To overcome drug resistance in relapsed ovarian cancer, an isolated perfusion system was used to generate a higher local exposure to cytostatic drugs. In addition to cisplatin as the cytostatic agent of choice, the present study combined adriamycin and mitomycin in a three drugs regime due to their increased cytotoxicity under hypoxia. A total of 107 patients, including 87 patients with relapses after previous platinum-containing therapies, 46 stage IIIC and 41 stage IV cases, were enrolled in the present study. A total of 25 patients were chemonaive, including 20 stage IIIC. The systemically pretreated patients in stage IIIC survived a median of 12.8 months, and those in stage IV 10.9 months. The overall clinical response rate of stages IIIC and IV combined was 69%. A complete decrease in ascites was found in 43% of all patients, a significant reduction in 19%. Toxicity and side effects were very mild and the bone marrow suppression was mostly grade I and never exceeded grade II. The primary clinical symptom in patients with post-therapeutic tumor necrosis, which occurred in 10-15% of all cases, was fever, fatigue and poor performance. The isolated hypoxic abdominal perfusion treatment is a potent instrument to break an existing chemoresistance without significant side effects with a good quality of life and comparatively long survival time.
Clinical research has noticeably improved progression-free survival and overall survival over the past few decades. Nevertheless, ovarian cancer is still the leading cause of death among all gynecological malignancies. The insidiousness of the disease is the early peritoneal spread, the rapid development of chemoresistance and the bypassing of the hosts immune response (
In order to keep the systemic toxicity within acceptable limits, and to maintain the quality of life, chemofiltration was carried out directly after the therapy (
The study included 107 patients in the FIGO stages IIIC and IV, who were treated in one institution between 1997 and 2017. 87 patients were previously treated with platinum-containing combination chemotherapies, mostly taxanes and had recurrent epithelial ovarian cancers, resistant to platinum-based drug combination. 46 patients were stage FIGO IIIC and 41 were stage IV. An additional 20 patients who had refused prior therapies were all stage IIIC. 34 patients had G3 degree malignancies (
Investigations were performed in compliance with the principles of good clinical practice outlined in the Declaration of Helsinki and federal guidelines, and had approval by the Medias Institutional Review Committee. Informed consent was obtained from each participant or participant's guardian. Patients were required to have an ECOG performance status of 3 or less. Exclusion criteria included cardiovascular disease, uncontrolled diabetes and serious infections. The white blood count had to be no less than 2,500/µl, and should under no circumstances be in decline before starting therapy. The same applied to the platelet count with a limit of no less than 100,000/µl.
The procedure (
The isolated hypoxic abdominal perfusion is conducted in four cycles in three to four weeks intervals each. The blood count is checked weekly, and, while approaching the lowest Nadir, controls are carried out every second day until the blood count starts to reemerge. The tumor marker CA12-5 is checked before each therapy and a CT monitoring was performed two weeks after the second and fourth perfusion each. The extent of the residual tumor load and the tumor response were assessed according to the course of the tumor marker, the amount of residual ascites and the CT findings as well as the general condition of the patient. In case of progressive peritoneal lesions or distant metastases the treatment was discontinued.
Statistics have been calculated with 95% confidence limits. Survival times were estimated using the Kaplan-Meier product limit estimator and follow up for the surviving patients was minimum 12 months. Statistical analyses were performed using MediasStat software, version 28.5.14.
The most important endpoints of the trial were quality of life and overall survival, followed by the response rates. The latter was derived from the clinical response rate in the form of the tumor marker CA 12-5, the computer tomographic control and not least, quality of life.
QoL was in particular measured in the form of the decline or complete disappearance of ascites and especially, the substantial improvement in pain and the often described general discomfort. Patients who had prior systemic followed by regional chemotherapy filled in questionnaires comparing the intensity of the most common side effects after the respective therapies in a scale from one to six. Patients perceived regional perfusion therapy less stressing than conventional chemotherapy.
A positive influence on clinical response rates was noted among 69% of all patients in stage IIIC and IV. The rate of complete remissions was 19,6% in stage IIIC and 14,6% in stage IV, partial remissions 47,8 and 56,1% respectively. Complete disappearance of ascites was observed in 43% of patients after only two perfusions, and 19% of patients reported a 50% or more reduction of abdominal pressure and fluid volume (
The median progression-free survival (PFS) of all 87 patients was 8 months, the median overall survival 11.9 months (
Bone marrow depression ranged between WHO grade 1 and 2. Only patients with a reduced bone marrow reserve after stressful third and fourth-line therapy had leucopenia and thrombocytopenia grade 3 even after perfusion therapy with chemofiltration. WHO grade 4 toxicity and neutropenic fever as well as neuropathy in terms of hand-foot-syndrome were never observed. In the event of rapid tumor necrosis, which can occur during the first three post-therapeutic days, the patient report tiredness and fatigue with a simultaneous increase in LDH and tumor marker, which falls below the initial value within a few days. The syndrome occurs in 10-15% of patients, accompanied by fever and lassitude (
Ovarian cancer is the leading cause of death, and cure rates between 12-14% have changed little over the past few decades. Debulking operations in terms of complete cytoreduction and platinum-based chemotherapy are considered the cornerstones of current therapy.
On the remaining options, an increase in dose in systemic chemotherapy is limited by the increasing toxicity (
Primary surgery for complete cytoreduction is not possible in advanced stage IV ovarian cancers; these patients can only be treated with chemotherapy.
The DESKTOP III study, comparing chemotherapy and tumor debulking surgery vs. chemotherapy alone was the first prospectively randomized trial showing an overall survival benefit of debulking surgery in recurrent ovarian cancer (
HIPEC pursues the purpose of increased exposure to all peritoneal surfaces after debulking surgery and the best results are expected after debulking to zero or at least less than 1 cm residual disease because the depth of penetration of cytostatics under hyperthermic peritoneal irrigation is at most 2 mm (
On the other hand, novel methodologies are under investigation, such as PIPAC, pressurized intraperitoneal aerosol chemotherapy (
The goal of all efforts in the treatment of ovarian cancer, and especially advanced ovarian cancer, is to increase the efficiency of the therapy used without affecting the quality of life due to unacceptable toxicity. It is a well-known rule that a higher local active drug concentration causes a better response. The limiting factor in higher exposure to cytostatics that may be effective is toxicity. With high-dose therapy limited to one region of the body only (
Hypoxic abdominal perfusion with chemofiltration on the other hand, is relatively uncomplicated with some vascular surgery experience (
The authors wish to acknowledge Mr. Giuseppe Zavattieri (Department for Surgical Oncology, Medias Klinikum Burghausen, Burghausen, Germany) for his help and assistance in preparing the manuscript and statistics used in this report.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
KRA, SG and KA conceived the study. KRA and SG developed the methodology and assessed the authenticity of the data. KRA, SG and KA validated the data. KRA and KA performed formal analysis. KRA and SG performed the investigation. KRA and KA provided resources. KRA, SG and KA curated the data. KRA wrote the original draft. KRA and KA reviewed and edited the manuscript. KRA was involved in visualization. KRA supervised the study. KRA was responsible for project administration. All authors read and approved the final manuscript.
Investigations were performed in compliance with the principles of good clinical practice outlined in the Declaration of Helsinki and federal guidelines, and had approval by the Medias Institutional Review Committee (permit number MIRB20200515; Burghausen, Germany). Written informed consent was obtained from each participant or participant's guardian.
Consent for publication was obtained from any individual person whose data are included in this manuscript.
The authors declare that they have no competing interests.
Schematic of isolated hypoxic abdominal perfusion through cannulation of the femoral artery and vein. The balloon catheters are positioned beneath the diaphragm and connected with an extracorporeal roller pump. Art., arterial; ven., venous.
PFS and OS of all pretreated patients (n=87) in FIGO stage IIIC and IV. PFS, progression-free survival; OS, overall survival; FIGO, Fédération Internationale de Gynécologie et d'Obstétrique; RCT, regional chemotherapy.
Overall survival of all pretreated patients in FIGO stage IIIC and IV. OS, overall survival; FIGO, Fédération Internationale de Gynécologie et d'Obstétrique.
Overall survival in FIGO stage IIIC pretreated vs. non-pretreated patients. OS, overall survival; FIGO, Fédération Internationale de Gynécologie et d'Obstétrique; RCT, regional chemotherapy.
Patient characteristics (n=107).
Value | ||
---|---|---|
Variable | Pretreated (n=87) | Non-pretreated (n=20) |
Median age, years | 56.6 | |
Stage, n (%) | ||
FIGO IIIC | 46(53) | 20(100) |
FIGO IV | 41(47) | 0 (0) |
Grading, n (%) | ||
G3 | 34(30) |
FIGO, Fédération Internationale de Gynécologie et d'Obstétrique.
Time interval between prior treatments and hypoxic abdominal perfusion with chemofiltration.
Stage | No. | Median platinum-free interval before perfusion |
---|---|---|
FIGO IIIC non-pretreated | 20 | No pretreatment |
FIGO IIIC pretreated | 46 | 7 months |
FIGO IV pretreated | 41 | 9 months |
FIGO, Fédération Internationale de Gynécologie et d'Obstétrique.
Response rates of pretreated Fédération Internationale de Gynécologie et d'Obstétrique stage IIIC and IV patients with recurrent disease.
Response | Stage IIIC, % | Stage IV, % | Stage IIIC/IV, % | Ascites, % |
---|---|---|---|---|
PD | 6.5 | 9.8 | 8.0 | 0.0 |
SD | 26.1 | 19.5 | 23.0 | 0.0 |
PR | 47.8 | 56.1 | 51.7 | 19.0 |
CR | 19.6 | 14.6 | 17.3 | 43.0 |
CR+PR | 67.4 | 70.7 | 69.0 | 62.0 |
PD, progressive disease; SD, stable disease; CR, complete response; PR, partial response.
Annual survival rates of 1-4 years of all pretreated FIGO stage IIIC and IV patients (n=87) with recurrent disease.
Stage | 1-year OS, % | 2-year OS, % | 3-year OS, % | 4-year OS, % | 13-year OS, % |
---|---|---|---|---|---|
FIGO IIIC/IV (n=87) | 47.1 | 23.8 | 16.4 | 9.8 | - |
FIGO IIIC (n=46) | 54.3 | 25.2 | 19.2 | 12.8 | 3.1 |
FIGO IV (n=41) | 39.0 | 22.0 | 13.2 | 9.5 | - |
FIGO, Fédération Internationale de Gynécologie et d'Obstétrique; OS, overall survival.
Toxicity profile after isolated hypoxic abdominal perfusion with cisplatin, adriamycin and mitomycin for advanced ovarian cancer.
Adverse event | Extent |
---|---|
Bone marrow suppression | WHO grade I/II |
Fatigue syndrome | 15-20% |
Transient elevation of creatinin | 15% |
Neutropenic fever | 0% |
Hand-foot-syndrome | 0% |
WHO, World Health Organization.