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Study protocol for resectabel cancer of the esophagus and gastro-esophageal junction.

Ethic approval: EPN Stockholm 2006/738-32, 2008-403-32

EudraCTnr 2006-001785-16

Approval Medical Products Agency of Sweden Dnr: 151:2006/24273

Coordinating investigator/sponsor:Lars Lundell, Professor of Surgery, Department of Surgery, Gastrocentrum, Karolinska University Hospital, Huddinge, Stockholm Sweden

Investigator signature………………………………………………………………………….

Date……………….


Site Investigator:Gunnar Adell, Department of Oncology, Karolinska University Hospital, Södersjukhuset Stockholm Sweden

Singe Friesland, Gun Wickart-Johansson, Department of Oncology, Karolinska University Hospital, Radiumhemmet, Solna, Stockholm Sweden

Karl Erik Johansson, Ass. Professor of Surgery, Department of Surgery, University Hospital, Linköping, Sweden

Torbjörn Myrnäs, Ass. Professor of Surgery, Department of Surgery, Norrlands University Hospital, Umeå, SwedenNielsHilmer Nielsen Department of Oncology, Norrlands University Hospital, Umeå, Sweden

Ingemar Näslund, Ass. Professor of Surgery, Department of Surgery, University Hospital, Örebro, Sweden, Mattias Elmlund, Department of Oncology

Gunnar Wagenius, Simon Ekman, Michael Bergqvist, MD, PhD. Department of Oncology, Akademiska sjukhuset, Uppsala, Sweden

Erik Johnsson, Kirurgiska Kliniken, Sahlgrenska Universitetssjukhuset, Göteborg, SwedenHedda Haugen, Department of Oncology, Sahlgrenska Universitetssjukhuset, Göteborg, Sweden

Ullevål University Hospital, Oslo: Egil Johnson, kirurgisk avdelingPetra Weber Hauge, onkologisk avdelning, Gunilla Frykholm, onkologisk avdelning

St Olav University Hosptal, Trondheim Gjermund Johnsen, kirurgisk avdelningIngunn Hatlevoll, onkologisk avdeling, Gunilla Frykholm, onkologisk avdeling

Universitetssykehuset i Nord-Norge, Tromsø Jørn Kjæve, kirurgisk avdelingLise Balteskard, onkologisk avdeling

Haukeland Universitetssykehus, Bergen Asgaut Viste, Kirurgisk avdelning

Radiumhospitalet, Oslo, Stephan Stoldt, Kirurg Kliniken, Anne-Birgitte Jacobsen, onkologisk avdelning.

Mälarsjukhuset, Eskilstuna, Pehr Lind, Onkologiska kliniken


1. Introduction – Background2. Study objectives3. SCHEDULE4. STUDY DESIGN5. PRETREATMENT EVALUATION6. ELIGIBILITY CRITERIA7. STRATIFICATION AND RANDOMIZATION8. TREATMENT PLAN9. ON-STUDY ASSESSMENT AND FOLLOW-UP10. QUALITY OF LIFE ASSESSMENT11. DEFINITIONS OF OUTCOMES12. STATISTICAL CONSIDERATIONS AND METHODOLOGY13. QUALITY ASSURANCE AND MONITORING14. Time plan15. PUBLICATION16. ETHICAL ASPECTS17. Study coordination, innovative analyses18. Principal investigators19. REFERENCES


Background:On a yearly basis roughly 4-500 patients present with carcinoma of the esophagus in Sweden. With regard to cancers originating in the gastro-esophageal junction (GEJ) it is some what more difficult to estimate the incidence figures due to difficulties in classification of the site of origin of the neoplastic process. A good estimate is, however, that GEJ cancers affect 150 – 200 patients each year in this country. There are some epidemiological data which are of importance for the management of the patients. First the number of adenocarcinomas is steadily increasing both in the body of the esophagus as well as in the GEJ. Concomitant with that, the corresponding figures for squamous cell cancer are decreasing. Second already at the time of first presentation of these patients, the tumours have usually reached an advanced stage in the vast majority of the cases. It can therefore be estimated that roughly only one third of these patients are only amenable to a treatment with curative intent. These facts emphasis the importance of the urgency of development of palliative management strategies.

Even in those individuals, who are candidates for treatment with curative intent, long-term follow up have consistently demonstrated that tumour free survival can only be expected to plateau at a level of 20 %. The main mechanism behind these dismal figures resides in the preponderance for these tumours to metastasis to loco-regional lymph nodes already when penetrating through the muscularis mucosae. In fact careful investigations have demonstrated that tumours which have penetrated into the superficial third of the mucosa already in 25 % had developed local lymph node metastases.

Until quite recently surgical therapy has been considered the gold standard in the treatment of carcinoma of the esophagus and GEJ. Recent studies have been carried out to challenge this basic therapeutic concept in these tumour manifestations, but until now radio-chemotherapy alone has not been shown to offer benefits which are superior to surgery alone. Therefore surgery will remain the basic therapeutic modality in these cancers although it seems to offer a therapeutic efficacy which is far from optimal.

During the recent decade a number of studies have been carried out to determine the value of neoadjuvant or adjuvant treatment given in addition to surgery. It is clear that postoperative treatment can not be recommended. However, when it comes to neoadjuvant treatment it remains to be determined whether radio-chemotherapy offers advantages above what can be achieved by chemotherapy alone. The down side of combination neoadjuvant therapy might well be that the risks associated with surgery are enhanced.

Although the ultimate objective of the actual multi modality regimen is to improve the survival, the research methodology aspects that hereby emerge are overwhelming, in terms of recruiting patients enough into respective therapy arm. There are, however, alternative complementary methodology strategies available that relate to the relationships between the degree of histological response and the subsequent over all survival. It has repeatedly been shown that a complete eradication of tumour cells, when evaluated in the resected specimen, directly translates into a better survival of the patient. Due to the basic design of a similar study all patient will have a resection, the opportunity emerges to use a surrogate variable as the primary end point. By the definition of the rate of complete histological response, as the primary objective in a similar study, the preconditions for the power calculations, the enrolment of patients and the conduct of the trial change most favourably.


Study objectives:

Primary objective: To evaluate whether combined radiochemotherapy gives higher complete

histological response (pCR) after resection than chemotherapy alone in patients with resectable carcinoma of the esophagus and gastric cardia.

Secondary objectives: To evaluate the safety of respective neoadjuvant therapies To assess the safety profile of carrying out radical surgery after respective

neoadjuvant therapy To study the overall and disease free survival in respective groups To evaluate if pretreatment tumor characteristics predict the pCR and

incomplete pCR rates

SCHEDULE


Patient population Histologically confirmed squamous cell carcinoma or adenocarcinoma of the esophagus

and gastric cardia.

Suitable for surgery alone.

T1N1, T2N0, T2N1, T3N0, T3N1.

M1a

Stratification

Histology Arm A:Chemoradiation + SurgeryRANDOMISATION

Arm B: Chemotherapy + SurgeryT-stage

N-stage Tumor location (prox, mid or distal esophagus, gastric cardia)

Institution

3. STUDY DESIGN

3.1 The study is designed as a two-arm phase III randomized, open, multicentre, controlled trial.

3.2 The study population will consist of patients with squamous cell or adenocarcinoma of the esophagus (Siewert type I) and adenocarcinoma of the gastric cardia (Siewert type II), with stages as defined in inclusion criteria.

3.3 Patients will be randomised between induction chemotherapy or chemoradiotherapy, all followed by surgery

4 ELIGIBILITY CRITERIA


Inclusion criteria4.1 Histologically verified squamous cell carcinoma, adenocarcinoma of the esopohagus or

gastric cardia (type II)

4.2 Tumour located in cervical oesophagus, not requiring laryngo-esophagectomy.

4.3 Patients with performance status 0-1 according to WHO scale and with resectable tumours, as assessed at the prerandomisation evaluation.

4.4 Adequate haematological function, defined as having WBC > 3 x 109/litre and platelets > 100 x 109/litre

4.5 Adequate renal function defined as having normal serum creatinine level and/or calculated glomerular filtration rate > 60 ml/min

4.6 Tumour stage : T1N1, T2N0, T2N1, T3N0, T3N1. M1a

4.6 Written informed consent 4.8 Age <75 years

4.9 No major illness that make chemoradiotherapy unsuitable, life expectancy at least 3 months

Exclusion criteria4.10 Pregnancy and/or lactation. Women of childbearing ages can be included provided that

adequate contraceptive methods are used

4.11 Patients with diabetes complications (e.g. retinopathy, neuropathy) as well as patients with uncontrolled cardiac disease or myocard infarction within 12 months are considered unsuitable for chemoradiotherapy.

4.12 Concomitant malignancy (< 5 years since diagnosis) that can interfere the interpretation of study results, ongoing antitumoral treatment

4.13 Patients being unable to comply with the protocol

4.14 Tumor stage T1 N0, T4 NX or TXNXM1b


5 STRATIFICATION AND RANDOMISATION

5.1 Prior to randomization, patients will be stratified by histology (squamous cell carcinoma, adenocarcinoma), location of the tumor, institution and by T and N stage

5.2 Randomisation will be carried out by use of a computer based randomization programme operational at the Regional Oncological Center Stockholm

5.3 Randomization will be processed through the following contact persons and addresses:

Telephone number: 0046 8 51772981 Fax number: 0046 851775444 Onkologiskt Centrum M80 Stockholm Gotland

6 PRETREATMENT EVALUATION

The following investigations are required prior to protocol entry.

6.1 Histological confirmation of diagnosis of invasive squamous cell carcinoma or adenocarcinoma of the esophagus.

6.2 Pre-randomisation endoscopic assessment of the primary lesion. This will include length, location, (cm from the incisors), and sampling for histopatological confirmation performed within 1 month of the randomization.

6.3 Laboratory studies: Full blood count with differential and platelet counts, creatinine, liver function tests, LD (optional) performed within 1 month of the randomization.

6.4 Respiratory (dynamic and static spirometry) and cardiac function tests (exercise ECG surveilled bicycle test) performed within 2 months of the randomization

6.5 CT of the thorax and upper abdomen to assess tumour status performed within 1 month of the randomization.

6.6 Laparoscopy is recommended for carcinomas in the distal third of the esophagus primarily for those originating in the gastric cardia (performed within 1 month of the randomization)

6.7 Bronchoscopy (optional) when indicated.

6.8 PET-CT scan performed within 1 month of the randomization ( for centres outside Stockholm region, optional)

6.9 Barium esophagogram (optional).

6.10 Endoscopic ultrasonography performed within 1 month of the randomization 6.11 Audiogram


7 TREATMENT PLAN

7.1 Patients will be randomized betweenChemoradiation followed by surgery (Three cycles of chemotherapy + 40 Gy)Chemotherapy followed by surgery (Three cycles of chemotherapy)

Neoadjuvant therapy has to be commenced at the latest 2 weeks after randomization!

7.2 Chemotherapy (CHT) Treatment weeks in the schedule for CHT; 1, 4 and 7.Cisplatin 100 mg/m2 day 15-Fluorouracil 750 mg/m2/24 hours, infusion day 1-5Length of cycle 21 daysCHT - chemotherapyRT - radiotherapy

Arm A

1 2 3 4 5 6 7 8 9 10 w

CHT weeks 1, 4, 7RT starting week 4 and continuing until week 7

Arm B

1 2 3 4 5 6 7 8 9 10 w

Surgery will be performed 4-6 weeks after CHRT or CHT

Dose modificationsDay 1 Nadir Platinol 5-FU LPK TPK LPK TPK> 2.5 > 75 > 1.0 > 75 100 % 5 days

> 1.0 < 75 50 % 50 % 5 days< 1.0 xx 50 % 50 % 5 days

> 2.5 < 75 0 % 0 days< 2.5 xx 0 % 0 days

Dose adjusted according to current LPK and TPK values. Day 1 Values directly according to actual dose.xx Independently of TPK values.

Dose modifications: In case of neutropenia at day 22 and CHT has to be delayed, also the start of radiotherapy is suggested to be delayed one week. G-CSF is mandatory to be given as prophylactic treatment after each course. In case of delayed CHT, G-CSF should be considered.

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(Neulasta, Neupogen etc)

If a patient suffers from moderate or severe hearing impairment and/or moderate or severe tinnitus cisplatin can be replaced. In case of an adenocarcinoma oxaliplatin, 130 mg/m2 should be used. In case of a squamous cell carcinoma carboplatin, AUC 5 should be used. Cisplatin can be replaced before starting treatment, or during the treatment course

If renal function is moderately impaired (GFR less than 50 ml/min) during treatment cisplatin should be replaced. In case of an adenocarcinoma oxaliplatin 130 mg/m2 should be used. In case of a squamous cell carcinoma carboplatin, AUC 5 should be used. If renal function is severely impaired during treatment, chemotherapy should be discontinued.

Arm A: if the second course has to be delayed, start RT as planned week 4, consider to give Neupogen 300mg/day for 5 days and give the CHT week 5 instead. If the CHT has to be delayed > 2 weeks, continue only with RT. It is mandatory to give Neulasta, Neupogen etc even after the second and third course in such case.

Arm B: if the second course has to be delayed, consider to give Neulasta, Neupogen etc 300mg/day for 5 days and give the CHT week 5 instead. It is mandatory to give Neulasta, Neupogen etc even after the second course in such a case. If the chemotherapy has to be delayed more than 2 weeks, no more CHT should be given and the patient should be referred to surgery immediately.

7.3 RadiotherapyAll dose planning shall be performed with a CT-based three-dimensional treatment planning system. All patients included in the study shall be able to receive 40 GY to the target volume without exceeding absorbed doses to the organs at risk.

Patient positioning and immobilisationThe patient should be positioned in a supine position with e.g. the head on a standard head-rest and arms preferably above the head, allowing a multiple field technique.

Patient data acquisitionMultiple CT-scans, covering the entire PTV and total lung volume. The CT investigation shall be made in the treatment position.

Target volumeThe different volumes of interest shall be defined in agreement with ICRU Report 50.

GTV Primary esophageal tumor and gross lymph node metastases. Lymph node metastases are defined from diagnostic CT and EUS examinations.

CTV GTV (gross tumour volume) + local subclinical extension. A dose of 40 Gy is meant to encompass gross tumour volume (GTV) and regional lymph nodes. For tumours located at or above the level of carina, the caudal border of CTV was 5 cm below diagnosed tumour, whereas the supraclavicular nodes defined the cranial border. For

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tumours located mainly below the carina level, the cranial border of CTV included 5 cm of radiographically uninvolved esophagus, while the coeliac lymph nodes were included in the target volume, at the same time defining the caudal border, down to upper part of L1. In lateral, anterior and posterior directions CTV should encompass GTV and paraoesophageal area with a margin of 1 cm but not including anatomical barriers as pleura, pericard og bone.

PTV Appropiate margins (as small as possible) should be added to the CTV to take into account the effects of organ and patient movements and inaccuracies in beam and patient set-up in order to ensure that the prescribed dose is actually absorbed in the CTV.

Organs at riskThe spinal cord, the lung and the heart..

Simulation procedureA simulation procedure is mandatory for all fields. The position of all shielding blocks should be indicated on the simulation films.

Treatment techniqueA multiple field technique with optimal beam entry directions and beam weights in order to obtain as homogeneous a dose as possible in the PTV while at the same time minimizing the dose to the organs at risk.

Normal tissue sparingField shaping should be performed with customized blocks (individually cut) or with a multileaf collimator.

Dose to organs at riskSpinal cordThe maximum dose to the spinal cord is 40 Gy

LungNormal pulmonary tissue should be spared as much as possible. The beam geometry should be arranged in such a way that the lung tissue is spared as much as possible. The volume for the dose > 20 Gy to the lungs should be minimized as much as possible and should not exceed one third of the lung volume. Attention should be given, especially to patients with low pulmonary function, in view of risk of radiation induced pneumonitis and subsequent radiation fibrosis

HeartThe volume for the dose > 30 Gy to the heart should be minimized as much as possible

KidneyThe total dose to both kidneys should be kept as low as possible and not exceed 12 Gy and not more than 20 Gy for a single kidney

Dose computationA three-dimensional computerized dose planning with inhomogeneity correction shall be performed.

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Dose specificationThe dose specification should be in terms of the ICRU Reference point (see ICRU Report 50) which should be located in the center of the PTV, and if possible on or near the central axis of the beams.

Fractionation schedulePTV: 40 Gy in 20 fractions (2.00 Gy/fraction) in a course of 4 weeks (approximately 28days), 1 fraction per day and 5 fractions per week. In case of bank holidays or machine breakdown, the treatment time should be extended. It is not allowed to give 2 fractions per day.

Treatment verification, minimum requirementsSimulator port filmsTreatment verification at least at the first, in the middle and at the end of the treatment.Measurements of entrance dose or other equivalent methods to ensure that the correct calculated dose is given to the patient.Radiation treatment charts shall be saved as well as the dose plans, portal and verification films.

AbbreviationsGTV (Gross Tumour Volume) is the gross palpable or visible/demonstrable extent and

location of malignant growth

CTV (Clinical Target volume) is a tissue volume that contains a demonstrable GTV and/or subclinical microscopic malignant disease, which has to be eliminated. This volume thus has to be treated adequately in order to achieve the aim of therapy, cure or palliation.

PTV (Planning Target Volume) is a geometrical concept, and it is defined to select appropiate beam sizes and beam arrangements, taking into consideration the net effect of all the possible geometrical variations, in order to ensure that the prescribed dose is actually absorbed in the CTV.

7.4 Surgical treatmentPreoperative investigationsPreoperative evaluation of operability is performed according to the protocol above regarding functional status. The inclusion criteria preclude that all patients resectable. If the colon is planned to be utilized as the esophageal substitute, a colonoscopy is performed before operation.Surgery has to be carried out 4-6 weeks after completion of the respective induction, neoadjuvant therapies

The operative treatment is standardized as follows. All participating centers shall have a documented experience in surgery directed towards cancers of the esophagus and gastric cardia. This constitutes a vital prerequisite to ensure high quality of the procedure and to minimize morbidity and postoperative mortality. Furthermore, all operating surgeons should be trained and familiar with the concept of two-field lymphadenectomy. Basically all operations are performed as thoracoabdominal resections with intrathoracic anastomosis for cancers in the distal third and cardia whereas three stage resection is carried out for

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those in the middle and upper part of the organOperative and postoperative data will be transferred directly into the CRF from the national register for surgery for cancer of the esophagus and stomach (ENREV) and thereby made available for those involved in the follow-up process.

8. ON-STUDY ASSESSMENT, SAFETY AND FOLLOW-UP

8.1 Monitoring of treatmentPatients randomised to receive chemoradiation, should be reviewed weekly during their radiation treatment. Side effects related to therapy are to be assessed using the NCI CTCAE v 3.0 scale (see Appendix 1),nutritional support and local analgesics are to be administered if and when necessary.Patients receiving chemotherapy alone, should be monitored every 3rd week.

For all patients weekly full blood counts and serum creatinine level determinations should be made after chemotherapy until the neutrophile count is > 1.0 x 109/L and platelets are > 100 x 109/L.

8.2 Safety assessmentsAll Adverse Events (AEs) or Serious Adverse Events (SAEs) are recorded in appropriate CFR forms and be reported using NCI-CTCAE v3.0 scale. All SAEs are reported on specific SAE form and sent to the ROC (Telephone number: 0046 8 51772981 Fax number: 0046 85177544). The copy of SAE should even be faxed to the coordinating investigator (Lars Lundell, fax nr 0046 8 58586450) as soon as possible but no later than 1 week after the SAE. The site investigator at respective site is responsible to that it will be done according to GCP roules.

A Serious Adverse Event (SAE) is an event which Results in death Is life-threatening Is disabling Requires hospitalization, whether initial or prolonged, and does not include planned

hospitalization Requires intervention to prevent permanent impairment/damage

The term “life-threatening” in the definition of “serious” refers to an event in which the patientwas at risk of death at the time of the event; it does not refer to an event which hypotheticallymight have caused death had it been more severe.

8.3 Follow-up assessmentFollow-up examination for symptoms and signs of local recurrence, appearance of metastases and treatment complications should be made every 3 months during the first 2 years and thereafter twice yearly.Endoscopy and other investigations are reserved for specific problems Table 1. Summary of investigations and follow-up required for this study.

1) Baseline 2) DuringCT/RT

3) PostCT/RT

4) Post surgery

5) Follow up

Physical examination

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PS, Weight

Nutritional route, p.o., PEG, CF-tube

Endoscopy+ EUS

Endoscopy When

clinically indicated

Computerized Tomography of thorax & upper abdomen

When

clinically indicated

PET/CT (optional)

Spirometry, cardiac function test (exercise ECG surveilled bicycle test)

WBC, Hb, TpKCreatinine

(wkly)

Laparoscopy (Siewert type II)

Bronchoscopy (optional)

Barium oesophogram (optional)

Quality of Life assessment once yearly

6)

Audiogram

if PET/CT is performed, no additional CT should be done

1) Physical examination (including PS, weight) and blood counts 1 week before start of therapy, all other investigations within 1 month before randomization 2) weekly for patients in Arm A and every 3rd week for patients in Arm B3) 3 weeks after completion of either CHT or CHRT4) 1 months after surgery5) every 3rd month starting 1 month after surgery during first 2 years, thereafter twice yearly up to 5 years after completion of therapy6) at month 12, 24, 36, 48 and 60 after completion of therapy

9 QUALITY OF LIFE ASSESSMENT

Specific attention is to be directed towards quality of life, particularly swallowing function. To this end, simple quality of life assessment questionnaires using a self-assessment linear analogue scale to measure physical well-being, mood, pain, nausea and vomiting, appetite, swallowing and tiredness, will be administered once every 3 months and at the time of the

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first relapse (see Appendix 3). This will be completed with EORTC QLQ-C30 to which is added the OES 18 module.

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10 DEFINITIONS OF OUTCOMES

10 Complete Histological Response (pCR) as defined after serial sectioning of the operative specimen and tissue sections evaluated according to a predefined investigational protocol (see appendix)

11 Crude survival= Overall survival, is counted from time to randomization to death or end of follow-up

12 Time to recurrent disease. CT thorax and abdomen should be performed to document a clinical suspicion of recurrent disease. If possible recurrent disease should be verified histologically or by percutaneous puncture

13 Quality of LifeQuality of life will be measured pretreatment, after completion of neoadjuvant therapy and at yearly intervals during the follow up, using linear analogue self-assessment scales for physical well-being, mood, pain, nausea and vomiting, appetite, swallowing and tiredness (see Appendix 3). The EORTC QLQ-C30 will also be used.

13.1 SurgeryType of surgery will be recorded and also postoperative assessment. Residual disease will be recorded and also postoperative complications.

10.6 Toxicity/ChemoradiotherapyToxicity will be scored according to the NCI CTCAE v 3.0 scale (see Appendix 1).

11 STATISTICAL CONSIDERATIONS AND METHODOLOGY

11.1 Sample sizeThe sample size considerations are based on the primary endpoint CHR. The aim is to achieve an improvement in the CHR from 20 % to 35 % with a power of 80 % using a two-sided log-rank test with significance level 5 %. Then it is necessary to include 86 patients per arm: n= P1x(100-P1)+P2x(100-P2) x f(alfa,beta)

(P1-P2)2

To have 172 eligible patients for analyses, 8 more patients are included in the study, e.g. 90 patients/arm will be included, the total amount will be180 patients.

11.2 Analysis planThe main analyses will be based on the intention to treat principle. Demographic treatment and clinical data will be reported by treatment arm.

A multivariate Cox survival analysis will be carried out to study prognostic factors and to estimate the adjusted treatment difference.

Subgroup analyses are planned for stage groups since one could expect a larger treatment difference in higher stages.

Quality of life as measured by using linear analogue self-assessment scale, the

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EORTC QLQ-C30 and the special form for Esophagus cancer (form Q) will be accounted for by treatment arm and time after treatment (9).

Toxicity due to chemoradiotherapy, chemotherapy and postoperative complications will be presented by treatment arm.

11.3 Interim analyses, monitoring and stopping rulesToxicity of chemotherapy and radiation therapy will be evaluated and protocol modification considered if excessive toxicity is observed. Late toxicities will be evaluated by Quality of Life. A formal analysis for safety and toxicity will be undertaken after 25 % of the projected accrual has been done.

An interim analysis will be performed after 66 % of the events have been observed (i.e. number of patients completed the preoperative treatment protocol), with significance level of 1.5% for the analysis. In order to maintain an overall significance level of 5% the final analysis will then be performed on the level 4%. If at this analysis one of the arms is found to be significantly inferior in terms of safety, the data monitoring committee shall inform the study coordinators to assemble the principal investigators and advisory boards. They decide whether to stop the trial or not.

An independent Safety and Data Monitoring Committee will review toxicity and survival data. It will also make recommendations on changes to the protocol and/or stopping the trial. The committee will include four individuals representing the participating regions of the country

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12 QUALITY ASSURANCE AND MONITORING

Quality assurance and monitoring will be done according to GCP rules:

a. Treatment, main treatment according to randomization and later alternative therapy.

b. Follow-up, side effects, survival, cause of deaths.

c. Data reporting and management.Case Record Forms (CRFs) should be sent on a continuous basis to the Regional Oncology Centre in Stockholm.

d. All operative procedures and related postoperative courses are concomitantly recorded in the Swedish Quality Assurance Register

13. Time plan

First patient in Q1 2007. During Q1 2008 one patient per week will be enrolled. From Q2 2008, 2 patients will be enrolled per week. Based on these calculations the last patient in will be reached Q 4 2009.

14. PUBLICATION

Any publication based on the data from this study has to be divided into one of two categories but the following general principles will be followed. Authors of the publication are those who actively participate in processing of the study protocol, recruiting patients, compiling the results and putting together the article. However, all participating clinics will be named in a special appendix, and contacts identified. First the steering committee determines who will be actively participating in the analyses of data and writing of manuscripts of all scientific reports addressing the primary and secondary end-points, defined in the protocol from this study. The details of the decision making principles within the committee are detailed under 16. The steering committee decides who will be the 1st author of respective publications as well as the co-authors regarding publications referred to above. Co-authorship will be offered any institution where > 20 patients have been enrolled. The second principle is applicable to other subgroup studies and analyses which are referred to under 16.

15. ETHICAL ASPECTS

The investigator will ensure that this study is conducted in full conformance with principles of the”Declaration of Helsinki” (as amended in Tokyo, Venice and Hong-Kong), or with the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual.

16. Study coordination, innovative analyses

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A steering committee is established which represents all regions of the country. In a situation where other countries (regions) will enter the study, this committee will expand so that a balanced representation will be pursued. Provided that one center is unable to enroll patients to the level which motivates a position in the committee the continuation and representation of that centre in the committee will be decided upon at these regular meetings. The committee will take decisions with simple majority as the basic principle in case a consensus based decision can otherwise not be taken. The committee contains one surgeon and one oncologist from each region. The committee will meet at least once yearly after which a study report will be distributed to each participating center. The committee will ensure that all participants are encouraged to engage themselves in substudies as well as in translational research projects originating from the basic study population. If individual trialists or centers are interested in specific subanalyses or specific subgroup studies, the committee has to be addressed through a formal application and the committee will give approval with delineation of the details of the conduct of the study as well as the publication principles. In order to speed up the processing of similar applications the committee will be able to take decisions through mailing and/or telephone conferencing. Again simple majority principles will be applied. The committee will be competent to make decisions provided that half of the delegates are present or have given their written approval. If a delegate will not answer this will be interpreted in favor of the opinion of the majority of the present members of the committee.

Steering committee:Lars Lundell (chairman) Professor of Surgery, Department of Surgery, Gastrocentrum, Karolinska University Hospital, Huddinge, Stockholm SwedenSigne Friesland ,MD, PhD Department of Oncology, Karolinska. University hospital, Radiumhemmet, Stockholm, SwedenGunnar Adell,MD PhD , Department of Oncology, Karolinska. University hospital, Södersjukhuset, Stockholm, SwedenKarl Erik Johansson, MD PhD, Department of Surgery, University Hospital, Linköping, SwedenMaria Albertsson MD PhD Department of Oncology, University Hospital, Linköping, SwedenTorbjörn Myrnäs, MD, Department of Surgery, Norrlands University Hospital, Umeå, SwedenNielsHilmer Nielsen Department of Oncology, Norrlands University Hospital, Umeå, SwedenIngemar Näslund, MD, PhD, Department of Surgery, University Hospital, Örebro, SwedenTBA Department of Oncology, University Hospital, Örebro, SwedenMagnus Sundbom MD PhD, Ass. Professor, Department of Surgery, Akademiska sjukhuset, Uppsala, SwedenGunnar Wagenius, Simon Ekman MD PhD, Department of Oncology, Akademiska sjukhuset, Uppsala, SwedenErik Johnsson, MD, PhD. Department of Surgery, Sahlgrenska University HospitalHedda Haugen MD, Department of Oncology, Sahlgrenska University Hospital, Göteborg, SwedenUllevål University Hospital, Oslo:Egil Johnson, kirurgisk avdeling, Gunilla Frykholm, onkologisk avdelingSt Olav University Hospital, Trondheim Gjermund Johnsen, kirurgisk avdelingGunilla Frykholm, onkologisk avdelingUniversitetssykehuset i Nord-Norge, Tromsø Jørn Kjæve, kirurgisk avdelingLise Balteskard, onkologisk avdelingHaukeland Universitetssykehus, Bergen Asgaut Viste, Kirurgisk avdelning

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Rikshospitalet, Oslo, Stephan Stoldt, Kirurg Kliniken, Anne-Birgitte Jacobsen, onkologisk avdelning.

17. Investigators:

Coordinating investigator:Lars Lundell, Professor of Surgery, Department of Surgery, Gastrocentrum, Karolinska University Hospital, Huddinge, Stockholm SwedenInvestigators at participating sites:Gunnar Adell, MD, PhD, Department of Oncology, Södersjukhuset, Karolinska Universityhospital, Stockholm, SwedenGun Wichardt-Johansson,MD, Department of Oncology, Radiumhemmet, Karolinska.se niversityhospital, Stockholm, SwedenKarl Erik Johansson, MD PhD, Department of Surgery, University Hospital, Linköping, SwedenMaria Albertsson Department of Oncology, University Hospital, Linköping, SwedenTorbjörn Myrnäs, MD, Department of Surgery, Norrlands University Hospital, Umeå, SwedenNielsHilmer Nielsen Department of Oncology, Norrlands University Hospital, Umeå, SwedenIngemar Näslund, MD PhD, Department of Surgery, University Hospital, Örebro, SwedenMattias Elmlund, MD Department of Oncology, University Hospital, Örebro, SwedenGunnar Wagenius, Simon Ekman, Michael Bergvist MD PhD, Department of Oncology, Akademiska sjukhuset, Uppsala, SwedenErik Johnsson, MD, PhD. Department of Surgery, Sahlgrenska University HospitalHedda Haugen MD, Department of Oncology, Sahlgrenska University Hospital, Göteborg, SwedenUllevål University Hospital, Oslo:Egil Johnson, kirurgisk avdeling, Petra Weber Hauge, onkologisk avdeling, Gunilla Frykholm, onkologisk avdelingSt Olav University Hosptal, Trondheim Gjermund Johnsen, kirurgisk avdeling, Ingunn Hatlevoll, onkologisk avdeling, Gunilla Frykholm, onkologisk avdelingUniversitetssykehuset i Nord-Norge, Tromsø Jørn Kjæve, kirurgisk avdeling, Lise Balteskard, onkologisk avdelingHaukeland Universitetssykehus, Bergen Asgaut Viste, Kirurgisk avdelningRikshospitalet, Oslo, Stephan Stoldt, Kirurg Kliniken, Anne-Birgitte Jacobsen, onkologisk avdelning.

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18. REFERENCES

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