Advanced ovarian cancer: Neoadjuvant chemotherapy plus surgery and HIPEC as up-front treatment

Abstract

Epithelial ovarian cancer (EOC) is one of the most common malignancies and one of the principal causes of death in gynecological neoplasms. The majority of EOC patients present with an advanced International Federation of Gynecology and Obstetrics stage disease. The current standard treatment for these patients consists of complete cytoreduction and combined systemic chemotherapy of a platinum agent and paclitaxel. Even if the majority of patients with EOC respond to first-line platinum based chemotherapy, almost 20% of them are resistant or refractory. According to these data, the main risk is for a certain number of patients to have undergone cytoreductive surgery (CRS) and subsequent hyperthermic intraoperative peritoneal chemotherapy (HIPEC) in a useful way. Radical surgery, especially in advanced cases, is associated with a high incidence of postoperative morbidity and mortality, which could be increased by the HIPEC. Every effort should be made for previously selected patients to improve outcome and optimize resources. Over the last decade, new options have been introduced to prolong survival. Improved long-term results can be achieved using CRS in combination with intraoperative HIPEC. This combination has also been used in an up-front setting. Controversial outcomes have been reported for neoadjuvant platinum-based chemotherapy. Different papers have been published reporting discordant results. Further studies are needed.

Key Words: Epithelian ovarian cancer, Hyperthermic intraoperative peritoneal chemotherapy, Up-front, Neoadjuvant, Treatment, Oncology, Cytoreductive surgery, Chemotherapy

EDITORIAL

Epithelial ovarian cancer (EOC) is one of the most common malignancies and one of the principal causes of death in gynecological neoplasms. The majority of EOC patients (about 70%) present with an advanced International Federation of Gynecology and Obstetrics (FIGO) stage disease (i.e., III or IV)[1-4]. The current standard treatment for these patients consists of complete cytoreduction and combined systemic chemotherapy of a platinum agent and paclitaxel[5]. The extent of cytoreduction has a direct impact on survival and maximal cytoreduction was found to be one of the most powerful determinants of survival among patients with stage III or IV EOC in a meta-analysis of almost 7000 patients[6] and in other studies[7-8]. The aim of cytoreductive surgery (CRS) is to remove all the macroscopic disease. Optimal cytoreduction is usually defined as a residual disease of less than 0.5-2 cm. However, it has been demonstrated that the achievement of an optimal cytoreduction, mainly in advanced EOC, is not always possible. Factors which mainly influence suboptimal cytoreduction are: the extent of the disease at the presentation, medical co-morbidities and the surgeon’s expertise[9-11]. Sub-optimal and incomplete CRS results in losing the chance to improve survival. In our opinion, however, optimal cytoreduction should no longer be defined as a variable (0.5-2 cm) residual tumor but should be started to be considered as the complete absence of macroscopic residual disease. For this reason, patients should receive treatment only at centers able to undertake complex cytoreductive procedures[12]. Furthermore, phase III randomised controlled trials have established the superiority [i.e., improved progression-free survival (PFS) and overall survival (OS) rates] of intraperitoneal cisplatin-based chemotherapy compared to the systemic delivery of the agent for the treatment of small-volume residual advanced EOC[13-15]. Less evidence is available for either medical[16] or surgical[17,18] management of recurrent EOC. Over the last decade, new options have been introduced to prolong survival.

A meta-analysis from Bristow et al[18] demonstrated poor outcomes for using neoadjuvant platinum-based chemotherapy instead of primary surgery in advanced EOC. However, this meta-analysis also demonstrated the increase of survival with debulking surgery with a better interval and the negative survival effect of increasing the number of chemotherapy cycles prior to interval surgery. Chua et al[19] suggested that the treatment of this malignancy should primarily involve a massive surgical effort for complete cytoreduction and neo-adjuvant chemotherapy (NAC) may be considered in situations where the extension of the disease provokes big limitations to the possibility of achieving a complete cytoreduction[19]. They also excluded the possibility of using the NAC to select a favourable prognostic group of chemo-responsive patients to undergo aggressive surgical cytoreduction[19]. Another meta-analysis by Kang and Nam[20] stated that NAC helps to obtain an increased rate of optimal cytoreduction in patients at a high risk for suboptimal debulking and/or unfavorable general conditions. However, it is not likely that the increased optimal debulking rate with NAC will result in improved survival outcome of patients with advanced EOC. The last meta-analysis by Tangjitgamol stated that no conclusive evidence could be obtained to determine whether NAC would improve or decrease survival rate[9].

A randomized trial comparing primary debulking surgery with NAC in EOC showed that similar OS and PFS may be achieved compared to standard primary debulking and with lower complication and post-operative mortality rate[21,22].

Improved long-term results can be achieved in highly selected patients using CRS, including parietal and visceral peritonectomy procedures, in combination with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC)[23-31]. Recent data from a multi-center phase II trial using CRS and HIPEC with cisplatin and doxorubicin in up-front treatment of EOC reported good results[31]. The authors accrued 26 patients over 6 years in 4 different centers, achieving macroscopically complete cytoreduction in 15 patients and only minimal residual disease (≤ 2.5 mm) in the remaining 11. Although major complications occurred in four patients, including one postoperative death, 25 of the 26 patients started systemic chemotherapy within a median of 46 d after surgery. A five year OS of 60.7% and a PFS of 15.2% were obtained. Another pilot experience reported good results in using CRS + HIPEC in an up-front setting[30,32]. Literature results are encouraging. In any case, as stated by different authors[18,33], the absence of phase-III trials suggests a few considerations before validating CRS + HIPEC as a strategy for up-front treatment of advanced EOC.

Even if the majority of patients with EOC (up to 80%) respond to the first-line platinum based chemotherapy, almost 20% of them are resistant or refractory[17]. According to these data, the main risk is for a certain number of patients to have undergone CRS and subsequent HIPEC in a useful way. Radical surgery, especially in advanced cases, is associated with a high incidence of postoperative morbidity and mortality[34-36], which could even be increased by the HIPEC. HIPEC remains a burdensome procedure: every effort is needed to select patients who will achieve the maximum benefit from it. NAC brings, as a marginal effect, the “ex-iuvantibus” determination of chemo-sensitivity of the tumor. This could have a few advantages: for those patients who will certainly not benefit from HIPEC, not to have it. Even if NAC followed by CRS + HIPEC does not show better results in terms of PFS and OS[21,22], valuing the patients’ response to NAC could be a strategy to select the patients who showed a chemo-sensitivity to platinum and taxanes for HIPEC only. NAC, by reducing the surgical load, should allow surgery to result in no residual tumor in the vast majority of this set of patients; less required radical surgery is associated with lesser peri-operative complications, permitting a shorter recovery before starting adjuvant chemotherapy; and lastly, this strategy could be offered to a high proportion of women with advanced EOC[2,5].

There are a few studies reporting a total of 334 patients with primary EOC treated with CRS and HIPEC in an up-front setting[1,16,24-30,37-41]. All these phase II observational studies included patients where in most cases a great surgical effort has been necessary and the chemo-sensitivity state was unknown: in only 107 cases (36.3%) the patients had undergone NAC to test in vivo chemo-sensitivity before CRS + HIPEC.

Bearing in mind the advantages of HIPEC associated with CRS, randomized controlled trials (RCTs) testing its efficacy have been requested by many clinicians at all time points of the natural history of advanced EOC, especially in up-front settings[6,13,14], as already has been done for colon and gastric cancer[42,43].

Actually, there are five ongoing RCTs evaluating the effectiveness of CRS and/or HIPEC in primary or recurrent EOC[15,44-46]. The one proposed by The Netherlands Cancer Institute (OVHIPEC trial) is intended to evaluate the efficacy of secondary cytoreduction with or without HIPEC[46]. In this study, HIPEC is used in an up-front setting after primary chemotherapy. In our center, a RCT called CHORINE (Cytoreduction and Hipec in the treatment of OvaRIaNcancEr) is starting. This study is a multicenter phase III prospective RCT, comparing CRS + HIPEC (cisplatin + paclitaxel) vs CRS alone in Stage IIIC unresectable EOC with partial or complete response after 3 systemic cycles of carboplatin + paclitaxel (NAC), followed by a further 3 cycles of carboplatin + paclitaxel (adjuvant chemotherapy). The primary outcome is two year disease-free survival. Only patients with complete or partial clinical response after the 3 cycles of neoadjuvant therapy are eligible for the study and, after signing the informed consent form, are submitted to CRS with radical intent. The randomization (HIPEC vs no HIPEC) will be applied after adequate CRS (residual tumor ≤ 2.5 mm): patients with suboptimal cytoreduction (residual tumor > 2.5 mm) are not suitable for randomization and will be excluded.

Paclitaxel has been demonstrated to be effective and safe in intraperitoneal hyperthermic use. Different in vitro and in vivo studies showed that hyperthermia enhances the cytostatic and cytotoxic effect of paclitaxel[47-50]. This drug’s characteristics make it a very good candidate to be administered intraperitoneally[51]. Some authors suggest a lower complication rate when paclitaxel is administered in a mono-therapy regimen[52].

On one hand, the advantages of the CHORINE study would be the following: firstly, NAC selects only patients for inclusion in the study in whom there is a clinical response (test of in vivo chemosensitivity) and then a response to HIPEC is expected; secondly, the response to NAC should reduce the cytoreductive effort, increasing the occurrence of complete CRS and presumably lowering the morbidity. The reduction of the surgery load after the NAC has been demonstrated to reduce the morbidity but to not influence the OS and the DFS. This probably happens because the macroscopic disease reduced by the NAC is not completely healed. The remnant microscopic disease could be the main cause of disease early progression. The HIPEC treatment has the precise role to reach the diffuse microscopic disease to complete the surgery effort. This is the reason platinum-paclitaxel based chemotherapy is administered. No study has used this combination before; thirdly, the only variable in the study is HIPEC, making it possible to evaluate its effectiveness regardless of CRS, because a radical and complete cytoreduction would be required in either the experimental arm or the control group, as suggested by many authors in the literature[6].

On the other hand, the major limitation of the study is that the control group is not the recognized standard treatment for advanced EOC, namely maximal CRS followed by systemic platinum-based adjuvant chemotherapy. The CHORINE study has already been approved by our review board and we are in the process of completing the administrative requirements and recruiting other participating centers.

CONCLUSION

In conclusion, few studies point out the favorable results in terms of survival after up-front CRS and HIPEC for advanced EOC, but we believe that in the up-front setting, NAC can better select chemoresponsive patients, thus reducing the surgical stress and perioperative complications. Furthermore, by reducing the disease diffusion in responsive patients, NAC could facilitate the dissection and reaching of a real completeness of cytoreduction, evaluated as no macroscopic residual of disease.