PHILADELPHIAPreoperative chemoradiotherapy with irinotecan
(CPT-11, Camptosar), fluorouracil (5-FU), and radiation showed a significant
ability to downsize rectal adenocarcinomas and is being studied further in
clinical trials, Edith P. Mitchell, MD, reported. Due to problems associated
with the central venous access required for continuous infusion 5-FU,
capecitabine (Xeloda) is being substituted for 5-FU in ongoing studies. Dr.
Mitchell is clinical professor of medicine at Thomas Jefferson University in
The risk of recurrence after surgery rises rapidly with stage
of rectal cancer: 5% to 10% for stage I, 25% to 30% for stage II, and more than
50% for stage III. "This is an important point because there are few diagnostic
tests that enable us to accurately stage rectal cancer prior to surgery," Dr.
Surgical considerations include the size of the tumor, of the
prostate or uterus, and of the patient, the extent of local invasion, tumor
stage, co-existent disease, and the biological behavior of the tumor such as
poor differentiation, vascularity, or lymphatic invasion.
Dr. Mitchell said that lower risk of local recurrence is
associated with lower tumor stage, smaller tumor size, fewer nodal metastases,
metastases that do not extend past the nodal capsule, and absence of
perivascular or intravascular tumor invasion. Other favorable factors are more
proximal tumor, female gender, removal of a larger number of nodes, and
mesorectal excision of the tumor.
Dr. Mitchell said that analysis of rectal cancer treatment from
1988 through 1995 revealed the following patterns:
Stage I disease is being diagnosed less frequently.
Chemoradiotherapy is being used more often for stage II or
stage III disease.
Chemoradiotherapy downstaged many patients with locally
advanced or unresectable disease and made them candidates for resection.
Mesorectal excision followed by radiation therapy is more
effective at preventing local recurrence than surgery alone.
"Radiotherapy reduces local-regional recurrence rates but has
little effect on disease-free survival or on overall survival," she said.
Dr. Mitchell and colleagues conducted a phase I/II trial of
weekly irinotecan and continuous 5-FU with concomitant preoperative radiation
therapy in previously untreated patients with T3 or T4 rectal adenocarcinomas.
Eligibility criteria included adenocarcinomas below 15 cm above the anal verge,
distal border of the tumor below the peritoneal reflection, and clinical stage
of II or III.
Chemotherapy included irinotecan in escalating doses from 30
mg/m2 to 60 mg/m2 IV over 60 minutes, given weekly on
days 1, 8, 15, and 22. The researchers attempted to continue irinotecan
throughout radiation therapy but the combination was too toxic, Dr. Mitchell
noted. 5-FU was given by continuous infusion at 300 mg/m2/day for 5
days during radiation therapy. Radiation was given at 1.8 Gy/day to a total of
Of the 67 patients enrolled in the study, 51 had undergone
surgery and were evaluable for response. The most common grade 3 or 4
toxicities were diarrhea and catheter infections or clots (see
High Response Rates
Dr. Mitchell reported that 100% of tumors were downsized
following preoperative chemoradiotherapy. Clinical complete responses occurred
in 24 (47%), and pathologic complete responses in 13 (25%). Clinical partial
responses occurred in 27 (53%) and pathologic partial responses in 32 (63%).
"In an additional six patients (12%), there was only minimal residual disease,
which was defined as even a single tumor cell seen on pathologic examination of
the tumor specimen," Dr. Mitchell said.
Patients with high levels of microsatellite instability (MSI)
had the highest complete response rates. "We currently have an ongoing phase I
study of irinotecan, capecitabine, and radiation therapy with capecitabine
substituted for continuous infusion 5-FU because of the catheter problems," Dr.
"Our conclusions thus far are that this preoperative
chemoradiotherapy approach is feasible and well tolerated. The maximum
tolerated chemotherapy doses are 50 mg/m2 for irinotecan with 225
mg/m2 of continuous infusion 5-FU and radiotherapy."