Maintenance therapy for long-term control of high-grade endometrial stromal sarcoma

Abstract

High-grade endometrial stromal sarcoma (HG-ESS) is a malignant uterine tumour with a poor prognosis. This study aimed to demonstrate the usefulness of maintenance chemotherapy with paclitaxel (PTX) and carboplatin (CBDCA) for HG-ESS recurrence, by examining a case of HG-ESS tumour progression as a result of maintenance therapy interruption because of the COVID-19 pandemic. The patient was a woman in her 60s who presented with lower abdominal pain, nausea and a pelvic tumour, which was diagnosed as HG-ESS. Chemotherapy with PTX (175 mg/m² day 1) + CBDCA (area under the concentration-time curve 5 day 1) every 21–28 days (TC therapy) was administered for long-term maintenance of HG-ESS. After 26 cycles, chemotherapy had to be postponed because of the COVID-19 pandemic, thus leading to disease progression and eventually death. In conclusion, TC therapy can prolong survival in patients with HG-ESS, and maintenance chemotherapy should not be postponed.

Background

High-grade endometrial stromal sarcoma (HG-ESS) is an aggressive tumour associated with high rates of progression, recurrence and mortality. There is relatively less evidence on the efficacy of chemotherapy for advanced or recurrent endometrial stromal sarcomas compared with that of leiomyosarcomas, and endometrial stromal sarcomas have not been included in most clinical trials. Due to the spread of COVID-19 in 2020, it was announced that chemotherapy with unknown life-prolonging effects should be postponed.¹ Accordingly, we discontinued the maintenance chemotherapy that we were administering to a patient with recurrent HG-ESS. Consequently, the patient’s condition worsened, and she died eventually. In this study, we present the HG-ESS case we encountered along with a related literature review.

Case presentation

A woman in her 60s visited our department with lower abdominal pain, groin pain, nausea and a pelvic tumour. Transvaginal ultrasonography revealed a 12 cm mass in the uterine cavity. Endometrial stromal sarcoma was suspected on endometrial histological examination.

Investigations

The patient had a cancer antigen (CA) 125 level of 10.3 IU/mL (normal: <35.0 IU/mL), CA 19–9 level of 10.5 IU/mL (normal: <37.0 IU/mL) and lactic acid dehydrogenase level of 369 IU/L (normal: >245 IU/L). Contrast-enhanced MRI showed a well-defined space-occupying lesion of 11.5 × 9.2 × 9.2 cm in the uterine cavity. The contrast effect was slow and poor, suggesting a uterine sarcoma, with no metastases identified (figure 1).

Figure 1.

Preoperative sagittal section on T2-weighted MRI. A 12 cm large tumour is seen in the uterine body. There is a heterogeneous medium-to-high signal in the internal structures of the tumour.

Treatment

Total hysterectomy with bilateral salpingo-oophorectomy was performed. During the surgery, we found that the tumour had invaded the right pelvic bone, right external mesenteric artery and ureter; therefore, it could not be completely removed. The residual pelvic floor lesion at the time of surgery was approximately 3 cm diameter, which was about the same size as the pelvic infiltrate seen in retrospect on the preoperative CT scan (figure 2).

Figure 2.

Preoperative CT image of the site of pelvic wall invasion identified intraoperatively (arrowhead).

Histologically, the tumour cells were identified as poor cytoplasmic cells with round nuclei, and there were 16 mitotic figures per visual field (figure 3). The tumour area was diffusely positive for CD10 (figure 4) and negative for the oestrogen and progesterone receptors by immunostaining.

Figure 3.

H&E-stained specimen of the tumour area of the surgically removed uterus (40× magnification). The tumour cells were identified as poor cytoplasmic cells with round nuclei, and there were 16 mitotic figures per visual field.

Figure 4.

CD10 immunostained specimen of the surgically removed uterine tumour (20× magnification). Tumour cells are diffusely CD10 positive.

The final pathological diagnosis was HG-ESS (International Federation of Obstetrics and Gynecology, FIGO, stage IIIC). One month after surgery, the solitary pelvic floor lesion had already increased to 82 mm. We administered 50.4 Gy of radiation therapy to the entire pelvis. Two months later, metastases were observed in the lung (single, 34 mm), first lumbar vertebra (unmeasurable), right ureter (20 mm) and inferior vena cava (unmeasurable) (figures 5 and 6; the sum of tumour diameters of the target lesion was 54 mm), according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.²

Figure 5.

CT image of the lung field at the time of recurrence. Multiple lung metastases are observed (arrowheads).

Figure 6.

CT image of the abdomen at the time of recurrence. Tumour invasion in the inferior vena cava and vertebral metastasis at the first lumbar vertebra are observed (arrowheads).

The patient received doxorubicin (60 mg/m² day 1 every 21 days) and cisplatin (40 mg/m² day 1 every 21 days) (AP chemotherapy) according to Japan Society of Gynecologic Oncology guidelines 2013.³ After six courses, complete disappearance of the lesions was observed. Three months later, however, the lesions recurred in the lung and pelvis (one lung metastasis, 30 mm in diameter, and one pelvic metastasis, 20 mm in diameter; the sum of tumour diameters was 50 mm). The patient was administered docetaxel (70 mg/m² on day 8 every 21 days) and gemcitabine (900 mg/m² on days 1 and 8 every 21 days) (DG therapy) as second-line chemotherapy; but, 4 months later, multiple uncountable new lesions developed in the lung fields, confirming disease progression (the sum of tumour diameters according to RECIST was 68 mm). Eribulin monotherapy (eribulin 1.4 mg/m² on days 1 and 8 every 21 days) was started according to the National Comprehensive Cancer Network (NCCN) guideline (category 2B)⁴ as third-line chemotherapy, the lesions in the lung field increased and disease progression was confirmed 5 months later (figure 7: sum of tumour diameters was 108 mm). At that time, there was no drug that could be used in our facility; thus, we had a detailed discussion with the patient, and paclitaxel (175 mg/m² day 1 every 21–28 days) and carboplatin (area under the concentration-time curve 5 day 1, every 21–28 days) (TC therapy) were administered according to Szlosarek’s method.⁵

Figure 7.

CT image 1 month after eribulin monotherapy and before the start of paclitaxel plus carboplatin therapy. Multiple lung metastases are observed (arrows).

Although multiple lung metastases remained, a partial response was achieved after three courses (figure 8: sum of tumour diameters was 74 mm and a tumour shrinkage rate of 31%). After nine courses of TC chemotherapy, the treatment interval was extended to 28 days to control the fatigue.

Figure 8.

CT image after three courses of paclitaxel plus carboplatin. Mild shrinkage of the largest lung lesion in figure 7 was observed (arrows).

Outcome and follow-up

Twenty-six courses of treatment were completed. CT scans were performed every 3 months to assess patient response during maintenance chemotherapy. A CT scan of the target lesion immediately before the 25 courses of TC therapy showed a sum of tumour diameters of 82 mm and a tumour shrinkage rate of 24%, which is equivalent to stable disease (figure 9).

Figure 9.

CT image immediately before treatment with 25 courses of paclitaxel plus carboplatin showing, according to the sum of tumour diameters, that the disease was stable.

However, the treatment was temporarily suspended because of the COVID-19 recommendations for chemotherapy in high-risk patients. One month after the discontinuation of treatment, the patient experienced respiratory failure due to exacerbation of the lung metastases. The tumour diameter of the target lesion was 180 mm with a 67% increase from before the start of TC therapy (figure 10), thus requiring oxygen administration.

Figure 10.

CT image 1 month after the discontinuation of treatment. The tumour diameter of the target lesion was 180 mm with a 67% increase from before the start of paclitaxel plus carboplatin therapy.

Chemotherapy was reinitiated 2 months later; however, the patient continued to experience respiratory failure and died. Overall, the patient’s HG-ESS was maintained using TC therapy for 26 months.

Discussion

In our patient, TC therapy had controlled disease progression for a long period of time; however, HG-ESS progressed when chemotherapy was postponed because of the COVID-19 pandemic. Uterine sarcomas have the highest mortality rate of all uterine malignancies, with a reported 5-year overall survival rate of 25%–68% according to their histology and stage.^{6 7}

We searched PubMed for articles published between January 2011 and December 2021 using the key words ‘uterine sarcoma’, ‘stage 3’ and ‘prognosis’. No reports on prognosis were found in the search. However, it has been reported that the 5-year survival rate for HG-ESS is 42.1%, and the overall 5-year survival rate for stage 3 ESS is 61.5%.⁸ Therefore, the 5-year survival rate for stage 3 HG-ESS that cannot be completely resected by surgery, as in this case, is probably lower than 40%.

HG-ESS is an aggressive tumour associated with high rates of progression, recurrence and mortality. Few studies regarding chemotherapy for advanced or recurrent endometrial stromal sarcomas have been reported, and most clinical trials do not include this type of tumour. Chemotherapy has been used to treat progressive and recurrent HG-ESS in addition to palliative radiation therapy and surgery. Drugs such as anthracyclines, ifosfamide, dacarbazine, vinorelbine, gemcitabine, docetaxel and temozolomide are used to treat soft-tissue sarcomas. These agents may be administered alone or in combination—for example, docetaxel/gemcitabine, doxorubicin/ifosfamide, doxorubicin/dacarbazine, gemcitabine/dacarbazine or gemcitabine/vinorelbine.^{9 10}

As the disease progressed, radiation therapy was followed by AP, DG and eribulin. Since the patient was already using 500 mg/m² of doxorubicin as AP therapy, doxorubicin/ifosfamide or doxorubicin/dacarbazine could not be used, and, after a discussion with the patient and family, TC therapy using Szlosarek’s method was preferred. Szlosarek’s method was not initiated sooner because alternative treatments were recommended first according to NCCN Guidelines V.1.2018.¹¹ Although not completely successful, TC therapy was able to control the disease for 26 months. The side effects of TC therapy include peripheral sensory neuropathy due to paclitaxel, which tends to become more severe with repeated treatments.¹² This patient developed grade 2 peripheral sensory neuropathy; limiting instrumental activities of daily living involving her upper and lower limbs after the second course of TC therapy. However, the numbness was adequately controlled with pregabalin and duloxetine and did not worsen until 26 months, and chemotherapy dose reduction was not required to control neuropathy. The effect of maintenance with TC therapy on HG-ESS is currently unknown. In this case, peripheral sensory neuropathy and cancer progression were controllable; therefore, the patient opted for maintenance with TC therapy. Due to the COVID-19 pandemic, treatment could not be completed, although continued TC therapy was effective.

In recent ovarian cancer treatments, when complete remission is achieved after initial surgery and subsequent chemotherapy, maintenance chemotherapy with cytotoxic agents is not recommended due to the high incidence of adverse events.^13–15 On the other hand, the efficacy of maintenance therapy after primary chemotherapy is well established in some solid tumours, such as colorectal cancer, lung cancer and breast cancer.^16–18 In addition, there are no studies on the disadvantages of maintenance chemotherapy in recurrent uterine sarcoma, and several reports suggest that maintenance chemotherapy with cytotoxic agents may be effective.^19–21 Since TC therapy was able to control the disease for 26 months in the present case, maintenance chemotherapy with TC therapy was considered a therapeutic option for the treatment of the advanced HG-ESS.

In the chemotherapy toxicity risk assessment using the Cancer Aging Research Group calculator²² at the time of chemotherapy discontinuation, the toxicity risk score was 14 points, and the risk of chemotherapy toxicity was 90%. Given the high risk of chemotherapy toxicity, the discontinuation of treatment in our patient could have been considered appropriate. However, after 26 courses of treatment, the toxicity was acceptable considering our patient’s activities of daily living, and appropriate toxicity management may have allowed for longer survival if the treatment had not been postponed.

In conclusion, TC therapy can prolong survival in patients with HG-ESS, and maintenance chemotherapy for uterine malignancies should not be postponed.

Learning points.

• Combination therapy with paclitaxel and carboplatin may be effective for HG-ESS that is resistant to multiple treatments.

• Maintenance chemotherapy including paclitaxel can be continued for an extended period once peripheral neuropathy is controlled, but aggressive drug intervention is also necessary to maintain the quality of daily life.

• Maintenance chemotherapy for high-grade endometrial stromal sarcoma should not be postponed.

Ethics statements

Patient consent for publication

Consent obtained from next of kin.