Prophylactic Hysterectomy During Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for High Grade Tumors Is Associated with Fewer Pelvic Recurrences

INTRODUCTION

No guidelines exist regarding the management of the uterus in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for metastatic non-gynecologic malignancies without direct uterine involvement. While some clinicians consider a hysterectomy necessary for a complete pelvic peritonectomy, others do not.^1–3 Patients may desire preservation of the uterus for a variety of reasons if it is not directly involved.⁴ The aim of this analysis is to explore the relationship between hysterectomy at time of CRS/HIPEC and patterns of recurrence.

METHODS

We performed a single institution retrospective cohort analysis of patients treated with CRS/HIPEC for non-gynecologic malignancies between 2016 and 2022. The primary outcome was site of first recurrence, defined as pelvic or non-pelvic. Pelvic recurrence was defined as recurrence in a pelvic organ (uterus, ovary, sigmoid colon, rectum, vaginal cuff) or pelvic peritoneal surfaces. Women who had a hysterectomy prior to diagnosis of carcinomatosis, or those whose uterus was pathologically involved at the time of CRS/HIPEC were excluded.

RESULTS

A total of 124 female patients underwent CRS/HIPEC during the study period: 84 were excluded, leaving a total of 40 patients who either underwent hysterectomy at the time of CRS/HIPEC, but had no pathologic involvement of the uterus (n = 26), or who did not undergo a hysterectomy during cytoreduction (n = 14) (Fig. 1). Median age was 63 years and did not differ between the hysterectomy and no hysterectomy group (66 versus 56, p = 0.17). All patients received mitomycin-C at a concentration of 25 mg/m² for 90 min at a temperature of 42 °C during CRS/HIPEC.

Figure 1.

Selection of patient cohort

A proportion of 47.5% patients (n = 19) had recurrence at a median of 11 months postoperatively. Overall rates of recurrence and time to recurrence did not differ between groups (Table 1). However, patients that did not have a hysterectomy were significantly more likely to have a pelvic recurrence than patients who had a pathology-negative hysterectomy (35.7% versus 7.7%, p < 0.05) (Table 1). Rates of pelvic peritonectomy did not differ between groups (54% versus 50%, p = 0.18).

Table 1.

Cohort Characteristics

Variable/Characteristic	Total (N = 40)	Hysterectomy at HIPEC (N = 26)	No Hysterectomy at HIPEC (N = 14)	p-value
Preoperative Characteristics
Age, years, median (IQR)	63 (51–70)	66 (53–71)	56 (47–64)	0.17
Primary Site, n (%)				0.46
Appendix	17 (42.5)	12 (46.2)	5 (35.7)
Colon	19 (42.7)	12 (46.2)	7 (50.0)
Gastric	3 (7.5)	1 (3.8)	2 (14.3)
Mesothelioma	1 (2.5)	1 (3.8)	0 (0)
Histology, n (%)				0.90
Adenocarcinoma, non-mucinous	16 (40.0)	9 (34.6)	7 (50.0)
Adenocarcinoma, mucinous	13 (32.5)	8 (30.7)	5 (35.7)
Signet ring	2 (5.0)	1 (3.8)	1 (7.1)
Goblet cell	4 (10.0)	3 (11.5)	1 (7.1)
Other	5 (12.5)	5 (19.2)	0 (0.0)
Neoadjuvant Therapy, n (%)	23 (57.5)	15 (57.7)	8 (57.1)	0.97
Operative Characteristics
PCI, median (IQR)	6.5 (4–10)	7 (4–12)	4 (3–10)	0.59
CC score, n (%)
0–1	40 (100.0%)	26 (100.0%)	14 (100.0%)	0.99
Pelvic Peritonectomy Performed, n (%)	21 (52.5)	14 (53.8)	7 (50.0)	0.81
Positive Pathology	9 (42.8)	6 (42.8)	3 (42.8)	0.99
Positive Pathology+ Pelvic Recurrence	4 (44.4)	1 (16.7)	3 (100.0)	<0.05*
Patient Follow Up
Adjuvant Therapy, n (%)	20 (50.0)	12 (46.2)	8 (57.1)	0.51
Cancer Recurrence, n (%)	19 (47.5)	12 (46.2)	7 (50.0)	0.75
Time to first recurrence, months, median (IQR)	11 (6–22)	8 (4–15)	21 (9–43)	0.13
Location of first recurrence, n (%)				<0.05*
Pelvic recurrence	7 (17.5)	2 (7.7%)	5 (35.7)
Non-pelvic recurrence	12 (30.0)	10 (38.4)	2 (14.3)
Cancer specific mortality, n (%)	5 (12.5)	2 (7.7)	3 (21.4)	0.32
1-year all-cause mortality, n (%)	2 (5.0)	1 (3.9)	1 (7.1)	0.64
2-year all-cause mortality, n (%)	3 (7.5)	1 (3.9)	2 (14.3)	0.31
3-year all-cause mortality, n (%)	6 (15.0)	3 (11.5)	3 (21.4)	0.39
Follow up duration, months, median (IQR)	36 (22–52)	35 (22–56)	36 (21–51)	0.99

^*Statistically significant at a p-value of <0.05 by means Chi squared test for categorical variables and Mann-Whitney test for continuous variables.

Abbreviations: HIPEC, hyperthermic intraperitoneal chemotherapy; IQR, interquartile range; PCI, peritoneal cancer index; CC, completeness of cytoreduction

Of the patients with pathologic involvement of the pelvic peritoneum only 17% (1/6) of patients that had a hysterectomy had a pelvic recurrence; 100% (3/3) of patients with pathologic involvement of the pelvic peritoneum but who did not have a hysterectomy had pelvic recurrence (p < 0.05) (Table 1). Four of the seven patients who did not undergo a hysterectomy had uterine recurrence (57%) and, of these, half underwent hysterectomy at a later date. Other postoperative outcomes, such as length of stay, receipt of post operative red blood transfusion, overall and serious morbidity, and readmission rates, did not differ between the groups.

CONCLUSIONS

In this retrospective analysis of 40 female patients treated with CRS/HIPEC for non-gynecologic malignancies, patients who did not undergo hysterectomy at time of surgery were more likely to have pelvic recurrence of their disease than women who did. This is the first study to explore the correlation between prophylactic hysterectomy and patterns of pelvic recurrence in patients treated with CRS/HIPEC.

Presently, no guidelines exist regarding the management of the uterus in patients who have peritoneal carcinomatosis, but no gross evidence of uterine involvement, during CRS/HIPEC. Although it has been shown that higher peritoneal cancer index (PCI) is associated with an increased incidence of disease progression, the presence of microscopic residual disease might not be obvious.^2,5 In one cohort, 73% of patients with no gross evidence of gynecologic organ involvement during CRS/HIPEC actually had microscopic disease on final pathology.² This suggests that failure to remove the uterus during CRS/HIPEC may contribute to disease recurrence by harboring residual disease and may also contribute to an incomplete peritonectomy. Our data supports this conclusion, as all patients who did not undergo hysterectomy at the time of HIPEC, but had a positive pelvic peritonectomy, had pelvic recurrence.

Our findings suggest that a hysterectomy, as a more aggressive approach to cytoreduction during CRS/HIPEC, may be warranted to mitigate the risk of recurrence. However, this approach may not be desirable for women wishing to preserve fertility as pregnancy after HIPEC can be achieved with long durations of disease-free survival after fertility-sparing CRS/HIPEC.³ In fact, 1/4 of our patients under the age of 45 requested uterus preservation for this reason. This highlights the need for better informed discussion regarding pregnancy and pelvic recurrence in women undergoing CRS/HIPEC, all within the context of their prospects for survival.

Limitations to this analysis include lack of statistical power due to a small cohort size, heterogeneity of primary tumor types, and short duration of follow-up. However, given the paucity of literature guiding the management of the uterus in patients with peritoneal metastasis, this study can serve as the first of a growing body of literature to help counsel patients at risk of hysterectomy at the time of CRS/HIPEC and drive further research into this topic.