The role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the treatment of ovarian cancer relapse
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- Saladino, E., Fleres, F., Irato, S. et al. Updates Surg (2014) 66: 109. doi:10.1007/s13304-013-0229-9
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Nowadays the standard clinical management for advanced epithelial ovarian cancer is constituted by primary cytoreductive surgery associated to adjuvant systemic chemotherapy. Even if this first-line chemotherapy shows a high rate of complete responses, the disease recurrences occur especially in stage-III patients. Actually an option for this subset of patients is represented by secondary cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy that represents a promising therapy, having shown positive results in terms of median overall survival, progression free survival and overall survival. However, a much more research is still required especially by prospective randomised trials to improve outcomes in recurrent ovarian cancer.
KeywordsCRSHIPECEpithelial ovarian cancerRecurrence
Epithelial ovarian cancer (EOC) is one of the most frequent gynaecological tumours and represents the fifth cause of death from cancer in women . Nowadays the standard clinical management for advanced EOC is constituted by primary cytoreductive surgery (CRS) followed by carboplatin/taxol-based systemic chemotherapy. Even if this first-line chemotherapy shows a good response rate, with a high proportion of complete responses [2–4], the disease recurrences occur in up to 70 % of stage-III patients and, often, are not curable for the presence of extraperitoneal metastasis that represent instead a contraindication to CRS plus HIPEC. The duration of survival depends by the time interval from initial treatment to the recurrence, with reported long-term survival rates of only 20–30 % [2–6]. In particular, platinum-resistant and platinum-sensitive patients have response rates and median survival of up to 28 and 77 % and of 6–12 and 12–40 months, respectively . A recent report of Deraco et al.  has shown that combined CRS plus hyperthermic intraperitoneal chemotherapy (HIPEC) in recurrent platinum-resistant EOC is able to give to the resistent patients the same prognostic chances of the sensitive ones . The evidences accumulated show that the best candidates for this type of procedure are represented by patients with good performance status, a long disease-free interval, few isolated intra-abdominal metastases, absence of ascites, and optimal cytoreduction at the time of primary treatment [10–13]. Actually this combined approach is still controversial, also because in a recent cost analysis reported by Baratti et al.  the mean cost for one hospital stay was euro 36,015.89 (range 28,435.24–82,189.08) with a mean length of stay was 24.3 days (range 9–108) and since the Italian current diagnosis-related groups classification does not include cytoreduction and HIPEC, this results in a relevant economic deficit for the centres offering this treatment option to their patients and so that with a slow diffusion of the technique in our country. However, a number of factors suggest that it should be employed in the advanced EOC treatment. In fact the disease shows a predilection to disseminate intraperitoneally, remaining inside the peritoneal cavity for most of its natural history and therefore, it can be amenable to local–regional treatment . Furthermore, there is a strong evidence that the residual disease represents the most important prognostic factor in the platinum era [16, 17]. Lastly, there is a consensus in the intraperitoneal administration of drugs over the systemic route, in the adjuvant setting [18, 19].
Regional intraperitoneal chemotherapy in ovarian cancer
Dedrick et al.  were the first in 1978 who emphasised that the intraperitoneal delivery of some chemotherapeutic drugs could lead a significant increase in peritoneal cavity agent exposure respect to that in the systemic vascular compartment. EOC should be a good target for intraperitoneal treatment because it is relatively chemosensitive and it remains confined within the peritoneal cavity for much of its natural history . These consideration has been supported by GOG-172 phase III trial that favoured the intravenous (IV) plus intraperitoneal (IP) chemotherapy over IV chemotherapy in primary stage-III EOC  and successively by a Cochrane meta-analysis of all randomised IP versus IV trials that showed a hazard ratio of 0.79 for disease-free survival (DFS) and 0.79 for overall survival (OS), favouring the IP arms [21, 22]. Actually various agents association for EOC have been tested, except anti-angiogenetic drugs, molecular targeting agents, etc., for which nowadays there is no reported in the literature any purpose in this scenery. However, several parameters should guide the choice of the drug as the pharmacokinetic profile, tumour chemosensibility and toxicity. Ideally the drug must be water-soluble and of high molecular weight to guarantee a low peritoneal clearance . The penetration ability of drug in the tumour is a function of passive diffusion (related to the AUCpe/AUCpl ratio), removal from by the capillary blood flow, and temperature modulation. For the drugs most active in EOC the ratio of their intraperitoneal to plasma concentrations varies from 18 to 20× for carboplatin and cisplatin to 120 to >1,000× for the taxanes, docetaxel and paclitaxel . Finally, the influence of temperature in the cytotoxicity should also be of concern. Actually there is no consensus for the optimal choice of the drugs in EOC treatment, but the agents that have already been employed are: cisplatin, doxorubicin, caelyx, mitomycin C, carboplatin, oxaliplatin, gemcitabine and paclitaxel .
Rationale for hyperthermia in ovarian cancer
The association of hyperthermia to IP chemotherapy is based on a strict scientific rationale. In fact, the heat, besides having a recognised direct cytotoxic effect, presents a synergistic activity with some chemotherapeutic agents, allowing the following advantages: a greater intracellular accumulation of drugs, a reduction of the repair of CDDP-DNA complexes, a reduction of intracellular drugs detoxification, a reduction of cellular proliferation, an increase of the apoptotic fraction and a greater tissue penetration. Such mechanisms are further amplified by the chaotic structure of the tumoral vascularity that, being in charge of a reduction of the pH and the glucose and oxygen concentrations, leads to a more sensitive microenvironment to the chemohyperthermic action in respect to healthy tissues . The possible synergy between hyperthermia and chemotherapy treatment has been showed by positive outcome results achieved for PC from appendiceal cancer , colorectal cancer , peritoneal mesothelioma , gastric cancer  and endometrial cancer . The standard initial treatment of EOC following an attempt at maximal CRS involves combination normothermic platinum/taxane regimens previously given intravenously only and now often including combined intravenous/intraperitoneal  with results that showed a median OS ranged from 22 to 64 months and a median DFS ranging from 10 to 57 months . For the management of recurrent EOC several drugs have showed activity in addition to platinums and taxanes, with response rates between 20 and 77 % in platinum-sensitive disease and up to 28 % in platinum-resistant disease .
Role of CRS in the treatment of ovarian cancer
The role of CRS in the treatment of EOC was initially demonstrated by an inverse relationship between the largest diameter of disease remaining after CRS and survival . In fact Bristow et al.  confirmed this finding showed as for each 10 % increase in the percentage of patients undergoing maximal CRS there was a 5.5 % increase in median survival duration, concluded that the maximal cytoreduction is one of the most powerful determinants of survival. The reason because CRS is thought to be effective when combined with chemotherapy is that it allows reduction of the neoplastic mass and, on the other hand, by means of induction of the cell-growth phase, the elimination of the chemoresistant clones and the improvement of the antiblastic perfusion, increasing tumoral chemosensitivity . Even though optimal residual disease at completion of initial CRS for EOC was accepted as being any nodule <2 cm in dimension, it is now established that the most favourable prognosis is in patients with no macroscopic residual disease at all . However, although universally accepted as standard of care there is no consensus about the issue of optimal cytoreduction and advisable limits of radicality. For the first point based on in vitro and in vivo evidence that diffusion of intraperitoneally delivered chemotherapy agents into peritoneal tumours is to a maximum of 2.5–5 mm even with hyperthermia. Some drugs such as doxorubicin, carboplatin and oxaliplatin have much lower intratumoural penetration capacity. Some 90 % of the ovary consensus panel (OCP) felt that the objective should be a residual lesion size of 2.5 mm or less . In fact in support of this evidence a recent retrospective review  in patients with stage IV EOC has shown a median OS for microscopic, 0.1–5.0 cm, and >5.0 cm residual disease (RD) was 64, 30, and 19 months. For the second point relative to actual impact of complete cytoreduction on outcome, Eisenkop and Spirtos  have reported for patients with stage IIIC EOC a median and estimated 5-year survival of 75.8 months and 54 %, respectively, observed that the need to remove a large number of peritoneal implants correlates with biological aggressiveness and diminished survival, but not significantly enough to preclude long-term survival or justify abbreviation of the operative effort. In support to this result a recent report  has showed as an aggressive surgical policy resulted in increased optimal cytoreduction rates and significantly improved oncological outcome.
CRS plus HIPEC in the treatment of ovarian cancer relapse
On the base of the considerations above-mentioned, actually the secondary CRS plus HIPEC represents the only relevant therapeutic option for patients with recurrent EOC, reported survival of 44–60 months  in those patients with no gross residual after the treatment. These results are associated with a favourable prognostic profile, a disease-free interval of more than 12 months, platinum-sensitive disease, absence of ascites, number of recurrent sites, and a low tumour burden [10–13, 35]. Nowadays even if the use of CRS plus HIPEC in the treatment of the recurrence ovarian cancer is still lacking by a general consensus from randomised trials, however, several reports have shown encouraging results with this procedure reported a median OS and progression free survival (PFS) that ranges from 19 to 57 (as confirmed also by our experience with a median survival of 37 months) and from 10 to 31 months, respectively [8, 36–46], with a 2-year, 3-year and when reported 5-year OS rates ranging from 55 to 60 %, 37.5 to 55 % and 17 %, respectively [39, 47–51]. Nevertheless, it is difficult to ascertain if such a survival benefit results from the selection of a population with tumours of diminished aggressiveness or from an actual positive impact of surgery on the long-term health of patients. In fact in the light of the considerations above-mentioned, two approaches can be identified for the surgical management of EOC. The first utilises the advantage of the high initial chemosensitivity of tumours and defer multivisceral resections to avoid morbidity. The second approach, instead asserts that the residual disease after CRS is the most important factor that affects the prognosis and so tends to push the limits of surgical radicality as far as is technically possible, irrespective of increased morbidity. Moreover, Deraco et al.  have demonstrated as the theoretical negative influences of the initial tumour burden and the biological aggressiveness of the tumour on outcome are neutralised by the maximal surgical effort. In fact, not only patients with limited diseases (between three and five sing localisations) but also those with peritoneal carcinomatosis (PCI < 20) may equally benefit from CRS and HIPEC . Therefore, we can assert that this type of procedure is safe for the patient even if should be performed only at a tertiary referral centre, no in general hospital, in consideration of the mortality rate that ranged from 0 to 10 %, and especially for the management of the minor and major morbidity that ranged from 7 to 90 % and 0 and 49 %, respectively . Furthermore, it is also safe for the surgeon, in fact the only study  that evaluate the safety of operating room personnel during HIPEC has reported that all assessments (urine members, air sampled, sterile gloves examination) were found to be in compliance with established safety standards stated by Gonzalez-Bayon et al.  that concern: selection and education of operative room personnel, restriction of personnel inside operative room, used of rigid containers, protective barrier garments, disposable, impervious gown, high power filtration mask, smoke evacuator and avoided spills.
The CRS plus HIPEC represents a promising therapeutic option in the management of the recurrent EOC, in fact this combined procedure actually could be used for a wider subset of patients otherwise doomed to a conventional secondary debulking surgery without HIPEC. However, a much more research is still required especially by prospective randomise trials to improve outcomes in recurrent EOC.
Conflict of interest
The authors declare that they have no conflict of interest.