Neoadjuvant Chemotherapy in Advanced Ovarian Cancer

Abstract and Introduction

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy and is the seventh most common cancer among women worldwide. The primary debulking surgery (PDS) followed by adjuvant chemotherapy (ACT) is a standard treatment of advanced EOC. However, there are still several limitations, such as high recurrence rate and subsequent chemoresistance. To date, many studies have reported that neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) shows non-inferior survival outcome and is associated with less postoperative morbidity compared with PDS. Therefore, NACT-IDS might be an alternative treatment strategy in advanced EOC. Nevertheless, the efficacy of NACT-IDS and selection of patients who would gain benefit from NACT-IDS are still on debate. To date, several studies have been conducted to predict the response of NACT using various methods, such as imaging studies and molecular biology techniques. In this article, the optimal indications for NACT using various methods will be discussed.

Introduction

Epithelial malignancies of ovarian, fallopian tube and peritoneal origin demonstrate similar clinical characteristics and behavior. So these malignancies have been categorized together as epithelial ovarian cancer (EOC) in clinical trials or clinical practice. According to the World Health Organization report, the annual incidence of EOC is estimated as 225,500 with 140,200 deaths worldwide, affecting 3.7% of all female cancers and 4.2% of cancer deaths.^[1] Approximately 80% of EOC cases are diagnosed at advanced stage, the International Federation of Gynaecology and Obstetrics (FIGO) stage III and IV, resulting in poor survival outcome.^[2] Most patients experience disease relapse within the first 5 years despite primary aggressive treatment, whereas only 20–25% of cases are cured. Furthermore, the 5-year survival rate of patients with advanced EOC has not been improved in the last decade.

Current standard therapy for patients with advanced EOC is primary debulking surgery (PDS), followed by adjuvant chemotherapy (ACT) with a combination of paclitaxel and carboplatin.^[3] Complete or optimal cytoreductive surgery, defined as grossly no residual cancer or <10 mm of residual disease at the end of surgery, respectively, is known as the most important prognostic factor. Recently, interval debulking surgery (IDS) after a short course of neoadjuvant chemotherapy (NACT) has become an alternative treatment strategy for EOC patients expecting non-optimal cytoreduction during PDS. Several randomized controlled trials (RCTs) have reported that patients who underwent NACT-IDS had significantly lower adverse effect and surgical mortality rate after IDS than those who underwent PDS.^[4] Survival outcomes, such as progression-free survival (PFS) and overall survival (OS), were similar between NACT-IDS and PDS.^[5–7] The use of NACT gradually increased from 16% during 2003 to 2010 to 34% during 2011 to 2012 in stage IIIC disease, and from 41% to 62% in stage IV disease.^[8]

In accordance with the increased use of NACT, the efficacy of NACT-IDS and selection of patients who would gain benefit from NACT-IDS are still on debate. In this review, we will describe the up to date evidence and indications of NACT, using various diagnostic attempts to improve treatment outcomes of NACT.

Table 1. Comparison of outcomes of four randomized controlled trials for NACT-IDS *vs.* PDS
Clinical trial	Author, year	Enrollment criteria	Study arm	Patient number (eligible)	Median PFS, Months	Median OS, months	Operation time, min
EORTC	Van Der Burg et al., 1995	Biopsy-proven stage IIB to IV EOC; residual lesions: >1 cm in diameter; pathologic CR: absence of macroscopic and microscopic tumor at surgery	Arm 1: PDS followed by six cycles of the cyclophosphamide/carboplatin	138	18	26	NA
EORTC	Van Der Burg et al., 1995		Arm 2: IDS after three cycles of triweekly NACT with cyclophosphamide and carboplatin followed by three cycles of the same regimen	140	13	20	NA
EORTC 55971	Vergote et al., 2010	Biopsy-proven stage IIIC or IV EOC or fine-needle aspirate proven adenocarcinoma in patient with advanced EOC on image; ratio of CA-125/CEA >25	Arm 1: PDS followed by at least six cycles of platinum-based chemotherapy	310	12	29	165
EORTC 55971	Vergote et al., 2010		Arm 2: IDS after three cycles of platinum-based NACT, followed by three more cycles of ACT	322	12	30	180
CHORUS	Kehoe et al., 2015	Stage III or IV EOC based on image studies and ratio of CA-125/CEA >25 then biopsy after randomization	Arm 1: PDS followed by six cycles ACT with triweekly paclitaxel/cisplatin or carboplatin alone	276	10.7	22.6	120
CHORUS	Kehoe et al., 2015		Arm 2: three cycles of NACT followed by IDS	274	12	24.1	120
JCOG 0602	Onda et al., 2016	Stage III or IV EOC based on image studies and cytology. CA-125>200 U/mL and CEA <20 ng/mL	Arm 1: PDS followed by eight cycles of triweekly paclitaxel/carboplatin	130	NA	NA	341
JCOG 0602	Onda et al., 2016		Arm 2: four cycles of NACT followed by IDS, and four cycles of ACT	150	NA	NA	273

ACT, adjuvant chemotherapy; CA-125, cancer antigen 125; CEA, carcinoembryonic antigen; CHORUS, CHemotherapy OR Upfront Surgery trial; CR, complete response; EOC, epithelial ovarian cancer; EORTC, European Organization for the Research and Treatment of Cancer; IDS, interval debulking surgery; JCOG, Japan Clinical Oncology Group; NACT, neoadjuvant chemotherapy; NA, not available; OS, overall survival; PDS, primary debulking surgery; PFS, progression-free survival.

Table 2. Ongoing phase III RCT for NACT
Characteristics of clinical trials	Study of Upfront Surgery Versus Neoadjuvant Chemotherapy in Patients With Advanced Ovarian Cancer (SUNNY)	Surgical Complications Related to Primary or Interval Debulking in Ovarian Neoplasm (SCORPION)	Paclitaxel and Carboplatin With or Without Bevacizumab in Treating Patients With Stage II, Stage III, or Stage IV Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer
Condition of disease	Stage IIIC or IV epithelial ovarian cancer, fallopian tube cancer, or peritoneal carcinoma	Stage IIIC epithelial ovarian cancer	Stage IIA to IV epithelial ovarian cancer, fallopian tube cancer, or peritoneal carcinoma
Intervention	PDS vs. NACT/IDS	PDS vs. NACT/IDS	PDS/adjuvant chemotherapy with bevacizumab vs. NACT with bevacizumab/IDS
Number of estimated enrollments	456	171	692
Country	China, Korea	Italy	US, Canada, Korea
Primary outcome	OS	Early and late surgical complications; PFS	PFS
Secondary outcome	PFS; post-operative complication; quality of life assessments	OS; quality of life assessments	OS; quality of life assessments
Status	Recruiting	Active, not recruiting	Active, not recruiting
ClinicalTrials.gov identifier	NCT02859038	NCT01461850	NCT01167712

ACT, adjuvant chemotherapy; IDS, interval debulking surgery; NACT, neoadjuvant chemotherapy; OS, overall survival; PDS, primary debulking surgery; PFS, progression-free survival.

Table 3. Current indications of NACT
Biopsy proven advanced epithelial ovarian, peritoneal, and fallopian tubal cancers
Poor performance status and/or medical condition CT findings with: diaphragmatic disease >2 cm; extra-peritoneal disease such as lung and brain metastases; multiple liver parenchymal metastases requiring total resection of liver; pancreatic head and body metastasis; involvement of the porta hepatis; suprarenal para-aortic lymphadenopathy