A dose-finding study of lanreotide (a somatostatin analog) in patients with colorectal carcinoma.
BACKGROUND
Laboratory data suggest that insulin-like growth factor-1 (IGF-1) may stimulate the growth of different human tumors. At least in acromegalic patients, somatostatin (SMS) analogs, such as lanreotide, suppress the serum levels of growth hormone (GH) and IGF-1.


METHODS
To evaluate the tolerability and biologic activity of different doses of lanreotide in patients with advanced colorectal carcinoma, consecutive groups of 3 patients each were subcutaneous treated with lanreotide at doses of 1, 2, 3, 4, 5, or 6 mg three times a day for 2 months. In the event of Grade 3 side effects, 3 additional patients were treated with the same dose before the next dose escalation. Serum samples were obtained on Days 0, 15, 30, and 60 for serum GH, IGF-1, and lanreotide assessment.


RESULTS
Twenty-four patients were enrolled and all were evaluable. Except for the 3 and 6 mg doses, for which the observation of a Grade 3 side effect required that an additional three patients be treated, it was sufficient to treat 3 patients at each dose. The overall incidence of side effects was as follows: changes in bowel habits, 83%; abdominal cramps, 79%; diarrhea, 17%; vomiting, 17%; nausea, 21%; steatorrhea, 78%; hyperglycemia, 35%; laboratory hypothyroidism, 39%; gallstones, 13%; and weight loss, 17%. No evidence of an increase in the incidence, intensity, or duration of side effects was observed with dose escalation. Serum IGF-1 levels were as follows: Day 15: 63%, 60%, and 67% of the baseline values for the low (1-2 mg), intermediate (3-4 mg), and high (5-6 mg) dose groups, respectively; Day 30: 63%, 59%, and 51%, respectively; and Day 60: 73%, 69%, and 47%, respectively. Serum lanreotide levels declined during treatment in all of the dose groups (90 ng/mL on Day 15, and 35 ng/mL on Day 60 for the 5-6 mg group; 10 ng/mL on Day 15, and 1.5 ng/mL on Day 60 for the 1-2 mg group). No antitumor activity or tumor marker reduction was observed.


CONCLUSIONS
No increase in toxicity was observed when subcutaneous lanreotide doses were escalated to 6 mg three times a day for 2 months. The highest doses seemed to maintain reduced serum IGF-1 levels; with the lowest doses, a "rebound" in serum IGF-1 levels was observed during treatment. Nevertheless, intermittent subcutaneous injections do not ensure constant serum drug concentrations over time.
Di Leo
A
A
Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Bajetta
E
E
Ferrari
L
L
Biganzoli
L
L
Mariani
L
L
Carnaghi
C
C
Camerini
E
E
Buzzoni
R
R
Ruiz
J M
JM
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D013004:Somatostatin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010456:Peptides, Cyclic; C060347:lanreotide; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone