Surgery Plus Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) Versus Surgery Alone in Patients With Platinum-sensitive First Recurrence of Ovarian Cancer: a Prospective Randomized Multicenter Trial.
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%
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
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
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment
Estimate of progression free interval (PFI) in the two trial arms.
The progression-free interval (PFI) will be evaluated from the time of secondary cytoreduction (± HIPEC) to the evidence of a second recurrence of disease.
Italy: Ethics Committee, Catholic University of the Sacred Hearth