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Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a multicentre randomised controlled phase II trial--the PRODIGE 22--ECKINOXE trial.

Karoui M, Rullier A, Luciani A, Bonnetain F, Auriault ML, Sarran A, Monges G, Trillaud H, Le Malicot K, Leroy K, Sobhani I, Bardier A, Moreau M, Brindel I, Seitz JF, Taieb J - BMC Cancer (2015)

Bottom Line: Optimum systemic therapy at the earliest possible opportunity may be more effective at eradicating distant metastases than the same treatment given after the delay and immunological stress of surgery.Added to this, shrinking the primary tumor before surgery may reduce the risk of incomplete surgical excision, and the risk of tumor cell shedding during surgery.The primary endpoint of the study is the histological Tumor Regression Grade (TRG) as defined by Ryan.

View Article: PubMed Central - PubMed

Affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Digestive and Hepato-Pancreato-Biliary Surgery, University Institute of Cancerology (Paris VI), Pierre & Marie Curie University (Paris VI), 47-83 Boulevard de l'Hôpital, 75013, Paris, France. mehdi.karoui@psl.aphp.fr.

ABSTRACT

Background: In patients with high risk stage II and stage III colon cancer (CC), curative surgery followed by adjuvant FOLFOX-4 chemotherapy has become the standard of care. However, for 20 to 30% of these patients, the current curative treatment strategy of surgical excision followed by adjuvant chemotherapy fails either to clear locoregional spread or to eradicate distant micrometastases, leading to disease recurrence. Preoperative chemotherapy is an attractive concept for these CCs and has the potential to impact upon both of these causes of failure. Optimum systemic therapy at the earliest possible opportunity may be more effective at eradicating distant metastases than the same treatment given after the delay and immunological stress of surgery. Added to this, shrinking the primary tumor before surgery may reduce the risk of incomplete surgical excision, and the risk of tumor cell shedding during surgery.

Methods/design: PRODIGE 22--ECKINOXE is a multicenter randomized phase II trial designed to evaluate efficacy and feasibility of two chemotherapy regimens (FOLFOX-4 alone and FOLFOX-4 + Cetuximab) in a peri-operative strategy in patients with bulky CCs. Patients with CC deemed as high risk T3, T4 and/or N2 on initial abdominopelvic CT scan are randomized to either colectomy and adjuvant chemotherapy (control arm), or 4 cycles of neoadjuvant chemotherapy with FOLFOX-4 (for RAS mutated patients). In RAS wild-type patients a third arm testing FOLFOX+ cetuximab has been added prior to colectomy. Patients in the neoadjuvant chemotherapy arms will receive postoperative treatment for 4 months (8 cycles) to complete their therapeutic schedule. The primary endpoint of the study is the histological Tumor Regression Grade (TRG) as defined by Ryan. The secondary endpoints are: treatment strategy safety (toxicity, primary tumor related complications under chemotherapy, peri-operative morbidity), disease-free and recurrence free survivals at 3 years, quality of life, carcinologic quality and completeness of the surgery, initial radiological staging and radiological response to neoadjuvant chemotherapy, and the correlation between histopathological and radiological response. Taking into account a 50% prevalence of CC without RAS mutation, accrual of 165 patients is needed for this Phase II trial.

Trial registration: NCT01675999 (ClinicalTrials.gov).

No MeSH data available.


Related in: MedlinePlus

The Tumor Regression Grade (TRG), as simplified to three categories by Ryan (19). TRG1: Major response; TRG2: Intermediate response; TRG3: No response
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Fig2: The Tumor Regression Grade (TRG), as simplified to three categories by Ryan (19). TRG1: Major response; TRG2: Intermediate response; TRG3: No response

Mentions: The primary objective is to assess the histopathological response to neoadjuvant chemotherapy measured by the Tumor Regression Grade (TRG), as simplified to three categories by Ryan [19]. The TRG-Ryan is based on the relationship between fibrosis and the amount of residual tumor cells is defined as follows (Fig. 2). The histopathological finding of fibrous stroma containing few viable tumor cells can be naturally present in almost 10 % of CCs not treated with chemotherapy prior to surgery [15]. Therefore, this parameter represents an objective measure of evaluation in the control (no pre-operative chemotherapy) and study (neoadjuvant chemotherapy) arms. This limits the risk of wrongly concluding therapy efficacy, thereby meeting the methodological standards of a Phase II randomized study. The histopathological response to neoadjuvant chemotherapy will be centrally assessed by 2 of the 3 members of our Central Review Committee of Pathologists who will be blinded to the patients’ treatment. The objective of the blinded comparison of TRG by two independent pathologists is to assess: (i) the inter-observer reproducibility of this grading system in CC after neoadjuvant chemotherapy; (ii) the specificity of histological "regression" criteria by comparing, without knowing the treatment arms, the histological features of tumors operated on immediately versus that of tumors treated by neoadjuvant chemotherapy.Fig. 2


Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a multicentre randomised controlled phase II trial--the PRODIGE 22--ECKINOXE trial.

Karoui M, Rullier A, Luciani A, Bonnetain F, Auriault ML, Sarran A, Monges G, Trillaud H, Le Malicot K, Leroy K, Sobhani I, Bardier A, Moreau M, Brindel I, Seitz JF, Taieb J - BMC Cancer (2015)

The Tumor Regression Grade (TRG), as simplified to three categories by Ryan (19). TRG1: Major response; TRG2: Intermediate response; TRG3: No response
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4497499&req=5

Fig2: The Tumor Regression Grade (TRG), as simplified to three categories by Ryan (19). TRG1: Major response; TRG2: Intermediate response; TRG3: No response
Mentions: The primary objective is to assess the histopathological response to neoadjuvant chemotherapy measured by the Tumor Regression Grade (TRG), as simplified to three categories by Ryan [19]. The TRG-Ryan is based on the relationship between fibrosis and the amount of residual tumor cells is defined as follows (Fig. 2). The histopathological finding of fibrous stroma containing few viable tumor cells can be naturally present in almost 10 % of CCs not treated with chemotherapy prior to surgery [15]. Therefore, this parameter represents an objective measure of evaluation in the control (no pre-operative chemotherapy) and study (neoadjuvant chemotherapy) arms. This limits the risk of wrongly concluding therapy efficacy, thereby meeting the methodological standards of a Phase II randomized study. The histopathological response to neoadjuvant chemotherapy will be centrally assessed by 2 of the 3 members of our Central Review Committee of Pathologists who will be blinded to the patients’ treatment. The objective of the blinded comparison of TRG by two independent pathologists is to assess: (i) the inter-observer reproducibility of this grading system in CC after neoadjuvant chemotherapy; (ii) the specificity of histological "regression" criteria by comparing, without knowing the treatment arms, the histological features of tumors operated on immediately versus that of tumors treated by neoadjuvant chemotherapy.Fig. 2

Bottom Line: Optimum systemic therapy at the earliest possible opportunity may be more effective at eradicating distant metastases than the same treatment given after the delay and immunological stress of surgery.Added to this, shrinking the primary tumor before surgery may reduce the risk of incomplete surgical excision, and the risk of tumor cell shedding during surgery.The primary endpoint of the study is the histological Tumor Regression Grade (TRG) as defined by Ryan.

View Article: PubMed Central - PubMed

Affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Digestive and Hepato-Pancreato-Biliary Surgery, University Institute of Cancerology (Paris VI), Pierre & Marie Curie University (Paris VI), 47-83 Boulevard de l'Hôpital, 75013, Paris, France. mehdi.karoui@psl.aphp.fr.

ABSTRACT

Background: In patients with high risk stage II and stage III colon cancer (CC), curative surgery followed by adjuvant FOLFOX-4 chemotherapy has become the standard of care. However, for 20 to 30% of these patients, the current curative treatment strategy of surgical excision followed by adjuvant chemotherapy fails either to clear locoregional spread or to eradicate distant micrometastases, leading to disease recurrence. Preoperative chemotherapy is an attractive concept for these CCs and has the potential to impact upon both of these causes of failure. Optimum systemic therapy at the earliest possible opportunity may be more effective at eradicating distant metastases than the same treatment given after the delay and immunological stress of surgery. Added to this, shrinking the primary tumor before surgery may reduce the risk of incomplete surgical excision, and the risk of tumor cell shedding during surgery.

Methods/design: PRODIGE 22--ECKINOXE is a multicenter randomized phase II trial designed to evaluate efficacy and feasibility of two chemotherapy regimens (FOLFOX-4 alone and FOLFOX-4 + Cetuximab) in a peri-operative strategy in patients with bulky CCs. Patients with CC deemed as high risk T3, T4 and/or N2 on initial abdominopelvic CT scan are randomized to either colectomy and adjuvant chemotherapy (control arm), or 4 cycles of neoadjuvant chemotherapy with FOLFOX-4 (for RAS mutated patients). In RAS wild-type patients a third arm testing FOLFOX+ cetuximab has been added prior to colectomy. Patients in the neoadjuvant chemotherapy arms will receive postoperative treatment for 4 months (8 cycles) to complete their therapeutic schedule. The primary endpoint of the study is the histological Tumor Regression Grade (TRG) as defined by Ryan. The secondary endpoints are: treatment strategy safety (toxicity, primary tumor related complications under chemotherapy, peri-operative morbidity), disease-free and recurrence free survivals at 3 years, quality of life, carcinologic quality and completeness of the surgery, initial radiological staging and radiological response to neoadjuvant chemotherapy, and the correlation between histopathological and radiological response. Taking into account a 50% prevalence of CC without RAS mutation, accrual of 165 patients is needed for this Phase II trial.

Trial registration: NCT01675999 (ClinicalTrials.gov).

No MeSH data available.


Related in: MedlinePlus