University of Groningen
Localized extremity soft tissue sarcoma: towards a patient-tailored approach
Stevenson, Marc Gilliam
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Stevenson, M. G. (2018). Localized extremity soft tissue sarcoma: towards a patient-tailored approach. Rijksuniversiteit Groningen.
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1
General introduction &
outline of this thesis
1. General introduction & outline of this thesis
11
General introduction
Soft tissue sarcomas (STS) are relatively rare malignancies accounting for less than 1% of all cancers in adults, resulting in approximately 600-700 new cases in The Netherlands an-nually.1 STS form a group of heterogeneous tumors which originate from mesenchymal
progenitor cells. These progenitor cells show differentiation into various mesenchymal tissues, e.g. adipose tissue, fibrous tissue and muscle tissue, and over 50 histologic STS subtypes have been described in the latest World Health Organization classification.2,3
The most common subtypes are pleomorphic undifferentiated sarcoma (including malignant fibrous histiocytoma), leiomyosarcoma, liposarcoma, malignant peripheral nerve sheath tumor and synovial sarcoma, which combined account for approximately three fourths of all STS.2 STS can occur at any anatomic location, while most commonly
(50-60%) they arise in the extremities.2-4 Other common locations are the head/neck
area, trunk and retroperitoneum. The etiology of most STS remains unknown. While, in rare cases STS development has been associated with preceding radiation therapy, im-mune deficiency, viral infections and genetic and environmental factors.2
The incidence of STS rises with increasing patients’ age and it shows a slight male pre-dominance.2-5 The potential of STS to metastasize and thereby to influence patients’
sur-vival and prognosis is mainly determined by the tumor grade and the histologic sub-type.2,6,7 Lymfogenic metastases are rare,2,6 while hematogenic metastases, mainly to the
lungs, are relatively common i.e. approximately 50% of all STS patients develop distant metastases during the course of their disease.8,9 Besides tumor grade and subtype,
pa-tients’ age and maximum tumor size have been shown to influence the development of distant metastases and (disease-specific) survival. Subsequently, these four parameters have been incorporated into various nomograms to predict patients’ outcome.10,11
Prior to treatment, a MRI scan followed by a core-needle biopsy of the suspected lesion are performed, and combined they provide essential information needed for the diag-nosis and accordingly for adequate treatment of the tumor. Benign soft tissue tumors, mostly lipomas, outnumber STS by 100:1.2 If a STS is diagnosed, a baseline chest CT scan
is made to exclude lung metastases prior to the start of treatment. In extremity myxoid liposarcomas also a staging abdominal CT scan, to exclude abdominal metastases, is currently advised in the latest guidelines of the European Society for Medical Oncol-ogy.12 In case of distant metastases at diagnosis, curative-treatment is no longer feasible
in most STS, except in a few chemosensitive subtypes as embryonal rhabdomyosarco-ma.2 However, the role of (neo)adjuvant systemic chemotherapy in the non-metastatic
Treatment of localized extremity soft tissue sarcomas (ESTS)
Historically the treatment of non-metastatic (localized) ESTS comprised amputation of the affected limb. However, patients who underwent limb-amputation were shown to have similar survival rates when compared with patients who underwent limb-spar-ing surgery (LSS) combined with external beam radiotherapy (EBRT).16-19 Accordingly,
limb-sparing treatment has become the treatment of choice in localized ESTS since the 1980s. EBRT has been used regularly in addition to LSS to gain local control, and local control rates of 90% can be achieved nowadays.19-25 The timing of the EBRT has
been studied extensively, and no differences in patients’ survival were found between preoperatively and postoperatively irradiated patients.21,26-30 Besides, EBRT might not be
essential to obtain local control in some carefully selected patients, i.e. in case of low-grade tumors which are resected with a >1cm resection margin.31,32 The data available
addressing the association between local recurrence development, and subsequently the development of distant metastases and/or the risk for (disease-specific) death are contradictory. Hence, local recurrence development was found to be a predictor for the development of distant metastases and (disease-specific) death in some studies, while this finding was not confirmed in other studies.24,33-40
At diagnosis, some ESTS are deemed primarily non-resectable or locally advanced, mainly due to tumor size, proximity to vital structures and/or bony involvement. In these cases, a multimodality treatment-approach consisting of hyperthermic isolated limb perfusion (HILP), surgical resection and in some cases EBRT has been used in over 40 sarcoma centers throughout Europe.41 Using this multimodality treatment, local
tu-mor control can be achieved resulting in a limb-salvage rate of approximately 80-90% in these patients who would otherwise be considered for limb-amputation.42-47
Assessment of treatment efficacy
Over time, the treatment of ESTS improved and changed from limb-amputation into a more limb-sparing approach. This approach is based on a multimodality treatment-setting, e.g. neoadjuvant EBRT, systemic chemotherapy and/or HILP have been used to achieve optimal local control and to prevent limb-amputation, even in locally advanced ESTS.44,46,48 Neoadjuvant treatment-regimens are used in daily-practice, and as a
con-sequence multiple studies were conducted to establish the changes in these tumors during and following the treatment.
Since the 1990s, fluorine-18-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET-CT) scans have been used to study the changes
in metabolic tumor activity induced by HILP in locally advanced ESTS.49 Furthermore,
tumor activity of the tumor prior to and following neoadjuvant treatment, the histolog-ic appearance of the tumor at histopathologhistolog-ical examination has been studied. It was shown that the percentage of tumor necrosis following neoadjuvant treatment does not predict patients’ survival,53 as treatment-induced necrosis cannot be distinguished
from tumor necrosis already present at diagnosis. Therefore, the percentage of viable tumor cells in pretreated STS might have more predictive value for survival. Recently, the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) published recommendations regarding the histopatho-logical examination of pretreated STS,54 including a 5-tier STS response score based on
the percentage of stainable, possibly viable, tumor cells.
Outline of this thesis
Part I - Treatment of resectable extremity soft tissue sarcoma
In resectable ESTS, wide surgical resection of the tumor is the mainstay of treatment. In addition, (neo)adjuvant EBRT is commonly used to achieve local tumor control. How-ever, EBRT use harbors an increased wound complication risk, especially in the preop-erative setting. Chapter 2 aims to identify predictors for wound complications following radiotherapy and surgical resection in ESTS treatment.
Part II - Treatment of locally advanced extremity soft tissue sarcoma
This part highlights the treatment of locally advanced ESTS. At first, a new treatment reg-imen, consisting of neoadjuvant HILP, preoperative radiotherapy and surgery for locally advanced ESTS is described (chapter 3). Subsequently, the indications for amputation and the oncological outcome i.e. local control and survival, following limb-amputation in (locally advanced) ESTS are determined in chapter 4.
Part III - Metabolic and histopathological tumor responses in pretreated
extremity soft tissue sarcoma
This part addresses the metabolic and histopathological tumor responses in pretreated ESTS. Chapter 5 discusses the use of various volume of interest delineation techniques to study and quantify the changes in metabolic tumor activity using 18F-FDG PET-CT
scans during the multimodality neoadjuvant ESTS treatment as described in chapter 3.
Chapter 6 evaluates the histopathological tumor response, based on the percentage of
1. General introduction & outline of this thesis
14 15
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