Irinotecan and Thalidomide in Metastatic Colorectal Cancer

Introduction

Colorectal cancer is one of the major causes of morbidity and
mortality in this country, with about 130,000 cases diagnosed per year and
50,000 to 55,000 deaths per year. It is the third leading cause of death in this
country for both men and women.

No Effective Therapy

Fluorouracil (5-FU) has been the only chemotherapeutic agent
available for the treatment of metastatic colorectal cancer over the past 40
years. Although 5-FU has been used in a number of different schedules, the
response rate has been less than 25%, and complete responses have been extremely
rare.[1,2] In 1996, the US Food and Drug Administration (FDA) approved
irinotecan (CPT-11, Camptosar), a topoisomerase I inhibitor, as a second-line
salvage regimen for patients with metastatic colorectal cancer.

In various trials conducted in Europe and North America, the
response rate to irinotecan has been around 20%, complete responses being <
1%.[3-6] In three phase II and III trials, irinotecan was administered at 300 to
350 mg/m² every 21 days (Europe), and 125 mg/m²
weekly (North America). In the two large, randomized, phase III trials, complete
responses were either not seen or not cited.[3-6]

Initial Protocol
Development

Two important features of thalidomide (Thalomid) are its
antiangiogenic properties and its ability to inhibit tumor necrosis factor-alpha
(TNF-alpha). This latter feature has made thalidomide especially useful in the
treatment of patients with Crohn’s disease.[7,8] The control of diarrhea in
these patients, mediated by suppression of TNF-alpha, may partially explain the
antidiarrheal effect of thalidomide. The protocol for our study is based on this
information and anecdotal experience with thalidomide in treating a patient with
metastatic colorectal cancer.

Our initial patient was a 48-year-old man whose cancer
progressed after he received the standard Mayo Clinic regimen (5-FU plus
leucovorin) for stage III colon cancer. He had liver metastases, which were
treated by local therapy with radiofrequency ablation and hepatic artery-directed
chemotherapy. After three cycles, the patient developed pulmonary and multiple
liver metastases. At that time, and at the patient’s request, we started him
on 350 mg/m² of irinotecan IV for 90 minutes
every 21 days and 400 mg/d of thalidomide. Six months after starting this
regimen, there was no radiologic evidence of disease. The thalidomide dose of
400 mg/d was based on experience at our institution using thalidomide in
combination with chemotherapy.

All patients received a baseline computed tomography (CT) scan
or x-ray and measurement of carcinoembryonic antigen (CEA) level. Responses were
assessed after three cycles by CT scans or x-rays. According to the protocol,
those who responded and those with stable disease would proceed to receive
further treatment and to be reassessed after three additional cycles. The plan
is to continue two cycles of irinotecan after complete response or until disease
progression. In all patients who have complete response, thalidomide will be
continued for 1 year.

Eligibility and
Response Criteria

Eligibility criteria are outlined in Table
1. The responses were defined as complete, partial, or minimal response, or
as stable disease or progression according to the following criteria:

• Complete response: no evidence of disease

• Partial response: ³ 50% tumor
  reduction

• Minimal response: < 50% tumor reduction

• Stable disease: no change in measurable disease

• Progression: tumor size increased by ³
  25%

Data Collection

Until the protocol was formally opened, we were treating
patients on a compassionate basis. Data from the pilot study were therefore
collected separately from the official protocol, though all the criteria were
strictly followed. We treated 11 patients in the pilot study, 9 men and 2 women,
ranging in age from 29 to 79 years, with stage IV colorectal cancer (see Table
2). All patients were treated with prior 5-FU with or without leucovorin. In
addition, some patients received fluorodeoxyuridine (FUDR) and radiation
therapy.

Of these 11 patients, 10 were evaluable (1 ineligible due to
pretreatment with irinotecan), and responses were noted in 4. Two patients had
complete responses to the irinotecan/thalidomide regimen after eight and six
cycles of treatment, although one patient subsequently progressed; another two
had partial responses after eight and three cycles of treatment.

The UARK 99-057 Protocol

The official protocol is called UARK (University of Arkansas)
99-057 and so far has accrued four patients (three men and one woman) between
the ages of 51 and 58 with confirmed metastatic colorectal cancer. All patients
had been treated previously with 5-FU. In addition, one patient had received
FUDR and radiation therapy (Table 3).

Of these four patients, two experienced a decrease in CEA levels
after two cycles of the irinotecan/thalidomide regimen. One patient showed a
decrease in CEA level from 12 to 5.3 ng/mL, and a second a decrease from 239 to
130 ng/mL (with the 239 ng/mL representing a progression from an initial CEA
level of 59 ng/mL). No response was noted in the two other patients, one of whom
developed a grade 3 rash and was taken off the study. In this latter patient, he
was hospitalized with grade 4 diarrhea 48 hours after thalidomide was
discontinued. He remained in the hospital for 2 weeks.

Toxicity

Among all 15 patients—11 treated in the pilot and 4 treated in
the UARK 99-057 study—the main side effects were constitutional (see Table
4). Three patients experienced grade 3/4 hematologic toxicity with febrile
neutropenia. Six patients had grade 2 nausea/vomiting and constipation; in two
of the six patients, constipation was severe (grade 2/3). In the patient removed
from UARK 99-057 due to the grade 3 rash, nausea worsened, becoming grade 3/4.
One patient developed bradycardia and three patients developed skin rash. There
was one death and one grade 1 neuropathy. One patient was hospitalized with
diarrhea after stopping thalidomide for skin rash. One patient had constipation
and, subsequently, blood in the stool.

Discussion

Diarrhea occurred in nearly 80% to 85% of patients in previous
studies, especially in the North American ones, where grade 3/4 diarrhea
occurred in approximately 34% of patients. Excluding the one patient who
developed grade 3 diarrhea after discontinuation of thalidomide, none of the
patients in this study required intravenous fluids due to diarrhea. This was a
striking observation (Table 5).

Case Histories

UARK 99-057 was developed based on our experience with the first
patient in the pilot study. He was a 48-year-old man with metastatic colon
cancer who developed progressive pulmonary and hepatic metastases after
treatment with 5-FU and FUDR. Complete response was achieved after 6 months on
the irinotecan/thalidomide regimen.

In a second case, a 78-year-old woman with liver metastases was
treated on a Southwest Oncology Group (SWOG) protocol with high-dose 5-FU and
leucovorin. She did not respond and her liver metastases were treated with
cryoablation. The patient again progressed and developed pulmonary metastases,
at which time she was treated on our protocol. After six cycles of
irinotecan/thalidomide, the pulmonary metastases had disappeared, and her liver
metastases were almost gone. At this time, she has received eight cycles of
chemotherapy and is due to be reassessed.

A 29-year-old man with rectal cancer had a tumor mass that
extended all along the rectal wall. He was treated with standard preoperative
radiation therapy, along with 5-FU. Exploratory surgery was performed, and the
tumor was determined unresectable. The patient received a colostomy. He was
started on the protocol with irinotecan and thalidomide. After three cycles of
irinotecan/thalidomide, radiologic evaluation revealed that the tumor mass was
no longer visible along the whole rectal wall, though there was some evidence of
the tumor in the coronal sections of the MRI. The patient was classified as a
partial response, and further assessment is needed.

Summary

To date, 15 patients with a median age of 56 years have been
entered onto the irinotecan/thalidomide regimen—11 in a pilot study and 4 in
UARK 99-057. Of these, 10 are evaluable. A total of 53 irinotecan cycles have
been administered, with a range of one to eight cycles per patient. None of
those patients have stopped therapy due to side effects of irinotecan, even
though in previous studies of irinotecan many patients stopped treatment within
the first month due to side effects.

The median dose of thalidomide was 400 mg. In one patient, the
dose was reduced because of somnolence. The current maximum duration of
thalidomide therapy is 12 months. Of the 10 evaluable patients originally in the
pilot study, disease has progressed in six. The median time to response is about
9 weeks from the first time we assessed the patient.

Future Directions

The optimal dose of thalidomide to be given in combination with
irinotecan remains to be determined, as does the optimal dose of irinotecan to
be given in combination with thalidomide. Further, the toxicities and responses
of the combination need to be evaluated. The FDA has approved 5-FU/leucovorin
and irinotecan as first-line chemotherapeutic agents. Our next aim is to study
5-FU/leucovorin in combination with irinotecan and thalidomide.