Comparison of treatment invasiveness between upfront debulking surgery versus interval debulking surgery following neoadjuvant chemotherapy for stage III/IV ovarian, tubal, and peritoneal cancers in a phase III randomised trial: Japan Clinical Oncology Group Study JCOG0602

Abstract

Background

We conducted a phase III, non-inferiority trial comparing upfront primary debulking surgery (PDS) and interval debulking surgery (IDS) following neoadjuvant chemotherapy (NAC) for stage III/IV ovarian, tubal, and peritoneal cancers (JCOG0602). Two earlier studies, EORTC55971 and CHORUS, demonstrated non-inferior survival of patients treated with NAC. However, they could not evaluate true treatment invasiveness because of adding diagnostic laparotomy or laparoscopy before treatment in over 30% of both arms of EORTC55971 and in 16% of NAC arm of CHORUS.

Methods

Patients were randomised into the standard arm (PDS followed by eight cycles of paclitaxel and carboplatin [TC]) and NAC arm (four cycles of TC, IDS, and four cycles of TC). In the standard arm, IDS was optional for patients who had undergone suboptimal or incomplete PDS. Treatment invasiveness was compared between arms (UMIN000000523).

Results

Between November 2006 and October 2011, 301 patients were randomised. In the standard arm, 147/149 underwent PDS and 49 underwent IDS. In the NAC arm, 130/152 underwent IDS. The NAC arm required fewer surgeries (mean 0.86 versus 1.32, p < 0.001) and shorter total operation time (median 273 min versus 341 min, p < 0.001) than the standard arm and required a lower frequency of abdominal organ resection (23.7% versus 37.6%, p = 0.012) or distant metastases resection (3.9% versus 10.7%, p = 0.027). In the NAC arm IDS, blood/ascites loss was smaller (median 787 ml versus 3235 ml, p < 0.001) and albumin transfusion and G3/4 adverse events after surgery in total were less frequent (26.2% versus 58.5%, p < 0.001; 4.6% versus 15.0%, p = 0.005, respectively).

Conclusion

Our findings demonstrated that NAC treatment is less invasive than standard treatment. NAC treatment may become the new standard treatment for advanced ovarian cancer when non-inferior survival is confirmed in the planned primary analysis in 2017.

Introduction

Several retrospective analyses regarding advanced ovarian, tubal, and peritoneal cancer treatments revealed that optimal debulking proportions are improved in interval debulking surgery (IDS) following neoadjuvant chemotherapy (NAC) compared with those in primary debulking surgery (PDS); overall survival is comparable between patients treated with NAC followed by IDS (NAC therapy [NACT]) and those treated with PDS followed by chemotherapy (standard therapy [STDT]), although the NACT group had more advanced disease and poorer performance status (PS) [1], [2], [3], [4], [5], [6]. Several retrospective studies revealed that the invasiveness of surgery diminished in IDS in NACT compared with that in PDS in STDT in the parameters of blood transfusion frequency [6], [7], bowel resection [3], [6], [7], [8], splenectomy [3] or surgical complications [7], [8], hospital stay duration [6], [7], [9].

Based on these favourable results of NACT, several groups started randomised clinical trials for NACT as non-inferior trials. The European Organisation for Research and Treatment of Cancer (EORTC) conducted a phase III study comparing NACT with STDT (EORTC55971 study) [10] and Medical Research Council Clinical Trials Unit in United Kingdom conducted a phase II/III study (CHORUS study) [11]. The two trials added diagnostic laparotomy or laparoscopy before treatment, which is not included in essential practice of STDT and NACT. Laparotomy or laparoscopy was performed in 34.5% of STD arm patients and 38.3% of NAC arm patients in EORTC55971 study before enrolment and in 16% of NAC arm patients in CHORUS study before treatment to confirm diagnosis. We, the Japan Clinical Oncology Group (JCOG), conducted a feasibility study of NACT (JCOG0206) [12], [13], and based on results of this phase II trial, we started a phase III randomised trial (JCOG0602) [14] without adding diagnostic surgery before protocol treatment following the aforementioned two trial groups (UMIN000000523). Earlier studies demonstrated non-inferior survival of patients treated with NACT compared with those treated with STDT. However, NACT has not yet been accepted as a new standard treatment for advanced ovarian, tubal, and peritoneal cancers for three reasons: (1) NACT invasiveness has not yet been fully and properly analysed; (2) A preoperative staging system by imaging studies for patients receiving NAC has not yet been established; (3) Appropriate maximum debulking may not be performed judging from the lower frequency of optimal or complete debulking surgeries (PDS or IDS) in earlier studies. Especially, we believe it is necessary to demonstrate reduced treatment invasiveness besides non-inferior survival in NACT.

The major purposes of this study were to confirm non-inferiority of efficacy and to show a decrease in adverse events owing to reduced surgical invasiveness of NACT compared with STDT. We completed patient accrual on October 2011 and we are now in a 5-year follow-up period. Survival analysis will be conducted after a follow-up period and safety results will be presented.