Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer

Incomplete

Sauer et al.. "Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer". New England Journal of Medicine. 2004. 351(17):1731–1740.
PubMed • Full text • PDF

Clinical Question

Among patients with locally advanced resectable rectal cancer (T3/4, any N), does preoperative chemoradiotherapy improve overall survival or disease recurrence compared to postoperative chemoradiotherapy?

Bottom Line

In patients with locally advanced rectal cancer, preoperative chemoradiotherapy significantly reduced the 5-year local recurrence rate compared to postoperative chemoradiotherapy (6% vs. 13%), and was associated with reduced treatment toxicity. There was no difference in 5-year overall or disease-free survival.

Major Points

The German Rectal Cancer Trial (CAO/ARO/AIO-94) was the first randomized phase III trial to compare long-course preoperative vs. postoperative chemoradiotherapy in patients with resectable, locally advanced rectal cancer (T3/4, any N). It found that preoperative chemoradiotherapy significantly reduced the 5-year cumulative incidence of local recurrence from 13% in the post-operative treatment group to 6%. In long-term follow-up, this benefit persisted, with the 10-year local recurrence rate remaining lower in the preoperative group (7% vs. 10%) . Additionally, the trial demonstrated neoadjuvant chemoradiotherapy was better tolerated (reduced acute and long term toxicity) and improved patient adherence to the treatment regimen. These results were later mirrored in short-course trials and helped establish preoperative chemoradiotherapy as a foundational component of total neoadjuvant therapy (TNT) for rectal cancer.

Guidelines

• American Society for Radiation Oncology (ASTRO) 2024 Rectal cancer guidelines: The German rectal cancer trial establishes the use of 28 cycles of 5040 cGy reduces local recurrence and toxicity
  • https://www.practicalradonc.org/action/showPdf?pii=S1879-8500%2824%2900304-7

• National Comprehensive Care Network (NCCN) v2.2025

Design

• Trial Type: Randomized, multicenter, open-label, phase III trial
• N: 823 patients randomized
  • Experimental Arm (N = 405) Preoperative chemoradiotherapy
  • Standard Arm (N = 394): Postoperative chemoradiotherapy
• Setting: 26 academic or regional centers with experience in rectal cancer surgery in Germany and Austria
• Enrollment: February 1995 – September 2002
• Mean Follow-up: Median 46 months (range 3–102)
• Analysis: Intention-to-treat
  • Per-treatment analysis for toxicity
• Primary Outcome: Overall survival
• Secondary Outcomes:
  • Cumulative incidence of local recurrence
  • Disease-free survival
  • Grade 3–4 acute and long-term toxicity
  • Sphincter preservation in patients initially deemed to require abdominoperineal resection

Population

Inclusion Criteria

• Age ≥ 18 years
• Histologically confirmed adenocarcinoma of the rectum
  • Tumor located ≤16 cm from the anal verge by rigid proctoscopy
• Clinical stage T3 or T4 and/or node-positive disease
  • Determined by endorectal ultrasound or CT scan
• No evidence of distant metastasis (M0)
• Medically fit for both chemoradiotherapy and surgery

Exclusion Criteria

• Age >75 years
• Prior cancer other than nonmelanoma skin cancer
• Prior chemotherapy
• Prior radiotherapy to the pelvis
• Distant metastases (M1 disease)
• Contraindications to chemoradiotherapy

Baseline Characteristics

"Preoperative Radiation Cohort "

• Age
  • Median: 62 years (30–76)
• Sex
  • Male: 286 (71%)
  • Female: 119 (29%)
• Clinical tumor category
  • T1/T2: 19 (5%)
  • T3: 277 (68%)
  • T4: 23 (6%)
  • Unknown: 86 (21%)
• Nodal category
  • Node-negative: 168 (41%)
  • Node-positive: 217 (54%)
  • Unknown: 20 (5%)
• Distance of tumor from anal verge
  • <5 cm: 157 (39%)
  • 5–10 cm: 166 (41%)
  • >10 cm: 47 (12%)
  • Unknown: 35 (9%)

Interventions

• Preoperative Chemoradiotherapy Arm
  • Chemoradiotherapy: 50.4 Gy in 28 fractions, 5 days per week + 5-fluorouracil (5-FU) 1000 mg/m²/day by continuous infusion during weeks 1 and 4
  • Total mesorectal excision: 6 weeks after completion of chemoradiotherapy

• Postoperative Chemoradiotherapy Arm
  • Upfront total mesorectal excision
  • Postoperative chemoradiotherapy: 50.4 Gy in 28 fractions, 5 days per week + 5-FU 1000 mg/m²/day by continuous infusion during weeks 1 and 4, starting 4 weeks postoperatively

• Both groups received postoperative chemotherapy: Four cycles of 5-FU

Outcomes

"Comparisons are preoperative chemoradiotherapy vs. postoperative chemoradiotherapy"

Primary Outcome

Overall survival at 5 years

76% vs. 74% (HR 0.96; 95% CI 0.70–1.31; P = 0.80)

Secondary Outcomes

Local recurrence at 5 years

6% vs. 13% (HR 0.46; 95% CI 0.26–0.82; P = 0.006)

Disease-free survival at 5 years

68% vs. 65% (HR 0.87; 95% CI 0.67–1.14; P = 0.32)

Distant Recurrence

36% vs. 38% (RR 0.97; 95% CI 0.73–1.28; P = 0.84)

Grade 3–4 acute toxicity

27% vs. 40% (P = 0.001)

Grade 3–4 long-term toxicity

14% vs. 24% (P = 0.01)

Subgroup Analysis

• N=194 patients determined to require APR pre-randomization

Sphincter preservation

(45/116) 39% vs. (15/78) 19% (P = 0.004)

Adverse Events

• 8 patients (4 per group) experienced in hospital mortality (1%)

Criticisms

• This trial did not include the addition of oxaliplatin to 5-FU, which is more common in modern regimens
• 5-FU was delivered by continuous infusion rather than oral capecitabine, which is more common today.
• Staging was not performed with MRI, which may have better stratified pre-treatment stage
• Sphincter preservation was based on subgroup analysis and based on surgeon judgement without MRI technology, which may limit applicability to modern practice.

Funding

• Supported by the German Cancer Society (Deutsche Krebshilfe)

Further Reading

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