Trial Title:
Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) in Ovarian Cancer Recurrence
NCT ID:
NCT01539785
Condition:
First Recurrence of Ovarian Cancer
Conditions: Official terms:
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Recurrence
Hyperthermia
Fever
Conditions: Keywords:
HIPEC
Hyperthermic
ovarian cancer
recurrence
Study type:
Interventional
Study phase:
N/A
Overall status:
Unknown status
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
Double
Intervention:
Intervention type:
Procedure
Intervention name:
Secondary citoreduction
Description:
The eligible patients, after anesthesia preparation will be submitted to a surgical
complete cytoreduction attempt that consist in the removal of all macroscopically visible
tumor nodules from the visceral and parietal peritoneum. To obtain a complete
cytoreduction, different procedures are required, as described by Sugarbaker (30), which
may include omentectomy, splenectomy, diaphragmatic, pelvic,parietal peritonectomy and /
or visceral, bowel resection, hepatic resection and cholecystectomy.
Arm group label:
Secondary cytoreduction
Intervention type:
Procedure
Intervention name:
Hyperthermic intra-peritoneal chemotherapy (HIPEC)
Description:
If the patient is randomized to make chemo-hyperthermia, surgery will be followed by
HIPEC with the closed technique, that consist in the perfusion of the abdominal cavity
with a solution containing cisplatin (CDDP) 75 mg/m2 in 2L/m2 heated saline. The solution
is heated and perfused with two special pumps (Hyperex, Korea or Stoeckert munich). The
temperature of inflow and outflow of the solution, will be maintained, respectively,
between 41 ° and 42.5 ° C. The intraperitoneal temperature will be maintained at 41.5 ° C
and monitored by thermometers inserted into the subphrenic space and into the pelvis.
After 60 minutes of perfusion the surgical incision will be open after removal of the
entire solution. 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.
Arm group label:
Hyperthermic intra-peritoneal chemotherapy (HIPEC)
Summary:
The purpose of this study is to determine the role of surgery followed by hyperthermic
intra-peritoneal chemotherapy (HIPEC) versus surgery alone in patients with
platinum-sensitive first recurrence of ovarian cancer. Moreover it is a prospective
randomized multicenter trial, aimed to investigate the prognostic role of surgery plus
HIPEC versus surgery alone in terms of progression free interval, overall survival,
morbidity and mortality, second recurrence pattern, quality of life with EORTC QLQ-C30
and QLQ OV28 questionnaires.
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, in platinum-sensitive recurrent EOC patients, whom
potentially could undergo complete cytoreduction on the basis of the pre-and
intraoperative evaluation.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Age over 18 and under 70 years
- Patients affected by a first recurrence of ovarian cancer with measurable lesions or
not, but evaluable (upwards of Ca125 for 2 consecutive assessments).
- ECOG-performance status ≤ 2
- Ovarian cancer limited to the abdominal cavity with or without extraperitoneal
spread considered resectable at intraoperative evaluation
- Evidence of tumor recurrence diagnosed after 6 months from primary treatment
- Previous-based chemotherapy of carboplatin and taxanes
- Positive Peritoneal Washing in the presence of other abdominal disease surgically
resectable
- Adequate respiratory, hepatic, cardiac, kidney and bone marrow function (absolute
neutrophil count > 1500/mm3, platelets > 150,000/μl, creatinine clearance > 60
mL/min according to Cockroft formula)
- Patient-compliant and psychologically able to follow the trial procedures
Exclusion Criteria:
- Non-epithelial ovarian cancer or borderline ovarian tumor
- Pregnancy or breastfeeding
- Patients affected by major depressive disorder even in treatment or minor mood
disorders
- Patients with severe impairment of respiratory, hepatic or renal function
- Patients with cardiac, neurological or metabolic uncontrolled pharmacologically
disease
- Patients with active infection or other neoplastic disease in progress
- Patients with bowel obstruction
- Inadequate bone marrow, liver, kidney function
- No clear-peritoneal disease at surgical exploration
- Patients with ascites > 500 ml (the TAC)
- Patients on maintenance therapy with Antiangiogenic drugs
- Patients with secondary or tertiary recurrence, or already submitted to HIPEC
- Patients who have already made the second or third line chemotherapy.
Gender:
Female
Minimum age:
18 Years
Maximum age:
70 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Catholic University of Sacred the Hearth
Address:
City:
Rome
Zip:
00100
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Catholic University of Sacred the Hearth
Phone:
+39 063 015 627 9
Investigator:
Last name:
Fagotti Anna, MD, PhD
Email:
Principal Investigator
Investigator:
Last name:
Fanfani Francesco, MD
Email:
Principal Investigator
Investigator:
Last name:
Costantini Barbara, MD
Email:
Principal Investigator
Investigator:
Last name:
Perelli Federica, MD
Email:
Principal Investigator
Start date:
September 2012
Lead sponsor:
Agency:
Catholic University of the Sacred Heart
Agency class:
Other
Source:
Catholic University of the Sacred Heart
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT01539785
