We aimed to establish the superiority (or noninferiority if superiority was not achieved) in terms of time to progression (TTP) of irinotecan/5-fluorouracil (IF) over cisplatin/5-fluorouracil (CF) in ...chemonaive patients with adenocarcinoma of the stomach/esophagogastric junction.
Patients received either IF: i.v. irinotecan 80 mg/m2 30 min, folinic acid 500 mg/m2 2 h, 5-fluorouracil (5-FU) 2000 mg/m2 22 h, for 6/7 weeks or CF: cisplatin 100 mg/m2 1–3 h, with 5-FU 1000 mg/m2/day 24 h, days 1–5, every 4 weeks.
In all, 333 patients were randomized and treated (IF 170, CF 163). Patient characteristics were balanced except more IF patients had Karnofsky performance status 100%. TTP for IF was 5.0 months 95% confidence interval (CI) 3.8–5.8 and 4.2 months (95% CI 3.7–5.5) for CF (P = 0.088). Overall survival (OS) was 9.0 versus 8.7 months, response rate 31.8% versus 25.8%, time to treatment failure (TTF) 4.0 versus 3.4 months for IF and CF, respectively. The difference in TTF was statistically significant (P = 0.018). IF was better in terms of toxic deaths (0.6% versus 3%), discontinuation for toxicity (10.0% versus 21.5%), severe neutropenia, thrombocytopenia and stomatitis, but not diarrhea.
IF did not yield a significant TTP or OS superiority over CF, and the results of noninferiority of IF were borderline. However, IF may provide a viable, platinum-free front-line treatment alternative for metastatic gastric cancer.
To compare the efficacy and safety of orally administered capecitabine (Xeloda; Roche Laboratories, Inc, Nutley, NJ), a novel fluoropyrimidine carbamate designed to mimic continuous fluorouracil ...(5-FU) infusion but with preferential activation at the tumor site, with that of intravenous (IV) 5-FU plus leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer.
We prospectively randomized 602 patients to treatment with capecitabine 1,250 mg/m(2) administered twice daily days 1 to 14 every 3 weeks, or to the 4-weekly Mayo Clinic regimen (5-FU/LV) until disease progression or unacceptable toxicity.
The primary objective, to demonstrate at least equivalent response rates in the two treatment groups, was met. The overall response rate was 18.9% for capecitabine and 15.0% for 5-FU/LV. In the capecitabine and 5-FU/LV groups, respectively, median time to disease progression was 5.2 and 4.7 months (log-rank P =.65); median time to treatment failure was 4.2 and 4.0 months (log-rank P =.89); and median overall survival was 13.2 and 12.1 months (log-rank P =.33). The toxicity profiles of both treatments were typical of fluoropyrimidines. However, capecitabine led to significantly lower incidences (P <.00001) of stomatitis and alopecia, but a higher incidence of cutaneous hand-foot syndrome (P <.00001). Capecitabine also resulted in lower incidences (P <.00001) of grade 3/4 stomatitis and neutropenia, leading to a lower incidence of grade 3/4 neutropenic fever and sepsis. Only grade 3 hand-foot syndrome (P <.00001) and uncomplicated grade 3/4 hyperbilirubinemia (P <.0001) were reported more frequently with capecitabine.
Oral capecitabine achieved an at least equivalent efficacy compared with IV 5-FU/LV. Capecitabine demonstrated clinically meaningful safety advantages and the convenience of an oral agent.
Background: This multicenter adjuvant phase III trial evaluated the addition of irinotecan to LV5FU2 in colon cancer patients at high risk of relapse. Patients and methods: A total of 400 patients ...with histologically proven primary colon cancer with postoperative N1 detected by occlusion/perforation or N2 were randomised to: A—LV5FU2 leucovorin 200 mg/m2, 2-h infusion, 5-fluorouracil (5-FU) 400 mg/m2 bolus, 600 mg/m2 22-h continuous infusion, days 1 and 2 or B—LV5FU2 + IRI (irinotecan 180 mg/m2 90-min infusion day 1 + LV5FU2) fortnightly for 12 cycles. Primary end point was disease-free survival (DFS). Results: Median follow-up was 63 months. Significantly more T4 tumours and 15 or more positive lymph nodes were observed in arm B. 5-FU relative dose intensity (RDI) was >0.80 for 94% and 77% in arms A and B, respectively (P < 0.001). Irinotecan RDI was >0.80 for 70% patients. There were more grades 3 and 4 neutropenia in arm B (4% versus 28%, P < 0.001). The 3-year DFS was 60% 95% confidence interval (CI) 53% to 66% and 51% (95% CI 44% to 58) in arms A and B, respectively. No difference was observed hazard ratio (HR) = 1.12, 95% CI 0.85–1.47, P = 0.42 even when adjusted for prognostic factors (adjusted HR = 0.98, 95% CI 0.74–1.31, P = 0.92). The 5-year overall survival (OS) was 67% (95% CI 59% to 73%) and 61% (95% CI 53% to 67%) in arms A and B, respectively. Conclusion: Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.
Abstract Background Supportive care in cancer (SCC) was further enhanced in the Second National Cancer Act decreed in December 2009. The aim of our study was to assess current SCC efficacy. Patients ...and methods The French speaking association for supportive care in cancer (AFSOS) conducted an observational study to evaluate practices, organisations and information given to patients. A specific 32 point questionnaire was sent to 1621 French physicians (MDs) caring for cancer patients. Results Three different organisations were evaluated: the individual MDs, the transversal team and its particular structure specialised in global patient care specifically developed at comprehensive cancer centres – CCC. During their disease, 68% of patients received SCC, which was more available during the palliative period (90%) than at the diagnosis (44%). Our results found that 71% of cancer departments had a specific interdisciplinary cross-team to provide SCC, particularly in CCC (62%; p = 0.01) while 37% had specific inpatient units. A specific organisation dedicated to home care was greater in CCC than in public or private centres (69%, 45%, 20% respectively; p = 0.01). Adverse event information was performed more by an oncologist than other specialists ( p = 0.01). Conclusion Our results suggest that the specific SCC organisation could be a useful management tool to improve supportive care for cancer patients.
Oxaliplatin (
l-OHP) is a new platinum analogue that has shown antitumour activity against colon cancer both
in vitro and
in vivo and is now used in the chemotherapeutic treatment of metastatic colon ...and rectal cancer.
l-OHP like cisplatin (CDDP), is detoxified by glutathione (GSH)-related enzymes and forms platinum (Pt)–DNA adducts lesions that are repaired by the nucleotide excision repair system (NER). We investigated the cytotoxicity and the pharmacology of
l-OHP and CDDP on a panel of six colon cell lines
in vitro. We showed that GSH and glutathione S-transferase (GST) activity were not correlated to oxaliplatin cytotoxicity. Pt–DNA adducts formation and repair were correlated with CDDP, but not with
l-OHP cytotoxicity. The determination of
ERCC1 and
XPA expression, two enzymes of the NER pathway, by reverse transcriptase-polymerase chain reaction (RT-PCR), demonstrated that
ERCC1 expression was predictive of
l-OHP sensitivity (
r
2=0.67,
P=0.02) and
XPA level after oxaliplatin exposure was also correlated to
l-OHP IC
50 (
r
2=0.5;
P=0.04). The knowledge of such correlations could help predict the sensitivity of patients with colon cancer to
l-OHP.
Purpose To evaluate the safety profile of capecitabine using data from a large, well-characterized population of patients with metastatic colorectal cancer treated in two phase III studies. In these ...trials, capecitabine achieved significantly superior response rates, equivalent time to disease progression and equivalent survival compared with 5-fluorouracil (5-FU)/leucovorin. Patients and methods Patients (n = 1207) were randomized to either oral capecitabine (1250 mg/m2 twice daily, on days 1–14 every 21 days) or intravenous (i.v.) bolus 5-FU/leucovorin (Mayo Clinic regimen). Results Capecitabine demonstrated a safety profile superior to that of 5-FU/leucovorin, with a significantly lower incidence of diarrhea, stomatitis, nausea, alopecia and grade 3 or 4 neutropenia leading to significantly fewer neutropenic fever/sepsis cases and fewer hospitalizations. All patients in the capecitabine group received a starting dose of 1250 mg/m2 twice daily and the majority (66%) did not require dose modification for adverse events. In the 5-FU/leucovorin group, 58% of patients did not require dose reduction for toxicities. The capecitabine dose-modification scheme reduced the recurrence of key toxicities without compromising efficacy. In both treatment arms, patients with moderate renal impairment at baseline (estimated creatinine clearance 30–50 ml/min) experienced a higher incidence of grade 3 or 4 toxicities. This increase was more pronounced with 5-FU/leucovorin. Conclusions Capecitabine is at least as effective, better tolerated and more convenient than i.v. 5-FU/leucovorin as treatment for patients with metastatic colorectal cancer. Analysis of data from two large phase III trials demonstrates that efficacy is not compromised in patients requiring a dose reduction for adverse events. The phase III data and an additional pharmacokinetic study support a lower starting dose in patients with moderate renal impairment at baseline (calculated creatinine clearance 30–50 ml/min) and a contra-indication in patients with severely impaired creatinine clearance at baseline (<30 ml/min). For patients with normal or mildly impaired renal function at baseline, the standard starting dose is well tolerated. The incidence and severity of adverse events in patients with moderate renal impairment at baseline who were treated with 5-FU/leucovorin was more pronounced, indicating that capecitabine provides a better-tolerated alternative.
Chemotherapy has a proven palliative role in advanced gastric cancer, significantly improving quality of life and prolonging survival compared with best supportive care alone. Although there is no ...standard of treatment, 5-fluorouracil (5-FU)/cisplatin doublets and the combination of epirubicin, cisplatin and 5-FU (ECF) have both achieved response rates in the range of 40–50% and median overall survival of 8–10 months. Either could claim the status of a reference regimen. Single-agent irinotecan achieved response rates (RR) of 18% and 23% in phase II studies, and 48% when combined with cisplatin. However, a randomized trial of irinotecan plus cisplatin versus irinotecan plus 5-FU/folinic acid (FA) showed that the latter regimen achieved a higher RR (34% versus 28%) and significantly longer median survival (10.7 versus 6.9 months). Hematological toxicity was lower with the irinotecan/5-FU/FA combination. This regimen has therefore been taken forward into a randomized phase III comparison against a 5-FU/cisplatin doublet. Use of irinotecan-based combinations should also be investigated as an adjuvant treatment (probably in combination with radiotherapy) and in the neoadjuvant setting.
Background: To identify the most effective of two combinations, irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) and irinotecan/cisplatin, in the treatment of advanced gastric cancer, for ...investigation in a phase III trial. Patients and methods: Patients were randomized to receive irinotecan 80 mg/m2 intravenously (i.v.), FA (500 mg/m2 i.v.) and a 22-h infusion of 5-FU (2000 mg/m2 i.v.), weekly for 6 weeks with a 1-week rest, or irinotecan (200 mg/m2 i.v.) and cisplatin (60 mg/m2 i.v.), on day 1 for 3 weeks. Results: A total of 115 patients were eligible for analysis in the per-protocol population. The overall response rate in the irinotecan/5-FU/FA arm (n=59) was 42.4%, with a complete response rate of 5.1%. Corresponding figures for the irinotecan/cisplatin arm (n=56) were 32.1% and 1.8%, respectively. The median time to progression was 6.5 months (irinotecan/5-FU/FA) and 4.2 months (irinotecan/cisplatin) (P < 0.0001), with median survival times of 10.7 and 6.9 months, respectively (P=0.0018). The major toxicity was grade 3/4 neutropenia, which was more pronounced with irinotecan/cisplatin than with irinotecan/5-FU/FA (65.7% versus 27%). Diarrhea was the main grade 3/4 non-hematological toxicity with both irinotecan/5-FU/FA (27.0%) and irinotecan/cisplatin (18.1%). Conclusions: Both combinations were active, with acceptable safety profiles. Irinotecan/5-FU/FA was selected as the most effective combination for investigation in a phase III trial in advanced gastric cancer.
To assess the efficacy of irinotecan (CPT-11) in the treatment of advanced colorectal cancer in both chemotherapy-naive and pretreated patients.
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.
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.
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.
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