SALT LAKE CITYCompared with patients with locally
advanced rectal cancer who receive chemoradiotherapy postoperatively, those who
receive chemoradiotherapy preoperatively have a downstaging of their cancer at
surgery, a lower rate of local recurrence, a higher rate of sphincter
preservation when tumors are low lying, and a lower rate of adverse effects,
according to early results of the German Rectal Cancer Study (CAO/ARO/AIO-94).
Lead author Rolf Sauer, MD, director of the Strahlenklinik, Erlangen, Germany,
presented the results at the 45th Annual Meeting of the American Society for
Therapeutic Radiology and Oncology (ASTRO plenary session, abstract 2).
"Because of the radiobiological advantages that
preoperative radiotherapy or chemoradiotherapy provides, the German Rectal
Cancer Study Group in the mid-90s started this protocol, which compared
neoadjuvant vs adjuvant chemoradiotherapy," Dr. Sauer said.
Patients were enrolled in the phase III randomized trial
from 26 institutions; they had stage II or III rectal cancer (T3/T4 or
N-positive disease), as diagnosed by endorectal ultrasound or the Mason
procedure, and were younger than 75 years, Dr. Sauer said.
They were assigned to preoperative or postoperative
concurrent chemotherapy and radiation therapy, consisting of 50.4 Gy in 1.8-Gy
fractions and a continuous fluorouracil (5-FU) infusion over 120 hours during
the first and the fifth weeks of radiation therapy, and then four courses of
adjuvant maintenance 5-FU. Patients in the postoperative chemoradiotherapy arm
also received a 5.4-Gy boost.
All patients underwent total mesorectal excision at an
interval of 4 to 6 weeks from chemoradiotherapy. "To exclude the impact of
the surgeon as a well-known prognostic factor in rectal cancer treatment,
stratification was done on the individual surgeon. This is unique in all
randomized trials so far," Dr. Sauer said.
Outcomes were assessed during a median follow-up of 43
months (range, 4 to 89 months) in 405 patients given preoperative
chemoradiotherapy and 394 patients given postoperative chemoradiotherapy, Dr.
According to intention to treat, patients in the
preoperative chemoradiotherapy group had a 5-year rate of local recurrence that
was half that of patients in the other group (6% vs 12%, P = .006).
The 5-year rates of distant recurrence were similar (30% for
preoperative therapy vs 34% for postoperative therapy), and the two groups did
not differ with respect to rates of disease-free survival (65% vs 61%) and
overall survival (74%). "Until now, the incidence of distant metastases
has been equal in both groups, which is why we have not seen an improvement in
disease-free or overall survival," he noted.
About one third of patients in each treatment group
experienced any grade 3-4 acute toxicity from the chemoradiotherapy (28% vs
40%), but rates of severe diarrhea were markedly lower in the preoperative
chemoradiotherapy group. Patients in the preoperative chemoradiotherapy group
had a significantly lower rate of chronic toxicity in terms of anastomotic site
stenosis (4% vs 12%).
"There was no evidence of perioperative and
postoperative surgical complications after preoperative chemoradiation. The
complication rates have been very low," Dr. Sauer said.
Preoperative chemoradiotherapy resulted in a highly
significant downstaging of cancer at surgery, with about 8% of patients in this
group having a pathologically confirmed complete remission and stabilization of
lymph node metastases, Dr. Sauer reported.
The International Union Against Cancer (UICC) stage
distributions at surgery for patients in the preoperative and postoperative
groups, respectively, were as follows: stage I (25% vs 18%), stage II (29% vs
28%), stage III (26% vs 39%), and stage IV (6% vs 7%), with stage unknown for
some patients (6%, P = .0001).
Before randomization, surgeons predicted that 188 patients
with low-lying tumors would need abdominoperineal resection, Dr. Sauer said. In
this subgroup, rates of sphincter preservation at the time of surgery were
twice as high among patients who received preoperative chemoradiotherapy as
among those who received postoperative chemoradiotherapy (39% vs 19%, P
"The conclusion of these first results is that
preoperative chemoradiotherapy significantly improved local control, improved
sphincter preservation in low-lying tumors, and reduced acute and chronic
toxicity. And so we anticipate that preoperative chemoradiation should be the
new standard treatment for advanced rectal cancer, at least in Germany,"
Dr. Sauer said.