1. Introduction

Ovarian cancer is the fifth leading cause of cancer-related death among women in the USA [1]. Despite significant advancements in survival rates with combination chemotherapy utilizing taxane and platinum-based therapy [2], overall survival rates have not progressed as anticipated. Since, ovarian cancer cells tend to colonise on the peritoneum, intravenous route of chemotherapy (IVCT) may have limited penetration into this compartment [3]. Among patients with stage III and IV ovarian cancer who had responded to first line IVCT, recurrence often occurs within 2 years [4]. For this reason, therapeutic options through peritoneum were designed. Intraperitoneal chemotherapy (IPCT), proposed in the 1970’s [5], provides an easy access to the peritoneal cavity, enabling chemotherapy drugs to rapidly interact with tumor surfaces while maintaining prolonged local exposure [6]. Studies utilizing cisplatin [7] and carboplatin [8] have demonstrated that intraperitoneal administration results in 10–30 times higher drug concentrations within the peritoneum compared to intravenous (IV) routes.

Research comparing the efficacy of intraperitoneal and intravenous (IP/IV) to intravenous (IV) chemotherapies in optimally resected stage III ovarian cancer patients, along with meta-analyses, have consistently shown a statistically significant improvement in overall survival with IP treatment [9, 10, 11, 12, 13, 14]. Notably, the Gynecologic Oncology Group (GOG) 172 study, for instance, revealed a 16-month increase in median overall survival, despite only 42% of patients completing the intended six cycles [15]. Among those who discontinued IPCT, catheter related complications like infections or malfunctioning, were the most frequent causes (34%), followed by IPCT-related side effects like nausea or vomiting (26%) [15]. Despite its proven survival benefits, the popularity of IPCT waned following this study due to high discontinuation rates, even after the National Cancer Institute’s (NCI) endorsement approach in 2006 [16]. The primary reasons for discontinuation included catheter-related complications such as abdominal pain, infection, ileus, intestinal perforation, and dense membranous adhesions of the intestine [9, 14].

Despite advances in new chemotherapy drugs, effectively treating peritoneal disease or reducing recurrences via the IV route remains challenging. Over the last decade, combining hyperthermic intraperitoneal chemotherapy (HIPEC) with cytoreductive surgery has shown survival benefits [17]. However, HIPEC can only be performed once optimal cytoreduction is achieved and does not offer the opportunity for continuing therapy like IPCT. Recent studies on pressurized intraperitoneal aerosol chemotherapy (PIPEC), which enables pressurized drug delivery through trocars, have reported promising results [3, 18]. However, PIPEC requires general anaesthesia for every IPCT session. Despite these advancements, IPCT remains advantageous for providing ongoing maintenance therapy in outpatient settings. Given continuous improvements in chemotherapy drugs and drug delivery systems, reconsidering IPCT is warranted for a standard approach [19]. As catheter-related complications were the most frequent cause for discontinuation, optimizing catheter design or implantation techniques may improve outcomes. We believed that the modified technique for IPCT port placement could provide valuable insights. The primary objective of this study was to analyse the outcomes, including completion rates and median survival time, of this technique. Additionally, we aimed to evaluate the reasons for therapy discontinuation.

2. Materials and methods

A retrospective study was conducted among patients receiving IPCT in Leigh Valley Women’s Cancer Centre from January 2005 to May 2016. All port placement operations were performed by a single surgeon (GA) following the same technique, ensuring consistency. The distribution of cases throughout the time line was comparable, with 40 cases before January 2011 and 32 cases thereafter. The study was approved by the Committee on Human Research at Koc University with the protocol number: 2024.384.IRB2.166. All subjects provided informed consent prior to port placement operation. Patient selection was based on billing codes for IP catheter placement and IV/IP chemotherapy administration. All patients who had IP catheter placement were included in the analyses, and no patients were excluded from the overall analysis. Only one patient was excluded from the survival analysis. Demographic and surgicopathologic characteristics, including the extent of surgical procedures during cytoreductive surgery, timing of catheter placement, laparoscopic port placement findings, complications associated with catheter placement, chemotherapy side effects, and timing of port removal, were collected by reviewing patients’ charts. Survival duration was calculated from the date of first cytoreductive surgery to the last visit or time of death. For patients who experienced recurrence, survival duration was calculated from the last cytoreductive operation before catheter placement.

At the end of debulking surgery, anti-adhesive products were placed at the retroperitoneal sites and intestinal surfaces prior to closing the abdominal wall in all patients.

The modified technique involved the placement of two ports, one in the upper right quadrant and the other in the upper left quadrant, either laparoscopically or during laparotomy. In the laparoscopic approach, the procedure was performed 4–6 weeks after cytoreductive surgery. A 10-mm trocar and laparoscope were inserted from the palmar point, with two additional ports were inserted from the lateral umbilical region and one port from the suprapubic regions. Peritoneal washings, adhesiolysis, and biopsies were performed as indicated. For port placement, two separate 5-cm incisions were made in the left upper and right upper quadrants just inferior to the thorax at the midclavicular line. Subcutaneous tissue was dissected, and pockets were developed to place the port chambers to the level of the fascia. Tenckhoff catheters were then placed from the lateral trocars and brought through a subcutaneous tunnel to the site of the portal chambers. The tip of the left catheter was directed towards the pelvis, and the right one towards the liver. To ensure catheter stability, 2 cm tunnels were created between the muscles and peritoneum, allowing the 10-cm catheters to remain securely within the peritoneal cavity. Anti-adhesive gel was applied around them to further reduce adhesion formation. A purse-string suture was used to close the peritoneum and fascia around each IP port, and the portal chambers were securely anchored to the fascia. After confirming patency, the skin incisions were closed, and several litres of saline were left in the abdominal cavity to minimize adherence to the intestines at the conclusion of the surgery (Fig. 1).

Fig. 1.Figure showing the steps of port placement. (A) Schematic drawing of ports (P) placement. In this technique two ports are placed, one in the upper right quadrant the other is in the upper left quadrant either laparoscopically or during laparotomy. Two separate 5-cm incisions on the skin are created for placement of the portal chambers in the left upper and right upper quadrants just inferior to thorax at the midclavicular line. The subcutaneous tissue is dissected and pockets are developed to the level of the fascia. The catheters are placed from the lateral trocars and then brought through a subcutaneous tunnel to the site of the portal chambers. The tip of the left catheter is placed towards pelvis and the right one towards liver (dotted lines). (B) Intrabdominal placement of the catheters: (1) Left catheter is taken intraabdominally from the left lateral trocar. (2) A retroperitoneal tunnel is formed on the left lateral abdominal wall. (3) and (4) The catheter is passed through the tunnel. (5) The tip of the catheter is placed towards the liver. (6) Right catheter is inserted into the abdomen from the right lateral trocar. (7) A retroperitoneal tunnel is formed on the right lateral abdominal wall. (8) The right catheter is passed from the tunnel and placed facing the pelvis. (9) Postoperative picture of the abdomen showing the places of the ports.

The main target of this technique was to finish 6 cycles of IPCT. In patients with good conditions the protocol was extended to 8 cycles. The IV/IP chemotherapy consisted of intraperitoneal platinum-based drugs (carboplatin or cisplatin) combined with IV/IP taxane. All IPCT were administered at the institution by trained nurses. Upon completion of treatment the IP ports were removed either using local anaesthesia or under general anaesthesia in the operating room.

The data were expressed as mean ± standard error of mean. Variables with non-normal distribution, as determined by the Kolmogorov-Smirnov test, were expressed as medians (range). All statistical analyses were performed using SPSS v 22 program (IBM, New York, NY, USA). The t-test was used to compare means between two groups, while Pearson’s chi-square test was applied to examine significance difference between reasons of IP discontinuation. Binary logistic regression was applied to evaluate the relation of the discontinuation reasons. Kaplan Meier survival graph was plotted to evaluate survival outcomes. A p-value less than 0.05 was considered statistically significant.

3. Results

A total of 72 patients underwent intraperitoneal port placement from January 2005 to May 2016. One patient transferred to another institution after port placement, and her data was unavailable. Additionally, two patients did not undergo chemotherapy: one developed a peritoneovaginal fistula following cytoreductive surgery, while the other declined IPCT and had her ports were removed. Regarding the patient who changed institutions, we included her in the baseline analysis but excluded her from the survival analysis. As for the two patients who did not receive any intraperitoneal chemotherapy, they were included in the survival analysis and classified as having received 0 cycles. Consequently, all 71 remaining patients were included in the IPCT evaluation.

The average age of the patients was 58.11 ± 1.16 years and the mean Body Mass Index (BMI) was 29.87 ± 0.82 kg/m². A summary of patient characteristics is presented in Table 1.

The majority of patients were diagnosed with stage III-C ovarian cancer. Neoadjuvant chemotherapy (NACT) was administered to 18 patients (25%) prior to surgery, and 15 patients (20.8%) underwent secondary debulking before port placement. Optimal cytoreduction was achieved in 64 patients (88.9%), and bowel resection was performed in 20 patients (27.8%). Of the 72 patients, 11 had IP ports placed during laparotomy, while the remaining 61 underwent laparoscopic port placement following initial cytoreductive surgery (Table 2).

The median number of IPCT cycles was higher in patients without adhesions (8 (range: 0–8)), compared to those with adhesions (6 (range: 0–8)) (p = 0.014, Mann Whitney U test). Among patients without adhesions, 15 out of 22 (72.7%) completed 7 or more IP cycles, whereas only 15 out of 39 (36.7%) among those with adhesions completed the same (p = 0.026).

The median number of IPCT cycles administered was six. Of the patients, 52 (73.2%) completed 4 cycles, 47 (66.2%) completed 6 cycles, and 29 (40.84%) completed 8 cycles. The average survival duration for patients who completed 6 or fewer cycles of IPCT was 41.27 ± 5.77 months, compared to 64.76 ± 5.38 months for those who completed 7 cycles or more (p = 0.04, Supplementary Table 1). Kaplan-Meier analysis further illustrates that survival was significantly higher in the latter group (Fig. 2, p < 0.05).

Fig. 2.Kaplan Meier survival graph comparing two groups of those who had 6 and less cycles and those who had 7 cycles and more. Survival was increased in those who had 7 cycles and more intraperitoneal chemotherapy significantly (p < 0.05).

An analysis of the reasons for discontinuation among patients who did not complete the intended 6 cycles of IPCT revealed that port-related complications as the primary cause (11.1%, Table 3). Although port infections were common, they were limited to the incision site and were effectively managed with antibiotics or removal of a single port, allowing most patients to continue IPCT. Among chemotherapy-related symptoms, abdominal pain and nausea were the most frequent. However, only 3 patients discontinued therapy due to these symptoms. Interestingly, incidence of abdominal pain and nausea increased with the number of cycles administered. Patients who received 4 or more cycles of chemotherapy experienced more frequent abdominal pain compared to those who received fewer cycles (34 out of 51 vs. 6 out of 17, p = 0.023). Additionally, two patients developed fistulas, one before IPCT and the other after completing 6 cycles (Table 3).

The majority of patients received a cisplatin with paclitaxel regimen. Only 9 patients had a change in chemotherapy regimen, with no significant difference in survival between cisplatin and carboplatin. Regimen changes were primarily due to severe nausea and neuropathy associated with cisplatin. Notably, the effect of cisplatin or carboplatin on moderate or severe abdominal pain was not significantly different (18 out of 43 vs. 13 out of 25, p = 0.577). One patient receiving doxorubicin developed chemotherapy-induced cardiopathy, leading to discontinuation of the drug (Supplementary Table 2).

Patients who completed 7 or more IPCT cycles experienced a 23-month survival advantage. Their average age was 56.62 ± 8.77 years, with a BMI of 30.80 ± 6.81 kg/m² and an average survival of 64.76 ± 31.40 months. In contrast, the patients who didn’t complete 7 cycles had an average age of 59.63 ± 10.55 years, a BMI of 29.35 ± 7.16 kg/m² and a shorter survival duration of 41.27 ± 35.09 months (Independent samples T-test; p-values: 0.195, 0.385 and 0.004, respectively). Factors associated with IPCT discontinuation before 7 cycles are detailed in Table 4. Significant predictors of early discontinuation included NACT, a family history of genitourinary cancer, adhesions, port infections, severe abdominal pain and other infections (Table 4, p < 0.05).

From the statistically significant parameters binary logistic analysis was performed. Among these, receiving NACT was significantly associated with a lower number of IPCT cycles (p = 0.014, Table 5).

A stratified analysis was performed for patients with Stage III and IV ovarian cancer. In stage III patients, completing seven or more IPCT cycles was associated with significantly improved survival, while discontinuation was primarily linked to severe abdominal pain, other infections, and adhesions (p < 0.05, Supplementary Table 3). However, no significant associations were observed for survival in Stage IV patients, probably due to smaller sample size (n = 15, p > 0.05, Supplementary Table 3). NACT and port infections were identified as significant risk factors for failing to achieve 7 cycles (n = 15, p < 0.05, Supplementary Table 3).

4. Discussion

Numerous studies have demonstrated that IPCT improves survival rates in patients with stage III ovarian cancers [9, 10, 11, 12, 13, 14]. Despite its benefits, IPCT is not widely favoured among physicians due to high rates of discontinuation, primarily attributed to catheter-related complications such as abdominal pain, infection, ileus, intestinal perforation and dense membranous adhesions of the intestine. Compared to HIPEC, which is administered intraoperatively under general anaesthesia, IPCT offers the advantage of repeated administration in an outpatient setting, potentially extending treatment benefits [6]. Similarly, while PIPEC provides pressurized intraperitoneal drug delivery, its requirement for general anaesthesia for each cycle limits its feasibility for long-term maintenance [20]. Given these factors, optimizing IPCT techniques remains relevant in peritoneal surface oncology.

In our retrospective analysis, we found that modified technique for port insertion was associated with decreased port-related complications and discontinuation rates. With the utilization of two catheters, there was better distribution of IPCT drugs. Additionally, if one catheter needs to be removed for some issue, treatment could still be continued through the remaining port. Furthermore, we observed an increased survival advantage with a higher number of cycles delivered, as patients completing 7 or more cycles experiencing a survival of over 5 years (64 months). We also believe that this technique may better mimic the intraperitoneal liquid flow, potentially enhancing drug distribution [21].

Milczek et al. [22] conducted a retrospective study comparing complications between patients receiving four versus six cycles of IPCT, reporting completion rates of 76% and 38%, respectively. Their findings highlighted catheter-related complications as the primary reason for discontinuation [22]. However, unlike our study, they didn’t find an improvement in survival with increasing number of cycles, emphasizing that most of the benefits of IPCT occurred early during the initial courses. One possible explanation for this difference may be due to patient selection. In our cohort, patients with good performance status were encouraged to complete additional cycles, potentially contributing to the observed survival advantage. Another critical factor is the study design and data collection period. Wilczek’s IPCT protocol was revised after 2004, yet his study analysed data from 1996 to 2006. Consequently, patients who received four cycles were drawn from an eight-year dataset, whereas those completing six cycles were from only two years of experience. This imbalance may have introduced bias, particularly if treatment strategies, patient management, or supportive care measures changed over time, ultimately affecting survival outcomes.

Additionally, Sakuragi emphasized that catheter-related complications is proportional to the duration since installation [23]. However, our analysis revealed that only abdominal pain was directly proportional to the number of cycles administered. Contrary to Milczek’s findings, we observed a significant increase in survival with the number of IPCT cycles. This is consistent with the findings of Yen et al. [24], who developed a nomogram to identify patients benefiting the most from IPCT in ovarian cancer. Their analysis showed that the patients who completed at least five IP cycles significantly had longer overall survival rates [24]. Furthermore, Tewari who re-analysed data of GOG 114 and 172 studies showed 12% reduction in death risk in at each completed cycle [25].

Makhija et al. [26] reported a 93% completion rate of IPCT in their institution, with catheter-related complications occurring in 30 patients—6.3% due to malfunction and 3.7% due to infection. They attributed their low complication rate to delayed catheter insertion in patients undergoing bowel resection [26]. In contrast, Landrum found no significant difference in catheter-related complications between laparotomy and laparoscopy, reporting a 60% completion rate and 13% incidence of catheter-related complications [27]. Similarly, Ivy et al. [28] reported a low rate of catheter-related complications, regardless of the type of ports used, with most complications attributed to hematologic complications related to chemotherapy. Consistent with these findings, our use of two ports was associated with no discontinuations due to port malfunction, despite some instances of port malfunction. Additionally, no correlation was found between catheter complications and the timing of port placement.

Skaznik-Wikiel et al. [29] reported a completion rate of 79% for IPCT in patients undergoing secondary cytoreduction, noting that most patients who had previously treated with IV chemotherapy were able to tolerate and completing additional IPCT cycles. In contrast, we observed lower completion rates in patients taking neo-adjuvant chemotherapy before port placement due to recurrences or generalized disease. After logistic regression analysis, only NACT was associated with receiving fewer IPCT cycles. This aligns with the findings of Lee et al. [30], which reported that NACT group had less IPCT but an increased survival outcome of 15 months, though not statistically significant. They interpreted this finding to the aggressive nature of the illness and the potential presence of de novo platin-resistance in tumours.

While previous studies have suggested that IPCT with carboplatin may result in higher completion rates and fewer catheter-related complications compared to cisplatin [8, 31], our analysis did not find a significant association between discontinuation and chemotherapy regimen with cisplatin compared to GOG 172 study [15]. Additional, although adding bevacizumab to IPCT has been associated with increased survival rates [32], our study did not find a significant relationship, likely due to the small number of patients.

Wright et al. [9] reported a 50% increase in the preference for IPCT in their prospective cohort study, with younger patients and those with fewer comorbidities being more likely to complete IPCT. However, Mueller et al. [33] found no survival benefit with IPCT compared to IV chemotherapy in their recent study, possibly due to a lower number of IPCT cycles (median of 3 IP cycles) administered.

Our analysis revealed that having first or second degree relative with genitourinary cancer significantly effects treatment discontinuation. BRCA 1 positivity was close to significance (p value was 0.055). Due to insurance coverage only 48 patients were tested for genetic background. If the number of the patients had been increased the analysis could have changed. For the first time we showed that having first or second degree relative with genitourinary cancer and BRCA positivity may contribute to IPCT discontinuation. This suggests a potential psychological aspect in discontinuation, as BRCA carriers are known to be more sensitive to chemotherapy [34]. A study conducted in Sweden, has shown that patients diagnosed with the same cancer as their parents, particularly those whose parents had died within 10 years of diagnosis has significantly worse survival for breast, colorectal and prostate cancer than those whose parents survived beyond 10 years from diagnosis [35]. Given the poor prognosis of ovarian cancer, patients with a family history may be more likely to discontinue treatment due to emotional distress. Psychological support has been shown to increase the probability of disease acceptance and adherence to therapy in breast cancer patients [36]. Given the emotional burden associated with hereditary cancers, similar interventions may enhance adherence in ovarian cancer patients undergoing IPCT. Future studies should explore whether structured psychological support, particularly for BRCA-positive individuals and those with a strong family history of cancer, as this can improve chemotherapy completion rates.

This study has some limitations, including its retrospective nature and heterogeneity of patients. The data included all the patients who undergone IP port placement, making it challenging to control for variations in clinical characteristics. It is well known that the risk of infection increases with the number of interventions. However, despite the use of 2 ports, infection rates in our cohorts were similar or less than those compared to conventional techniques in the literature. Discontinuation due to IPCT related complications such as abdominal pain or bowel complication were less in our cohort. Although none of the studies mention the rate of venous port changes, we had 25 patients who undergone venous port changes due to infection or malfunction. Notably, the IVCT continued despite these complications. The fact that IPCT catheter complications were less than venous port complications suggest that IPCT, though often regarded as an experimental method, may offer a viable alternative with an acceptable safety profile.

Beyond clinical benefits, a key consideration is the potential economic impact of our modified technique. By reducing catheter-related complications, this approach may lower hospitalization rates and the need for additional interventions, thereby decreasing overall treatment costs. A formal cost-effectiveness analysis could further quantify these benefits, providing additional justification for adopting this technique in clinical practice.

While the use of HIPEC and PIPEC continue to rise, IPCT remain a valuable option for the treatment of peritoneal diseases and offers potential for drug delivery systems with advances in nanotechnology or cell-based immunotherapy [3, 37, 38, 39]. Unlike PIPEC, that has the disadvantage of requiring general anaesthesia for each cycle and HIPEC, which can be performed once to selected patients after debulking surgery, IPCT provides the opportunity for maintenance therapy in outpatient settings [3].

5. Conclusions

In conclusion, our study suggests that IPCT is strongly associated with improved survival, and this technique increases the likelihood of completing IPCT cycles. The laparoscopic approach allows for adhesiolysis further increasing the probability of achieving more IPCT cycles. With advances in the chemotherapy regimens, early intervention in managing side effects and psychological support could also increase the number of IP cycles received. Future directions should include prospective trials to validate the benefits of this modified technique. Additionally, the combination of IPCT with immunotherapy represents an exciting area for research, as emerging evidence suggests that localized drug delivery may enhance immune responses against peritoneal metastases [6, 38, 40]. Further research into nano-drugs and tailored side-effect management is essential to enhance its feasibility and acceptance.

Availability of data and materials

Data can be shared upon request.

Author contributions

GA—implemented the modified IPCT technique. SGÇ—performed the research and analyzed the data. SGÇ and GA—wrote the manuscript, designed the research study. Both authors contributed to editorial changes in the manuscript. Both authors read and approved the final manuscript.

Ethics approval and consent to participate

The study was approved by the Committee on Human Research at Koc University with the protocol number: 2024.384.IRB2.166. We confirm that all subjects provided informed consent prior to the port placement operation.

Acknowledgment

Not applicable.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

Supplementary material associated with this article can be found, in the online version, at https://oss.ejgo.net/files/article/1956178214320521216/attachment/Supplementary%20material.docx.