Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) in Ovarian Cancer Recurrence

Among the malignancies of the female genital tract, ovarian cancer is the second most common cancer after the endometrial tumor, but the more lethal, representing the fifth leading cause of death among women in industrialized countries. For the most part, these are epithelial tumors (>70%), who begin with vague gastrointestinal symptoms, general malaise, abdominal bloating, weight loss and fatigue. Because of the non-specificity oh the symptoms and the often late presentation, about 70% of the diagnosis is made at an advanced stage of disease (IIIC). In the last two decades only a modest improvement in survival was achieved. Moreover, even after optimal cytoreduction followed by adjuvant chemotherapy based on platinum and taxane, which is currently the standard for this type of disease, most patients with stage III disease developed a recurrence.

Rational of HIPEC in recurrent ovarian cancer: the cytoreduction. Contrary to what happens in the primary disease is not yet clear what is the standard treatment in recurrent epithelial ovarian cancer (EOC).

Patients who experience a recurrence within 6 months from the end of the first-line chemotherapy are considered platinum-resistant and have applied for a salvage treatment with second line drugs with low response rates and poor survival. Patients who recur after 6 months are considered platinum-sensitive and, therefore, subject to a new chemotherapy treatment with a platinum compound possibly in combination with paclitaxel (re-challenge). In these patients it is possible to achieve a clinical response rate similar to the primary treatment, with median survival reported between 12 and 24 months. Recently surgery affirmed a major role not only in the primary treatment but also in recurrent chemo-sensitive ovarian cancer. A meta-analysis of 2019 patients has shown that obtain an optimal secondary cytoreduction independently correlates with survival (OS) after recurrence. However, a recent Cochrane, showed that, from the studies available nowadays, is not possible to substantiate a difference in prognosis between the exclusive chemotherapy treatment and the association of surgery with adjuvant chemotherapy.

The results of the multicenter trial DESKTOP I show that, even in the presence of peritoneal carcinomatosis, the 2-year survival improves if an optimal cytoreduction is obtained.

Rational of HIPEC in recurrent ovarian cancer: intraperitoneal chemotherapy Many patients who undergo optimal cytoreduction may benefit from adjuvant chemotherapy administered intraperitoneally (IP). Several randomized trials have demonstrated improved survival associated with IP platinum-based chemotherapy as first-line adjuvant therapy after optimal cytoreduction, although it is still unclear which patients might benefit most, or what would be the best drug , its dose or the right number of cycles. The adjuvant IP therapy, however, seems to have more side effects than intravenous therapy (IV) and consequently a worsening of the quality of life (QOL).

Rational use of HIPEC in recurrent ovarian cancer: hyperthermia The association of hyperthermia plus chemotherapy to the surgery based its rational on the cytotoxic effect of hyperthermia, which not only cause a rupture of cell membranes due to protein denaturation (direct effect), but also an increase in the permeability of new vessels and an impairment of receptor protein complexes (indirect effect). The sensitivity of the solid tumors to hyperthermia is probably linked to the creation of a microenvironment with a low pH, low oxygen tension, low glucose levels in response to high temperature. Inactivation of tumor cells is time and temperature dependent, and starts at 40-41 ° C. Experimental data show that human tumor cell lines are more sensitive to a moderate hyperthermia (41-42 ° C).

Furthermore, the ability of its cytotoxic chemotherapeutic agents, including mitomycin C, doxorubicin, cisplatin and oxaliplatin, is enhanced by hyperthermia itself.

Secondary cytoreduction (CRS), HIPEC and ovarian cancer Since its first appearance in 1980, the HIPEC associated with surgery has had an increasingly important role in the treatment of several types of cancer with peritoneal dissemination.

The rational for this therapeutic approach is based on the achievement of higher drug concentrations in contact with the peritoneal surface with a lower systemic concentrations, resulting in a decrease in the systemic toxicity of treatment. The addition of hyperthermia proved to be able to have a cytotoxic effect on tumor cells directly and indirectly, and a synergistic effect with several cytotoxic agents.

Two recent trials including heterogeneous populations of patients with EOC have demonstrated that the use of the HIPEC in association with CRS is followed by an overall survival (OS) of three years after the recurrence that vary between 20-63%. Data from a trial which took place at this Institution and was recently published about the use of HIPEC platinum-sensitive recurrent EOC patients, showed a median disease-free interval (PFS) and OS of 24 and 38 months respectively, with an estimated PFS and OS at 3 years of 44% and 92% respectively. These data not only confirm those previously reported in the literature, but are more significant, probably because of the highly selected population, a characteristic that contrasts with the wide heterogeneity of most of the other trials made until now.

In fact, as demonstrated by the meta-analysis by Bristow et al, the median survival after recurrence in the same group of patients treated with CRS and standard adjuvant chemotherapy alone was 30.3 months. This difference in survival compared with that of our trial could be justified by the increased rate of optimal cytoreduction obtained in our Institution (95.3% vs. 52.2%).

In addition, on the basis of the criteria developed by Markman, that any second-line treatment after recurrence which reaches a PFS similar or comparable to that after the primary disease is considered to be effective, our data show an additional benefit obtained by HIPEC. In the series of patients underwent CRS + HIPEC at this Institution, in fact, the median PFS after primary disease was substantially equal to that after recurrence with values of 25 and 24 months respectively (p = ns). Therefore treatment with CRS associated with HIPEC in with platinum-sensitive recurrent EOC patients would seem to offer the same opportunities in terms of prognosis than primary treatment.

Regarding the complications linked to this procedure, the trials completed at our Institution, showed morbidity and mortality rates about of 35% and 0%, consistent with the data presented by recent review (12 - 52% and 0,9-5,8% respectively), which are however more heterogeneous due to differences between the considered studies. In addition, the analysis divided into two blocks per year of execution of the procedure, has demonstrated a significant reduction in the percentage of complications (up to 26.7%) with a statistically significant difference.

Currently, despite the presence of a strong biological and pharmacological rational and the over 10 years application in EOC, the use of HIPEC in the clinical practice continues to receive mixed reviews. The limit to the confidence in this procedure is the lack of randomized clinical trials and the heterogeneity of the different phase II studies conducted, which resulted in a lack of scientific evidence level I-II. Moreover, the finding of high rates of the related morbidity and mortality, has precluded the use of this procedure to many patients with peritoneal disease.

The primary objective of this trial is therefore to assess whether the use of CRS in combination with HIPEC is able to offer an effectively advantage in terms of survival compared to the exclusive optimal CRS, in platinum-sensitive recurrent EOC patients, whom potentially could undergo complete cytoreduction on the basis of the pre-and intraoperative evaluation.