Capecitabine and mitomycin C as third-line therapy for patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan

Chong, Geoff; Dickson, James L. B.; Cunningham, David; Norman, A.; S, Rao; Hill, Mark; Price, Tim; Oates, J.; Tebbutt, Niall C.

doi:10.1038/sj.bjc.6602733

Cited by 54 publications

(40 citation statements)

References 16 publications

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“…The 'ethical condition' to evaluate the clinical effect of an irinotecan metronomic treatment in this patient population depended on the fact that there was no evidence that a third/fourth line of chemotherapy could produce an improvement in terms of clinical benefit or efficacy in patients with mCRC already treated with both oxaliplatin-and irinotecan-based chemotherapy. The results of several phase II clinical studies showed that a third/fourth line of fluoropyrimidine-based chemotherapy in this setting of patients generally produces a poor response rate (around or less than 10%), with a median PFS between 2 and 3 months and with a median OS of approximately 6 -9 months (Chong et al, 2005;McCollum et al, 2006;Scartozzi et al, 2006). Besides the weak antitumour activity, these treatments are limited by a substantial toxicity Xgrade 3 (NCI scale) reported in about 10 -15% of all patients.…”

Section: Discussionmentioning

confidence: 99%

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

et al. 2008

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The pharmacokinetics (PK) and pharmacodynamics (PD) of metronomic irinotecan have not been studied in cancer patients. The aim of the study is to investigate the PK/PD profile of irinotecan/SN-38 administered by metronomic schedule. Twenty chemotherapyrefractory or chemotherapy-resistant patients with metastatic colorectal carcinoma were enrolled. Irinotecan was infused continuously as follows: irinotecan 1.4 mg m À2 day À1 (n ¼ 7), 2.8 mg m À2 day À1 (n ¼ 5) and 4.2 mg m À2 day À1 (n ¼ 8). Drug levels were examined by HPLC, whereas ELISAs and real-time RT-PCR were used, respectively, for the measurement of plasma levels and gene expression in peripheral blood mononuclear cells of vascular endothelial growth factor/thrombospondin-1. Pharmacokinetic analysis demonstrated that the steady-state levels (C ss ) of SN-38 were between 1 and 3.3 ng ml À1 . From a PD point of view, higher thrombospondin-1 (TSP-1) plasma levels (153.4±30.1 and 130.4±9.2% at day 49 vs pretreatment values at 1.4 and 2.8 mg m À2 day À1 dose levels, respectively) and increased gene expression in PBMC were found during the metronomic irinotecan infusion, especially at the lower doses. Four patients (20%) obtained a stable disease (median 3.9 months) despite progressing during previous standard irinotecan schedule. Toxicities 4grade 1 were not observed. Metronomic irinotecan administration is very well tolerated and induces an increase of gene expression and plasma concentration of TSP-1 at low plasma SN-38 concentrations.

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Section: Discussionmentioning

confidence: 99%

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

et al. 2008

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“…Firstly, we would like to reiterate our comments in the discussion that this regimen represents a viable option for patients with metastatic colorectal cancer who have previously received fluorouracil and irinotecan (Chong et al, 2005). The results of our study should not necessarily be extrapolated to patients who have previously received oxaliplatin or targeted agents.…”

Section: Sirmentioning

confidence: 88%

Reply: Capecitabine and mitomycin C in patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan

Chong

Cunningham

2006

Br J Cancer

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Sir,We acknowledge Dr Alliot's letter and would like to respond to the many points raised. Firstly, we would like to reiterate our comments in the discussion that this regimen represents a viable option for patients with metastatic colorectal cancer who have previously received fluorouracil and irinotecan (Chong et al, 2005). The results of our study should not necessarily be extrapolated to patients who have previously received oxaliplatin or targeted agents.For a single-arm study of third-line therapy for advanced colorectal cancer, the utility of biochemical prognostic factors in interpreting treatment efficacy is likely to be small. Therefore, these data have not been included. Of the 36 patients enrolled, 31 had liver metastases, and in eight patients, the primary tumour was in situ. Nevertheless, the treatment efficacy of a third-line regimen is not likely to be influenced by whether patients initially presented with synchronous or metachronous metastatic disease. With regard to the first-line 5-fluorouracil (5FU) regimen, a majority of patients received bolus 5FU/leucovorin (LV) according to the Mayo schedule; two patients received LV5FU2. There is no evidence that LV5FU2 vs bolus 5FU/LV influences the efficacy of subsequent chemotherapy.The limited efficacy of capecitabine monotherapy for patients who are 5FU-refractory has been well demonstrated previously (Hoff et al, 2004). However, there are preclinical data suggesting that the addition of mitomycin C (MMC) to capecitabine may be synergistic. In patients with untreated advanced colorectal cancer, the addition of MMC to capecitabine has been shown to produce higher response rate than expected with capecitabine alone, (Rao et al, 2004). The 15.4% response rate for the combination of MMC and capecitabine observed in our study of pretreated patients is therefore consistent with these data.There are substantial data on the incidence of haemolytic uraemic syndrome (HUS) in patients treated with MMC. The incidence for patients receiving less than 30 mg m À2 is very low (Ross et al, 1997(Ross et al, , 2002Tebbutt et al, 2002). However, we agree that patients receiving MMC, regardless of cumulative dose, should be closely monitored for the development of HUS.Clearly, our data are not directly applicable to patients who have received first-or second-line oxaliplatin, bevacizumab or cetuximab. However, for patients who have not had (and will not have) access to these drugs, the combination of capecitabine and MMC is a potentially active one for patients with advanced colorectal cancer. REFERENCES

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“…Combination with MMC resulted in a response rate of 15% in irinotecan-resistant cancer, but its efficacy fell to 5% when the cancer was resistant to both irinotecan and oxaliplatin. Other combinations with trimetrexate or irinotecan did not show any additional benefit either (Chong et al, 2005;Gubanski et al, 2005;Matin et al, 2005).…”

Section: Discussionmentioning

confidence: 98%

A phase II trial of S-1 monotherapy in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens

et al. 2006

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This is the first phase II study of S-1 monotherapy for patients with metastatic colorectal cancer after failure of both irinotecan-and oxaliplatin-containing regimens. The initial dose of S-1 was 35 mg m À2 , administered twice daily for 14 days every 3 weeks. Treatment was repeated until the occurrence of disease progression. Twenty-eight patients were enrolled. S-1 was administered to 21 patients as third-line therapy and to the remaining seven patients as fourth-line therapy. Of 26 evaluable patients, the overall response rate was 14.3% (95% CI, 0.4 -28.1), and the disease control rate was 42.9% (95% CI, 23.3 -62.4). With a median follow-up period of 227 days, median time to progression and overall survival duration were 91 and 414 days, respectively. The 1-year survival rate of all patients was 60.7%. There was no grade 4 toxicity. Grade 3 haematological toxicities were documented only in two patients. In conclusion, S-1 shows potential as a salvage regimen in heavily pretreated colorectal cancer patients. The twice-daily dose of 35 mg m À2 was well tolerated and can be used in designing further combination chemotherapy.

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Capecitabine and mitomycin C as third-line therapy for patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan

Cited by 54 publications

References 16 publications

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

Reply: Capecitabine and mitomycin C in patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan

A phase II trial of S-1 monotherapy in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens

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