P-189 Correlation between of expression of the enzyme topoisomerase I and p53 and result of irinotecan based therapy in patients with metastatic colorectal cancer

PURPOSE AND METHODS: For more than three decades, the therapeutic options for patients with advanced colorectal cancer have almost exclusively been based on fluoropyrimidines. With the recognition that topoisomerase-I (TOP-I) is an important therapeutic target in cancer therapy, irinotecan, a semisynthetic TOP-I–interactive camptothecin derivative, has been clinically established in the treatment of colorectal cancer. RESULTS: Irinotecan was investigated as second-line chemotherapy after prior treatment with fluorouracil (FU)-based regimens in two large randomized phase III trials comparing irinotecan with either best supportive care or an infusional FU/leucovorin (LV) regimen. The outcomes of these trials established irinotecan as the standard therapy in the second-line treatment of colorectal cancer. The therapeutic value of irinotecan in the first-line treatment of metastatic colorectal cancer was investigated in two large randomized phase III trials comparing the combination of irinotecan and FU/LV with FU/LV alone. Both trials demonstrated significant superior efficacy for the combination of irinotecan and FU/LV in terms of response rate, median time to disease progression, and median survival time. Consequently, the combination of irinotecan and FU/LV has been approved as first-line chemotherapy for patients with metastatic colorectal cancer and constitutes the reference therapy against which other treatment options must be tested in the future. CONCLUSION: In this review, the clinical rationale and update of the present clinical status of irinotecan in the treatment of colorectal cancer and future prospects of irinotecan-based combinations are discussed.

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Irinotecan is an active agent in untreated patients with metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.3.709 ◽

1996 ◽

Vol 14 (3) ◽

pp. 709-715 ◽

Cited By ~ 213

Author(s):

J A Conti ◽

N E Kemeny ◽

L B Saltz ◽

Y Huang ◽

W P Tong ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Topoisomerase I ◽

Active Agent ◽

Response Duration ◽

Median Response ◽

Strict Adherence ◽

Severe Diarrhea ◽

Grade 3 ◽

Tumor Biopsies

PURPOSE To determine the response rate, survival, and toxicity of the new anticancer agent, irinotecan (CPT-11), in the treatment of metastatic colorectal cancer. PATIENTS AND METHODS Forty-one chemotherapy-naive patients with measurable metastatic colorectal cancer were treated with a 90-minute infusion of irinotecan 125 mg/m2 administered weekly for 4 weeks every 6 weeks. Pretreatment tumor biopsies to assess topoisomerase-I (Topo-I) activity were obtained from 11 patients. The pharmacokinetics for irinotecan and its active metabolite, SN-38, were determined in 18 patients. RESULTS Thirteen of 41 patients (32%) had a partial response (PR; 95% confidence interval, 18% to 46%). The median response duration was 8.1 months (range, 4.0 to 16.0) and the median survival time was 12.1 months (range, 2.1 to 21.7) for all 41 patients. Grade 3 or 4 toxicities were diarrhea (29% of patients) and neutropenia (22% of patients). Grade 3 or 4 diarrhea was substantially more prevalent in the initial 18 patients on study, with an incidence rate of 56%; a significant reduction in the incidence of severe diarrhea to 9% was noted with strict adherence to an antidiarrheal regimen of loperamide and diphenyldramine. No correlations were seen between pharmacokinetics of irinotecan/SN-38 and the clinical parameters of response, survival, or incidence of diarrhea. CONCLUSIONS Irinotecan has activity in the treatment of patients with metastatic colorectal cancer. Strict adherence to an antidiarrheal regimen of diphenhydramine/loperamide significantly reduced the incidence of diarrhea; the agent was thereafter well tolerated in the majority of patients.

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Assessment of the topoisomerase I gene copy number as a predictive biomarker of objective response to irinotecan in metastatic colorectal cancer

Scandinavian Journal of Gastroenterology ◽

10.3109/00365521.2013.856464 ◽

2013 ◽

Vol 49 (1) ◽

pp. 84-91 ◽

Cited By ~ 13

Author(s):

Sune Boris Nygård ◽

Ib Jarle Christensen ◽

Signe Lykke Nielsen ◽

Hans Jørgen Nielsen ◽

Nils Brünner ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Copy Number ◽

Topoisomerase I ◽

Objective Response ◽

Gene Copy Number ◽

Predictive Biomarker ◽

Gene Copy ◽

I Gene

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Phase II and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.9.2540 ◽

1996 ◽

Vol 14 (9) ◽

pp. 2540-2545 ◽

Cited By ~ 42

Author(s):

G J Creemers ◽

C J Gerrits ◽

J H Schellens ◽

A S Planting ◽

M E van der Burg ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Continuous Infusion ◽

Phase Ii ◽

Topoisomerase I ◽

Single Agent ◽

Locally Advanced ◽

Specific Inhibitor ◽

Continuous Exposure ◽

Median Response

PURPOSE Topotecan is a specific inhibitor of topoisomerase I. Preclinical data have indicated that topoisomerase I inhibitors demonstrate more efficacy and have a greater therapeutic index with prolonged continuous exposure. The feasibility of this concept in humans using a 21-day continuous infusion of topotecan has been reported. We conducted a phase II study of this 21-day continuous topotecan administration schedule in patients with locally advanced, unresectable or metastatic colorectal cancer. PATIENTS AND METHODS Topotecan, initially applied at a dose of 0.6 mg/m2/d, was administered as a continuous infusion via an ambulatory pump for 21 days repeated every 4 weeks. The starting dose was reduced to 0.5 mg/m2/d, because in five of the first 11 patients, the second course had to be delayed due to prolonged myelosuppression. Forty-two patients entered the study; one patient was ineligible and was excluded from further analyses. RESULTS The overall response rate was 10%, with one complete and three partial responses. The median response duration was 7 months (range, 4 to 11). With this schedule, the major toxicity was prolonged cumulative myelosuppression, including a marked inhibition of erythropoiesis. A total transfusion of 250 U of erythrocytes was needed to maintain a hemoglobin level greater than 6.0 mmol/L. Other side effects were mild, and included alopecia (47%), periodic nausea (40%)/vomiting (22%), and fatigue (16%). Pharmacokinetic evaluation showed a mean steady-state plasma concentration (Css) of topotecan of 0.62 ng/mL (range, 0.33 to 1.1), with a significant relationship between the Css of topotecan and common cytotoxicity criteria (CTC) grade of leukocytopenia. CONCLUSION Topotecan administered as a 21-day continuous infusion exerts minor activity as single-agent therapy in patients with metastatic colorectal cancer.

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Polymorphisms correlated with the clinical outcome of locally advanced or metastatic colorectal cancer patients treated with ALIRI vs. FOLFIRI

Pteridines ◽

10.1515/pterid-2013-0021 ◽

2013 ◽

Vol 24 (1) ◽

pp. 69-79 ◽

Cited By ~ 2

Author(s):

Ana Barcelos ◽

Elisa Giovannetti ◽

Robert de Jonge ◽

Mina Maftouh ◽

Pieter Griffioen ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Outcome ◽

Metastatic Colorectal Cancer ◽

Topoisomerase I ◽

Univariate Analysis ◽

Locally Advanced ◽

Progression Free Survival ◽

Copy Number Variations ◽

Rank Test ◽

Functional Polymorphisms

AbstractLeucovorin-modulated 5-fluorouracil (5-FU) plus irinotecan (FOLFIRI) is the most common treatment of metastatic colorectal cancer (CRC). 5-FU inhibits thymidylate synthase (TS) and irinotecan topoisomerase I, leading to inhibition of DNA replication and repair. FOLFIRI efficacy suggested that other TS inhibitors might synergize with irinotecan, and Phase I/II studies for second-line treatment showed promising results of combinations with the multitargeted antifolate pemetrexed (PMX), which exerts its effects primarily via TS inhibition. However, a randomized Phase II trial of PMX + irinotecan (ALIRI) showed similar efficacy and safety, but significantly shorter progression-free survival (PFS) compared with FOLFIRI in locally advanced or metastatic CRC. In our previous aCGH study, we evaluated genome-wide copy number variations, whereas in the current study we evaluated relationships between functional polymorphisms and PFS. Candidate polymorphisms were studied by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) (TSER-2R/3R) or Taqman-PCR (MTHFR-1958G>A, MTR-2756A>G, MTHFR-1298A>C, SHMT1-1420C>T, ATIC-347C>G, AMPD-134C>T, MTRR-66A>G and SLC-19A180G>A) in 84 patients (40 FOLFIRI, 44 ALIRI). The Kaplan-Meier method was used to plot PFS, and the log-rank test to compare curves. At univariate analysis the homozygous variants of both MTR-2756A>G and SHMT1-1420C>T were associated with significantly shorter PFS. Conversely, a significantly longer PFS (7.3 months) was observed when ATIC-347C>G CC+CG genotypes were grouped vs. GG. At multivariate analysis the genotypes MTR-2756A>G AA+AG, SHMT1-1420C>T TT+CT and ATIC-347C>G CC+CG emerged as significant predictors for PFS. Because MTR, SHMT1 and ATIC are all involved in folate pathways, we further explored the effect of a combination of their risk genotypes on PFS, showing that patients carrying two risk genotypes had a significantly shorter PFS (3.9 months, p<0.001). The correlations of polymorphisms in genes with clinical outcome underscore the importance of a candidate gene-based approach. Ultimately, the validation of the role of these polymorphisms in prospective multicenter trials might optimize currently available treatments in selected CRC patients (e.g., FOLFIRI) or PMX-based treatments in other tumor types.

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