Recommendations from the Epithelioid Sarcoma Collaborative: A White Paper

September 2021 Vol 12, No 9

Categories:

Sarcoma Perspectives
M. Voermans
Epithelioid Sarcoma Survivor and Advocate
M. Bui, MD, PhD
Moffitt Cancer Center & Research Institute
E. Conrad
The University of Texas Health Science Center at Houston
G. D'Amato, MD
University of Miami Health System
J. Goodwin
Catherine J. Malatesta Foundation;
Sarcoma Foundation of America
A. O'Driscoll, MBA, MPA
Sarcoma Alliance
R. Ratan, MD, MEd
The University of Texas MD Anderson Cancer Center
D. Reinke, MS, NP, MBA
Sarcoma Alliance for Research through Collaboration;
Sarcoma Coalition
E. Peregrine Antalis, MPH, PhD
Sarcoma Alliance for Research through Collaboration

Epithelioid sarcoma (ES) is a rare soft tissue sarcoma (STS) first described in the 1970s by Enzinger.1 STSs comprise approximately 1% of adult cancers and 7% to 15% of pediatric cancers annually, and ES accounts for <1% of STS diagnoses.2 The rarity of ES leads to multiple challenges for patients diagnosed with ES beginning with but not limited to the diagnosis journey, confounded by the subdivision of patients into 2 subtypes—distal (classic) ES and proximal-type ES, and by the presentation. Classic ES is more frequent in adolescent and young adult (AYA) males, commonly affects the upper extremity, and is typically present as superficial, nonpainful, indolent growths on the hands and arms followed by chronic nonhealing ulcers with raised margins.3,4 Proximal-type ES is less frequently diagnosed than classic ES and can affect young and middle-aged adults and is also slightly more common among males. Proximal-type ES tends to present as deep soft tissue masses found in locations such as the trunk, pelvis, proximal limbs, and limb girdles presenting as deep or visceral tumors.3,5 The painless quality of the lump or growth/soft tissue mass can lead patients and clinicians to initially characterize the growth as benign. The suite of nonspecific symptoms of ES necessitates pathologic diagnosis, which is done by examining a piece of tissue from the lump or growth. A confident diagnosis of ES is defined by the loss of INI1 expression.5 Unfortunately, ES frequently recurs, with classic ES recurring as multinodular soft tissue masses, whereas proximal-type ES is associated with spread of the disease to distant locations (metastatic disease). Unlike other STSs, ES has a high incidence of lymphatic or regional metastases as it metastasizes via the lymphatic system.6 Improved ES patient staging and imaging would improve patients’ initial diagnoses and their subsequent treatment assessment. Wide surgical resection is the most recommended treatment modality for localized disease. Adjuvant radiation therapy has not had a role for assisting with local control in addition to surgical resection. Traditional systemic therapy with cytotoxic agents has demonstrated limited efficacy, with no single chemotherapy regimen identified as the preferred treatment. Currently, there are no consensus guidelines for the systemic treatment, staging, and imaging of ES patients.4,7 Current treatment options provide little hope for patients with advanced disease, who face inevitable progression and death.

As is the case with other rare diseases, new therapies are urgently needed for ES. However, designing and conducting trials to identify new effective therapies are limited by the small patient volume and lack of effective preliminary systemic trials.4,7 Efforts in therapeutic research in ES can be further hampered by challenges of delayed and inaccurate diagnoses experienced in the patient’s journey, which share some characteristics with other rare cancers but are specific to ES. To better understand the challenges experienced by patients diagnosed with ES, a multidisciplinary focus group including patient advocates (patients and caregivers) and sarcoma medical experts convened to discuss shared characteristics of the ES patient experience and identify priority areas. The purpose of this white paper is to outline challenges shared by the ES patients’ experience, propose potential solutions to support ES patients and their caregivers, and improve patient outcomes.

The Diagnosis Journey

A key factor identified by the collaborative that impacted patient outcomes is a lengthy or prolonged journey from disease presentation to disease diagnosis, to treatment and care, otherwise referred to as a diagnostic delay as described in other sarcomas and rare malignancies. These intervals can be broken into discrete stages to create a standardized framework of comparison, of which several models exist, but collectively will be referred to as the diagnosis journey in this white paper. Prolonged time to diagnosis and treatment is recognized to impact patient outcomes based on the assumption that early diagnosis leads to better local control and overall survival. A systematic review encompassing many different cancer diagnoses supports an association between shorter diagnosis interval and improved survival, earlier disease stage, and quality of life.8 The diagnostic journey overall is recognized to be prolonged among patients diagnosed with a sarcoma compared with other cancers.9,10 Greater diagnostic delay has also been recognized to be associated with patients with limitations in healthcare coverage, older populations, and lower socioeconomic profiles (ie, Medicare and Medicaid). The ES patient experience demonstrates commonality with other rare cancers, although factors that cause delays may be exacerbated in the case of ES due to the rarity, the lower incidence of disease compared with other diagnoses, lack of guidelines for follow-up care, and insurance barriers.

Using the model developed by Olesen and colleagues,11 the diagnosis journey can be subdivided into the time periods between symptoms and treatment, each of which has potential for delay in the diagnosis journey. At each of the 3 intervals defined—the patient delay, the general practitioner (GP) delay, and the system delay—the ES patient experience adds an additional layer of potential delay.

The patient delay describes the period where the patient experiences and responds to symptoms. The nonspecific, nonpainful indolent growths, in the case of classic ES, and the deep, visceral location of growth in the case of proximal ES, adds an additional layer of delay for ES patients. The warning signs of STSs, which include a nontender, soft tissue mass that is bigger than a golf ball, are not widely known by patients and family members.

The GP delay describes the period when the symptoms are first described by a patient to a clinician, often a GP, to the consideration of the symptoms as cancer. In the case of ES patients, the clinicians who are first consulted tend to be primary care physicians, sports medicine doctors, or dermatologists who are typically not familiar with ES and sarcoma symptoms, and this can significantly delay diagnosis or lead to misdiagnosis, contributing to an extended GP or diagnostic delay. This delay may be compounded by inadequate imaging (ultrasound imaging) or the misinterpretation of appropriate MRI imaging by radiologists unfamiliar with ES and STSs.

The third delay is characterized as a system delay or healthcare provider delay, the clinical pathway from GP referral until diagnosis and treatment. As in the first 2 intervals of the ES diagnosis journey, the ES patient experiences multiple delays, including limited access to a sarcoma specialist due to financial, geographical, work, or family limitations, leading to an unclear diagnosis path in which multiple misdiagnoses are common. The cascade of delays and consequences along the diagnosis journey culminates in more aggressive malignancies and limited treatment options due to the growth of the tumor and/or metastasis, necessitating systemic treatment rather than surgical resection.

Access to Expert, Experienced Sarcoma Centers

The rarity of ES necessitates the involvement of a specialist in sarcoma, resulting in the need to travel to a center with a dedicated multidisciplinary sarcoma program that has expertise and experience in diagnosis and treatment of sarcoma.12 Traveling for care imposes a unique set of challenges that adds an additional layer to the diagnostic delay for the patient, including time to referral, insurance barriers to coverage, out-of-pocket costs, and other transportation barriers. A recent analysis of the SEER database revealed a disparity in disease-specific survival among patients with sarcoma who had Medicaid insurance and those with non-Medicaid insurance, citing diagnosis and treatment delays, distance traveled to treatments and transportation barriers, out-of-pocket burdens, and education and literacy status as potential targets.13 An analysis of short-term and long-term survival outcomes among patients with retroperitoneal sarcoma demonstrated that patients who traveled long distances to receive care at a high-volume sarcoma center had improved outcomes compared with the counterparts who traveled a short distance to a low-volume hospital.14 Patients who traveled were younger, more likely to identify as white, had more comorbidities, a higher tumor grade, and received a more radical resection of their tumor, demonstrating the importance of overcoming system delays in seeking care for sarcoma patients, especially those with rare tumor types, including ES. Similar associations have been observed in cancers necessitating surgical resection, including esophageal, pancreatic, and rectal cancers.15-17 Finally, a descriptive analysis of prognostic factors of 35,784 sarcoma patients who received surgery in 1 of 26 reference centers endorsed by the National Cancer Institute were found to be associated with improved adherence to clinical practice guidelines, improved quality of surgical management, and reduced risk of relapse or death.18 Overcoming the system-level barriers of geographical access and transportation burden are key factors in improving outcomes for patients with ES.

AYA Patients with ES

AYA patients diagnosed with cancer are recognized as having needs specific to their social and developmental trajectories and encountering barriers to care, both of which contribute to the diagnosis journey.19 ES is most frequent in AYA males and has a peak age of incidence of 35 years.20 Designated as a rare disease, ES is one of the rarest cancers in the world, diagnosed in less than 1% of sarcomas per year and often striking young adults in their prime. In fact, the median age of patients in a recent clinical trial was 34 years.21 Although the needs of teenagers and young adults in their 20s and 30s vary, there are common experiences shared across these age-groups that, like the delays in the diagnosis journey, are exacerbated by the rarity of ES. AYA patients encounter medical considerations, such as future fertility, risk of cardiotoxicity, and mobility, especially in amputation cases, earlier than their peers.22 AYA patients are also at risk of poor healthcare access and experience feelings of isolation due to the experience of a life-threatening illness. While many cancer centers are including AYA programs and AYA-specific services, geographical barriers and limitations to support services remain barriers to AYA patients overall. The rarity of ES further exacerbates feelings of isolation among ES patients and leaves AYA programs and services lacking ES-specific care.23 Access to these services and to care options are often jeopardized if the patient’s insurance is interrupted or student loans are put into repayment if the patient withdraws or takes a leave of absence from a university.24,25

Recommendations

Overcoming delays inherent in each interval of the diagnosis journey is recommended. A first step of increasing awareness of STS overall among patients and providers may be to reduce the patient delay in recognizing symptoms of ES. Increased awareness coupled with providing ES resources and educating healthcare providers about the different types of STS may also reduce the GP delay in considering the presentation as a possible cancer and improving the patient–care partner–physician dialogue. The GP delay may be further reduced by providing tools to support timely differential diagnosis. Recommendations include: (1) adding STS to the list of potential conditions a primary care provider or dermatologist considers when presented with a lump, cyst, or wart that persists to prevent distal ES from going undiagnosed; and (2) adding proximal STS to the list of conditions orthopedists and sports medicine physicians consider when presented with a lump that is growing that may or may not be painful, have limited movement, etc. Finally, overcoming system delays to increase timely medical care and reduce misdiagnosis or delays in diagnosis necessitates solutions to the cascade of delays. One proposed solution is to establish an ES standard of diagnosis for widespread adoption among healthcare providers that includes a recommended timeline, such as a 6-week follow-up and imaging, followed by a second opinion, followed by diagnosis confirmed by an expert pathologist.

Increasing access to expert, experienced sarcoma centers is an essential component of improving outcomes among patients with ES and includes partnerships with advocacy groups to support the cost of patient travel (eg, gas, lodging, air travel). We propose employing technological solutions to help close the geographical gap to help ensure ES patients have a sarcoma specialist and an expert pathologist involved in the diagnosis. The use of virtual tumor boards and telemedicine in diagnosis and management can make great inroads in closing the geographical gap. Including mechanisms to overcome insurance barriers and support patient travel to high-volume sarcoma surgical centers are also needed.

Overcoming delays in the diagnosis journey for many ES patients necessitates targeted, curated resources that specifically address the unique needs of AYA patients, including additional sarcoma center AYA programs and information that addresses medical, emotional, social, and financial issues faced by AYA patients.

Conclusion

In conclusion, increasing awareness and understanding of ES is a necessary first step to improve the diagnosis journey by (1) decreasing the time to correct diagnosis; (2) reducing barriers to timely treatment and access to expert, experienced sarcoma centers; and (3) raising awareness among GPs and other care providers who may be the first point of contact for these patients. In addition, establishing a standard for ES diagnosis will create a consistent, reliable clinical evaluation threshold. In a rare disease with significant unmet need, the development of effective new therapies would be a game changer for patients. The development of new ES resources and information, including those tailored to AYA patients, can further support newly diagnosed and existing patients with ES, as well as their caregivers. Finally, collaboration with the National Comprehensive Cancer Network can facilitate the updating of existing STS guidelines to include ES to further support a more streamlined diagnosis journey and improve outcomes of patients with ES.

References

  1. Enzinger FM. Epithelioid sarcoma. A sarcoma simulating a granuloma or a carcinoma. Cancer. 1970;26:1029-1041.
  2. Shaikh S, Djeridi F. The challenges of diagnosing soft tissue sarcomas. Multi-Knowledge Electronic Comprehensive Journal For Education And Science Publications. 2020;37:1-8.
  3. Thway K, Jones RL, Noujaim J, Fisher C. Epithelioid sarcoma: diagnostic features and genetics. Adv Anat Pathol. 2016;23:41-49.
  4. Siontis BL, Chugh R, Schuetze SM. The potential of emerging therapeutics for epithelioid sarcoma. Expert Opinion on Orphan Drugs. 2017;5(12):983-989.
  5. Hornick JL, Dal Cin P, Fletcher CD. Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol. 2009;33:542-550.
  6. Outani H, Imura Y, Tanaka T, et al. Clinical outcomes of patients with epithelioid sarcomas: impact and management of nodal metastasis. Int J Clin Oncol. 2018;23:181-188.
  7. Touati N, Schöffski P, Litière S, et al. European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group experience with advanced/metastatic epithelioid sarcoma patients treated in prospective trials: clinical profile and response to systemic therapy. Clin Oncol (R Coll Radiol). 2018;30:448-454.
  8. Neal RD, Tharmanathan P, France B, et al. Is increased time to diagnosis and treatment in symptomatic cancer associated with poorer outcomes? Systematic review. Br J Cancer. 2015;112(suppl 1):S92-S107.
  9. Soomers VL, Husson O, Desar IM, et al. Patient and diagnostic intervals of survivors of sarcoma: results from the SURVSARC study. Cancer. 2020;126:5283-5292.
  10. Gerrand C, Francis M, Dennis N, et al. Routes to diagnosis for sarcoma – describing the sarcoma patient journey. Eur J Surg Oncol. 2015;41:1393-1399.
  11. Olesen F, Hansen RP, Vedsted P. Delay in diagnosis: the experience in Denmark. Br J Cancer. 2009;101(suppl 2):S5-S8.
  12. National Comprehensive Cancer Network. NCCN Guidelines for Patients. Soft Tissue Sarcoma (Version 6.2019). National Comprehensive Cancer Network. 2020.
  13. Smartt AA, Jang ES, Tyler WK. Is there an association between insurance status and survival and treatment of primary bone and extremity soft-tissue sarcomas? A SEER database study. Clin Orthop Relat Res. 2020;478:527-536.
  14. Schmitz R, Adam MA, Blazer DG III. Overcoming a travel burden to high-volume centers for treatment of retroperitoneal sarcomas is associated with improved survival. World J Surg Oncol. 2019;17:180.
  15. Speicher PJ, Englum BR, Ganapathi AM, et al. Traveling to a high-volume center is associated with improved survival for patients with esophageal cancer. Ann Surg. 2017;265:743-749.
  16. Lidsky ME, Sun Z, Nussbaum DP, et al. Going the extra mile: improved survival for pancreatic cancer patients traveling to high-volume centers. Ann Surg. 2017;266:333-338.
  17. Chioreso C, Del Vecchio N, Schweizer ML, et al. The association between hospital and surgeon volume and rectal cancer surgery outcomes in rectal cancer patients treated since 2000: systematic literature review and meta-analysis. Dis Colon Rectum. 2018;61:1320-1332.
  18. Blay JY, Honoré C, Stoeckle E, et al. Surgery in reference centers improves survival of sarcoma patients: a nationwide study. Ann Oncol. 2019;30:1143-1153.
  19. Smith AW, Keegan T, Hamilton A, et al. Understanding care and outcomes in adolescents and young adults with cancer: a review of the AYA HOPE study. Pediatr Blood Cancer. 2019;66:e27486.
  20. Czarnecka AM, Sobczuk P, Kostrzanowski M, et al. Epithelioid sarcoma—from genetics to clinical practice. Cancers (Basel). 2020;12:2112.
  21. Gounder M, Schöffski P, Jones RL, et al. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol. 2020;21:1423-1432.
  22. Murphy D, Orgel E, Termuhlen A, et al. Why healthcare providers should focus on the fertility of AYA cancer survivors: it’s not too late! Front Oncol. 2013;3:248.
  23. Kent EE, Smith AW, Keegan TH, et al. Talking about cancer and meeting peer survivors: social information needs of adolescents and young adults diagnosed with cancer. J Adolesc Young Adult Oncol. 2013;2:44-52.
  24. Salsman JM, Bingen K, Barr RD, Freyer DR. Understanding, measuring, and addressing the financial impact of cancer on adolescents and young adults. Pediatr Blood Cancer. 2019;66:e27660.
  25. Kaddas HK, Pannier ST, Mann K, et al. Age-related differences in financial toxicity and unmet resource needs among adolescent and young adult cancer patients. J Adolesc Young Adult Oncol. 2020;9:105-110.
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Last modified: August 10, 2023

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