Stage III / IV epithelial ovarian cancer with macroscopic residual disease after 1st line Chemotherapy: a multicentric prospective randomised study comparing loco regional approach + systemic chemotherapy vs systemic chemotherapy alone
(CIPOV)

Progetto: SITILO-ONLUS CNR-MIUR
Responsibles: Carlo Riccardo Rossi and Francesco Raspagliesi
Coordinator: Marcello Deraco
Data manager: Shigeki Kusamura
Statistician: Luigi Mariani
Randomization: Martina Adorni (02.23902910)

Proponent: National Cancer Institute of Milan
Italy, 2002

Index
SUMMARY
1 INTRODUCTION
1.1. Clinical scenario
1.2. Primary cytoreductive surgery (CRS): the limits of radicality and biological aggressiveness
1.3. Preoperative evaluation of cytoreducible disease
1.4. First line chemotherapy
1.5. Second line therapies
1.6. Secondary CRS
1.7. LRT for peritoneal surface malignancies
1.7.1. Intraperitoneal chemotherapy under normothermia
1.7.2. The rationale of IPHP
1.7.3. Technical variations of LRT
1.8. LRT for ovarian cancer
2. OBJECTIVES
2.1. Primary endpoint
2.2. The secondary endpoints
3. BRIEF DESCRIPTION OF STUDY
3.1 Study design
3.2 Variables definition
Variables related to the patient
Variables related to the tumour
Variables related to the primary therapy
Variables related to the LRT
Variables related to complications associated with LRT
Variables related to follow-up and response to therapy
4. ELIGIBILITY CRITERIA
5. TREATMENT ASSIGNMENT
6. TREATMENT DESCRIPTION
6.1. Primary chemotherapy
6.2. LRT
6.2.1 Secondary CRS
6.2.1.1 Preparation
6.2.1.2 Laser-mode electro surgery
6.2.1.3 Surgical Steps
6.2.2 Intraperitoneal hyperthermic perfusion (IPHP)
6.2.2.1 The device
6.2.2.2 The priming
6.2.2.3 The drugs schedule
6.2.2.4 Modalities of execution: open and closed abdominal techniques
6.2.2.5 Precautions and monitoring of cardiovascular, temperature and laboratory parameters
6.2.3 Immediate post operative period
6.3 Second line chemotherapy
7. EVALUATION CRITERIA
8. FOLLOW-UP
9. STATISTICAL ANALYSIS
9.1 Sample size calculation
9.2 Survival analysis
9.3 Treatment related morbidity, toxicity and mortality.
9.4 Comparisons of grade III/IV toxicity between the arms
10. ORGANIZATIONAL ASPECTS
10.1 Study chairman
10.2. Scientific and Ethical committee (SEC)
10.3. Executive subcommittee
10.4. Advisory review subcommittee
10.5. Local coordination
10.6. Randomisation and Data processing committee (RDPC)
10.7. Treatment effect monitoring committee (TEMC)
11. FORMS
12. ETHICAL ASPECTS
13. REFERENCES
APPENDIX: TABLES AND FIGURES
Table 1: Effect of salvage therapies as a function of first-line platinum response
Table 2: Survival after secondary cytoreduction at second-look operation
Table 3: Pharmacokinetic profile of some chemotherapies when delivered intraperitoneally associated with hyperthermia
Table 4: Response rate of intraperitoneal chemotherapy in ovarian cancer according to the drug
Table 5: Ovarian epithelial cancer histologic classifications (WHO)
Table 7: Evaluation of treatment response
Table 8: Treatment related morbidity and mortality classification
Table 9: Performance status score
Table 10: Preoperative abdominopelvic CT scan
criteria for optimal cytoreduction
Figure 1: Flowchart of eligible patients
Figure 3: Diagram of completeness of cytoreduction according to the diameter of largest residual disease [168]

SUMMARY
Purpose: Randomized multicentric phase III trial to study the effectiveness of loco regional therapy (LRT) followed by second line systemic chemotherapy as compared to second line chemotherapy only in patients affected by stage III/IV epithelial ovarian cancer with partial response to first line chemotherapy.
Primary endpoint: overall and progression free survivals.
Secondary endopoints: 1) determine complications related to the LRT; 2) determine risk factors for LRT related morbidity; 3) compare toxicity rates between the treatment arms; 4) evaluate the extent to which the performance of LRT increases toxicities rates of subsequent second line chemotherapy; 4) identify prognostic and predictive factors for response to therapy in the experimental arm.
Protocol outline: this is a randomized, multicentric study. Patients will be stratified according to participating centre. Patients with epithelial ovarian cancer stage III/IV submitted to surgical staging and 6 courses of first line chemotherapy with platinum based chemotherapy will be evaluated with respect treatment response by clinical examination, ca125 and abdominopelvic CT scan. Those with persistent but clinically resectable disease will be randomly allocated to one of treatment groups:
Study group: LRT which consists of secondary cytoreduction followed by intraperitoneal hyperthermic perfusion (IPHP) and second line chemotherapy.
Control group: second line chemotherapy.
Patients will be followed every 3 months for 2 years, and then every 6 months for 3 years or until death.
Eligibility: 1) histological diagnosis of stage III/IV epithelial invasive ovarian carcinoma or carcinoma of fallopian tube; 2) age less than 75 years; 3) patients who were submitted to primary surgical staging and front line primary chemotherapy; 4) partial response to first line chemotherapy with persistent disease at the end of adjuvant treatment; 5) leukocyte count >3500/mm3, neutrophyl count >1500/mm3, and platelet count > 100.000/mm3; 6) adequate renal function with serum creatinine level < 1.5 mg/dl; 7) performance status (ECOG) 0, 1 or 2; 9) Informed consent from the patients; 8) cytoreducible disease evaluated by preoperative abdominopelvic CT scan.
Statistical considerations: the expected absolute improvement in survival is 20% with a 40% expected survival at 5 year in the study group vs 20% in the control group. Sample size for each group is 100. Calculations were performed assuming 0.05 significance level (one-tailed test), a 90% power, 3 years for patients accrual followed by 2 additional years period of follow-up.

1 INTRODUCTION
1.1. Clinical scenario
Ovarian cancer remains the most lethal of all gynaecological malignancies [1], being responsible for about 50% of all deaths for female genital tract cancer [2]. It ranks high as a cause of female deaths in Canada, New Zealand, Israel and Northern Europe. Tumors of epithelial origin account for 80-90% of ovarian malignancies and approximately 75% of cases are diagnosed at advanced stage III or IV [2,3,4].
Prognosis in ovarian cancer is influenced by several factors, but multivariate analyses suggest that the most important favourable factors include younger age, good performance status, cell type other than mucinous and clear cell, lower stage, well differentiated tumour, smaller disease volume prior to any surgical debulking, absence of ascites, and smaller residual tumour following primary CRS [5-9].
The conventional clinical approach for advanced ovarian cancer is based on debulking surgery followed by systemic chemotherapy. Clinical studies have shown that cisplatin or taxol-based first-line chemotherapy achieves the highest response rates (around 70-80%), with a high proportion of complete responses, in patients with epithelial ovarian cancers [10,11]. However, negative second-look laparotomy, which is attainable in only 20-40% of cases [12-18], does not necessarily mean the patient is cured. Up to 47% of these patients relapse within 5 years; disease-free survival does not generally exceed 18 months, and 5-year survival ranges from 42 to 80% [19-21].
1.2. Primary cytoreductive surgery (CRS): the limits of radicality and biological aggressiveness
Over the past 25 years it has become largely established, through retrospective analysis, that optimal resection of metastatic epithelial ovarian cancer has a favourable impact on survival of patients with advanced staged disease [8,22-24]. The most recent report supporting the importance of CRS in the treatment of ovarian cancer was published by Bristow et al. They evaluated retrospectively the relative effect of percent maximal CRS and other prognostic variables on survival among 81 cohorts of patients (total of 6,885) with stage III/IV ovarian carcinoma, treated with cisplatin based chemotherapy. Linear regression models, with weighted correlation calculations, were used to assess the effects on log median survival time of the proportion of each cohort undergoing maximal cytoreduction, dose-intensity of the platinum compound administered, proportion of patients with stage IV, median age, and year of publication. A statistical significant correlation between percent of maximal cytoreduction and log median survival time emerged and this link remained significant after controlling for other variables (p<.001). The conclusion was that maximal cytoreduction was one of the most powerful determinants of cohort survival among patients with advanced ovarian cancer.
Moreover, in the single prospective trial of interval debulking conducted by EORTC, a 33% reduction in mortality was reported in patients submitted to cytoreduction, even though they were considered unresectable prior to chemotherapy. Patients were randomized after undergoing sub optimal debulking surgery and 3 courses of chemotherapy, to interval debulking followed by further 3 courses of chemotherapy versus 3 cycles of chemotherapy only. The results demonstrated a prolongation in both progression free survival and the median survival in the interval-debulking arm (5 and 6 months respectively). Multivariate analysis revealed interval debulking as independent prognostic factor [25].
However, some authors have challenged the independent influence of cytoreduction on final outcome with regards the inherent biological aggressiveness of tumour. Some argue that complete cytoreduction in most cases is attained thanks to relatively small tumour burdens and presumed diminished biological aggressiveness of neoplasms rather than to maximal surgical effort. In other words, it has been suggested that survival benefit reported to be from surgery could come from different tumour biology [8,26]. Extending this hypothesis to clinical ground one could devise that not only the residual tumour after the surgery but also the initial tumour mass influence the prognosis.
Data from literature is contradictory in this sense. Some studies have shown differences in survival between patients who are already optimal at the beginning of operation and the ones who are optimal as a result of the first operation [8,27]. Hoskin et al, in order to determine the role of CRS in the survival, performed an additional review of the records of patients who participated in the Protocol 52 of Gynecologic Oncology Group. The original scope of this study was to perform a randomized comparison of cisplatin and cyclophosphamide with or without doxorubicin in “optimal” Stage III epithelial ovarian cancer. They noted that the volume of initial extrapelvic disease remained a significant prognostic factor, after multivariate analysis, when gross disease was present in the omentum and in other extrapelvic sites. It was concluded that the initial CRS would not allow a patient presenting with large volume ovarian cancer to have the same chance for survival as a patient found to have small-volume disease [8]. In the same way, Hacker et al reported that patients with metastatic disease >10 cm in diameter had a worse prognosis than patients with small initial tumour burden, regardless of the extent of cytoreduction [23].
On the other hand, other authors have demonstrated the opposite. Le et al examined the role of CRS in the management of stage II and III epithelial ovarian cancer patients. Five year survival rates for patients with initial microscopic disease (group 1) and patients with large volume of disease at the time of exploration and tumour reduced to microscopic residuals (group 2), were 62% and 56%, respectively. This difference was not statistically significant. In addition, the groups were equivalents regarding known prognostic factors [28].
Critics of cytoreduction in ovarian cancer claim that tumour debulking can only benefit a small proportion of patients, since the majority of them are rendered with sub optimal residual disease. In fact, the rate of optimal cytoreduction has ranged from 25% to 40%, according to current literature [29-37]. Thus, ultra radical procedure has been proposed by some surgeons as a method to increase the rate of optimal cytoreduction, in order to enhance the survival benefit resultant from surgery. With technological advances such as the ultrasonic surgical aspirator and argon beam coagulator, and methods such as peritoneal stripping, splenectomy, and en bloc resections of the ovaries, and sigmoid colon, optimal cytoreduction rates have been reported as high as 91% [26,38-44]. There is no consensus whether the level of intervention can be translated to survival benefit, nor that it necessarily results in increased risk of morbidity. Potter et al retrospectively analysed 302 patients with epithelial ovarian malignancies submitted to extensive debulkings. It was shown that patients who underwent extensive procedure including bowel resection and peritoneal stripping did not fare as well as those who did not undergo these procedures and yet had residual disease remaining [44].
In contrast, Eisenkop et al evaluated 213 stage III ovarian cancer patients submitted to cytoreduction using procedures such as extrapelvic bowel resection, diaphragm stripping, full-thickness diaphragm resection, modified posterior pelvic exenteration, peritoneal implant ablation and/or aspiration, and excision of grossly involved retroperitoneal lymph nodes [45]. They evaluated if the necessity to employ those procedures to attain complete cytoreduction correlates with biologic aggressiveness of tumour and independently influences survival. They verified that survival was independently influenced only by the extent of peritoneal carcinomatosis that required removal and that other procedures as well as type of adjuvant chemotherapy did not impact the final outcome. The authors concluded that the need to resect a widespread peritoneal carcinomatosis correlates with biological aggressiveness and diminished survival, but not significantly enough to justify abbreviation of the operative effort.

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