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Adjuvant versus Neoadjuvant Combined Modality Treatment for Locally Advanced Rectal Cancer: First Results of the German Rectal Cancer Study (CAO/ARO/AIO-94)
Reviewer: Roberto Santiago, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 20 de octubre del 2003
Presenter: Rolf Sauer, M.D.
Presenter's Affiliation: German Rectal Cancer Group
Type of Session: Plenary
The addition of adjuvant chemoradiotherapy (CRT) to the surgical resection of stage II-III rectal cancers has been proven to improve the local control and survival of patients when compared to surgery alone. Building on these results and those of the Swedish trial (which demonstrated a survival advantage to preoperative radiotherapy when compared with surgery alone), neoadjuvant chemoradiotherapy has been investigated with encouraging results. This phase III randomized clinical trial (CAO/ARO/AIO-94) compares the efficacy of neoadjuvant CRT to standard postoperative CRT.
Materials and Methods
- Patients with rectal cancer determined to have resectable T3-T4 tumors and/or involved lymph nodes by endorectal ultrasound were randomly assigned to pre or postoperative CRT.
- Radiotherapy consisted of 50.4 Gy (28 fractions of 1.8 Gy) to the tumor and the pelvic lymph nodes in both arms.
Chemotherapy consisted of a 120 hour continuous infusion of 5-FU (1000 mg/m2/d) during the first and 5th week of radiotherapy as well as four additional cycles of adjuvant bolus 5- FU (500 mg/m2/d).
- The time interval between CRT and surgery was 4-6 weeks in both arms.
Surgery in this trial was standardized and included total mesorectal excision.
- Stratification was done according to each individual surgeon.
Primary endpoints of the study were 5-year survival, local and distant control.
- Secondary endpoints included the rate of curative (R0) resections, sphincter saving procedures, toxicity of CRT, and surgical complications.
- Pretreatment patient and tumor characteristics were equally distributed in both arms. Median follow-up was 43 months.
- 805 patients were randomized from 26 institutions.
- 24 were excluded from analyses for various reasons and analyses were based on intention to treat.
- 5-year local recurrence rate was 12% vs. 6% (p = 0.02) favoring the preoperative treatment.
- There were no significant differences in the 5-year distant relapse (39% vs. 35%, p = 0.52), disease-free (55% vs. 59%, p = 0.23) and overall-survival (73% and 78%, p = 0.38) rates.
- The incidence of acute grade 3/4 toxicity was ~30% in each arm.
However, there was significantly less chronic anastomotic stenosis following preop CRT vs. postop CRT (2.7% vs. 8.5%, p = 0.001).
- Postop morbidity was not increased after preop CRT
- The principal toxicity in both arms was diarrhea.
- Preop CRT resulted in significant tumor downstaging with a 8% pCR rate.
In the subgroup of 188 patients with low-lying tumors who were declared by the surgeon prior to randomization to require an abdominoperineal resection, 19% (16/83) underwent a sphincter preserving procedure in the postop CRT arm vs. 39% (41/105) in the preop CRT arm (p = 0.004).
- Compared with postop CRT, preop CRT significantly improved local control.
Also, preop CRT was associated with a two-fold increase in the rate of sphincter preservation for low lying tumors.
- Neoadjuvant CRT was well tolerated and did not result in a higher risk for postoperative morbidity. In fact, there was a trend to reduced acute toxicity and significantly less chronic toxicity at the anastomotic site.
- In contrast to trials of similar design in North America, this is the only trial to accrue patients successfully towards a comparison between neoadjuvant CRT and postoperative CRT.
- The use of a standard radiotherapy schedule, the standardization of surgery, and the stratification by surgeon give this trial global relevance.
- The findings of this trial, especially when considered together with the results of early studies of neoadjuvant CRT from MSKCC, strongly suggest that the preoperative approach should be considered as the standard of care for stage II-III distal rectal cancers.
- Although there may be some patients overtreated by this approach (because of clinical overestimation of their disease), this appears to be only a minority. This risk should decrease as our clinical staging tools continue to improve.
- Similar to the results from a European trial demonstrating a local control benefit with the addition of radiotherapy to total mesorectal excision, this approach appears to be favorable even when added to excellent surgery.
- Some questions that remain to be answer are:
- It has been shown that the number of lymph nodes involved predicts for local failure. Thus it would be interesting to know how the results of neoadjuvant CRT vary when patients are stratified by number of involved lymph nodes.
- How will the integration of newer chemotherapeutic agents like oxaliplatin impact the results of neoadjuvant CRT.
- Is there a subset of patients (perhaps those with proximal T3 tumors and no lymph node involvement) that do not need the addition of CRT or radiotherapy?
- Is neoadjuvant CRT employing hypofractionated radiotherapy feasible and as effective?
- Can molecular markers identify targets for the integration of biological therapies to neoadjuvant CRT? Will this result in less toxicity?
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