Epithelial ovarian cancer is usually diagnosed when the tumor has already disseminated at the peritoneal surfaces. The standard treatment at this stage is cytoreductive surgery combined with systemic chemotherapy [
Even if a complete cytoreduction has been performed with no macroscopically visible tumor, microscopic tumor will always remain at the peritoneal surfaces. A potentially therapeutic result is possible if the residual tumor is eradicated. Intraperitoneal chemotherapy is effective in eradicating cancer emboli with maximal diameter less than 2-3 mm.
In practice, hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC) has been used in locally advanced epithelial ovarian cancer as an adjuvant treatment after cytoreductive surgery with promising results [
The purpose of the prospective nonrandomized study is to determine the efficacy of HIPEC after maximal cytoreductive surgery in women with locally advanced epithelial ovarian cancer.
Women with locally advanced epithelial ovarian cancer (both primary and recurrent) were enrolled from 2006 to 2010 for maximal cytoreductive surgery with standard peritonectomy procedures combined with HIPEC.
The diagnosis was established by physical examination, hematological-biochemical examinations, tumor markers (CEA, CA 19-9, CA-125), and abdominal and thoracic CT scan. The performance status, age, the extent of prior surgery, the extent and distribution of peritoneal dissemination, the tumor volume, the completeness of cytoreduction (CC score), the presence of ascites, and the presence of metastatic disease were assessed and correlated to survival, recurrences, sites of recurrence, morbidity, and hospital mortality.
The physical status of the patients was assessed using the Karnofsky performance scale.
The extent of prior surgery was assessed using prior surgery score (PSS) [
The extent and distribution of peritoneal dissemination was assessed by using the peritoneal cancer index (PCI). Two transverse and two sagittal planes divided the abdomen in 9 regions. The upper transverse plane was the lowest part of the costal margin and the lower plane the anterior superior iliac spine. The small bowel was assessed as a separate entity, divided into 4 segments (upper and lower jejunum, upper and lower ileum). The peritoneal cancer index was the sum of the tumor volume in each one of the 13 abdominopelvic regions. The tumor volume was assessed as small if the largest tumor nodules were <0.5 cm in their largest diameter and as large if the nodules were >0.5 cm [
The completeness of cytoreduction was indicated by CC-0 to CC-3. A CC-0 indicated that no visible tumor had been left behind after surgery. A CC-1 indicated that the residual tumor was <0.25 cm in its largest diameter. If after cytoreductive surgery tumor >0.25 cm and <2.5 cm was left behind, it was indicated as CC-2 surgery, and when the largest diameter of the residual tumor was >2.5 cm this was indicated by CC-3 surgery. Only CC-0 operations were considered complete cytoreductions [
The presence of metastatic disease to remote lymph nodes that had no anatomic relationship to the primary site was considered as distant metastasis.
During the immediate postoperative period all patients were assisted in an intensive care unit for 24 hours. If early postoperative intraperitoneal chemotherapy (EPIC) was used then the patients were assisted for 5 days in the ICU. Chemotherapy toxicity was scored using the WHO criteria. Treatment-related morbidity was classified as grade 1: uncomplicated patient, grade 2: minor complications, grade 3: major complications requiring intervention (ICU readmission or reoperation), and grade 4: in-hospital mortality.
The protocol was approved by the Ethical Committee of the hospital, and an informed consent was signed by all patients.
Patients with: (a) acceptable physical status (Karnofsky performance status >50%), (b) normal liver and renal function, (c) normal hematological profile, and (d) no evidence of other malignancy or at risk for recurrence, except for basal cell carcinoma or in situ cervix cancer properly treated, were considered eligible for maximal cytoreductive surgery and HIPEC.
The patients underwent surgery with the intention of performing a complete cytoreduction. The standard peritonectomy procedures used for maximal cytoreduction of the tumor volume were pelvic peritonectomy, greater omentectomy with or without splenectomy, lesser omentectomy, right and left subdiaphragmatic peritonectomy, cholecystectomy with resection of the omental bursa, and parietal peritonectomy. Resection of other organs, small and/or large bowel, and stomach was performed if necessary for achieving complete cytoreduction.
After the resection of the tumor and before the reconstruction of the gastrointestinal tract HIPEC was performed using the Coliseum technique [
The patients were followed up every 4 months during the first year after surgery and every 6 months later with physical examination, hematological-biochemical examinations, tumor markers (CEA, CA-125), and CT abdominal scan. The recurrences and the sites of recurrence were recorded.
Statistical analysis was made using the SPSS (Statistical Package for Social Sciences). The proportions of patients with a given characteristic were compared by chi-square analysis or by Pearson’s test. Differences in the means of continuous measurements were tested by the Student’s
From 2006 to 2010, 43 women with primary or recurrent ovarian cancer were enrolled in the study and underwent maximal cytoreductive surgery and HIPEC. The mean age of the patients was
Characteristics of the patients.
Number of patients | % | |
---|---|---|
Performance status | ||
90–100% | 34 | 79.1 |
70–80% | 8 | 18.6 |
50–60% | 1 | 2.3 |
Tumor volume | ||
Large volume | 34 | 79.1 |
Small volume | 9 | 20.9 |
PSS | ||
PSS-0 | 23 | 53.5 |
PSS-1 | 4 | 9.3 |
PSS-2 | 8 | 18.6 |
PSS-3 | 8 | 18.6 |
PCI | ||
PCI < 15 | 23 | 53.5 |
PCI > 15 | 20 | 46.5 |
CC | ||
CC-0 | 30 | 69.8 |
CC-1 | 11 | 25.6 |
CC-2 | 2 | 4.7 |
Ascites | 27 | 62.8 |
Remote lymph nodes | 4 | 9.3 |
Systemic chemotherapy | 23 | 53.5 |
Morbidity | 22 | 51.2 |
Hospital mortality | 2 | 4.7 |
Recurrence | 13 | 30.2 |
Peritonectomy procedures.
Peritonectomy | Number of procedures | % |
---|---|---|
Right subdiaphragmatic | 21 | 8.7 |
Left subdiaphragmatic | 13 | 5.4 |
Greater omentectomy | 37 | 15.4 |
Lesser omentectomy | 12 | 5 |
Splenectomy | 20 | 8.3 |
Pelvic peritonectomy | 43 | 17.8 |
Cholecystectomy + resection of the omental bursa | 23 | 9.5 |
Right parietal | 20 | 8.3 |
Left parietal | 20 | 8.3 |
Segmental intestinal resection | 12 | 5 |
Right colectomy | 6 | 2.5 |
Subtotal colectomy | 8 | 3.4 |
Abdominopelvic lymph node resection | 2 | 0.8 |
Antrectomy | 4 | 1.6 |
Grade 1 morbidity was recorded in 21 patients (48.8%). Grade 2 morbidity was recorded in 16 patients (35.2%) that had pleural effusion, neutropenia grade II that did not require medical treatment, pneumonitis, fistulas, and wound infection, grade 3 morbidity was recorded in 4 patients (9.3%) that had enterocutaneous fistulas, and grade 4 morbidity in 2 patients (4.7%) with anastomotic failure that developed sepsis (Table
Complications.
Complication | Number of patients | % |
---|---|---|
Grade I | 21 | 48.8 |
Grade II | ||
Pleural effusion | 2 | 4.7 |
Wound infection | 7 | 14.2 |
Neutropenia grade II | 3 | 6.9 |
Pneumonitis | 2 | 4.7 |
Enterocutaneous fistulas | 2 | 4.7 |
Grade III | 4 | 9.3 |
Enterocutaneous fistulas | ||
Grade IV | 2 | 4.7 |
Anastomotic failure |
Histopathology revealed serous adenocarcinomas in 25 cases (58.1%), cystadenocarcinomas in 8 cases (18.6%), endometrioid in 6 cases (13.9%), and clear-cell carcinomas in 4 cases (9.4%).
The overall 5-year survival rate was 54% (Figure
Overall 5-year survival rate.
Survival according to CC score. The continuous line is for patients with CC-O and the dotted line is for patients with CC-1, CC-2 (
Survival according to PCI. The continuous line is for patients with PCI < 15 and the dotted line for patients with PCI > 15 (
Survival according to PSS. The continuous line is for patients with PSS-0 and the dotted line for patients with PSS-1, PSS-2, and PSS-3 (
By multivariate analysis it was found that the prognostic indicators of survival were the PSS (HR = 5.844,
No patient was lost during followup. During followup 13 patients (30.2%) developed recurrence. The recurrence was distant in 5 patients and locoregional in 8. Of the 43 patients, 28 (65.1%) are alive without evidence of disease, 3 patients (7.1%) died for reasons unrelated to disease, 8 patients (18.6%) died because of recurrence, and 2 patients (4.6%) are alive with recurrence. By univariate analysis the recurrence was found to be related to pathological values of CA-125 (
The survival rate of epithelial ovarian cancer has improved because the tumor is one of the few most chemosensitive to platinum derivatives [
The most powerful tool in the treatment of ovarian cancer with peritoneal dissemination is cytoreductive surgery. Complete (CC-0) or near-complete (CC-1) cytoreduction is feasible in more than 75% of the cases [
One of the most significant variables of survival is the extent of prior surgery. It has not been given much attention and only in one study that the PSS has been reported as a prognostic variable of survival [
Intraperitoneal chemotherapy has been documented as the standard treatment of peritoneal malignancy from nongynecologic cancer [
The method has been performed with the use of the open abdominal technique (Coliseum technique) that enables the uniform distribution of the heat and the cytostatic drugs in the abdominal cavity. In addition, during perfusion the surgeon has the advantage to surgically eradicate small nodules located at the mesentery of the small bowel and as a consequence to shorten the operative time.
Severe morbidity (grade 3 and 4) has been recorded in 6 patients (14%). It is obvious that the most severe complication is the anastomotic failure. Anastomotic failure has been reported in other series as the most frequent complication [
Severe side effects attributed to HIPEC have not been recorded. Grade 3/4 toxicity is rare and does not exceed 5% [
Maximal cytoreductive surgery with standard peritonectomy procedures combined with intraperitoneal chemotherapy is a well-tolerated and feasible method for treatment of advanced epithelial ovarian cancer. It appears to improve long-term survival securing that complete or near complete cytoreduction is possible in the vast majority as well as the eradication of the microscopic residual tumor.