Clinical trial NCT03693248: Reduction Of Cycles of neOadjuvant Chemotherapy for Advanced Epithelial Ovarian, Fallopian and Primary Peritoneal Cancer
Official title: Multi-center, Randomized Controlled, Phase III Trials to Evaluate the Safety and Effectiveness After Cycles Reduction of Neoadjuvant Chemotherapy for Advanced Epithelial Ovarian, Fallopian and Primary Peritoneal Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Ovarian Cancer Stage IIIC
Ovarian Cancer Stage IV
Fallopian Tube Cancer
Peritoneal Cancer
Keywords: advanced ovarian cancer
advanced fallopian cancer
advanced peritoneal cancer
neoadjuvant chemotherapy
cycles of chemotherapy
survival
Lead sponsor: Seoul National University Hospital
Sponsor class: OTHER
First posted: 2018-10-02
Enrollment: 298
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Comparison of clinical outcomes between two and three cycles of neoadjuvant chemotherapy followed by interval debulking surgery.
Primary purpose: TREATMENT

Brief summary: Te hypothesized that two cycles of neoadjuvant chemotherapy followed by interval debulking surgery would improve survival in advanced epithelial ovarian, fallopian, and primary peritoneal cancer because reduction of one cycle of chemotherapy can lead to the removal of more tumor burden, compared with three cycles of neoadjuvant chemotherapy.

So the investigators aim to compare survival, rate of successful optimal cytoreductive surgery, post-operative complications, and quality of life between two and three cycles of neoadjuvant chemotherapy followed by interval debulking surgery for advanced epithelial ovarian, fallopian, and primary peritoneal cancer.

Detailed description: Primary debulking surgery (PDS) followed by adjuvant chemotherapy is the standard treatment for advanced epithelial ovarian, fallopian and primary peritoneal cancer. However, three or four cycles of neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) has been introduced in clinical setting because four randomized controlled trials related have shown a lower rate of complications in NAC followed by IDS despite the similar efficacy between PDS and NAC followed by IDS in advanced epithelial ovarian, fallopian and primary peritoneal cancers. However, these trials have some limitations that the rate of optimal cytoreduction defined as the size of residual tumor \<1 cm was about 40%, which was a disappointed result not showing the surgical effect improving survival. Nevertheless, more treatment strategies using NAC followed by IDS should be investigated because NAC followed by IDS has been already known as another standard treatment due to the safety.

A recent meta-analysis has reported that reduction of one cycle of neoadjuvant chemotherapy may increase overall survival of 4.1 months because it can induce surgical resection of more visible tumors with drug-resistant. Moreover, a related clinical trial has shown that hyperthermic intraperitoneal chemotherapy (HIPEC) may increase survival in patients with advanced ovarian cancer who received three cycles of neoadjuvant chemotherapy because HIPEC can kill drug-resistant invisible tumor cells which were not resected during IDS. Thus, the investigators designed a phase 3, multicenter, randomized controlled trial for comparing survival, clinical outcomes and quality of life between two and three cycles of NAC followed by IDS, and thereby will investigate the efficacy and safety of reduction of one cycle of NAC.

Eligibility criteria: Inclusion Criteria:

1. Age: 20-80 years old
2. Advanced epithelial ovarian, fallopian or primary peritoneal cancer diagnosed with the following methods

   * Histologic confirmation by diagnostic laparoscopic or laparotomy ② Histologic malignancy originated from female genital tract on fine needle aspiration if histological confirmation is difficult or cytologic confirmation of adenocarcinoma in ascites if fine needle aspiration is difficult, meeting the following criteria

     * Existence of the pelvic or ovarian mass
     * Identification of tumor \>2 cm beyond the pelvis on CT, malignant pleural effusion by thoracentesis, extraperitoneal lymph node metastasis (cardio-phrenic, internal mammary, mediastinal, para-tracheal, supraclavicular lymph nodes or inguinal lymph nodes)
     * Cancer antigen 125 (CA-125, kU/L)/carcinoembryonic antigen (CEA, ng/ml) \>25
     * if CA-125 (kU/L)/CEA (ng/ml) is 25 or less, no primary lesion on colonoscopy, gastroscopy and mammography within six weeks before randomization.
3. International Federation of Gynecology and Obstetrics (FIGO) stage IIIC to IVB disease
4. World Health Organization performance status 0-2
5. The following criteria should be met if synchronous or metachronous tumors exists.

   ① Complete remission of metachronous malignancy for at least 5 years

   ② Follicular or papillary thyroid cancer treated completely with only surgery as a synchronous tumor

   ③ Early gastric or colon cancer treated completely with only endoscopic mucosal resection as a synchronous tumor
6. Normal hematologic, renal and liver function with the following criteria White blood cell (WBC) ≥3,000/ul Absolute neutrophil count (ANC) ≥1,500/ul Platelet ≥100×103/ul Aspartate aminotransferase (AST) ≤100 IU/L Alanine aminotransferase (ALT) ≤100 IU/L Serum total bilirubin ≤1.5 mg/dL Serum creatinine ≤1.5 mg/dL
7. Absence of psychological, and socioeconomic limitations affecting participation to this trial
8. Informed consent

Exclusion Criteria:

1. Diagnosis of metachronous malignancy within five years before enrollment
2. Synchronous tumors except follicular or papillary thyroid cancer treated completely with only surgery and early gastric or colon cancer treated completely with only endoscopic mucosal resection
3. Carcinoma in situ, non-epithelial, or borderline tumor in ovary, fallopian tube, and peritoneum
4. Pregnancy
5. Medical conditions (hypertension, diabetes mellitus, infectious or cardiac disease etc.) influencing on survival
6. Clinical evidence of brain or leptomeningeal metastasis, bone metastasis
7. Other treatments affecting clinical outcomes during participation to this trial (hyperthermic intraperitoneal chemotherapy, onco-thermia, herbal medicine, etc.)
8. No informed consent

Primary outcomes:
measure: Progression free survival
timeFrame: From date of randomization until the date of first documented progression or date of death (by any cause, in the absence of disease progression) whichever came first, assessed up to 60 months
Secondary outcomes:
measure: Overall survival
timeFrame: From the date of randomization until death due to any cause, assessed up to 60 months
measure: Time to progression
timeFrame: From date of randomization until the date of first documented progression in the absence of death by any cause, assessed up to 60 months
measure: Tumor response 1
timeFrame: 3 weeks after completion of neoadjuvant chemotherapy, up to 6 weeks
measure: Tumor response 2
timeFrame: 3 weeks after completion of interval debulking surgery, up to 6 weeks
measure: Tumor response 3
timeFrame: 3 weeks after completion of adjuvant chemotherapy, up to 6 weeks
measure: Radiologic evaluation of residual tumor
timeFrame: 3 weeks after interval debulking surgery, up to 6 weeks
measure: Functional assessment of residual tumor
timeFrame: 3 weeks after neoadjuvant chemotherapy, up to 6 weeks
measure: Assessment of quality of life1
timeFrame: From the date of screening to the date before treatment start, 3 weeks after interval debulking surgery within 6 weeks, 3 weeks after completion of adjuvant chemotherapy up to 6 weeks, on date of visit at 6 months after completion of primary treatment
measure: Assessment of quality of life2
timeFrame: From the date of screening to the date before treatment start, 3 weeks after interval debulking surgery within 6 weeks, 3 weeks after completion of adjuvant chemotherapy up to 6 weeks, on date of visit at 6 months after completion of primary treatment
measure: Assessment of quality of life3
timeFrame: From the date of screening to the date before treatment start, 3 weeks after interval debulking surgery within 6 weeks, 3 weeks after completion of adjuvant chemotherapy up to 6 weeks, on date of visit at 6 months after completion of primary treatment
measure: Assessment of quality of life4
timeFrame: From the date of screening to the date before treatment start, 3 weeks after interval debulking surgery within 6 weeks, 3 weeks after completion of adjuvant chemotherapy up to 6 weeks, on date of visit at 6 months after completion of primary treatment
measure: Adverse events
timeFrame: From the date of first day of chemotherapy to the day before starting next cycle. Each cycle is 21 days.
measure: Success rate of optimal cytoreduction
timeFrame: On the date of completion of interval debulking surgery, up to 24 hours
measure: Surgical complexity score (SCS)
timeFrame: On the date of completion of interval debulking surgery, up to 24 hours
measure: Postoperative complications 1
timeFrame: Early complications: after interval debulking surgery, up to 30 days
measure: Postoperative complications 2
timeFrame: Late complications: 31 days after interval debulking surgery through study completion, an average of 1 year
measure: Estimated blood loss
timeFrame: after interval debulking surgery up to 3 months
measure: Operation time
timeFrame: after interval debulking surgery up to 3 months
measure: Transfusion
timeFrame: after interval debulking surgery up to 3 months
measure: days of hospitalization
timeFrame: after interval debulking surgery up to 3 months
measure: days of management in intensive care unit
timeFrame: after interval debulking surgery up to 3 months
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
Study officials:
affiliation: Seoul National University Hospital
name: Hee Seung Kim, MD/PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Park SJ, Shim SH, Ji YI, Kwon SH, Lee EJ, Lee M, Chang SJ, Park S, Kim SY, Lee SJ, Kim JW, Roh JW, Lee SH, Song T, Kim HS. Reduction of cycles of neoadjuvant chemotherapy for advanced epithelial ovarian, fallopian or primary peritoneal cancer (ROCOCO): study protocol for a phase III randomized controlled trial. BMC Cancer. 2020 May 6;20(1):385. doi: 10.1186/s12885-020-06886-2.