scholarly journals Retrospective analysis of the effect of CAPOX and mFOLFOX6 dose intensity on survival in colorectal patients in the adjuvant setting

2016 ◽  
Vol 23 (3) ◽  
pp. 171 ◽  
Author(s):  
A. Mamo ◽  
J. Easaw ◽  
F. Ibnshamsah ◽  
A. Baig ◽  
Y.S. Rho ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dose Reduction ◽  
Real Life ◽  
Disease Free Survival ◽  
Dose Intensity ◽  
Sensory Neuropathy ◽  
Stage Iii ◽  
Cancer Centre ◽  
Peripheral Sensory ◽  
Disease Free

Background Despite lack of a true comparative study, the FOLFOX (5-fluorouracil–leucovorin–oxaliplatin) and CAPOX (capecitabine–oxaliplatin) regimens are believed to be similar in their efficacy and tolerability in the treatment of stage III colorectal cancer. However, that belief has been disputed, because real-life data suggest that the CAPOX regimen is more toxic, leading to more frequent reductions in the delivered dose intensity—thus raising questions about the effect of dose intensity on clinical outcomes.Methods A retrospective data review for two Canadian institutions, the Segal Cancer Centre and the Tom Baker Cancer Centre, considered patients diagnosed with stage III colorectal cancer during 2006–2013. Primary endpoints were dose intensity and toxicity, with a secondary endpoint of disease-free survival.Results The study enrolled 180 eligible patients (80 at the Segal Cancer Centre, 100 at the Tom Baker Cancer Centre). Of those 180 patients, 75 received CAPOX, and 105 received mFOLFOX6. In the CAPOX group, a significant dose reduction was identified for capecitabine compared with 5-fluorouracil in mFOLFOX6 group (p = 0.0014). Similarly, a significant dose reduction was observed for oxaliplatin in mFOLFOX6 compared with oxaliplatin in CAPOX (p = 0.0001). Compared with the patients receiving CAPOX, those receiving mFOLFOX6 were twice as likely to experience a treatment delay of more than 1 cycle-length (p = 0.03855). Toxicity was more frequent in patients receiving mFOLFOX6 (nausea: 30% vs. 18%; diarrhea: 47% vs. 24%; peripheral sensory neuropathy: 32% vs. 3%). At a median follow-up of 40 months, preliminary data showed no difference in disease-free survival (p = 0.598). Pooled data from both institutions were also separately analyzed, and no significant differences were found.Conclusions Our results support the use of CAPOX despite a lack of head-to-head randomized trial data.

Long-term followup of bi-shRNAfurin and GMCSF augmented autologous tumor cell immunotherapy treated colorectal cancer patients in phase I and IIa studies.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15100-e15100
Author(s):  
Minal A. Barve ◽  
Anton M. Melnyk ◽  
Luisa Manning ◽  
Gladice Wallraven ◽  
Martin Birkhofer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cell ◽  
Phase I ◽  
Checkpoint Inhibitors ◽  
Disease Free Survival ◽  
Stage Iii ◽  
Autologous Tumor Cell ◽  
Autologous Tumor ◽  
Disease Free

e15100 Background: Vigil is an immuno-stimulatory autologous tumor cell therapy, which uses patient tumor cells transfected with a plasmid encoding genes to upregulate GM-CSF and down regulate TGFβ 1&2. It is administered monthly by intra-dermal injection. In Phase I and IIa trials patients with over 19 different tumor types were safely treated. Rapid and durable systemic immune activation was demonstrated using an IFNγ ELISPOT assay. Methods: Data are summarized for a group of 9 patients with advanced colorectal cancer followed for up to 3.5 years. Results: Six women and 3 men with Stage III or IV colorectal cancer were treated between March, 2010 and September, 2013. Six patients received Vigil as a monotherapy and 3 in combination with FOLFOX chemotherapy. Results: Demographics and treatment details are displayed below. Two patients with Stage III disease received combination therapy after complete surgical resection, and remain disease free over 3 years from surgery. The patients received 9 and 12 Vigil injections with a brisk and durable ELISPOT reactions. Conclusions: Preliminary results suggest that Vigil can be combined safely with FOLOX chemotherapy and still elicit a systemic immune response. Long term disease free survival has been observed in several patients justifying further exploration of this combination. More detailed molecular characterization and neoantigen identification of patient tumor will be undertaken in future studies. A combination with immune checkpoint inhibitors may also be explored. [Table: see text]

scholarly journals Folate pathway genes linked to mitochondrial biogenesis and respiration are associated with outcome of patients with stage III colorectal cancer

Tumor Biology ◽  
2019 ◽  
Vol 41 (6) ◽  
pp. 101042831984623 ◽  
Author(s):  
Elisabeth Odin ◽  
Arvid Sondén ◽  
Göran Carlsson ◽  
Bengt Gustavsson ◽  
Yvonne Wettergren
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Mitochondrial Biogenesis ◽  
Disease Free Survival ◽  
Stage Iii ◽  
Free Survival ◽  
Folate Pathway ◽  
Colorectal Cancer Patients ◽  
Disease Free

5-fluorouracil in combination with the folate leucovorin is the cornerstone in treatment of colorectal cancer. Transport of leucovorin into cells, and subsequent metabolic action, require expression of several genes. The aim was to analyze if tumoral expression of genes putatively involved in leucovorin transport, polyglutamation, or metabolism was associated with outcome of patients with stage III colorectal cancer treated with adjuvant chemotherapy. A total of 363 stage III colorectal cancer patients who received adjuvant bolus 5-fluorouracil + leucovorin alone, or in combination with oxaliplatin according to Nordic bolus regimes were included. Expression of 11 folate pathway genes was determined in tumors using quantitative real-time polymerase chain reaction and related to disease-free survival. The median follow-up time was 5 years. During follow-up, 114 (31%) patients suffered from recurrent disease. A high tumoral expression of the genes SLC46A1/PCFT, SLC19A1/RFC-1, ABCC3/MRP3, GGH, and MTHFD1L, which are involved in folate transport, polyglutamation, or metabolism, was associated with longer disease-free survival of the patients. Each of these genes either encodes mitochondrial enzymes or is being regulated by mitochondrial transcription factors. Expression of the SLC46A1/PCFT gene was most strongly associated with disease-free survival, regardless of treatment regimen. In conclusion, the results show that expression of folate pathway genes are associated with outcome of colorectal cancer patients treated with adjuvant 5-fluorouracil in combination with leucovorin. A prospective study needs to be conducted to determine if expression of these genes can be used to predict response to leucovorin and other folates that are now being tested in clinical studies. Moreover, there seems to be a link between folate metabolism and mitochondrial biogenesis and respiration that deserves further exploration.

Phase II trial of adjuvant mFOLFOX6 after metastasectomy for pulmonary metastasis of colorectal cancer: WJOG5810G.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4097-4097
Author(s):  
Nozomu Machida ◽  
Takehiro Okumura ◽  
Junji Kishimoto ◽  
Narikazu Boku ◽  
Tomohiro Nishina ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Pulmonary Metastasis ◽  
Disease Free Survival ◽  
Sensory Neuropathy ◽  
Eligibility Criteria ◽  
Phase 2 Trial ◽  
Grade 3 ◽  
Ecog Ps ◽  
Peripheral Sensory

4097 Background: Resection of pulmonary metastasis (PM) is widely accepted to improve the prognosis in selected patients (pts) with metastatic colorectal cancer (CRC). However, the clinical implication of adjuvant chemotherapy after metastasectomy of PM is unknown. We conducted a multi-center phase 2 trial of adjuvant chemotherapy with mFOLFOX6 after metastasectomy of PM-CRC. Methods: Main eligibility criteria were first curative metastasectomy of 4 or less PMs and no prior chemotherapy except for adjuvant chemotherapy with fluoropyrimidine monotherapy after curative resection of primary or extrathoracic CRC metastasis. The study treatment was 12 courses of mFOLFOX6 (oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, 5-fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion, every 2 w). The primary endpoint was overall survival (OS). The secondary endpoints included disease-free survival (DFS), adverse events (AEs), and recurrence sites. The sample size was determined to be 93 expecting 5-year OS rate of 50% with threshold 35% (90% power, alpha error 5%). Results: Fifty-two pts from 34 institutions were enrolled between July 2011 and July 2014. Patient enrollment was closed prematurely because of slow accrual. Four patients were ineligible after enrollment and the safety and efficacy cohort comprised 52 and 48 patients, respectively. Patient backgrounds were as follows: gender (male/female) 31/21, median age (range) 63 (42-75) years, ECOG PS (0/1) 48/4, primary site (colon/rectum) 18/34, number of PM (1/2/3/4) 36/9/5/2, synchronous/metachronous PM 11/41, and unilateral/bilateral PM 40/12. With the median follow-up time of 6.0 (1.8-7.7) years, 5-year OS rate was 86% (95% CI: 72-93) and 5-year DFS rate was 59% (95% CI: 43-71). Tumors recurred in 19 patients (13 lung, 3 liver and 7 others). Total 41 pts (79%) completed 12 courses of mFOLFOX6 (reasons for discontinuation: AEs in 3, refusal due to AEs in 8). AEs ( > Grade 3) were neutropenia 50%, fatigue 8%, peripheral sensory neuropathy 8%, appetite loss 4%, diarrhea 4%, febrile neutropenia 2% and allergic reaction 2%. There was no treatment related death. Conclusions: Adjuvant mFOLFOX6 is feasible and may be effective after metastasectomy for PM-CRC, considering much better OS than we had expected. Clinical trial information: UMIN000005693 .

The study of efficacy and safety of chemotherapy plus bevacizumab with oxaliplatin stop-and-go strategy in first-line treatment for metastatic colorectal cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 761-761
Author(s):  
Nao Takano ◽  
Goro Nakayama ◽  
Yasuhiro Kodera
Keyword(s):  
Colorectal Cancer ◽  
Maintenance Therapy ◽  
Metastatic Colorectal Cancer ◽  
Dose Intensity ◽  
Sensory Neuropathy ◽  
Efficacy And Safety ◽  
First Line ◽  
Peripheral Sensory Neuropathy ◽  
Stop And Go ◽  
Peripheral Sensory

761 Background: In metastatic colorectal cancer (mCRC), the benefit of the molecular targeted drugs added to chemotherapy has been reported and a combination therapy of capecitabine (CAP) and oxaliplatin (CapeOX) plus bevacizumab (BEV) is an established first-line therapy for mCRC. However, the management of the cumlateve neurotoxicity of oxaliplatin still remains. We evaluated the efficacy and safety of CapeOX plus BEV with oxaliplatin stop and go strategy. Methods: Two prospective clinical trials of previously untreated unresectable mCRC were analyzed. Fifty four patients were treated with CapeOX plus BEV with oxaliplatin stop and go strategy (CCOG-0902). They were treated 4 cycles of CapeOX plus BV therapy followed by maintenance therapy of 8 cycles of Capecitabine plus BV and oxaliplatin reintroduction was scheduled after maintenance therapy or upon tumor progression. On the other group, forty seven patients were treated with mFOLFOX6 plus BEV (CCOG-0801). Progression free survival (PFS), overall survival (OS), response rate (RR), disease control rate (DCR), relative dose intensity (RDI), and frequency of peripheral sensory neuropathy (PSN) were evaluated. Results: Patient characteristics were balanced between the two groups. The median RDI of oxaliplatin in CCOG-0902 group was significantly higher, 92% than in CCOG-0801 group, 80%. RR and DCR were 61.5% and 96.3% respectively, in CCOG-0902 group, compared with 61.7% and 89.4% respectively, in CCOG-0801 group. Median PFS was 13.6 and 30.5 months, respectively, compared with 11.7 and 31.6 months, respectively, in CCOG-0801 group (p=not significant). The frequency of peripheral sensory neuropathy (PSN) was 19.0% (>Grade3: 1.9%) of patients in CCOG-0902 group compared with 72.3% (>grade 3: 17.0%) in CCOG-0801 group. Conclusions: CapeOX plus BV with oxaliplatin stop and go strategy could have same efficacy as continuing oxaliplatin with avoiding PSN. Clinical trial information: UMIN000006478.

Efficacy and feasibility of S-1 plus oxaliplatin (C-SOX) for stage III colon cancer patients who underwent curative resection (KSCC1303).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 739-739
Author(s):  
Nobutomo Miyanari ◽  
Yasunori Emi ◽  
Akihito Tsuji ◽  
Kenji Sakai ◽  
Hideaki Anai ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Survival Rate ◽  
Cancer Patients ◽  
Curative Resection ◽  
Disease Free Survival ◽  
Dose Intensity ◽  
Stage Iii ◽  
Free Survival ◽  
Stage Iii Colon Cancer ◽  
Disease Free

739 Background: Adjuvant chemotherapy is an accepted treatment method to improve the survival rate of Stage III colon cancer patients. Recently, regimens including oxaliplatin were proven superior to 5-FU only regimens. The purpose of this study was to examine the efficacy and feasibility of S-1 plus oxaliplatin (C-SOX) for Stage III colon cancer patients who underwent curative resection. Methods: Colon cancer patients who had undergone curative resection were enrolled in this study. They received oral S-1 40-60 mg twice daily on days 1 to 14 every 3 weeks plus intravenous oxaliplatin 130 mg/m2 on day 1 for 24 months. The primary endpoint was 3-year disease-free survival. The secondary endpoints were the rate of treatment completeness, adverse events, relative dose intensity, disease-free survival and overall survival. Results: Between 2014 February and 2014 December, eighty-nine patients were enrolled in this study. One patient had to be excluded due to ineligibility. The other eighty-eight patients were analyzed. The rate of protocol treatment completeness was 72.3%. Relative dose intensity of S-1 and oxaliplatin were 72 and 76.3, respectively. Hematological severe adverse events (Grade 3/4) were neutropenia (21.3%) and thrombocytopenia (15.7%). The most frequent symptom was diarrhea (Grade 3/4: 5.6%). Six-month disease-free survival rate was 94.3% (95% confidential interval: 86.9-97.6%). Six-month overall survival rate was 98.9% (95% C.I.: 92.2-99.8%). Conclusions: C-SOX for Stage III colon cancer patients who underwent curative resection was safe and feasible. The long-term outcome should be evaluated in future studies. Clinical trial information: 000012618.

Improved Overall Survival With Oxaliplatin, Fluorouracil, and Leucovorin As Adjuvant Treatment in Stage II or III Colon Cancer in the MOSAIC Trial

2009 ◽  
Vol 27 (19) ◽  
pp. 3109-3116 ◽  
Author(s):  
Thierry André ◽  
Corrado Boni ◽  
Matilde Navarro ◽  
Josep Tabernero ◽  
Tamas Hickish ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Adjuvant Treatment ◽  
Disease Free Survival ◽  
Sensory Neuropathy ◽  
Stage Ii ◽  
Stage Iii ◽  
Curative Intent ◽  
Grade 3 ◽  
Peripheral Sensory

Purpose Three-year disease-free survival (DFS) was significantly improved in patients who had undergone resection with curative intent for stage II or III colon cancer who received bolus plus continuous-infusion fluorouracil plus leucovorin (LV5FU2) with the addition of oxaliplatin (FOLFOX4). Final results of the study, including 6-year overall survival (OS) and 5-year updated DFS, are reported. Patients and Methods A total of 2,246 patients were randomly assigned to receive LV5FU2 or FOLFOX4 for 6 months. The primary end point was DFS. Secondary end points were OS and safety. Results Five-year DFS rates were 73.3% and 67.4% in the FOLFOX4 and LV5FU2 groups, respectively (hazard ratio [HR] = 0.80; 95% CI, 0.68 to 0.93; P = .003). Six-year OS rates were 78.5% and 76.0% in the FOLFOX4 and LV5FU2 groups, respectively (HR = 0.84; 95% CI, 0.71 to 1.00; P = .046); corresponding 6-year OS rates for patients with stage III disease were 72.9% and 68.7%, respectively (HR = 0.80; 95% CI, 0.65 to 0.97; P = .023). No difference in OS was seen in the stage II population. The incidence of second noncolorectal cancers was 5.5% and 6.1% in the FOLFOX4 and LV5FU2 groups, respectively. Among patients receiving oxaliplatin, the frequency of grade 3 peripheral sensory neuropathy was 1.3% 12 months after treatment and 0.7% at 48 months. Conclusion Adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and 6-year OS in the adjuvant treatment of stage II or III colon cancer and should be considered after surgery for patients with stage III disease.

Preoperative hepatic and regional arterial chemotherapy in the prevention of liver metastasis after colorectal cancer surgery

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4090-4090
Author(s):  
J. Xu ◽  
Y. Zhong ◽  
W. Niu ◽  
X. Qin ◽  
Y. Wei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Liver Metastasis ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Stage Iii ◽  
Control Group ◽  
Free Survival ◽  
Significant Difference ◽  
Disease Free

4090 Background: To investigate whether preoperative hepatic and regional arterial chemotherapy are able to prevent liver metastasis and improve overall survival in patients receiving curative colorectal cancer resection. Methods: Patients with Stage II or Stage III colorectal cancer (CRC) were randomly assigned to receive preoperative hepatic and regional arterial chemotherapy (PHRAC group, n=256) or surgery alone (control group, n=253). The primary endpoint was disease-free survival, whereas the secondary endpoints included liver metastasis-free survival and overall survival. Results: There were no significant differences in overall morbidity between PHRAC and Control groups. During the follow-up period (median, 42 months), the median liver metastasis time for patients with stage III CRC was significantly longer in the PHRAC group (16±3 months v.s. 8±1 months, P=0.01). In stage III patients, there was also significant difference between the two groups with regard to the incidence of liver metastasis (18.9% vs 27.3%, P=0.01), 5-year disease-free survival (70.2% vs 52.0%, P=0.0076), 5-year overall survival (80.3% vs 69.5%, P=0.020) and the median survival time (40.1± 4.6 months vs 36.3 ± 3.2 months, P=0.03). In the PHRAC arm, the risk ratio of recurrence was 0.63 (95% CI, 0.51–0.79, P=0.0001), of death was 0.50(95% CI, 0.32–0.67; P=0.005), and of liver metastasis was 0.70 (95% CI, 0.52–0.86; p=0.01). In contrast, PHRAC seemed to be no benefit for stage II patients. Toxicities, such as hepatic toxicity and leucocyte decreasing, were mild and could be cured with medicine. Conclusions: Preoperative hepatic and regional arterial chemotherapy, in combination with surgical resection, could be able to reduce and delay the occurrence of liver metastasis and therefore improve survival rate in patients with stage III colorectal cancer. No significant financial relationships to disclose.

scholarly journals TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Sha Zhou ◽  
Jianhong Peng ◽  
Liuniu Xiao ◽  
Caixia Zhou ◽  
Yujing Fang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Disease Free Survival ◽  
Free Survival ◽  
Epigenetic Regulator ◽  
Crc Management ◽  
Disease Free ◽  
Resistance To Chemotherapy

AbstractResistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Here, we identified TRIM25 as an epigenetic regulator of oxaliplatin (OXA) resistance in CRC. The level of TRIM25 in OXA-resistant patients who experienced recurrence during the follow-up period was significantly higher than in those who had no recurrence. Patients with high expression of TRIM25 had a significantly higher recurrence rate and worse disease-free survival than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after OXA treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3 ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting OXA resistance. Our study contributes to a better understanding of OXA resistance and indicates that inhibitors against TRIM25 might be an excellent strategy for CRC management in clinical practice.

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