Intraperitoneal Radioactive Chromic Phosphate is a Well-Tolerated Adjuvant Treatment in Patients with Endometrial Cancer

Abstract

Background: The data assessing overall survival with regard to different adjuvant treatment in the setting of advanced-stage endometrial cancer are limited, as such, the appropriate adjuvant therapy for patients with this condition remains unclear. Objective: The purpose of this study was to evaluate outcomes and demographics of patients with endometrial cancer who received intraperitoneal radioactive chromic phosphate (³²P) as part of their cancer treatment. Materials and Methods: This single-institution retrospective review ran from January 2005 to December 2009. All patients underwent comprehensive surgical staging followed by infusion of intraperitoneal ³²P and possible chemotherapy, hormonal therapy, or radiation treatment. The follow-up time period ranged from 20 to 68 months. Results: Eight patients with stage III node-negative endometrial cancer with positive cytology who received ³²P were identified. The mean follow-up was 45.4 months. The mean time from surgery to intraperitoneal ³²P was 4 months. Seven of 8 patients received adjuvant single-agent platinum or combination platinum/taxane chemotherapy. No grade 3 or 4 complications were noted. There has been no evidence of recurrent disease in these patients noted to date. Conclusions: Adjuvant intraperitoneal ³²P for treating endometrial cancer patients at risk for intraperitoneal recurrence is well-tolerated with minimal toxicity. (J GYNECOL SURG 31:67)

Introduction

The presence of extrauterine spread is a well-established poor prognostic factor for patients with endometrial cancer, affecting both recurrence rates and overall survival. Possible adjuvant treatments for advanced endometrial cancer include chemotherapy, whole-abdomen irradiation, hormonal treatment, and intraperitoneal radioactive chromic phosphate (³²P). However, because there are limited data assessing overall survival for these different treatment modalities, appropriate adjuvant therapy for patients with advanced-stage endometrial cancer remains unclear.

Intraperitoneal ³²P has previously been utilized as an adjuvant therapy and has been associated with minimal toxicities for both ovarian and endometrial cancers. For patients who are thought to be at particular risk for isolated peritoneal recurrence, treatment with intraperitoneal ³²P may be a suitable option. Although the literature is very limited, decreased rates of recurrence and improved survival rates have been reported in patients with endometrial cancer and positive peritoneal cytology that was treated with intraperitoneal ³²P.^1–3 However, because of its maximum penetration of 8 mm, adjuvant vaginal cuff brachytherapy is necessary when there is concern regarding potential vaginal recurrence.

Features that may be associated with recurrence, both local and distant, include lymphovascular space invasion (LVI), high-grade nonendometrioid histology, peritoneal dissemination, gross residual disease, and presence of periaoritc lymph-node involvement.⁴ However, despite several published reports, it remains difficult to predict site of recurrence in patients with advanced-stage endometrial cancer. Factors that predict intraperitoneal recurrence are not well-defined, but may include peritoneal metastasis, positive peritoneal cytology, and ovarian metastasis.

Stage III endometrial cancer affects a heterogeneous group of patients for which there are no standardized treatment recommendations. The Gynecologic Oncology Group 122 trial demonstrated that patients with stage III or IV endometrial cancer treated with doxorubicin-cisplatin had improved progression-free and overall survival, compared with whole-abdominal irradiation.⁵ However, as a single treatment modality, chemotherapy does not result in a high rate of locoregional control. Radiation therapy has been shown to have good pelvic and abdominal locoregional control and to decrease the risk of recurrence in early stage intermediate-risk endometrial cancer; however, radiation therapy may be associated with significant adverse side-effects and with only a modest effect on disease-specific survival.^6,7 Patients who receive both chemotherapy and radiation have improved overall survival and progression-free survival, compared to patients treated solely with chemotherapy or radiotherapy.⁸ Hormonal treatments have also been used in patients with recurrent or advanced low-grade endometrial cancer, with response rates of ≤20%; however these responses were usually of short duration.⁹

As such, it still remains unclear which treatment modalities are best used as adjuvant therapy for locoregional versus distant control. The aim of this case series was to report the outcomes and demographics of a subset patients with stage III node-negative disease±positive peritoneal cytology, who were treated with surgery followed by a multimodal approach consisting of intraperitoneal ³²P, with possible chemotherapy, hormonal therapy, or radiation.

Materials and Methods

This study was a single-institution retrospective review. Included patients underwent complete surgical staging including total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic±periaortic lymph-node dissection, ±omentectomy and peritoneal cytology. Patients were excluded if there was extra-abdominal disease, if they had previously received radiation or systemic chemotherapy, or had histories of malignancy within the preceding 5 years. Staging was determined according to the 1988 pathologic International Federation of Gynecology and Obstetrics (FIGO) staging system.

After undergoing initial staging surgery and systemic chemotherapy, each study patient had a multiperforated dialysis catheter placed into the peritoneal cavity for administering the ³²P. Patients underwent a technetium distribution study prior to treatment to ascertain adequate distribution within the abdomen. A dose of 15 mCi of ³²P was infused intraperitoneally. Each patients was then instructed to lie flat but rotate 90° every 15 minutes for 2 hours after completion of instillation.

Demographics, adjuvant treatments, and pathology reports were reviewed for all patients in the study. Clinical information reviewed included age, body mass index (BMI), survival status, adjuvant treatments, and date of last visit. Data abstracted from pathology reports included histology, grade, depth of myometrial invasion, presence of LVI, peritoneal cytology, and lymph-node status. The study was approved by the institutional review board of the University of South Florida, Tampa, FL.

Results

From January 2005 to December 2009, 8 patients with stage III node-negative disease with positive peritoneal cytology, who received intraperitoneal ³²P were identified. They had all undergone staging surgery including lymph-node dissection,±omentectomy, and cytology of peritoneal washings. All patients were treated at the University of South Florida and Tampa General Hospital. The patients' characteristics are shown in Table 1. All 8 patients had endometrioid histology. LVI was noted in 2 patients (25%). The mean age of the patients was 49.5 years (range: 26–63 years), and the mean BMI was 32 kg/m² (range: 21.6–44.6 kg/m²). Five patients were classified as stage IIIA on the basis of positive malignant cytology; of these 5 patients, 1 had grade 3 disease with a large tumor size (8×6 cm), 1 had positive LVI, and 1 had>1/2 myometrial invasion.

Table 1.

Patient Characteristics (n=8)

Characteristics	Number
Age (years)
≤50	4
51–60	2
≥61	2
Cell type
Endometrioid	8
Grade
1	3
2	3
3	2
BMI
≤24	2
25–29	2
≥30	4
Myometrial invasion
Inner third	2
Middle third	4
Outer third	2
LVI
No	6
Yes	2
Cervical invasion
No	8
Yes	0
Adnexa
Negative	6
Positive	2
Parametrial involvement
No	7
Yes	1
Malignant peritoneal cytology
Negative	0
Positive	8
ER
No	4
Yes	4
PR
No	5
Yes	3

BMI, body mass index; LVI, lymphovascular invasion; ER, estrogen receptor; PR, progesterone receptor.

As shown in Table 2, 7 patients received adjuvant chemotherapy, which was comprised of single-agent platinum in 1 patient and a combination platinum/taxane regimen in the other 6 patients. Six patients received intraperitoneal ³²P after completing chemotherapy. One patient underwent ³²P infusion prior to chemotherapy. Another patient did not receive systemic chemotherapy and underwent infusion of ³²P 8 weeks after surgery. The mean time period from surgery to infusion of ³²P was 4 months. All estrogen receptor–positive patients (4/8) were treated with megace (80 mg daily) and tamoxifen (20 mg daily). Three patients received high-dose rate vaginal brachytherapy; tumor characteristics of these patients included involvement of the lower uterine segment in 2 patients and a large tumor size in the third patient (8×6 cm). The mean follow-up period was 45.4 months (range: 20–68 months).

Table 2.

Treatment and Outcomes

Patient	Age (yrs)	Lymph nodes evaluated	Chemotherapy	³²P infusion (months after surgery)	Hormonal therapy	Brachytherapy	Grade 3/4 toxicity	Follow-up (months)	Status
1	58	Pelvic/aortic	Carbo/taxol	4	Yes	None	None	31	NED
2	61	Pelvic	Carbo/taxol	5	Yes	Yes/HDR	None	42	NED
3	26	Pelvic	Carbo/taxol	4	None	Yes/HDR	None	36	NED
4	59	Pelvic	Carbo/taxol	7	Yes	None	None	60	NED
5	42	Pelvic/aortic	Carbo/taxol	4	None	None	None	54	NED
6	63	Pelvic	Carbo/taxol	4	Yes	None	None	52	NED
7	47	Pelvic	None	2	None	Yes/HDR	None	20	NED
8	40	Pelvic	Carbo	2	None	None	None	68	NED

yrs, years; ³²P, radioactive chromic phosphate; HDR, high-dose rate; NED, no evidence of disease.

No grade 3 or 4 complications were reported. No late toxicity or evidence of recurrent disease has been noted to date.

Discussion

Stage III endometrial cancer, particularly stage IIIA (FIGO, 1988), encompasses a heterogeneous group of diseases, ranging from the presence of malignant cytology to gross extrauterine disease. As such, there is no consensus regarding optimal adjuvant therapies for such a broad range of possible disease states.

This study describes the outcomes and characteristics of a select group of patients with stage III node-negative endometrial cancer treated with a multimodal therapy approach, including intraperitoneal ³²P.

Bowel complications, such as bowel perforation, have previously been reported with the administration of intraperitoneal ³²P. However, these complications usually occurred when treatment was combined with external pelvic radiation therapy.^10,11 The patients in the current study tolerated intraperitoneal ³²P well, without reports of grade 3 or 4 toxicities. Morbidity was not increased when treatment was combined with vaginal brachytherapy.

The mean age in the current study's patients, 49.5 years, was younger than the reported average age of diagnosis for uterine cancer in the United States; however, the small sample size limited any significant interpretations. The youngest patient, age 26, had risk factors including morbid obesity (a BMI of 41.5 kg/m²) and diabetes mellitus.

Because of the small size of the current study and the fact that most patients received other adjuvant treatments in addition to the infusion of intraperitoneal ³²P, no statistically significant conclusions can be drawn with reference to oncologic outcomes with the use of ³²P. However, to date no reported recurrences in this group of patients have been noted.

Five patients were classified as being in stage IIIA solely on the presence of malignant cytology alone. However, the updated FIGO staging system from 2009 for endometrial cancer did not include positive peritoneal cytology as a stage-defining variable. While extrauterine disease is an accepted poor prognostic factor, the prognostic significance of isolated malignant cytology, with disease otherwise confined to the uterus, is a controversial issue. Several studies, albeit with conflicting results, have focused on determining the prognostic significance of positive cytology. Some studies have identified positive cytology as an independent predictor of prognosis while others failed to identify any correlation between positive cytology and survival or recurrence.^12–14 Mariani et al. noted similar 5-year disease-related survival for patients with malignant cytology (86%), compared to those with tumors involving serosa or adnexa (93%).¹⁵ The presence of malignant cytology with nonendometrioid histology, histologic grade 3, and LVI has been associated with poor prognosis.¹⁶ In the current study, of the 5 stage IIIA patients with malignant cytology, 1 had high-grade disease and 1 had LVI. Current management of patients with positive peritoneal cytology with disease otherwise confined to the pelvis or uterus remains unclear; however, recent data demonstrate that the presence of positive peritoneal cytology should still be taken into account when risk-stratifying patients and determining adjuvant treatments.¹⁷

Conclusions

Despite controversies on optimal adjuvant treatments for these patients, the current study's findings are in accordance with prior studies demonstrating that intraperitoneal ³²P is a well-tolerated adjuvant therapy for stage III endometrial cancers.^2,3 However, further studies are needed to provide an accurate assessment of the efficacy and tolerability of intraperitoneal ³²P.

Footnotes

Disclosure Statement

The authors report no conflicts of interest with respect to this article.

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