The majority of patients with ovarian cancer (OC) are diagnosed with advanced disease that has spread beyond the ovaries to cause peritoneal metastasis (PM), and this advanced stage accounts for the highest mortality of all gynecologic cancers [
Over the past three decades, aggressive cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has been developed as a comprehensive treatment package integrating multivisceral resections to remove macroscopic residual tumors, and HIPEC has been used to treat residual cancer cells after CRS [
Bakrin et al. [
A retrospective analysis was conducted in this study to assess the efficacy and safety of CRS+HIPEC as a front-line surgical regimen in 100 patients with AOC.
From December 1, 2007, to January 1, 2020, 100 patients diagnosed with FIGO stage III/IV OC underwent CRS+HIPEC as a first-line surgery strategy at our center. Informed consent was obtained from all patients, and the study was approved by the institutional review board and the ethics committee.
The main inclusion criteria were as follows: (1) no history of PM-related surgery; (2)
The major exclusion criteria were as follows: (1) history of PM-related surgery; (2) any lung, liver, or prominent retroperitoneal lymph node metastases found during preoperative assessment; (3) imaging examination showing obvious contractures of the mesentery; (4)
Patients were evaluated according to the Chinese expert consensus [
All CRS+HIPEC procedures were conducted by a designated team focusing on PM treatment. Briefly, abdominal exploration was performed through a midline xiphoid-to-pubis incision after administering general anesthesia, and the peritoneal cancer index (PCI) was evaluated and recorded. Then, maximal CRS was performed, including curative or palliative resection of the primary tumor with acceptable margins an any involved adjacent structures, lymphadenectomy, and peritoneal resection, and then, the completeness of cytoreduction (CC) score was calculated.
Open HIPEC was implemented with each drug dissolved in 3 L of heated saline at
After the operation, the patients were transferred to the intensive care unit for recovery and then to the ward when they stabilized.
Adjuvant chemotherapy was delivered within 6 to 8 weeks after CRS+HIPEC, including platinum/taxane-based systematic chemotherapy (SC) and perioperative intraperitoneal chemotherapy (IPC) through the IPC port once every 4 to 6 weeks. DDP 100 mg/m2 and paclitaxel/DTX 100 mg/m2 were administered.
All patients were regularly followed up once every 3 months for the first 2 years, every 6 months for years 3 to 5, and every year thereafter to obtain detailed information on disease status. The most recent follow-up was performed on January 1, 2020, and no patients have been lost.
(1) Clinicopathological characteristics: age, history of adjuvant therapy, KPS score, and preoperative tumor markers; (2) CRS+HIPEC-related parameters: duration of surgery, number of organs and peritoneal resected, number of anastomotic stoma, HIPEC regimens, PCI, CC score, and intraoperative volume; (3) survival: survival status, median overall survival (mOS), and median progression-free disease (mPFS); and (4) adverse events
(1) The primary endpoints of this study were OS and PFS. OS was defined as the time interval from the first surgery to tumor-related death or last follow-up. PFS was calculated from the date of surgery until the last follow-up that met the following criteria: the patients who underwent surgery-based curative comprehensive treatment developed any clinical manifestations, the CA 125 level rose again after surgery, medical imaging discovered any mass in the operation field, and the biopsy confirmed the diagnosis. (2) The secondary endpoints were perioperative serious adverse events (SAEs), which were defined as complications directly attributable to the treatment within 30 days of CRS+HIPEC and were evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [
Graphical representation of PCI and CC score according to the Sugarbaker [
The patient information was systematically integrated into a prospectively established database. Data analysis was conducted using the Statistical Package for Social Sciences version 24.0 (SPSS, Inc., Chicago, IL). Descriptive data are expressed as medians [range or 95% confidence intervals (CIs)] for quantitative variables and as numbers (percentage) for qualitative data. The hypothesis test was performed by the
In total, 100 AOC patients were treated with 106 CRS+HIPEC procedures, including 6 patients who each underwent 2 CRS+HIPEC procedures due to tumor recurrence. The median age was 58.5 (28-87) years, and the median KPS score was 80 (50-100); according to histopathological classification, 91 (91/100, 91.0%) patients had serous adenocarcinoma, and 9 (9/100, 9.0%) patients had other types of tumors. For the areas of surgical excision, the median number of organ resections was 4 (3-9), and the number of peritoneal resections was 4 (1-9). Regarding adjuvant therapies, preoperatively, SC was applied in 48 (48/100, 48.0%) cases, and IPC was applied in 16 (16/100, 16.0%) cases; postoperatively, SC was applied in 76 (76/100, 76.0%) cases, and IPC was applied in 46.0 (46/100, 46.0%) cases. The clinicopathological characteristics are listed in Table
Demographic and clinical characteristics of 100 AOC patients.
Items | Value |
---|---|
Clinical characteristics | |
Age (median, range) (y) | 58.5 (28-87) |
KPS score (median, range) | 80 (50-100) |
History of chemotherapy ( | |
Yes | 52 (52.0) |
No | 48 (48.0) |
Histopathology ( | |
Serous carcinoma | 91 (91.0) |
Other types | 9 (9.0) |
Cycles of SC before surgery (median, range) | 3 (0-45) |
Cycles of IPC before surgery (median, range) | 1 (0-9) |
Cycles of SC after surgery (median, range) | 4 (0-26) |
Cycles of IPC after surgery (median, range) | 6 (0-8) |
SC before surgery ( | 48 (48) |
IPC before surgery ( | 16 (16) |
SC after surgery ( | 76 (76) |
IPC after surgery ( | 46 (46) |
CRS+HIPEC relevant parameters | |
Organ regions resected ( | |
1-3 resections | 39 (39.0) |
>4 resections | 61 (61.0) |
Peritoneal regions resected ( | |
0-3 resections | 37 (37.0) |
4-6 resections | 40 (40.0) |
>6 resections | 23 (23.0) |
Number of anastomosis ( | |
0-1 | 34 (34.0) |
≥1 | 66 (66.0) |
PCI score ( | |
≤19 | 53 (53.0) |
>19 | 47 (47.0) |
CC score ( | |
0-1 | 79 (79.0) |
2-3 | 21 (21.0) |
Lymph node dissection ( | |
Pelvic lymph node | 100 (100) |
Abdominal aortic lymph node | 68 (68) |
Iliac lymph nodes | 100 (100) |
Fluid output volume at surgery (median, range) | |
Blood loss (ml) | 550 (0-3,000) |
Urine output (ml) | 1,500 (300-4,500) |
Ascites (ml) | 270 (0-8,000) |
≤1000 ( | 68 (68.0) |
>1000 ( | 32 (32.0) |
Fluid intake volume at surgery (median, range) | |
Plasma (ml) | 600 (0-4,000) |
RBC (U)a | 2 (0-12.0) |
Other fluids (ml)b | 6,735 (100-13,950) |
CRS+HIPEC duration (median, range) (min) | 600 (80-910) |
Stay in hospital (median, range) (d) | 27 (0-120) |
a
The median follow-up was 36.8 (0.8-159.3) months. At the time of analysis, 25 (25/100, 25%) patients had died, and 75 (75/100, 75.0%) patients were alive; the mOS was 87.6 (95% CI: 72.1-103.0) months, and the 1-, 2-, 3-, 4-, and 5- year survival rates were 94.1%, 77.2%, 68.2%, 64.2%, and 64.2%, respectively (Figure
OS and PFS in the AOC patients. (a) OS of 100 AOC patients. (b) PFS of 79 AOC patients with complete CRS+HIPEC.
A univariate analysis identified 5 covariates indicative of improved survival, including
Overall survival of 100 AOC patients with correlation factors. (a) Age; (b) KPS score; (c) ascites; (d) PCI score; (e) CC score; (f) adverse events.
Univariate and multivariate analyses on predictors of OS for 100 AOC patients.
Variables | Univariate analysis | Multivariate analysis | ||||||
---|---|---|---|---|---|---|---|---|
HR | 95% CI | HR | 95% CI | |||||
CC score (CC 2-3 | 11.4 | <0.001 | 4.2 | 1.8-9.8 | 6.8 | 0.009 | 3.2 | 1.3-7.5 |
Age (>58 y | 4.8 | 0.021 | 2.7 | 1.1-6.5 | ||||
KPS score (≥80 | 5.0 | 0.015 | 0.3 | 0.1-0.9 | ||||
PCI score (>19 | 3.8 | 0.049 | 2.5 | 1.0-6.0 | ||||
Ascites (>1000 ml | 4.2 | 0.037 | 2.3 | 1.0-5.0 |
CI: confidence interval; HR: hazard ratio.
At the time of analysis, there were 4 (4/100, 4.0%) patients with an OS of over 10 years and without any evidence of tumor recurrence; their OS durations were 149.2, 129.9, 121.5, and 120.9 months. The detailed clinical course of these four patients is listed in Table
Major clinicopathological features of 4 patients with OS over 10 years.
No | Age (y) | KPS score | Histopathology | CRS | HIPEC | PCI score | CC score | Recurrence | Survival status | OS (mo) |
---|---|---|---|---|---|---|---|---|---|---|
1 | 41 | 100 | High-grade serous carcinoma | Hysterectomy and resection of bilateral ovarian/fallopian tubes, pelvic lymphadenectomy, ascending colon resection, sigmoidectomy, left and right diaphragmatic peritoneum, greater/lesser omentectomy, round ligament of liver resection, right paracolic sulci peritoneum, mesenteric fulguration | 19 | 1 | No | Survival | 149.2 | |
2 | 52 | 90 | High-grade serous carcinoma | Hysterectomy and resection of bilateral ovarian/fallopian tube, pelvic lymphadenectomy, greater/lesser omentectomy | MMC 40 mg | 13 | 1 | No | Survival | 129.9 |
3 | 49 | 80 | High-grade serous carcinoma | Hysterectomy and resection of bilateral ovarian/fallopian tube, pelvic lymphadenectomy, sigmoidectomy, cholecystectomy, greater/lesser omentectomy | 11 | 1 | No | Survival | 121.5 | |
4 | 32 | 80 | High-grade serous carcinoma | Hysterectomy and resection of bilateral ovarian/fallopian tubes, pelvic lymphadenectomy, greater/lesser omentectomy | 15 | 1 | No | Survival | 120.9 |
MMC: mitomycin C; DDP: cisplatin; DTX: docetaxel; y: year; mo: months.
Adverse events (AEs) from grades I to V occurred in 31 (31/100, 31.0%) patients, including anemia and hypoproteinemia in 5 (5/100, 5.0%) patients, urinary fistula in 4 (4/100, 4.0%) patients, ileus in 4 (4/100, 4.0%) patients, respiratory infection in 4 (4/100, 4.0%) patients, deep vein thrombosis (DVT) in 3 (3/100, 3.0%) patients, wound infection in 3 (3/100, 3.0%) patients, renal dysfunction in 2 (2/100, 2.0%) patients, and urinary tract infection in 2 (2/100, 2.0%) patients. Grades III to V SAEs occurred in 4 (4/100, 4.0%) patients, including 2 (2/100, 2.0%) patients who died within 30 days of acute renal failure, 1 (1/100, 1.0%) patient with blood loss, and 1 (1/100, 1.0%) patient with ascending colon leakage. The detailed information is listed in Table
Adverse events rate of 100 AOC patients.
Items | |
---|---|
SAE (grades III-V) | 4 (4.0) |
Perioperative mortality | 2 (2.0) |
Blood loss | 1 (1.0) |
Colon leakage | 1 (1.0) |
AE (grades I-II) | 27 (27.0) |
Anemia and hypoproteinemia | 5 (5.0) |
Urinary fistula | 4 (4.0) |
Ileus | 4 (4.0) |
Respiratory infection | 4 (4.0) |
DVT | 3 (3.0) |
Wound infection | 3 (3.0) |
Renal dysfunction | 2 (2.0) |
Urinary tract infection | 2 (2.0) |
AE: adverse event; SAE: serious adverse event; DVT: deep venous thrombosis.
A subgroup analysis was conducted. Seventy-nine (79/100, 79.0%) AOC patients achieved CC scores of 0-1, the mPFS was 67.8 (95% CI: 48.3-87.4) months (Figure
The treatment of AOC remains an open and critical question. Despite clinical remission after palliative surgery and platinum/taxane-based systematic chemotherapy [
We aimed to investigate the efficacy and safety of CRS+HIPEC as a first-line surgery strategy in100 patients with AOC. In essence, by comparing long-term survival, we were able to evaluate whether CRS+HIPEC, as a comprehensive therapy strategy, can be a suitable for the routine treatment for AOC. The results showed that the mOS was 87.6 months, and the 1-, 3-, and 5-year survival rates were 94.1%, 68.2%, and 64.2%, respectively. Complete CRS was achieved in 79.0% of patients, and the mPFS was 67.8 months. Of special note are four patients with high-grade serous disease who achieved an
van Driel et al. [
The more extensive surgery to minimize tumor burden led to the success of CRS+HIPEC, which is an independent prognostic factor for patients with AOC [
Previously published studies for AOC patients with complete CRS in recent 5 years.
No. | Author | Year | No. (%) | mOS (mo) | mPFS (mo) | SAE (%) | Mortality (%) |
---|---|---|---|---|---|---|---|
1 | Coccolini et al. [ | 2015 | 54 (100.0) | 32.9 | 12.5 | 35.2 | 5.6 |
2 | Kocic et al. [ | 2016 | 28 (96.8) | 51.0 | 19.0 | NA | NA |
Sun et al. [ | 2016 | 28 (60.9) | 79.5 | 8.5 | 10.0 | 0.0 | |
3 | Manzanedo et al. [ | 2017 | 59 (97.0) | NA | 17.0 | NA | NA |
4 | Magge et al. [ | 2017 | 68 (90.6) | 41.8 | 13.3 | NA | NA |
5 | Pavlov et al. [ | 2017 | 112 (97.0) | 40.3 | 26.7 | 9.5 | 0.8 |
6 | Di Giorgio et al. [ | 2017 | 371 (72.6) | 52.4 | 16.6 | 17.4 | 0.0 |
7 | Mendivil et al. [ | 2017 | 68 (100.0) | 33.8 | 25.1 | 0.0 | 0.0 |
8 | Mercier et al. [ | 2018 | 155 (92.5) | 69.3 | 30.3 | NA | NA |
9 | van Driel et al. [ | 2018 | 106 (87.0) | 45.7 | 14.2 | 27.0 | 0.0 |
10 | This study | 2019 | 79 (79.0) | 95.2 | 67.8 | 4.0 | 2.0 |
NA: not available; mo: months.
As such, every attempt should be made to achieve complete CRS, which means a high risk for AEs and mortality. The safety of CRS+HIPEC has been fully verified, with a perioperative mortality rate of 0 to 10.0% and an incidence of SAEs of 22.0% to 28.0% [
Apart from its retrospective design, the limitations of this study are the use of single-center cohort with a short median follow-up, but the results showed a tendency towards long survival and safety benefits for AOC patients who underwent CRS+HIPEC as an upfront surgery strategy at experienced high-volume peritoneal cancer centers.
In summary, this study has provided evidence that CRS+HIPEC, as a preferred surgical strategy, could prolong the survival of AOC patients, especially for those with a
Ovarian cancer
Peritoneal carcinoma
Advanced ovarian cancer
Cytoreductive surgery
Hyperthermic intraperitoneal chemotherapy
Upper limit of normal
Alanine aminotransferase
Aspartic aminotransferase
Serum creatinine
Karnofsky performance status
Carbohydrate antigen 125
Carbohydrate antigen 199
Carcinoembryonic antigen
Computed tomography
Docetaxel
Mitomycin C
Cisplatin
Systematic chemotherapy
Intraperitoneal chemotherapy
Overall survival
Progress-free survival
Adverse events
Serious adverse events
Peritoneal cancer index
Completeness of cytoreduction
Confidence intervals.
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
The protocol of this prospective investigation was granted by the Institutional Review Board at Beijing Shijitan Hospital (code number 2019054). All methods were performed in accordance with the relevant guidelines and regulations or Declaration of Helsinki as patients were involved.
Written informed consent was obtained from all subjects or, if subjects are under 18, from a parent and/or legal guardian.
This manuscript has been presented as a preprint in http://Researchsquare.com.
The authors declare that they have no competing interests.
This study was supported by the grants supporting Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20180701), Special Fund for the Capital Characteristic Clinical Medicine Development Project (Z161100000516077), Beijing Municipal Grant for Medical Talents Group on Peritoneal Surface Oncology (2017400003235J007), Key Discipline Development Fund of Beijing Shijitan Hospital affiliated to the Capital Medical University (2016fmzlwk), Beijing Natural Science Foundation (7172108), Health Science Promotion Project of Beijing (2018-TG-27), and Hubei Provincial Natural Science Foundation of China (2017CFB177). Thanks for the support of journal of Cancer Research and Clinic (a domestic journal of China), in which the data from this article was published on November, 2020, issue 32 (8): 574-578. With the permission and authorization of the journal, we updated the data and translated it into English and submitted to the journal of Biomed Research International.