ABSTRACT
BACKGROUND: Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI. PATIENTS AND METHODS: A pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5-24) and thin patients (BMI <18.5). Interaction tests were performed between BMI effect and sex, age and the addition of antiangiogenics to chemotherapy. RESULTS: The rate of BMI ≥25 patients was 41.5%, ranging from 37.6% (1991-1999 period) to 41.5% (2000-2006 period) and 44.8% (2007-2013 period). Comparison of overweight patients versus normal BMI range patients revealed a significant improvement of median overall survival (OS) (18.5 versus 16.3 months, HR = 0.88 [0.80-0.98] p = 0.02) and objective response rate (ORR) (42% versus 36% OR = 1.23 [1.01-1.50] p = 0.04) but a comparable median progression-free survival (PFS) (7.8 versus 7.2 months, HR = 0.96 [0.87-1.05] p = 0.35). Subgroup analyses revealed that overweight was significantly associated with better OS in men. OS and PFS were significantly shorter in thin patients. CONCLUSION: Overweight patients had a prolonged OS compared with normal weight patients with mCRC. The association of overweight with better OS was only observed in men. The pejorative prognosis of BMI <18.5 was confirmed.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Body Mass Index , Colorectal Neoplasms/drug therapy , Overweight/physiopathology , Aged , Angiogenesis Inhibitors/administration & dosage , Clinical Trials as Topic , Colorectal Neoplasms/pathology , Colorectal Neoplasms/physiopathology , Female , Humans , Kaplan-Meier Estimate , Male , Neoplasm Metastasis , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , PrognosisABSTRACT
INTRODUCTION: In advanced gastric cancer, doublet regimen including platinum salts and fluoropyrimidine is considered as a standard first-line treatment. The addition of docetaxel (75â¯mg/m2â¯q3w) to cisplatin (75â¯mg/m2â¯q3w) and 5-fluorouracil has been shown to improve efficacy. However, this regimen (DCF) was associated with frequent severe toxicities (including more complicated neutropenia), limiting its use in clinical practice. Interesting alternative docetaxel-based regimens have been developed that need to be validated. AIM: GASTFOX study is a randomized phase III trial comparing FOLFOX alone or with docetaxel at 50â¯mg/m2 (TFOX regimen) in first-line treatment for advanced gastric cancer. In both arms, cycle is repeated every 2 weeks until disease progression or unacceptable toxicity. MATERIALS AND METHODS: Main eligibility criteria: histologically proven locally advanced or metastatic gastric or esogastric junction adenocarcinoma, HER negative status, measurable disease, ECOG performance status 0 or 1, and adequate renal, hepatic and bone marrow functions. RESULTS: The primary endpoint is radiological/clinical progression-free survival (PFS). A difference of 2 months for the median PFS in favor of TFOX is expected (HRâ¯=â¯0.73) Based on a two-sided α risk of 5% and a power of 90%, 454 events are required to show this difference. Secondary endpoints included overall survival, overall response rate, safety, quality of life and the therapeutic index. CONCLUSION: This study is planned to include 506 patients to demonstrate the superiority of TFOX over FOLFOX in first-line advanced gastric cancer treatment (NCT03006432).
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Stomach Neoplasms/drug therapy , Taxoids/adverse effects , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease-Free Survival , Docetaxel , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Infusions, Intravenous , Intention to Treat Analysis , Kaplan-Meier Estimate , Leucovorin/administration & dosage , Leucovorin/adverse effects , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Taxoids/administration & dosageABSTRACT
The technique of hepatic arterial infusion (HAI) for the treatment of liver metastases from colorectal cancer has been developed over more than 30 years. Although the indications and protocols for this technique have evolved with time, HAI is not routinely performed in clinical practice. Studies have been heterogeneous, with different regimens of intra-arterial drugs, associated or not with systemic chemotherapy, and with unconvincing outcomes. Technical difficulties for catheter placement have limited the implementation of this method in routine practice. The aim of this review is to present recent studies, highlighting technical improvements and promising combinations of oxaliplatin-based HAI with systemic treatments. HAI is being investigated in both the metastatic setting - in the first line and beyond - and in the adjuvant setting, and we will discuss its potential place in current and future patient management.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colorectal Neoplasms/drug therapy , Liver Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Colorectal Neoplasms/pathology , Hepatic Artery , Humans , Infusions, Intra-Arterial , Liver Neoplasms/secondary , Organoplatinum Compounds/administration & dosage , OxaliplatinABSTRACT
Colorectal cancer is one of the most commonly diagnosed cancers worldwide and nearly half of patients will develop metastatic disease at some point during the course of their disease. The goal of anticancer therapy in this context is to extend survival, while trying to maximise the patient's health-related quality of life. To this end, we need to understand how to incorporate patient-reported outcomes into clinical trials and routine practice to accurately assess if treatment strategies are providing clinical benefit for the patient. This review reflects the proceedings of a 2016 European Society of Digestive Oncology workshop, where the authors discussed the use of patient-reported outcomes to measure health-related quality of life when evaluating treatment during the management of colorectal cancer. A summary of the challenges associated with implementing patient-reported outcomes in clinical trials is provided, as well as a review of the current clinical evidence surrounding patient-reported outcomes in metastatic colorectal cancer.
ABSTRACT
INTRODUCTION: Hepatic arterial infusion chemotherapy (HAIC) is a treatment used for liver metastases (LM) of colorectal cancer (CRC). Because of its technical conditions, it has been used in only a few experienced centers in France. Our aim was to evaluate its feasibility, efficacy and tolerance in 4 centers. METHODS: Clinical, biological, and radiological data of patients treated with HAIC for unresectable LM from CRC in 4 institutions from October 2011 to January 2016 were retrospectively analyzed. RESULTS: Sixty-one patients with unresectable LM from CRC were included. Patients had previously received systemic chemotherapy in 95% of patients and 82.8% had previous oxaliplatin treatment. Oxaliplatin was administered using an intra-arterial route combined with intravenous (I.V.) Five-fluorouracil (5-FU) with leucovorin alone in 43.3% of patients, or combined with other I.V. chemotherapies or monoclonal antibodies in 56.7% of patients. Grade 3 to 4 clinical toxicities were reported in 16% of patients, including 9.8% of neurotoxicity, and Grade 3 to 4 biological toxicities were reported in 24.6% of patients including 22.2% with neutropenia. Catheter-related complications were observed in 31.1%. Tumor response rate in first- and second-line was 26.5% and third- and fourth-line was 11%. Median overall survival (OS) in first- and second-line was 13.5 months and third- and fourth-line was 8.3 months (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.39-1.12; P = .1729). Median progression-free survival (PFS) in first- and second-line was 9 months and third- and fourth-line were 6 months (HR, 0.53; 95% CI, 0.18-0.659; P = .0037). A secondary R0 resection was possible in 10 cases (16.4%) allowing a 2-year survival of 80%. CONCLUSION: These data confirm that in centers that recently developed HAIC using oxaliplatin, this treatment is feasible and has acceptable tolerance. The results, in terms of hepatic PFS, PFS, OS, and the rate of secondary resections of LM, are in the range of published data, and they confirm the interest of HAIC in patients in progression after multiple I.V.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colorectal Neoplasms/drug therapy , Liver Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Colorectal Neoplasms/pathology , Disease-Free Survival , Female , Fluorouracil/administration & dosage , France , Hepatic Artery , Humans , Infusions, Intra-Arterial , Leucovorin/administration & dosage , Liver Neoplasms/secondary , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Retrospective Studies , Survival RateABSTRACT
PURPOSE: The purpose of this prospective observational study was to evaluate the efficacy and tolerability of transarterial chemoembolization (TACE) for neuroendocrine liver metastases using a combination of streptozocin, Lipiodol, and tris-acryl microspheres. PATIENTS AND METHODS: A total of 16 men and 9 women aged 59.6 ± 11.3 years, all with predominant liver disease, underwent 54 courses of TACE using an emulsion of 1.5 g of streptozocin and 10 ml of Lipiodol. Additional embolization was performed using 300-500 µm tris-acryl microspheres. Morphological response was evaluated using the RECIST criteria on multi-detector computed tomography or MRI. Clinical efficacy was evaluated particularly in patients with carcinoid syndrome. RESULTS: The primary tumor was located in the small bowel or pancreas in 21 (84%) patients. Eleven (44%) patients presented with a carcinoid syndrome. Nineteen (76%) patients presented with more than 10 liver nodules. One delayed case of ischemic cholecystitis was treated conservatively. After a median follow-up of 36.1 months, 1 (4%) patient had a complete response, 12 (48%) patients had a partial response, and 7 (28%) patients had a stable disease corresponding to a disease control rate of 80%. All patients with carcinoid syndrome had significant improvement. Median time to progression was 18.8 months and overall survival was 100, 100, and 92% at 1, 2, and 3 years, respectively. Seven patients presented with extrahepatic progression with abdominal lymphadenopathies or metastases to the brain, ovary, adrenal gland, or lung. CONCLUSION: Optimized TACE using a combination of streptozocin, Lipiodol, and tris-acryl microspheres is effective and well tolerated.
Subject(s)
Acrylic Resins/administration & dosage , Chemoembolization, Therapeutic/methods , Endocrine Gland Neoplasms/pathology , Gelatin/administration & dosage , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Streptozocin/administration & dosage , Adult , Aged , Antibiotics, Antineoplastic/administration & dosage , Ethiodized Oil/administration & dosage , Female , Humans , Liver/diagnostic imaging , Liver Neoplasms/diagnostic imaging , Magnetic Resonance Imaging , Male , Middle Aged , Prospective Studies , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
BACKGROUND: Early tumour shrinkage has been associated with improved survival in patients receiving cetuximab-based systemic chemotherapy for liver metastases from colorectal cancer (LM-CRC). We tested this hypothesis for previously treated LM-CRC patients receiving cetuximab (500 mg/m2) and triplet hepatic artery infusion (HAI) within European trial OPTILIV. METHODS: Irinotecan (180 mg/m2), 5-fluorouracil (2800 mg/m2) and oxaliplatin (85 mg/m2) were given as chronomodulated or conventional delivery. Patients were retrospectively categorised as early responders (complete or partial RECIST response after three courses) or non-early responders (late or no response). Prognostic factors were determined using multivariate logistic or Cox regression models. RESULTS: Response was assessed in 57 of 64 registered patients (89%), who had previously received one to three prior systemic chemotherapy protocols. An early response occurred at 6 weeks in 16 patients (28%; 9 men, 7 women), aged 33-76 years, with a median of 12 liver metastases (LMs) (2-50), involving five segments (1-8). Ten patients had a late response, and 31 patients had no response. Grade 3-4 fatigue selectively occurred in the non-early responders (0% versus 26%; p = 0.024). Early tumour response was jointly predicted by chronomodulation-odds ratio (OR): 6.0 (1.2-29.8; p = 0.029)-and LM diameter ≤57 mm-OR: 5.3 (1.1-25.0; p = 0.033). Early tumour response predicted for both R0-R1 liver resection-OR: 11.8 (1.4-100.2; p = 0.024) and overall survival-hazard ratio: 0.39 (0.17-0.88; p = 0.023) in multivariate analyses. CONCLUSIONS: Early tumour response on triplet HAI and systemic cetuximab predicted for complete macroscopic liver resection and prolonged survival for LM-CRC patients within a multicenter conversion-to-resection medicosurgical strategy. Confirmation is warranted for early response on HAI to guide decision making. Protocol numbers: EUDRACT 2007-004632-24 NCT00852228.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Liver Neoplasms/drug therapy , Adenocarcinoma/secondary , Adult , Aged , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Cetuximab/administration & dosage , Colorectal Neoplasms/pathology , Fatigue/chemically induced , Female , Fluorouracil/administration & dosage , Hepatic Artery , Humans , Infusions, Intra-Arterial , Infusions, Intravenous , Irinotecan , Liver Neoplasms/secondary , Logistic Models , Male , Middle Aged , Multivariate Analysis , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Proportional Hazards Models , Retrospective Studies , Survival Rate , Time Factors , Treatment OutcomeABSTRACT
VIPoma is a rare neuroendocrine tumor (NET) with a high potential to develop hepatic metastases and poor prognosis. The primitive tumor is nonsymptomatic and usually localized within the pancreas. Liver metastasis drives the prognosis and induces profuse watery diarrhea or renal failure. We herein present severe renal failure or diarrhea in two patients hospitalized in intensive care justifying emergency treatment of liver metastasis. The two patients experienced severe diarrhea due to a hypersecretion of vasoactive intestinal peptide (VIP) from liver metastasis released into the blood circulation. Therapeutic management was discussed and liver transarterial chemoembolization (TACE) was performed with chemotherapy-loaded embospheres, which cause necrosis of tumor lesions. TACE controlled the hormonal syndrome and made patients eligible for curative surgery. Tumor necrosis occurred and VIP levels collapsed. Surgery was performed in one of the two cases after TACE and the patient was considered in remission. Both patients were still alive after 3 years of follow up. Thus, TACE is feasible and appears to be an effective emergency treatment in patients with a VIP-hormonal syndrome due to liver metastases. Despite the biological disorder due to the hormonal secretion, an aggressive approach is warranted in VIP liver metastasis.
ABSTRACT
The use of imaging in colorectal cancer (CRC) has significantly evolved over the last twenty years, establishing important roles in surveillance, diagnosis, staging, treatment selection and follow up. The range of modalities has broadened with the development of novel tracer and contrast agents, and the fusion of technologies such as positron emission tomography (PET) and computed tomography (CT). Traditionally, the most widely used modality for assessing treatment response in metastasised colon and rectal tumours is CT, combined with use of the RECIST guidelines. However, a growing body of evidence suggests that tumour size does not always adequately correlate with clinical outcomes. Magnetic resonance imaging (MRI) is a more versatile technique and dynamic contrast-enhanced (DCE)-MRI and diffusion-weighted (DW)-MRI may be used to evaluate biological and functional effects of treatment. Integrated fluorodeoxyglucose (FDG)-PET/CT combines metabolic and anatomical imaging to improve sensitivity and specificity of tumour detection, and a number of studies have demonstrated improved diagnostic accuracy of this modality in a variety of tumour types, including CRC. These developments have enabled the progression of treatment strategies in rectal cancer and improved the detection of hepatic metastatic disease, yet are not without their limitations. These include technical, economical and logistical challenges, along with a lack of robust evidence for standardisation and formal guidance. In order to successfully apply these novel imaging techniques and utilise their benefit to provide truly personalised cancer care, advances need to be clinically realised in a routine and robust manner.
ABSTRACT
No standards for staging, systemic therapy or the timing of an operation are defined for patients newly diagnosed with synchronous metastases and a primary in the colon. An expert group of radiologists, medical, radiation and surgical oncologists therefore came together to discuss staging and treatment sequence for these patients and came up with a recommendation based on current evidence of potential therapeutic options. The discussion was organized to debate recommendations centred on 5 topics and therefore the position paper is built upon these titles and their subtitles.
Subject(s)
Antineoplastic Protocols , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Colon/pathology , Combined Modality Therapy , Drug Therapy , Hepatectomy , Humans , Liver/pathology , Neoplasm StagingABSTRACT
BACKGROUND: Ovarian metastases from gastrointestinal tumours frequently lead to locoregional complications and undermine quality of life. The chemosensitivity of ovarian metastases from gastric cancer is unknown. AIM: To evaluate the efficacy of modern chemotherapy regimens in first-line treatment for patients with ovarian metastases from gastric cancer. METHODS: All consecutive patients with ovarian metastases from gastric cancer who received at least one cycle of chemotherapy were included in this retrospective study. RESULTS: Thirty-five patients were included (median age, 50.5 years; synchronous ovarian metastases, 60%). Seventeen patients (48.6%) underwent oophorectomy. Patients were treated with first-line chemotherapy based on platinum (n=14), irinotecan (n=8), taxane plus platinum (n=4) or epirubicin plus platinum (n=9). The median PFS and OS were 6.8 and 18.8 months, respectively. The objective response rate (ORR) for extra-ovarian (13.6%) and ovarian (20.9%) metastatic sites was not significantly different (p=0.55). There was no significant difference in terms of ORR on ovarian metastatic site according to the first-line chemotherapy (p=0.21). In multivariate analysis, oophorectomy was an independent prognostic factor for OS (p<0.01). CONCLUSIONS: This study suggests that ovarian metastases from gastric cancer are not more resistant than extra-ovarian metastases, and that oophorectomy is an independent prognostic factor significantly linked to OS. Prospective studies are needed to confirm these results.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/secondary , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Bridged-Ring Compounds/therapeutic use , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Cisplatin/therapeutic use , Epirubicin/therapeutic use , Female , Fluorouracil/therapeutic use , France , Humans , Irinotecan , Kaplan-Meier Estimate , Magnetic Resonance Imaging , Middle Aged , Multivariate Analysis , Ovarian Neoplasms/mortality , Ovariectomy , Prognosis , Proportional Hazards Models , Retrospective Studies , Taxoids/therapeutic use , Tomography, X-Ray Computed , Treatment Outcome , Young AdultABSTRACT
High-dose FOLFIRI has an acceptable safety profile and promising efficacy. UDP-glucuronosyltransferase: (UGT1A1) polymorphism may be predictive of toxicity and efficacy of irinotecan. This phase II study aimed to evaluate the combination of high-dose FOLFIRI plus bevacizumab in patients with previously untreated metastatic colorectal cancer (MCRC) based on their UGT1A1 genotype. Patients with the UGT1A1 *1/*1 (group 1) or *1/*28 (group 2) genotype received bevacizumab plus high-dose FOLFIRI every 2 weeks. Using the Bryant and Day design with objective response rate and toxicity as the primary endpoints, 54 patients in each group were required with a planned interim analysis after inclusion of 17 patients per group. We planned to stop the trial at the interim analysis if ≤ 7 patients exhibited an objective response (OR) and/or ≥ 3 patients exhibited severe toxicity. At the interim analysis, ORs were higher than the number expected: 52.9% (group 1) and 58.8% (group 2). More than three toxic events occurred in both groups and, according to the interim analysis rule, the trial was closed due to unacceptable toxicity. Recruitment was stopped when 86 patients were included and an analysis on overall population was done for overall survival (OS) and progression-free survival (PFS). The median PFS was 10.7 months (group 1) and 10.4 months (group 2). The median OS was 25.5 months (group 1) and 23.9 months (group 2). This trial does not support the use of the intensive treatment with HD-FOLFIRI plus bevacizumab combination for MCRC in patients with the UGTA1*1/UGT1A1*1 or UGT1A1*1/UGT1A1*28 genotype.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bevacizumab/administration & dosage , Camptothecin/analogs & derivatives , Colorectal Neoplasms/drug therapy , Glucuronosyltransferase/genetics , Adolescent , Adult , Aged , Camptothecin/administration & dosage , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Genotype , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Metastasis , Polymorphism, GeneticABSTRACT
Neuroendocrine carcinomas (NEC) of the anus or the rectum are a rare disease, accounting for less than 1% of all digestive malignancies. Most are metastatic at diagnosis and treated with a platinum-based chemotherapy. No guidelines for localized tumors exist. The purpose of this study was to describe the characteristics of anorectal localized NEC, their management and their outcomes.We retrospectively reviewed patients from 11 French centers with anorectal localized NEC. We compared 2 therapeutic managements: surgery (group A) versus chemotherapy with or without radiation (group B). Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method.A total of 24 patients were identified with a median follow-up of 25 months (3-60 months). Median age was 63 years old and 17 had a rectal tumor (71%). Mean Ki-67 was 72% (range: 20-100), and 75% of the tumors had a high proliferative index (Ki-67 >â50%). Global PFS and OS were 13.1 and 44.1 months, respectively. Thirty-seven percent of patients were in group A and 63% in group B. There was no difference between group A and group B, whether in terms of PFS (13.0 months vs. 13.2 months, P = 0.75) or OS (49.1 months vs. 39.2 months, P = 0.42).In patients with anorectal localized NEC, chemotherapy with or without radiation obtained a similar outcome as surgery and this conservative approach could be deemed a reasonable option.
Subject(s)
Carcinoma, Neuroendocrine/therapy , Chemoradiotherapy , Rectal Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Carcinoma, Neuroendocrine/surgery , Disease-Free Survival , Female , Humans , Male , Middle Aged , Rectal Neoplasms/surgery , Retrospective StudiesABSTRACT
An international panel of multidisciplinary experts convened to develop recommendations for managing patients with colorectal cancer (CRC) and synchronous liver metastases (CRCLM). A modified Delphi method was used. CRCLM is defined as liver metastases detected at or before diagnosis of the primary CRC. Early and late metachronous metastases are defined as those detected ⩽12months and >12months after surgery, respectively. To provide information on potential curability, use of high-quality contrast-enhanced computed tomography (CT) before chemotherapy is recommended. Magnetic resonance imaging is increasingly being used preoperatively to aid detection of subcentimetric metastases, and alongside CT in difficult situations. To evaluate operability, radiology should provide information on: nodule size and number, segmental localization and relationship with major vessels, response after neoadjuvant chemotherapy, non-tumoral liver condition and anticipated remnant liver volume. Pathological evaluation should assess response to preoperative chemotherapy for both the primary tumour and metastases, and provide information on the tumour, margin size and micrometastases. Although the treatment strategy depends on the clinical scenario, the consensus was for chemotherapy before surgery in most cases. When the primary CRC is asymptomatic, liver surgery may be performed first (reverse approach). When CRCLM are unresectable, the goal of preoperative chemotherapy is to downsize tumours to allow resection. Hepatic resection should not be denied to patients with stable disease after optimal chemotherapy, provided an adequate liver remnant with inflow and outflow preservation remains. All patients with synchronous CRCLM should be evaluated by a hepatobiliary multidisciplinary team.
Subject(s)
Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/surgery , Consensus , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/surgery , Meta-Analysis as Topic , Randomized Controlled Trials as TopicABSTRACT
PURPOSE: The phase III CRYSTAL study demonstrated that addition of cetuximab to fluorouracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival, progression-free survival, and objective response in the first-line treatment of patients with KRAS codon 12/13 (exon 2) wild-type metastatic colorectal cancer (mCRC). Outcome was reassessed in subgroups defined by extended RAS mutation testing. PATIENTS AND METHODS: Existing DNA samples from KRAS exon 2 wild-type tumors from CRYSTAL study patients were reanalyzed for other RAS mutations in four additional KRAS codons (exons 3 and 4) and six NRAS codons (exons 2, 3, and 4) using beads, emulsion, amplification, and magnetics technology. No tissue microdissection was performed. A ≥ 5% mutant allele cutoff was used to call mutations. RESULTS: Mutation status was evaluable in 430 (64.6%) of 666 patients with KRAS exon 2 wild-type tumors. Other RAS mutations were detected in 63 (14.7%) of 430 patients. In those with RAS wild-type tumors, a significant benefit across all efficacy end points was associated with the addition of cetuximab to FOLFIRI. In patients with other RAS tumor mutations, no difference in efficacy outcomes between treatment groups was seen. The safety profile in RAS subgroups was similar and in line with expectations. CONCLUSION: In the first-line treatment of mCRC, patients with RAS wild-type tumors derived a significant benefit from the addition of cetuximab to FOLFIRI; patients with RAS tumor mutations did not. Molecular testing of tumors for all activating RAS mutations is essential before considering anti-epidermal growth factor receptor therapy, thereby allowing the further tailoring of cetuximab administration to maximize patient benefit.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , ErbB Receptors/antagonists & inhibitors , Mutation , ras Proteins/genetics , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Biomarkers, Tumor/metabolism , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Cetuximab , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Disease-Free Survival , Female , Fluorouracil/administration & dosage , GTP Phosphohydrolases/genetics , Genetic Testing , Humans , Kaplan-Meier Estimate , Leucovorin/administration & dosage , Male , Membrane Proteins/genetics , Middle Aged , Molecular Targeted Therapy/methods , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins p21(ras) , Treatment OutcomeABSTRACT
AIM OF THE STUDY: Gastro-intestinal neuroendocrine tumours (GI-NETs) are chemotherapy-resistant tumours. Bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), has shown promising results in several phase II trials of gastro-entero-pancreatic-NETs. We assessed bevacizumab combined with capecitabine, specifically in GI-NET patients. PATIENTS AND METHODS: BEvacizumab in The Treament of neuroEndocrine tumoRs (BETTER) was a multicentre, open-label, non-randomised, two-group phase II trial. Here we present the group of patients with progressive, metastatic, well-differentiated GI-NETs. Patients Eastern Cooperative Oncology Group-performance status (ECOG-PS)⩽2, Ki-67 proliferation rate <15% and no prior systemic chemotherapy were treated with bevacizumab (7.5 mg/kg/q3w) and capecitabine (1000 mg/m2 twice daily, orally d1-14, resumed on d22) for 6-24 months. The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), response rate, safety and quality of life. RESULTS: Of the 49 patients included, 53% were men, median age was 60 years (41-82), primary tumour site was ileal in 82% patients and Ki-67 was <15% in 48 patients and not available for one patient. After a maximum of 24 month follow-up per patient, the median PFS by investigator assessment was 23.4 months [95% confidence interval (CI): 13.2; not reached] and the overall disease control rate was 88% (18% partial response, 70% stable disease). The 2-year survival rate was 85%. Median OS was not reached. The most frequent grade 3-4 adverse events were hypertension (31%), diarrhoea (14%) and hand-foot syndrome (10%). CONCLUSION: The combination of bevacizumab and capecitabine showed clinical activity and a manageable safety profile in the treatment of GI-NETs that warrant confirmation in a randomised phase III trial.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Gastrointestinal Neoplasms/drug therapy , Neuroendocrine Tumors/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Bevacizumab , Capecitabine , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/analogs & derivatives , Gastrointestinal Neoplasms/mortality , Humans , Infusions, Intravenous , Male , Middle Aged , Neuroendocrine Tumors/mortality , Treatment OutcomeABSTRACT
PURPOSE: To compare epirubicin, cisplatin, and capecitabine (ECX) with fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatments in patients with advanced gastric or esophagogastric junction (EGJ) adenocarcinoma. PATIENTS AND METHODS: This open, randomized, phase III study was carried out in 71 centers. Patients with locally advanced or metastatic gastric or EGJ cancer were randomly assigned to receive either ECX as first-line treatment (ECX arm) or FOLFIRI (FOLFIRI arm). Second-line treatment was predefined (FOLFIRI for the ECX arm and ECX for the FOLFIRI arm). The primary criterion was time-to-treatment failure (TTF) of the first-line therapy. Secondary criteria were progression-free survival (PFS), overall survival (OS), toxicity, and quality of life. RESULTS: In all, 416 patients were included (median age, 61.4 years; 74% male). After a median follow-up of 31 months, median TTF was significantly longer with FOLFIRI than with ECX (5.1 v 4.2 months; P = .008). There was no significant difference between the two groups in median PFS (5.3 v 5.8 months; P = .96), median OS (9.5 v 9.7 months; P = .95), or response rate (39.2% v 37.8%). First-line FOLFIRI was better tolerated (overall rate of grade 3 to 4 toxicity, 69% v 84%; P < .001; hematologic adverse events [AEs], 38% v 64.5%; P < .001; nonhematologic AEs: 53% v 53.5%; P = .81). CONCLUSION: FOLFIRI as first-line treatment for advanced gastric and EGJ cancer demonstrated significantly better TTF than did ECX. Other outcome results indicate that FOLFIRI is an acceptable first-line regimen in this setting and should be explored as a backbone regimen for targeted agents.
Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophagogastric Junction/pathology , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Capecitabine , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Epirubicin/administration & dosage , Female , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Follow-Up Studies , France , Humans , Irinotecan , Leucovorin/administration & dosage , Male , Middle Aged , Prospective Studies , Quality of Life , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel. METHODS: This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase. FINDINGS: Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment-330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 months [95% CI 8·5-10·8] vs 7·4 months [95% CI 6·3-8·4], hazard ratio 0·807 [95% CI 0·678-0·962]; p=0·017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%]). INTERPRETATION: The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer. FUNDING: Eli Lilly and Company.