The objective of the CROSS trial is to compare median survival rates and quality of life (before, during and after treatment) between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma.
As secondary objectives we aim to compare pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs.
The CROSS trial is a multicenter, randomized phase III, clinical trial. The study started on 1 January 2004 and the duration of inclusion will be approximately 5 years. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm.
Patients with histologically proven squamous cell carcinoma or adenocarcinoma of the esophagus or gastro-esophageal junction will undergo extensive preoperative staging, including endosonography and spiral CT-scan of the chest and abdomen. The tumor must not extend more than 2 cm into the gastric cardia. Longitudinal tumor length must not exceed 8 cm, radial size must not exceed 5 cm. cT1N0 tumors are not eligible. Patients must have adequate hematological, renal, hepatic and pulmonary functions defined as: granulocytes ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, total bilirubin ≤ 1.5 × upper normal limit, creatinine ≤ 120 μmol/L and FEV1 ≥ 1.5 L. In the absence of local irresectability and/or distant dissemination patients with an acceptable general condition (ECOG performance status 0, 1, 2; weight loss < 10%) will be invited to participate in the randomized trial. After written, voluntary, informed consent and stratification for tumor type, treatment center, clinical lymph node status, and WHO performance status the patients will be randomized between the two treatment-arms (neoadjuvant chemoradiation followed by surgery versus surgery alone).
Paclitaxel 50 mg/m2 and Carboplatin AUC = 2 will be given by intravenous infusion on days 1, 8, 15, 22 and 29. All patients receiving Paclitaxel will receive half an hour before the start of the Paclitaxel infusion premedication: Dexamethason 10 mg i.v., Clemastine (Tavegil) 2 mg i.v. and Ranitidine (Zantac) 50 mg i.v..
At hour 0, the total calculated dose of Paclitaxel, diluted in 500 ml of normal saline will be infused over one hour. After the completion of the Paclitaxel infusion, 100 ml NaCl 0.9% will be infused over 0.5 h, followed by an infusion of 8 mg Ondansetron or its equivalent diluted in 100 ml NaCl 0.9% over 0.5 hour. Hereafter the total calculated dose of Carboplatin, diluted in 500 ml glucose 5% will be infused over one hour (doses Carboplatin > 250 mg should be dissolved in 1000 ml glucose 5%). The absolute dose of Carboplatin will be calculated for the target AUC = 2 according to the following formula: the absolute dose of Carboplatin = [target AUC] × (Glomerular Filtration Rate + 25).
It is possible that some patients will experience asymptomatic bradycardia during the Paclitaxel infusion. In addition, hypersensitivity reactions are possible and generally occur within the first few minutes of initiating the infusion. For these reasons, it is recommended that there is constant supervision and that the vital signs are monitored every fifteen minutes during Paclitaxel administration. Thereafter, patients may be observed and heart rate and blood pressure checked if necessary, according to clinical symptoms.
A total dose of 41.4 Gy will be given in 23 fractions of 1.8 Gy, 5 fractions per week, starting the first day of the first cycle of chemotherapy. All patients will be radiated by external beam radiation, using 3-D conformal radiation technique. The patient will be positioned in supine position. Reproducibility will be assessed by orthogonal laser beams.
The Gross Tumor Volume (GTV) is defined by the primary tumor and any enlarged regional lymph nodes.[29
], and will be drawn on each relevant CT slice. The GTV will be determined using all available information (physical examination, endoscopy, EUS, CT-thorax/abdomen).
The Planning Target Volume (PTV) will provide a proximal and distal margin of 4 cm, in case of tumor extension into the stomach, a distal margin of 3 cm will be chosen. A 2 cm radial margin around the GTV will be provided to include the area of subclinical involvement around the GTV and to compensate for tumor motion and set-up variations.
Both lungs will be contoured. The heart will be contoured on all slices; its cranial border will include the infundibulum of the right ventricle and the apex of both atria.[30
], and will exclude the great vessels as much as possible. The caudal border will be defined as the lowest part of the left ventricle's inferior wall that is distinguishable from the liver. The spinal canal will be contoured and taken to represent the spinal cord. Prior to the start of the irradiation a planning CT scan will be made from the cricoid to L1 vertebra with a slice thickness of 5 mm, with the patient in treatment position. The isocenter will be determined at the planning-CT.
Radiation therapy will be delivered using a multiple field technique. Treatment can be given with the combination of anterior/posterior, oblique or lateral field. Customized blocks or a multi-leaf collimator will be used to shape the treatment fields. All patients will undergo a 3D planning. Beams-eye-view (BEV) displays will be used to ensure optimal target volume coverage and optimal normal tissue sparing. The most appropriate technical solutions (e.g. beam quality, field arrangement, conformal therapy planning) will be chosen as long as they comply with the International Commission on Radiation Units and Measurements (ICRU) 50/62 safety margins and homogeneity requirements.
Dose-Volume-Histograms (DVHs) of both lungs, the heart and spinal cord will be obtained for all patients. DVHs will mainly be used to document the normal tissue damage. DVHs may also help to select the most appropriate treatment plan. The volume of lung tissue that receives 20 Gy or more will not exceed 30% of the total lung volume (V20 Gy lung < 30%). The volume of the heart that receives 40 Gy will not exceed 30% of the heart volume (V40 Gy heart < 30%) and the volume of the liver that receives 30 Gy will not exceed 60% of the total liver volume (V30Gy liver < 60%). There is no limit for the maximal length of involved esophagus as long as the normal tissue criteria are not exceeded.
The risks for severe pneumonitis for patients treated under this protocol will be minimized as the volume of both lungs will be limited by the use of BEV planning and field-shaping (with optimal sparing of both lungs). The spinal cord tolerance (50 Gy) will not be exceeded with this technique.
Radiation therapy will be delivered with megavoltage equipment with photon energies of equal to or greater than 6 MV. A multileaf collimator or individually shaped blocks will be used to shape the irradiation portal according to the planning target volume.
The prescription dose will be specified at the ICRU 50/62 reference point, which will be the isocenter for most patients. The daily prescription dose will be 1.8 Gy at the ICRU reference point and the 95% isodose must encompass the entire planning target volume (PTV). The maximum to the PTV must not exceed the prescription dose by > 7% (ICRU 50/62 guidelines). Tissue density inhomogeneity correction will be used. Portal images will be obtained during the first fraction of all fields. On indication portal images will be repeated.
If on day 8, 15, 22, 29, and 36 the WBC are < 1.0 × 109/L and/or platelets < 50 × 109/L, chemotherapy will be delayed by 1 week until recovery above these values. In case of febrile neutropenia (granulo's < 0.5 × 109/L and fever > 38.5°C) or in case of severe bleeding or requiring ≥ 2 units of platelet transfusions further chemotherapy will be withheld.
Hypersensitivity reactions will be classified as mild, moderate or severe. Definitions and management guidelines are outlined in table . Other toxic reactions and the prescribed management of these reactions are outlined in table .
Hypersensitivity reactions after chemotherapy: classification and management
toxic reactions and prescribed management
Radiotherapy, especially concurrent with chemotherapy can lead to acute esophagitis. In some cases medical support and/or a feeding tube will be necessary. In the event of grade 4 radiation induced esophagitis both chemotherapy and radiotherapy will be withheld until the esophagitis has recovered to grade 3. Other acute complications of the radiation therapy are erythema, cough, nausea, fatigue and weight loss. In the first weeks to six months after the irradiation radiation pneumonitis or fistula formation can occur.
Patients randomized for surgery alone will be treated as soon as possible after randomization. In the chemoradiation arm, surgery will be performed preferably within 6 weeks after the completion of the chemoradiation. For carcinomas proximal to the tracheal bifurcation a transthoracic esophageal resection with a two field lymph node dissection is preferred. For carcinomas distal of the tracheal bifurcation but proximal to the gastro-esophageal junction, a transthoracic approach with a two field lymph node dissection or a transhiatal approach can be performed, depending on both patient characteristics and local expertise.[31
] For distal tumors involving the gastro-esophageal junction a transhiatal esophageal resection is preferred.
A wide local excision including the N1 lymph nodes is carried out in both techniques including a standard excision of the lymph nodes around the celiac axis (separately collected with left gastric artery marked by a suture). The continuity of the digestive tract will be restored by a gastric tube reconstruction or a colonic interposition procedure with an anastomosis in the neck.
The resection specimen will be evaluated essentially using the standard protocol (margins, tumor type and extension, lymph nodes). The most recent UICC protocol is used for TNM-classification and stage grouping.[32
] In these resection specimens special attention will be given to the effects of the neoadjuvant chemoradiation, i.e. tumor reduction and therapy effects. The effect of the chemoradiation varies from zero to 100%. In many cases a multifocal tumor appearance is present with intertwined therapy effects. In some cases only scattered tumor cells are visible, often with bizarre morphologies. Therapy effects include necrosis, inflammation with multinucleated giant cells, fibrosis and calcifications. In general fibrosis is the most remarkable effect, and it can be used to judge the extension of the untreated tumor. The Mandard score is used to quantify the anti-tumor effect.[34
] The lymph node dissection should contain at least 10 nodes derived from both regional (mediastinal, esophageal) and distant sites (celiac region).
The pathology report should contain the following: site of the tumor/lesion, type and grade of the tumor, extension into the esphageal wall, resection margins, therapy effects (Mandard score), lymph node status including the site and the number of nodes with therapy effects.
After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment, to document late toxic effects and, if applicable, disease relapse or progression, and death. Patients in the chemoradiation arm will be asked to fill out quality of life questionnaires before and after therapy and every three months during the first year of follow up. Patients randomized for surgery alone will fill out the questionnaires before surgery and every three months during the first year of follow-up.
Data will be analyzed according to the 'Intention to treat' principle. We believe that an estimated difference in median survival of 16 months (surgery alone arm) versus 22 months (multimodality treatment arm) would justify applying this regimen in the future. We calculated that for this purpose 350 patients, 175 patients per arm, have to be enrolled. We assumed a two-sided significance level of 0.05 and a power of 0.80.[35
] Survival will be dated from the date of randomization to death. Estimates of median overall survival will be based on the Kaplan-Meier method and log-rank tests will be used to determine significance. Cox regression analyses will be conducted to identify prognostic factors for survival benefit, which will be used in adjusted analyses of the treatment effect.
The responsible physician will inform the patient about the background and present knowledge on the drugs under study with special reference to known activity and toxicity. It must be emphasized that the patient is allowed to refuse the treatment either before or at any time during the study. Before the patient is entered in the study the patient's written consent will be obtained. The principal investigator (AvdG) will ensure that this study will be carried out in agreement with the "Declaration of Helsinki, Tokyo, Venice" or the laws and regulation of the country, whichever provides greater protection of the individual. The study has been approved by the institutional ethical review committee.
Any unexpected clinical adverse event or abnormal laboratory test value that is serious, including death or overdose, occurring during the course of the study, irrespective of the treatment received by the patient, must be reported to the study coordinator within one working day of occurrence.
An adverse event is serious if it is fatal or life threatening, permanently disabling, requiring hospitalization other than for planned treatment or if it is an overdose. A death occurring during treatment within 4 weeks after stopping treatment, whether treatment-related or not must be reported to the study coordinator.