Irinotecan and Thalidomide in Metastatic Colorectal Cancer

December 2, 2000

Fifteen patients with metastatic colorectal cancer were treated with irinotecan (CPT-11, Camptosar) at 300 to 350 mg/m2 every 21 days and thalidomide (Thalomid) at 400 mg/d. Of the 15 patients, 11 were in a pilot study and 4

ABSTRACT: Fifteen patients with metastatic colorectal cancer were treated with irinotecan (CPT-11, Camptosar) at 300 to 350 mg/m2 every 21 days and thalidomide (Thalomid) at 400 mg/d. Of the 15 patients, 11 were in a pilot study and 4 were in an ongoing phase II protocol. There were 12 men and 3 women, with a median age of 56 years (range: 29 to 79 years). Patients were treated with a median of three cycles (range: one to eight cycles). The four patients enrolled in the formal protocol were not evaluable for response at the time of this report. Of the 11 patients in the pilot study, 10 were evaluable for response; there were two complete responses, two partial responses, and six progressions. Investigators noted a remarkable absence of grade 3/4 gastrointestinal toxicities, and concluded that further testing of the complete response and toxicity profile of the irinotecan/thalidomide regimen was warranted. [ONCOLOGY 14(Suppl 13):29-32, 2000]


Colorectal cancer is one of the major causes of morbidity andmortality in this country, with about 130,000 cases diagnosed per year and50,000 to 55,000 deaths per year. It is the third leading cause of death in thiscountry for both men and women.

No Effective Therapy

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

In various trials conducted in Europe and North America, theresponse 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 to350 mg/m2 every 21 days (Europe), and 125 mg/m2weekly (North America). In the two large, randomized, phase III trials, completeresponses were either not seen or not cited.[3-6]

Initial ProtocolDevelopment

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

Our initial patient was a 48-year-old man whose cancerprogressed after he received the standard Mayo Clinic regimen (5-FU plusleucovorin) for stage III colon cancer. He had liver metastases, which weretreated by local therapy with radiofrequency ablation and hepatic artery-directedchemotherapy. After three cycles, the patient developed pulmonary and multipleliver metastases. At that time, and at the patient’s request, we started himon 350 mg/m2 of irinotecan IV for 90 minutesevery 21 days and 400 mg/d of thalidomide. Six months after starting thisregimen, there was no radiologic evidence of disease. The thalidomide dose of400 mg/d was based on experience at our institution using thalidomide incombination with chemotherapy.

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

Eligibility andResponse Criteria

Eligibility criteria are outlined in Table1. The responses were defined as complete, partial, or minimal response, oras 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 treatingpatients on a compassionate basis. Data from the pilot study were thereforecollected separately from the official protocol, though all the criteria werestrictly 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 Table2). All patients were treated with prior 5-FU with or without leucovorin. Inaddition, some patients received fluorodeoxyuridine (FUDR) and radiationtherapy.

Of these 11 patients, 10 were evaluable (1 ineligible due topretreatment with irinotecan), and responses were noted in 4. Two patients hadcomplete responses to the irinotecan/thalidomide regimen after eight and sixcycles of treatment, although one patient subsequently progressed; another twohad 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) betweenthe ages of 51 and 58 with confirmed metastatic colorectal cancer. All patientshad been treated previously with 5-FU. In addition, one patient had receivedFUDR and radiation therapy (Table 3).

Of these four patients, two experienced a decrease in CEA levelsafter two cycles of the irinotecan/thalidomide regimen. One patient showed adecrease in CEA level from 12 to 5.3 ng/mL, and a second a decrease from 239 to130 ng/mL (with the 239 ng/mL representing a progression from an initial CEAlevel of 59 ng/mL). No response was noted in the two other patients, one of whomdeveloped a grade 3 rash and was taken off the study. In this latter patient, hewas hospitalized with grade 4 diarrhea 48 hours after thalidomide wasdiscontinued. He remained in the hospital for 2 weeks.


Among all 15 patients—11 treated in the pilot and 4 treated inthe UARK 99-057 study—the main side effects were constitutional (see Table4). Three patients experienced grade 3/4 hematologic toxicity with febrileneutropenia. Six patients had grade 2 nausea/vomiting and constipation; in twoof the six patients, constipation was severe (grade 2/3). In the patient removedfrom 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. Therewas one death and one grade 1 neuropathy. One patient was hospitalized withdiarrhea after stopping thalidomide for skin rash. One patient had constipationand, subsequently, blood in the stool.


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

Case Histories

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

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

A 29-year-old man with rectal cancer had a tumor mass thatextended all along the rectal wall. He was treated with standard preoperativeradiation therapy, along with 5-FU. Exploratory surgery was performed, and thetumor was determined unresectable. The patient received a colostomy. He wasstarted on the protocol with irinotecan and thalidomide. After three cycles ofirinotecan/thalidomide, radiologic evaluation revealed that the tumor mass wasno longer visible along the whole rectal wall, though there was some evidence ofthe tumor in the coronal sections of the MRI. The patient was classified as apartial response, and further assessment is needed.


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

The median dose of thalidomide was 400 mg. In one patient, thedose was reduced because of somnolence. The current maximum duration ofthalidomide therapy is 12 months. Of the 10 evaluable patients originally in thepilot study, disease has progressed in six. The median time to response is about9 weeks from the first time we assessed the patient.

Future Directions

The optimal dose of thalidomide to be given in combination withirinotecan remains to be determined, as does the optimal dose of irinotecan tobe given in combination with thalidomide. Further, the toxicities and responsesof the combination need to be evaluated. The FDA has approved 5-FU/leucovorinand irinotecan as first-line chemotherapeutic agents. Our next aim is to study5-FU/leucovorin in combination with irinotecan and thalidomide.


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8. Ehrenpreis ED, Kane SV, Cohen LB, et al: Thalidomide therapyfor patients with refractory Crohn’s disease: An open label trial.Gastroenterology 117:1271-1277, 1999.