Outcome of Cytoreductive Surgery with HIPEC in Ovarian Versus Gastrointestinal Peritoneal Carcinomatosis: A 7-Year Single Centre Experience

Keywords

Peritoneal Carcinomatosis - Peritoneal Carcinomatosis Index - Cytoreductive surgery - Hyperthermic Intraperitoneal Chemotherapy. Overall Survival - Disease Free Survival

Introduction

The spread of tumors over the peritoneal surface lining of the abdomen is known as peritoneal carcinomatosis (PC), and it continues to have a bad prognosis.[1] The worst prognosis was noted in numerous investigations, particularly for secondary PC from certain cancers such as gastric cancer (GC). Results for other cancers, such as colon and appendiceal cancer (AC), appear to be better, particularly in early diagnosis.[2] The 5-year overall survival (OS) for Ovarian cancer (OC) is less than 30%, and about two-thirds of cases are presented in an advanced stage.[3]

Since the absence of residual disease is the most significant prognostic factor, vigorous cytoreductive surgery (CRS) is the cornerstone of treatment to eradicate all macroscopic lesions.[4]

Though its function is still up for question, there is mounting evidence that adding hyperthermic intraperitoneal chemotherapy (HIPEC) to CRS improves patient prognosis.[5] Up to 25%-30% of all recurrent or metastatic colorectal cancers (CRCs) occur as peritoneal carcinomatosis (PC). PC is the only site of metastasis in 25% of patients.[6] After much investigation and technological development, CRS combined with HIPEC has shown encouraging outcomes and increased survival.[7]

Mucinous neoplasms of the appendix form a group of neoplasms ranging from adenomas to adenocarcinomas. These tumors are categorized as low and high-grade in order to simplify this broad range of illnesses.[8] These tumors have been categorized by others as peritoneal mucinous carcinomatosis (PMCA) and disseminated peritoneal adenomucinosis (DPAM).[9] Because treatment can demonstrably extend disease-free survival (DFS) and (OS), CRS-HIPEC is regarded as the gold standard treatment for peritoneal mesothelioma and pseudomyxoma peritonei of appendiceal origin.[10]

Only high-volume centers offer difficult operations known as CRS-HIPEC, which calls for skilled surgical teams and significant infrastructure. It is linked to morbidity even in these circumstances, which is what inspired the authors to carry out this investigation to report our own experience regarding morbidities, complications, and survival outcomes in CRS and HIPEC in tumors of gastrointestinal vs ovarian origin.

Patients and Methods

Study Design

The current prospective observational study was conducted at the General Surgery Department and Obstetrics and Gynecology Department, Benha University throughout the time from December 2017 till December 2024.

The study was conducted following the ethical code of Helsinki declarations.

The current study included 62 patients who were admitted by peritoneal Carcinomatosis and eligible for CRS and HIPEC

Eastern Cooperative Oncology Group (ECOG)[11] ([Fig. 1]) performance ≤1 without extra-abdominal illness was the primary inclusion criterion. Patients who refused to participate in the trial had systemic metastases or had an ECOG greater than one was not included. Only those patients with resectable hepatic metastases were eligible for inclusion.

Fig. 1 ECOG performance status.

Two groups of patients were created based on the main tumor site.

PCs of gastrointestinal origin, primarily colorectal cancers, with a small number of stomach and appendiceal tumors, were included in Group A.

However, those of ovarian origin were included in Group B.

A thorough preoperative evaluation that included CT, PET, MRI, colonoscopy, and exploratory laparoscopy was performed on all patients included. Additionally, the patient had to have a peritoneal illness that could be debulked.

CRC and GC were staged using the 7th TNM classification, whilst OC was staged using the International Federation of Gynecology and Obstetrics (FIGO) classification.[2] An essential part of managing every patient was the intraoperative evaluation of the peritoneal carcinoma index.

The prognosis and operability of peritoneal metastases can be ascertained with the aid of the peritoneal cancer index (PCI), which is a helpful tool for evaluating the extent of the disease.[4] According to this classification scheme, the small bowel is divided into four sectors, and the belly into nine sectors. The overall score is calculated by adding the lesion size scores for each area ([Fig. 2]).[12]

Fig. 2 PCI.

Procedure

The PCI was computed, and the peritoneal spread was noted. Regardless of the primary tumor location, omentectomy ([Fig. 3]) and peritonectomy ([Fig. 4]) for the involved peritoneal were a mandatory step. In patients with OC, rectosigmoid resection was avoided ([Fig. 5]). If pelvic peritonectomy was done and the rectum or sigmoid colon was not involved. An en-bloc hysterectomy with bilateral salpingooopherectomy together with recto sigmoidectomy was carried out in cases of extensive peritoneal involvement ([Fig. 6]). Other procedures were planned radical gastrectomy ([Fig. 7]), right hemicolectomy for right-sided colonic malignancies or appendiceal tumors. Colorectal resections were planned according to the location. ([Figs. 8] and [9])

Fig. 3 Omentectomy and omental cake.

Fig. 4 Subdiaphragmatic peritonectomy.

Fig. 5 Pan hysterectomy, omentectomy, peritonectomy and lymphadenectomy.

Fig. 6 Pan hysterectomy with colectomy.

Fig. 7 Radical Gastrectomy.

Fig. 8 a. appendectomy. b,c right hemicolectomy. D left hemicolectomy.

Fig. 9 a. Extended right hemicolectomy. B. left hemicolectomy. c,d. Total colectomy.

Depending on the spread of peritoneal cancer, several peritonectomy treatments were performed, including limited liver resection, splenectomy, excision of hepatic capsule nodules, and visceral resection; additionally, the healthy peritoneum was never removed. Dissection of paraaortic and Iliac Lymph nodes was A mandatory step ([Fig. 10])

Fig. 10 a. paraaortic lymphadenectomy. b. paraaortic and iliac lymphadenectomy. c. Bilateral pelvic lymphadenectomy. d.celiac lymphadenectomy.

High voltage "cute mode" electrocautery was used to eliminate superficial carcinosis nodules causing tissue loss through vaporization, particularly if the nodules affected the meso of the small intestine. To reduce the danger of perforation, cold saline was sprayed over the walls of hollow organs. Following cytoreductive surgery, Sugarbaker's categorization was used to record the completeness of the cytoreduction score (CCS). [13]

CC0—complete cytoreduction

CC1—minimal residual disease > 2.5 mm

CC2—residual disease of 2.5 mm - 2.5 cm

CC3—residual disease <2.5 cm.

Only patients with CCS 0–1 underwent HIPEC.

HIPEC Technique[14]

Five drains in all were placed into the abdominal cavity in the manner described below: There are two input drains on the left and two outflow drains on the right.

Backhaus forceps were used to hang the incision skin from an auto-static oval retractor that was fixed to the operating table. After that, the drainage tubes were linked to a multipurpose extracorporeal circulation system that combined temperature detection, liquid heating, and perfusion into one unit.

The HIPEC procedure was running for 90 minutes. Using a "closed-HIPEC with open abdomen technique with an inflow temperature of 42–43 °C and an outflow temperature of 40–41 °C. The chemotherapy regimens included: adriblastin 15 mg/L of perfusate, 100 mg/m2 of cisplatin, 175 mg/m2 of paclitaxel, and 35 mg/m2 of mitomycin-C (MMC) (or 16 mg/m2 MMC if cisplatin was included). The reconstructive time was then carried out after the perfusate was emptied.

Follow-up and Outcomes

The primary objective of research was successful CRS and HIPEC with minimal postoperative morbidities and mortality.

The 2ry objective of the research was to compare the overall Survival and DFS in both groups.

Following surgery, every patient had their perioperative mortality, reintervention rate, adverse events, intensive care unit (ICU) stay, and hospital stay evaluated.

Patients began receiving chemotherapy six weeks following CRS plus HIPEC.

During the first two years, patients received follow-up care, which included radiological assessment/ 6 months and tumor marker/ 3 months. After that, until the end of the fifth year following the treatment, there will be outpatient visits, tumor marker/6 months, and annual radiological assessment.

OS, DFS, and oncological results were reported.

Statistical Analysis

The sample size was established based on the 1ry outcome with a power of 80%and effect size of 0.7 was considered using the G-power 3.1 software (Universities, Dusseldorf, Germany).

For the statistical study, IBM Corp., Armonk, New York, USA, provided SPSS, version 25. For quantitative traits that were reported using mean ± SD, the student t-test was employed. Qualitative indicators given as frequency with percentage were subjected to the χ2 test. If a P-value was less than 0.05, it was deemed significant.

Results:

The age of eligible patients was 40.6 ± 3.9 and 39.2 ± 4.6 years in patients with gastrointestinal PC and those with OC respectively. No reported significant difference between both groups regards the ASA score or preoperative comorbidities [Table 1]

Table 1 Sociodemographic data in both groups

		Group A Gastrointestinal tumors N = 31	Group B Ovarian tumors N = 31	P value
Age	Mean ± SD	40.6 ± 3.9	39.2 ± 4.6	0.71
Sex Females     Males	N(%)	19 12	31 0	–
ASA score	Mean ± SD	2.26 ± 0.39	2.14 ± 0.61	0.92
Comorbidities
DM	N(%)	4 (12.9%)	3 (9.7%)	0.089
IHD	N(%)	2 (6.45%)	2 (6.45%)	1.00
HTN	N(%)	5 (16.12%)	6 (19.35%)	0.084

[Table 2] presented that the main gastrointestinal primary tumor in group 1 was Colorectal malignancies followed by the appendix then the GC. The mucinous carcinoma was the main type in Group A while the serous type was the main presenting type in Group B. most cases in group B presented in Stage III the same as group A. In both groups HIPEC was planned for the primary tumor that was synchronously associated with PC. No significant difference between both groups as regards the PCI was reported.

Table 2 Tumor characteristics in both groups

		Group A Gastrointestinal tumors N = 31	Group B Ovarian tumors N = 31	P value
1ry Tumor location	N(%)	Colorectal 23 Appendix 5 Gastric 3	Ovary	–
Tumor histology	N(%)	Mucinous adenocarcinoma 13(41.9%) Signet ring adenocarcinoma 6 (6 (19.35%) Peritoneal mucinous carcinomatosis 3 (9.7%) disseminated peritoneal adenomucinosis: 2 (6.45%) others: 7 (22.5%)	Serous: 23(74.2%) undifferentiated: 8 (25.8%)
HIPEC for, n (%) Primary tumor Recurrence	N(%)	22 (71%) 9 (29%)	23(74.2%) 8 (25.8%)	0.82
Tumor stage	N(%)	I: 1 (3.2%) II: 5 (16.1%) III: 7 (22.6%) IV: 18 (58.1%)	I: 0 (0%) II: 0 (0%) IIIIC: 26(83.9%) IV: 5(16.1%)	0.001* 0.001* 0.001* 0.001*
Type of PC Synchronous PC Metachronous PC Prophylactic PC	N(%)	23 (74.2%) 8 (25.8%) 0 (0%)	25 ( 80.65%) 6 (19.35%) 0 (0%)	0.073 0.061 1.00
Liver metastasis	N(%)	3 (9.7%)	3 (9.7%)	1.00
Neoadjuvant chemotherapy	N(%)	19(61.3%)	28 (90.3%)	0.001*

The reported mean PCI was less in Group B but was not significant (p = 0.056). The number of intestinal anastomoses was significantly higher in PC following Gastrointestinal tumors. No reported difference between both groups regarding intra-hospital mortality, postoperative complication rate, rate of reintervention, or even the length of hospital stay. However, the ICU stay was significantly less in Patients with OC. [Table 3]

Table 3 intraoperative findings and postoperative follow up of both Groups

		Group A Gastrointestinal tumors N = 31	Group B Ovarian tumors N = 31	P value
PCI	Mean ± SD	11.1 ± 8.9	9.9 ± 8.6	0.056
Number of anastomoses, n	Mean ± SD	1.2 ± 0.7	0.6 ± 0.5	0.043*
Complications
Intra-operative mortality	N (%)	0 (0%)	0 (0%)	1.00
Intra-hospital mortality	N (%)	1 (3.2%)	1 (3.2%)	1.00
Complications rate	N (%)	10 (32.25%)	9 (29%)	0.91
Re-interventions,	N (%)	5 (16.12%)	4 (12.9%)	0.063
ICU stay, days	Mean ± SD	5.2 ± 1.9	3.2 ± 2.3	0.01*
LOS, days	Mean ± SD	21.7 ± 13.9	20.5 ± 11.3	0.76
Adjuvant CHT (after HIPEC),	N (%) Yes NO	27 (87.1%) 4 (12.9%)	28 (90.3%) 3 (9.7%)	0.089
OS months	Mean ± SD	31.2 ± 6.2	39.1 ± 4.22	0.047*
DFS	Mean ± SD	13.2 ± 2.4	16.4 ± 4.6	0.046*
5 year survival	Mean ± SD	6 (19.35%)	8 (25.8% )	0.053

[Table 3] reported a mean OS of 31.2 ± 6.2 and 39.1 ± 4.22 in group A and B respectively with A significant more OS and DFS reported in Group B (P = 0.046*). The reported 5-year Survival was insignificantly different between both groups.

Discussion

CRS was first used to treat ovarian and testicular malignancies considering the principle of decreasing the tumor's volume to improve the efficacy of subsequent treatments. This idea was later used to treat mucinous carcinomas of the appendix or colon.[15]

Complete tumor excision was part of CRS and HIPEC, and treatment with 5-fluorouracil and mitomycin C was then infused intraperitoneally. While normal tissue was protected by an intact cooling blood flow, the tumors in HIPEC were treated with hot chemotherapy, which caused thermal damage. However, only patients with satisfactory performance status are selected for CRS-HIPEC due to the procedure's increased risk of postoperative morbidity.[16]

The use of CRS and HIPEC to treat PCs has grown in popularity in recent years.[6] The results of oncological patients were improved by advances in surgical procedures, pharmacokinetic investigations, physiopathology mechanisms of peritoneal dissemination, and perioperative chemotherapeutic therapy improvements.[17]

The 30-day mortality and morbidity rates described in the literature are 1–10% and 20–50%, respectively, and the CRS + HIPEC surgery is still difficult for patients.[18]

In the current study, the reported overall intrahospital mortality was 3.2 in both groups with the incidence of perioperative morbidity in Group A of 32.25 while it was 29% in Group B matching the results of Montori G et al [2] who reported morbidities in 38% of cases and perioperative mortality of 2.7%. It is evident that these findings relate to distinct diseases with varying tumor biology and cytoreduction strategies.

In the current study the overall survival for Group A was 31.2 ± 6.2 While the reported OS for the ovarian cancer group was 39.1 ± 4.22 while the DFS was 13.2 ± 2.4 and 16.4 ± 4.6 In Groups A, B respectively these findings were comparable to the results of Montori G et al[2] who reported an OS of about 51 months in patients with OS which was significantly higher than those of gastrointestinal tumors ranging from 18 months in GC and 35 months in CRC the shorter OS in Group A can be explained by the fact that the outcome of GC is poor with short time OS.

A recent study by van Driel WJ et al [19] reported OS of 45.7 months in the surgery-plus-HIPEC group for CO with no increase in the side effects compared to 33.9 months in the surgery group only. These results were comparable to those of the current study. Additionally, van Driel WJ et al.[19] reported that patients with CRS alone had a median recurrence-free survival of 10.7 months, whereas those who received supplemental HIPEC as part of their treatment plan had a median recurrence-free survival of 14.2 months.

The current study reported 5-year OS of 19.4 and 25.8% in groups A and B respectively and this was less than many authors[20] [21] who reported 5-year OS up to 51% and this can be explained by the inclusion of cases with relatively higher PCI in the our study. However, this matched Waite K et al [22] who reported a 27% five-year OS in patients with CRC. According to the 38.5% 5-year OS reported by the Peritoneal Surface Oncology Group International (PSOGI) group, CRS + HIPEC may be safe for very specific individuals in uncommon situations.[23]

Regarding prophylactic HIPEC, no conclusive findings have been published.[24] However, based on available evidence, CRS + HIPEC appears to be very beneficial for patients with colorectal cancer (CRC) who are at high risk of peritoneal dissemination (obstructed, perforated tumor, and mucinous tumors).[25]

There is still debate on the effectiveness of prophylactic HIPEC in individuals with high-risk gastrointestinal cancers. It has been discussed if HIPEC is a good way to prevent PM in people with high-risk colorectal cancer. Metachronous PM is more likely to develop in people with T4, N2, right-sided tumors, vascular invasion, and mucinous tumors.[16] [26] However, as Arrizabalaga et al [27] point out, using prophylactic HIPEC in these situations could lead to overtreating people who do not develop PM. Additionally, we did not use this strategy in the current investigation, which is contrary to Arjona-Sánchez et al.'s recommendation that preventive HIPEC be used in T4 tumors to reduce the recurrence rate.[28]

Additionally, there was no difference in the incidence of recurrence between the two groups of patients with T4N0-M0 stage or perforated colon cancer who were randomly assigned to either HIPEC followed by adjuvant chemotherapy or adjuvant chemotherapy alone following colonic cancer resection in the COLOPEC trial.[29] Another large multicenter French PROPHYLOCHIP study used a second look six months after HIPEC and surveillance for primary colorectal cancer, resected ovarian metastases, and synchronous localized CRPM or perforated colonic tumors. It found that patients who had HIPEC had a significant improvement in OS without a change in DFS.[30]

Study Limitation

The study has many limitations despite these encouraging findings. The first is a monocentric database that assesses the results of various illnesses. Additionally, the study spanned seven years, and improvements in the learning curve and the rise in cases allowed for improved outcomes, particularly in recent years.

Conclusions

In certain patient groups with PC from gastrointestinal and Ovarian malignancies, CRS + HIPEC could produce long-term OS with tolerable morbidity and mortality with better outcome OS and DFS in patients with OC.

To manage PC and further enhance outcomes, significant expertise is required.

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