Abstract
Background
Small bowel obstruction (SBO) affects ~ 30% of ovarian cancer (OC) patients, leading to readmission, debilitating symptoms, and death within one year. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) effectively controls peritoneal disease. We investigated primary CRS/HIPEC’s impact on SBO and obstruction-free survival (OFS) in OC patients.
Methods
A retrospective single-center cohort study of stage III/IV OC patients treated with primary optimal CRS (2014–2022) was performed. Patients who underwent upfront CRS/HIPEC vs. CRS only were matched for histology, age (> 65 years), extent of disease, FIGO stage, and surgery year, using a propensity scored full matching algorithm. CRS/HIPEC effect on OFS was determined using a weighted cox-regression model. OFS was measured from surgery to SBO/death.
Results
Overall, 102 patients were included, 29 underwent CRS/HIPEC and 73 CRS only. CRS/HIPEC had higher median number of upper abdominal procedures (4 [IQR: 3–5] vs. 1 [IQR: 0–4], p < 0.01). Postoperative major morbidity was similar (p = 0.62). After a median follow-up of 88.8 months, SBO occurred in 24.1% (n = 7) CRS/HIPEC vs. 42.0% (n = 34) CRS only (p = 0.12). Most SBOs were partial (CRS/HIPEC: 71.4%, CRS: 55.9%) and managed conservatively (CRS/HIPEC: 71.4%, CRS: 67.6%). Median OFS was 42.9 vs. 20.0 months (HR: 0.50 [95% CI 0.27–0.93], p = 0.028). One-year survival after initial SBO was 85.7% vs. 44.7%, respectively (HR: 0.79 [95% CI 0.39–1.61], p = 0.512).
Conclusions
SBO after upfront CRS/HIPEC for OC occurred less frequently, was delayed, and had lower 1-year mortality compared to CRS alone. CRS, which includes upper abdominal exploration/surgery, coupled with HIPEC could enhance long-term peritoneal disease control in OC patients.
Keywords: Ovarian neoplasms, Intestinal obstruction, Hyperthermic intraperitoneal chemotherapy, Peritoneal neoplasms
Background
A major concern for advanced ovarian cancer (OC) patients is the risk for small bowel obstruction (SBO) following peritoneal recurrence. SBO affects 17–51% of recurrent OC patients [1–5]. The symptoms are often debilitating, causing significant distress for both patients and caregivers, and impacting quality of life [6–8]. Survival rates after SBO are notably poor, especially among patients who require invasive surgical management [4].
With low survival (~ 30% at 5 years) [9] and high recurrence rates (> 60% after 2 years of complete cytoreductive surgery [CRS] and adjuvant chemotherapy) [10], recent treatment efforts for advanced OC have focused on delaying the time to recurrence and need for second-line therapy. Beyond prolonging survival, delaying recurrence may enhance response to subsequent therapies and help prevent SBO [11, 12]. Interval CRS plus hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has recently demonstrated benefits in prolonging both recurrence-free and overall survival (OS) compared to surgery alone in OC [13]. Furthermore, interval CRS/HIPEC may influence recurrence patterns, potentially reducing peritoneal recurrences [14]. Considering the established effectiveness of HIPEC in conjunction with CRS for controlling peritoneal disease in ovarian cancer and other gastrointestinal malignancies [14, 15], obstruction-free survival (OFS) has been proposed as a meaningful endpoint to assess its therapeutic impact [6].
Limited data on the potential benefit of primary CRS/HIPEC in OC is restricting its implementation mainly to the research setting [12, 16]. However, given the demonstrated success of HIPEC in the interval setting for OC and other malignancies with similar presentation, it may be a promising strategy to reduce the risk of SBO in OC patients, potentially improving survival and quality of life. In this study, we investigated the impact of primary CRS/HIPEC on SBO incidence and OFS in OC patients, using a matched control cohort of patients treated with CRS alone.
Methods
Study design
A retrospective single-center propensity score matched (PSM) cohort study was conducted.
Patients
Patients who underwent primary CRS for advanced OC (International Federation of Gynecology and Obstetrics [FIGO] stage III/IV) treatment between 2014 and 2022 were identified using the institutional cancer registry. All patients were operated on at a high-volume cancer center by experienced gynecologic oncologists and/or surgical oncologists. Patients ≥ 18 years-old who had upfront optimal CRS and a follow-up ≥ 12 months were selected. Patients who presented with SBO at time of diagnosis or surgery were excluded.
Procedures
CRS was performed via vertical midline incision with the goal of complete cytoreduction. Organ resections were performed as needed to achieve optimal cytoreduction of all abdominal, pelvic, and retroperitoneal disease (< 1 cm of residual disease) [17, 18]. Based on prior work highlighting the prognostic and surgical relevance of upper abdominal disease in advanced OC, the number of upper abdominal procedures (UAP), defined as any procedure above the transverse colon mesentery (i.e. diaphragmatic resection and peritonectomy, liver capsule and wedge resections, porta hepatis dissection, cholecystectomy, partial gastrectomy, splenectomy, distal pancreatectomy, and splenic flexure mobilization) [19], was recorded as a measure of surgical extent and complexity. Intraoperative chest tube placements and bowel resections ± anastomosis were also recorded. The extent of disease was determined by the number of regions involved by tumor in the abdominal cavity as per the operative note. Following the Van Driel et al. methodology, the number of regions affected was classified in two groups (0–5 vs. 6–8) [20]. The extent of cytoreduction was determined by operative note review. Patients were considered optimally cytoreduced if explicitly mentioned or if no comment on any residual tumor at the end of surgery was reported. For patients in which a completeness of cytoreduction (CC) score was available, CC-0 (no residual disease) and CC-1 (residual tumor < 2.5 mm) were considered optimal [21]. Following CRS, HIPEC perfusion was performed by an experienced surgical oncologist with carboplatin (800 mg/m2) or cisplatin + doxorubicin (50 mg/m2 + 15 mg/m2) for 90 min at 41–43 °C using the closed technique. Patients perfused with carboplatin were part of a randomized clinical trial (NCT02124421). Patients perfused with cisplatin + doxorubicin were part of a prospective observational study (IRB#1230783). All anastomoses were performed after the perfusion. Patients were transferred to the intensive care unit for observation after surgery and then to the inpatient floor when clinically stable. Perioperative variables were recorded. Ninety-day postoperative complications and mortality were determined using the Clavien–Dindo (CD) classification. Grades III-IV were considered major complications [22]. Postoperative follow up occurred at 2 and 4 weeks’ post-discharge, every 3 months for 2 years, and every 6 months thereafter. Follow-up included physical exam, tumor markers, and computed tomography (CT)/ Positron Emission Tomography (PET)-CT of the chest, abdomen/pelvis. Number of cycles and completion of 6 cycles of platinum-based adjuvant intravenous (IV) chemotherapy were recorded. Tumor recurrence was diagnosed based on physical exam, rising tumor markers, imaging studies, biopsy results, and/or clinical presentation. Patients who recurred within 6 months of adjuvant chemotherapy completion or before chemotherapy completion were considered platinum resistant. Patients who recurred between 6 and 12 months or ≥ 12 months of adjuvant chemotherapy completion were considered platinum intermediate or platinum sensitive, respectively. Platinum resistance was not evaluated for patients who did not undergo or complete adjuvant chemotherapy [23, 24].
Small bowel obstruction
SBO was defined by the presence of clinical, radiological, and/or surgical parameters. Common presentations included absence of bowel movements and flatus (obstipation), accompanied by nausea, vomiting, and/or abdominal distension with pain, x-rays showing distended loops / air fluid levels, a CT scan revealing similar findings with limited passing of oral contrast, or intraoperative identification of adhesions, tumor, or collections causing bowel obstruction. SBO was classified as malignant (MBO) if concurrent intra-abdominal lesions were observed on imaging or intraoperatively and determined as the cause of obstruction. Cancer Antigen 125 (CA-125) levels at the time of SBO were recorded for all patients. Values were classified as elevated (CA-125 > 35 units per milliliter [U/mL]) or rising (increase > 5 U/mL) [25].
Clinical data was recorded for the first SBO episode, including date, diagnosis criteria, location (small vs. large bowel), type (partial vs. complete), and treatment (conservative vs. surgical). The number of recurrent episodes was also recorded.
Matching
To account for potential confounding factors, PSM was performed using a full matching algorithm. First, the propensity score for each patient was calculated using a logistic regression model, with CRS/HIPEC as the dependent variable and baseline covariates, including age at surgery (< 65 vs. ≥ 65 years old), FIGO stage (III vs. IV), number of regions involved by tumor (continuous), and surgery year (continuous), as predictors. Patients were placed into matched sets based on their propensity scores and CRS/HIPEC exposure (CRS/HIPEC group vs. CRS only group). The matching was implemented with a caliper width of 0.2 on the propensity score scale to ensure adequate overlap in covariate distribution between groups. Additionally, an exact match was enforced on tumor histology (high-grade serous [HGS] vs. non-HGS) to further control for this key variable. Following matching, weights were assigned to each participant based on the matched sets, allowing each patient in the treatment group (CRS/HIPEC) to be matched to one or more controls. After matching, a covariate balance check was performed using univariate weighted logistic regression and graphical methods (quantile–quantile [Q–Q] plots, bar plots, and “Love plot” for propensity scores) [26].
Data analysis
Baseline demographics and perioperative characteristics were summarized using descriptive statistics. Perioperative variables between treatment groups were compared using weighted Mann–Whitney U and Chi-squared tests. The effects of treatment (CRS/HIPEC vs. CRS only) on OFS, progression-free survival (PFS), and OS, were assessed using a weighted Cox proportional hazards model. OFS was measured from the date of surgery to the date of the first bowel obstruction episode or death. PFS was measured from the date of surgery to the date of first recurrence or death. OS was measured from the date of surgery to the date of death by any cause. Statistical significance was considered when p-value < 0.05. All analyses were performed using R-RStudio V. 2023.06.0 for Windows, employing relevant packages such as MatchIt, survey, and survival.
Results
Cohort characteristics
Of 173 advanced OC patients who underwent upfront CRS ± HIPEC, 113 (65.3%) were eligible for matching. Thirty-two (28.3%) patients underwent optimal CRS/HIPEC and 81 (71.7%) optimal CRS only (Fig. 1). Before matching, CRS/HIPEC patients tended to be younger (age ≥ 65 years: 31.2% [n = 10] CRS/HIPEC vs. 58.0% [n = 47] CRS only, p = 0.03) and presented with a higher number of regions involved by tumor (median: 6 [5–7] for CRS/HIPEC vs. 3 [2–5] for CRS only, p < 0.01). Groups had similar histology (HGS: 75.0% [n = 24] CRS/HIPEC vs. 81.5% [n = 66] CRS only, p = 0.187), FIGO stage at presentation (FIGO stage IV: 34.4% [n = 11] CRS/HIPEC vs. 14.8% [n = 12] CRS only, p = 0.553), and surgical year distribution (p = 0.946).
Fig. 1.
Patient selection flow diagram: Patients who underwent optimal CRS ± HIPEC at a community hospital. CRS: cytoreductive surgery; FIGO: International Federation of Gynecology and Obstetrics; HIPEC: hyperthermic intraperitoneal chemotherapy; HGS: high-grade serous; IP: intraperitoneal; SBO: small bowel obstruction
Matched cohort characteristics
After matching, 29 patients were included in the CRS/HIPEC group and 73 in the CRS only group (Fig. 1). Groups were balanced by age (p = 0.916), FIGO stage (p = 0.758), histology (p = 1.0), number of regions affected (p = 0.924), and surgery year (p = 0.749) (Fig. 2). Fewer CRS/HIPEC patients were considered high risk surgical candidates (American Society of Anesthesiologists [ASA] score ≥ 3: 20.7% [n = 6] vs. 49.3% [n = 38], p = 0.034). There were no significant differences between groups regarding race (p = 0.134), Breast Cancer gene (BRCA) status (p = 0.666), and primary tumor site (p = 0.811) (Table 1).
Fig. 2.
Love plot before and after propensity score matching. Cohort balance before and after propensity score matching. The lower the absolute standardized mean differences (closer to 0.0) the more homogeneous the cohort. Variables are ordered by significance level (higher difference between groups) in the unadjusted (pre-match) sample. FIGO: International Federation of Gynecology and Obstetrics
Table 1.
Baseline characteristics
| Characteristics | CRS/HIPEC (n = 29) |
CRS only (n = 73) |
p value |
|---|---|---|---|
| Age, years, median (IQR) | 61 (56–65) | 62 (56–68) | 0.916 |
| Age ≥ 65 years old, n (%) | 9 (31.0) | 24 (32.9) | 0.855 |
| Race | |||
| White non-Hispanic, n (%) | 24 (82.8) | 46 (63.0) | 0.134 |
| Other, n (%) | 5 (17.2) | 27 (37.0) | |
| ASA score | |||
| 1–2, n (%) | 23 (79.3) | 36 (49.3) | 0.034 |
| 3–4, n (%) | 6 (20.7) | 36 (49.3) | |
| Unknown, n (%) | 0 (0) | 1 (1.4) | |
| Histology | |||
| HGS, n (%) | 24 (82.8) | 60 (82.2) | 1.00 |
| Non-HGS, n (%) | 5 (17.2) | 13 (17.8) | |
| FIGO stage | |||
| III, n (%) | 20 (69.0) | 53 (72.6) | 0.758 |
| IV, n (%) | 9 (31.0) | 20 (27.4) | |
| BRCA status | |||
| Mutated, n (%) | 5 (17.2) | 18 (24.6) | 0.666 |
| Wild type, n (%) | 20 (69.0) | 51 (69.9) | |
| Not available, n (%) | 4 (13.8) | 4 (5.5) | |
| Surgery year | |||
| 2014–2018, n (%) | 16 (55.2) | 42 (57.5) | 0.749 |
| 2019–2022, n (%) | 13 (48.8) | 31 (42.5) | |
| Primary tumor site | |||
| Primary peritoneal, n (%) | 3 (10.3) | 6 (8.2) | 0.811 |
| Tubo-ovarian, n (%) | 26 (89.7) | 67 (91.8) | |
| Number of regions affected, median (IQR) | 6 (4–7) | 5 (4–6) | 0.924 |
| 1–5, n (%) | 14 (48.3) | 38 (52.0) | 0.821 |
| 6–8, n (%) | 15 (51.7) | 35 (48.0) | |
Significant p values are bold
ASA American Society of Anesthesiologists, CRS cytoreductive surgery, FIGO International Federation of Gynecology and Obstetrics, HGS high grade serous, HIPEC hyperthermic intraperitoneal chemotherapy, IQR interquartile range
Surgical outcomes
CRS/HIPEC patients had a higher median number of UAP (4 [Interquartile Range - IQR: 3–5] vs. 1 [IQR: 0–4], p < 0.01), as well as higher rates of chest tube placement (79.3% [n = 23] vs. 15.1% [n = 11], p < 0.01) and diaphragmatic peritonectomy (82.7% [n = 24] vs. 52.0% [n = 38], p = 0.024). There were no significant differences in median operative time (p = 0.196), median estimated blood loss (p = 0.434), rates of diaphragmatic resection (p = 0.481), bowel resection with anastomosis (p = 0.147), ostomy creation (p = 0.318), omentectomy (p = 1.0), or median hospital stay (0.206). Rates of major postoperative complications (CD III-IV: 31.0% [n = 9] vs. 27.4% [n = 20], p = 0.620), readmissions (44.8% [n = 13] vs. 60.3% [n = 44], p = 0.381), and postoperative mortality (6.9% [n = 2] vs. 8.2% [n = 6], p = 0.865) were also similar. Bowel-related surgical complications, specifically rates of anastomotic leak/fistula (p = 0.669) and intra-abdominal collections (0.970), were similar between groups. CRS/HIPEC patients tend to have fewer wound complications (13.8% [n = 4] vs. 35.6% [n = 26], p = 0.086) (Table 2).
Table 2.
Patient outcomes
| Outcomes | CRS/HIPEC (n = 29) |
CRS only (n = 73) |
p value |
|---|---|---|---|
| Operative time, min, median (IQR) | 483 (440–565) | 423 (314–515) | 0.196 |
| Upper abdominal procedures, median (IQR) | 4 (3–5) | 1 (0–4) | < 0.01 |
| Chest tube(s) placement, n (%) | 23 (79.3) | 11 (15.1) | < 0.01 |
| Diaphragmatic peritonectomy, n (%) | 24 (82.7) | 38 (52.0) | 0.024 |
| Diaphragmatic resection, n (%) | 15 (51.7) | 30 (41.1) | 0.481 |
| Omentectomy, n (%) | 29 (100) | 73 (100) | 1.00 |
| Bowel resection with anastomosis, n (%) | 25 (86.2) | 51 (69.9) | 0.147 |
| Estimated blood loss, mL, median (IQR) | 1000 (500–1500) | 1000 (500–1250) | 0.434 |
| Ostomy, n (%) | 3 (10.3) | 15 (20.5) | 0.318 |
| Length of hospital stay, days, median (IQR) | 10 (9–14) | 10 (7–12) | 0.206 |
| 90-day postoperative morbidity | |||
| CD I–II, n (%) | 27 (93.1) | 66 (90.4) | 0.716 |
| CD III–IV, n (%) | 9 (31.0) | 20 (27.4) | 0.620 |
| Anastomotic leak / fistula, n (%) | 6 (20.7) | 20 (27.4) | 0.669 |
| Intra-abdominal collection, n (%) | 8 (27.6) | 20 (27.4) | 0.970 |
| Wound-related complications, n (%) | 4 (13.8) | 26 (35.6) | 0.086 |
| 90-day hospital readmissions, n (%) | 13 (44.8) | 44 (60.3) | 0.381 |
| 90-day postoperative mortality, n (%) | 2 (6.9) | 6 (8.2) | 0.865 |
| Time to adjuvant chemotherapy, days, median (IQR) | 59 (56–66) | 48 (36–60) | 0.071 |
| Adjuvant chemotherapy completion, n (%) | 23 (79.3) | 49 (67.1) | 0.382 |
| Adjuvant chemotherapy cycles, median (IQR) | 6 (5–6) | 6 (4–6) | 0.706 |
| Platinum resistance | 0.191 | ||
| Platinum resistant (< 6 months), n (%) | 3 (10.3) | 22 (30.1) | 0.061* |
| Platinum intermediate (≥ 6–<12 months), n (%) | 3 (10.3) | 7 (9.6) | - |
| Platinum sensitive (≥ 12 months), n (%) | 18 (62.1) | 26 (35.6) | - |
| Platinum naive, n (%) | 5 (17.3) | 18 (24.7) | 0.565* |
Significant p values are bold
CD Clavien–Dindo, CRS cytoreductive surgery, HIPEC hyperthermic intraperitoneal chemotherapy, IQR interquartile range, min minutes
*Direct rate comparison
Small bowel obstruction
Forty-one primary SBO events were recorded for all patients. No episodes of large bowel obstruction were identified. The CRS/HIPEC group had fewer SBO (24.1% [n = 7]) compared to the CRS only group (42.0% [n = 34]) (p = 0.120). For both groups, most SBO cases were diagnosed using abdominal CT, were partial SBO, and managed conservatively, including gastric decompression with nasogastric tube and bowel rest (nothing by mouth) followed by diet progression (Table 3). For the CRS/HIPEC group, surgical management was required in two (28.6%) patients, including a venting gastrostomy placement (n = 1) and exploratory laparotomy (n = 1). In the CRS only group, surgical management for 11 (32.4%) patients involved exploratory laparotomy with bowel resection (n = 1) / entero-colostomy (n = 1) and percutaneous endoscopic gastrostomy (n = 9). Recurrent SBO occurred in 57.1% (n = 4/7) CRS/HIPEC patients and 29.4% (n = 10/34) CRS only patients (p = 0.268). MBO was determined for one (14.3%) CRS/HIPEC patient based on imaging findings (obstruction caused by tumor implant). MBO occurred in 73.5% (25/34) CRS only patients, with one (4.0%) having corroborated pathological evaluation, one (4.0%) having tumor identified during surgery, and 23 (92.0%) based on imaging. At the time of SBO, CA-125 was positive or rising in 57.1% (n = 4/7) of CRS/HIPEC patients, including the one patient with MBO. In the CRS only group, 38.2% (n = 13/34) of patients had rising or elevated CA-125 levels at the time of their first SBO event, including nine patients with MBO. CA-125 levels were not available at the time of the first SBO event for 47.0% (n = 16/34) of patients from the CRS only cohort.
Table 3.
Small bowel obstruction characteristics
| Characteristics | CRS/HIPEC (n = 7) |
CRS only (n = 34) |
p value |
|---|---|---|---|
| SBO type | |||
| Partial, n (%) | 5 (71.4) | 19 (55.9) | 0.545 |
| Complete, n (%) | 2 (28.6) | 15 (44.1) | |
| SBO diagnosis | |||
| Abdominal CT scan, n (%) | 6 (85.7) | 30 (88.2) | 0.838 |
| X-ray abdominal series, n (%) | 1 (14.3) | 4 (11.8) | |
| SBO treatment | |||
| Conservative, n (%) | 5 (71.4) | 23 (67.6) | 0.859 |
| Surgical, n (%) | 2 (28.6) | 11 (32.4) | |
| Recurrent SBO, n (%) | 4 (57.1) | 10 (29.4) | 0.268 |
| Malignant SBO diagnosis | 1 (14.3) | 25 (73.5) | 0.009 |
| Pathologically confirmed, n (%) | 0 (0) | 1 (4.0) | – |
| Surgically confirmed, n (%) | 0 (0) | 1 (4.0) | – |
| Determined by imaging, n (%) | 1 (100) | 23 (92.0) | – |
| Positive/raising CA-125, n (%) | 4 (57.1) | 13 (38.2)* | 0.554 |
Significant p values are bold
CA-125 cancer antigen 125, CRS cytoreductive surgery, CT computed tomography, HIPEC hyperthermic intraperitoneal chemotherapy, SBO small bowel obstruction
*CA-125 level was unknown for 16 patients in the CRS only group
Overall survival and other survival outcomes
After a median follow-up of 88.8 months, median OS was longer in the CRS/HIPEC group (71.6 [IQR: 34.6- not available] vs. 31.5 [IQR: 15.4–78.8] months) (Fig. 3A). No association between HIPEC and OS (Hazard Ratio [HR]: 0.52 [95% CI 0.26–1.0], p = 0.062) was observed. Median PFS was longer in the CRS/HIPEC group (27.8 [IQR: 17.3- not available] months) compared to the CRS only group (13.5 [IQR: 9.5–42.0] months) (Fig. 3B). CRS/HIPEC was associated with a lower hazard of tumor progression compared to CRS only (HR: 0.50 [95% CI 0.28–0.89], p = 0.018). In the CRS/HIPEC group, 18 patients had disease recurrence, most were either isolated extraperitoneal (38.9%, n = 7/18) or combined (simultaneous intra- and extraperitoneal) (38.9%, n = 7/18), followed by isolated intraperitoneal (22.2%, n = 4/18). In the CRS only group, 54 patients experienced disease recurrence, which were mostly isolated intraperitoneal (48.1%, n = 26/54), followed by extraperitoneal (35.2%, n = 19/54) and combined (16.7%, n = 9/54). Differences in recurrence patterns between groups were not significant (p = 0.367). Fewer patients were platinum resistant in the CRS/HIPEC group (10.3% [n = 3] vs. 30.1% [n = 22], p = 0.061). Median time to adjuvant chemotherapy initiation was longer in the CRS/HIPEC group (59 [IQR:56–66] vs. 48 [IQR: 36–60] days, p = 0.071). Adjuvant IV chemotherapy completion rates (p = 0.382), and median number of cycles (p = 0.706) were similar between groups (Table 2).
Fig. 3.
A Overall and B progression-free survival and by treatment group. Unweighted Kaplan-Meier survival curves are provided for descriptive purposes only, to visually illustrate differences in outcomes between groups. The effects of CRS/HIPEC on overall and progression-free survival were assessed using a weighted Cox proportional hazards model. Significant p values are bold. CRS cytoreductive surgery, HIPEC hyperthermic intraperitoneal chemotherapy
Obstruction-free survival
OFS was longer in the CRS/HIPEC group with a median of 42.9 (IQR: 26.7—not available) vs. 20.0 (IQR: 5.8–64.1) months in the CRS only group (Fig. 4A). CRS/HIPEC was associated with a significantly lower hazard of bowel obstruction or death compared to CRS only (HR: 0.50 [95% CI 0.27–0.93], p = 0.028). Survival following the first SBO event was also higher in the CRS/HIPEC group (CRS/HIPEC: 85.7% at 1-year and 71.4% at 3-years vs. CRS only: 44.7% at 1-year and 31.7% at 3-years) (Fig. 4B). However, CRS/HIPEC exposure was not significantly associated with survival after SBO (HR: 0.79 [95% CI 0.39–1.61], p = 0.512). In a multivariable cox hazards model adjusting for baseline differences between groups (ASA score, number of UAP, and platinum resistance), CRS/HIPEC remained associated with a reduced risk of bowel obstruction or death (HR: 0.37 [95% CI 0.17–0.84], p = 0.017) (Fig. 5).
Fig. 4.
A Obstruction-free survival after CRS ± HIPEC and B overall survival after small bowel obstruction (SBO) by treatment group. Unweighted Kaplan-Meier survival curves are provided for descriptive purposes only, to visually illustrate differences in outcomes between groups. The effects of CRS/HIPEC on obstruction-free (OFS) and overall survival (OS) after the first SBO were assessed using a weighted Cox proportional hazards model. OFS was measured from surgery date to the first SBO event/death. OS was measured from the first SBO event to death. Significant p values are bold. CRS cytoreductive surgery, HIPEC hyperthermic intraperitoneal chemotherapy, SBO small bowel obstruction
Fig. 5.
Forrest plot of the Cox proportional hazards model assessing the effect of CRS/HIPEC on OFS. Cox proportional hazards model was adjusted for factors significantly different between groups including ASA score, number of UAP, and platinum resistance. Significant p values are bold. ASA American Society of Anesthesiologists, CI confidence interval, CRS cytoreductive surgery, HIPEC hyperthermic intraperitoneal chemotherapy, OFS obstruction-free survival, SBO small bowel obstruction, UAP upper abdominal procedures
Discussion
We report the potential benefit of incorporating HIPEC during primary CRS in reducing the incidence of SBO in advanced OC patients. Patients who underwent optimal upfront CRS/HIPEC had longer OFS compared to those treated with optimal CRS alone. CRS/HIPEC was associated with a reduced hazard of SBO or death. Notably, the CRS/HIPEC group underwent a more aggressive surgical approach, where patients had more UAP. Additionally, we observed a trend toward altered recurrence patterns in the CRS/HIPEC group, with a shift from intraperitoneal to extraperitoneal spread, along with longer PFS and a lower hazard for tumor progression.
The incidence of SBO during OC progression is poorly understood. Autopsy-based epidemiological studies have estimated intestinal obstruction rates as high as 51% [27, 28]. Retrospective clinical studies report variable rates. Sartori et al. documented a 28% bowel obstruction incidence in a cohort of 75 patients, 95% of whom had advanced disease [3]. In a large Surveillance, Epidemiology and End Results (SEER)-Medicare database study including 8,607 °C patients, 19.5% were hospitalized for SBO following diagnosis [5]. However, the authors disclosed potential underestimation due to factors such as early-stage disease (FIGO IC/II) in 12.3% of the cohort. Tran et al. reported SBO in 22% (68/311) of OC patients, which increased to 41% (46/112) after excluding patients with unknown obstruction status (45.6%, 142/311), unknown stage (11.5%, 36/311), or early stage disease (I/ II: 12.9%, 40/311) [2]. Notably, none of these studies provided data on OC management beyond primary tumor resection. In our study, SBO incidence after primary treatment for advanced OC was 42.0% in the CRS only group, comparable to rates reported by Sartori and Tran [2, 3], and 24.1% in the CRS/HIPEC group. Due to differences in reporting and cohort diversity, the true incidence of SBO after primary treatment for advanced OC remains uncertain. Nonetheless, SBO represents a frequent and clinically significant problem for OC patients.
SBO poses a significant threat to quality of life in patients with peritoneal carcinomatosis [8, 29]. Consequently, OFS has been recognized as a meaningful endpoint that reflects both disease control and quality of life [29, 30]. Chow et al. demonstrated a meaningful OFS of 17 months in 30 appendix/colorectal cancer patients with peritoneal metastases managed with CRS/HIPEC [15]. Data specific to OC is limited. In a study of 16 ovarian carcinosarcoma patients, Lopez-Ramirez et al. reported a median OFS of 21.3 months and a 1-year OFS rate of 86.7%, with only 3 cases of MBO after CRS/HIPEC [31]. In our study, patients in the CRS/HIPEC group showed similar or improved outcomes, with a median OFS of 42.9 months and a 1-year OFS rate of 85.4%. Conversely, the CRS only group exhibited a significantly shorter median OFS (20.0 months) and lower 1-year OFS rate (63.5%). Notably, in both univariable and multivariable Cox regression analyses (adjusted for ASA score, UAP, and platinum resistance), CRS/HIPEC was found to be significantly associated with a 50% reduction in the risk for SBO or death, suggesting that incorporating HIPEC may be an effective strategy to prevent SBO in advanced OC patients [8]. These findings warrant further exploration in larger, prospective studies. As OFS continues to gain recognition as a clinically relevant endpoint that captures both disease control and patient-centered outcomes, future research should validate its role and explore its relation with treatment response and outcomes.
Given the similar baseline characteristics and comparable postoperative management between groups, we attribute the observed differences in OFS primarily to the extent of tumor control achieved through aggressive CRS, with or without HIPEC. Residual disease following CRS is widely recognized as the most critical determinant of survival in primary OC patients [18, 32]. Rodriguez et al., analyzing a propensity-matched cohort from the GOG 182 trial, showed that incorporating upper abdominal surgery significantly increased the likelihood of achieving complete CRS (odds ratio: 4.68 [2.92 to 7.51]), with associated trends towards improved OS and PFS [33]. More recent studies have linked aggressive surgery, including extensive UAP, with lower intraperitoneal recurrence rates (HR: 0.49, 95% CI 0.34–0.71) [34]. In the context of CRS/HIPEC, an aggressive surgical approach aims to leave only microscopic residual disease that can be effectively targeted by HIPEC perfusion [35]. In our study, patients in the CRS/HIPEC group had significantly more UAP without a corresponding increase in complication rates—potentially contributing to the longer OFS observed. These findings support the notion that aggressive surgery, when performed by experienced surgical and gynecological oncologists, can improve outcomes in advanced OC without increasing morbidity or compromising quality of life [19, 36].
Evidence suggests that loco-regional therapies, such as intraperitoneal chemotherapy (IP) or HIPEC following CRS, may offer superior control of microscopic disease, significantly reducing peritoneal relapse [37, 38]. In the GOG-172 trial, 41.1% of patients treated with adjuvant IP chemotherapy experienced their first recurrence outside the peritoneal cavity [39]. Similarly, Tanner et al. reported that patients receiving adjuvant IP chemotherapy were less likely to develop lower abdominal or pelvic recurrences (36.7% vs. 13.6%, p < 0.01) and more likely to experience extra-abdominal recurrences (45.5% vs. 23.3%, p = 0.018) compared to those receiving adjuvant IV chemotherapy [40]. In the setting of interval CRS/HIPEC, Sinukumar et al. reported isolated peritoneal recurrences in only 14% (3/21) of patients [14]. Ceresoli et al., using a propensity-matched cohort, demonstrated that patients treated with interval CRS alone were more likely to experience isolated peritoneal recurrences (43% vs. 14%) compared to those who underwent interval CRS/HIPEC [41]. Conversely, in a study of 34 patients undergoing upfront CRS/HIPEC, 37.5% (9/24 recurrences) were isolated peritoneal recurrences, suggesting an intermediate effect between interval CRS/HIPEC and historical reports (~ 60%) [42, 43]. In our cohort, we observed a similar trend, with fewer isolated intraperitoneal recurrences in the CRS/HIPEC group compared to the CRS only group (22.2% vs. 48.1%, p = 0.365), suggesting improved abdominal disease control through direct chemotherapy exposure.
While interval CRS/HIPEC has shown improved PFS and OS compared to IV chemotherapy in randomized trials, evidence supporting the use of upfront CRS/HIPEC is limited [13, 44, 45]. Most existing studies in the upfront setting are retrospective and vary widely in terms of perfusion agents and techniques. An umbrella review of meta-analyses highlighted a significant benefit in 3-year PFS (HR: 0.54, 95% CI 0.48–0.61) and OS (HR: 0.66, 95% CI 0.56–0.78) for patients undergoing primary CRS/HIPEC versus CRS alone [46]. However, the review did not distinguish between upfront and interval CRS/HIPEC. In contrast, in a pooled analysis by Kim et al., stratified by chemotherapy exposure (≥ 6 vs. < 6 months), found no PFS or OS benefit in the non-recent group (> 6 months), which included both upfront (chemotherapy naïve) and recurrent (not recently chemotherapy exposed) patients [47]. Consistently, Della Corte et al. showed no significant PFS differences between patients undergoing upfront CRS/HIPEC and CRS alone (mean difference: −5.53 months, p = 0.45) [48]. Interestingly, in our study, an aggressive upfront CRS/HIPEC approach was associated with a significant PFS benefit compared to a PSM CRS-only cohort (HR: 0.5 [0.3–0.9], p = 0.018), although no significant OS advantage was observed (p = 0.062). While these findings are encouraging, they should be interpreted with caution given the sample size limitations, particularly at later time points, and potential uncontrolled differences in event timing between groups, which may reduce precision and obscure meaningful effects. Several ongoing trials are expected to substantiate these findings [49, 50]. Until more definitive data is available, routine use of upfront CRS/HIPEC should be limited to the research setting [51].
The primary limitation of our study is its retrospective design, which precludes establishing causal relationships between CRS/HIPEC, reduced SBO incidence, and prolonged OFS. Additionally, the single-center setting and relatively small sample size may limit the generalizability of our findings and power of our results. For example, although median operative time was approximately one hour longer in the CRS/HIPEC group, the difference was not statistically significant (p = 0.196), likely due to limited power, overlapping distributions, and inherent variations in surgeon technique and intraoperative decision-making. To help mitigate confounding variables, we employed a PSM approach to balance baseline characteristics; however, residual confounding may persist—particularly given significant group differences in the extent of UAP and platinum resistance rates. To address this, we performed a multivariable cox regression, which supported our primary findings. Despite these limitations, our study is among the few to assesses OFS as a meaningful outcome following upfront CRS/HIPEC in advanced OC. With a follow-up period exceeding 5 years, this data offers valuable insights into the long-term effects of aggressive CRS coupled with HIPEC on local disease control, bolstering existing literature supporting its efficacy. Prospective validation is needed in a clinical trial setting.
Conclusions
Patients who underwent CRS/HIPEC demonstrated a reduced risk of SBO or death, with lower SBO rates and longer OFS than those who underwent CRS alone. The improved peritoneal disease control achieved by a thorough CRS (including upper abdominal exploration/surgery), combined with HIPEC, provides a plausible rationale for these findings.
Acknowledgements
The authors thank Dr. Carol Nieroda, for her support during the manuscript review process. The authors also thank Miss Kathleen Pawlikowski for her assistance with data collection.
Abbreviations
- ASA
American Society of Anesthesiologists
- BRCA
Breast Cancer Gene
- CA-125
Cancer Antigen 125
- CC
Completeness of cytoreduction
- CC-0
Completeness of cytoreduction with no residual disease
- CC-1
Completeness of cytoreduction with residual tumor < 2.5 mm
- CD
Clavien–Dindo
- CRS
Cytoreductive surgery
- CT
Computed tomography
- FIGO
International Federation of Gynecology and Obstetrics
- HR
Hazard ratio
- HIPEC
Hyperthermic intraperitoneal chemotherapy
- HGS
High-grade serous
- IP
Intraperitoneal chemotherapy
- IQR
Interquartile range
- IV
Intravenous
- MBO
Malignant bowel obstruction
- OC
Ovarian cancer
- OFS
Obstruction-free survival
- OS
Overall survival
- PET
Positron emission tomography
- PFS
Progression-free survival
- PSM
Propensity score matched
- Q-Q
Quantile–quantile
- SBO
Small bowel obstruction
- SEER
Surveillance, Epidemiology and End Results
- UAP
Upper abdominal procedures
- U/mL
Units per milliliter
Author contributions
LFFZ: Conceptualization, methodology, data curation, formal analysis, investigation, writing original draft, visualization; AS: Conceptualization, methodology, supervision, visualization, writing, review and editing, funding acquisition; MCK: Conceptualization, Data curation, formal analysis, visualization, writing, review and editing, project administration; FLR: Conceptualization, methodology, visualization; VK: Data curation, analysis, visualization; SI: Data curation, visualization; TDM: Conceptualization, methodology, supervision, visualization, writing, review and editing; VG: Conceptualization, methodology, supervision, formal analysis, visualization, writing, review and editing, funding acquisition. All authors have made substantial intellectual contributions to the conception, design, and execution of this study. Each author has actively participated in drafting the work, revising it critically for important intellectual content, and has given final approval for the version to be published. Furthermore, all authors agree to be accountable for all aspects of the work, ensuring that questions related to any part of the work are appropriately investigated and resolved.
Funding
This research was funded by an annual fundraising event, Heat It to Beat It. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Competing interests
The authors declare no competing interests.
Ethical approval and consent to participate
The study has been approved by Mercy Medical Center Institutional Review Board (IRB# 2014-17; 1230783).
Consent for publication
The informed consent of this study has been obtained from patients.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.