PHILADELPHIAA phase II study in patients with locally
advanced rectal cancer showed that the combination of irinotecan (Camptosar),
fluorouracil (5-FU), and concomitant radiation given preoperatively is well
tolerated and appears to have enhanced activity. Reporting the results, Edith
Peterson Mitchell, MD, noted that ongoing phase II studies will determine the
pathologic response rates and patterns of disease recurrence. Dr. Mitchell is
clinical professor of medicine, Division of Medical Oncology, Kimmel Cancer
Center of Thomas Jefferson University, Philadelphia.
To emphasize the need for better treatment, Dr. Mitchell cited
the risk of recurrence following surgical resection. "Local recurrence
alone or in combination with distant recurrence occurs in 25% to 50% of
patients," she said. "The recurrence rate is 5% to 10% for stage I
patients, 25% to 30% for stage II patients, and over 50% for stage III
patients, with local recurrence as a major factor."
Downstaging with Chemoradiation
Improved diagnostic methods have enhanced staging procedures,
allowing for more accurate determination of advanced disease and better
selection of patients who might potentially benefit from more aggressive
therapies. "Chemoradiation can downstage many patients with locally
advanced or unresectable disease," Dr. Mitchell said. "We also now
know that the results of mesorectal excision are better than those reported by
standard surgical resection followed by radiotherapy with or without
chemotherapy." Although radiation reduces locoregional recurrence rates,
used alone it has little effect on disease-free or overall survival in rectal
"5-FU-based chemotherapy combined with pelvic irradiation
is superior to either modality in reducing locoregional failures and improving
disease-free and overall survival of patients with stage II or III rectal
carcinoma," Dr. Mitchell said. "However, the most effective
combination of drugs, optimal mode of administration, and best sequence of
radiation and chemotherapy have not been determined."
Preoperative chemoradiation may surpass postoperative
administration in part because of the biological, physical, functional, and
clinical advantages associated with preoperative radiation therapy. Combining
chemotherapy with radiation increases resectability and pathologic complete
responses compared to radiation alone, and preoperative chemoradiation is also
associated with less toxicity.
"Preoperative chemoradiation also decreases tumor seeding
while the numbers of oxygenated cells during surgery are increased, eliminates
postsurgical small bowel fixation in the pelvis, and is more effective in
reducing local failure," Dr. Mitchell said. ‘‘There is generally
diminished acute toxicity because there is less small bowel in the radiation
port before resection and postsurgical small bowel fixation."
Dr. Mitchell advised that special care should be taken when
giving preoperative chemoradiotherapy to individuals who have had previous
pelvic surgery such as hysterectomy.
Irinotecan as Radiosensitizer
Irinotecan used in part as a radiosensitizer is being studied
in combination with 5-FU and radiation in an ongoing study at Roswell Park
Cancer Institute (Figure 1). Early results of this study have been
encouraging," Dr. Mitchell said.
Dr. Mitchell and colleagues at Jefferson conducted a phase I
study to determine the maximum tolerated dose (MTD) of weekly irinotecan
combined with 5-FU and concomitant RT given preoperatively. Patients had
primary or recurrent stage T3/T4 rectal adenocarcinoma previously untreated
with chemotherapy or radiation. This regimen was then used in a phase II trial
"We wait 8 to 10 weeks after chemoradiation to perform
surgery to allow the tissues to heal adequately. We have also observed
continued shrinkage of tumor after completion of the radiation, and the delay
permits completion of this process," Dr. Mitchell said. The major toxicity
was catheter-related infection or thrombus. Other toxicities included diarrhea,
neutropenia, and stomatitis.
Downsizing of Tumor
Every patient in this trial had a downsizing of tumor in
response to therapy. Among the 46 patients, there were 12 complete responses, 5
patients with minimal residual disease, and 17 patients with a clinical
response plus minimal residual disease.
The study includes analysis of tumor markers including p53 p21,
thymidylate synthase, and microsatellite instability (MSI). "MSI has the
best predictive ability. All patients with high MSI had pathologic complete
responses to treatment," Dr. Mitchell said.
Since most toxicities were catheter related, the investigators
would like to avoid infusions and so are substituting capecitabine (Xeloda) for
5-FU infusions in future trials.