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1.
Clin Colorectal Cancer ; 17(4): 313-319, 2018 12.
Article in English | MEDLINE | ID: mdl-30463680

ABSTRACT

BACKGROUND: The Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation (ICECREAM) study assessed the efficacy of cetuximab monotherapy compared with cetuximab combined with chemotherapy for quadruple wild-type (KRAS, NRAS, BRAF, or P13KCA exon 20) metastatic colorectal cancer. PATIENTS AND METHODS: Patients were enrolled in an open-label, multicenter, phase II trial and randomly assigned to cetuximab 400 mg/m2, then 250 mg/m2 cetuximab weekly, with or without irinotecan 180 mg/m2 every 2 weeks. The primary endpoint was 6-month progression-free survival; secondary endpoints were response rate, overall survival, toxicity, and quality of life. RESULTS: From 2012 to 2016, 48 patients were recruited. Two were ineligible, and 2 were not evaluable for response. Characteristics were balanced, except gender (male, 62% vs. 72%) and primary sidedness (left, 95% vs. 68%). For cetuximab compared with cetuximab-irinotecan, progression-free survival was 14% versus 41% (hazard ratio, 0.39; 95% confidence interval, 0.20-0.78; P = .008); response rate was 10% (2 partial responses) versus 38% (1 complete, 8 partial); P = .04. Grade 3 to 4 toxicities were less with cetuximab monotherapy (23% vs. 50%); global and specific quality of life scores did not differ. CONCLUSION: In comparison with cetuximab alone, cetuximab plus irinotecan increases the response rate and delays progression in irinotecan-resistant RAS wild-type colorectal cancer. This echoes data from molecularly unselected patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Colorectal Neoplasms/drug therapy , Liver Neoplasms/drug therapy , Adult , Aged , Cetuximab/administration & dosage , Class I Phosphatidylinositol 3-Kinases/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Female , Follow-Up Studies , GTP Phosphohydrolases/genetics , Humans , Irinotecan/administration & dosage , Liver Neoplasms/genetics , Liver Neoplasms/secondary , Male , Membrane Proteins/genetics , Middle Aged , Mutation , Prognosis , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Survival Rate
2.
J Geriatr Oncol ; 9(1): 32-39, 2018 01.
Article in English | MEDLINE | ID: mdl-28807738

ABSTRACT

OBJECTIVES: Aflibercept (ziv-aflibercept) significantly improves progression-free (PFS) and overall survival (OS) when added to 5-fluorouracil, leucovorin and irinotecan (FOLFIRI), compared with FOLFIRI alone, in patients with metastatic colorectal cancer previously treated with oxaliplatin-based therapy. This subset analysis of the VELOUR study investigates aflibercept plus FOLFIRI versus placebo plus FOLFIRI according to age. METHODS: Efficacy and safety were analyzed by treatment arm and age (≥ or <65years). RESULTS: Overall, 443 patients were ≥65years old (205 in aflibercept arm; 238 in placebo arm) and 783 were <65years old (407 in aflibercept arm; 376 in placebo arm). Median OS was 12.6 versus 11.3months (hazard ratio [HR]: 0.85; 95.34% CI 0.68-1.07) in patients ≥65years old and 14.5 versus 12.5months (HR: 0.80; 95.34% CI 0.67-0.95) in those patients <65years old, for patients receiving FOLFIRI plus aflibercept or placebo, respectively. There was no interaction between treatment and age. Treatment-emergent adverse events (AEs) were comparable for patients <65years and ≥65years old. The incidence of grade 3/4 AEs was higher for patients ≥65years old than for those <65years old in both the aflibercept (89.3% versus 80.5%) and placebo (67.4% versus 59.4%) arms. Interaction tests for grade 3/4 antiangiogenic agent-related AEs suggested no heterogeneity between the older and younger patient populations (p>0.1). CONCLUSION: A limited but consistent benefit on both OS and PFS was associated with the addition of aflibercept to FOLFIRI compared with placebo in patients <65 and ≥65years old, with a marked but manageable increase in the toxicity profile in older patients. TRIAL REGISTRATION: clinicaltrials.govNCT00561470.


Subject(s)
Adenocarcinoma/drug therapy , Angiogenesis Inhibitors/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Camptothecin/analogs & derivatives , Colorectal Neoplasms/drug therapy , Receptors, Vascular Endothelial Growth Factor/administration & dosage , Recombinant Fusion Proteins/administration & dosage , Age Factors , Aged , Aged, 80 and over , Angiogenesis Inhibitors/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/adverse effects , Disease-Free Survival , Double-Blind Method , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Kaplan-Meier Estimate , Leucovorin/administration & dosage , Leucovorin/adverse effects , Male , Middle Aged , Neoplasm Metastasis , Recombinant Fusion Proteins/adverse effects
3.
J Clin Oncol ; 34(34): 4194-4195, 2016 12.
Article in English | MEDLINE | ID: mdl-27621391
4.
J Clin Oncol ; 34(15): 1723-31, 2016 05 20.
Article in English | MEDLINE | ID: mdl-26903575

ABSTRACT

PURPOSE: SIRFLOX was a randomized, multicenter trial designed to assess the efficacy and safety of adding selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)-based chemotherapy in patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Chemotherapy-naïve patients with liver metastases plus or minus limited extrahepatic metastases were randomly assigned to receive either modified FOLFOX (mFOLFOX6; control) or mFOLFOX6 plus SIRT (SIRT) plus or minus bevacizumab. The primary end point was progression-free survival (PFS) at any site as assessed by independent centralized radiology review blinded to study arm. RESULTS: Between October 2006 and April 2013, 530 patients were randomly assigned to treatment (control, 263; SIRT, 267). Median PFS at any site was 10.2 v 10.7 months in control versus SIRT (hazard ratio, 0.93; 95% CI, 0.77 to 1.12; P = .43). Median PFS in the liver by competing risk analysis was 12.6 v 20.5 months in control versus SIRT (hazard ratio, 0.69; 95% CI, 0.55 to 0.90; P = .002). Objective response rates (ORRs) at any site were similar (68.1% v 76.4% in control v SIRT; P = .113). ORR in the liver was improved with the addition of SIRT (68.8% v 78.7% in control v SIRT; P = .042). Grade ≥ 3 adverse events, including recognized SIRT-related effects, were reported in 73.4% and 85.4% of patients in control versus SIRT. CONCLUSION: The addition of SIRT to FOLFOX-based first-line chemotherapy in patients with liver-dominant or liver-only metastatic colorectal cancer did not improve PFS at any site but significantly delayed disease progression in the liver. The safety profile was as expected and was consistent with previous studies.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brachytherapy , Colorectal Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Combined Modality Therapy , Female , Fluorouracil/adverse effects , Fluorouracil/therapeutic use , Humans , Leucovorin/adverse effects , Leucovorin/therapeutic use , Male , Middle Aged , Neoplasm Metastasis , Organoplatinum Compounds/adverse effects , Organoplatinum Compounds/therapeutic use
5.
BMC Cancer ; 15: 802, 2015 Oct 26.
Article in English | MEDLINE | ID: mdl-26503593

ABSTRACT

BACKGROUND: This prospective, open-label phase II study assessed the impact of liver-directed therapy with selective internal radiation therapy (SIRT) and systemic chemotherapy on progression-free survival (PFS) in liver-dominant metastatic pancreatic adenocarcinoma. METHODS: Patients received yttrium-90-labelled ((90)Y) resin microspheres (SIR-Spheres; Sirtex Medical Limited, Sydney, Australia) as a single procedure on day 2 of the first weekly cycle of 5-fluorouracil (5FU; 600 mg/m(2)) with the option to switch to gemcitabine (1000 mg/m(2)) after 8 weeks of 5FU. Statistical analysis was conducted using Microsoft Excel (Microsoft Corporation, Redmond, Washington, USA). The primary endpoint of the study was PFS in the liver, with a median of ≥ 16 weeks defined as the threshold for clinical significance. PFS and overall survival (OS) were summarised by the Kaplan-Meier method using non-parametric estimates of the survivor function. RESULTS: Fourteen eligible patients were enrolled; ten had primary tumour in situ and eight had liver-only metastases. Patients received a median (90)Y activity of 1.1 GBq and 8 weekly doses of 5FU; seven patients received a median of two doses of gemcitabine. Disease control in the liver was 93% (two confirmed partial responses [PR], one unconfirmed PR, ten stable disease). Median reduction in cancer antigen 19-9 was 72%. Median PFS was 5.2 months in the liver, which met the primary endpoint of the study, and 4.4 months at any site. PFS was prolonged in those with a resected primary compared with patients with primary in situ (median 7.8 vs. 3.4 months; p = 0.017). Median OS was 5.5 months overall and 13.6 months in patients with a resected primary. Grade 3/4 adverse events occurred in eight (57%) patients during days 0-60. There was one sudden death and another patient who died from possible treatment-related liver failure 7.0 months after SIRT. CONCLUSIONS: SIRT and chemotherapy appears to be an effective treatment for liver metastases from pancreatic cancer, likely to be of most benefit in selected patients with a resected primary tumour and liver only disease. Significant toxicity was observed and the safety of this approach in patients with metastatic pancreatic cancer will need to be confirmed in subsequent studies. Further study is warranted with SIRT and modern chemotherapies. TRIAL REGISTRATION: ACTRN12606000015549.


Subject(s)
Fluorouracil/therapeutic use , Liver Neoplasms/drug therapy , Liver Neoplasms/radiotherapy , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/radiotherapy , Yttrium Radioisotopes/administration & dosage , Aged , Antimetabolites, Antineoplastic/therapeutic use , Combined Modality Therapy/methods , Female , Humans , Liver Neoplasms/diagnosis , Liver Neoplasms/secondary , Male , Middle Aged , Pancreatic Neoplasms/diagnosis , Prospective Studies , Pancreatic Neoplasms
6.
Eur J Cancer ; 51(1): 18-26, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25466509

ABSTRACT

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) previously-treated with oxaliplatin benefit significantly from the addition of aflibercept to FOLFIRI in relation to overall survival, progression-free survival and response rate. PATIENTS AND METHODS: The results for efficacy and safety over the time course of the VEGF Trap (aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen trial were analysed based on data from 1226 patients randomised to receive FOLFIRI plus either aflibercept (n=612) or placebo (n=614). Hazard ratios (HR) by 6-month time period were estimated using a piecewise Cox proportional hazard model. Severity of adverse events (AEs) was graded using National Cancer Institute Common Terminology Criteria, version 3.0. RESULTS: The estimated probabilities of survival were 38.5% versus 30.9% at 18 months, 28.0% versus 18.7% at 24 months and 22.3% versus 12.0% at 30 months, for the aflibercept- and placebo-treated arms, respectively. The proportional improvement in the HR over time was consistent with the survival probability results; survival at 24 months was improved by 50% and almost doubled at 30 months. The majority of worst-grade AEs occurred within the first four cycles of treatment and in a small percent of treatment cycles and were mostly reversible. Common chemotherapy- and anti-vascular epithelial growth factor (VEGF)-associated AEs occurred rarely and in a small proportion of cycles with the majority being of single occurrence. CONCLUSIONS: The addition of aflibercept to FOLFIRI showed a continued and persistent improvement in overall survival over time in patients with mCRC. Although grade 3-4 AEs were more frequent in the aflibercept arm, they occurred in early treatment cycles and decreased sharply following initial presentation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Fluorouracil/therapeutic use , Leucovorin/therapeutic use , Organoplatinum Compounds/therapeutic use , Receptors, Vascular Endothelial Growth Factor/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Biomarkers, Pharmacological , Camptothecin/adverse effects , Camptothecin/pharmacology , Camptothecin/therapeutic use , Colorectal Neoplasms/pathology , Disease Progression , Disease-Free Survival , Female , Fluorouracil/adverse effects , Fluorouracil/pharmacology , Humans , Irinotecan , Leucovorin/adverse effects , Leucovorin/pharmacology , Male , Neoplasm Metastasis , Oxaliplatin , Proportional Hazards Models , Receptors, Vascular Endothelial Growth Factor/adverse effects , Receptors, Vascular Endothelial Growth Factor/pharmacology , Recombinant Fusion Proteins/adverse effects
7.
BMC Cancer ; 14: 897, 2014 Dec 01.
Article in English | MEDLINE | ID: mdl-25487708

ABSTRACT

BACKGROUND: In colorectal cancer (CRC), unresectable liver metastases are linked to poor prognosis. Systemic chemotherapy with regimens such as FOLFOX (combination of infusional 5-fluorouracil, leucovorin and oxaliplatin) is the standard first-line treatment. The SIRFLOX trial was designed to assess the efficacy and safety of combining FOLFOX-based chemotherapy with Selective Internal Radiation Therapy (SIRT or radioembolisation) using yttrium-90 resin microspheres (SIR-SpheresR; Sirtex Medical Limited, North Sydney, Australia). METHODS/DESIGN: SIRFLOX is a randomised, multicentre trial of mFOLFOX6 chemotherapy+/-SIRT as first-line treatment of patients with liver-only or liver-predominant metastatic CRC (mCRC). The trial aims to recruit adult chemotherapy-naive patients with proven liver metastases with or without limited extra-hepatic disease, a life expectancy of >=3 months and a WHO performance status of 0-1. Patients will be randomised to receive either mFOLFOX6 or SIRT+mFOLFOX6 (with a reduced dose of oxaliplatin in cycles 1-3 following SIRT). Patients in both arms can receive bevacizumab at investigator discretion. Protocol chemotherapy will continue until there is unacceptable toxicity, evidence of tumour progression, complete surgical resection or ablation of cancerous lesions, or the patient requests an end to treatment. The primary endpoint of the SIRFLOX trial is progression-free survival (PFS). Secondary endpoints include: PFS in the liver; tumour response rate (liver and any site); site of tumour progression; health-related quality of life; toxicity and safety; liver resection rate; and overall survival. Assuming an increase in the median PFS from 9.4 months to 12.5 months with the addition of SIRT to mFOLFOX6, recruiting >=450 patients will be sufficient for 80% power and 95% confidence. DISCUSSION: The SIRFLOX trial will establish the potential role of SIRT+standard systemic chemotherapy in the first-line management of mCRC with non-resectable liver metastases. TRIAL REGISTRATION: SIRFLOX ClinicalTrials.gov identifier: NCT00724503. Registered 25 July 2008.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Yttrium Radioisotopes/administration & dosage , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Chemoradiotherapy , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/radiotherapy , Fluorouracil/administration & dosage , Humans , Leucovorin/administration & dosage , Liver Neoplasms/drug therapy , Liver Neoplasms/radiotherapy , Microspheres , Organoplatinum Compounds/administration & dosage
8.
Clin Cancer Res ; 20(3): 744-53, 2014 Feb 01.
Article in English | MEDLINE | ID: mdl-24218517

ABSTRACT

PURPOSE: Cetuximab improves survival in patients with K-ras wild-type advanced colorectal cancer. We examined the predictive and prognostic significance of additional biomarkers in this setting, in particular BRAF, PIK3CA, and PTEN. EXPERIMENTAL DESIGN: Available colorectal tumor samples were analyzed from the CO.17 study. BRAF mutations were identified in tumor-derived DNA by direct sequencing and PIK3CA mutations were identified using a high-resolution melting screen with confirmation by sequencing. PTEN expression by immunohistochemistry (IHC) was performed on tissue microarrays. For each biomarker, prognostic and predictive effects were examined using a Cox model with tests for treatment-biomarker interaction. RESULTS: A total of 572 patients with pretreated colorectal cancer were randomly assigned to receive cetuximab or best supportive care (BSC). Of 401 patients assessed for BRAF status, 13 (3.2%) had mutations. Of 407 patients assessed for PIK3CA status, 61 (15%) had mutations. Of 205 patients assessed for PTEN, 148 (72%) were negative for IHC expression. None of BRAF, PIK3CA, or PTEN was prognostic for overall or progression-free survival in the BSC arm. None was predictive of benefit from cetuximab, either in the whole study population or the K-ras wild-type subset. In the K-ras wild-type subgroup, the overall survival adjusted HR according to BRAF mutation status was 1.39 (interaction P = 0.69), PIK3CA mutation status HR = 0.79 (interaction P = 0.63), and PTEN expression HR = 0.75 (interaction P = 0.61). CONCLUSIONS: In chemotherapy-refractory colorectal cancer, neither PIK3CA mutation status nor PTEN expression were prognostic, nor were they predictive of benefit from cetuximab. Evaluation of predictive significance of BRAF mutations requires a larger sample size.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/analysis , Colorectal Neoplasms/genetics , Cetuximab , Class I Phosphatidylinositol 3-Kinases , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/mortality , DNA Mutational Analysis , Disease-Free Survival , Humans , Immunohistochemistry , Kaplan-Meier Estimate , PTEN Phosphohydrolase/analysis , PTEN Phosphohydrolase/biosynthesis , PTEN Phosphohydrolase/genetics , Phosphatidylinositol 3-Kinases/analysis , Phosphatidylinositol 3-Kinases/biosynthesis , Phosphatidylinositol 3-Kinases/genetics , Prognosis , Proto-Oncogene Proteins B-raf/analysis , Proto-Oncogene Proteins B-raf/biosynthesis , Proto-Oncogene Proteins B-raf/genetics , Tissue Array Analysis , Treatment Outcome
9.
Eur J Cancer ; 50(2): 320-31, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24140268

ABSTRACT

PURPOSE: The antiangiogenic agent aflibercept (ziv-aflibercept in the United States) in combination with 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) significantly improved survival in a phase III study of patients with metastatic colorectal cancer (mCRC) previously treated with an oxaliplatin-based regimen. In the present analysis, outcomes were evaluated in prespecified subgroups to assess the consistency of the treatment effect. METHODS: Patients were randomised to receive FOLFIRI plus aflibercept or placebo every 2weeks until disease progression or unacceptable toxicity occurred. Efficacy and safety outcomes were analysed with respect to demographic and baseline characteristics, and stratification factors (prior bevacizumab treatment and Eastern Cooperative Oncology Group performance status). RESULTS: Median overall survival (OS, months [95.34% confidence interval (CI)]) for aflibercept versus placebo was 12.5 (10.8-15.5) versus 11.7 (9.8-13.8) in patients with prior bevacizumab treatment and 13.9 (12.7-15.6) versus 12.4 (11.2-13.5) in patients with no prior bevacizumab treatment. The p value for interaction was 0.5668, indicating there was no heterogeneity in these subgroups. For OS and progression-free survival (PFS), there was a significantly greater benefit (at the 2-sided 10% level) of treatment for patients with liver only metastases versus patients with no liver metastases/liver metastases with other organ involvement (p value for interaction: 0.0899 [OS]; 0.0076 [PFS]). There was no evidence of heterogeneity in treatment effect in any of the other subgroups examined. CONCLUSIONS: The benefits of aflibercept in combination with FOLFIRI in patients with mCRC previously treated with oxaliplatin were maintained across the specified patient subgroups, including in patients with or without prior bevacizumab treatment.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Colorectal Neoplasms/pathology , Diarrhea/chemically induced , Double-Blind Method , Drug Administration Schedule , Fatigue/chemically induced , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Irinotecan , Kaplan-Meier Estimate , Leucovorin/administration & dosage , Leucovorin/adverse effects , Middle Aged , Neoplasm Metastasis , Neutropenia/chemically induced , Prospective Studies , Receptors, Vascular Endothelial Growth Factor/administration & dosage , Receptors, Vascular Endothelial Growth Factor/adverse effects , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/adverse effects , Treatment Outcome
10.
J Clin Oncol ; 30(28): 3499-506, 2012 Oct 01.
Article in English | MEDLINE | ID: mdl-22949147

ABSTRACT

PURPOSE: Treatment for metastatic colorectal cancer (mCRC) commonly involves a fluoropyrimidine-based chemotherapy regimen such as infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) or fluorouracil, leucovorin, and oxaliplatin, often combined with bevacizumab or an epidermal growth factor receptor monoclonal antibody. We studied the effect of adding the novel antiangiogenic agent aflibercept (also known as ziv-aflibercept in the United States) to FOLFIRI in patients with mCRC previously treated with oxaliplatin, including patients who received prior bevacizumab. PATIENTS AND METHODS: Patients were randomly assigned to receive aflibercept (4 mg/kg intravenously; 612 patients) or placebo (614 patients) every 2 weeks in combination with FOLFIRI. Treatment was administered until disease progression or unacceptable toxicity. The primary end point was overall survival. RESULTS: Adding aflibercept to FOLFIRI significantly improved overall survival relative to placebo plus FOLFIRI (hazard ratio [HR], 0.817; 95.34% CI, 0.713 to 0.937; P = .0032) with median survival times of 13.50 versus 12.06 months, respectively. Aflibercept also significantly improved progression-free survival (PFS; HR, 0.758; 95% CI, 0.661 to 0.869; P < .0001), with median PFS times of 6.90 versus 4.67 months, respectively. The effects on overall survival and PFS exhibited a consistent trend across prespecified subgroup analyses, including bevacizumab pretreated patients. Response rate was 19.8% (95% CI, 16.4% to 23.2%) with aflibercept plus FOLFIRI compared with 11.1% (95% CI, 8.5% to 13.8%) with placebo plus FOLFIRI (P = .0001). Adverse effects reported with aflibercept combined with FOLFIRI included the characteristic anti-vascular endothelial growth factor effects and also reflected an increased incidence of some chemotherapy-related toxicities. CONCLUSION: Aflibercept in combination with FOLFIRI conferred a statistically significant survival benefit over FOLFIRI combined with placebo in patients with mCRC previously treated with oxaliplatin.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Recombinant Fusion Proteins/administration & dosage , Adult , Aged , Aged, 80 and over , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Disease-Free Survival , Double-Blind Method , Female , Fluorouracil/therapeutic use , Humans , Leucovorin/therapeutic use , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Receptors, Vascular Endothelial Growth Factor , Survival Rate , Young Adult
11.
Eur J Cancer ; 47(12): 1826-36, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21665462

ABSTRACT

BACKGROUND: Second-line treatment with irinotecan for advanced or metastatic colorectal cancer prolongs survival. It is uncertain whether irinotecan is better administered with 5-fluorouracil or alone in patients previously treated with a fluoropyrimidine. We compared toxicity (particularly diarrhoea), quality of life, and efficacy of combination chemotherapy and irinotecan in these patients. METHODS: In DaVINCI, a randomised phase II trial, patients with advanced colorectal cancer were randomly allocated to: Combination therapy (FOLFIRI), irinotecan (180 mg/m(2) IV over 90 min, day 1), 5-fluorouracil (400mg/m(2) IV bolus and 2400 mg/m(2) by 46-hour infusion from day 1) and folinic acid (20mg/m(2) IV bolus, day 1), 2-weekly; or Single-agent, irinotecan (350 mg/m(2) IV over 90 min), 3-weekly. Toxicity was evaluated every treatment cycle; QOL and response 6-weekly. Analysis was by intention to treat. The trial, amended from a larger factorial design, was terminated early due to slow recruitment. Results were also combined with other second-line irinotecan trials. FINDINGS: We randomised 44 patients to combination and 45 to single agent. Eight patients in the irinotecan arm and 4 in the combination arm had grade 3/4 diarrhoea (P=0.24). Treatment groups did not differ significantly in overall QOL changes, response rate or progression free or overall-survival. In a systematic review of 29 trials of second-line irinotecan-based treatment, single-agent irinotecan was associated with more diarrhoea and alopecia than the combination but efficacy was similar. INTERPRETATION: Combination treatment compared with single-agent irinotecan reduces alopecia and diarrhoea without compromising efficacy on clinical outcomes. Both regimens remain as reasonable treatment options. FUNDING: Research grant (Pfizer).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Alopecia/chemically induced , Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/therapeutic use , Chemotherapy, Adjuvant , Diarrhea/chemically induced , Drug Administration Schedule , Female , Fluorouracil/administration & dosage , Humans , Infusions, Intravenous , Injections, Intravenous , Irinotecan , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Staging , Research Design , Treatment Outcome
12.
J Clin Oncol ; 28(19): 3191-8, 2010 Jul 01.
Article in English | MEDLINE | ID: mdl-20516443

ABSTRACT

PURPOSE: To determine whether adding bevacizumab, with or without mitomycin, to capecitabine monotherapy improves progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) in an open-label, three-arm randomized trial. PATIENTS AND METHODS: Overall, 471 patients in Australia, New Zealand, and the United Kingdom with previously untreated, unresectable mCRC were randomly assigned to the following: capecitabine; capecitabine plus bevacizumab (CB); or capecitabine, bevacizumab, and mitomycin (CBM). We compared CB with capecitabine and CBM with capecitabine for progression-free survival (PFS). Secondary end points included overall survival (OS), toxicity, response rate (RR), and quality of life (QOL). RESULTS: Median PFS was 5.7 months for capecitabine, 8.5 months for CB, and 8.4 months for CBM (capecitabine v CB: hazard ratio [HR], 0.63; 95% CI, 0.50 to 0.79; P < .001; C v CBM: HR, 0.59; 95% CI, 0.47 to 0.75; P < .001). After a median follow-up of 31 months, median OS was 18.9 months for capecitabine and was 16.4 months for CBM; these data were not significantly different. Toxicity rates were acceptable, and all treatment regimens well tolerated. Bevacizumab toxicities were similar to those in previous studies. Measures of overall QOL were similar in all groups. CONCLUSION: Adding bevacizumab to capecitabine, with or without mitomycin, significantly improves PFS without major additional toxicity or impairment of QOL.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Australasia , Bevacizumab , Capecitabine , Colorectal Neoplasms/pathology , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Diarrhea/chemically induced , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/analogs & derivatives , Humans , Hypotension/chemically induced , Kaplan-Meier Estimate , Male , Middle Aged , Mitomycin/administration & dosage , Mitomycin/adverse effects , Neoplasm Metastasis , Quality of Life , Thrombocytopenia/chemically induced , Treatment Outcome
13.
J Clin Oncol ; 27(25): 4089-95, 2009 Sep 01.
Article in English | MEDLINE | ID: mdl-19652069

ABSTRACT

PURPOSE: Liver metastases are the principal cause of death in patients with advanced colorectal cancer (CRC). Irinotecan is a chemotherapeutic agent used in the treatment of CRC and has demonstrated synergistic potential when used with radiation. Radioembolization with yttrium-90 microspheres has demonstrated increased response and survival rates when given with fluorouracil chemotherapy. This study's goal was to evaluate the maximum-tolerated dose of concomitant irinotecan and radioembolization in fluorouracil-refractory patients with CRC hepatic metastases. PATIENTS AND METHODS: Twenty-five irinotecan-naive patients who had experienced relapse after previous chemotherapy were enrolled onto three dose-escalating groups. Irinotecan was administered at 50, 75, or 100 mg/m(2) on days 1 and 8 of a 3-week cycle for the first two cycles, and full irinotecan doses (ie, 100 mg/m(2)) were administered during cycles 3 to 9. Radioembolization was administered during the first chemotherapy cycle. RESULTS: Most patients experienced acute, self-limiting abdominal pain and nausea. Mild lethargy and anorexia were common. Grades 3 to 4 events were seen in three of six patients at 50 mg/m(2) (obstructive jaundice, thrombocytopenia, diarrhea), in five of 13 patients at 75 mg/m(2) (neutropenia, leukopenia, thrombocytopenia, elevated alkaline phosphatase, abdominal pain, ascites, fatigue) and in four of six patients at 100 mg/m(2) (diarrhea, deep vein thrombosis, constipation, leukopenia). Eleven (48%) of 23 patients had a partial response, and nine patients (39%) had stable disease. The median progression-free survival was 6.0 months; the median survival was 12.2 months. CONCLUSION: Concomitant use of radioembolization plus irinotecan did not reach a maximum-tolerated dose. The recommended dose of irinotecan in this setting is 100 mg/m(2) on days 1 and 8 of a 3-week cycle.


Subject(s)
Brachytherapy , Camptothecin/analogs & derivatives , Colorectal Neoplasms/secondary , Drug Resistance, Neoplasm , Enzyme Inhibitors/administration & dosage , Liver Neoplasms/drug therapy , Liver Neoplasms/radiotherapy , Radiopharmaceuticals/administration & dosage , Yttrium Isotopes/administration & dosage , Adult , Aged , Antimetabolites, Antineoplastic/therapeutic use , Australia , Camptothecin/administration & dosage , Camptothecin/adverse effects , Chemotherapy, Adjuvant , Disease-Free Survival , Drug Administration Schedule , Enzyme Inhibitors/adverse effects , Female , Fluorouracil/therapeutic use , Humans , Infusions, Intravenous , Irinotecan , Liver Neoplasms/secondary , Male , Maximum Tolerated Dose , Microspheres , Middle Aged , Radiopharmaceuticals/adverse effects , Radiotherapy, Adjuvant , Time Factors , Topoisomerase I Inhibitors , Treatment Outcome , Yttrium Isotopes/adverse effects
14.
J Clin Oncol ; 25(9): 1099-106, 2007 Mar 20.
Article in English | MEDLINE | ID: mdl-17369573

ABSTRACT

PURPOSE: Liver metastases represent the principal cause of death in patients with advanced colorectal cancer (CRC). Injection of resin microspheres (SIR Spheres)--containing the beta-emitter, yttrium-90--into the arterial supply of the liver can cause radioembolization of metastases. This treatment has not been tested with the radiosensitizing chemotherapy, oxaliplatin, which appears synergistic in the treatment of CRC when combined with fluorouracil and leucovorin (FOLFOX). PATIENTS AND METHODS: A phase I study of SIR-Spheres therapy with modified FOLFOX4 systemic chemotherapy was conducted in patients with inoperable liver metastases from CRC who had not previously received chemotherapy for metastatic disease. Oxaliplatin (30 to 85 mg/m2) was administered for the first three cycles with full FOLFOX4 doses from cycle 4 until cycle 12. The primary end point was toxicity. RESULTS: Twenty patients were enrolled onto the study. Five patients experienced National Cancer Institute (NCI; Bethesda, MD) grade 3 abdominal pain, two of whom had microsphere-induced gastric ulcers. The dose-limiting toxicity was grade 3 or 4 neutropenia, which was recorded in 12 patients. One episode of transient grade 3 hepatotoxicity was recorded. Mean splenic volume increased by 92% following 6 months of protocol therapy. Partial responses were demonstrated in 18 patients and stable disease in two patients. Two patients underwent partial hepatic resection following protocol therapy. Median progression-free survival was 9.3 months, and median time to progression in the liver was 12.3 months. CONCLUSION: The maximum-tolerated dose was 60 mg/m2 of oxaliplatin for the first three cycles, with full FOLFOX4 doses thereafter. This chemoradiation regime merits evaluation in phase II-III trials.


Subject(s)
Adenocarcinoma/therapy , Antineoplastic Agents/therapeutic use , Brachytherapy/methods , Colorectal Neoplasms/pathology , Embolization, Therapeutic/methods , Liver Neoplasms/therapy , Yttrium Radioisotopes/therapeutic use , Adenocarcinoma/drug therapy , Adenocarcinoma/radiotherapy , Adenocarcinoma/secondary , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Australia , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Humans , Leucovorin/administration & dosage , Liver Neoplasms/drug therapy , Liver Neoplasms/radiotherapy , Liver Neoplasms/secondary , Male , Maximum Tolerated Dose , Microspheres , Middle Aged , Organoplatinum Compounds/administration & dosage , Radiopharmaceuticals/therapeutic use , Radiotherapy, Adjuvant , Time Factors , Treatment Outcome , United Kingdom , Vitamin B Complex/administration & dosage
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