6.2.2.4 Modalities of execution: open and closed abdominal techniques
In the closed technique the skin of abdominal wall will be temporary closed with a running suture and the Tenckhoff catheters connected to the circuit, in order to initiate the IPHP [175]. In the open modality, also known as Coliseum technique [97], the abdomen is covered with a plastic sheet and drug vapour is evacuated to protect the operating room personnel.
The catheters will be connected to the extra-corporeal circuit and the preheated polysaline perfusate containing Cisplatin and Adriamycin will be instilled in the peritoneal cavity using the heart-lung pump at a mean flow of 600 - 1000 ml/min for 60 minutes. In order to achieve intrabdominal temperature of 42.5?C, we will maintain the inflow temperature of approximately 44?C. Throughout the perfusion, if the opened technique is adopted, the surgeon will continuously manipulate the viscera to distribute both heat and chemotherapy. Following perfusion, the perfusate will be quickly drained and the abdomen closed after careful intraperitoneal inspection.
6.2.2.5 Precautions and monitoring of cardiovascular, temperature and laboratory parameters
The main intraoperatory potential complication is the generalized hyperthermia that can be avoided submitting the patient to hypothermia. This can be obtained by the application of cooling packages in the flexing faces of joints and in the head. The bladder will be instilled with cooling physiologic solution during hyperthermia to avoid mucosal damage. The optimal temperature expected for the patient before the beginning of IPHP is 32-330C; and this can be achieved passively just maintaining the abdomen opened during the surgery, without any heating. During IPHP, continuous peritoneal temperature monitoring will be performed by 6 thermocouples placed in the abdominal cavity, peritoneal site and rhino pharynx for core temperature. The cardiovascular parameters such as central venous pressure mean arterial pressure will also be continuously monitored. In the same way, the haemoglobin level, coagulation system parameters and arterial partial oxygen and carbonic gases pressures as well as arterial pH will be determined every 30 minutes.
6.2.3 Immediate post operative period
In the postoperative period, patients submitted to LRT will be assisted in an Intensive Care Unit for at least 72 hours. Based on reported results [176-178] which showed significant changes in proteins levels, due to haemodilution induced by the perfusion, all patients will receive preventive treatment with 10-20 g/day of albumin (D0 - D+7) and 250 ml of fresh plasma (D0 - D+3). In order to prevent possible renal failure due to the high dose administration of CDDP patients will be treated with dopamine (3mcg/kg/min) for 72 hours postoperatively and almost 3,500 ml/day of polysaline solution (D0 - D+7). They will be evaluated with laboratory exams to assess haematological, renal and hepatic function every 24 hours in the first 7 days; every 3 days in the second week; and every week until the fourth week.
6.3 Second line chemotherapy
Decision regarding the second line chemotherapy after the random treatment allocation will be taken at the discretion of each participating centre, based on clinical profile of the patient: age, performance status, type of first line chemotherapy, response to first line chemotherapy, development of toxicity to previous treatment.
7. EVALUATION CRITERIA
While on primary systemic chemotherapy, patients will be monitored with the following schedule: 1) clinical examination comprising gynecologic and general physical examination associated with measurement of serum Ca 125 every day 1 of each cycle; 2) complete blood cell counts weekly for the first two cycles and every day 1 of each cycle, thereafter; 3) abdominal CT scan and/or sonography, chest radiography, creatinine clearance every 3 cycles. Evaluation of toxicity will be performed every cycle (see Appendix, Table 6). Every 3 cycles a formal assessment will be performed, and patients will be categorized with regard to their current disease status. By use of clinical and/or radiologic and/or laboratory (Ca 125), the patients will be assigned to one of four subgroups (see Appendix, Table 7): a) complete clinical response (cCR), partial clinical response (cPR), clinically with stable disease (cSD), clinically disease progression (cDP).
The CT scan will be performed using a third-generation facility, and each examination is expected to last approximately 30 minutes. Patients will receive an oral dose of approximately 750 ml of 2% Gastrographin (to all patients) plus intravenous administration of approximately 200ml of a noninonic contrast medium, such as iomexol 350 or iopamidol 370 (to all non-iodine-allergic patients). Multiple sections, at 8 mm intervals from the diaphragmatic dome to the lower pubic symphysis, will be examined. In selected cases, a double contrast visualization for the sigmoid colon will be performed. 2 independent observers will perform the image interpretation. In case of discrepant result the 2 observers will re-evaluate the case in conjunction, until consensus is reached.
After the randomisation, during the second line chemotherapy, the assessment of treatment response and toxicity will be performed with the same schedule employed during the first line chemotherapy.
8. FOLLOW-UP
Physical examination comprising gynecologic and general physical examination associated with measurement of serum Ca 125 will be performed every 3 months during the first 2 years after the end of second line therapy and every 6 months until the 5th year; 2) abdominopelvic CT scan and sonography, chest radiography will be performed every 6 months up to the 5th year. For assessment of overall survival the unfavorable event will be death of any cause while for assessment of progression free survival the unfavorable event will be progression of disease as defined in section 3.2.
9. STATISTICAL ANALYSIS
9.1 Sample size calculation
It has been calculated that a total of 100 assessable patients per arm would permit the detection of a 20% improvement in the 5 year overall survival (from an anticipated 20% baseline survival to 40%) of patients in the LRT arm at a one-sided significance level of 5% and with a power of 90%. These calculations will be based on an accrual time of 36 months, followed by 24 months after the trial is closed to patient entry.
9.2 Survival analysis
Overall and progression free survival will be measured from the date of randomisation. The duration of survival will be measured up to the date of death or the date of last contact if the patient is alive at the time of last contact. The duration of progression-free survival will be the minimal amount of time until the onset of clinical progression or death. All eligible cases will be included in the analysis of overall and progression-free survivals. All causes of death will be included to calculate survival, and the estimation of the cumulative proportion surviving will be based on Kaplan-Meier procedures [179]. The analysis of overall and progression free survival will be performed based on the intent to treat policy (All randomly assigned patients will be analysed according to the arm to which they will be assigned).
The independence of progression-free survival, overall survival, and randomised treatment will be assessed with a one tailed unstratified log-rank test [180], To adjust for confounding covariates, we will also estimate the treatment effect by Cox’s proportional hazard regression model [181] and check the proportional hazards assumptions [182].
9.3 Treatment related morbidity, toxicity and mortality.
For analysis of LRT related morbidity the univariate analysis of each clinical variable will be performed to determine the probability of association with each morbidity variable. Continuous variables will be analysed by using an unpaired Student’s t-test. Fisher’s exact test wil be used to analyse categorical variables. A logistic regression model will be used in a multivariate analysis to determine a correlation between clinical variables and morbidity variables.
9.4 Comparisons of grade III/IV toxicity between the arms
Comparisons of the rates of grade III and IV toxicity will be carried out between the 2 arms, during the second line therapy. Comparisons of proportions between the 2 arms will be done by use of a two sided chi-square test or a two sided Fisher’s exact test if the number of expected patients in a given category is less than five [183]. The two-sided Kruskal-Wallis test will be used to compare the treatment effects of continuous variables [184].
All statistical analysis will be conducted by using SAS for Windows, Version 8.0 (SAS Institute, Cary, NC).
10. ORGANIZATIONAL ASPECTS
10.1 Study chairman
1. Serves as senior executive officer of the investigative group;
2. Chairs the Scientific and Ethical committee;
3. Serves as principal spokesman for the study;
4. Maintain communications within the study with the others committees, participating centres and with the sponsor.
10.2. Scientific and Ethical committee (SEC)
1. assumes responsibility for general design and conduct of the trial, including preparation of essential study documents, such as manual of operations, data forms, treatment protocol;
2. visits participating centers to identify and correct remediable deficiencies;
3. considers and adopts changes in study procedures as necessary and desirable during the course of the trial;
4. appoints and disband subcommittees needed for execution of the trial;
5. makes decision on resource allocations and on priorities for meeting competing demands in the trial;
6. reviews progress of study in achieving its main goal and take steps required to enhance likelihood of success in achieving them;
7. has two main subcommittees: Executive subcommittee (ESC) and Advisory review subcommittee (ARSC);
8. review and implement recommendations from the Advisory review subcommittee (ARSC) and Treatment effect monitoring committee (TEMC) for treatment protocol change, such as termination of treatment because of lack of efficacy and/or unacceptable and unexpected adverse effects;
9. review and react to other general advice or recommendations from ARSC and TEMC.
10.3. Executive subcommittee
1. acts as the administrative and executive arm of the SEC;
2. makes decisions on behalf of the SEC on day-to -day operational issues requiring immediate action;
3. assigns priorities for activities in the trial, consistent with dictates of the SEC;
4. perform executive functions for the trial, including scheduling meetings, preparations of SEC and other meeting agendas;
5. coordinate preparation of progress reports requested by the sponsoring agency in conjunction with funding renewal requests and as needed at other times;
6. perform other functions assigned by the SEC.
10.4. Advisory review subcommittee
1. Advises the SEC and sponsor on important policy issues related to:
1a. The performance of the trial and whether funding for it should be continued;
1b. The patients recruitment experience and whether it is necessary additional participating centres;
1c. Termination of support of centres when warranted because of poor performance or for other reasons;
1d. Treatment protocol changes, such as termination of treatment because of lack of efficacy and/or unacceptable morbidity, mortality or toxicity;
2. Reviews performance monitoring reports prepared by the TEMC to detect deficiencies in the data collection or intake processes and recommend corrective action when necessary;
3. Assume responsibility for external review of the RDPC and other resource centres in the trial.
10.5. Local coordination
Each participating centre will have a local coordinator which the following responsibilities:
1 To administer the study in his respective centre according to the guidelines established in the protocol;
2 To supply the forms to RDPC;
3 Preliminary quality control of data
4 To maintain a constant communication with RDPC to clarify every problem and doubts emerged in the course of protocol implementation.
10.6. Randomisation and Data processing committee (RDPC)
1 Verifies the eligibility of candidates to the study;
2 Registers and perform randomisation of eligible patients;
3 Reviews data collection, practices and procedures;
4 Supplies the ESC with the necessary data for the preparation of progress report;
10.7. Treatment effect monitoring committee (TEMC)
1 Directs or carries out data analyses needed for assessing treatment effects during the trial;
2 Reviews interim reports prepared by RDPC for evidence of adverse or beneficial treatment effects;
3 Recommends changes in the treatment protocol to the SEC, when it is judged to be necessary, as a function of eventual unacceptable morbidity/mortality/toxicity emerged in one of treatments arms;
4 Provides advice to the SEC on operational procedures affecting the quality of the trial;
The chairman of the study, in conjunction with the Scientific and Ethical committee (SEC) provides the general leadership for the trial, with the support of administrative structure offered by Executive subcommittee (ESC).
The Scientific and Ethical committee (SEC) has the responsibility to create or dissolve any additional committees during the protocol implementation, as it was outlined above. No more committees than necessary should structured and for each new committee created a chairman and vice-chairman should be designated. A written charge for every committee outlining the following items will be provided:
• A strictly defined function. The creation of committees with overlapping domains of responsibility should be avoided as they are at greatest risk of having obscure lines of authority; essential activities must be carefully separated in order to avoid duplication of effort and internal squabbles;
• Specification concerning the decision-making authority of committee. Here is worth pointing that any delegation of responsibility should be done with delegation of corresponding authority. Otherwise ambiguities in the decision-making structure in the group may occur due to the failure of the leaders to empower specific members of the group with the authority needed to perform designated tasks;
• Specification concerning the membership criteria;
• An individual designated to be the secretary of committee;
• Specification about the methods to be used for rotation of members (if any), for filling vacancies, and for replacing non-functioning members;
• Specifications about conditions that disqualify individuals from filling a committee position, including conflicts of interest;
• Specifications about voting rules (quorum requirement for conduct of committee business, Identifications of voting and nonvoting positions);
• An up-to-date list of committee members, their respective terms of office, and voting rights;
• Relationship of one committees to another and the communication structure for committee-committee interactions;
• Periodic reviews in which committee charges are updated and committee-to-committee communication structures revised, where appropriate;
• Criteria for dissolution of committee.
11. FORMS
12. ETHICAL ASPECTS
The Scientific and Ethical committee (SEC) will have to assure the respect to the principles stated in Helsinki declaration [185], during the whole period of study implementation. Every investigator involved in the treatment administration will be required to make certain that a patient about to enter the trial fully understands the nature of the risks and benefits that may accrue from the treatments options to be offered. The consent process will comprise two stages separated by a period of one month (between the 6th cycle of first line chemotherapy and subsequent visit). The first stage will be designed to acquaint the patient with the study and its requirements. It will involve a conversation with the patient in a setting that is conducive to a two-way exchange. The information imparted will be supplemented with a written material, including a copy of the informed consent for the patient to take home to review at his leisure. The second stage will be used to answer questions raised by the patient and to review what would be required of her if she agrees to enrol. The informed consent will have to be signed at the end of this stage otherwise she will be judged ineligible for the trial (see Appendix, Informed consent).

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