Experts Call for Improved Management Strategies for Dedifferentiated Liposarcoma

Sarcoma experts from across the UK and the US agree that management of dedifferentiated liposarcoma (DDLPS) could benefit from critical changes that include fulfilling unmet needs, clarifying clinical trial expectations, and raising awareness of care gaps, according to survey findings recently published in ESMO Open.¹

DDLPS is a fast-growing and more aggressive type of soft tissue sarcoma that originates as a well-differentiated sarcoma and has a typical diagnosis age of 40 to 60 years.^2,3 It also is considered rare, noted the present study authors, despite being a common liposarcoma subtype, and has a poor prognosis. There is no therapy specifically indicated for DDLPS, they added, although anthracycline-based systemic treatment is standard of care (SOC) in the first line.

In the present study, 12 sarcoma experts were interviewed through 2 anonymous surveys, each of which contained predefined statements that were scored via a 9-point Likert scale (1 = strongly disagree, 9 = strongly agree), an adaptable rating system that evaluates attitudes, opinions, and perceptions toward a given subject or area of expertise.⁴

The investigators of this study say they hope their research can provide additional clarification on patient needs and management of dedifferentiated liposarcoma | Image Credit: natali_mis-stock.adobe.com

“Despite established diagnostic and treatment guidelines for DDLPS, critical clinical gaps remain driven by diagnostic challenges, symptom burden and the lack of targeted, safe and effective treatments,” investigators wrote.¹ “Unmet needs are high in the management of DDLPS patients.”

The experts they interviewed hailed from France, Germany, Italy, Spain, the UK, Belgium, and the US, and criteria for inclusion included affiliation with a specialized cancer center, 10 to 30 years of experience post residency or fellowship, and active participation in sarcoma clinical trials (where relevant).

Overall, there was consensus on 43 of 55 (78.1%) predefined statements across the 2 surveys, which evaluated the experts’ attitudes toward DDLPS disease burden, treatment paradigms, unmet needs, clinically meaningful end points, absolute value of progression-free survival (PFS), translation of PFS results to overall survival (OS) impact, and crossover trial design.

Disease burden. The experts concurred on 1-year survival rate (50%-70%), average PFS (3-5 months) with SOC treatment, that late diagnosis is common, and that the disease burden is high or varies but the impact on quality of life (QOL) is great for both patients and caregivers.

Treatment paradigm. The experts were in agreement on their dissatisfaction with current first- and second-line treatments, because of the efficacy and safety concerns attached to first-line therapies. Doxorubicin, in particular, is an area of great concern, the authors highlighted. Despite being a current SOC (administered as monotherapy or part of a combination regimen), adverse effects (AEs) include joint pain, rapid weight gain, unusual weakness, premature menopause, decreased sperm count, red urine, and fast/irregular heartbeat.⁵

Unmet need. The experts agreed that current DDLPS treatments are subpar because of a lack of significantly improved patient outcomes, patient symptomatic burden, and QOL.¹ Because of these, they also agree that first-line treatments could be more effective and safe. Early diagnosis is a challenge for some, while other thought early diagnosis and referral were adequate. Overall, however, they agree that early identification and diagnosis of resectable DDLPS are challenging.

Clinically meaningful end points. From most clinically meaningful and relevant to patients to the least, they ranked these end points: OS and PFS, overall response rate (ORR), duration of response (DOR), disease control rate (DCR), AE incidence, and patient-reported outcomes (PROs). Drilling down to secondary end points, they agreed that ORR, DOR, DCR, and PROs were clinically meaningful and relevant but are not substitutes for PFS and OS.

Absolute value of PFS. Emphasizing the rarity of DDLPS, the 12 experts agreed on the utility of PFS as a clinical end point in trials investigating first-line treatments because it can be robust, objective, and demonstrate treatment benefit while OS data are being analyzed; PFS is also measured over a shorter period. However, they also agreed that PFS could require shorter follow-ups, which may serve to increase treatment access.

Translation of PFS results to OS impact. Opinions were mixed regarding translating PFS into OS, because of limited research to support the move and that subsequent treatments can affect OS-related outcomes. But there was agreement on using PFS as a primary end point if OS was unavailable, because of the potential for a clinically meaningful association between the 2 end points.

Crossover trial design. There was unanimous agreement that this type of trial can support recruitment efforts by encouraging more patients to sign up and stay enrolled. Also, they consider this trial type to have ethical benefits. But there are potential drawbacks in that the multiple lines of treatments these trials evaluate can muddy OS analysis.

The investigators concluded that their findings “can help bridge the gap in the existing data in DDLPS and guide clinical research in this rare indication with high unmet need.” Also, that they hope their research can provide additional clarification on patient needs and DDLPS management, and lead to further discussion on how to improve patient QOL and prognosis.

References

1. Schöffski P, Jones RL, Agulnik M, et al. Current unmet needs in locally advanced (unresectable) or metastatic dedifferentiated liposarcoma, the relevance of progression-free survival as clinical endpoint, and expectations for future clinical trial design: an international Delphi consensus report. ESMO Open. 202428;9(7):103487. doi:10.1016/j.esmoop.2024.103487

2. Liposarcoma. Cleveland Clinic. Accessed July 2, 2024. https://my.clevelandclinic.org/health/diseases/21142-liposarcoma

3. Dedifferentiated liposarcoma. ScienceDirect. Accessed July 2, 2024. https://www.sciencedirect.com/topics/medicine-and-dentistry/dedifferentiated-liposarcoma

4. What is a likert scale? Qualtrics. Accessed July 2, 2024. https://www.qualtrics.com/experience-management/research/likert-scale/

5. Doxorubicin (intravenous route). Mayo Clinic. Accessed July 2, 2024. https://www.mayoclinic.org/drugs-supplements/doxorubicin-intravenous-route/side-effects/drg-20063553?p=1#:~:text=Call%20your%20doctor%20right%20away,or%20unusual%20tiredness%20or%20weakness