Evaluation of the 5-fluorouracil plasma level in patients with colorectal cancer undergoing continuous infusion chemotherapy.

5-Fluorouracil (5-FU) dosing has traditionally been based on the body surface area (BSA) in colorectal cancer treatment. However, there is accumulating evidence that dosing based on BSA may be of limited use. The purpose of the present study was to evaluate the changes in 5-FU plasma levels and tumor response as well as the severity of adverse events in patients with cancer treated with 5-FU combined chemotherapy. The dosing amount of 5-FU was determined based on the BSA. Blood samples were collected, and 5-FU plasma levels in 15 patients with colorectal cancer were measured three times (0, 22 and 40 h before and after the start of infusion) during constant-infusion of 5-FU for 46 h by an immunoassay. 5-FU plasma levels were significantly higher at 22 and 40 h compared with at 0 h (P<0.001), when all 15 patients were analyzed. Notably, the tumor response of the partial response/stable disease group showed significant increases in 5-FU plasma levels at 40 h compared with at 22 h (P<0.01), while the progressive disease group showed no significant increase. In addition, the 5-FU plasma level in the adverse event level of grade ≥2 was higher than that of grade <2 at 40 h after the start of infusion. Collectively, these observations indicated that during continuous infusion of 5-FU, the 5-FU plasma level increased significantly, and the tumor response (such as partial response, stable or progressive disease) may be influenced by the increase of 5-FU plasma level from the start of infusion. Therefore, the 5-FU plasma level may be a predictive factor for maximizing the tumor response and minimizing the risk of severe adverse events.

Impact of primary tumor location as a predictive factor in patients suffering from colorectal cancer treated with cytotoxic anticancer agents based on the collagen gel droplet-embedded drug sensitivity test.

In recent studies, better clinical outcomes for patients with left-sided colon cancer (CC) compared with right-sided CC have been reported; however, in such investigations, the chemotherapy regimens included molecular-targeting agents. To the best of our knowledge, the impact of primary tumor location as a predictive factor in patients suffering from CC treated with cytotoxic anticancer agents alone has not been investigated. The aim of the present study was to determine the impact of the primary tumor location as a predictive factor of patients undergoing the following cytotoxic anticancer agent regimens: Leucovorin and fluorouracil + oxaliplatin (FOLFOX) or Leucovorin and fluorouracil + irinotecan (FOLFIRI), using the collagen gel droplet-embedded drug sensitivity test (CD-DST). Between March 2008 and April 2017, tumor specimens were obtained from 133 patients suffering from colorectal cancer (CRC) who had not received preoperative chemotherapy. CD-DST was performed and the growth inhibition rate (IR) was determined in FOLFOX and FOLFIRI regimens. The associations between tumor location and IR values for each condition were evaluated. In the present study, the prognosis of patients receiving palliative chemotherapy as well as treatment with molecularly-targeted agents was also investigated. There were no significant differences in the IRs (%) of the two regimens using CD-DST for right-sided tumors compared with left-sided tumors, including or excluding the rectum. The median survival times of patients with right CC and left CC who had received palliative chemotherapy and treatment with molecularly-targeted agents were 960 and 1,348 days, respectively. Primary tumor location did not represent a predictive factor for the efficacy of treatment with cytotoxic anticancer agent regimens using CD-DST. However, patients suffering from left-sided CC were revealed to exhibit better clinical outcomes compared with patients suffering from right-sided CC when molecularly-targeted agent regimens were administered. Therefore, the results of the present study suggested that molecularly-targeted agents rather than cytotoxic anticancer agents may result in improved clinical outcomes for patients with CRC suffering from left-sided tumors.

Impact of the individualization of the first-line chemotherapy for advanced colorectal cancer based on collagen gel droplet-embedded drug sensitivity test.

Leucovorin (FOL) and fluorouracil (5-FU) plus oxaliplatin (l-OHP; FOLFOX) or FOL and 5-FU plus irinotecan (SN-38; FOLFIRI) are widely used as first-line chemotherapy regimens in the treatment of advanced colorectal cancer (CRC). However, second-line chemotherapy must be abandoned in certain cases due to disease progression, adverse effects or high medical cost. Therefore, the most effective regimen should be selected as first-line chemotherapy. We reported that individualization of first-line treatment (FOLFOX/FOLFIRI/Dual/Poor responder) was possible using the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) and that individualized first-line chemotherapy with CD-DST may improve the prognosis of patients with unresectable CRC. The aim of the present prospective cohort study was to evaluate the individualization of first-line chemotherapy using CD-DST, with a focus on prognosis. Between March 2008 and December 2015, tumor specimens were obtained from 120 patients with CRC who had not received preoperative chemotherapy. CD-DST was performed and the growth inhibition rate (IR) was determined by exposure for 24 h with 5-FU and l-OHP (6.0 and 3.0 µg/ml, respectively) and 5-FU and SN-38 (6.0 and 0.2 µg/ml, respectively). The cumulative distribution of IR values under each condition was evaluated on the basis that the clinical response to FOLFOX and FOLFIRI is equivalent (~50%). The prognosis of dual responder was improved compared with that of poor responders, however this difference was identified to be significant. There was no different prognosis between patients treated with an appropriate first-line regimen and patients treated with an inappropriate first-line regimen in dual responders. However, in poor responders, there were significant differences of prognosis between patients treated with an appropriate first-line regimen and patients treated with an inappropriate first-line regimen (P=0.036). In conclusion, the results from the present study suggest that administration of the recommended first-line regimen using CD-DST for patients with unresectable CRC is important for the improvement of prognosis, particularly in poor responders.

Mechanism underlying the transient increase of serum iron during FOLFOX/FOLFIRI therapy.

In patients with advanced colorectal cancer (CRC), a transient significant increase of serum iron is observed during chemotherapy with leucovorin and fluorouracil plus oxaliplatin (FOLFOX) or leucovorin and fluorouracil plus irinotecan (FOLFIRI). Serum iron may be a useful and convenient predictor of the response to chemotherapy; however, the mechanism underlying its increase has not been fully elucidated. Accordingly, the mechanism underlying the elevation of serum iron during chemotherapy was investigated in 20 patients with advanced CRC who were treated between September, 2012 and July, 2013. The levels of iron, ferritin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), hemoglobin (Hb), hepcidin-25, interleukin (IL)-6 and soluble transferrin receptor (sTfR) were measured before and 48 h after chemotherapy. The serum levels of iron and hepcidin-25 were found to be significantly increased after chemotherapy (P<0.0001), whereas those of IL-6 were significantly decreased (P=0.0057). There were no significant changes in any of the other parameters. The lack of significant changes in AST, ALT and Hb suggested that the elevation of serum iron was not due to the destruction of hepatocytes, whereas the stable sTfR level suggested no destruction of erythroblasts. Hepcidin-25 regulates iron metabolism and decreases serum iron levels; it is increased by an iron load and IL-6, but is decreased under anemic or hypoxic conditions. The suppression of erythropoiesis increases serum iron levels and chemotherapy suppresses erythropoiesis. As serum iron and hepcidin-25 were both significantly increased and IL-6 was significantly decreased, with no significant changes in sTfR, it appears that the elevation of serum iron during chemotherapy may be secondary to reduced iron consumption by erythropoiesis, leading to increased expression of hepcidin-25 and suppression of Il-6 via negative feedback.

Serum iron levels as a new biomarker in chemotherapy with leucovorin and fluorouracil plus oxaliplatin or leucovorin and fluorouracil plus irinotecan, with or without molecularly-targeted drugs.

Serum iron levels have been reported to increase following the administration of various anticancer drugs. An increase in serum iron levels during therapy with leucovorin and fluorouracil plus oxaliplatin (FOLFOX) or leucovorin and fluorouracil plus irinotecan (FOLFIRI) was also observed. The aim of this study was to investigate the correlation between serum iron levels and prognosis in advanced colorectal cancer (CRC) patients treated with FOLFOX/FOLFIRI ± molecularly-targeted drugs. Serum iron levels were measured prior to and at 48 h after treatment with FOLFOX/FOLFIRI ± molecularly-targeted drugs in 72 advanced CRC patients, all of whom succumbed to the disease between December, 2005 and February, 2012. No patients received radiotherapy. Taking the median rate of increase in serum iron levels as the cut-off value in each therapy, the patients were divided into cohort I (increase rate greater than the cut-off value in at least one therapy) or cohort II (increase rate less than the cut-off value in all therapies). The χ2 test and the t-test were used to compare patient characteristics between the two cohorts. Prognosis was evaluated between the two cohorts using the Kaplan-Meier method, the log-rank test and the Cox proportional hazards regression analysis. No significant bias in patient characteristics (including the frequency of chemotherapy or number of patients treated with molecularly-targeted drugs) was observed between the two cohorts. Serum iron levels were transiently elevated following treatment (P<0.001), returning to baseline within 2 weeks. Median survival time (MST) in cohort I (n=44) and cohort II (n=28) was 430 and 377 days, respectively. The MST was significantly higher in cohort I (P=0.0382). The multivariate analysis identified a small increase in serum iron levels as an independent risk factor for overall survival (OS). These results suggest that serum iron levels may be used as a new predictive factor in FOLFOX/FOLFIRI ± molecularly-targeted drug therapy. Serum iron levels may therefore prove to be a useful and convenient biomarker for OS in CRC patients.

Individualized chemotherapy for colorectal cancer based on the collagen gel droplet-embedded drug sensitivity test.

The leucovorin (FOL) and fluorouracil (5-FU) plus oxaliplatin (l-OHP; FOLFOX) or FOL and 5-FU plus irinotecan (SN-38; FOLFIRI) regimens with or without molecularly-targeted drugs are widely used as first-line chemotherapy in the treatment of advanced colorectal cancer (CRC). Whether FOLFOX or FOLFIRI is administered first is not significant, however, it is essential that full administration of the targeted dosages of all 3 drugs, 5-FU, l-OHP and SN-38, is achieved. However, this is not always possible and second-line chemotherapy must be abandoned in certain cases. Where possible, the most effective regimen should be selected as the first line of treatment. The aim of this study was to determine whether first-line chemotherapy may be individualized using the collagen gel droplet-embedded drug sensitivity test (CD-DST). Specimens of primary tumors were obtained from 43 CRC patients who had received no preoperative chemotherapy. Informed consent to measure drug sensitivity was obtained from all patients. The CD-DST allows evaluation of drug sensitivity using isolated, 3-dimensionally cultured tumor cells in a small collagen gel droplet. The CD-DST was performed and the growth inhibition rate (IR) was obtained under incubation conditions (5-FU with l-OHP at 6.0 and 3.0 µg/ml, or 5-FU with SN-38 at 6.0 and 0.2 µg/ml, respectively, for 24 h). The cumulative distributions of the growth IRs under each condition were evaluated based on the evidence that the clinical response rates to FOLFOX and FOLFIRI were almost the same. Individualization of first-line treatment was possible in all patients, with FOLFOX and FOLFIRI showing higher efficacy in 26 and 15 patients, respectively, and equal efficacy in 2 cases. This method has the potential to facilitate the establishment of individualized first-line chemotherapy for CRC and improve the prognosis in such patients.

Good response to leucovorin and fluorouracil plus oxaliplatin and cetuximab therapy in a patient with metastatic ascending colon cancer harboring a KRAS p.G13D mutation.

The effectiveness of cetuximab (Cmab) against KRAS p.G13D mutant-type tumors has been reported. In this study, we report a case of metastatic ascending colon cancer harboring a KRAS p.G13D mutation in a 65-year-old female. Considering the absence of symptoms and the post-operative risk of respiratory system complications due to multiple lung metastases, particularly at the entrance to the left main bronchus, anticancer drug therapy was selected as first-line therapy. With informed consent, FOLFOX4 [folinic acid (FOL), fluorouracil (F) plus oxaliplatin (OX)] + Cmab therapy was administered as preoperative chemotherapy. A good preoperative response was obtained to the chemotherapy, with a metastatic lesion disappearing from the entrance to the left main bronchus. Subsequent resection was performed successfully with no post-operative complications. Although a histopathological examination of the resected tissue specimen revealed residual cancer cells, it also showed the marked efficacy of the chemotherapy regimen used. In this study, we describe a case of metastatic ascending colon cancer harboring a KRAS p.G13D mutation in which the patient responded well to first-line therapy with FOLFOX4 + Cmab.