WHAT IS ALREADY KNOWN ON THIS TOPIC

Doxorubicin combined with trabectedin is an effective treatment in uterine sarcomas, which is better than doxorubicin alone. In addition, an increase in progression-free survival has been shown if combination treatment is prolonged by single-agent trabectedin.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYIntroduction

Uterine sarcomas include 60–80% uterine leiomyosarcomas, 10% low-grade and 5% high-grade endometrial stromal sarcomas. This heterogeneous group of malignant mesenchymal tumors accounts for 3–7% of all uterine cancers.1 2 International guidelines recommend cytoreductive surgery, but there is no consensus on the indication for adjuvant treatment.3–5 Many cytotoxic adjuvant chemotherapies in non-metastasized uterine sarcoma have been tested with poor outcomes.2 4 Treatment of advanced and recurrent uterine sarcoma is challenging.1 5 In metastatic leiomyosarcomas, median progression-free survival is usually reported with only 4–7 months and overall survival of 12–17 months.6–8 To date, doxorubicin alone or in combination with ifosfamide has been considered as first-line therapy in metastasized leiomyosarcoma with response rates of approximately 25%.7 9 The short duration of the response remains the major treatment limitation.10

Prior studies in metastatic leiomyosarcoma, advanced soft tissue sarcoma, and breast cancer have suggested an increase in progression-free survival using the combination of doxorubicin with trabectedin.6 11 The mode of action of the anthracycline doxorubicin includes, on the one hand, the inhibition of topoisomerase II with a consecutive arrest of cell division and, on the other hand, the induction of oxidative stress through the formation of free radicals, resulting in apoptosis of malignant and non-malignant cells.12 13 Trabectedin, a natural drug derivate derived from the marine tunicate Ecteinascidia turbinate,14 mainly acts as a DNA intercalating agent at the minor groove, causing double-strand breaks and, as a transcriptional regulator, interrupts the cell cycle but also affects the tumor microenvironment.15 16 It has been reported that trabectedin inhibits the mdr-1 gene and consequently reduces P-glycoprotein, resulting in a higher intracellular accumulation and an increased cytotoxic effect of doxorubicin when given in combination.17 18 Takahashi et al were able to show a synergistic interaction of these two compounds in vitro using the two soft tissue sarcoma cell lines HT-1080 and HS-18.19

While doxorubicin is associated with cumulative cardiotoxicity predefining a maximum of administrable cycles,20 21 the main dose-limiting toxicity of trabectedin combined with doxorubicin is caused by bone marrow suppression, particularly neutropenia, which is reported to be the most common adverse event.20 22 In an open-label phase III trial published in 2022, the rate of serious adverse events (grade ≥3) was 52% in the single-agent doxorubicin arm compared with 96% in patients receiving doxorubicin and trabectedin. Notably, febrile neutropenia was the most frequent adverse event, with 9% in the single-agent doxorubicin arm and 28% in the doxorubicin plus trabectedin arm.21

Pegylated liposomal doxorubicin has shown anti-tumor effects and a favorable toxicity profile in platinum-resistant ovarian cancer,23 24 metastatic breast cancer,25 as well as other advanced solid tumors.26 This is due to favorable pharmacokinetic and pharmacodynamic properties, increasing bioavailability, and cytotoxicity.23 In addition, no hair loss has been observed as an adverse event.22 27 Previous studies on dose-dependent cardiotoxicity of conventional anthracyclines have shown a higher risk in patients aged >65 years, pre-existing cardiac risk factors, or previous anthracycline therapy.28 In patients with metastatic breast cancer treated with pegylated liposomal doxorubicin, however, significantly less cardiotoxicity was shown compared with patients receiving conventional doxorubicin.29 A phase I trial examining the safety and pharmacokinetics of trabectedin in combination with pegylated liposomal doxorubicin in patients with advanced malignancies showed clinical efficacy (overall response rate 16.7%, n=36), while the combination was well tolerated in pre-treated patients.22 The most reliable data regarding feasibility and toxicity of the combination of pegylated liposomal doxorubicin and trabectedin originate from the large phase III INOVATYON trial performed in recurrent ovarian cancer. This study showed an excellent toxicity profile: the most frequent grade ≥3 adverse event was neutropenia in 39.5% (n=617), followed by gastrointestinal adverse events in 17.4%.30

Recently, the LMS-04 study, which for the first time implemented prolongation of systemic treatment in metastatic and unresectable leiomyosarcoma, challenged conventional doxorubicin single-agent therapy against the combination of trabectedin and doxorubicin for six cycles followed by trabectedin alone as maintenance therapy for a maximum of 17 cycles. The experimental arm showed superiority with a hazard ratio (HR) of 0.41 and doubled the median progression-free survival from 6.2 months to 12.2 months.21 Although overall survival data must be awaited, a considerable debate has already started on whether this novel treatment strategy should be considered a new standard of care.

To assess the feasibility of treatment prolongation in uterine sarcoma with a combination showing a more favorable and non-cumulative toxicity profile, we retrospectively studied the therapeutic index of trabectedin plus pegylated liposomal doxorubicin and compared it with available data from other clinical trials where the combination of trabectedin and conventional doxorubicin was used.

Methods

Twenty-one patients with histologically confirmed advanced or recurrent leiomyosarcomas or endometrial stromal sarcomas were included in this retrospective cohort study between January 2011 and April 2023 at the University Hospital in Innsbruck. Medical history, demographic data, previous cytostatic therapies, previous responses to treatments, the total applied dosage, dose reductions, and cycle delays, as well as all adverse events were collected in patients. All patients had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) when starting the treatment. Pegylated liposomal doxorubicin 30 mg/m2 as a 60 min infusion followed by trabectedin 1.5 mg/m2 as a 24 hour infusion were administered every 3 weeks via central venous access with a maximum of 11 cycles.

The choice to treat patients with uterine sarcomas with pegylated liposomal doxorubicin and trabectedin was based on a general institutional decision to substitute classical doxorubicin with pegylated liposomal doxorubicin due to its better tolerability. Cases included in the present retrospective evaluation were those patients who, in routine practice, would have been eligible for doxorubicin-trabectedin therapy in first and subsequent lines of treatment. They were finally treated with the combination of pegylated liposomal doxorubicin and trabectedin. All patients underwent surgery, including hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and tumor debulking in cases of disseminated disease at primary diagnosis.

All patients received pre-(treatment) medication consisting of 20 mg dexamethasone 30 min before starting pegylated liposomal doxorubicin. Twenty-four hours after the end of treatment pegylated granulocyte colony-stimulating factor (6 mg, pegfilgrastim) was given subcutaneously. Adequate hematologic, renal, and liver function (absolute neutrophil count ≥1.5×109 cells/L, platelet count ≥100×109 cells/L, hemoglobin ≥10 g/L) were mandatory for receiving chemotherapy. Before the first cycle and after the sixth cycle, ECG, echocardiography, and measurement of left ventricular ejection fraction were performed. In the case of grade 4 adverse events, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, dose reductions were performed: trabectedin was reduced from 1.5 mg/m2 to 1.1 or 0.9 mg/m2 and pegylated liposomal doxorubicin from 30 mg/m2 to 25 mg/m2. The maximum number of administered cycles was not limited, and treatment was continued until progression or unacceptable toxicity.

Positron emission tomography-computed tomography (PET-CT) was performed at the initial diagnosis and repeated every three cycles and every 3 months during follow-up. The overall response rate and clinical benefit rate were determined according to the RECIST. Statistical analysis was performed using Statistical Package for Social Science (SPSS) Version 26. Overall survival and progression-free survival were analyzed with the Kaplan–Meier method.

Results

A total of 21 patients were included, 12 (57%) with leiomyosarcomas and nine (43%) with endometrial stromal sarcomas. Detailed characteristics of the patients are shown in Table 1. The median age was 59 years (range 43–74). Fifty-seven percent of patients included had advanced disease (stages III and IV) according to the International Federation of Gynecology and Obstetrics classification. One hundred and seven cycles were administered with a median of six cycles (range 1–11) per patient. In 14 patients (67%), pegylated liposomal doxorubicin plus trabectedin was administered as first-line therapy, while seven patients previously received other chemotherapies.

Table 1

Characteristics of patients with uterine sarcoma

After the response evaluation at six cycles, the overall response rate was 24% (n=5). One patient (5%) showed a complete response and four patients (19%) showed a partial response. In 19% of patients (n=4) stable disease was achieved, thus resulting in a clinical benefit rate of 43% (n=9). Accordingly, progressive disease was recorded in 57% (n=12). Two patients (6%) decided to discontinue after the initial chemotherapy. Six cycles were administered in eight patients and nine or more cycles were administered in three patients. One patient is still on treatment. Five patients (24%) continued to show a response at 9 months of treatment. The median duration of response was 14 months (range 3–74 months).

The clinical outcome is shown in a swimmer plot in Online Supplemental Figure 1. Only minor differences in response rates were observed when response evaluation was done separately according to histological sub-groups. In patients with uterine leiomyosarcomas (n=12), an overall response rate of 50% was obtained after the first three cycles while, in patients with endometrial stromal sarcomas (n=9), the overall response rate was 44%. The clinical benefit rate in uterine leiomyosarcomas was 58%, compared with 67% in the endometrial stromal sarcomas sub-group. At 9 months of treatment, 33% of uterine leiomyosarcomas (n=4) and 11% of endometrial stromal sarcomas (n=1) were still responding. In the survival Kaplan–Meier curve the clinical outcome of the 14 chemo-naïve patients was comparable to the seven pre-treated patients, with an overall response rate of 50% (1 complete response, 6 partial response) in comparison to 43% (0 complete response, 3 partial response) after 3 months of treatment (data not shown). After 9 months, three (21%) chemo-naïve patients and two (29%) pre-treated patients continued to show a response.

Median progression-free survival was 6.0 months (95% CI 1 to 11 months) (Figure 1) and median overall survival was 26 months (95% CI 9 to 43 months) (Figure 2). Fifteen patients (71%) were still alive 1 year after the end of treatment. When considering patients with histological leiomyosarcomas only, the median progression-free survival extended to 9 months (95% CI 1 to 24 months) (see Online Supplemental Figure 2). Furthermore, the median overall survival for this subgroup was 27 months (95% CI 11 to 63 months) (see Online Supplemental Figure 3). However, progression-free survival was not significantly different between chemo-naïve and pre-treated patients.

Figure 1

Progression-free survival of all patients.

Figure 2

Overall survival of all patients.

Adverse Events

Twenty adverse events of hematologic toxicity (grade ≥3), including leukopenia, anemia, thrombocytopenia, and febrile neutropenia, were registered in six different patients (29%), with leukopenia being the most frequent (29%) (Table 2). In three patients, raised alanine aminotransferase levels were recorded (Table 3), resulting in the most common non-hematological toxicity; however, this did not result in any dose delay. Regarding cardiac toxicity, three patients (14%) experienced a reduction in left ventricular ejection fraction. Two patients had a mild reduction (grade 1) resulting in a left ventricular ejection fraction of 50% while, in one patient, discontinuation of pegylated liposomal doxorubicin was required due to a moderate reduction (grade 3) with a left ventricular ejection fraction of 35%. Palmar-plantar erythrodysesthesia occurred in one patient resulting in cycle postponement. In eight patients (38%) no adverse effects were observed.

Table 2

Hematologic and non-hematologic serious adverse events (grade ≥3) of pegylated liposomal doxorubicin plus trabectedin

Table 3

Adverse events of all grades

Cycle delays occurred in 16 cases (57%), with a median delay of 6 days. Hematological toxicity was the most common reason for cycle postponements. A dose reduction was mandatory in five cases due to toxicity (pancytopenia, performance status, palmar-plantar erythrodysesthesia and alanine aminotransferase elevation). Among these five patients (24%), four (19%) required a reduction of both agents due to febrile neutropenia. Trabectedin was reduced in one patient due to alanine aminotransferase elevation. The most frequent reason for early treatment discontinuation was disease progression in 38% of patients (n=8), followed by unacceptable toxicity in 6% (n=2) and one patient’s personal decision to discontinue.

DiscussionSummary of Main Results

To our knowledge, this is the first study investigating pegylated liposomal doxorubicin in combination with trabectedin in patients with metastatic or advanced uterine sarcomas. Our data show similar anti-tumor effects to previous studies with an overall response rate of 24% (n=5) and a clinical benefit rate of 43% (n=9). The progression-free survival was 6 months and the overall survival 26 months. Considering patients with histological uterine leiomyosarcomas only, an increase in the progression-free survival and overall survival to 9 and 27 months, respectively, was observed.

Results in the Context of Published Literature

Several studies have shown a poor prognosis of patients with metastatic or advanced leiomyosarcomas with a progression-free survival usually reported around 5 months and an overall survival of 24–30 months.20 The results of the LMS-02 trial of patients with advanced uterine leiomyosarcomas treated with conventional doxorubicin and trabectedin showed a progression-free survival of 8.2 months (95% CI 7.0 to 9.0 months) and a median overall survival of 20.2 months (95% CI 15.1 to not reached).8 At least in uterine leiomyosarcomas, the oncologic outcome does not appear to be inferior to the drug combination tested here.

In our study grade 3–4 adverse events occurred in 39% of patients, while 96% of patients with uterine or soft tissue leiomyosarcoma in the LMS-04 trial treated with doxorubicin plus trabectedin and trabectedin as maintenance therapy experienced grade 3–4 adverse events, showing a more toxic profile compared with the single agent doxorubicin group (52% grade ≥3). With regard to hematologic toxicity, in the present study febrile neutropenia occurred in 19% compared with 28% of patients treated with doxorubicin plus trabectedin and trabectedin as maintenance therapy in the LMS-04 trial and 24% of patients in the experimental arm of the LMS-02 trial.8 21

Regarding non-hematologic toxicities, cardiotoxicity is of particular interest. Doxorubicin is associated with cumulative cardiotoxicity and was therefore restricted to six cycles, while pegylated liposomal doxorubicin shows a more feasible cardiac toxic profile and can be administered for a significantly greater number of cycles. With a maximum cumulative dose of more than 1000 mg/m2, treatment prolongation could be realized by combining trabectedin and pegylated liposomal doxorubicin.31 Vertechy et al analyzed trabectedin combined with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer compared with a control group receiving platinum-based therapy. No patient receiving pegylated liposomal doxorubicin combined with trabectedin showed grade 3–4 cardiotoxic events,27 while in our study one patient experienced a grade 3 adverse event. Consistent with previous studies, we assume an improved cardiac safety profile of pegylated liposomal doxorubicin compared with conventional doxorubicin. Previous studies have shown milder and greatly reduced numbers of alopecia with pegylated liposomal doxorubicin treatment compared with non-liposomal doxorubicin.26 29 32 No patient in our study reported alopecia.

Recently, in the LMS-04 study, Pautier et al were able to demonstrate significantly longer progression-free survival with a mean of 12.2 months despite higher toxicity when trabectedin was continued as single-agent treatment with a maximum of 17 cycles as maintenance therapy given after six initial cycles of conventional doxorubicin plus trabectedin in comparison to treatment with doxorubicin alone.21 Similarly, Monk et al investigated trabectedin with a maximum of 29 cycles as first-line therapy in advanced, persistent, or recurrent uterine leiomyosarcomas. They found that long-duration treatment with trabectedin showed substantial oncologic activity and is a safe and well-tolerated treatment option.33 The advantage of considering prolonged treatment is corroborated by two patients in our study who showed a late complete response. While the first showed stable disease, the other patient experienced a partial response after three cycles. Both patients had a partial response after six cycles, resulting in a complete response after receiving nine cycles of treatment. It is noteworthy that both patients were so-called long-term responders and are still alive 3 years and 7 years, respectively, after their initial treatment with pegylated liposomal doxorubicin and trabectedin.

Strengths and Weaknesses

This real-world experience is of value in light of the recently reported favorable data obtained by treatment prolongation in the LMS-04 study.21 However, the main limitations of our study are, on the one hand, the small sample size, which makes it difficult to extrapolate the results to a broader population, the prolonged duration of recruitment and, on the other hand, the retrospective character of the evaluations.

Implications for Practice and Future Research

As 11 of the patients included in this study received ≥6 cycles and three patients received ≥9 cycles, and the fact that toxicity was not cumulative and by far not the main reason for study withdrawals, pegylated liposomal doxorubicin plus trabectedin appears to represent an ideal drug combination for further explorative clinical trials focusing on treatment prolongation in uterine sarcomas. Particularly for the ‘prolonged stage’ of treatment, a head-to-head comparison between single-agent trabectedin and its combination with pegylated liposomal doxorubicin is highly warranted.

Conclusion

In view of the more favorable toxicity compared with the toxicity assessment in the LMS-02 and LMS-04 trials,8 21 we consider that the combination of pegylated liposomal doxorubicin and trabectedin may be a suitable treatment option in frail and elderly patients with compromised cardiovascular co-morbidity.

In addition, our study indicates that increasing the number of cycles is a meaningful strategy resulting in an improved rate of clinical benefit, especially in patients with histological leiomyosarcomas.

Data availability statement

Data are available for independent analysis by a selected team by the Editorial Team for additional data analysis or the reproducibility of this study in other centers if such is requested.

Ethics statementsPatient consent for publication

Not applicable.

Ethics approval

This study involves human participants and was approved by the Ethics Committee of the Medical University Innsbruck, ID 1381/2023. Participants gave informed consent to participate in the study before taking part.