CAO / ARO / AIO 94

Präoperative Radiochemotherapie und postoperative Chemotherapie mit Fluorouracil und Oxaliplatin versus Fluorouracil allein bei local fortgeschrittenem Rektumkarzinom

prae OP

FU-Arm

50,4Gy RT

5-FU 1000mg/qm als Infusion d1—5, d29—33

FU+ Oxaliplatin - Arm

50,4Gy RT

5-FU 250mg/qm als Infusion d1—5, d29—33

Oxaliplatin 50mg/qm d1,8,22,29

TME

post OP

FU-Arm

5-FU 500 mg/qm als Bolus, d1—5, q29

FU+ Oxaliplatin - Arm

Oxaliplatin 100 mg/qm d1 d15

5-FU 2400 mg/qm als Infusion d1 d2 d15 d16

Leucovorin 400 mg/qm d1 d15

Ergebnisse

Kriterium	FU	FU+ Oxaliplatin	Statistik
pCR bei OP	13%	17%	p=0·04
distante Metastasen bei OP	6%	4%	p=0·04

Studie

multicentrische, offene, randomisierte Phase - III - Studie

Patienten

1265 Patienten 2006 - 2010

Tumor

lokal fortgeschritten
bis 12cm ab ano
T3 oder T4 oder N+

Teil von

Rektum - Karzinom: Studien

Rektum - Karzinom

Gastro - Intestinale Tumore

Quellen

1.) Rödel C, et al. on behalf of the German Rectal Cancer Study Group:
Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial.
The Lancet Oncology 13(2012):679-687

2.) Fokas E, et al.:
Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO/ARO/AIO-94 trial.
J Clin Oncol 2014;32:1554-1562

3.) Sauer R, Liersch T, Merkel S, et al.:
Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: Results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years.
J Clin Oncol 2012;30:1926-1933

Impressum Zuletzt geändert am 18.11.2015 20:36

Summary: In this update of the German Rectal Trial (CAO/ ARO/AIO-94), the surgical specimens of patients who un- derwent preoperative chemoradiation followed by radical surgery were analyzed to determine the tumor regression grade (TRG) and the relationship of the TRG to oncologic outcomes. Originally, 406 patients were randomly assigned to receive chemoradiation, of which 386 patients had TRG information available. Radiation consisted of 50.4 Gy at 1.8 Gy/fraction using a conventional 3-ﬁeld or 4-ﬁeld technique to the primary tumor, mesorectum, presacral nodes, and internal iliac nodes. The patients received concurrent continuous infusion 5- ﬂuorouracil (1000 mg/m 2 ) on days 1 to 5 and 29 to 33. Surgery was mandated to be a total mesorectal excision 4 to 6 weeks after the completion of chemoradiation. Pathologic response assessment was determined by the Dworak TRG scale: grade 0, no regression; grade 1, minor regression (dominant tumor mass with obvious ﬁbrosis in 25% of tumor mass); grade 2, moderate regression (dominant tumor mass with obvious ﬁbrosis in 26% to 50% of tumor mass); grade 3, good regression (dominant ﬁbrosis outgrowing tumor mass 50% tumor regression); and grade 4, total regression (no viable tumor cells; ﬁbrotic mass only). The investigators grouped specimens into the following categories: (1) complete regression (TRG 4); (2) intermediate regression (TRG 2 and 3); and (3) poor regression (TRG 0 and 1). Overall, the TRG rates observed were as follows: TRG 0, 8.3%; TRG 1, 15%; TRG 2, 13.7%; TRG 3, 52.6%; and TRG 4, 10.4%. No pretreatment clinical factors including clinical stage predicted for TRG, whereas ypN1-2 (P Z .001), ypT3-4 (P Z .03), and venous invasion (P Z .03) correlated with poorer response. The 10-year cu- mulative risks of local and distal recurrence were 6.8% and 30.2%, respectively. TRG did not correlate with the risk of local recurrence. However, TRG signiﬁcantly correlated with disease-free survival and distant recurrence. The cumulative rates of distant metastases were 10.5% for TRG 4, 29.3% for TRG 2-3, and 39.6% for TRG 0-1 (P Z .005). Disease-free sur- vival was 89.5% for TRG 4, 73.6% for TRG 2-3, and 63% for TRG 0-1. Factors associated with local recurrence were distance from the anal verge (P Z .036), clinical T stage (P Z .045), ypT stage (P < .001) and ypN stage (P < .001), margin status (P Z .006), and lymphatic invasion (P < .001). The authors found that ypT stage (P < .001), ypN stage (P < .001), venous invasion (P Z .002), and lymphatic inva- sion (P < .001) were signiﬁcantly associated with distant metastasis and disease-free survival. Margin status corre- lated with distant metastases (P Z .011) but not disease-free survival (P Z .079). Finally, on multivariate analysis, only ypN stage (P < .001) and lymphatic invasion (P Z .026) correlated with local recurrence, whereas only ypN stage and TRG correlated with both distant metastases (P < .001 and P Z .035, respectively) and disease-free survival (P < .001 and P Z .039, respectively). Comment: The German Rectal Trial was a landmark trial (8) that established the role of preoperative as opposed to postoperative chemoradiation for locally advanced rectal cancer, and it has remained the standard to which all sub- sequent trials are compared. An update to this trial showed a durable signiﬁcant improvement in local control after 11 years of follow-up (18). This additional publication serves the purpose of providing robust data on the value of chemoradiation-induced tumor downstaging and subse- quent oncologic outcomes (8). The 5-year results were published showing similar ﬁndings of the relationship be- tween TRG and disease-free survival (19). The value of tumor regression in predicting long-term survival is not ﬁrmly established. Many trials have reported preliminary results of com- plete pathologic response rates without outcome data, given the lack of follow-up (20-22), which for rectal cancer typically needs to be at least 4 to 5 years for a proper assessment of survival and recurrence. These updated data with a median of 11 years of follow-up further strengthen the case of pathologic response being a potential early surrogate for long-term outcome. The strengths of this analysis are that it is based on a large, well-designed, and well-conducted prospective clinical trial and that it pro- vides a follow-up time of more than 10 years. In addition, this study showed that the degree of response using TRG also correlated with disease outcome. In other words, in the absence of a complete pathologic response, intermediate regression (TRG 2-3) was better than poor regression (TRG 0-1). Several studies have shown that patients who achieve a pathologic complete response have superior survival, although many of these studies are retrospective in nature (23-25). Others have suggested a lack of correlation of response and survival (26). The authors of this update provide an excellent discus- sion regarding this controversial issue, and although it is not resolved necessarily, it lays the foundation for future clinical trials to prospectively use pathologic response for risk stratiﬁcation. Response has already been used to determine treatment courses for patients, as shown in the data from the Brazilian group, highlighted in the prior Oncology Scan, where nonoperative treatment of complete clinical responders after chemoradiation has been associ- ated with excellent control and survival rates (27). Further studies should rigorously test pathologic response as a surrogate of disease outcome. If validated, this early endpoint could be used for risk stratiﬁcation of patients and determine the need for subsequent adjuvant therapy after resection (an important issue highlighted by the next publication to be discussed). It could also tie into several other potentially important areas of research, such as imaging and molecular markers that can predict for complete response and therapeutic strategies to increase the complete response rate.