IPHC in Patients With Platinum-sensitive Recurrent Ovarian Cancer
Condition: Ovarian Epithelial Cancer Recurrent
MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Recurrence
Study type: Interventional
Phase: Phase 2

Summary: 
      In patient with a platinum sensitive ovarian cancer recurrence is demonstrated that the
      re-challenge with a compound of platinum-based, or a treatment with carboplatin in
      combination with paclitaxel , determines a rate of clinical response similar to the primary
      treatment, which is all the more important as the longer the time to progression from the
      primary therapy.In the clinical setting there are many studies that have shown activity of
      oxaliplatin and docetaxel in patients with advanced ovarian cancer. Two recent studies have
      shown clinical efficacy of the combination carboplatin / docetaxel in the first line
      oxaliplatin / paclitaxel to recurrence of disease, confirming the data already obtained from
      studies of activity in a single agent.In surgery it has been demonstrated in a meta-analysis
      including approximately 7000 patients in advanced stages of disease, that the extent of
      cytoreduction is the most powerful determinant of survival.The role of secondary surgical
      cytoreduction in case of recurrent disease has yet to be determined because of the lack of
      prospective randomized clinical studies that may highlight the superiority of such aggressive
      treatment.The combination of aggressive cytoreductive surgery and hyperthermic
      intraperitoneal intraoperative chemotherapy (CHIP) used in recent clinical studies showed a
      prolonged time to progression and disease-free survival in patients with ovarian cancer.
      However, these studies were conducted on groups of patients with very different among
      themselves and with other drugs, it is difficult to draw definitive conclusions.Given the
      activities of oxaliplatin and docetaxel and their non-cross-resistance we designed a Phase 2
      clinical trial on treatment of patients with recurrent ovarian cancer, platinum-sensitive,
      treated with surgical cytoreduction with hyperthermic oxaliplatin-based intraoperative
      intraperitoneal chemotherapy and following consolidation treatment with oxaliplatin and
      docetaxel systemically every 21 days.
    

Detailed description: 
      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 or the only chemotherapy, in platinum-sensitive
      recurrent EOC patients.
    

Intervention name(s): HIPEC
Intervention type(s): Procedure
Intervention description(s): surgery plus HIPEC with the closed technique(perfusion of the abdominal cavity with a solution containing oxaliplatin 460 mg/m2 in 2L/m2 heated saline at 42°C).The global temperature will be measured by thermometer inserted into the esophagus and rectum. A Swan-Ganz catheter will be kept in place during the HIPEC for monitoring cardiovascular function.
Other intervention name(s): IPHC; Hypertermic intraperitoneal chemotherapy
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HIPEC; ovarian cancer; recurrence