Risks and Outcomes of Early Dose Reduction in Adjuvant CAPOX Therapy for Colorectal Cancer.

BACKGROUND/AIM: Adjuvant capecitabine and oxaliplatin (CAPOX) therapy is standard strategy for colorectal cancer with risk of recurrence. Early dose reduction (EDR) of CAPOX therapy is commonly used in real-world practice. However, there is limited evidence regarding the effectiveness of CAPOX for patients who had EDR. Therefore, this study aimed to clarify the risks of EDR and its effect on long-term outcomes and body composition factors. PATIENTS AND METHODS: Patients who received CAPOX therapy after radical surgery for colorectal cancer between June 2013 and December 2021 were included. EDR was defined as dose reduction within four courses of CAPOX therapy. Body composition factors were measured for 1 year following surgery to determine the EDR effects. RESULTS: Eighty-four patients were included; 35 (42%) of them had EDR. The multivariate analysis revealed that underweight [odds ratio (OR)=4.95, 95% confidence interval (CI)=1.13-21.7, p=0.03] was a risk factor for EDR. Relapse-free survival (RFS) was significantly better in the non-EDR group (p=0.01). The 5-year RFS rates for the non-EDR and EDR groups were 88.7% and 65.4%, respectively. The multivariate analysis revealed that age >65 years [hazard ratio (HR)=3.97; 95% CI=1.16-13.62, p=0.03] and EDR (HR=7.62; 95% CI=1.71-33.91, p=0.005) were associated with poorer RFS. The 1-year body composition analysis revealed decreases in all factors in the EDR group. CONCLUSION: Preoperative underweight status was associated with EDR, which resulted in decreased RFS and body composition factors when compared with the non-EDR group. Therefore, avoiding EDR and early nutritional intervention after EDR may improve outcomes.

Immune modulation of the liver metastatic colorectal cancer microenvironment via the oral CAPOX-mediated cGAS-STING pathway.

We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell-mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy.

Real-world tolerance and outcomes of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer-Does dose intensity matter?

INTRODUCTION: Fluoropyrimidine and oxaliplatin-based adjuvant chemotherapy delivered as 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), or capecitabine and oxaliplatin (CAPOX) is the standard of care for resected stage III colon cancer. Without randomized trial data, we compared real-world dose intensity, survival outcomes, and tolerability of these regimens. METHODS: Records of patients treated with FOLFOX or CAPOX in the adjuvant setting for stage III colon cancer across four institutions in Sydney during 2006-2016 were reviewed. The relative dose intensity (RDI) of fluoropyrimidine and oxaliplatin of each regimen, disease-free survival (DFS), overall survival (OS), and incidence of grade ≥2 toxicities were compared. RESULTS: Characteristics of patients receiving FOLFOX (n = 195) and CAPOX (n = 62) were evenly matched. FOLFOX patients had a higher mean RDI for both fluoropyrimidine (85% vs. 78%, p < 0.01) and oxaliplatin (72% vs. 66%, p = 0.06). In spite of a lower RDI, CAPOX patients trended toward a better 5-year DFS (84% vs. 78%, HR = 0.53, p = 0.068) and similar OS (89% vs. 89%, HR = 0.53, p = 0.21) compared to the FOLFOX group. This difference was most pronounced in the high-risk (T4 or N2) group where 5-year DFS was 78% versus 67% (HR = 0.41, p = 0.042). Patients receiving CAPOX experienced more grade ≥2 diarrhea (p = 0.017) and hand-foot syndrome (p < 0.001) but not peripheral neuropathy or myelosuppression. CONCLUSION: In a real-world setting, patients who received CAPOX had similar OS rates when compared to those receiving FOLFOX in the adjuvant setting in spite of lower RDI. In the high-risk population, CAPOX appears to demonstrate a superior 5-year DFS over FOLFOX.

Does statin suppress oxaliplatin-induced peripheral neuropathy in patients with colorectal cancer? A single-center observational study.

BACKGROUND: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common and dose-limiting toxicity that markedly limits the use of oxaliplatin and affects quality of life. Statins have been shown to exert neuroprotective effects in preclinical settings. The aim of the present study was to clarify whether statins prevented OIPN in patients with colorectal cancer (CRC) receiving adjuvant CAPOX therapy. METHODS: We examined 224 patients who received adjuvant CAPOX therapy for CRC between July 2010 and December 2021 at our hospital. Patients were divided into "Statin" and "Non-statin" groups based on statin use. Details on and the adverse events of adjuvant CAPOX therapy were examined in association with statin use. RESULTS: Thirty-one patients (14%) were treated with statins. There were no intergroup differences in the relative dose intensity or number of CAPOX cycles between the Statin and Non-statin groups. In total, 94% of patients in the Statin group and 95% of those in the Non-statin group developed OIPN (p=0.67). The severity of OIPN was similar between the two groups (p=0.89). The frequency of treatment delays in CAPOX did not significantly differ between the Statin and Non-statin groups (16% vs. 11%, p=0.45). CONCLUSIONS: The efficacy of statins to attenuate OIPN during adjuvant CAPOX therapy was not apparent in the current study. Further studies are needed to confirm the present results.

Clinical implications and chemo-sensitivity of adjuvant chemotherapy in patients with poorly cohesive cells-gastric cancer.

PURPOSE: Poorly cohesive cells-gastric cancer (PCC-GC) represents distinct features within the GC spectrum. The present study investigated the clinicopathologic characteristics and chemo-sensitivity for a relatively large cohort of PCC-GC patients. MATERIALS AND METHODS: A total of 268 patients diagnosed with stage II or III PCC-GC were included. GC cell lines were also analyzed for drug sensitivity to 5-fluorouracil (5-FU) and oxaliplatin in vitro. RESULTS: One hundred fifteen (42.9%) patients were stage II and 153 (57.1%) were stage III. Two hundred twenty-three (83.2%) patients received adjuvant therapy. Among these patients, 139 (62.3%) received CAPOX and 84 (37.7%) received S-1. With a median follow-up of 38.9 (1.6-137.8) months, the estimated 5-year disease-free survival (DFS) and overall survival (OS) rates were 52.3% and 61.0%, respectively. In the univariate analysis, survival was significantly better in the adjuvant chemotherapy group than in the surgery only group. In the subgroup analysis, there was no significant difference in DFS or OS between the types of adjuvant chemotherapy for either disease stage. In vitro cell line analysis, different responses to 5-FU and oxaliplatin were observed in SRC and non-SRC, where the treatment in KATOIII cell lines with oxaliplatin had less effect at a higher concentration compared to non-SRC cell lines. CONCLUSION: The current study found that adjuvant chemotherapy was not significantly associated with survival benefit for patients with resected stage II and III PCC-GC. Plus, S-1 showed numerically longer DFS and OS compared to CAPOX in PCC-GC patients, although no significant in the multivariate analysis.

Comparison of the Efficacy and Safety of 3 Months of CAPOX Followed by 3 Months of Capecitabine and 6 Months of CAPOX/FOLFOX in the Adjuvant Treatment of Low-Risk Stage III Colon Cancer Treated Surgically.

INTRODUCTION: In the adjuvant treatment of low-risk stage III colon cancer treated surgically, 3 months of CAPOX followed by 3 months of capecitabine is not a common clinical practice. Since there are no data on this practice in the literature, we have no idea how often it is used. However, it should be noted that this application is used in some centers due to the cumulative neurotoxicity of oxaliplatin but there are insufficient data in the literature on its efficacy. METHODS: The data of patients with colon cancer treated surgically who were followed up in 12 different oncology centers in Turkey between November 2004 and June 2022 were analyzed retrospectively. RESULTS: The study included 194 patients. The treatment arms were as follows: 3 months of CAPOX followed by 3 months of capecitabine = arm A and CAPOX/FOLFOX (6 months) = arm B. There were 78 patients (40.2%) in arm A and 116 patients (59.8%) in arm B. The median age and sex distribution were similar between the treatment arms. The median follow-up period of all patients was 34.4 months (95% confidence interval, 29.1-39.7). When arm A was compared with arm B, 3-year disease-free survival (DFS) was 75.3% versus 88.4% and 5-year DFS was 75.3% versus 82.8%, respectively. There were similar DFS outcomes between the treatment arms (p = 0.09). Rates of any grade of neuropathy were numerically lower in arm A, but the difference between the treatment arms was not statistically significant (51.3% vs. 56.9%; p = 0.44). The frequency of neutropenia was similar between the treatment arms. CONCLUSION: In this study, the efficacy and safety of the 3 months of CAPOX followed by 3 months of capecitabine chemotherapy regimen in the adjuvant treatment of low-risk stage III colon cancer treated surgically were proven. This result may also support the discontinuation of oxaliplatin at 3 months while continuing fluoropyrimidines, which is a common clinical practice but lacks sufficient data.

Comparison of the pathological response to 2 or 4 cycles of neoadjuvant CAPOX in II/III rectal cancer patients with low/intermediate risks: study protocol for a prospective, non-inferior, randomized control trial (COPEC trial).

BACKGROUND: For patients with low- and intermediate-risk stage II/III rectal cancer, current studies have reached a consensus that preoperative radiotherapy may be dispensed with, and neoadjuvant chemotherapy (NCT) alone might achieve an accepted local control. Our previous phase II study has evidenced that the morphological response of NCT could be better judged at a relatively early stage. Low- and intermediate-risk stage II/III rectal cancer patients could achieve a high rate of tumor shrinkage and downgrade after only 4 cycles of NCT and obvious tumor morphological changes could be observed after 2 cycles of NCT. However, there is still a lack of more detailed stratification and evidence for pathological criteria. The aim of the present study (comparison of the pathological response to 2 or 4 cycles of neoadjuvant CAPOX in II/III rectal cancer patients with low/intermediate risks, COPEC trial) is to determine the pathological tumor regression grade (pTRG) rate of 2 or 4 cycles of NCT in low- and intermediate-risk stage II/III rectal cancer and verify the feasibility of early identification of chemotherapy-insensitive population. METHODS/DESIGN: This is a multicenter, prospective, non-inferior, randomized controlled trial (RCT) initiated by West China Hospital of Sichuan University and designed to be conducted in fourteen hospitals around China. Eligible patients will be centrally randomized into 2 or 4 cycles of CAPOX in a 1:1 ratio using the central automated randomization system offered by the O-trial online system ( https://plus.o-trial.com/ ) and accept total mesorectal excision after 2 or 4 cycles of CAPOX (oxaliplatin 130 mg/m2, once daily on day 1, every 21 days and capecitabine 1000 mg/m2, twice daily on days 1 to 14, every 21 days). The primary endpoint is the proportion of patients with pathological no-tumor regression (pTRG 3), which is determined postoperatively by each sub-center and verified by the primary center. DISCUSSION: COPEC trial is designed to verify that the preoperative CAPOX chemotherapy for low- and intermediate-risk stage II/III rectal cancer could achieve a good response judgment after 2 cycles and obtain the tumor pathological response rate after 2 cycles of CAPOX. We hope the COPEC trial could help in establishing a consensus standard of low- and intermediate-risk rectal cancer and the early identification of stage II/III rectal patients with low- and intermediate-risk who are poorly responding to NCT. TRIAL REGISTRATION: Clinicaltrial.gov NCT04922853. Registered on June 4, 2021.

Immune checkpoint inhibitors plus capecitabine and oxaliplatin in unresectable or advanced biliary tract cancer patients: A retrospective study.

Objective: Immune checkpoint inhibitors (ICIs) have recently been increasingly used in cancer treatment, whereas their clinical application in biliary tract cancer (BTC) patients is uncommon. This study aimed to evaluate the efficacy and safety of ICIs plus capecitabine and oxaliplatin (CAPOX) in the treatment of BTC patients. Methods: This retrospective study reviewed 26 unresectable or advanced BTC patients who received ICIs plus CAPOX. The treatment continued until disease progression, uncontrollable adverse event (AE) occurrence, intolerable toxicity occurrence, or voluntary withdrawal. Results: The median treatment cycles were 5.5 [interquartile range (IQR): 3.8-8.0]. Complete response, partial response, stable disease, and progressive disease rates were 0.0%, 46.2%, 23.1%, and 30.8%, respectively. Objective response rate (ORR) and disease control rate (DCR) were 46.2% and 69.2%, correspondingly. Regarding survival, the median progression-free survival (PFS) and overall survival (OS) were 6.1 (95% CI: 4.4-7.7) months and 16.5 (95% CI: 5.0-28.0) months; moreover, the 1-year PFS and OS rates were 21.5% and 54.3%, respectively. An Eastern Cooperative Oncology Group (ECOG) score of 1-3 (vs. 0) was associated with declined DCR, PFS, and OS (all p < 0.050). The most common AEs of ICIs plus CAPOX were thrombocytopenia (61.5%), neutropenia (26.9%), and reactive cutaneous capillary endothelial proliferation (RCCEP) (23.1%). Moreover, 13 (50.0%) patients suffered from grade 3-4 AEs, including thrombocytopenia (50.0%), neutropenia (7.7%), liver dysfunction (7.7%), and RCCEP (3.8%). Notably, the majority of AEs were controllable. Conclusion: ICIs plus CAPOX chemotherapy exhibit a good efficacy and a manageable safety profile in the treatment of patients with unresectable or advanced BTC.

Adjuvant Capecitabine and Oxaliplatin for Elderly Patients with Colorectal Cancer.

INTRODUCTION: Adjuvant chemotherapy improves the prognosis of patients with colorectal cancer (CRC) following radical resection. However, the safety and efficacy of oxaliplatin-based chemotherapeutic regimens for elderly patients remains to be elucidated. The aim of the present study was to examine the tolerability and efficacy of adjuvant CAPOX (capecitabine and oxaliplatin) therapy for elderly patients in comparison with young patients. METHODS: We examined 138 Japanese patients who received adjuvant CAPOX therapy for high-risk stage II or III CRC between July 2010 and June 2021 at our hospital. Patients were divided according to an age of 70 years. Treatment details of CAPOX therapy were analyzed in association with age. Moreover, prognosis of stage III CRC was compared between the patient groups. RESULTS: Twenty-three patients (17%) were ≥70 years old. Male patients were predominant in the ≥70 years group (p = 0.006). Patients ≥70 years old had more comorbidities (diabetes, p = 0.014; cardiovascular disease, p < 0.001; renal disease, p = 0.042) than patients <70 years old. There were no age-dependent differences in dose intensity, the number of cycles, or DLTs of CAPOX therapy. CSS and RFS were also similar between the ≥70 and <70 years old patients with stage III CRC. CONCLUSIONS: Adjuvant CAPOX therapy was tolerable in elderly Japanese patients. The prognosis of elderly patients with stage III CRC was similar to that of their younger counterparts. Advanced age itself may not be a contraindication for adjuvant chemotherapy in CRC. Future studies with a larger patient cohort are required to confirm the present results.

Efficacy of S-1 or Capecitabine Plus Oxaliplatin Adjuvant Chemotherapy for Stage II or III Gastric Cancer after Curative Gastrectomy: A Systematic Review and Meta-Analysis.

Background: Adjuvant chemotherapy (AC) regimens tegafur/gimeracil/oteracil (S-1) and capecitabine plus oxaliplatin (CAPOX) have predominated, however, there has been a lack of studies on their differences in efficacy. Methods: We conducted pairwise meta-analyses comparing the efficacy of S-1 and CAPOX regimens for overall survival (OS) and disease-free survival (DFS) in stage II or III GC patients. Results: Three studies were enrolled and analyzed using a forest plot for meta-analysis. Two of them were propensity score matching studies, and the remaining one was a retrospective observational study. In all stages, the five-year OS was not different between the two regimens (HR 0.96, 95% CI 0.78-1.17; p = 0.56). Additionally, the 5-year DFS was not different at any stage (HR 1.00, 95% CI 0.85-1.18; p = 0.21). After omitting the retrospective observational study, the five-year OS (HR 1.40, 95% CI 0.53-3.73) and DFS (HR 1.41, 95% CI 0.57-3.44) of S-1 tended to be better in stage II, and the five-year OS (HR 0.81, 95% CI 0.56-1.16) and DFS (HR 0.85, 95% CI 0.63-1.13) of CAPOX tended to be better in stage III, without statistical significance. Conclusions: In the present meta-analysis, the five-year OS and DFS for stage II or III GC patients were comparable between S-1 and CAPOX regimens as AC.

Diverting ileostomy is a risk factor for renal impairment during CAPOX therapy.

PURPOSE: Temporary ileostomy is sometimes created after colorectal surgery and may cause renal impairment. However, the impact of ileostomy on renal function during adjuvant chemotherapy for colorectal cancer (CRC) remains unknown. The aim of the present study was to examine the effects of ileostomy on renal function during adjuvant chemotherapy. METHODS: We examined 184 patients who received adjuvant CAPOX therapy (capecitabine and oxaliplatin) for CRC with or without ileostomy between January 2011 and December 2020 at the University of Tokyo Hospital. Clinicopathological factors, including renal function, were retrospectively reviewed in association with temporary ileostomy. Factors associated with reductions in the estimated glomerular filtration rate (eGFR) during CAPOX therapy were analyzed. RESULTS: Eighteen patients (10%) underwent temporary ileostomy. The maximum decrease in eGFR during CAPOX therapy was significantly higher in patients with than in those without ileostomy (- 16.1 vs. - 5.6 mL/min/1.73m2, p = 0.003). A multivariate analysis identified ileostomy as one of factors independently associated with reductions in eGFR during CAPOX therapy (p = 0.003). The cumulative number of readmission due to dehydration was also higher in patients with ileostomy (33% vs. 1%, p < 0.001). CONCLUSIONS: Ileostomy significantly reduced eGFR during adjuvant CAPOX therapy. Therefore, renal function needs to be monitored during CAPOX therapy, particularly in patients with ileostomy.

Short-term outcomes of neoadjuvant chemotherapy with capecitabine plus oxaliplatin for patients with locally advanced rectal cancer followed by total or tumor-specific mesorectal excision with or without lateral pelvic lymph node dissection.

BACKGROUND: The standard strategy in Japan for locally advanced rectal cancer is total mesorectal excision plus adjuvant chemotherapy. However, large tumors significantly restrict pelvic manipulation of the distal side of the tumor during surgery;therefore, from an oncological point of view, it is better to shrink the tumor as much as possible preoperatively to optimize the circumferential resection margin. In recent years, advances in systemic chemotherapy have significantly improved the tumor reduction effect, enabling such drug therapy prior to surgery for locally advanced rectal cancer. We herein retrospectively evaluated the clinical, short-term outcomes of patients treated by neoadjuvant chemotherapy (NAC) using capecitabin and oxaliplatin (CAPOX), focusing on overall safety as well as clinical and pathological staging responses to NAC. METHODS: We applied the preoperative chemotherapy protocol to T3-4, any N, M0 or M1a (with resectable metastases) (UICC 8th) Ra/Rb rectal cancers. The chemotherapy regimen consisted of four cycles of CAPOX. After NAC, curative intent surgery with total mesorectal excision/tumor-specific mesorectal excision with/without metastasectomy was performed. Adverse effects (AEs) and compliance with NAC, surgical complications, clinical and pathological staging were evaluated. All patients undergoing the protocol between January 2017 and June 2021 at Fukushima Medical University were enrolled. RESULTS: Twenty cases were enrolled. No severe AEs were observed either preoperatively or perioperatively. Preoperative assessment of NAC showed no cases of progressive disease (PD). Radical resection was achieved in all cases. Histological therapeutic grading after NAC revealed one grade 3, four grade 2, three grade 1b, eleven grade 1a and one grade 0 among all cases. CONCLUSION: This study suggests that NAC for locally advanced rectal cancer is likely to be acceptable because there were no severe AEs pre- or perioperatively, radical resection was achieved in all cases, and there were no cases of PD.

Efficacy and safety of capecitabine and oxaliplatin (CAPOX) treatment in colorectal cancer: An observational study from a tertiary cancer center in South India.

Background: ">5-fluorouracil (5-FU) was the standard treatment care for colorectal cancer (CRC), however, its efficacy was limited due to safety concerns. Capecitabine and oxaliplatin (CAPOX) treatment was found equivalent to 5-FU in efficacy and preferred now due to easy management and convenience in administration. Hence, the present study aims to determine the efficacy and safety associated with CAPOX treatment in a real world non clinical setting. Methods: ">145 treatment-naive and newly diagnosed CRC patients were recruited in the study. Each patient received oxaliplatin 130 mg/m2 infusion over 2 hours on day 1 and oral capecitabine 1000 mg/m2 in divided doses twice daily for the next 14 days of a 21-day cycle. Results: In the adjuvant setting, the observed disease-free survival rate was 62% (n=34) in the colon and 67% (n=15) in the rectum cancer patients at 2 years. The observed overall survival rate in the colon and rectal cancer was 80% (n=44) and 83% (n=18) respectively at 2 years. In the palliative setting the observed progression-free survival rate was 28% (n=13) in the colon and 33% (n=7) in rectal cancer patients at 2 years. The observed OSR at 2 years was 64% (n=30) in the colon and 67% (n=14) in the rectal cancer patients. Thrombocytopenia (17, 11.7%) and diarrhea (8, 5.5%) were the most commonly observed grade 3/4 hematological and gastrointestinal toxicities. Hand-foot syndrome and peripheral neuropathy were the major contributors for dose reduction (14, 9.6%), treatment delay (8, 5.4%), and drug discontinuation (9, 6.1%) in the study cohort. Conclusion: CAPOX treatment was found to be effective but associated with several dose-limiting toxicities.

Multicenter phase II clinical study of the efficiency and safety of capecitabine plus intermittent oxaliplatin with bevacizumab as first-line therapy in patients with metastatic colorectal cancer (VOICE trial).

PURPOSE: The aim of this phase II study was to evaluate the efficacy and safety of combination therapy with five-cycle CAPOX (capecitabine plus oxaliplatin) plus bevacizumab, followed by five-cycle maintenance therapy with capecitabine plus bevacizumab and reintroduction of CAPOX plus bevacizumab for five cycles, with a preplanned intermittent oxaliplatin strategy in metastatic colorectal cancer (mCRC). METHODS: Patients with untreated mCRC were administered CAPOX (130 mg/m2 oxaliplatin on day 1, 2000 mg/m2/day capecitabine on days 1-14, every 21 days) + bevacizumab (7.5 mg/kg) every 3 weeks for five cycles, maintenance treatment without oxaliplatin for five cycles, and CAPOX + bevacizumab reintroduction for five cycles or upon tumor progression. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the time to treatment failure (TTF), overall survival, response rate (RR), and safety. RESULTS: Forty-seven patients who fulfilled the inclusion criteria were enrolled in the evaluation of efficacy and safety. Median PFS was 14.1 months (95% confidence interval [CI], 8.6-19.5), and median TTF was 12.3 months (95% CI, 10.3-14.3). The objective RRs were 51.1% (24/47) during induction therapy, 58.3% (21/36) during maintenance therapy, and 63.6% (14/22) during reintroduction therapy. The frequency of patients with neutropenia, diarrhea, peripheral sensory neuropathy, venous thromboembolism, or grade ≥ 3 allergic reactions was 2.1%. CONCLUSION: CAPOX plus bevacizumab therapy with a preplanned intermittent oxaliplatin strategy consisting of brief five-cycle induction therapy, five-cycle maintenance therapy with capecitabine plus bevacizumab, and five-cycle reintroduction therapy consisting of CAPOX plus bevacizumab is safe and effective for mCRC patients. TRIAL REGISTRATION: UMIN ID: 000,005,732, date of registration: June 7, 2011.  https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000006695.

Suboptimal Completion Rates, Adverse Events, Costs, Resource Utilization, and Cost Impact of Noncompletion in Oral Adjuvant Capecitabine-Based Chemotherapy in Patients With Early-Stage Colon Cancer.

BACKGROUND: Suboptimal completion of chemotherapy, which may involve reduced patient adherence, remains a serious issue and leads to reduced treatment efficacy. This study assessed the completion rates, risk factors for noncompletion, and cost impact for noncompletion in patients on capecitabine monotherapy (Cape) or capecitabine with oxaliplatin (CAPOX) for the adjuvant treatment of early-stage colon cancer. METHODS: Patients with a diagnosis of early-stage colon cancer between April 2013 and March 2017 were retrospectively identified. Treatment completion was evaluated. Multivariate logistic regressions analyses were used to assess the baseline factors associated with noncompletion. Adverse events, costs, healthcare resource utilization, and cost impact for noncompletion were investigated. RESULTS: A total of 673 patients met the eligibility criteria, of which 382 (57%) were treated with Cape and 291 (43%) with CAPOX. The overall completion rate for adjuvant therapy was 40% (Cape 46%; CAPOX 33%). Noncompletion was associated with CAPOX treatment and higher healthcare costs within 6 months prior to chemotherapy. The 6-month unadjusted total healthcare costs were $44,444 for Cape and $71,247 for CAPOX. The nonchemotherapy costs were 41% higher for noncompleters than completers in both treatment groups (P = .002). CONCLUSIONS: The real-world completion rates for adjuvant capecitabine-based chemotherapy in early-stage colon cancer patients are low. Noncompletion of therapy is associated with higher baseline healthcare costs. The nonchemotherapy costs are significantly higher in noncompleters than completers, highlighting the financial burden of managing adverse events and preexisting comorbidities, which may lead to early discontinuation of therapy. Effective strategies to optimize completion of oral chemotherapy may consider adherence monitoring.

Hepatectomy Followed by Adjuvant Chemotherapy with 3-Month Capecitabine Plus Oxaliplatin for Colorectal Cancer Liver Metastases.

LESSONS LEARNED: Three-month adjuvant capecitabine plus oxaliplatin in combination (CAPOX) appeared to reduce recurrence, with mild toxicity in postcurative resection of colorectal cancer liver metastases (CLM). Recurrence in patients who underwent the 3-month adjuvant CAPOX after resection of CLM was most commonly at extrahepatic sites. BACKGROUND: The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable colorectal cancer liver metastases (CLM) is still unclear. We evaluated the feasibility of 3-month adjuvant treatment with capecitabine plus oxaliplatin in combination (CAPOX) for postcurative resection of CLM. METHODS: Patients received one cycle of capecitabine followed by four cycles of CAPOX as adjuvant chemotherapy after curative resection of CLM. Oral capecitabine was given as 1,000 mg/m2 twice daily for 2 weeks in a 3-week cycle, and CAPOX consisted of oral capecitabine plus oxaliplatin 130 mg/m2 on day 1 in a 3-week cycle. Primary endpoint was the completion rate of adjuvant chemotherapy. Secondary endpoints included recurrence-free survival (RFS), overall survival (OS), dose intensity, and safety. RESULTS: Twenty-eight patients were enrolled. Median age was 69.5 years, 54% of patients had synchronous metastases, and 29% were bilobar. Mean number of lesions resected was two, and mean size of the largest lesion was 31 mm. Among patients, 20 (71.4%; 95% confidence interval, 53.6%-89.3%) completed the protocol treatment and met its primary endpoint. The most common grade 3 or higher toxicity was neutropenia (29%). Five-year recurrence-free survival and overall survival were 65.2% and 87.2%, respectively. CONCLUSION: Three-month adjuvant treatment with CAPOX is tolerable and might be a promising strategy for postcurative resection of CLM.

The updated five-year overall survival and long-term oxaliplatin-related neurotoxicity assessment of the FACOS study.

PURPOSE: We previously reported the first evidence of oncological benefits from a Japanese phase II trial of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (the FACOS study). We herein report the long-term survival and persistent oxaliplatin-related peripheral sensory neuropathy (PSN) for patients enrolled in this trial. METHODS: Patients were scheduled to receive the mFOLFOX6 or CAPOX regimen in the adjuvant setting. The five-year overall survival (OS) rate and persistent PSN were evaluated. RESULTS: A total of 130 patients (mFOLFOX6, n = 73; CAPOX, n = 57) were eligible. The 5-year OS rate was 91.4%. No significant difference in the OS rate was observed between regimens (mFOLFOX6, 94.4%; CAPOX, 87.4%; P = 0.25). The incidence of PSN during adjuvant treatment was 55.4% in grade 1 (G1), 30.0% in G2, and 4.6% in G3. No patients showed G3 PSN at 12 months, but G1 or G2 residual PSN after 5 years was observed in 21.8% (G1, 20%; G2, 1.8%). CONCLUSIONS: Updated results from the FACOS study support the benefits of oxaliplatin-based adjuvant chemotherapy in terms of the long-term survival among Japanese patients with stage III colon cancer. However, long-term persistent PSN occurs in about 20% of survivors, counterbalancing the favorable OS.

Impact of the IDEA Collaboration Study Results on Clinical Practice in France for Patients With Stage III Colon Cancer: A National GERCOR - PRODIGE Survey.

BACKGROUND: The IDEA collaboration showed that the type and duration of adjuvant chemotherapy in stage III colon cancer (CC) could be adjusted according to the schedule of chemotherapy and the level of risk. We aimed at evaluating the implementation of IDEA's results in real-life practice for stage III CC. MATERIAL AND METHODS: All clinicians registered in the French oncology cooperative groups GERCOR, FFCD, and UNICANCER GI mailing lists were invited to participate to an online anonymized nationwide survey from January 30, 2019 to March 31, 2019. Proportions were compared using the χ2 test. RESULTS: A total of 213 physicians answered the survey. Of these, 173 (81%) considered that 3 months of adjuvant chemotherapy was the new standard of care for low-risk (pT1-3/N1) stage III CC, and 99% considered that 6 months remained the standard of care for high-risk (pT4 and/or pN2) stage III CC. In patients under 70 years, capecitabine and oxaliplatin (CAPOX) for 3 months was prescribed by 74% of the participants in low-risk CC, whereas 6 months of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was preferred for high-risk CC in 94% of cases. For patients over 70 years with good performance status and no comorbidities, 172 (81%) physicians prescribed oxaliplatin-based chemotherapy for low-risk CC (3 months, 144 of 172%; 88%), and 200 (94%) physicians prescribed oxaliplatin-based adjuvant chemotherapy for high-risk CC (6 months, 199 of 200%; 99.5%). CONCLUSIONS: The IDEA results have been practice-changing as French physicians have implemented 3 months of CAPOX for patients with low-risk stage III CC, substituting from 6 months of FOLFOX, which remains the preferred regimen for high-risk patients.

Oxaliplatin retreatment in metastatic colorectal cancer: Systematic review and future research opportunities.

BACKGROUND: Oxaliplatin represents a main component of cytotoxic treatment regimens in colorectal cancer (CRC). Given its efficacy, oxaliplatin is frequently re-administered in the context of the continuum of care in metastatic CRC (mCRC). However, efficacy and tolerability of this therapeutic strategy has not been comprehensively assessed. METHODS: We performed a systematic review of the literature on September 19th 2020, according to PRISMA criteria 2009. The research was performed on PubMed, ASCO Meeting Library, ESMO library and ClinicalTrials.gov for citations or ongoing trials. RESULTS: 64 records were retrieved and 13 included in the systematic review: 8 full-text articles, 4 abstracts and 1 ongoing clinical trial. According to readministration timing, studies were classified as rechallenge/reintroduction (n = 8) or stop & go/intermittent therapeutic strategies (n = 4). The studies presented wide heterogeneity in terms of efficacy (Response Rate 6-31%; Disease Control Rate 39-79%; median Progression-Free Survival 3.1-7 months). Those patients who received retreatment after prior adjuvant oxaliplatin or exploiting a stop-&-go strategy appeared to achieve better outcomes. However, no formal comparisons on treatment outcomes were feasible. The most frequent grade 3 or higher adverse events were hematologic toxicities (5-27%), peripheral neuropathy (5-14%) and hypersensitivity reactions (5-20%). CONCLUSIONS: Retreatment with oxaliplatin for mCRC is practiced based on scarce and heterogeneous data indicating efficacy and manageable toxicity. The best strategy to exploit this approach remains to be defined, and the most promising research avenue to improve therapeutic index of oxaliplatin is represented by selection of responder patients whose tumors harbor molecular defects in the DNA damage repair pathway.

Influence of ABCB-1, ERCC-1 and ERCC-2 gene polymorphisms on response to capecitabine and oxaliplatin (CAPOX) treatment in colorectal cancer (CRC) patients of South India.

WHAT IS KNOWN AND OBJECTIVE: High interindividual response variability was reported with capecitabine and oxaliplatin (CAPOX) regimen in colorectal cancer (CRC). The single nucleotide polymorphisms (SNPs) of the genes related to drug efflux transport (ABCB1) and DNA repair (ERCC) could result in altered tumour response. Hence, this study was designed to assess the influence of ABCB1, ERCC-1 and ERCC-2 gene polymorphisms on tumour response to CAPOX treatment in CRC patients of South Indian origin. PATIENTS AND METHODS: A total of 145 newly diagnosed CRC patients were included in the final analysis. Response to CAPOX treatment in the adjuvant setting was assessed in terms of disease-free survival rate (DFSR) and overall survival rate (OSR) at 3 years, whereas in the palliative setting, the response was assessed as progression-free survival rate (PFSR) and OSR at 3 years. Five millilitres of the venous blood sample was collected from each patient for genomic DNA extraction by the manual phenol-chloroform method. Genotyping and allelic discrimination analysis were done using real-time PCR (RT-PCR). RESULTS AND DISCUSSION: With ABCB1 gene polymorphism rs1045642 (A > G), patients with AG/GG genotype showed better DFSR [P value = .02, OR = 2 (CI: 1.5-3)] and PFSR [P value = .02, OR = 1.6 (CI: 1.1-2.5)] when compared to AA genotype in the adjuvant and palliative settings, respectively. Similarly with rs1128503 (A > G) polymorphism, patients with AG/GG genotype were found to have better DFSR [P value = .02, OR = 1.9 (CI: 1.3-3)] and PFSR [P value = .01, OR = 2 (CI: 1.1-3.7)] when compared to AA genotype. However, we did not find any association between CAPOX response and ABCB1 gene polymorphisms in a binary logistic regression when non-genetic predictors were considered for analysis. We did not find any association with ERCC1 (rs11615 A > G) and ERCC2 (rs13181 T > G) gene polymorphisms with respect to CAPOX response in either of the treatment settings. WHAT IS NEW AND CONCLUSION: The response to CAPOX treatment was found to be influenced by the ABCB1 gene variants (rs1128503 and rs1045642), thereby strengthening their predictive role. No association was found between ERCC1 (rs11615 A > G), ERCC2 (rs13181 T > G) gene polymorphisms and tumour response to CAPOX treatment in CRC patients of South Indian origin.