Trial on Radical Upfront Surgery in Advanced Ovarian Cancer

Both randomised groups are treated with surgery for complete resection following guideline
recommendations and including median laparotomy, complete adhesiolysis, hysterectomy,
bilateral salpingo-oophorectomy, omentectomy and (partial) resection of all affected organs
(e.g. small or large bowel, peritoneum, spleen, pancreas, peritoneum, urinary tract etc.) as
well as pelvic and paraaortic lymphadenectomy if indicated. Patients with significant pleural
effusion (>500 mL in the right chest or any pleural effusion in the left chest, assessed
either through ultrasound or CT scan) need to undergo video assisted thoracoscopy or open
assessment of the pleura prior or during debulking surgery to detect and if possible remove
intrathoracic disease.

Group 1: Primary debulking surgery Patients allocated to the primary debulking group undergo
surgery followed by 6 cycles of platinum and taxane based chemotherapy.

Recommended systemic treatment Group 1:

It is recommended to start systemic treatment after sufficient regeneration from surgery
[45], which will be ideally 2 to 6 weeks (but at the latest 8 weeks) after surgery. The
following treatments are recommended:

1. Participation in a prospective randomized trial, as long as participation is possible in
case of randomization in either arm of the current study

2. Carboplatin AUC 5-6 / paclitaxel 175 mg/m² q21 / bevacizumab 15mg/KG q21, 6 cycles
followed by bevacizumab maintenance therapy for a total of 15 months or until disease
progression.

3. Carboplatin AUC 5-6 / paclitaxel 175 mg/m² q21, 6 cycles. Substitution of paclitaxel by
docetaxel (75mg/m²) in cases of contraindications to paclitaxel is possible.
Maintenance/consolidation therapy inside prospective trials or according to national
standard treatments is allowed. Additional treatment outside prospective studies is not
recommended.

4. Carboplatin AUC 5 - 6, q21 , 6 cycles in the case of contraindications of combination
chemotherapy

Group 2: Interval debulking surgery Patients allocated to the interval debulking surgery
group undergo biopsy to confirm ovarian cancer and then 3 cycles of neoadjuvant preoperative
platinum and taxane based chemotherapy. Then interval debulking surgery is performed followed
by 3 cycles of postoperative platinum and taxane based chemotherapy

Recommended systemic treatment Group 2:

It is recommended to start systemic treatment as soon as possible after biopsy confirmation
of ovarian cancer.

The following treatments are recommended for neoadjuvant chemotherapy:

1. Participation in a prospective randomized trial, as long as participation is possible in
case of randomization in either arm of the current study

2. Carboplatin AUC5-6 / paclitaxel 175 mg/m² q21, 3 cycles. Substitution of paclitaxel by
docetaxel (75mg/m²) in cases of contraindications to paclitaxel is possible.

3. Carboplatin AUC 5-6, q21 , 3 cycles in the case of contraindications of combination
chemotherapy

It is recommended to start postoperative chemotherapy after sufficient regeneration from
interval debulking surgery, which will be ideally 2 to 6 weeks after surgery. The following
treatments are recommended:

1. Participation in a prospective randomized trial, as long as participation is possible in
case of randomization in either arm of the current study

2. Carboplatin AUC 5-6 / paclitaxel 175 mg/m² q21 / bevacizumab 15mg/KG q21, 3 cycles
followed by bevacizumab maintenance therapy for a total of 15 months or until disease
progression.

3. Carboplatin AUC5-6 / paclitaxel 175 mg/m² q21, 3 cycles. Substitution of paclitaxel by
docetaxel (75mg/m²) in cases of contraindications to paclitaxel is possible.
Maintenance/consolidation therapy inside prospective trials or according to national
standard treatments is allowed. Additional treatment outside prospective studies is not
recommended.

4. Carboplatin AUC 5-6, q21 , 3 cycles in the case of contraindications of combination
chemotherapy

Inclusion Criteria:

- suspected or histologically confirmed, newly diagnosed invasive epithelial ovarian
cancer FIGO stage IIIB-IV (IV only if resectable metastasis)

- Females aged ≥ 18 years

- Patients who have given their written informed consent

- Good performance status (ECOG 0/1)

- Good ASA score (1/2)

- Preoperative CA 125/CEA ratio ≥ 25 (if CA-125 is elevated)*

- If <25 and/or biopsy with non-serous, non-endometroid histology,
esophago-gastro-duodenoscopy (EGD) and colonoscopy mandatory to exclude
gastrointestinal primary cancer

- Assessment of an experienced surgeon, that based on all available information, the
patient can undergo the procedure and the tumor can potentially be completely resected

- Adequate bone marrow function: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. This ANC
cannot have been induced or supported by granulocyte colony stimulating factors.

- Platelet count ≥ 100 x 109/L.

- Renal function: Serum-Creatinine ≤ 1.5 x institutional upper limit normal (ULN).

- Hepatic function:

- Bilirubin ≤ 1.5 x ULN.

- SGOT ≤ 3 x ULN

- Alkaline phosphatase ≤ 2.5 x ULN.

- Neurologic function: Neuropathy (sensory and motor) less than or equal to CTCAE Grade
1.

Exclusion Criteria:

- Non epithelial ovarian malignancies and borderline tumors

- Secondary invasive neoplasms in the last 5 years (except synchronal endometrial
carcinoma FIGO IA G1/2, non melanoma skin cancer, breast cancer T1 N0 M0 G1/2) or with
any signs of relapse or activity.

- Recurrent ovarian cancer

- Prior chemotherapy for ovarian cancer or abdominal/pelvic radiotherapy

- Unresectable parenchymal lung metastasis, liver metastasis or bulky lymph-nodes in the
mediastinum in CT chest and abdomen/pelvis

- Clinical relevant dysfunctions of blood clotting (including drug induced)

- Any significant medical reasons, age or performance status that will not allow to
perform the study procedures (estimation of investigator)

- Pregnancy

- Dementia or significantly altered mental status that would prohibit the understanding
and giving of informed consent

- Any reasons interfering with regular follow-up