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Background: Trifluridine/tipiracil (TAS-102) is an oral anticancer drug with adequate efficacy in unresectable colorectal cancer, but frequently also induces chemotherapy-induced nausea and vomiting (CINV). To investigate the occurrence of CINV and antiemetic therapy in patients with colorectal cancer treated with TAS-102 (JASCC-CINV 2001)., Methods: We conducted a multicenter, prospective, observational study in patients with colorectal cancer who received TAS-102 without dose reduction for the first time. Primary endpoint was the incidence of vomiting during the overall period. Secondary endpoints were the incidence of nausea, significant nausea, anorexia, other adverse events (constipation, diarrhea, insomnia, fatigue, dysgeusia) and patient satisfaction. Patient diaries were used for primary and secondary endpoints. All adverse events were subjectively assessed using PRO-CTCAE ver 1.0. and CTCAE ver 5.0., Results: Data from 100 of the 119 enrolled patients were analyzed. The incidence of vomiting, nausea, and significant nausea was 13%, 67%, and 36%, respectively. The incidence of vomiting in patients with and without prophylactic antiemetic therapy were 20.8% and 10.5%, respectively. Prophylactic antiemetics were given to 24% of patients, of whom 70% received D 2 antagonists. Multivariate Cox proportional hazards analysis showed that experience of CINV in previous treatment tended to be associated with vomiting (hazard ratio [HR]: 7.13, 95% confidence interval [CI]: 0.87-58.5, P = 0.07), whereas prophylactic antiemetic administration was not (HR: 1.61, 95 CI: 0.50-5.21, P = 0.43). With regard to patient satisfaction, the proportion of patients who were "very satisfied," "satisfied," "slightly satisfied" or "somewhat satisfied" was 81.8%., Conclusions: The low incidence of vomiting and high patient satisfaction suggest that TAS-102 does not require the use of uniform prophylactic antiemetic treatments. However, patients with the experience of CINV in previous treatment might require prophylactic antiemetic treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Several studies have reported an association between severe neutropenia and long-term survival in patients treated with trifluridine-tipiracil (TAS-102). Because some of these studies failed to address immortality time bias, however, their findings should be interpreted with caution. Additionally, the association between severe neutropenia and survival in patients receiving TAS-102 in combination with bevacizumab (Bmab) remains unclear., Patients and Methods: We conducted a single-center retrospective cohort study in patients with colorectal cancer who received Bmab + TAS-102. We compared overall survival (OS) between patients who developed grade ≥ 3 neutropenia during the treatment period and those who did not. To account for immortal time bias, we used two approaches, time-varying Cox regression and landmark analysis., Results: Median OS was 15.3 months [95% CI: 14.1-NA] in patients with grade ≥ 3 neutropenia and 10.0 months [95% CI: 8.1-NA] in those without. In time-varying Cox regression, onset grade ≥ 3 neutropenia was significantly related to longer survival after adjustment for age and modified Glasgow Prognostic Score. Additionally, 30-, 60-, 90-, and 120-day landmark analysis showed that grade ≥ 3 neutropenia was associated with longer survival after adjustment for age and modified Glasgow Prognostic Score, with respective HRs of 0.30 [0.10-0.90], 0.65 [0.30-1.42], 0.39 [0.17-0.90], and 0.41 [0.18-0.95]., Conclusion: We identified an association between long-term survival and the development of severe neutropenia during the early cycle of Bmab + TAS-102 using an approach that addressed immortality time bias., (© 2023. The Author(s).)

Background/aim: Although combination chemotherapy with trifluridine/tipiracil (TAS-102) and bevacizumab (BEV) is highly effective for metastatic unresectable colorectal cancer (mCRC), this combination chemotherapy often induces nausea and vomiting. To identify risk factors for nausea and vomiting, we investigated the occurrence of nausea and vomiting in mCRC patients treated with TAS-102 and BEV., Patients and Methods: Study patients with mCRC received TAS-102 and BEV between March 2016 and December 2021. The status of nausea, vomiting, and antiemetic measures in each course were investigated, and factors involved in the occurrence of nausea and vomiting were analysed by logistic regression analysis., Results: Data from 57 patients were analysed. The incidence rates of nausea and vomiting during the overall period were 57.9% and 17.5%, respectively. Nausea and vomiting were frequent not only in the early courses but also after the sixth course. Multivariate logistic regression analysis showed that the experience of nausea and vomiting in previous treatment with other agents was significantly associated with nausea and vomiting with TAS-102 and BEV., Conclusion: The experience of nausea and vomiting in previous treatment was associated with increased risk for nausea and vomiting in mCRC patients treated with TAS-102 and BEV., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The association between capecitabine efficacy and proton pump inhibitors (PPIs) is controversial. Here, we determined whether co-administration of PPIs affects the real-world effectiveness of capecitabine. This retrospective observational study included consecutive patients with stage II-III colorectal cancer (CRC) who received adjuvant capecitabine monotherapy or CapeOX (capecitabine and oxaliplatin) between January 2009 and December 2014 at nine participating institutions. The primary endpoint was the difference in relapse-free survival (RFS) between patients who received PPIs and those who did not and was estimated using the Kaplan-Meier method. Overall survival (OS) was the secondary endpoint. Multivariable analysis of RFS and OS was performed using a Cox proportional hazards model, propensity score adjustment, and inverse probability of treatment weighting (IPTW) analyses. Data from 606 patients were evaluated, 54 of whom had received a PPI. PPI-treated patients tended to have poorer RFS and OS than patients treated without PPIs. The hazard ratio for RFS with capecitabine monotherapy was 2.48 (95% confidence interval: 1.22-5.07). These results were consistent with sensitivity analyses performed using propensity score adjustment and IPTW methods. Co-administration of PPIs may reduce the effectiveness of capecitabine and negatively impact patients with stage II-III CRC., (© 2022. The Author(s).)

Background: Regorafenib is recognized as a later-line standard treatment in patients with metastatic colorectal cancer (mCRC). In this study, we examined the association of the albumin-bilirubin (ALBI) score in patients with mCRC receiving later-line chemotherapy with regorafenib., Patients and Methods: We retrospectively analyzed data from patients with mCRC treated with regorafenib in a later line between January 2013 and December 2019. Patients were divided into a Normal-ALBI group (ALBI grade 1) and a High-ALBI group (ALBI grades 2 and 3). Primary endpoint was median overall survival (OS) and secondary endpoints were median time to treatment failure (TTF) and incidence of adverse events (AEs)., Results: Data from 60 patients were analyzed (Normal-ALBI group: 32 patients and High-ALBI group: 28 patients). Median OS [10.23 vs. 3.70 months, hazard ratio (HR): 1.79, 95% confidence interval (CI) 1.02-3.13, p = 0.041] and median TTF (2.27 vs. 1.78 months, HR: 1.78, 95%CI 1.02-3.09, p = 0.042) were significantly longer in the Normal-ALBI group than High-ALBI group. On Cox proportional hazard analysis, ALBI score was significantly correlated with OS. The incidence of liver dysfunction (grade ≥ 2) was significantly higher in the High-ALBI than the Normal-ALBI group (42.9% vs. 15.6%, p = 0.041), whereas other AEs were comparable between the two groups., Conclusion: ALBI was strongly associated with the prognosis of patients with mCRC treated with regorafenib and with the occurrence of liver-related adverse events. These findings may imply that patients with a high ALBI score should not be treated with regorafenib.

Delayed chemotherapy-induced nausea and vomiting (CINV) is not well controlled in colorectal cancer (CRC) patients undergoing oxaliplatin (L-OHP)-based chemotherapy. Whether neurokinin-1 receptor antagonist addition to a first-generation 5HT 3 antagonist (1st 5-HT 3 RA) and dexamethasone (DEX) is beneficial to these patients remains controversial. Furthermore, whether palonosetron (PALO) or aprepitant (APR) is more effective in controlling delayed CINV is unclear. We, therefore, investigated whether PALO+DEX or 1st 5-HT 3 RA+DEX+APR was more effective in controlling delayed CINV, and the risk factors for delayed CINV, in CRC patients undergoing L-OHP-based chemotherapy. Data were pooled from two prospective observational Japanese studies and a phase III trial to compare CINV incidence between the PALO + DEX (PALO) and 5-HT 3 RA+DEX+APR (APR) groups by propensity score-matched analysis. CINV risk factors were identified using logistic regression models. The CINV incidence was higher in the PALO group than in the APR group. Logistic regression analysis revealed alcohol consumption, motion sickness, and the PALO+DEX regimen as independent risk factors for delayed nausea, and female sex and the PALO+DEX regimen as those for delayed vomiting. Compared with prophylactic PALO + DEX, 1st 5-HT 3 RA+DEX+APR was more effective in controlling delayed CINV. Thus, CRC patients receiving L-OHP-based chemotherapy should be treated with three antiemetics, including APR., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aim: We compared the efficacy and safety of second-line FOLFIRI with bevacizumab (Bmab) or aflibercept (AFL) in patients with unresectable metastatic colorectal cancer (mCRC) to clarify selection criteria for anti-angiogenic agents., Patients and Methods: The subjects were patients with mCRC who received second-line FOLFIRI in combination with Bmab or AFL. The primary endpoint was median overall survival (OS). Secondary endpoints were median time to treatment failure (TTF), overall response rate (ORR) and incidence of adverse events., Results: Data from 26 patients in the Bmab group and 19 in the AFL group were analyzed. Median OS was slightly longer in the AFL group compared to the Bmab group, whereas median TTF was similar. ORR tended to be higher in the AFL group. The incidence of ≥grade 2 diarrhea and proteinuria was significantly higher in the AFL group than the Bmab group., Conclusion: In patients given combination treatment with FOLFIRI for second-line treatment of mCRC, AFL can increase response rates compared to Bmab, which may contribute to longer survival., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The effect of renal dysfunction on the toxicity and efficacy of oxaliplatin remains unclear. We investigated the association between creatinine clearance (Ccr), a marker of renal function, and the toxicity and efficacy of oxaliplatin in patients with metastatic colorectal cancer (mCRC)., Patients and Methods: Patients with mCRC who received oxaliplatin-based chemotherapy as first-line treatment were included in this study. Primary outcome was peripheral neuropathy (Grade ≥2), while secondary outcomes included neutropenia (Grade ≥3), thrombocytopenia (Grade ≥2) and overall survival (OS)., Results: A total of 145 patients with mCRC were eligible. Incidence rates of peripheral neuropathy (Grade ≥2), neutropenia (Grade ≥3) and thrombocytopenia (Grade ≥2) were 30.3%, 37.2% and 16.6%, respectively, and median OS was 29.1 months. Cox proportional hazards analysis indicated that there was no significant relationship between Ccr and any adverse event, or between Ccr and OS., Conclusion: Dose reduction of oxaliplatin based on Ccr is not recommended in patients with mCRC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: TAS-102 is effective for treating patients with metastatic colorectal cancer (mCRC). This study determined whether combining bevacizumab (Bmab) with TAS-102 improves clinical outcomes in refractory mCRC., Patients and Methods: We retrospectively analyzed data from Japanese patients with refractory mCRC who received TAS-102 (35 mg/m 2 , twice a day) with (T-B group) or without Bmab (TAS-102 monotherapy; T group) between July 2014 and December 2018. The primary endpoint was median overall survival (OS), and secondary endpoints were median time to treatment failure, overall response rate, and the incidence of adverse events. Clinical outcomes were compared using propensity score matched analysis., Results: Data from 57 patients were analyzed (T-B group: 21 patients, T group: 36 patients). Median OS was significantly longer in the T-B group than the T group (14.4 months vs. 4.5 months, p < .001). Cox proportional hazard analysis showed that combination therapy with Bmab was significantly correlated with OS. Propensity score matched analysis confirmed that the median OS was significantly longer in the T-B group than the T group (14.4 months vs. 6.1 months, p = .006) and that there was a significant correlation between Bmab and OS. The incidence of hypertension (grade ≥2) as an adverse event was significantly higher in the T-B group than the T group (23.8% vs. 0.0%, p = .005), whereas other adverse events were comparable between the two groups., Conclusion: Treatment with Bmab in combination with TAS-102 is significantly associated with improved clinical outcomes in patients with mCRC refractory to standard therapies., Implications for Practice: Combining bevacizumab (Bmab) with TAS-102 significantly improved overall survival and several prognostic indicators in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, with manageable toxicities. Treatment with Bmab in combination with TAS-102 is significantly associated with improved clinical outcomes in patients with mCRC., (© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Background/aim: To clarify whether renal dysfunction affects the incidence of adverse events associated with oxaliplatin, the present study was designed to investigate the relationship between creatinine clearance (Ccr) and the incidence of oxaliplatin-related adverse events., Patients and Methods: A total of 287 CRC patients who received the first cycle of oxaliplatin-based chemotherapy were eligible. Adverse events, including nausea, vomiting, neutropenia and thrombocytopenia, were graded, and the relationship between Ccr and the incidence of adverse events was examined using multivariable logistic regression analysis., Results: A multivariable analysis indicated that the incidence of grade ≥2 nausea increased, while the incidence of other adverse events tended to be higher, as the Ccr decreased. Particularly, renal dysfunction (Ccr <60 ml/min) was a significant risk factor for grade ≥2 nausea (p=0.042)., Conclusion: Care should be taken to avoid adverse events associated with oxaliplatin in patients with renal dysfunction., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Chemotherapy with moderate emetic risk (MEC), including irinotecan-based and oxaliplatin-based chemotherapy regimens, are predominantly used for colorectal cancer chemotherapy. Chemotherapy-induced nausea and vomiting (CINV) remain unsatisfactorily controlled., Patients and Methods: The rates of prevalence of antiemetic medication and the control of CINV were investigated from medical records in patients with colorectal cancer who received the first cycle of irinotecan-based or oxaliplatin-based regimens. Risks for CINV were determined by multivariate logistic regression analysis., Results: A total of 179 patients received the first cycle of MEC regimens and the number of overall cycles was 2,176 during the study period from January 2013 to December 2015. Guideline-consistent antiemetic medication was performed in most cases. The rate of no-CINV was nearly 90% during the overall period. Female sex and age under 50 years were significant risks for CINV. Comparison considering only the group aged 50 years or more indicated that the control of CINV was significantly worse in irinotecan-based regimens than in the oxaliplatin-based regimens., Conclusion: Female sex and age younger than 50 years were significant risks for CINV in patients receiving MEC for colorectal cancer. Moreover, the control of CINV was less sufficient for irinotecan-based than for oxaliplatin-based regimens., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: Anti-EGFR monoclonal antibody is effective for KRAS wild-type metastatic colorectal cancer (mCRC), but frequently causes several adverse reactions, including hypomagnesemia and skin disorders. The present study was designed to investigate the relationship between the incidence of adverse reactions and therapeutic effects in mCRC patients receiving anti-EGFR monoclonal antibody in combination with first-line chemotherapy., Methods: Forty-three mCRC patients who received cetuximab or panitumumab between April 2012 and December 2015 were the subjects of the present study. All patients were pretreated with oral minocycline in combination with skin treatment using moisturizer for prevention of skin rash. Hypomagnesemia and acneiform rash were graded according to the Common Terminology Criteria for Adverse Events, version 3.0. Overall response rate (ORR) and time to treatment failure (TTF) were compared between patients with and without these adverse events., Results: The incidence rates of hypomagnesemia and acneiform rash were 32.6 % (grade 1: 20.9 %, grade 2: 11.6 %) and 93.0 % (grade 1: 41.9 %, grade 2: 41.9 %, grade 3: 9.3 %), respectively. ORR was significantly higher in patients with hypomagnesemia than in those without it (71.4 vs 34.5 %, P = 0.048). Median TTF tended to be longer, though not significantly, in patients with hypomagnesemia than in those without it. However, no significant difference in both ORR and median TTF was observed between patients with and without acneiform rash., Conclusion: Hypomagnesemia may become a predicting factor for therapeutic effects of anti-EGFR monoclonal antibody in mCRC patients.

Purpose: Although anti-EGFR monoclonal antibodies, including cetuximab and panitumumab, are highly effective in KRAS wild-type advanced colorectal cancer, these drugs frequently cause several adverse events. These events include hypomagnesemia and acneiform rash, which may lead to the dose reduction or discontinuation of therapy. In the present study, we retrospectively investigated the incidence of hypomagnesemia and acneiform rash in patients with metastatic colorectal cancer (mCRC). We examined the relationship between the incidence of such adverse events and the therapeutic effect., Methods: Thirty-four mCRC patients receiving anti -EGFR monoclonal antibody as a first-line therapy during April 2012 to March 2015 were the subjects of the present study. The symptoms of hypomagnesemia and acneiform rash were graded in accordance with the Common Terminology Criteria for Adverse Events, v4.0., Results: The incidence rates of hypomagnesemia (all grades) and the acneiform rash (≥grade 2) were 29%and 50%, respectively. Eight patients (24%) exhibited both of these adverse events. The tumor response rate was notable, as it was significantly higher in patients who experienced both of these adverse events compared to those who did not(88% vs 38% for complete response plus partial response, p=0.039). However, the tumor response rate tended to be higher, although not significantly, in patients with either of these adverse events compared to those without it., Conclusion: Concurrent onset of hypomagnesemia and acneiform rash may become a reliable factor capable of predicting the therapeutic effect of anti-EGFR monoclonal antibody.

Background: Although the anti-EGFR monoclonal antibody panitumumab is effective in treating colorectal cancer, the occurrence of severe skin disorders often discontinues therapy. Herein, we investigated by a retrospective chart review the effect of prophylactic oral minocycline in combination with skin treatment using moisturizer on the incidence of skin disorders and tumor response in metastatic colorectal cancer patients who received panitumumab., Patients and Methods: In a total of 55 patients, 38 patients were eligible, consisting the pre-emptive group (N=25) and reactive group (N=13). Acneiform rash and other adverse events were graded according to the CTCAE v4.0., Results: The occurrence of acneiform rash (grade ≥2) was significantly lower in pre-emptive group than in reactive group (44.0% vs. 84.6%, p=0.04). No significant differences in the occurrence of other adverse events were observed between the two groups. Tumor response was not significantly different between the two groups (36.0% vs. 7.7%, OR, 6.75; 95% confidence interval (CI)=0.75-60.76, p=0.12). Mean time to treatment failure was 149.7 days and 110.2 days in the pre-emptive group and reactive treatment group, respectively (HR=0.58; 95% CI= 0.26-1.28, p=0.18)., Conclusion: Prophylactic oral minocycline combined with skin care reduced panitumumab-induced acneiform rash without a significant influence on tumor response., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Prevention of chemotherapy-induced nausea and vomiting (CINV) according to the clinical practice guidelines is particularly important. In the present study, we investigated the adherence to the guidelines for antiemetic medication and the control of CINV in 61 patients with colorectal cancer receiving the first course of chemotherapy of moderate emetic risk at our outpatient cancer chemotherapy clinic. Furthermore, we carried out intervention to improve evidence-based antiemetic medication in another 64 patients. The rate of adherence to the antiemetic guidelines was only 6.6%; non-adherence was due mostly to the lack of dexamethasone treatment on days 2 and 3. In the interventional group, antiemetic medication adherence was markedly enhanced to 89%, which led to a significant enhancement of complete protection from nausea and vomiting during-delayed period (days 2-5 after chemotherapy) from 54% to 74% (p<0.05), although the daily dose of dexamethasone was 4 mg, lower than that recommended by the guidelines (8 mg). Finally, we evaluated the effect of dexamethasone at a daily dose of 4 mg, since little is known about the efficacy of such dose. Dexamethasone at this dose was found to be effective at elevating the rate of complete protection from nausea and vomiting during-delayed period (increase of 20%, p<0.05). These findings suggest that medication intervention to reduce the gap between guidelines and clinical practice improves the emetic control in patients with colorectal cancer receiving moderately-emetic chemotherapy.

The efficacy and safety of generic and brand name levofolinate injectable drugs were evaluated in 42 chemotherapy-naïve patients with colorectal cancer who received the combination chemotherapy of levofolinate, 5-fluorouracil, and oxaliplatin with or without bevacizumab. The tumor response rate was similar between generic drug group and brand drug group, in which the efficacy rate (complete response plus partial response) was 50% for generic drug group and 42% for brand name drug (odds ratio: 1.400, 95% confidence intervals: 0.409-4.788, P = 0.756). The rates of the decrease in plasma tumor markers such as carcinoembryonic antigen and carbohydrate antigen 19-9 were not different between the two groups. The incidence of adverse drug reactions was not significantly different between the two groups, although the incidence rates of adverse events associated predominantly with 5-fluorouracil such as hand-and-foot syndrome, diarrhea, and oral mucositis were rather higher, though not significantly, in generic drug group than in brand drug group (16 vs. 4% for hand-and-foot syndrome; 33 vs. 25% for diarrhea; 33 vs. 25% for oral mucositis). These findings suggest that both the effectiveness and safety profiles of the generic name levofolinate are comparable to those of the brand name drug, when used in combination with 5-fluorouracil and oxaliplatin in patients with colorectal cancer.