Safety and efficacy of outpatient treatment with CPT-11 plus bolus folinic acid/5-fluorouracil as first-line chemotherapy for metastatic colorectal cancer

Abstract

The combination of irinotecan (CPT-11), bolus 5-fluorouracil (5-FU) and folinic acid (FA) (Saltz regimen) has recently been questioned as first-line chemotherapy for metastatic colorectal cancer after high early death rates due to gastrointestinal and thromboembolic events were reported in two US trials. Therefore, we carefully evaluated the safety and efficacy of this regimen, with high value placed on the management of delayed diarrhea. Forty-six patients with metastatic colorectal cancer received this first-line treatment in nine German outpatient clinics. Dose reductions were mandatory from the first cycle in case of toxicity grade >2. Chemotherapy was administered only to diarrhea-free patients. During a total of 175 cycles administered treatments were delayed for 1 week in 11.6% and given at a reduced dose in 14.5%. All and 40 patients were evaluable for toxicity and response, respectively. Grade 3/4 toxicities included diarrhea (n=10), leukopenia (n=9), neutropenia (n=3) and anemia (n=4). One non-fatal pulmonary embolism occurred. Four complete responses (CR) and 10 partial responses were seen, for an overall response rate of 35%. In addition, 16 patients (40%) had stable disease. Resectability of liver metastases was achieved in three patients, including one pathologically confirmed CR. Median progression-free and overall survival were 5 and 13 months, respectively. We conclude that outpatient treatment with the Saltz regimen was well tolerated. Severe gastrointestinal toxicity and thromboembolic events were rarely observed and never fatal. As down-staging was possible, combinations of CPT-11 and FA/5-FU should be further investigated in neoadjuvant protocols.

Irinotecan plus folinic acid/continuous 5-fluorouracil as simplified bimonthly FOLFIRI regimen for first-line therapy of metastatic colorectal cancer

“…Furthermore, we observed improved physical and emotional status and an increase in global health status during treatment [24]. This is in concordance with our previously reported data [25]. Tournigand et al demonstrated an increase in weight of at least 5% in 35% and an improved physical status in 35% of the irinotecan/FA/5-FU treated patients, respectively [14].…”

“…After unexpectedly high early death rates, due to gastrointestinal toxicity and thromboembolic events, which were reported in two subsequent trials due to gastrointestinal toxicity and thromboembolic events, the safety of the Saltz regimen became a subject of considerable debate [18,19]. However, in our previous experience with this regimen we did not observe any major complications [25]. Moreover, additional comprehensive data showed that combinations of irinotecan with continuous FA/5-FU, either weekly or bi-monthly, resulted in higher response rates and better survival.…”

“…Patients with loperamide-resistant diarrhea defined as loose stools persisting for more than 24 hours despite adequate treatment with loperamide would receive a trial of the oral steroid budesonide (9 mg per day for a maximum of 4 days) [23]. Atropine was given for irinotecan-related cholinergic symptoms if needed [25]. Antiemetic treatment was performed using metoclopramide or HT5 antagonists in a sequential manor.…”

Weekly irinotecan plus UFT and leucovorin as first-line chemotherapy of patients with advanced colorectal cancer

“…5-FU was initially administered as monotherapy, but more recently it has been combined with new drugs like irinotecan (CPT-11), therefore improving the outcome of CRC treatment [1,3]. CPT-11 is a topoisomerase I inhibitor active as first-line chemotherapy against metastatic CRC both as single agent [4][5][6] or combined with 5-FU/leucovorin (LV) [7][8][9][10]. Hence, CPT-11 is increasingly combined with 5-FU/LV as first-line treatment of metastatic CRC because this combination increases response rates, time to disease progression and survival [11].…”

Sequential Administration of 5-Fluorouracil (5FU)/Leucovorin (LV) Followed by Irinotecan (CPT-11) at Relapse versus CPT-11 Followed by 5-FU/LV in Advanced Colorectal Carcinoma

“…We also noticed that, as second-line chemotherapy, after 5-FU/LV failure, CPT-11 achieved the same or a higher percentage of response, ranging from 14 to 35% when used as monotherapy [13][14][15][16][17] , and in 22-45% when used in combination with 5-FU/LV [25][26][27][28][29][30][31] .…”