Primary:• In this project, we propose to study the use of this aspiration fluid from the intraperitoneal cavity as a biomarker for the efficacy of chemotherapy intervention.The research questions for this study are:• Monitor the effect of…
ID
Source
Brief title
Condition
- Reproductive neoplasms female malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Patient data
Patient data on age, tumor type, grade and stage, surgery type and outcome,
I.P. chemotherapy dosing and toxicity, CA 125 and progression free survival
(PFS ) site of recurrence (intraperitoneal versus extraperitoneal), overall
survival (OS) .
Immune Lab data
The immune cells will be phenotyped to determine their nature (T cells,
regulatory T cells, natural killer cells, dendritic cells, Myeloid-derived
suppressor cells or macrophages M1 and M2 type), cytokine secretion and their
functionality. If possible, cells will be frozen down for future analysis. STAT
protein activation status of these cells will be determined alongside.
Concurrently, a peripheral blood sample will be taken (5x 10 ml peripheral
blood in heparin tubes on day 1 and day 8 of each round before i.p. chemo; to a
maximum of 300 ml/year) and subjected to the same flowcytometry analysis of
immune cell numbers, activation state and cytokine secretion as described
above.
Pharmacokinetic data:
6 ml of EDTA blood samples will be collected at 0, 15, 30, 60 min and at 2 h,
4 h, 8h, 16h, 24 h, 48hr and 72hr at the first i.p cycle of chemotherapy. to
assess the concentrations of cisplatin and paclitaxel in the peripheral blood
after IP administration.Also 3 ml intra-peritoneal fluid will be collected at
time points -30 min 0 min, 15 min, 30 min, 60 min, 2hr , 4hr, 8h, 24h, 48 and
72 hr after i.p. infusion of cisplatin and paclitaxel.
Secondary outcome
Not applicable.
Background summary
Intra-peritoneal (i.p) chemotherapy with cisplatin and paclitaxel is currently
the most effective treatment for patients with FIGO stage III ovarian cancer,
improving life expectancy from 50 to 66 months. The current most evidence based
schedule is day 1 start with paclitaxel135mg/m2 in 24hours intravenously
(i.v.), day 2: cisplatin 100mg/m2 i.p. and day 8 paclitaxel 60mg/m2 i.p. to
be repeated every 3 weeks for 6 courses. The improvement in life expectancy is
achieved despite the fact that almost 30% of the patients do not complete the
planned 6 courses of chemotherapy, mainly due to its toxicity. These results
indicate that for some patients less than 6 courses of chemotherapy are
sufficient. In other words, several patients are receiving unnecessary
treatment, which have an enormous effect on quality of life. Hence, there is an
obvious need for a predictive biomarker that can be used to tailor this
treatment to individual patients.
It*s becoming increasingly evident that the efficacy of chemotherapeutic
intervention is, in part, dependent on the modulation of the immune system. On
a molecular level this is due to the modulation of signaling pathways such as
the STAT protein family by these drugs. STAT proteins play an important role
during tumorigenesis as well in the maintenance of an immunosuppressive tumor
microenvironment. We have recently shown that platinum compounds like cisplatin
can block STAT protein signaling in the tumor microenvironment[1-3].
Subsequently immunosuppressive networks present in the tumor are down
regulated. Concurrently, platinum chemotherapy can also boost the immune
response by enhancing dendritic cell function. Furthermore, in a small
retrospective study, the expression of STAT6 in tumor cells had both predictive
and prognostic value for platinum chemotherapy.
Since ovarian cancer suppresses the immune system, it is worthwhile to assess
the effect of chemotherapy on the ovarian cancer cells and the immune system.
Patients who are eligible for intra-peritoneal chemotherapy receive a port a
cath (PAC)to infuse NaCl 0.9% and cisplatin and paclitaxel according to
protocol into the intra-peritoneal cavity but also this device gives us the
opportunity to aspirate intra-peritoneal fluid to monitor he tumor
microenvironment, malignant cells and the immune system in the peritoneal
cavity during chemotherapy.
The distribution of cisplatin and paclitaxel chemotherapy from the peritoneal
cavity to the circulation is not known. According to the toxicity profile of
these drugs with nephropathy, neuropathy, hearing loss and myelosuppression,
they have to be distributed to the central circulation. Whether plasma levels
of these drugs are conform intravenously infused drugs is currently unknown, as
is the distribution of recurrences in and outside the abdominal cavity.
Study objective
Primary:
• In this project, we propose to study the use of this aspiration fluid from
the intraperitoneal cavity as a biomarker for the efficacy of chemotherapy
intervention.
The research questions for this study are:
• Monitor the effect of chemotherapy on intra-peritoneal tumor cells in the
peritoneal cavity before and over the course of the intra-peritoneal
chemotherapy regimen and if possible also after cessation of intraperitoneal
chemotherapy when replacement with i.v. chemotherapy occurs.
• Monitor the effect of chemotherapy on immune cells present in the
intra-peritoneal cavity over the course of the intra-peritoneal chemotherapy
regimen.
• Correlate the presence and amount of tumor cells in peritoneal fluid with the
debulking efficacy and CA 125 levels
Secondary:
• To determine the pharmacokinetics of cisplatin and paclitaxel when
administered in the intraperitoneal cavity in the central circulation (plasma)
as well as in the peritoneal fluid.
Study design
Prospective observational explorative study
Study burden and risks
For the patient no extra invasive actions are needed apart from the standard
chemotherapy.
The only burden is that more blood will be sampled until a maximum of 432 ml
over a period of 18 weeks.
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
Primary epitelial ovarían carcinoma FIGO stage III
Optimal primary debulking (tumor rests <=1cm )
WHO 0-2
Adequate hematological, renal and liver function tests, conform standard protocol for chemotherapy
Creatinine clearance >60 ml/min (Cockroft)
Bilirubin and/or transaminases < 1,25 UNL
WBC>= 3. 10^6/L en Platelets >= 100. 10^6/L
Exclusion criteria
Intestinal stoma proximal to the flexura lienalis
Sepsis postoperative after primary debulking
Extended intraperitoneal adhesions
Neurotoxicity grade >1
Previous chemotherapy for ovarian carcinoma
Symptomatic hearing loss
Age >70 years old
Haemoglobin < 6.0 mmol/L
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL50438.091.15 |