Reduction Of Cycles of neOadjuvant Chemotherapy for Advanced Epithelial Ovarian, Fallopian and Primary Peritoneal Cancer

NCT03693248UNKNOWNPHASE3INTERVENTIONAL

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.

Key Facts

Lead Sponsor

Seoul National University Hospital

Enrollment

298

Start Date

2018-12-19

Completion Date

2023-12-31

Study Type

INTERVENTIONAL

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

Interventions

Two cycles of neoadjuvant chemotherapy

Conditions

Ovarian Cancer Stage IIICOvarian Cancer Stage IVFallopian Tube CancerPeritoneal Cancer

Eligibility

Age Range

20 Years – 80 Years

Sex

FEMALE

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

Outcome Measures

Primary Outcomes

Progression free survival

the time interval from randomization date to disease recurrence or progression date

Time frame: 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

Overall survival

the time interval from randomization date to death or end of study date

Time frame: From the date of randomization until death due to any cause, assessed up to 60 months

Time to progression

the time interval from randomization date to disease recurrence or progression except death date

Time frame: From date of randomization until the date of first documented progression in the absence of death by any cause, assessed up to 60 months

Tumor response 1

Tumor response after neoadjuvant chemotherapy

Time frame: 3 weeks after completion of neoadjuvant chemotherapy, up to 6 weeks

Tumor response 2

Surgical response after interval debulking surgery

Time frame: 3 weeks after completion of interval debulking surgery, up to 6 weeks

Tumor response 3

Tumor response after adjuvant chemotherapy

Time frame: 3 weeks after completion of adjuvant chemotherapy, up to 6 weeks

Radiologic evaluation of residual tumor

Size of post operative residual tumor on computed tomography (CT) after interval debulking surgery

Time frame: 3 weeks after interval debulking surgery, up to 6 weeks

Functional assessment of residual tumor

Standardized uptake positron emission tomography (PET) CT

Time frame: 3 weeks after neoadjuvant chemotherapy, up to 6 weeks

Assessment of quality of life1

Scoring of quality of life assessment using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)

Time frame: 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

Assessment of quality of life2

Scoring of quality of life assessment using the EORTC ovarian cancer module (EORTC QLQ-Ov28)

Time frame: 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

Assessment of quality of life3

Scoring of quality of life assessment using the Functional Assessment of Cancer Therapy (FACT-O)

Time frame: 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

Assessment of quality of life4

Scoring of quality of life assessment using the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L)

Time frame: 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

Adverse events

Evaluation of chemotherapy induced toxicity

Time frame: From the date of first day of chemotherapy to the day before starting next cycle. Each cycle is 21 days.

Success rate of optimal cytoreduction

Evaluation of optimal cytoreduction and extent of resection based on modified Korean Gynecologic Oncology Group (KGOG) operation record form and tumor burden index

Time frame: On the date of completion of interval debulking surgery, up to 24 hours

Surgical complexity score (SCS)

Evaluation of difficulty of surgical skills based on surgical complexity score Minimal 0 to maxial 18 point. Each surgery will classified into low (point ≤3), intermediate (4-7), high (≥8) Higher value means more complex surgery.

Time frame: On the date of completion of interval debulking surgery, up to 24 hours

Postoperative complications 1

Incidence of early complications, and severity of complications based on Memorial Sloan Kettering Cancer Center Surgical Secondary Events Grading System

Time frame: Early complications: after interval debulking surgery, up to 30 days

Postoperative complications 2

Incidence of late complications, and severity of complications based on Memorial Sloan Kettering Cancer Center Surgical Secondary Events Grading System

Time frame: Late complications: 31 days after interval debulking surgery through study completion, an average of 1 year

Estimated blood loss

Estimated blood loss (ml) based on Modified KGOG Operation Record Form

Time frame: after interval debulking surgery up to 3 months

Operation time

Operation time (min) based on Modified KGOG Operation Record Form

Time frame: after interval debulking surgery up to 3 months

Transfusion

Transfusion (count by volume of transfused RBC) based on Modified KGOG Operation Record Form

Time frame: after interval debulking surgery up to 3 months

days of hospitalization

days of hospitalization based on Modified KGOG Operation Record Form

Time frame: after interval debulking surgery up to 3 months

days of management in intensive care unit

days of management in intensive care unit based on Modified KGOG Operation Record Form

Time frame: after interval debulking surgery up to 3 months

Locations

Seoul National University Hospital, Seoul, South Korea

Linked Papers

2020-05-06

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

Abstract Background Primary debulking surgery (PDS) and adjuvant chemotherapy is the standard treatment for advanced ovarian, fallopian or primary peritoneal cancer. However, neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) has been introduced as an alternative, showing similar efficacy and decreased postoperative complications compared with PDS. Although there is still no evidence for whether three or four cycles of NAC used clinically could be adequate, reducing one cycle of NAC is expected to remove more visible tumours and thereby improve prognosis. Thus, we proposed with this study to evaluate the efficacy and safety of reducing one cycle of NAC for advanced ovarian, fallopian or primary peritoneal cancer. Methods This study is a prospective, multi-centre, open-label, randomized phase III trial. A total of 298 patients with advanced ovarian, fallopian or primary peritoneal cancer will be recruited and randomly assigned to either three (control group) or two cycles of NAC (experimental group). After the NAC, we will conduct IDS with maximal cytoreduction and then administer the remaining three or four cycles for a total of six cycles of adjuvant chemotherapy. The primary end point is progression-free survival, and the secondary end points are time to tumour progression, overall survival, tumour response after NAC, IDS and adjuvant chemotherapy, radiologic investigation after IDS, tumour response by positron emission tomography-computed tomography after NAC, quality of life, adverse events, success rate of optimal cytoreduction, surgical complexity, postoperative complications and safety of IDS. We will assess these factors at screening, at every cycle of chemotherapy, at IDS, after the completion of chemotherapy, every 3 months for the first 2 years after the planned treatment and every 6 months thereafter for 3 years. Discussion We hypothesize that reducing one cycle of NAC will contribute to more resection of visible tumours despite 10% reduction of optimal cytoreduction, which could improve survival. Moreover, two cycles of NAC may increase postoperative complications by 5% compared with three cycles, which may be acceptable. Trial registration This study has been prospectively registered at ClinicalTrials.gov on Oct. 2nd, 2018 (NCT03693248, URL: https://clinicaltrials.gov/ct2/show/NCT03693248).

Linked Investigators

Hee Seung Kim