Cytoreduction Plus Hyperthermic Intraperitoneal Chemotherapy in Primary and Recurrent Ovarian Cancer: A Single-Center Cohort Study

Abstract

Epithelial ovarian cancer (EOC) is the most frequent cause of death among women with gynecologic malignant tumors. Primary debulking surgery (PDS) with maximal surgical effort to reach completeness of cytoreduction, followed by chemotherapy, has become the standard of care; moreover, some experiences have shown that a comprehensive treatment approach of surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) could improve the prognosis of ovarian cancer. We carried out a retrospective analysis of all consecutive sixty-six patients diagnosed with primary advanced or recurrent ovarian cancer who underwent debulking surgery plus HIPEC in a single center between September 2005 and October 2020. For 33 patients with primary EOC, with a median follow-up period of 70 months, the median overall survival was 56 months (range: 48.1–96.9); and the median disease-free survival (DFS) was 13 months (range: 19.9–53.7). In the recurrent population, the median follow-up period was 78 months, the median overall survival (OS) was 82 months (range: 48.1–96.9), and the median DFS was 17 months (range: 19.7–53.0). In our study, we have found that CRS plus HIPEC is feasible, with very low rates of major complications and good results in terms of overall survival.

1. Introduction

Epithelial ovarian cancer (EOC) is the most frequent cause of death among women with gynecologic malignant tumors [1]. Primary debulking surgery (PDS) with maximal surgical effort to reach completeness of cytoreduction, followed by chemotherapy, has become the standard of care in advanced EOC since the 1980s [2]. The achievement of no residual tumors (R0) after PDS is the most important prognostic factor for survival [3]. In patients with EOC unfit for PDS, neoadjuvant chemotherapy (NACT) followed by cytoreductive surgery (CRS) can be considered [4,5]. In this context, some experiences have shown that a comprehensive treatment approach of surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) could improve the prognosis of ovarian cancer [6]. Globally, investigators have explored the effects of CRS plus HIPEC for patients with primary or recurrent ovarian cancer. The previous studies were mainly based on retrospective cohorts or single-arm trials. Spiliotis et al. published the first randomized clinical trial (RCT) results of CRS plus HIPEC for recurrent ovarian cancer patients in 2015 [7]. Subsequently, with the publication of the results of the multicenter, “open-label,” phase three study comparing CRS plus HIPEC to CRS alone for advanced ovarian cancer [8], the issue of HIPEC has once again caught the attention of clinicians worldwide. The aim of our study was to analyze the survival outcomes of patients with primary advanced or recurrent ovarian cancer who underwent CRS plus HIPEC in a single oncological institution and to verify the reproducibility of the benefits of this type of treatment, even in the daily experience of a medium-volume center.

2. Materials and Methods

This study was a retrospective analysis of a prospective database, which includes all consecutive patients (sixty-six) diagnosed with advanced-stage ovarian cancer (FIGO II-IV stage, according to the International Federation of Gynecology and Obstetrics classification) [9] or recurrent ovarian cancer who underwent CRS plus HIPEC in the General and Oncologic Surgery of Morgagni-Pierantoni Hospital, Forlì (Italy) between September 2005 and October 2020.

The protocol was approved by the Hospital Ethics Committee Protocol code 0/23453/F2RP and date of approval 4 June 2004), and written informed consent was signed by all patients.

The inclusion criteria were as follows: (1) age ≥ 18 years; (2) histological confirmation of fallopian tube or ovarian origin of carcinosis in the final specimen; (3) upfront cytoreductive surgery (CRS) plus HIPEC or interval debulking surgery (IDS) plus HIPEC or CRS + HIPEC in recurrent ovarian cancer; and (4) a World Health Organization (WHO) performance status score of 0 to 2.

The exclusion criteria included the following: (1) tumors with peritoneal carcinosis of extraovarian origin; (2) CRS or IDS without HIPEC; (3) informed consent refusal; (4) extra-abdominal disease; (5) no-response to NACT; (6) patients treated for malignancies in the previous 5 years; and (7) age >75 years.

Patients with a primary tumor after completing staging with a thoraco-abdominal CT scan underwent laparoscopy. If the peritoneal disease was judged to be completely resectable, the patients underwent upfront surgery, otherwise, the patients were referred for neoadjuvant chemotherapy before undergoing CRS and HIPEC. An assessment of the disease spread at laparoscopy was performed according to the Peritoneal Cancer Index (PCI), proposed by Sugarbaker, which involves the identification of 13 abdominal fields, each of which is assigned a “lesion size score,” with a final score that can range between 0 and 39 (0 if there is an absence of disease; 1 if there are lesions with a diameter of less than 5 mm; 2 if there are lesions with a diameter between 5 mm and 5 cm; 3 if the diameter is greater than 5 cm, or in the presence of confluent nodules) [10]. In patients with disease recurrence, the assessment of the tumor extent and subsequent judgment of respectability was made only on CT images.

All patients were evaluated within the multidisciplinary ovarian cancer oncology team, consisting of at least two oncologists, a general surgeon, a gynecologist, a radiologist, and a pathologist.

The patients were grouped according to surgical treatment timing, as follows: group 1: upfront debulking surgery (UDS); group 2: interval debulking surgery after partial response to NACT (at laparotomy PCI ≥ 4); group 3: interval debulking surgery after a clinically complete response (at laparotomy PCI ≤ 3); group 4: surgery after first recurrent ovarian cancer; and group 5: surgery from the second recurrence onwards. To be more explicit regarding the assignment to groups 2 and 3, the response to NACT was assessed at two stages.

The first step was performed through the comparison between pre- and post-treatment CT scans. In this phase, the Response Evaluation Criteria in Solid Tumors (RECIST) was used [11]. The second step was performed during the surgical procedure based on the peritoneal carcinomatosis index (PCI). Based on this score, patients were definitively placed in group 2 or group 3.

The patient was placed in the dorsal lithotomy position with both legs in Allen stirrups. A multilumen central venous catheter was placed. Bilateral “open-end” ureteral stents were placed under fluoroscopic guidance before incising the skin to make the ureters more easily recognizable and avoid ureteral damage. A three-way bladder tube was placed for possible bladder lavage, if needed. To reduce heat loss after anesthetic induction, minimal fresh gas flow and active rewarming of the patient by infusion of heated fluids were administered. A median xipho-umbilical-pubic incision was made. At laparotomy, the peritoneal spread was recorded according to the Peritoneal Cancer Index (PCI) [11]. In all patients with primary ovarian cancer, CRS routinely included omentectomy and pelvic peritonectomy. In patients with a low disease burden in the pelvis, a pelvic peritonectomy was performed, sparing rectosigmoid colon resection. In extensive pelvic peritoneal involvement, an “en-bloc retrograde hysterectomy with bilateral salpingo-oophorectomy and recto-sigmoid colectomy with pelvic peritonectomy” was performed, according to Hudson’s technique [12]. Visceral resection, splenectomy, removal of liver capsule nodules, limited liver resection, and other peritonectomy procedures were carried out depending on the distribution of malignancy in the peritoneum; furthermore, healthy peritoneum was never excised, according with the technique described by P.H. Sugarbaker [13]. Superficial carcinosis nodules (especially if affecting the meso of the small bowel) were destroyed using high voltage “cute mode” electrocautery in and at the source, which resulted in tissue destruction via vaporization. Electrocautery was used without cooling on the mesentery, ligaments, hepatic dome, and parietal peritoneum; however, on the walls of hollow organs, it was used by jetting cold saline to prevent perforation risks. At the end of cytoreductive surgery, the completeness of cytoreduction score (CCS) was recorded according to Sugarbaker’s classification. The CCS provides a score between 0 and 3 (in detail: 0 = no residual disease, 1 = presence of disease residue with diameter < 0.25 cm, 2 = diameter of disease residue between 0.25 and 2.5 cm, 3 = disease residue with diameter > 2.5 cm) [13]. Only patients with CCS 0–1 underwent HIPEC. At the end of the cytoreductive phase, the perfusion phase began. We used the semi-closed colosseum method [14]. A total of 5 drains were inserted into the abdominal cavity, as follows: 3 drains on the left (2 for inflow) and 2 on the right (for outflow), which were introduced through accessory mini-incisions at the flank level, along the prolongation of the middle axillary line, with Y-connections to the extracorporeal circulation circuit. The incision skin was suspended with Backhaus forceps from an autostatic oval retractor anchored on the operating table to create an abdomen cavity that could be perfused. The oval was placed approximately 20 cm above the patient. The central opening was covered with a polyvinyl chloride sheet, in which a cross-shaped incision was made, allowing the passage of the surgeon’s hand, to mix fluid during perfusion. A smoke extractor was placed on top of said sheet. The purpose of all of these arrangements was to minimize the dispersion of antiblastic-containing vapors into the surrounding environment. The drainage tubes were then connected to an integrated multifunction extracorporeal circulation system that concentrated perfusion, liquid heating, and temperature sensing in a single device. During treatment, perfusate inlet and outlet temperatures were monitored with probes inside the drains, while the intraperitoneal temperature was monitored with the use of at least one probe placed in the pelvis. The amount of fluid circulated was about 4 L of peritoneal dialysis solution (2.2 L/sq m body surface area), in which the chemotherapy drug was diluted. Doxorubicin (7.5 mg/peritoneal dialysis fluid liter) and cisplatin (43 mg/peritoneal dialysis fluid liter) were administered as chemotherapeutic agents at a rate of 1200 cc/min. Hyperthermic intraperitoneal chemotherapy perfusion was started after reaching 42 °C of intraperitoneal temperature and was maintained at 42–43 °C for 60 min. Thirty minutes before hyperthermic perfusion, active warming was stopped. Fifteen minutes before and for the duration of the perfusion, the patient was actively cooled through the placement of cooling bags on the head and neck, infusions of cold fluids, and possible bladder lavage with cold saline. If the patient’s body temperature reached 40 degrees Celsius, perfusion was discontinued. Thirty minutes before antiblastic perfusion, Ondansetron 8 mg was administered over 15 min. To reduce the risk of acute renal failure, our protocol involved administering amifostine 550 mg/mq to maintain a diuresis of at least 100–120 mL/10 min (600–720 mL/h) during the HIPEC phase. The amifostine infusion began when the intra-abdominal temperature reached 40 degrees and was administered for 15 min [15,16]. During the HIPEC phase, patients were routinely transfused with fresh frozen plasma, while blood transfusion was used only if the Hb values < 9 mg/dL. At the end of perfusion, a lavage of the abdominal cavity was performed to remove drug residues. Any intestinal anastomoses were made after the cytoreduction phase. Any ostomy placement was performed after hemostasis. At least three drains were placed, as follows: one in the right hypochondrium, one in the left hypochondrium, and one in the pelvic cavity. In cases of extensive diaphragmatic peritonectomy, one or two pleural drains were placed for the purpose of draining fluid that might have accumulated in the pleural cavity, as is often the case.

At the end of surgery, all patients were admitted to the intensive care unit (ICU) for vital parameter monitoring. Complications were recorded according to the Clavien–Dindo classification, and surgical mortality was defined as death of any cause within 30 to 90 days after surgery [17]. Within 6 weeks after CRS plus HIPEC, patients started chemotherapy. Patients’ follow-ups included in the first 2 years were as follows: an outpatient visit and tumor marker testing every 3 months and diagnostic imaging every 6 months. Thereafter, outpatient visit and tumor marker testing every 6 months and yearly diagnostic imaging until the completion of the 5th year after the procedure.

Statistical analysis: Median and interquartile range (IQR) were used to present continuous variables while categorical variables were shown as frequencies and percentages. The Kaplan-Meier function was exploited for survival analyses, and differences were evaluated with the Log Rank test.

3. Results

Sixty-six patients undergoing CRS plus HIPEC in our hospital were evaluated. The median age was 60 (range: 39–75) years. Our cohort consisted of 33 patients with primary ovarian cancer (group 1: 6 patients; group 2: 23 patients; group 3: 4 patients) and 33 with recurrent ovarian cancer (group 4: 21 patients; group 5: 12 patients). The patients undergoing NACT received three cycles of carboplatin plus paclitaxel. The patient characteristics are shown in

Table 1. Patients’ characteristics.

	N	PCI (Range)	CC-Score (N) (%)
			CC-0	CC-1
All cases (N)	66	10.7 (0–30)	60 (91)	6 (9)
Primary EOC (N)	33	12.7 (0–30)	28 (84.9)	5 (15.1)
group 1	6	9 (0–22)	5 (83.3)	1 (16.7)
group 2	23	16 (4–30)	19 (82.6)	4 (17.4)
group 3	4	1 (0–3)	4 (100)
Recurrent EOC (N)	33	8.5 (0–28)	32 (97)	1 (3)
group 4	20	7 (0–28)	20 (100)
group 5	13	10.5 (2–22)	12 (92)	1 (8)
Age (Median) (Range)	60 (39–75)
Histology (N) (%)
Primary EOC
Serous	32 (97%)
Endometrioid	1 (3%)
Recurrent EOC
Serous	28 (85%)
Endometrioid	4 (12%)
Anaplastic	1 (3%)

Group 1: Upfront debulking surgery. Group 2: Interval debulking surgery after partial response to neoadiuvant chemotherapy (at laparotomy Peritoneal Cancer Index ≥ 4). Group 3: Interval debulking surgery after clinically complete response (at laparotomy Peritoneal Cancer Index ≤ 3). Group 4: Surgery after first recurrent ovarian cancer. Group 5: Surgery from the second recurrence onwards. PCI: Peritoneal Cancer Index. CCS: Complete Cytoreduction Score. EOC: Epithelial ovarian cancer.

. One bowel anastomosis was packed in 30 patients, two anastomoses in 6 patients, and three anastomoses in 1 patient. An ostomy was packed in 21 patients. The details of the CRS and the HIPEC procedures are reported in

Table 2. Surgical procedures.

	N (%)
Omentectomy (greater omentum) with resection of the gastrocolic ligament	53 (80.3)
Pelvic peritonectomy	50 (75.7)
Lesser omentum resection	49 (74.2)
Lombo-Aortic lymphadenectomy	34 (51.5)
Ilio-obturator lymphadenectomy	33 (50)
Sigmoid resection	33 (50)
Parietal peritoneal dissection of right paracolic gutter	33 (50)
Cholecystectomy	31 (47)
Hysterectomy	29 (43.9)
Right subphrenic (diaphragmatic) peritonectomy	28 (42.4)
Parietal peritoneal dissection of left paracolic gutter	26 (39.4)
Left subphrenic (diaphragmatic) peritonectomy	17 (25.7)
Appendicectomy	14 (21.2)
Splenectomy	11 (16.7)
Ileco-colic resection	9 (13.6)
Other colic resection	4 (6)
Other intestinal resection	3 (4.5)

, while the perioperative outcomes are reported in

Table 3. Perioperative outcomes.

Variables
Surgical time in minutes: Median (range)	686 (356–926)
PCI median (range)Complete Cytoriduction score	9 (0–30)N (%)
CCS 0	60 (91)
CCS 1	6 (9)
Major Complications (N) (%)
Grade IIIa	3 (4.5)
Grade IIIb	4 (6)
Grade IVa	1 (1.5)
Grade IVb	0
Grade V	0
	Days
Hospital stay in days: Median (range)	9.5 (8–39)
ICU stay in days Median (range)	3 (1–16)

CCS: Complete Cytoreduction Score. PCR: Peritoneal Cancer Index. Complication according to Clavien–Dindo classification.

. The median PCI score was 9 (range: 0–30). Complete cytoreduction (CC-0) was achieved in 60 patients (91%). The median operating time was 686 (356–926) minutes. The median length of hospital stay was 19.5 days (range: 8–39), and the median ICU stay was 3.3 days (range: 1–16). Major surgical complications occurred in eight patients (12%), as follows: three grade IIIA (one lymphocele and two pleural effusions), four grade IIIB (four eviscerations), one grade IVA (massive pulmonary embolism). No postoperative deaths were recorded.

In a multivariate analysis performed to assess whether there were any risk factors related to complications of a class greater than two, according to the Clavien–Dindo classification, no parameters among those analyzed (type of surgical procedure performed, presence of chest tube, age, number of anastomoses, and presence of ostomy) were found to be statistically significant, except left diaphragmatic peritonectomy.

For the 33 patients with primary EOC, with a median follow-up period of 70 months, the median overall survival (OS) was 56 months (range: 48.1–96.9) and the median disease-free survival (DFS) was 13 months (range: 19.9–53.7). In the recurrent population, the median follow-up period was 78 months, the median OS was 82 months (range: 48.1–96.9), and the median DFS was 17 months (range: 19.7–53.0). The details of the OS and primary and recurrent ovarian cancer are shown in Figure 1. The small size of the study cohort did not allow for an adequate analysis of the OS according to the five different surgical times. The Kaplan–Mayer analysis guides the hypothesis that the best outcomes are associated with the UDS approach (group 1) and IDS in case of complete clinical response (group 3). These results are shown in Figure 2.

4. Discussion

Formerly, the management of ovarian cancer included surgery followed by systemic chemotherapy or interval surgery after three cycles of chemotherapy; however, the survival results remain largely unsatisfactory [4,18]. HIPEC has been offered as a promising therapy approach based on a number of theoretical reasons. Firstly, intraperitoneal chemotherapy is certainly efficacious in the treatment of ovarian cancer, as stated in the literature [19]. Secondly, hyperthermia increases the sensitivity of cancer cells to the cytotoxic effect of chemotherapeutic agents, inducing apoptosis, inhibiting angiogenesis, and promoting the denaturation of proteins [20,21,22]. Furthermore, it is possible that hyperthermic intraperitoneal chemotherapy at the end of CRS could improve survival, considering that a 7-day delay in chemotherapy initiation resulted in an 8.7% increase in the death rate in patients with complete surgical debulking [23]. Nevertheless, there is disagreement among the most important institutions in gynecologic oncology about the role of HIPEC in advanced ovarian cancer, as the published data are heterogeneous.

A positive study about the effectiveness of HIPEC was published in 2018 by Van Driel et al. It was a multicenter phase three trial (OVHIPEC trial), in which 245 patients were randomly assigned to HIPEC vs. no HIPEC during interval debulking surgery performed after three cycles of NACT. The authors reported a hazard ratio for disease recurrence or death of 0.66 (95% CI 0.50–0.87), with a significant statistical difference (p = 0.003) between the two groups. The median recurrence-free survival was 10.7 in the surgery group vs. 14.2 months in the surgery-plus-HIPEC group (p = 0.02), the median overall survival was 33.9 in the surgery group vs. 45.7 months in the surgery-plus-HIPEC group, and no significant differences between the two groups regarding adverse events of any grade were reported. The authors concluded that the addition of HIPEC in an interval debulking surgery setting resulted in improved recurrence-free and overall survival [8].

In 2019, Vergote et al. reviewed the OVHIPEC trial, producing various criticisms of the study, such as the following: the PFS in two arms (HIPEC vs. no HIPEC) was shorter than expected (14.2 vs. 24 months in the HIPEC arm and 10.7 vs. 18 months in the no-HIPEC arm); the timing of the randomization changed during the accrual; and, in the original protocol, it was planned before the first cycle of chemotherapy, then, the accrual was permitted before the interval debulking surgery. Further criticism included the small sample size (240 patients per arm), the imbalance of unfavorable non-high-grade serous ovarian cancer among the two arms (13 patients with unfavorable non-high-grade serous in the no-HIPEC arm vs. 3 patients in the HIPEC arm), and a lack of stratification for important prognostic factors such as the BRCA status, substage FIGO, and NACT response. Furthermore, according to the authors, there was no quality assurance of the participating centers and surgeons. The conclusion was that HIPEC could not be considered the standard of care for ovarian cancer, neither at the first line or at the recurrence [24].

Even though there are so many limitations, the Van Dried study led to the addition of HIPEC to international [25] and national [26] guidelines as a treatment option for patients undergoing interval debulking surgery. The most recently published OVHIPEC-1 10-year results confirm the significant improvement in progression-free and overall survival with the addition of HIPEC to ICS in patients with extensive disease for whom UDS is not considered feasible. The data give prompts to the biological characteristics of the tumor. In an exploratory post hoc analysis, the overall survival observed demonstrated an improvement, due to the biological characteristics of the tumor and not to the use of subsequent therapies [27].

In 2015, Chiva et al. reported a systematic review of HIPEC in ovarian cancer, in which 1450 patients of twenty-two studies were included. Of these, 493 patients underwent HIPEC during primary debulking surgery and 957 did so after secondary debulking surgery. The authors concluded that any apparent advantages for patients without the pathogenic BRCA1/2 mutation were from the use of HIPEC, both with advanced primary and recurrent ovarian cancer [28]. However, another systematic review and metanalysis of cytoreductive surgery plus HIPEC vs. cytoreductive surgery in ovarian cancer in 2018 showed a statistically significant difference in the overall survival (HR = 0.56, 95% CI = 0.41–0.76, p < 0.01) and disease-free survival (HR = 0.61, 95% CI = 0.48–0.77, p < 0.01) in patients who underwent surgery plus HIPEC compared with patients who underwent surgery only. A subgroup analysis showed an improvement in OS (HR = 0.57, 95% CI = 0.40–0.83, p = 0.04) and DFS (HR = 0.61, 95% CI = 0.47–0.80, p < 0.01) for primary ovarian cancer in favor of the HIPEC group. However, patients with recurrent ovarian cancer who received HIPEC showed only significant improvement in OS (HR = 0.48, 95% CI = 0.24–0.96, p < 0.01) but not DFS (HR = 0.59, 95% CI = 0.33–1.08, p = 0.09 [6].

Furthermore, in regard to safety, our data confirm that HIPEC following CRS does not appear to significantly increase the mortality or morbidity rates compared to the use of CRS alone [29].

Making a note on postoperative morbidity, it is reported in the literature that intraperitoneal cisplastin treatments are related to a high risk of acute renal failure. In patients undergoing cytoreductive surgery and HIPEC, the prevalence of postoperative acute kidney failure varies widely between 1.3% and 48% [29,30]. In our study, we never encountered this type of complication. This finding is probably related to the systematic use of amifostine [29,30,31,32].

In our study, we have found that CRS plus HIPEC is feasible, with very low rates of major complications and good results in terms of overall survival. However, this study has many limitations, such as the following: its retrospective nature with a small and heterogeneous number of patients and an imbalance of the groups for the extent of disease and completeness of surgery. Nevertheless, according to our experience, we believe that HIPEC can be added to CRS, both at the first line but also at recurrence, with an acceptable morbidity.

5. Conclusions

The precise indication and timing of HIPEC for ovarian cancer is debated to this day. No judgments can be made just yet, even if a number of studies seem to point to a benefit of HIPEC treatment in ovarian cancer. In fact, the studies that are now available have a number of limitations and biases, including the use of small, single institutions and non-homogeneous series (various drug dosages, schedules, exposure lengths, and various clinical contexts). On the other hand, RCTs, meta-analyses, and systematic reviews [6,7,8,27,28] suggest that HIPEC may play a very important part in improving patient outcomes, as well as for primary and recurrent disease.