Phase III Study of Capecitabine Plus Oxaliplatin Compared With Fluorouracil and Leucovorin Plus Oxaliplatin in Metastatic Colorectal Cancer: A Final Report of the AIO Colorectal Study Group

Porschen, Rainer; Arkenau, Hendrik Tobias; Kubicka, S.; Greil, Richard; Seufferlein, Thomas; Freier, W.; Kretzschmar, Albrecht; Graeven, Ullrich; Grothey, Axel; Hinke, Axel; Schmiegel, Wolff; Schmoll, Hans Joachim

doi:10.1200/jco.2006.09.2684

Cited by 253 publications

(139 citation statements)

References 23 publications

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“…Other schedules of oxaliplatin and capecitabine (CAPOX: 70 mg m À2 oxaliplatin on days 1 and 8 and 2000 mg m À2 day À1 capecitabine for 14 days with a 1-week rest) were compared with FUFOX. CAPOX was slightly inferior to FUFOX in TTP: median TTP 7.1 vs 8.0 months (P ¼ 0.117), and MST 16.8 vs 18.8 months (P ¼ 0.26) (Porschen et al, 2007). Both regimens were generally well tolerated, although grade 2 or 3 HFS occurred more often with CAPOX (10 vs 4%) (P ¼ 0.028).…”

Section: Discussionmentioning

confidence: 93%

Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

Yamada¹,

Tahara

Miya

et al. 2008

Br J Cancer

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Two phase II studies of S-1 monotherapy have shown promising response rates (RR) of 35 -40% with good tolerability in patients with untreated metastatic colorectal cancer. To investigate the usefulness of S-1 plus oxaliplatin (SOX) as an alternative to infusional 5-fluorouracil/leucovorin plus oxaliplatin, the recommended dose (RD) of SOX was determined, and its safety and preliminary efficacy were evaluated in a phase I/II study. Oxaliplatin was administered at a dose of 100 mg m À2 (level 1) or 130 mg m À2 (level 2) on day 1, and S-1 (80 -120) was given twice daily for 2 weeks followed by a 1-week rest. This schedule was repeated every 3 weeks. Level 2 was determined to be the RD. For the 28 patients who received the RD, the median treatment course was 6.5 cycles (2 -14), RR of 50% (1 CR and 13 PR: 95% CI 31 -69%), with a median progression-free survival of 196 days. Survival rate (1 year) was 79%. Peripheral neuropathy was observed in all patients but with no functional disorders. Major grade 3 or 4 adverse reactions at the RD were neutropaenia (14%), thrombocytopaenia (28%), and diarrhoea (3%). SOX regimen is effective and easily manageable without central vein access. Potassium oxonate is an orotate phosphoribosyl transferase inhibitor that is distributed primarily to the gastrointestinal tract. This component of S-1 decreases incorporation of 5-fluorouridine triphosphate into RNA in the gastrointestinal mucosa and reduces the incidence of diarrhoea. F-b-alanine (FBAL) is the main metabolite of 5-FU. F-b-alanine and fluorocitrate are thought to cause the neurotoxic and cardiotoxic effects of 5-FU by inhibiting the tricarboxylic acid cycle (Okeda et al, 1990;Robben et al, 1993;Diasio 1998). The CDHP component of S-1 inhibits DPD, the rate-limiting enzyme in the catabolic pathway of 5-FU. Consequently, the plasma FBAL concentration after oral administration of S-1 is significantly lower than that after continuous infusion of 5-FU (Yamada et al, 2003). Therefore, S-1 may decrease the incidence of neurotoxicity and cardiotoxicity. The response rate of S-1 monotherapy has been found to be 35-40% for patients with metastatic colorectal cancer (Ohtsu et al, 2000;Shirao et al, 2004), with grade 3 or 4 neutropaenia observed in 5-13%, thrombocytopaenia in 0-8%, diarrhoea in 2-3%, and grade 1 hand-foot syndrome (HFS) in 5%.Oxaliplatin is a third-generation platinum compound with less toxicity and improved convenience. The regimen of infusional 5-FU and leucovorin (LV) with oxaliplatin is the standard for firstand second-line chemotherapy in patients with metastatic colorectal cancer (de Gramont et al, 2000;Rothenberg et al, 2003;Goldberg et al, 2004). However, infusional 5-FU with LV has the disadvantages of increased inconvenience, cost, and morbidity related to the use of a portable infusion pump and a central venous catheter. Therefore, oral fluoropyrimidine monotherapy has been commonly used in Japan.The primary objectives of this phase I/II study were to determine the maximum tolerated dose (MTD) of S-1 plus oxal...

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Section: Discussionmentioning

confidence: 93%

Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

Yamada¹,

Tahara

Miya

et al. 2008

Br J Cancer

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“…For the reason that therapeutic effectiveness diminished following the multiple-line chemotherapies because of drug resistance or the decreased tumor response, we make our decision in first-line treatment regimen with cautious consideration. According to the latest NCCN (The National Comprehensive Cancer Network) clinical practice guidelines in Oncology version 1.2013, five chemotherapy regimens including FOLFOX (Tournigand et al, 2004), FOLFIRI (Tournigand et al, 2004;Colucci et al, 2005), CapeOx (Cassidy et al, 2004;Porschen et al, 2007;Cassidy et al, 2008), infusional 5-FU/LV or capecitabine (Petrelli et al, 1987;Jager et al, 1996) and FOLFOXIRI (Souglakos et al, 2006;Falcone et al, 2007) are recommended as the first-line treatment in metastatic CRCs. FOLFOX is the most common regimen.…”

Section: Serum Mir-19a Predicts Resistance To Folfox Chemotherapy In mentioning

confidence: 99%

Serum miR-19a Predicts Resistance to FOLFOX Chemotherapy in Advanced Colorectal Cancer Cases

Chen¹,

Xiao²,

Ge³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Colorectal cancer is the fourth most common cancer worldwide and the second leading cause of cancer-related death. FOLFOX is the most common regimen used in the first-line chemotherapy in advanced colorectal cancer, but only half of the patients respond to this regimen and we have almost no clue in predicting resistance in such first-line application. Methods: To explore the potential molecular biomarkers predicting the resistance of FOLFOX regimen as the first-line treatment in advanced colorectal cancer, we screened microRNAs in serum samples from drug-responsive and drug-resistant patients by microarrays. Then differential microRNA expression was further validated in an independent population by reverse transcription and quantitative realtime PCR. Results: 62 microRNAs expressing differentially with fold-change >2 were screened out by microarray analysis. Among them, 5 (miR-221, miR-222, miR-122, miR-19a, miR-144) were chosen for further validation in an independent population (N=72). Our results indicated serum miR-19a to be significantly up-regulated in resistance-phase serum (p=0.009). The ROC curve analysis showed that the sensitivity of serum miR-19a to discriminate the resistant patients from the response ones was 66.7%, and the specificity was 63.9% when the AUC was 0.679. We additionally observed serum miR-19a had a complementary value for cancer embryonic antigen (CEA). Stratified analysis further revealed that serum miR-19a predicted both intrinsic and acquired drug resistance. Conclusions: Our findings confirmed aberrant expression of serum miR-19a in FOLFOX chemotherapy resistance patients, suggesting serum miR-19a could be a potential molecular biomarker for predicting and monitoring resistance to first-line FOLFOX chemotherapy regimens in advanced colorectal cancer patients.

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“…Five phase III RCTs have been reported to establish non-inferiority of CAPOX compared with FOLFOX. Table 6 shows the efficacy results of these studies (Diaz-Rubio et al, 2007;Ducreux et al, 2007;Porschen et al, 2007;Cassidy et al, 2008;Rothenberg et al, 2008). Two studies did not meet the primary objective of demonstrating non-inferiority in PFS with CAPOX compared with FOLFOX (Diaz-Rubio et al, 2007;Porschen et al, 2007).…”

Section: Should Oral Fluoropyrimidines Substitute Infused Fluorouracimentioning

confidence: 99%

“…Table 6 shows the efficacy results of these studies (Diaz-Rubio et al, 2007;Ducreux et al, 2007;Porschen et al, 2007;Cassidy et al, 2008;Rothenberg et al, 2008). Two studies did not meet the primary objective of demonstrating non-inferiority in PFS with CAPOX compared with FOLFOX (Diaz-Rubio et al, 2007;Porschen et al, 2007). In the third study , a rather permissive non-inferiority margin was used with a primary end point being ORR -a questionable primary efficacy end point for first line advanced CRC trials in the modern era.…”

Section: Should Oral Fluoropyrimidines Substitute Infused Fluorouracimentioning

confidence: 99%

Treatment in advanced colorectal cancer: what, when and how?

Chau

Cunningham

2009

Br J Cancer

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Treatment of advanced colorectal cancer (CRC) increasingly requires a multidisciplinary approach and multiple treatment options add to the complexity of clinical decision-making. Recently novel targeted therapy against angiogenesis and epidermal growth factor receptor completed a plethora of phase III studies. The addition of bevacizumab to chemotherapy improved the efficacy over chemotherapy alone in both first and second line settings, although the magnitude of benefit may not be as great when a more optimal chemotherapy platform is used. Studies performed thus far did not address conclusively whether bevacizumab should be continued in subsequent lines of treatment. Anti-angiogenesis tyrosine kinase inhibitors have not shown any additional benefit over chemotherapy alone so far. Although some benefits were seen with cetuximab in all settings of treating advanced CRC, K-ras mutation status provides an important determinant of who would not benefit from such a treatment. Caution should be exercised in combining anti-angiogenesis with anti-EGFR strategy until further randomised data become available. In this review, we have focused on the implications of these trial results on the everyday management decisions of treating advanced CRC.

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Phase III Study of Capecitabine Plus Oxaliplatin Compared With Fluorouracil and Leucovorin Plus Oxaliplatin in Metastatic Colorectal Cancer: A Final Report of the AIO Colorectal Study Group

Cited by 253 publications

References 23 publications

Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

Serum miR-19a Predicts Resistance to FOLFOX Chemotherapy in Advanced Colorectal Cancer Cases

Treatment in advanced colorectal cancer: what, when and how?

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