- Email: [email protected]
Aspirin versus placebo in stage III or high-risk stage II colon cancer with PIK3CA mutation: A French randomised double-blind phase III trial (PRODIGE 50-ASPIK)
Accepted Manuscript Title: Aspirin versus placebo in stage III or high-risk stage II colon cancer with PIK3CA mutation: a French randomised double-blind phase III trial (PRODIGE 50-ASPIK) Authors: Pierre Michel, Valerie Boige, Thierry Andre, Thomas Aparicio, Jean Baptiste Bachet, Laetitia Dahan, Rosine Guimbaud, Cˆome Lepage, Sylvain Manfredi, David Tougeron, Julien Taieb, Janick Selves, Karine Le Malicot, Frederic Di Fiore, Emilie Maillard PII: DOI: Reference:
S1590-8658(17)31360-9 https://doi.org/10.1016/j.dld.2017.12.023 YDLD 3628
To appear in:
Digestive and Liver Disease
Received date: Accepted date:
18-7-2017 21-12-2017
Please cite this article as: Michel Pierre, Boige Valerie, Andre Thierry, Aparicio Thomas, Bachet Jean Baptiste, Dahan Laetitia, Guimbaud Rosine, Lepage Cˆome, Manfredi Sylvain, Tougeron David, Taieb Julien, Selves Janick, Le Malicot Karine, Di Fiore Frederic, Maillard Emilie.Aspirin versus placebo in stage III or high-risk stage II colon cancer with PIK3CA mutation: a French randomised double-blind phase III trial (PRODIGE 50-ASPIK).Digestive and Liver Disease https://doi.org/10.1016/j.dld.2017.12.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
TITLE Aspirin versus placebo in stage III or high-risk stage II colon cancer with PIK3CA mutation: a French randomised double-blind phase III trial (PRODIGE 50-ASPIK)
AUTHORS AND AFFILIATIONS
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Pierre MICHELa, Valerie BOIGEb, Thierry ANDREc, Thomas APARICIOd, Jean Baptiste BACHETe, Laetitia DAHANf, Rosine GUIMBAUDg, Côme LEPAGEh, Sylvain MANFREDIh,
SC R
David TOUGERONi, Julien TAIEBj, Janick SELVESk, Karine LE MALICOTl, Frederic Di FIOREm and Emilie MAILLARDl
Normandie Univ, UNIROUEN, Inserm 1245, IRON group, department of Hepato-
U
a
Department of medical oncology, Saint Antoine Hospital, Université Pierre et Marie Curie,
M
c
Department of Oncologic Medicine, Gustave Roussy, 94800 Villejuif, France
A
b
N
gastroenterology, Rouen University Hospital, 76000 Rouen, France
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Paris, France
d Department of Gastroenterology and Digestive Oncology, Saint Louis Hospital, APHP, University Paris 7, Sorbonne Paris Cité, Paris, France Department of Hepato-Gastroenterology and Digestive Oncology, Hôpital de la Pitié
EP
e
Salpetrière, APHP, University Paris 6, Paris, France Departement of Digestive Oncology, Aix-Marseille University –Assistance Publique
CC
f
Hôpitaux de Marseille, Marseille , France Department of medical Oncology, University Hospital Toulouse, Paul Sabatier University,
A
g
Toulouse, France h
Depatement of Hepatogastroenterology and Oncology Digestive, Burgundy Franche –
Conté University, INSERM LNC UMR 1231 EPICAD, University Hospital of Dijon, Dijon France
1
i
Gastroenterology department of Hepatogastroenterology, Poitiers University Hospital,
86000 Poitiers, France j
Department of Digestive Oncology, Université Paris Descartes, Hôpital Européen Georges
Pompidou, Paris, France k
Department of pathology, University Hospital Toulouse, Paul Sabatier University, Toulouse,
l
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France French Federation of Digestive Oncology (FFCD), INSERM LCN UMR 1231 EPICAD, Dijon
France
Normandie Univ, UNIROUEN, Inserm 1245, IRON group, department of Hepato-
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m
gastroenterology, Rouen University Hospital, department of Medical Oncology, centre Henri
U
Becquerel,F76000 Rouen, France
N
CORRESPONDING AUTHOR:
M
Germont, 76031 Cedex, France
A
Pierre MICHEL, Department of Hepato-gastroenterology, Rouen University Hospital, 1 rue de
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Phone: (33) 2 32 88 86 10; Fax: (33) 2 32 88 86 69; Email: [email protected]
Abstract
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Oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. Two recent retrospective studies
CC
strongly suggested that low-dose aspirin used (100 mg/d) after surgical resection of colorectal cancer with a PIK3CA mutation could act as a targeted therapy with a major
A
protective effect on the risk of recurrence. We propose a double-blind randomized phase III study to evaluate aspirin (100 mg/d during 3 years or until recurrence) versus placebo. Main inclusion criteria are patients aged 18 or 20), stage III or high risk stage II.
2
The primary endpoint of the study is 3-year disease-free survival (DFS). Hypotheses are to improve 3-years DFS from placebo: 72% to aspirin: 83% (HR=0.56). 94 events and 264 patients with PIK3CA mutation are required. The secondary endpoints are DFS at 5 years, the overall survival rate at 5 years, grade 3-4 severe bleeding.
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KEYWORDS : Colorectal cancer, aspirin, PI3KCA mutation
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1. Rationale and aims
The standard treatment for stage III colon cancers (CC) is based on surgical resection and
U
adjuvant chemotherapy with fluoropyrimidine and oxaliplatin [1]. However, the risk of
N
recurrence at 3 years remains up to 23 to 28% [2-5]. Some stages II CC (high-risk stage II)
A
have a similar prognosis to stage III cancers and justify post-operative chemotherapy [2-4].
M
The American Society of Clinical Oncology recommends that adjuvant treatment must be considered in patients with stage II CC in cases of perforation, T4 tumour, suboptimal lymph
TE D
node sampling, and poor differentiation. The French Thesaurus de Cancérologie Digestive provide similar guidelines, but adds colon obstruction, and lymphovascular or perineural invasion. The prognosis is also dependent on the molecular profile based on microsatellite
EP
instability (MSI), methylation islets CpG phenotype (CIMP) and RAS or BRAF somatic mutation [6]. The KRAS mutation (codon 12) and BRAF mutation are significantly associated
CC
with shorter disease-free survival in MSS stage III CC [7-9]. The protective effect of aspirin on the occurrence of colorectal cancer and disease
A
recurrence after surgery has been suggested by numerous studies [10-13]. A recent metaanalysis suggests that aspirin improves overall survival after CC diagnosis (HR = 0.74, 95% CI: 0.62 -0.89) [14]. Several biological effects of aspirin on tumour pathways have been described [15]. In a postoperative setting, the two main hypotheses are: a) an effect on prostaglandin-endoperoxide synthase 2 (PTGS2) [16,17] and b) an effect on the role of the
3
platelets in the circulating tumour cells [18]. Four retrospective studies were recently published on the efficacy of aspirin in patients with surgically resected CC. Two of these studies strongly suggested that low-dose aspirin (100 mg/d) after surgical resection of colorectal cancer with PIK3CA mutation could act as a targeted therapy with a major protective effect on the risk of recurrence [19,20]. In patients with a PIK3CA-mutant tumour,
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aspirin use after the diagnosis of cancer significantly decreased the risk of cancer-related death, HR = 0.18, 95% CI 0.06 to 0.61; p <0.001, and HR = 0.11, 95% CI 0.001 to 0.805; p =
0.023, respectively [19,20]. The two other studies did not confirm the benefit of aspirin in this
SC R
setting [21,22]. A meta-analysis reviewed three major recent studies and suggested the
beneficial effect of post-diagnosis aspirin use with a risk of death decreased by 16%
U
(HR=0.84; 95% CI 0.75-0.94). In aspirin consumers with a PIK3CA -mutated tumour, the HR was estimated at 0.58 (95% CI 0.37-0.90) resulting in a 42% decrease in the risk of death
N
[23]. All these studies were retrospective and were conducted in heterogeneous populations
A
with a rate of stage III colorectal cancer ranging between 27 and 50%. Few information are
M
available on the interaction between the potential effect of aspirin and chemotherapy.
TE D
Fluoropyrimidine cause mucosal damage to the stomach and duodenum in 50% of cases [24]. Because of the uncertainty efficacy of aspirin, a randomised study is needed, as
EP
recommended in the conclusion of the above-mentioned studies and meta-analyses [23,25].
CC
2. Study design
Based on the biological rationale, the methodology corresponds to an enrichment study [26].
A
Study design is a prospective phase III double-blind randomized study evaluating aspirin (100 mg/d during 3 years or recurrence) versus placebo in patients with CC curative resection. This study includes patients aged 18 years or older, curative (R0) resection of CC adenocarcinoma: stage III or MSS and T4bN0 or a T4aN0 stage II (tumour penetrating the
4
surface of the visceral peritoneum) or fewer than 12 nodes evaluated, and a tumor PIK3CA mutation (exon 9 or 20). A chest and abdominal CT scan to confirm the absence of distant metastasis should be performed at least 12 weeks before randomisation. All patients must give their informed consent for participation in this trial. Non-eligibility criteria include: rectal cancer, anticoagulant and/or antiplatelet treatment
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including clopidogrel, regular aspirin use (>3 doses per week for more than 3 months in the year previous CC diagnosis), contraindication to aspirin use (active or history of peptic ulcer, allergy to aspirin), known hereditary form of CC, history of asthma induced by the
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administration of salicylate or similar substances, including non-steroidal anti-inflammatory drugs, constitutional or acquired haemorrhagic disease, including gastrointestinal bleeding, a
U
history of haemorrhagic or thrombotic stroke and uncontrolled heart failure.
The study will be proposed following R0 surgical CC resection and written consent will be
N
signed. In a second step, molecular analysis of exon 9 and 20 of PIK3CA, RAS, BRAF, and
A
MMR will be performed and centralized (Rouen University Hospital). Patients without a
M
PIK3CA -mutated tumour will be invited to be included in a prospective clinical and biological
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database during the follow-up. Only patients with a PIK3CA -mutated tumour will be included and randomized using a 1:1 ratio. In this trial Aspirin Protect 100 mg® (BAYER) will be compared with placebo. The placebo tablets are identical to the aspirin, but contain no active
EP
substance (verum). Patients in arm A will take aspirin 1 tablet per day (100 mg) for 3 years, and those in arm B will take placebo 1 tablet per day for 3 years. The treatment must begin
CC
within 60 days after surgery. The randomisation will be stratified using a minimisation technique and according to the following four factors: (i) centre, (ii) stage II versus III, (iii)
A
[19,20]. RAS mutation, (iiii) chemotherapy with oxaliplatin versus no oxaliplatin (XELOX, FOLFOX, Capecitabine, LV5FU2). The treatment will be started within 10 days following the randomisation. Study sites must report the delivery and return of the study drug/placebo. The number of unused tablets will be recorded on the CRF by the investigator or study coordinator.
5
During the study, the follow-up will comprise a clinical examination and a CT-scan every 6 months minimum. A bio-bank of frozen blood will be constituted before treatment and every 6 months during the 3 years of the protocol for ancillary studies.
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2.1 Study endpoints
The primary endpoint of the study is 3-year disease-free survival (DFS). DFS is defined as the time from the date of randomization to the date of the first local or distant recurrence, or
SC R
second colorectal cancer, or death (from any cause), whichever occurs first.
The secondary endpoints are 5-year DFS, 5-year overall survival rate, severe grade 3-4
U
events bleeding (hospitalisation) according to NCI-CTC 4.0, adverse event reported and graded according to NCI-CTC version 4.0, compliance according to counting tablets (and in
A
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2.2 Ethical considerations
M
(RAS, BRAF) for DFS and overall survival.
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selected centres serum thromboxane B2 assay), subgroup analyses regarding mutations
This protocol, sponsored by Rouen University Hospital, was authorised in France by the
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Agence Nationale de Sécurité du Médicament et des produits de la santé (ANSM), number 160604A-12 on the 19/08/2016. The trial is registered on the clinicaltrials.gov website with
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the number NCT02945033. The study complies with the Declaration of Helsinki rules and the principles of Good Clinical Practice guidelines. The study is coordinated by the Fédération
A
Francophone de Cancérologie Digestive (FFCD) and opened to the whole PRODIGE group (FFCD, GERCOR and UNICANCER GI).
2.3 Statistical methods
6
The aim of the study is to determine the proportion of patients alive and without recurrence at 3 years in the two arms. The objective is to demonstrate a reduction of 44% of recurrence between the two arms. In the control arm (placebo), the risk of recurrence,is estimated at 28% [2-5]. The risk recurrence in the experimental arm (aspirin), estimated at 17%, is based on a meta-analysis, which suggests a reduced risk of death of 42% [23]. With a power of
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80% and a two-sided alpha error of 5%, 94 events are required. Taking into account a monthly rate of inclusion of five patients a inclusion duration of 24 months, follow-up of
patients for 60 months and a lost of follow-up rate of 10%, 264 patients with a PIK3CA -
SC R
mutated tumor will be randomised. Overall, 15% of CC exhibit a PIK3CA mutation (exon 9
and/or 20) [27]. In order to include 264 patients with a PIK3CA -mutated tumour, 1760
U
patients (without prior aspirin use) will be screened. All randomised patients will be analysed on the intent-to-treat principle. All baseline characteristics will be described in the overall
N
population and by treatment arm.
A
Toxicities and other baseline variables will be described using the usual statistics, for
M
quantitative variables: means, standard deviations, medians, inter-quartile intervals and
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ranges and for qualitative variables: frequencies and percentages. Survival analyses will be estimated using the Kaplan-Meier method and the two arms will be compared using the log-rank Test. A Cox model will be used for multivariate analyses.
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Comparisons between the two arms could be done using the Student t or Wilcoxon test for quantitative variables or the Chi² or Fischer’s Exact Test for qualitative variables. Patients will
A
CC
be followed on a regular basis until the end of the study.
Funding The Programme Hospitalier de Recherche Clinique (PHRC) is funding this study (PHRC-K 15-090). Fédération Francophone de Cancérologie Digestive (FFCD) is funding the bio-bank and molecular analysis. The Ligue contre le cancer provided financial support to FFCD. Bayer will support the study by providing the study Aspirin and placebo.
7
Conflict of interest for the article entitled : « Aspirin versus placebo in stage III or high-risk Conflict of interest none none none none none none none none none none none none none none none
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U
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Author name Pierre MICHEL Valerie BOIGE Thierry ANDRE Thomas APARICIO Jean Baptiste BACHET Laetitia DAHAN Rosine GUIMBAUD Côme LEPAGE Sylvain MANFREDI David TOUGERON Julien TAIEB Janick SELVES Karine LE MALICOT Frederic DI FIORE Emilie MAILLARD
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stage II colon cancer with PIK3CA mutation: a French randomised double-blind phase III trial (PRODIGE 50-ASPIK)”
A
Acknowledgements
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and statistical analysis.
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This study is supported by the FFCD, which is responsible for the study design, management
8
References
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14. Ye XF, Wang J, Shi WT, et al. Relationship between aspirin use after diagnosis of
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17. Boutaud O, Sosa IR, Amin T, Oram D, et al. Inhibition of the Biosynthesis of Prostaglandin E2 By Low-Dose Aspirin: Implications for Adenocarcinoma Metastasis. Cancer Prevention and Research 2016; 9:855-65.
18. Placke T, Örgel M, Schaller M, et al. Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Research 2012; 72: 440-8.
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19. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. The New England Journal of Medicine 2012; 367: 159606.
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cancer-specific survival in patients with colorectal cancer harboring a PIK3CA
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24. Sartori S, Trevisani L, Nielsen I, et al. Randomized trial of omeprazole or ranitidine
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S1590-8658(17)31360-9 https://doi.org/10.1016/j.dld.2017.12.023 YDLD 3628
To appear in:
Digestive and Liver Disease
Received date: Accepted date:
18-7-2017 21-12-2017
Please cite this article as: Michel Pierre, Boige Valerie, Andre Thierry, Aparicio Thomas, Bachet Jean Baptiste, Dahan Laetitia, Guimbaud Rosine, Lepage Cˆome, Manfredi Sylvain, Tougeron David, Taieb Julien, Selves Janick, Le Malicot Karine, Di Fiore Frederic, Maillard Emilie.Aspirin versus placebo in stage III or high-risk stage II colon cancer with PIK3CA mutation: a French randomised double-blind phase III trial (PRODIGE 50-ASPIK).Digestive and Liver Disease https://doi.org/10.1016/j.dld.2017.12.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
TITLE Aspirin versus placebo in stage III or high-risk stage II colon cancer with PIK3CA mutation: a French randomised double-blind phase III trial (PRODIGE 50-ASPIK)
AUTHORS AND AFFILIATIONS
IP T
Pierre MICHELa, Valerie BOIGEb, Thierry ANDREc, Thomas APARICIOd, Jean Baptiste BACHETe, Laetitia DAHANf, Rosine GUIMBAUDg, Côme LEPAGEh, Sylvain MANFREDIh,
SC R
David TOUGERONi, Julien TAIEBj, Janick SELVESk, Karine LE MALICOTl, Frederic Di FIOREm and Emilie MAILLARDl
Normandie Univ, UNIROUEN, Inserm 1245, IRON group, department of Hepato-
U
a
Department of medical oncology, Saint Antoine Hospital, Université Pierre et Marie Curie,
M
c
Department of Oncologic Medicine, Gustave Roussy, 94800 Villejuif, France
A
b
N
gastroenterology, Rouen University Hospital, 76000 Rouen, France
TE D
Paris, France
d Department of Gastroenterology and Digestive Oncology, Saint Louis Hospital, APHP, University Paris 7, Sorbonne Paris Cité, Paris, France Department of Hepato-Gastroenterology and Digestive Oncology, Hôpital de la Pitié
EP
e
Salpetrière, APHP, University Paris 6, Paris, France Departement of Digestive Oncology, Aix-Marseille University –Assistance Publique
CC
f
Hôpitaux de Marseille, Marseille , France Department of medical Oncology, University Hospital Toulouse, Paul Sabatier University,
A
g
Toulouse, France h
Depatement of Hepatogastroenterology and Oncology Digestive, Burgundy Franche –
Conté University, INSERM LNC UMR 1231 EPICAD, University Hospital of Dijon, Dijon France
1
i
Gastroenterology department of Hepatogastroenterology, Poitiers University Hospital,
86000 Poitiers, France j
Department of Digestive Oncology, Université Paris Descartes, Hôpital Européen Georges
Pompidou, Paris, France k
Department of pathology, University Hospital Toulouse, Paul Sabatier University, Toulouse,
l
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France French Federation of Digestive Oncology (FFCD), INSERM LCN UMR 1231 EPICAD, Dijon
France
Normandie Univ, UNIROUEN, Inserm 1245, IRON group, department of Hepato-
SC R
m
gastroenterology, Rouen University Hospital, department of Medical Oncology, centre Henri
U
Becquerel,F76000 Rouen, France
N
CORRESPONDING AUTHOR:
M
Germont, 76031 Cedex, France
A
Pierre MICHEL, Department of Hepato-gastroenterology, Rouen University Hospital, 1 rue de
TE D
Phone: (33) 2 32 88 86 10; Fax: (33) 2 32 88 86 69; Email: [email protected]
Abstract
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Oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. Two recent retrospective studies
CC
strongly suggested that low-dose aspirin used (100 mg/d) after surgical resection of colorectal cancer with a PIK3CA mutation could act as a targeted therapy with a major
A
protective effect on the risk of recurrence. We propose a double-blind randomized phase III study to evaluate aspirin (100 mg/d during 3 years or until recurrence) versus placebo. Main inclusion criteria are patients aged 18 or 20), stage III or high risk stage II.
2
The primary endpoint of the study is 3-year disease-free survival (DFS). Hypotheses are to improve 3-years DFS from placebo: 72% to aspirin: 83% (HR=0.56). 94 events and 264 patients with PIK3CA mutation are required. The secondary endpoints are DFS at 5 years, the overall survival rate at 5 years, grade 3-4 severe bleeding.
IP T
KEYWORDS : Colorectal cancer, aspirin, PI3KCA mutation
SC R
1. Rationale and aims
The standard treatment for stage III colon cancers (CC) is based on surgical resection and
U
adjuvant chemotherapy with fluoropyrimidine and oxaliplatin [1]. However, the risk of
N
recurrence at 3 years remains up to 23 to 28% [2-5]. Some stages II CC (high-risk stage II)
A
have a similar prognosis to stage III cancers and justify post-operative chemotherapy [2-4].
M
The American Society of Clinical Oncology recommends that adjuvant treatment must be considered in patients with stage II CC in cases of perforation, T4 tumour, suboptimal lymph
TE D
node sampling, and poor differentiation. The French Thesaurus de Cancérologie Digestive provide similar guidelines, but adds colon obstruction, and lymphovascular or perineural invasion. The prognosis is also dependent on the molecular profile based on microsatellite
EP
instability (MSI), methylation islets CpG phenotype (CIMP) and RAS or BRAF somatic mutation [6]. The KRAS mutation (codon 12) and BRAF mutation are significantly associated
CC
with shorter disease-free survival in MSS stage III CC [7-9]. The protective effect of aspirin on the occurrence of colorectal cancer and disease
A
recurrence after surgery has been suggested by numerous studies [10-13]. A recent metaanalysis suggests that aspirin improves overall survival after CC diagnosis (HR = 0.74, 95% CI: 0.62 -0.89) [14]. Several biological effects of aspirin on tumour pathways have been described [15]. In a postoperative setting, the two main hypotheses are: a) an effect on prostaglandin-endoperoxide synthase 2 (PTGS2) [16,17] and b) an effect on the role of the
3
platelets in the circulating tumour cells [18]. Four retrospective studies were recently published on the efficacy of aspirin in patients with surgically resected CC. Two of these studies strongly suggested that low-dose aspirin (100 mg/d) after surgical resection of colorectal cancer with PIK3CA mutation could act as a targeted therapy with a major protective effect on the risk of recurrence [19,20]. In patients with a PIK3CA-mutant tumour,
IP T
aspirin use after the diagnosis of cancer significantly decreased the risk of cancer-related death, HR = 0.18, 95% CI 0.06 to 0.61; p <0.001, and HR = 0.11, 95% CI 0.001 to 0.805; p =
0.023, respectively [19,20]. The two other studies did not confirm the benefit of aspirin in this
SC R
setting [21,22]. A meta-analysis reviewed three major recent studies and suggested the
beneficial effect of post-diagnosis aspirin use with a risk of death decreased by 16%
U
(HR=0.84; 95% CI 0.75-0.94). In aspirin consumers with a PIK3CA -mutated tumour, the HR was estimated at 0.58 (95% CI 0.37-0.90) resulting in a 42% decrease in the risk of death
N
[23]. All these studies were retrospective and were conducted in heterogeneous populations
A
with a rate of stage III colorectal cancer ranging between 27 and 50%. Few information are
M
available on the interaction between the potential effect of aspirin and chemotherapy.
TE D
Fluoropyrimidine cause mucosal damage to the stomach and duodenum in 50% of cases [24]. Because of the uncertainty efficacy of aspirin, a randomised study is needed, as
EP
recommended in the conclusion of the above-mentioned studies and meta-analyses [23,25].
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2. Study design
Based on the biological rationale, the methodology corresponds to an enrichment study [26].
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Study design is a prospective phase III double-blind randomized study evaluating aspirin (100 mg/d during 3 years or recurrence) versus placebo in patients with CC curative resection. This study includes patients aged 18 years or older, curative (R0) resection of CC adenocarcinoma: stage III or MSS and T4bN0 or a T4aN0 stage II (tumour penetrating the
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surface of the visceral peritoneum) or fewer than 12 nodes evaluated, and a tumor PIK3CA mutation (exon 9 or 20). A chest and abdominal CT scan to confirm the absence of distant metastasis should be performed at least 12 weeks before randomisation. All patients must give their informed consent for participation in this trial. Non-eligibility criteria include: rectal cancer, anticoagulant and/or antiplatelet treatment
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including clopidogrel, regular aspirin use (>3 doses per week for more than 3 months in the year previous CC diagnosis), contraindication to aspirin use (active or history of peptic ulcer, allergy to aspirin), known hereditary form of CC, history of asthma induced by the
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administration of salicylate or similar substances, including non-steroidal anti-inflammatory drugs, constitutional or acquired haemorrhagic disease, including gastrointestinal bleeding, a
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history of haemorrhagic or thrombotic stroke and uncontrolled heart failure.
The study will be proposed following R0 surgical CC resection and written consent will be
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signed. In a second step, molecular analysis of exon 9 and 20 of PIK3CA, RAS, BRAF, and
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MMR will be performed and centralized (Rouen University Hospital). Patients without a
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PIK3CA -mutated tumour will be invited to be included in a prospective clinical and biological
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database during the follow-up. Only patients with a PIK3CA -mutated tumour will be included and randomized using a 1:1 ratio. In this trial Aspirin Protect 100 mg® (BAYER) will be compared with placebo. The placebo tablets are identical to the aspirin, but contain no active
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substance (verum). Patients in arm A will take aspirin 1 tablet per day (100 mg) for 3 years, and those in arm B will take placebo 1 tablet per day for 3 years. The treatment must begin
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within 60 days after surgery. The randomisation will be stratified using a minimisation technique and according to the following four factors: (i) centre, (ii) stage II versus III, (iii)
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[19,20]. RAS mutation, (iiii) chemotherapy with oxaliplatin versus no oxaliplatin (XELOX, FOLFOX, Capecitabine, LV5FU2). The treatment will be started within 10 days following the randomisation. Study sites must report the delivery and return of the study drug/placebo. The number of unused tablets will be recorded on the CRF by the investigator or study coordinator.
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During the study, the follow-up will comprise a clinical examination and a CT-scan every 6 months minimum. A bio-bank of frozen blood will be constituted before treatment and every 6 months during the 3 years of the protocol for ancillary studies.
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2.1 Study endpoints
The primary endpoint of the study is 3-year disease-free survival (DFS). DFS is defined as the time from the date of randomization to the date of the first local or distant recurrence, or
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second colorectal cancer, or death (from any cause), whichever occurs first.
The secondary endpoints are 5-year DFS, 5-year overall survival rate, severe grade 3-4
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events bleeding (hospitalisation) according to NCI-CTC 4.0, adverse event reported and graded according to NCI-CTC version 4.0, compliance according to counting tablets (and in
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2.2 Ethical considerations
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(RAS, BRAF) for DFS and overall survival.
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selected centres serum thromboxane B2 assay), subgroup analyses regarding mutations
This protocol, sponsored by Rouen University Hospital, was authorised in France by the
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Agence Nationale de Sécurité du Médicament et des produits de la santé (ANSM), number 160604A-12 on the 19/08/2016. The trial is registered on the clinicaltrials.gov website with
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the number NCT02945033. The study complies with the Declaration of Helsinki rules and the principles of Good Clinical Practice guidelines. The study is coordinated by the Fédération
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Francophone de Cancérologie Digestive (FFCD) and opened to the whole PRODIGE group (FFCD, GERCOR and UNICANCER GI).
2.3 Statistical methods
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The aim of the study is to determine the proportion of patients alive and without recurrence at 3 years in the two arms. The objective is to demonstrate a reduction of 44% of recurrence between the two arms. In the control arm (placebo), the risk of recurrence,is estimated at 28% [2-5]. The risk recurrence in the experimental arm (aspirin), estimated at 17%, is based on a meta-analysis, which suggests a reduced risk of death of 42% [23]. With a power of
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80% and a two-sided alpha error of 5%, 94 events are required. Taking into account a monthly rate of inclusion of five patients a inclusion duration of 24 months, follow-up of
patients for 60 months and a lost of follow-up rate of 10%, 264 patients with a PIK3CA -
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mutated tumor will be randomised. Overall, 15% of CC exhibit a PIK3CA mutation (exon 9
and/or 20) [27]. In order to include 264 patients with a PIK3CA -mutated tumour, 1760
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patients (without prior aspirin use) will be screened. All randomised patients will be analysed on the intent-to-treat principle. All baseline characteristics will be described in the overall
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population and by treatment arm.
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Toxicities and other baseline variables will be described using the usual statistics, for
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quantitative variables: means, standard deviations, medians, inter-quartile intervals and
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ranges and for qualitative variables: frequencies and percentages. Survival analyses will be estimated using the Kaplan-Meier method and the two arms will be compared using the log-rank Test. A Cox model will be used for multivariate analyses.
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Comparisons between the two arms could be done using the Student t or Wilcoxon test for quantitative variables or the Chi² or Fischer’s Exact Test for qualitative variables. Patients will
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be followed on a regular basis until the end of the study.
Funding The Programme Hospitalier de Recherche Clinique (PHRC) is funding this study (PHRC-K 15-090). Fédération Francophone de Cancérologie Digestive (FFCD) is funding the bio-bank and molecular analysis. The Ligue contre le cancer provided financial support to FFCD. Bayer will support the study by providing the study Aspirin and placebo.
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Conflict of interest for the article entitled : « Aspirin versus placebo in stage III or high-risk Conflict of interest none none none none none none none none none none none none none none none
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Author name Pierre MICHEL Valerie BOIGE Thierry ANDRE Thomas APARICIO Jean Baptiste BACHET Laetitia DAHAN Rosine GUIMBAUD Côme LEPAGE Sylvain MANFREDI David TOUGERON Julien TAIEB Janick SELVES Karine LE MALICOT Frederic DI FIORE Emilie MAILLARD
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stage II colon cancer with PIK3CA mutation: a French randomised double-blind phase III trial (PRODIGE 50-ASPIK)”
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Acknowledgements
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and statistical analysis.
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This study is supported by the FFCD, which is responsible for the study design, management
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