arm, 18% versus 13% in the control arm.
  • There was no difference in terms of lymph node positivity in the resected specimens (ypN0 67% in each group)
  • Pathologic complete response rate slightly favored the Oxaliplatin arm: 16.5% vs 12.8% (p = 0.045)
  • Additional follow-up is needed to report disease free survival.

Authors' conclusions

  • This regimen of pre-operative chemoradiation with Oxaliplatin in addition to 5-FU was well-tolerated, with high compliance rates, and an observed improvement in pathologic complete response rates.
    • The authors stress that their regimen included a chemotherapy gap during the 3rd week of radiation to help reduce acute toxicity and thereby improve compliance.
  • The study had strict pathologic quality control with high rates of mesorectal plane (74%) and a median 15 lymph nodes removed.
  • The authors emphasize that their study, unlike the STAR-01 and ACCORD trials, incorporates Oxaliplatin both in the pre-operative and post-operative setting, which may be necessary to improve disease free survival, although additional follow-up is needed to determine DFS from this trial.

Clinical/Scientific Implications

  • This is a well-designed study that addresses an important question in the management of patients with locally advanced rectal cancer, a subset of patients in whom local control rates are excellent but distant recurrence remains a problem.
  • This study has several advantages including excellent pathologic quality control, which may help to further reduce the incidence of local failure in these patients.
  • The 2 previous studies evaluating the addition of Oxaliplatin to 5-FU in the neo-adjuvant setting, the STAR-01 and ACCORD trials, failed to demonstrate an improvement in pCR rates, and also demonstrated increased toxicity that compromised compliance.
    • Differences within the current trial that may explain the improved compliance rates include the lower cumulative pre-operative dose of Oxaliplatin, and the chemotherapy break during the 3rd week of radiation.
  • The improved compliance rates may have translated into the improved pCR rates observed in this trial.
  • However, whether pCR rates can be used as a surrogate endpoint remains a matter of debate.
  • Additional follow-up will reveal whether the addition of Oxaliplatin to 5-FU in the neo-adjuvant and adjuvant treatment of locally advanced rectal cancer leads to improved long-term survival, and will be of utmost importance in evaluation of the future role of Oxaliplatin in treatment of rectal cancer.