24 april 2014: Onderaan toegevoegd het abstract van de grote Fase III studie: Neoadjuvant therapy for rectal cancer: Mature results from NSABP protocol R-04. waarvan de resultaten op het laatste congres in januari 2014 werden gepubliceerd met niet mis te verstane conclusie:

CVI 5-FU or oral Cape combined with RT produced similar outcomes and toxicity profiles. Because use of oral Cape avoids the need for central venous catheters and ambulatory infusion pumps, it can be considered a new standard of care in this setting. The addition of Ox provided no improvement in outcomes but did add significant toxicity.

oftewel: Intraveneus 5-FU of oraal 5-FU (capecitabine - xeloda) gecombineerd met radiotherapie - bestraling van het bekken geeft dezelfde uitkomsten op ziektevrije tijd, progressievrije tijd en overall overleving. Omdat bij xeloda geen catheters en infuus moet worden gebruikt kan dit de nieuwe vorm van behandeling worden. De toevoeging van oxaliplatin geeft geen enkele meerwaarde aan de klinische effecten, zoals ziektevrije tijd, progressievrije tijd, overall overleving, maar wel veel grotere toxiciteit - bijwerkingen.

Wie FOLFOX krijgt aangeboden neem dit artikel mee. Het is de grootste, onafhankelijke studie die bewijst dat oxaliplatin geen enkele meerwaarde heeft naast bestraling bij endeldarmkanker, maar geeft ook weinig tot geen meerwaarde bij dikke darmkanker. Onderaan staat abstract van de studie.

Characteristics of studies included in the meta-analysis

10 maart 2014: lees ook dit artikel: KRAS en NRAS mutatie bepaling cruciaal voor effectieve anti-EGFR behandeling bij uitgezaaide darmkanker met FOLFOX4 + Panitumumab

Toegevoegd het abstract van de AVANT studie en gepubliceerd in The Lancet: Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial met als conclusie dat Avastin - bevacizumab niet wordt aanbevolen bij operabele darmkanker stadium 2 en 3, noch Oxaliplatin dus, zie artikel daaronder:

Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer. Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients. On the basis of these and other data, we do not recommend the use of bevacizumab in the adjuvant treatment of patients with curatively resected stage III colon cancer.

1 september 2012: bron: J Clin Oncol. Published online August 20, 2012

Oxaliplatin toegevoegd aan intraveneus fluorouracil 5-FU en leucovorin, het zogeheten FOLFOX regiem, blijkt geen enkel therapeutisch voordeel op te leveren bij zowel postoperatief operabele darmkanker stadium II en bij ouderen van 70 jaar en ouder met darmkanker in alle stadia. Dit blijkt uit een grote gerandomiseerde studie die eerdere uitkomsten uit andere gerandomiseerde studies bevestigt. In oncoline staat in de richtlijnen beschreven dat chemo bij darmkanker stadium II controversieel en niet bewezen effectief is en in principe wordt overgelaten aan de behandelend arts en de situatie van de individuele patiënt. Toch weten wij uit ervaring dat bijna elke darmkankerpatiënt zelfs bij geen gevonden uitzaaiïngen en succesvollle operatie in heel veel gevallen chemo krijgt als behandeling. Zelfs meestal nog met Avastin erbij. Dit tast de kwaliteit van leven enorm aan. En wederom is dus nu aangetoond dat intraveneus toegediende chemo bij darmkanker stadium II en bij ouderen in alle stadia geen enkele meerwaarde heeft.

Resultaten 2046 patiënten deden mee aan deze studie. Van alle patiënten hadden 899 patiënten darmkanker stadium II, met inbegrip van 330 patiënten met een laag risico en 569 hoog risico patiënten. Totaal 315 patiënten waren tussen de 70 en 75 jaar. Voor fase II patiënten was de hazard ratio (HR) vergeleken met FOLFOX4 met FL 0.84 (95% BI, 0,62 tot 01,14) voor de ziekte vrije overleving (DFS), 0,70 (95% BI, 0,49 tot 0,99) voor de tijd tot een recidief (TTR), en 1,00 (95% BI, 0,70 tot 1,41) voor de overall totale overleving (OS). Er was geen aangetoonde relatie tussen behandeling en leeftijd.
Laag risico stadium II patiënten hebben geen beter therapeutisch effect van oxaliplatin. Bij hoog risico stadium II patiënten, was de HR vergeleken met FOLFOX4 met FL 0,72 (95% BI, 0,51 tot 1,01) voor DFS, 0,62 (95% BI, 0,41 tot 0,92) voor TTR, en 0,91 (95% BI, 0,61 tot 1,36) voor OS. Bij oudere patiënten, was de HR vergeleken met FOLFOX4 met FL 0,93 (95% BI, 0,64 tot 1,35) voor DFS, 0,72 (95% BI, 0,47 tot 1,11) voor TTR, en 1.10 (95% BI, 0,73 tot 1,65) voor OS

Hieronder het abstract van de studie. Het volledige studierapport: Adjuvant Therapy With Fluorouracil and Oxaliplatin in Stage II and Elderly Patients (between ages 70 and 75 years) With Colon Cancer: Subgroup Analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer Trial kunt u tegen betaling inzien op de website van Journal of Clinical Oncology

Oxaliplatin addiotional to FL shows no statistically significant benefit (OS and DFS) as adjuvant treatment for either colon cancer stage II and elderly patients with colon cancer

Published online before print August 20, 2012, doi: 10.1200/JCO.2012.42.5645 JCO August 20, 2012 JCO.2012.42.5645

Adjuvant Therapy With Fluorouracil and Oxaliplatin in Stage II and Elderly Patients (between ages 70 and 75 years) With Colon Cancer: Subgroup Analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer Trial

+ Author Affiliations

Christophe Tournigand, Thierry André, Benoist Chibaudel, Luis Teixeira, Aimery de Gramont, Hôpital Saint-Antoine, Paris, France; Christophe Tournigand, Thierry André, Benoist Chibaudel, Jean-Baptiste Bachet, Luis Teixeira, Aimery de Gramont, Université Pierre et Marie Curie, Paris, France; Christophe Tournigand, Thierry André, Franck Bonnetain, Benoist Chibaudel, Gérard Lledo, Luis Teixeira, Aimery de Gramont, Groupe Coopérateur Multidisciplinaire en Oncologie, Paris, France; Christophe Tournigand, Thierry André, Benoist Chibaudel, Luis Teixeira, Aimery de Gramont, Institut National de la Santé et de la Recherche Medicale U938, Paris, France; Franck Bonnetain, Unité de biostatistiques et d’épidémiologie, EA 4184 Centre Georges François Leclerc, Dijon, France; Gérard Lledo, Clinique Jean Mermoz, Lyon, France; Tamas Hickish, Dorset Cancer Centre, Royal Bournemouth Hospital, Bournemouth, United Kingdom; Josep Tabernero, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain; Corrado Boni, Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy; Jean-Baptiste Bachet, Hôpital Pitié-Salpêtrière, Paris, France.

Corresponding author: Aimery de Gramont, MD, Hôpital Saint Antoine, 184 rue du Faubourg Saint Antoine, Paris 75012, France; e-mail: aimery.de-gramont@sat.aphp.fr.

Abstract

Purpose Oxaliplatin combined with fluoropyrimidine improves survival in patients with stage III colon cancer. However, adjuvant chemotherapy with oxaliplatin is controversial in stage II and elderly patients.

Patients and Methods We performed subgroup analyses of stage II and elderly patients randomly assigned fluorouracil with leucovorin (FL) ± oxaliplatin (FOLFOX4) in the Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer study. Comorbidities, severe adverse events, second cancers, management of relapse and death as a result of causes than other colon cancer were studied.

Results Two thousand two hundred forty-six patients were enrolled. Overall, 899 patients had stage II disease, including 330 low-risk and 569 high-risk patients. A total of 315 patients were ages 70 to 75 years. For stage II patients, the hazard ratio (HR) for comparing FOLFOX4 with FL was 0.84 (95% CI, 0.62 to 01.14) for disease-free survival (DFS), 0.70 (95% CI, 0.49 to 0.99) for time to recurrence (TTR), and 1.00 (95% CI, 0.70 to 1.41) for overall survival (OS). There was no interaction between treatment and stage or age. Low-risk stage II patients did not benefit from oxaliplatin. In high-risk stage II patients, the HR comparing FOLFOX4 with FL was 0.72 (95% CI, 0.51 to 1.01) for DFS, 0.62 (95% CI, 0.41 to 0.92) for TTR, and 0.91 (95% CI, 0.61 to 1.36) for OS. In elderly patients, the HR comparing FOLFOX4 with FL was 0.93 (95% CI, 0.64 to 1.35) for DFS, 0.72 (95% CI, 0.47 to 1.11) for TTR, and 1.10 (95% CI, 0.73 to 1.65) for OS.

Conclusion The results of these subset analyses show no statistically significant benefit (OS and DFS) for the addition of oxaliplatin to FL as adjuvant treatment for either stage II and elderly patients.

Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer. Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients.

The Lancet Oncology, Volume 13, Issue 12, Pages 1225 - 1233, December 2012 doi:10.1016/S1470-2045(12)70509-0

Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial.

Author information

Abstract

BACKGROUND:

Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer. Our aim was to assess the use of bevacizumab in combination with oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma.

METHODS:

Patients from 330 centres in 34 countries were enrolled into this phase 3, open-label randomised trial. Patients with curatively resected stage III or high-risk stage II colon carcinoma were randomly assigned (1:1:1) to receive FOLFOX4 (oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil 400 mg/m(2) bolus plus 600 mg/m(2) 22-h continuous infusion on day 1; leucovorin 200 mg/m(2) plus fluorouracil 400 mg/m(2) bolus plus 600 mg/m(2) 22-h continuous infusion on day 2) every 2 weeks for 12 cycles; bevacizumab 5 mg/kg plus FOLFOX4 (every 2 weeks for 12 cycles) followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks); or bevacizumab 7·5 mg/kg plus XELOX (oxaliplatin 130 mg/m(2) on day 1 every 2 weeks plus oral capecitabine 1000 mg/m(2) twice daily on days 1-15) every 3 weeks for eight cycles followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks). Block randomisation was done with a central interactive computerised system, stratified by geographic region and disease stage. Surgery with curative intent occurred 4-8 weeks before randomisation. The primary endpoint was disease-free survival, analysed for all randomised patients with stage III disease. This study is registered with ClinicalTrials.gov, number NCT00112918.

FINDINGS:

Of the total intention-to-treat population (n=3451), 2867 patients had stage III disease, of whom 955 were randomly assigned to receive FOLFOX4, 960 to receive bevacizumab-FOLFOX4, and 952 to receive bevacizumab-XELOX. After a median follow-up of 48 months (range 0-66 months), 237 patients (25%) in the FOLFOX4 group, 280 (29%) in the bevacizumab-FOLFOX4 group, and 253 (27%) in the bevacizumab-XELOX group had relapsed, developed a new colon cancer, or died. The disease-free survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1·17 (95% CI 0·98-1·39; p=0·07), and for bevacizumab-XELOX versus FOLFOX4 was 1·07 (0·90-1·28; p=0·44). After a minimum follow-up of 60 months, the overall survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1·27 (1·03-1·57; p=0·02), and for bevacizumab-XELOX versus FOLFOX4 was 1·15 (0·93-1·42; p=0·21). The 573 patients with high-risk stage II cancer were included in the safety analysis. The most common grade 3-5 adverse events were neutropenia (FOLFOX4: 477 [42%] of 1126 patients, bevacizumab-FOLFOX4: 416 [36%] of 1145 patients, and bevacizumab-XELOX: 74 [7%] of 1135 patients), diarrhoea (110 [10%], 135 [12%], and 181 [16%], respectively), and hypertension (12 [1%], 122 [11%], and 116 [10%], respectively). Serious adverse events were more common in the bevacizumab groups (bevacizumab-FOLFOX4: 297 [26%]; bevacizumab-XELOX: 284 [25%]) than in the FOLFOX4 group (226 [20%]). Treatment-related deaths were reported in one patient receiving FOLFOX4, two receiving bevacizumab-FOLFOX4, and five receiving bevacizumab-XELOX.

INTERPRETATION:

FUNDING:

Genentech, Roche, and Chugai.

Comment in

Adjuvant bevacizumab in colon cancer: where did we go wrong? [Lancet Oncol. 2012]

PMID:: 23168362; [PubMed - indexed for MEDLINE]

The addition of Oxaliplatin to Infusional 5-FU or capecitabine, provided no improvement in outcomes but did add significant toxicity.

Neoadjuvant therapy for rectal cancer: Mature results from NSABP protocol R-04.

Meeting:

2014 Gastrointestinal Cancers Symposium

Citation:

J Clin Oncol 32, 2014 (suppl 3; abstr 390)

Author(s):

Carmen Joseph Allegra, Greg Yothers, Michael J O'Connell, Mark S. Roh, Robert W. Beart, Nicholas J. Petrelli, Samia H. Lopa, Saima Sharif, Norman Wolmark; National Surgical Adjuvant Breast and Bowel Project; University of Florida, Gainesville, FL; National Surgical Adjuvant Breast and Bowel Project; Biostatistical Center and University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA; National Surgical Adjuvant Breast and Bowel Project Operations Office, Pittsburgh, PA; National Surgical Adjuvant Breast and Bowel Project; MD Anderson Cancer Center Orlando, Pittsburgh, PA; National Surgical Adjuvant Breast and Bowel Project; Glendale Memorial Hospital, Gelndale, CA; National Surgical Adjuvant Breast and Bowel Project and Helen F. Graham Cancer Center at Christiana Care Health System, Newark, DE; National Surgical Adjuvant Breast and Bowel Project and the National Surgical Adjuvant Breast and Bowel Project Biostatistical Center, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA; National Surgical Adjuvant Breast and Bowel Project and Allegheny General Hospital, Pittsburgh, PA; National Surgical Adjuvant Breast and Bowel Project; The Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA

Abstract:

Background: The primary aims were to: 1) compare capecitabine (Cape) and continuous intravenous infusion (CVI) 5-FU combined with pelvic radiation therapy (RT) given preoperatively for patients (pts) with stage II or III rectal cancer; 2) determine whether the addition of oxaliplatin (Ox) would improve pt outcomes. Preliminary results focusing on pathologic complete response, sphincter-sparing surgery, surgical downstaging, and toxicity were presented at ASCO 2011 (Roh: J Clin Oncol 29: 2011 Ab 3503).

Methods: Pts with clinical stage II or III rectal cancer undergoing preoperative RT (4,500cGy in 25 fractions over 5 wks + boost of 540cGy-1080cGy in 3-6 daily fractions) were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU (225mg/m² 5 days/wk), with or without intravenous Ox (50mg/m² /wk x 5) or oral Cape (825 mg/m² BID 5 days/wk), with or without Ox (50mg/m²/wk x 5). The primary endpoint of local-regional (L-R) tumor control included L-R tumor recurrence, less than an R0 resection (complete surgical resection), and no surgery.

Results: From July 2004 to August 2010, 1608 patients were randomly assigned and 99.2% were eligible. There were no significant differences in L-R tumor control, DFS, or OS between regimens for either the 5-FU-Cape (L-R p=0.98) or the Ox-none (L-R p=0.70) comparisons. The addition of Ox was associated with significantly more grade 3-4 diarrhea (p<0.0001). Analysis of the primary endpoint showed 3-yr rates of L-R tumor control ranged from 87.4%-88.2%. 3-yr rates of L-R recurrence among pts who underwent R0 resection ranged from 2-4 % for stage II pts, and from 4-11% for stage III pts. 16% of stage II and 26% of stage III pts developed distant metastases by 5 yrs. From 84% to 97% of pts received >80% of the ideal chemotherapy dose in combination with preoperative RT.

Conclusions: CVI 5-FU or oral Cape combined with RT produced similar outcomes and toxicity profiles. Because use of oral Cape avoids the need for central venous catheters and ambulatory infusion pumps, it can be considered a new standard of care in this setting. The addition of Ox provided no improvement in outcomes but did add significant toxicity. Clinical trial information: NCT00058474.

oxaliplatin, FOLFOX, chemo, stadium II, ouderen, darmkanker