Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy.
OBJECTIVE
To assess the efficacy of irinotecan (CPT-11) in the treatment of advanced colorectal cancer in both chemotherapy-naive and pretreated patients.


METHODS
Two hundred thirteen patients (aged 18 to 75 years) with metastatic colorectal cancer, World Health Organization (WHO) performance status < or = 2, and life expectancy > or = 3 months were treated with CPT-11 350 mg/m2 every 3 weeks. All 178 patients eligible for efficacy analysis had not received more than one prior fluorouracil (5-FU)-based chemotherapy regimen (adjuvant or palliative) and had adequate hematologic, renal, and hepatic function.


RESULTS
Primary tumor sites were the colon (71%) and rectum (28%). Sixty-six percent of the patients had > or = two metastatic sites. Ninety-eight percent of the patients had undergone previous surgery, and 77.5% had received prior chemotherapy. Thirty-two of 178 eligible patients achieved on objective response (four complete responses [CRs] and 28 partial responses [PRs]; response rate, 18%; 95% confidence interval, 12.6% to 24.4%), 65 were stable, and 59 progressed. The response rate was 17.7% in the pretreated group and 18.8% in the chemotherapy-naive group. Within the former subgroup, response rates of 16.1% were reported in patients who were progressive on prior 5-FU chemotherapy and 19.1% in patients who were progressive off such treatment. The median duration of objective response (9.1 months) and median time to achievement of a response (9.3 weeks) did not differ between chemotherapy-naive and pretreated patients. The most frequent adverse events were neutropenia, which developed in 80% of the patients, delayed diarrhea (87%), alopecia (88%), fatigue (81%), and nausea/vomiting (77%). All these adverse events were manageable. Severe (WHO grade 3 or 4) neutropenia was only observed in 18% of the cycles, leukopenia in 11%, delayed diarrhea in 11%, and nausea and vomiting in 3%. Development of simultaneous grade 3 or 4 neutropenia and delayed diarrhea during 4% of the cycles was the safety issue of greatest concern.


CONCLUSIONS
CPT-11 has definite activity in the treatment of advanced metastatic colorectal cancer both in chemotherapy-naive and in pretreated patients who experienced disease progression on 5-FU, which suggests a lack of cross-resistance between CPT-11 and 5-FU. Diarrhea and neutropenia, the major toxicities of CPT-11, contribute to the risk to develop febrile neutropenic sepsis.
Rougier
P
P
Institut Gustave Roussy, Villejuif, France.
Bugat
R
R
Douillard
J Y
JY
Culine
S
S
Suc
E
E
Brunet
P
P
Becouarn
Y
Y
Ychou
M
M
Marty
M
M
Extra
J M
JM
Bonneterre
J
J
Adenis
A
A
Seitz
J F
JF
Ganem
G
G
Namer
M
M
Conroy
T
T
Negrier
S
S
Merrouche
Y
Y
Burki
F
F
Mousseau
M
M
Herait
P
P
Mahjoubi
M
M
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003967:Diarrhea / Q000139:chemically induced; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D005334:Fever / Q000209:etiology; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D012004:Rectal Neoplasms / Q000188:drug therapy*; D012074:Remission Induction
D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin