Grade 3/4 neutropenia is a limiting factor in second-line FOLFIRI following FOLFOX4 failure in elderly patients with metastatic colorectal cancer

3550 Background: In the early 2000s, classic LV5FU2 (C) (folinic acid, 5FU bolus, then 5FU infusion on D1 and D2) was replaced with simplified LV5FU2 (S) (folinic acid and 5FU bolus on D1 only), considered as effective and less toxic. No trial proved this assertion. The LV5FU2 companion in the FOLFIRI or FOLFOX regimen was C or S. The FFCD 2001-02 study compared in a 2 x 2 factorial design, in not-pretreated elderly patients (75+) with metastatic colorectal cancer, C or S, with or without irinotecan. No significant differences in PFS and OS were observed in the comparison with or without irinotecan. The median OS was 15.2 months in C versus 11.4 months in S, HR = 0.71 (0.55–0.92) and objective response rate was 37.1% in C vs S 25.6% in S, p = 0.004. The aim of this study was to present the factors associated with these differences. Methods: Prognostic factors associated with OS were studied using a Cox model. The multivariate analysis used the significantly different items from the univariate analysis and the differences observed at the inclusion. For each of these items, a subgroup analysis was performed. The second- and third-line treatments were analysed. Results: The 282 patients from the intent-to-treat study were included in the model. In OS, the prognostic factors were C versus S, number of metastatic sites, alkaline phosphatases (AP) and CEA. The interaction test in each subgroup for OS was not significant but C was significantly better in the following subgroup: age > 80 years, male, Karnofsky 100%, 1-2 Charlson index, AP ≤ 2N, leucocyte count > 11,000, CEA > 2N, CA 19-9 ≤2N. No differences were observed in the NCI toxicities but 130 serious adverse events in S versus 102 in C. A second-line was used for 55% patients in C, 46% in S, 81% of them with oxaliplatin or irinotecan in C, 76% after S. The third-line administration (20%) and targeted therapy (15%) were similar in C and S. Conclusions: C-LV5FU2 was superior both in subgroups with better and lower prognostics and this difference cannot be explained by an imbalance between the populations. The toxicity was not higher and a second-line was more often possible after C. The switch from C to S without scientific proof was perhaps a mistake in our practices. Clinical trial information: NCT00303771.

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A comparison of FOLFIRI (Folinic Acid, Fluorouracil and Irinotecan) Plus Bevacizumab and FLOLFIRI Plus Aflibercept as Second-Line Treatment for Metastatic Colorectal Cancer

10.21203/rs.3.rs-127099/v1 ◽

2020 ◽

Author(s):

Min-Sang Lee ◽

Yong-Pyo Lee ◽

Hongsik Kim ◽

Jung Yong Hong ◽

Jeeyun Lee ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Folinic Acid ◽

Progression Free Survival ◽

Line Treatment ◽

Second Line ◽

Free Survival ◽

Treatment Groups ◽

Grade 3 ◽

Colorectal Cancer Patients

Abstract Background: To date, there are few clinical studies comparing the efficacy and safety of FOLFIRI (folinic acid, fluorouracil and irinotecan) plus bevacizumab or aflibercept in metastatic colorectal cancer patients (mCRC) pretreated with oxaliplatin-based chemotherapy. Methods: We analyzed the treatment outcomes of patients receiving FOLFIRI in combination with bevacizumab or aflibercept as second-line treatment for mCRC between October 2017 and March 2020. This analysis included 67 patients receiving FOLFIRI plus aflibercept and 83 receiving FOLFIRI plus bevacizumab. Results: The overall response rate (ORR) was 13.6% (95% CI: 4.85-22.34) in the FOLFIRI-aflibercept group and 14.7% (95% CI: 6.68-22.71) in the FOLFIRI-bevacizumab group. This difference in ORR was not statistically significant. The median progression free survival (PFS) was 8.6 months in the FOLFIRI-bevacizumab group and 8.5 months in the FOLFIRI-aflibercept group (P = 0.752) (Fig. 1). Patients in the FOLFIRI-bevacizumab group showed a median overall survival (OS) of 12.4 months, while patients in the FOLFIRI-aflibercept group had a median OS of 13.7 months (P = 0.276). There were no significant differences in survival between the two treatment groups. The adverse events were also largely similar between the two groups. However, hypertension of grade 3 or more was more frequent in the FOLFIRI-aflibercept group. Conclusion: FOLFIRI plus bevacizumab and FOLFIRI plus aflibercept had similar anti-tumor activities and toxicity profiles when used as second-line therapy in mCRC patients. Based on these data, both aflibercept and bevacizumab are suitable anti-angiogenic agents when used in combination with FOLFIRI for mCRC.

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A dose escalation study of nimotuzumab plus irinotecan as second-line treatment in metastatic colorectal cancer with wild-type K-ras.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e14122 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e14122-e14122 ◽

Cited By ~ 1

Author(s):

Jun Zhou ◽

Lin Shen ◽

Jing Gao

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Skin Rash ◽

Maximum Tolerated Dose ◽

Chinese Patients ◽

Line Treatment ◽

Second Line ◽

End Points ◽

Personal Reason ◽

Grade 3

e14122 Background: Nimotuzumab is a humanized monoclonal antibody of EGFR. We assessed the safety/tolerability and the efficacy of nimotuzumab combined with Irinotecan as the second-line treatment in Chinese patients with metastatic colorectal cancer (mCRC). Methods: Patients with mCRC refractory to oxaliplatin, K-ras WT, signed informed consent, target lesion(s), performance status (PS) ≤2, adequate organ functions, were eligible for this open-labelled, single-armed trial (NCT00972465). Irinotecan was given as 180mg/m2 d1, Q2w until progression or AEs or maximum 6 cycles. Nimotzumab was given as 200, 400, 600 or 800mg weekly until progression or AEs. The primary end points were objective response rate and toxicity. The second end points are PFS and OS. Results: A total of 31 patients (M/F = 22/9; median age 55; range 29-77) have been enrolled from July 2009 to Nov 2011. 4/11/12/4 patients received nimotuzumab as the dose of 200/400/600/800mg respectively. Most common grade 3/4 toxicity are leukopenia (14.8%,) and neutrocytopenia 18.5%). For all the patients, no grade 3/4 toxicity relating with Nimotuzumab was observed. 2 and 3 patients developed skin rash (grade 1) in 400 and 600mg arm respectively. 2 patients developed skin rash grade 2 in 600/800mg arm. The maximum tolerated dose has not yet been reached. Three patients (400/600mg: 2/1) quitted the trial because of personal reason. In 600mg arm, PR was 33.3% (4/12), SD was 25% (3/12); in 400mg arm, PR was 9.l%(1/11), SD was 36.4%(4/11); in 200mg arm, SD was 50%(2/4), PD was 50% (2/4); in 800mg arm, PR was 25%(1/4), PD was 75%(3/4). The follow-up of overall survival is ongoing. Conclusions: Addition of Nimotuzumab with 600mg weekly plus Irinotecan is safe and first data suggest a promising activity. The maximum tolerated dose of Nimotuzumab has not been reached yet.

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XELOX with bevacizumab in elderly patients age 75 or older with metastatic colorectal cancer: Results of a planned interim analysis for multicenter phase II ASCA study.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.502 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 502-502 ◽

Cited By ~ 2

Author(s):

Keiichiro Ishibashi ◽

Yoshinori Munemoto ◽

Masaki Matsuoka ◽

Taishi Hata ◽

Michiya Kobayashi ◽

...

Keyword(s):

Colorectal Cancer ◽

Renal Function ◽

Elderly Patients ◽

Metastatic Colorectal Cancer ◽

Phase Ii ◽

Performance Status ◽

Primary Objective ◽

Open Label ◽

Ecog Performance Status ◽

Grade 3

502 Background: Combination chemotherapy of capecitabine plus oxaliplatin (XELOX) with bevacizumab is commonly used as standard chemotherapy for metastatic colorectal cancer (mCRC). A previous meta-analysis showed that there was no difference between two age groups of <65 years and ≥65 years on overall survival (OS) after treatment with chemotherapy with bevacizumab. However, the safety and efficacy of XELOX with bevacizumab in elderly patients (pts) ≥75 years with mCRC remain unclear. Methods: This study was an open-label multicentre phase II study to evaluate the efficacy and safety of XELOX with bevacizumab in pts ≥75 years with metastatic CRC. The primary objective was to assess progression-free survival (PFS). The secondary endpoints were the safety, response rate (RR), time to treatment-failure (TTF) and OS. Results: 36 pts were enrolled. Pts characteristics were; median age 78 (range 75-86); male/female, 21/15; ECOG performance status 0/1, 30/6; colon/rectum 24/12, creatinine clearance (CCr) 60.2 ml/min (range 32.6-84.6). Median follow-up period was 220 days. RR was 55.6% and median TTF was 209 days. The median PFS and median OS are not reached. Grade 3 or 4 adverse events (AEs) were reported in 22 pts (62.8%). Common grade 3 or 4 AEs were hypertension (11.4%), leukopenia (20.0%), peripheral sensory neuropathy (14.3%), hand foot syndrome (8.6%), and fatigue (8.6%). Examining the relationship between renal function (CCr) and AEs, the incidence of Grade 3 or 4 AEs in the lower CCr group was significantly higher than that in the higher CCr group (61.6% vs. 47.8%; p=0.013); hematological toxicities (87.5% vs. 14.8%; p=0.0003) and non-hematological toxicities (61.5% vs. 11.1%; p=0.018). Conclusions: XELOX with bevacizumab is safely administered in elderly patients ≥75 years. Renal function (CCr) could be a good predictive marker for grade 3 or 4 AEs. Clinical trial information: UMIN000003500.

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Phase II trial of modified FOLIRI plus Panitumumab as first-line treatment in elderly patients with RAS wild-type metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15053 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15053-e15053

Author(s):

Athanasios Karampeazis ◽

Lampros Vamvakas ◽

Nikolaos K. Kentepozidis ◽

Athanasios Kotsakis ◽

Kostas Kalbakis ◽

...

Keyword(s):

Colorectal Cancer ◽

Elderly Patients ◽

Metastatic Colorectal Cancer ◽

Phase Ii ◽

Phase Ii Trial ◽

Line Treatment ◽

Wild Type ◽

First Line ◽

Grade 3 ◽

First Line Treatment

e15053 Background:The role of combination chemotherapy plus anti-EGFR treatment in older patients with metastatic colorectal cancer (mCRC) is unclear. We conducted an open label phase II trial in order to evaluate the safety and efficacy of modified FOLFIRI plus panitumumab as first-line treatment in elderly patients with RAS wild-type mCRC. Methods: Patients ≥70 years old with unresectable all-RAS wild-type mCRC were treated with Panitumumab 6mg/kg as 60min iv infusion followed by Irinotecan 130mg/m2 as 90min iv infusion, Leucovorin 400mg/m2 as 2h iv infusion and 5-Fluorouracil 400mg/m2 as bolus iv infusion on day 1 and 5-Fluorouracil 1.200 mg/m2 as continuous iv infusion for 46h, every 2 weeks. Sample size calculation was based on the minimax Simon two-step design: The null hypothesis was that the overall response rate (ORR) is ≤ 30% versus the alternative hypothesis of ORR ≥ 50% (α = 0.05, power 80%). Results: Forty-six patients were enrolled in the study. Two patients did not receive treatment because they were RAS mutant. Median age for the 44 treated patients was 76 years (range 70-88). Males were 32 and the PS was 0, 1 and 2 in 25%, 70.5% and 4.5% of patients, respectively. Rectal cancer accounted for 25% while 15.9% of patients had the primary tumour in situ. Twenty-one partial responses were observed for an ORR of 47.7% (95%CI: 32.9%-62.5%) while seven patients (15.9%) had stable disease. After a median follow-up of 36.0 months, the median progression-free survival was 6.1 months (95%CI: 3.6-8.7) and the median overall survival was 20.9 months (95%CI: 11.7-30.1). Grade 3-4 neutropenia was recorded in 4 (9%) and grade 3-4 diarrhea in 9 (20.4%) patients while one patient had a grade 4 bowel perforation. One patient experienced grade 3 mucositis, two patients grade 3 skin toxicity and two patients grade 3 fatigue. There were no toxic deaths while one patient died due to bowel obstruction and one due to postoperative complications after removal of the primary tumor. Conclusions: The modified FOLFIRI plus panitumumab combination presented significant efficacy with manageable toxicity in elderly patients with mCRC.

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A multinational, randomized, phase III trial of XELIRI with or without bevacizumab versus FOLFIRI with or without bevacizumab as second-line therapy for metastatic colorectal cancer: Safety analysis of Asian XELIRI project (AXEPT).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.681 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 681-681

Author(s):

Masato Nakamura ◽

Tae Won Kim ◽

Rui-hua Xu ◽

Young Suk Park ◽

Yong Sang Hong ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Safety Analysis ◽

Phase Iii ◽

Second Line ◽

Second Line Therapy ◽

Phase Iii Trial ◽

Line Therapy ◽

Significant Difference ◽

Grade 3

681 Background: Several studies have shown that capecitabine plus irinotecan (XELIRI) has promising efficacy and safety in patients with metastatic colorectal cancer. AXEPT is a non-inferiority, phase III comparison of XELIRI with or without bevacizumab vs 5-fluorouracil/folinic acid plus irinotecan (FOLFIRI) with or without bevacizumab as second-line therapy in patients with metastatic colorectal cancer. Methods: We undertook an open-label, non-inferiority, randomized phase III trial in South Korea, China and Japan. Patients were randomized 1:1 to XELIRI (irinotecan 200 mg/m2 on day 1 plus capecitabine 800 mg/m2 twice daily for 2 weeks in a 3-week cycle) with or without bevacizumab 7.5 mg/kg or FOLFIRI with or without bevacizumab. The primary endpoint was overall survival. Results: From December 2013 to August 2015, 650 patients were enrolled and 625 (311 in FOLFIRI and 314 in XELIRI) were included to safety analysis at the cutoff dates on August 31, 2016. Patient baseline characteristics including KRAS status and UGT1A1 gene polymorphism were similar between the two treatment arms. Prior chemotherapy with oxaliplatin was given to 97.4% in both arms. The overall incidence of grade 3-4 toxicity was 73% in FOLFIRI arm and 53.2% in XELIRI arm. Whereas FOLFIRI was associated with more grade 3-4 neutropenia (43.7% vs 16.2%), leucopenia (13.5% vs 7.3%) and all grades anemia (80.4% vs 69.4%) than XELIRI, XELIRI was associated with more all grades hand-foot syndrome (34.1% vs 14.8%) and grade 3-4 diarrhea (7.0% vs 3.2%). There was no significant difference in febrile neutropenia (4.2% in FOLFIRI and 2.9% in XELIRI). The addition of bevacizumab did not alter safety profiles between XELIRI and FOLFIRI. There was a treatment-related death in FOLFIRI arm (0.3%). Conclusions: Both FOLFIRI and XELIRI were safe and well tolerated, though there were differences in the rates and toxicity profiles at which adverse events occur. Clinical trial information: NCT01996306. UMIN000012263.

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Geriatric Factors Predict Chemotherapy Feasibility: Ancillary Results of FFCD 2001-02 Phase III Study in First-Line Chemotherapy for Metastatic Colorectal Cancer in Elderly Patients

Journal of Clinical Oncology ◽

10.1200/jco.2012.42.9894 ◽

2013 ◽

Vol 31 (11) ◽

pp. 1464-1470 ◽

Cited By ~ 128

Author(s):

Thomas Aparicio ◽

Jean-Louis Jouve ◽

Laurent Teillet ◽

Dany Gargot ◽

Fabien Subtil ◽

...

Keyword(s):

Colorectal Cancer ◽

Elderly Patients ◽

Metastatic Colorectal Cancer ◽

Predictive Factors ◽

Dose Intensity ◽

Screening Tools ◽

Phase Iii ◽

Severe Toxicity ◽

Phase Iii Study ◽

Grade 3

Purpose Elderly patients form a heterogeneous population. Evaluation of geriatric factors may help evaluate a patient's health status to better adapt treatment. Patients and Methods Elderly patients with previously untreated metastatic colorectal cancer (mCRC) were randomly assigned to receive fluorouracil (FU) -based chemotherapy either alone or in combination with irinotecan (IRI) in the Fédération Francophone de Cancérologie Digestive (FFCD) 2001-02 study. Sites participating in the geriatric substudy completed geriatric screening tools to perform prognostic factor analyses for treatment safety during the first 4 months after treatment initiation. Results The geriatric score was calculated in 123 patients (44%). Median age was 80 years (range, 75 to 91 years). The Charlson comorbidity index was ≤ 1 in 75%, Mini-Mental State Examination (MMSE) score was ≤ 27/30 in 31%, and Instrumental Activities of Daily Living (IADL) showed impairment in 34% of the patients. Seventy-one patients (58%) had grade 3 to 4 toxicity, 41 (33%) had a dose-intensity reduction of more than 33%, and 54 (44%) had at least one unexpected hospitalization during the first 4 months after starting treatment. In multivariate analysis, significant predictive factors for grade 3-4 toxicity were IRI arm (odds ratio [OR], 5.03), MMSE ≤ 27/30 (OR, 3.84), and impaired IADL (OR, 4.67); for dose-intensity reduction of > 33%, the significant predictive factors were alkaline phosphates > 2 × upper limit of normal (OR, 4.16) and IRI arm (OR, 6.85); and for unexpected hospitalization, significant predictive factors were MMSE ≤ 27/30 (OR, 4.56) and Geriatric Depression Scale ≤ 2 (OR, 5.52). Conclusion Geriatric factors (MMSE and IADL) are predictive of severe toxicity or unexpected hospitalization (MMSE) in a randomized prospective phase III study in mCRC. These results suggest that cognitive function and autonomy impairment should be taken into account when choosing a regimen for chemotherapy.

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Capecitabine (XE) plus Irinotecan (IRI) as second-line treatment (XELIRI) for metastatic colorectal cancer (MCRC) in elderly patients: Feasibility and safety results from a Phase II study

Journal of Clinical Oncology ◽

10.1200/jco.2005.23.16_suppl.3676 ◽

2005 ◽

Vol 23 (16_suppl) ◽

pp. 3676-3676 ◽

Cited By ~ 2

Author(s):

G. Fiorentini ◽

P. Dentico ◽

M. Cantore ◽

S. Rossi ◽

P. Pacetti ◽

...

Keyword(s):

Colorectal Cancer ◽

Elderly Patients ◽

Metastatic Colorectal Cancer ◽

Phase Ii ◽

Phase Ii Study ◽

Line Treatment ◽

Second Line

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First-line bolus IFL and second-line FOLFOX: A retrospective review of two hundred thirty patients

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13555 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13555-13555

Author(s):

D. Heng ◽

H. Kennecke ◽

S. Gill ◽

C. Kollmannsberger ◽

C. Lohrisch ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Median Survival ◽

Retrospective Review ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

Cancer Data ◽

Line Therapy ◽

Grade 3

13555 Introduction: The IFL regimen (irinotecan, 5-fluorouracil bolus and leucovorin) is active in metastatic colorectal cancer. Early treatment-related deaths in N9741 led to the utilization of a dose-reduced schema. An infusional regimen (FOLFIRI) replaced IFL because of superior tolerability. FOLFOX can be used as second-line therapy in patients treated previously with IFL. Methods: A retrospective review was performed at the British Columbia Cancer Agency to evaluate both the safety and outcome of all patients given IFL as first-line treatment for metastatic colorectal cancer. Data on second-line FOLFOX was also collected. Between March 31/2002 and April 1/2004, 230 patients were treated. Results: The mean number of IFL cycles delivered was 4.6 (18 doses) for a mean duration of 7.1 months. Toxicity was manageable with only 1 treatment-related death. 17% of patients had grade 3/4 toxicities that included neutropenia and diarrhea. Only 6% of patients required hospitalization during IFL treatment. The median survival of the entire group was 16.6 months (95% CI 14.3–18.6). One hundred twelve patients received second-line therapy. Forty-nine of these patients (44%) received infusional oxaliplatin (mFOLFOX 6) as second-line therapy. 27% had grade 3/4 toxicities and 10% required hospitalization. The median survival of these patients was 25.2 months (95% CI 20.1–30.3). Conclusion: This population-based study demonstrated that bolus IFL played a significant role in the treatment of metastatic colorectal cancer and had a manageable toxicity profile. Lastly, the sequence of IFL followed by FOLFOX resulted in a very meaningful patient survival of over 25 months. No significant financial relationships to disclose.

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Phase II trial of DJ-927, an oral tubulin depolymerization inhibitor, in the treatment of metastatic colorectal cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3591 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3591-3591 ◽

Cited By ~ 5

Author(s):

M. R. Moore ◽

C. Jones ◽

G. Harker ◽

F. Lee ◽

B. Ardalan ◽

...

Keyword(s):

Colorectal Cancer ◽

Peripheral Neuropathy ◽

Metastatic Colorectal Cancer ◽

Dose Reduction ◽

Phase Ii ◽

Phase Ii Trial ◽

Second Line ◽

Second Line Therapy ◽

Line Therapy ◽

Grade 3

3591 Background: DJ-927, a novel oral tubulin depolymerization inhibitor, causes apoptosis and DNA cell division arrest. It is not a substrate for the MDR and has excellent activity in preclinical colorectal cancer models. Methods: We are conducting a two-stage, multi-center, phase II trial to assess the efficacy of DJ-927 administered initially as second-line therapy following failure of irinotecan or oxaliplatin based therapy (n= 39). DJ-927 is given as a single oral dose on day 1 of a 21-day cycle at a dose range of 27 - 35 mg/m2. Results: Thirty-nine patients were enrolled, including 14 with prior irinotecan based therapy and 25 who had received prior oxaliplatin therapy. The median age was 56 years (range: 30–87) and the median ECOG PS at baseline was 1 (range: 0–2). A total of 155 courses (range: 1–24) have been administered with a median of 2 courses. Nine patients required dose reduction due to toxicity. Thirty-seven patients were evaluable for efficacy. There were 2 CRs and 2 PRs (10.3%) reported that were confirmed as per RECIST criteria. Fourteen patients (35.9%) had SD, including 6 patients (15.4%) with SD >12 weeks. The most common Grade 3 or 4 AEs were neutropenia (48.7%), fatigue (10.3%), neuropathy (7.8%), and nausea (5.0%).Six patients experienced febrile neutropenia, all requiring hospitalization but tolerated treatment with subsequent dose reduction. There were 13 episodes (33.3%) of peripheral neuropathy reported; however, only 3 (7.8%) were grade 3 or 4. Six patients withdrew due to adverse events. Conclusions: The results of this study indicate activity of DJ-927 as second line therapy in patients with metastatic colorectal cancer. Severe toxicity was generally limited to reversible neutropenia and peripheral neuropathy. This novel oral agent is well tolerated and warrants further evaluation in combination with other active agents. [Table: see text]

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