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PReoperative Chemoradiation (Paclitaxel-carboplatin or FOLFOX) for Resectable Esophageal and Junctional Cancer (PROTECT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02359968
Recruitment Status : Active, not recruiting
First Posted : February 10, 2015
Last Update Posted : August 1, 2022
Sponsor:
Collaborator:
National Cancer Institute, France
Information provided by (Responsible Party):
Centre Oscar Lambret

Brief Summary:

Resectable esophageal or junctional cancer requires medical treatment by radiotherapy and chemotherapy followed by surgery. Currently, one of the most commonly used chemotherapy treatment is the FOLFOX. It is a combination of three drugs administered intravenously: fluorouracil, oxaliplatin and folinic acid. This is the standard treatment.

Another protocol of chemotherapy is widely used by certain European and American teams, due to promising results : a combination of two drugs administered intravenously: Paclitaxel and Carboplatin (CarboP-pacliT). At present, no clinical study has shown the superiority of one treatment over the other.

The objective of this Phase II study is to clarify clinical practice by comparing these two chemotherapy treatments.


Condition or disease Intervention/treatment Phase
Esophageal Neoplasms Gastro-esophageal Junction Cancer Drug: FOLFOX Drug: CarboP-pacliT Phase 2

Detailed Description:

There is no standard preoperative (neoadjuvant) chemoradiation (NCRT) regimen for resectable esophageal cancer, because most if all trials failed to show any survival advantage favoring pCRT when compared to surgery only. This failure had been related to the lack of power of some trials, as well as the ability of chemoradiation to potentiate post-operative morbidity (including mortality), and therefore hampering the accrual of its own survival benefit. Hopefully, meta-analyses showed that NCRT increases survival when compared to surgery only. However, in the clinical practice, this does not make easier the choice of the best NCRT treatment. It appeared that the radiation regimen that were used in each randomized trials were heterogeneous with respect with dose, fraction, length of treatment, fields, dosimetry planning, and quality control. This applies also to chemotherapy with respect with the kind of cytotoxics that were used (including number of drugs), as well as dosage, and the number of cycles, although most of the time cytotoxics were fluorouracil and cisplatin.

Dutch colleagues recently showed that NCRT with weekly carboplatin and paclitaxel increase survival, without increasing postoperative mortality. Of note, most tumors in this trial arose from the lower third of the esophagus and esogastric junction and these habitually correlate with less postoperative morbidity compared to upper third tumors. Moreover, the lung volume spared from radiation was greater in junctional tumors than in upper third cancers - a critical point in the development of radiation-induced pneumonitis and subsequent postoperative mortality. It is difficult to understand how this taxane-based chemotherapy is active, as it did not make better that fluorouracil-based regimen in non-operable patients, and as NCRT with taxanes makes radiation-induced pneumonitis more likely. The favorable impact of this NCRT may lie on its radiation regimen. A moderate total dose of radiation, smaller radial margins than in other trials and modern dosimetry with 3D-planning all improve the safety of treatment and of subsequent surgery. Finally, the favorable impact of the Dutch NCRT regimen may lies on the fact that it does not include cisplatin, a compound which has been found related to the occurrence of more sudden deaths than a non cisplatin-based regimen such as the FOLFOX combination (fluorouracil, oxaliplatin, folinic acid) in the setting of definitive chemoradiotherapy.

Our aim is to evaluate the short-term benefit (complete resection rate) and safety (severe postoperative rate) of 2 preoperative regimen, (carboplatin-paclitaxel or fluorouracil-oxaliplatin-folinic acid), combined to the Dutch radiation backbone, in operable esophageal and junctional (Siewert I-II) cancer. The present trial offers the unique opportunity to compare two therapeutic strategies that have already been shown to be efficient in large randomized controlled trials offering level-1 evidence.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 106 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PReoperative Chemoradiation With Paclitaxel-carboplatin or With Fluorouracil-oxaliplatine-acide Folinique (FOLFOX) for Resectable Esophageal and Junctional Cancer - A Randomized Phase II Trial
Actual Study Start Date : February 26, 2015
Actual Primary Completion Date : January 8, 2021
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: FOLFOX
  • Fluorouracil 400 mg/m², IV bolus dose on day 1, followed by continuous IV infusion of fluorouracil 1600 mg/m² over 2 days
  • Oxaliplatin 85 mg/m², 2-hr IV infusion on day 1
  • Folinic acid 200 mg/m² 2-hr IV infusion on day 1
  • 3 cycles, q14
Drug: FOLFOX
radiochemotherapy before surgery
Other Names:
  • Fluorouracil
  • Oxaliplatin
  • Folinic acid
  • Elvorine

Experimental: CarboP-pacliT
  • Carboplatin (carboP) AUC=2, given by intravenous infusion
  • Paclitaxel (pacliT) 50 mg/m², given by intravenous infusion
  • on days 1, 8, 15, 22 and 29
Drug: CarboP-pacliT
radiochemotherapy before surgery
Other Names:
  • Carboplatine
  • paclitaxel




Primary Outcome Measures :
  1. Short-term benefit of 2 preoperative regimen: complete resection rate AND severe (grade ≥ 3) postoperative morbidity/mortality according to the Clavien-Dindo classification [ Time Frame: up to 30 days after surgery ]
    Complete resection rate (R0, that is "complete removal of all tumor with microscopic examination of margins showing no tumor cells") AND severe (grade ≥ 3) postoperative morbidity/mortality according to the Clavien-Dindo classification. Severe postoperative complication is defined by grade ≥III per-operative or post-operative complication occurring in the 30 days after surgery.


Secondary Outcome Measures :
  1. Rate of completion of full treatment without modification [ Time Frame: up to 58 days ]
  2. Evaluation of the efficacy of both regimen in term of overall survival [ Time Frame: From date of inclusion until the date of death from any cause assessed up to 36 months after the last surgery ]
    Overall survival using Kaplan-Meier method

  3. Evaluation of the efficacy of both regimen in term of disease-free survival [ Time Frame: From date of inclusion until the date of first documented progression whichever came first, assessed up to 36 months after the last surgery ]
    Disease-free survival using Kaplan-Meier method

  4. Evaluation of the safety of the evaluated regimens in terms of preoperative mortality. [ Time Frame: From registration to surgery ]
    Preoperative mortality (grade 5) rate, according to NCI-CTCAE v4.0 criteria

  5. Evaluation of the safety of the evaluated regimens in terms of preoperative morbidities, postoperative morbidities, respiratory morbidities. [ Time Frame: From start of treatment to end of study ]
    Pre-operative morbidities according to NCI-CTCAE v4.0 criteria, post-operative morbidities occurring in the 30 days after surgery with the main post-operative complication graded according to Clavien-Dindo, post-operative morbidities occurring more than 30 days after surgery graded according to NCI-CTCAE V4.0, postoperative respiratory morbidity rate according to the Clavien-Dindo classification.

  6. Evaluation of the efficacy of both regimen in term of Pathological response rate [ Time Frame: Surgery ]
    Complete pathological response (ypCR) rate

  7. Evaluation of the efficacy of both regimen in term of quality of life [ Time Frame: Up to 3 years after surgery ]
    Quality of life: QLQC30 and OES18


Other Outcome Measures:
  1. DVH (CoDose-Volume-Histogram (DVH) and postoperative respiratory morbidity [ Time Frame: up to 30 days after the beginning of radiotherapy ]
  2. Comparison of both arms in terms of safety and efficacy [ Time Frame: From date of inclusion until the date of death from any cause assessed up to 36 months after the last surgery ]

    Evaluation of preoperative mortality (grade 5) rate according to NCI-CTCAE v4.0 criteria, pre-operative morbidities according to NCI-CTCAE v4.0 criteria, post-operative morbidities occurring in the 30 days after surgery with the main post-operative complication graded according to Clavien-Dindo, post-operative morbidities occurring more than 30 days after surgery graded according to NCI-CTCAE V4.0, postoperative respiratory morbidity rate according to the Clavien-Dindo classification.

    Evaluation of overall survival and disease-free survivalusing Kaplan-Meier method, complete pathological response (ypCR) rate


  3. Net treatment benefit estimation [ Time Frame: From date of inclusion until the date of death from any cause assessed up to 36 months after the last surgery ]
    To estimate the net treatment benefit, combining efficacy and safety endpoints, using the Generalized Pairwise Comparisons Method - GPC method (Buyse, 2010)

  4. Prognostic factor and treatment effect controlling for possible confounding factors [ Time Frame: From date of inclusion until the date of first documented progression whichever came first, assessed up to 36 months after the last surgery ]
    To identify prognostic factors associated to disease-free survival, and evaluate the treatment effect controlling for possible confounding factors. Following factors will be studied: pre-therapeutic stage (II versus III), pre-therapeutic N (positive versus negative), post-surgery stage (ypT0N0 versus other), TRG (1-2 versus other) and resection (R0 versus other).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Resectable and operable esophageal cancer located under the carena (beyond 25 cm from the incisors) or junctional cancer (Siewert I or II)
  • Invasive adenocarcinoma or squamous cell type (to stick to the population included in the CROSS trial)
  • Patient who present with:

    • stage IIA (T3N0M0)
    • stage IIB (T1 N1 M0 or T2 N1 M0),
    • stage III (T3 N1 M0 or T4 N0 N1 M0) tumors
  • ECOG performance status 0, 1 or 2
  • Patient eligible for preoperative chemoradiation with either fluorouracil- oxaliplatin-folinic acid, or Paclitaxel-carboplatin
  • Age ≥ 18
  • Peripheral neuropathy ≤ NCI-CTC grade 1
  • Adequate bone marrow reserve, normal renal and liver functions:

    • Neutrophil count ≥ 1500/mm3
    • Platelet count ≥ 100 000/mm3
    • Hemoglobin ≥ 10 g/dl (after transfusion, if necessary)
    • Creatinin < 15mg/L
    • Clearance of creatinin (Cockcroft formulae) ≥ 60 ml/mn
    • Prothrombin time ≥ 60%
    • ASAT-ALAT ≤2.5 x ULN
    • Total bilirubin < 1.5 x ULN
    • Albumin greater the lower limit of normal
  • Start of treatment within 28 days after randomization
  • Negative pregnancy test (serum beta-HCG) performed within 1 week prior to start of study treatment in females with reproductive potential
  • Patient covered by government health insurance
  • Patient who provide a signed written informed consent form

Exclusion Criteria:

  • Patient who present with stage I or stage IIA (including T2 N0 M0) or stage IV
  • Patient who present with common contraindications for surgery related to patient status
  • Patient who present with common contraindications for surgery related to disease extension
  • Patient who present with common contraindication to radiochemotherapy with either fluorouracile-cisplatin or with paclitaxel-carboplatin

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02359968


Locations
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France
ICO Paul Papin
Angers, France
CHU Bordeaux
Bordeaux, France
University Hospital of Lille
Lille, France, 59000
Centre Oscar Lambret
Lille, France, 59020
Hôpital La Timone
Marseille, France
Hôpital Nord
Marseille, France
ICM - Val d'Aurelle
Montpellier, France
CH Lyon sud
Pierre-Bénite, France
Centre Eugène Marquis
Rennes, France
ICO René Gauducheau
Saint-Herblain, France
Sponsors and Collaborators
Centre Oscar Lambret
National Cancer Institute, France
Investigators
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Principal Investigator: Antoine ADENIS, MD Centre Oscar Lambret
Principal Investigator: Guillaume PIESSEN, MD University Hospital of Lille
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Centre Oscar Lambret
ClinicalTrials.gov Identifier: NCT02359968    
Other Study ID Numbers: PROTECT-1402
First Posted: February 10, 2015    Key Record Dates
Last Update Posted: August 1, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Centre Oscar Lambret:
resectable esophageal
junctional cancer
FOLFOX
paclitaxel-carboplatin
Additional relevant MeSH terms:
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Esophageal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Paclitaxel
Fluorouracil
Oxaliplatin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs