Value of neoadjuvant chemotherapy in advanced ovarian cancer

Abstract

Data regarding the role of neoadjuvant chemotherapy (NACT) are not definitive. Several randomized trials and meta-analyses demonstrate that this chemotherapy regimen decreases the morbidity and mortality rates and increases complete cytoreduction rates. If combined with hyperthermic intraperitoneal chemotherapy (HIPEC), NACT could potentially further improve upon these already promising results. Moreover the use of NACT could help in evaluating the chemo-sensitivity of the cancer, thus preventing unnecessary HIPEC procedures in chemo-resistant patients. NACT should definitely be considered as a preferred regimen in the management of advanced ovarian cancer, especially in association with cytoreductive surgery + HIPEC procedure in the context of a multidisciplinary team management in an experienced cancer centre.

Key Words: Epithelial ovarian cancer, Neoadjuvant, Chemotherapy, Hyperthermic intraperitoneal chemotherapy, Treatment, Oncology, Cytoreductive surgery

Core tip: Data about the use of neoadjuvant chemotherapy in advanced ovarian cancer are not sufficient to support its extensive application. However encouraging results came from the existing studies. Future well designed studies are needed to clarify some aspects of this chemotherapy regimen and its association with the other form of pharmacological and surgical therapy.

INTRODUCTION

One of the most common malignancies and one of the principal causes of death among gynaecological neoplasm is epithelial ovarian cancer (EOC)[1]. The majority of EOC patients (about 70%) present with an advanced FIGO (International Federation of Gynecology and Obstetrics) stage disease (III or IV)[2-5]. Currently the standard treatment for these patients consists of complete cytoreduction (CC) followed by combined systemic chemotherapy of a platinum agent and paclitaxel[1,6]. Optimal cytoreduction was found to be one of the strongest survival determinants among patients with advanced stage[7-12].

NACT AND INTERVAL DEBULKING SURGERY

Recently, interval-debulking-surgery (IDS) after a short course of neoadjuvant chemotherapy (NACT), usually three cycles, has been demonstrated to be a viable alternative in those patients with low probability to obtain a CC during primary debulking surgery (PDS)[13]. Three randomized controlled trials (RCT) have demonstrated that overall survival (OS) and progression-free survival (PFS) in patients who received NACT plus IDS were not different from patients who received PDS. However, patients who received NACT had significantly lower adverse events and lower mortality after IDS than after PDS[14-16].

The first RCT, by the European Organization for the Research and Treatment of Cancer (EORTC) evaluated the benefit of IDS after suboptimal PDS. One-hundred and forty patients treated with three cycles of cisplatin and cyclophosphamide chemotherapy followed by IDS plus three cycles of ACT were compared with 138 similar patients receiving the same chemotherapy regimen without IDS. Data obtained from this study showed that patients from the IDS group had a median survival time statistically significant longer (26 mo) than patients not treated with IDS (20 mo)[14].

The second RCT conducted by the Gynecologic Oncology Group, evaluated 550 patients (stage III-IV) with a residual disease > 1 cm after PDS[15]. All patients received three cycles of initial chemotherapy with cisplatin and paclitaxel followed by response evaluation. Patients with no disease progression were randomized to IDS plus three additional cycles of ACT or additional chemotherapy alone. No differences between the two groups were found with regard to PFS or OS[15].

The third RCT performed by EORTC with the National Cancer Institute of Canada (NCIC) compared PDS with NACT plus IDS[16]. Seven hundreds and eighteen patients with EOC, fallopian tube or primary peritoneal carcinoma were included. All patients had stage IIIC-IV disease and were randomized to PDS plus platinum chemotherapy or NACT plus IDS. The CC was optimal (residual disease ≤ 1 cm) in 41.6% of patients after PDS and in 80.6% after IDS. PFS and OS were similar in both groups. Postoperative complications and postoperative mortality were higher after PDS[16].

A meta-analysis from Bristow et al[17] showed poor results for NACT used instead of PDS in advanced EOC. However this meta-analysis also demonstrated increased survival with an easier IDS prior to NACT and decreased survival with increasing number of chemotherapy cycles prior to IDS. Chua et al[18] suggested that the treatment of advanced EOC should primarily involve a massive surgical effort for CC, and NACT may be considered when the extent of the disease decreases the possibility of achieving a CC[1]. Another meta-analysis by Kang and Nam[19] showed a positive correlation between use of NACT and increased rate of CC in patients at high risk for suboptimal debulking and/or unfavourable general conditions.

Tangjitgamol et al[20] stated in a third meta-analysis that no conclusive evidence could be obtained to determine whether NACT increased or decreased survival rate.

NACT AND CRS PLUS HIPEC

Extensive data from the last ten years demonstrate that improved long-term results can be achieved in select patients using cytoreductive surgery (CRS), including parietal and visceral peritonectomy procedures, in combination with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC)[18,21-30].

Data from the literature are encouraging though not entirely homogeneous[31]. Nevertheless, as stated by Markman[32], the absence of phase-III trials suggests a few considerations before definitively validating CRS plus HIPEC as a viable strategy for first-line treatment of advanced EOC[1].

While the majority of patients with EOC (up to 80%) respond to the first-line platinum based chemotherapy, almost 20% of patients are resistant or refractory[1,33]. The greatest risk is for patients requiring CRS plus HIPEC[1]. CC is associated with high postoperative morbidity and mortality rates especially in advanced cases[9,34,35]. This could potentially be increased by HIPEC as it remains a burdensome procedure. For this reason, the goal would be to select patients suitable to achieve the maximum benefit and to reduce the need for surgical resections[1]. Even if NACT followed by CRS plus HIPEC does not show better results in terms of PFS and OS[16,36], the evaluation of the NACT response may help in selecting for HIPEC-only patients who demonstrate chemo-sensitivity. In fact, NACT could have the additional benefit of providing the “ex-iuvantibus” chemo-sensitivity determination[1]. HIPEC with platinum compounds and taxanes in fact has been demonstrated as feasible and safe[30,37].

The addition of NACT to the current treatment regimen as documented in the literature provides some advantages with regards to morbidity reduction and completeness of cytoreduction, especially in preoperatively well-staged patients. As CC is one of the strongest predictors of survival, it is not yet well-understood why studies have failed to show an improvement in OS or DFS with NACT[7]. Nevertheless, NACT shows great promise in its potential to prevent unnecessary use of HIPEC and to reduce surgical load, thus decreasing post-operative morbidity and mortality.

CONCLUSION

The use of NACT in the treatment of advanced EOC is progressively increasing. Studies about its use in several setting are on-going. This chemotherapy regimen should be considered as a preferred regimen in the management of advanced EOC, especially when combined with CRS plus HIPEC procedure in the context of a multidisciplinary team management in an experienced cancer centre. Results from the on-going RCT will clarify several issues about the association and the real survival effects of NACT associated to CRS plus HIPEC. Future well-designed studies are needed to clarify some aspects of this chemotherapy regimen and its association with the other form of pharmacological and surgical therapy.