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

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.

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