A Phase II Trial of Celecoxib (CX), Irinotecan (I), 5-Fluorouracil (5FU), and Leucovorin (LCV) in Patients with Unresectable or Metastatic Colorectal Cancer (CRC)

Reviewer: Thomas Dilling, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 19, 2002

Presenter: C.D. Blanke
Presenter's Affiliation: Oregeon Health Sciences University
Type of Session: Scientific

Background

Previous studies have shown that cyclooxygenase-II (COX-2) is present in the majority of CRCs, with expression associated with worse prognosis.
Celecoxib is a selective COX-2 inhibitor which has demonstrable anti-angiogenesis properties in vivo, and benefit when combined with chemotherapy.
Based on these data, a multi-institutional phase 2 trial was undertaken.

Materials and Methods

Inclusion criteria were patients with measurable disease which was deemed unresectable or metastatic. ECOG Performance Status 0-2.
Patients were excluded if they had had treatment in the prior 12 months with any agents except 5FU, or if they had a history of thromboembolic disease.
Patients received CX at 400 bid x 2 weeks, then IFL chemotherapy (the "Saltz regimen") concurrent with CX x 4 cycles, q43 days, continuing treatment until disease progressed or treatment-related toxicity was achieved.
Initially, standard dosing of these agents was undertaken (125 mg/m2 I, 500 mg/m2 F, 20 mg/m2 L).
The trial was closed for several months while interim data were analyzed. The trial was then reopened, with amendments, including restriction to ECOG performance status 0-1, as well as mild reductions in chemotherapy dosage due to reported grade 2 toxicities.
To date, 21 patients are evaluable for toxicity and 18 for response.

Results

Grade 3/4 toxicities included neutropenia in 27%, diarrhea in 23%, nausea in 23%, and electrolyte disturbances in 18%.
Interestingly, the reported rate of neutropenia is lower than that previously described in patients undergoing IFL chemotherapy alone.
3 thromboembolic events were reported, including two cerebrovascular accidents, one of which resulted in death, and one myocardial infarction. These 3 patients all had underlying vascular disease.
Patients have received from 1-9 cycles of treatment.
24% had PR, with 43% demonstrating stable disease. 14% had frank progression. 19% were not assessed, but have been included in an intent-to-treat fashion
Median duration of PR was 6.0 months, with PFS of 6.8 months. Median survival is 10.1 months.

Author's Conclusions

To date, the trial has only accrued 1/2 of the patients planned, so these data are still somewhat immature.
Nonetheless, these very preliminary results do suggest some activity against CRC with COX-2 inhibition.

Clinical/Scientific Implications

As our knowledge of molecular functioning of tumor cells improves, researchers hope to create agents with increasing efficacy.
COX-2 inhibition is one of the important "first wave" of directed molecular therapies for oncologic tumors.
Additional patients will need to be accrued to this study to better ascertain the treatment toxicity profile, as well as the response rate of tumors to this therapy.
If these very early data are indicative, a phase 3 trial will probably be indicated to further ascertain the efficacy of this treatment modality.

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