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Abstract

Anthracycline-based chemotherapy remains the cornerstone of first-line systemic treatment for most subtypes of advanced soft tissue sarcoma (STS). However, cumulative cardiotoxicity and a decline in quality of life limit the treatment duration of free-form anthracycline, restricting its long-term benefits. Maintenance therapy—defined as the continuation of a less toxic systemic treatment following initial disease control—includes two main strategies: continuation maintenance and switch maintenance. Continuation maintenance involves the extended use of the same agent or one with a similar mechanism of action to preserve the efficacy of the prior treatment while minimizing the toxicities. By contrast, switch maintenance uses a different, potentially less toxic agent to extend disease control after prior treatment. Both approaches are established in other solid tumors and have been explored in STS. The LMS-04 trial demonstrated improved outcomes with doxorubicin plus trabectedin induction followed by trabectedin maintenance in leiomyosarcoma patients. However, this strategy is limited to leiomyosarcoma patients who received first-line doxorubicin plus trabectedin and is associated with high-grade toxicity (grade 3/4 adverse events in 97% of patients). Switch maintenance strategies, such as ridaforolimus and regorafenib, have limitations in efficacy and tolerability, preventing their widespread adoption. Pegylated liposomal doxorubicin (PLD), a liposome-encapsulated formulation of doxorubicin, offers a potential continuation maintenance option. With a similar mechanism of action to free-form anthracycline but reduced cumulative cardiac toxicity, PLD may be both effective and better tolerated in STS patients who have derived benefit from anthracycline-based chemotherapy. A clinical trial investigating continuation maintenance PLD in this patient population is warranted.

Keywords

cardiac toxicity maintenance therapy metastatic disease pegylated liposomal doxorubicin soft tissue sarcoma

Limitations of the current standard first-line treatment for advanced soft tissue sarcoma

Anthracycline-based chemotherapy has remained the standard first-line treatment for advanced soft tissue sarcoma (STS) for the past five decades.¹ However, progression-free survival (PFS) remains relatively short. Previous randomized controlled trials have shown that doxorubicin monotherapy achieves a PFS of 4–7 months, while doxorubicin plus ifosfamide extends PFS to 7.4 months.^2
–6 In addition, a retrospective study indicated that doxorubicin plus dacarbazine provides a longer PFS of 9.2 months, though this benefit is limited to leiomyosarcoma.⁷ The primary limitation of doxorubicin, however, is its cumulative cardiotoxicity, which restricts the total lifetime dose that can be safely administered.^8,9 Moreover, pooled patient-reported outcomes data from the phase III ANNOUNCE trial show that patients with advanced STS experience a rapid decline in quality of life (QoL) during doxorubicin-based chemotherapy.^4,10 Given these suboptimal clinical outcomes, further research is needed to develop first-line treatment strategies that prolong disease control while maintaining patients’ QoL.

Possible explanation for the lack of improvement: The impact of the limited duration of anthracycline-based treatment

The duration of anthracycline-based chemotherapy is generally limited to 6–8 cycles (approximately 4.5–6 months), after which treatment is typically discontinued—even if the disease remains controlled.^2
–6 In addition, a higher cumulative dose of doxorubicin is associated with an increased cardiotoxicity risk, even with dexrazoxane support. In the ANNOUNCE trial, which allowed dexrazoxane use at the investigator’s discretion, dexrazoxane was administered to 63.0% of patients receiving doxorubicin plus olaratumab (initiated at cycle 1 in 39.5% of cases) and to 65.1% of patients receiving doxorubicin plus placebo (initiated at cycle 1 in 25.9%). Despite the use of dexrazoxane, the risk of left ventricular ejection fraction (LVEF) deterioration increased with higher cumulative doses of doxorubicin—occurring in 51.6% of patients who received 450–600 mg/m² and 56.2% in those receiving 600 mg/m² or more.¹¹ This trial also reported that patients receiving a cumulative free-form doxorubicin dose of 450 mg/m² or more experienced declines in physical function and worsened fatigue symptoms.¹⁰ Thus, the duration of anthracycline-based chemotherapy is limited. However, our analysis of prior phase III trials indicates that, in the absence of systemic treatment, the median PFS following first-line anthracycline-based chemotherapy for patients with controlled disease is typically limited to 4 months or less (Figure 1 and Table 1).¹² This underscores the need to consolidate the efficacy of first-line treatment and delay tumor progression through maintenance treatment.

Figure 1.

The definition of median progression-free survival after first-line treatment for patients without disease progression after first-line treatment.

Table 1.

Median progression-free survival after first-line treatment for patients without disease progression after first-line treatment in current phase III trials.

Trial	First-line regimen (duration (months))	mPFS after first-line treatment for patients without disease progression after first-line treatment (months)*
EORTC 62012	Doxorubicin + ifosfamide (4.5)	4.38
EORTC 62012	Doxorubicin (4.5)	3.1
ANNOUNCE	Doxorubicin (6)**	2.05
GeDDis	Doxorubicin (4.5)	4
LMS-04	Doxorubicin (4.5)***	3.7
Brightline-1	Doxorubicin (4.5)	3.79

Only patients who did not experience disease progression after first-line treatment were included. The PFS duration for these patients was extracted from Kaplan–Meier curves in these trials, using data sourced from MD Anderson Cancer Center.¹¹ By subtracting the duration of first-line therapy from the total PFS of these patients, we calculated the remaining progression-free period. The median of this period is defined as the “median progression-free survival following first-line treatment for patients without disease progression during first-line therapy.”

Only include patients in the doxorubicin monotherapy arm with the maximum treatment duration of 8 cycles.

***

Only include patients in the doxorubicin monotherapy arm. These patients have not received trabectedin therapy if their disease is under control.

PFS, progression-free survival.

PFS after discontinuation of 6–8 cycles of first-line anthracycline treatment without clinical progression

To better understand the duration of extended PFS after the discontinuation of anthracycline-based treatment in clinical trials, we analyzed previous phase III trials that included first-line anthracycline-based chemotherapy. Specifically, we examined median PFS data for patients who did not experience disease progression or death during the first-line treatment period.¹² By subtracting the duration of 18 weeks (6 cycles) or 24 weeks (8 cycles) of first-line therapy from the total PFS of these patients, we calculated the remaining progression-free period. The median of these periods is defined as the “median PFS following first-line treatment for patients without disease progression during first-line treatment” (Figure 1). Using this method, in the absence of systemic treatment, the median PFS following first-line treatment for patients without disease progression during first-line treatment is no more than 4 months (Table 1). In the ANNOUNCE trials, the median PFS in the absence of systemic treatment was approximately 2 months, even for patients who did not experience disease progression or death during their 8-cycle first-line anthracycline-based treatment.⁴ This finding highlights the need to consolidate the efficacy of first-line treatment and further delay tumor progression. Maintenance therapy, referring to the use of additional treatment until disease progression for patients who achieved disease control with first-line therapy, could be a feasible solution.

Maintenance therapy as means to prolong disease control in STS while maintaining QoL

Maintenance therapy aims to prolong the benefit of prior line treatment in terms of survival, without causing unacceptable toxicity or deterioration in QoL.¹³ Its role has been extensively studied in other solid malignancies, including colorectal cancer, ovarian cancer, and urothelial cancer.^14
–19 Maintenance strategies in cancer therapy generally fall into two categories: continuation maintenance and switch maintenance. Continuation maintenance involves extending first-line therapy using a lower-intensity regimen of the same agent or class of agents that has already demonstrated clinical efficacy. The goal is to sustain disease control while minimizing cumulative toxicity, often through adjusted dosing schedules or alternative formulations. By contrast, switch maintenance entails transitioning to a different agent—typically one with a distinct mechanism of action and minimal cross-resistance. This approach aims to prolong disease control by targeting residual tumor cells through a novel pathway and avoiding the cumulative toxicity of prior line treatment. However, the efficacy of switch maintenance may be limited if the biological status of the residual disease is not well understood, possibly resulting in suboptimal benefit. A new class of drug could also provide unexpected toxicities. Both approaches have their advocates and critics, and the choice often depends on the therapeutic context, disease biology, and patient-specific factors.

The role of continuation maintenance has been established in several gastrointestinal malignancies. Taking colorectal and gastric cancer as examples, first-line oxaliplatin-based chemotherapy is the standard therapy, but is often limited by oxaliplatin-induced neurotoxicity. In such cases, continuation maintenance with fluoropyrimidine-based treatment could be considered after initial oxaliplatin-based treatment. For advanced colorectal cancer, one phase III trial and one phase II trial have supported the use of targeted therapies plus fluoropyrimidine as maintenance following oxaliplatin-based chemotherapy.^14,15 Similarly, for advanced gastric cancer, the role of maintenance capecitabine has been explored in a phase II randomized controlled trial and a prospective observational study.^20,21 For switch maintenance, PARP inhibitors and PD-L1 inhibitors have also shown benefits in ovarian cancer and urothelial cancer, respectively. In ovarian cancer, according to several phase III studies, PARP inhibitors-based maintenance treatment has demonstrated PFS and overall survival (OS) benefit after platinum-based first-line treatment.^{17,18,22
–24} In urothelial cancer, patients who received maintenance avelumab after platinum-based chemotherapy have longer PFS and OS than patients under active surveillance.^19,25

Both continuation and switch maintenance strategies could serve as approaches to prolong the efficacy of first-line treatment, potentially improving clinical outcomes in carcinomas and, possibly, in sarcomas as well.

Maintenance treatment studies in advanced STS

The concepts of both continuation maintenance therapy and switch maintenance therapy were initially investigated in the later-line settings for advanced STS patients. A randomized controlled trial from the French Sarcoma Group that investigated the role of continuous trabectedin maintenance in late-line advanced STS patients showed that continuing trabectedin beyond 6 cycles even after disease control significantly improved the 6-month PFS rate post randomization compared to treatment interruption (51.9% vs 23.1%, p = 0.02), albeit with no significant differences in median OS (27.9 vs 16.5 months, p = 0.12).²⁶ Similarly, a retrospective study showed that continuing trabectedin after achieving disease control with 6 cycles yields superior PFS and OS compared to cessation of treatment (median PFS: 10.5 vs 5.3 months, p = 0.001; median OS: 33.4 vs 13.9 months, p = 0.009).²⁷

In the first-line setting, continuation maintenance therapy with trabectedin also showed positive results in leiomyosarcoma patients. The LMS04 study demonstrated that patients who received induction therapy with 6 cycles of doxorubicin plus trabectedin followed by maintenance trabectedin had longer PFS and OS compared to those who received induction doxorubicin monotherapy followed by observation (median PFS: 12 vs 6 months; hazard ratio (HR): 0.37 (95% confidence interval (CI): 0.26–0.53); p < 0.0001; median OS: 33 vs 24 months; HR: 0.65 (95% CI: 0.44–0.95); p = 0.0235; Table 2).⁵

Table 2.

Previous maintenance treatment clinical trials for STS.

Trial	Experimental arm	Control arm	Histology	PFS (months)HR (95% CI)	OS (months)HR (95% CI)	Note
SUCCEED	Ridaforolimus	Placebo	STS and bone sarcomas	*4.43 vs 3.65 HR: 0.72 (0.61–0.85) p = 0.001	*22.65 vs 21.33 HR: 0.93 (0.78–1.12) p = 0.46	Both STS and bone sarcoma patients were enrolled. Not limited to first-line treatment
EREMISS	Regorafenib	Placebo	Non-adipocytic STS	*5.6 vs 3.5 HR: 0.53 (0.36–0.78) p = 0.001	*27.6 vs 20.5 HR: 0.78 (0.50–1.22) p = 0.28	Higher incidence of grade 3–4 adverse events with regorafenib (66% vs 11%)
LMS-04	Doxorubicin plus trabectedin followed by trabectedin maintenance	Doxorubicin followed by active surveillance	Leiomyosarcoma	12 vs 6 HR: 0.37 (0.26–0.53) p < 0.0001	33 vs 23.8 HR: 0.65 (0.44–0.95) p = 0.0253	Only patients who received combination treatment could receive maintenance therapy. More patients in the experimental arm received surgical resection.

Estimated from the completion of first-line anthracycline-based chemotherapy.

CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; STS, soft tissue sarcoma.

Regarding switch maintenance, there are two types of agents that have been investigated for their role in advanced STS. In the SUCCEED trial, patients with STS and bone sarcoma, who had achieved disease control with prior chemotherapy (first line: 62.9%; second line: 26.2%; third line or more: 9.9%), were randomized to receive either ridaforolimus, a mammalian target of rapamycin inhibitor, or placebo. Ridaforolimus significantly delayed disease progression (median PFS: 17.7 vs 14.6 weeks; HR: 0.72 (95% CI: 0.61–0.85); p = 0.0001; Table 2). Although the trial reached its primary endpoint, the marginal clinical benefit did not support further development of this drug in sarcoma.²⁸

Another clinical trial of switch maintenance therapy, the EREMISS trial, included patients with common STS subtypes, excluding liposarcoma. After achieving a partial response or stable disease with 6 cycles of first-line doxorubicin-based chemotherapy, patients were randomized to receive either regorafenib (120 mg/day, 3 weeks on, and 1 week off) or placebo. Regorafenib demonstrated a PFS benefit compared to placebo (5.6 vs 3.5 months; HR: 0.53 (95% CI: 0.36–0.78); p = 0.001; Table 2). However, high rates of grade 3–4 adverse events were observed (66% in the regorafenib arm vs 11% in the placebo arm), even with the reduced starting dose.²⁹ In addition, deploying a tyrosine kinase inhibitor in the maintenance setting could potentially compromise the efficacy of similar agents used in second-line treatment, such as pazopanib, which shares a similar mechanism of action.

Given the potential for increased toxicity and uncertain efficacy associated with switching to a new drug class, continuation maintenance may represent a more favorable strategy. In the LMS04 trial, patients who had already received trabectedin during the induction phase were less likely to develop new toxicities during continued treatment. However, several limitations in the LMS04 study should be considered.

First, the study provided maintenance trabectedin only to patients who had received induction therapy with a combination of doxorubicin and trabectedin. It remains unclear whether the observed improvements in PFS and OS were due to the combination induction therapy itself or the addition of maintenance trabectedin. As a result, it is uncertain whether patients who respond to induction doxorubicin plus trabectedin truly require continued trabectedin maintenance to achieve those survival benefits. Second, the trial was restricted to patients with leiomyosarcoma, limiting the generalizability of the findings to other STS subtypes. Third, the role of maintenance therapy in patients treated with anthracycline monotherapy remains undefined, as continuation of free-form anthracyclines is generally not feasible due to cumulative cardiotoxicity.

Therefore, further clinical trials investigating continuation maintenance strategies using agents with mechanisms similar to anthracyclines—but with improved safety profiles—are warranted to extend the benefits of first-line treatment to a broader population of patients with STS.

Pegylated liposomal doxorubicin: A potential continuation maintenance treatment with comparable efficacy and reduced toxicity for various subtypes of STS

Pegylated liposomal doxorubicin (PLD) is a formulation of doxorubicin enclosed within a polyethylene glycol-coated liposome, allowing for prolonged circulation and reduced cardiac toxicity. Compared to conventional doxorubicin, PLD has a significantly prolonged half-life (initial phase: 1–2 h; terminal phase: 30–90 h vs 5–10 min and 29 h, respectively) and a 60-fold higher area under the concentration-time curve.³⁰

The efficacy of PLD in STS has been evaluated in several clinical trials. A randomized phase II study published in 2001 found that PLD had comparable clinical outcomes to free-form doxorubicin, with OS of 320 versus 246 days, respectively.³¹ The overall response rates of all population were 10% in the PLD group and 9% in the free-form doxorubicin group. After removing the potential gastrointestinal stromal tumor (GIST) patients who were diagnosed with gastrointestinal leiomyosarcoma from this trial (15 of 50 in the PLD group and 12 of 45 in the free-form doxorubicin group), the overall response rates increased to 14% in the PLD arm and 12% in the doxorubicin arm. Additional prospective studies support the clinical activity of PLD, even in patients who have previously received treatment with anthracyclines. Skubitz³² conducted a phase II trial of PLD in pretreated STS. Excluding GIST, osteosarcoma, and Ewing sarcoma, a clinical benefit rate of 9 out of 22 (41%) was observed in uterine leiomyosarcomas and other STS subtypes.³² Similarly, Poveda et al.³³ evaluated the efficacy of PLD in 27 pretreated STS patients (including 5 with GIST). The overall PFS was 5.8 months. Among the 22 non-GIST patients, 12 (54.5%) achieved disease control with PLD. Notably, all seven patients with potentially doxorubicin-sensitive disease achieved disease control.³³ PLD-based combination therapy has also demonstrated non-inferiority compared to conventional anthracycline-based chemotherapy. A prospective trial combining PLD and ifosfamide in non-GIST STS reported a median PFS of 7.3 months and OS of 20.6 months³⁴—comparable to the EORTC 62012 study using doxorubicin plus ifosfamide (PFS: 7.4 months; OS: 14.3 months).³⁴ These findings further support the potential efficacy of PLD in STS. However, its role as maintenance therapy remains unexplored.

The cardiotoxicity profile of PLD is notably more favorable than free-form anthracycline. In a meta-analysis comparing liposomal doxorubicin (pegylated and non-pegylated) and conventional free-form anthracycline for metastatic breast cancer patients, liposomal doxorubicin (pegylated and non-pegylated) provided a significantly lower risk of cardiotoxicity (odds ratio = 0.46, 95% CI: 0.23–0.92, p = 0.03) and comparable efficacy (PFS: HR = 1.14, 95% CI. 0.96–1.34, p = 0.12; OS: HR = 1.00, 95% CI: 0.91–1.10, p = 0.93).³⁵ In addition, in the long-term follow-up of a phase III study on ovarian cancer involving 239 patients treated with PLD, there were no reported cases of decreased LVEF with a cumulative PLD dose ⩾300 mg/m².³⁶ Another retrospective study revealed that PLD administration in STS patients with prior exposure to conventional doxorubicin (median cumulative dose 450 mg/m², maximum dose up to 825 mg/m²) appears to be safe with limited cardiotoxicity. Notably, most of these STS patients received PLD within 2 years after conventional doxorubicin, and none of them experienced a LVEF decline of ⩾10%.³⁷ It has also been reported that there is a durable response with maintenance PLD with high cumulative dose after previous exposure to free-form anthracycline-based treatment.³⁸

With a similar mechanism of action to free-form anthracyclines but reduced cumulative cardiac toxicity, PLD also showed comparable efficacy and has the potential to serve as a continuation maintenance therapy for all histology subtypes of advanced STS patients who responded to anthracycline-based treatments. However, a longer duration of PLD exposure has probably been associated with a higher risk of bone marrow toxicity due to prolonged chemotherapy exposure. This toxicity can be mitigated using a lower dose without compromising efficacy. For example, in ovarian cancer, a reduced dose of PLD (40 mg/m² every 4 weeks) provided comparable efficacy to the conventional dose (50 mg/m² every 4 weeks) while resulting in reduced toxicity in second-line settings.³⁹ This lower dose also improves tolerability and QoL compared to the conventional dose. The possibility of dose interruption should be lower at a reduced dose level. In a single-arm phase II trial evaluating PLD in late-line treatment of STS—where 22 of 28 patients had received prior doxorubicin—PLD at 35 mg/m² every 3 weeks yielded a disease control rate of 51.8% while maintaining acceptable QoL.³³ Based on the authors’ experiences and the previously mentioned clinical evidence, we believe that PLD at 40 mg/m² every 4 weeks is a reasonable choice for prolonging treatment with a fair balance of efficacy, toxicity, and QoL.

Future directions: Evaluating PLD as a continuation maintenance treatment for STS patients

A clinical trial is warranted to assess the efficacy of PLD as a maintenance therapy in advanced STS. We propose enrolling chemo-responding sarcoma patients whose disease remains controlled following first-line anthracycline-based chemotherapy. Patients will be randomized to receive either maintenance PLD or active surveillance, with PFS and OS as primary endpoints. This study would provide critical data to establish whether extending maintenance therapy with PLD improves long-term outcomes in STS while preserving QoL.

Conclusion

Maintenance treatment strategies—including continuation and switch maintenance—may help prolong disease control in STS patients. Compared to current maintenance therapies such as trabectedin continuation and regorafenib switch, which have limitations in efficacy and tolerability across all subtypes of STS, PLD offers a promising alternative with a reduced risk of cumulative cardiac toxicity. By extending the benefits of first-line anthracycline-based therapy, continuation maintenance with PLD has the potential to improve survival outcomes and QoL in patients with advanced STS. Further clinical investigation is necessary to define its role in this setting and provide evidence to guide future treatment strategies.

Footnotes

Acknowledgements

was generated with the support of the calculator from Liu et al. (refer to Reference 12).

Declarations

ORCID iDs

Ming-Jing Lee

Yeh Chen Lee

Prabhat Bhargava

Zola Chia-Chen Li

Tom Wei-Wu Chen

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Maintenance therapy—a potential strategy to prolong the survival of advanced soft tissue sarcoma patients

Abstract

Keywords

Limitations of the current standard first-line treatment for advanced soft tissue sarcoma

Possible explanation for the lack of improvement: The impact of the limited duration of anthracycline-based treatment

PFS after discontinuation of 6–8 cycles of first-line anthracycline treatment without clinical progression

Maintenance therapy as means to prolong disease control in STS while maintaining QoL

Maintenance treatment studies in advanced STS

Pegylated liposomal doxorubicin: A potential continuation maintenance treatment with comparable efficacy and reduced toxicity for various subtypes of STS

Future directions: Evaluating PLD as a continuation maintenance treatment for STS patients

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References