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Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiation Oncology, Augustenburger Platz 1, 13353 Berlin, Germany
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiation Oncology, Augustenburger Platz 1, 13353 Berlin, GermanyBerlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, GermanyCharité – Universitätsmedizin Berlin, Berlin, GermanyGerman Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiation Oncology, Augustenburger Platz 1, 13353 Berlin, Germany
Charité – Universitätsmedizin Berlin, Berlin, GermanyGerman Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumor Immunology, Augustenburger Platz 1, 13353 Berlin, Germany
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charitéplatz 1, 10117 Berlin, Germany
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Surgery, Berlin, Germany
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiation Oncology, Augustenburger Platz 1, 13353 Berlin, GermanyCharité – Universitätsmedizin Berlin, Berlin, GermanyGerman Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiation Oncology, Augustenburger Platz 1, 13353 Berlin, GermanyCharité – Universitätsmedizin Berlin, Berlin, GermanyGerman Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany
Radiotherapy (RT) is a mainstay of treatment for high-grade soft tissue sarcomas (STS). We sought to examine the pattern of local recurrence (LR) with regards to target volume, clinical course, and tumor characteristics in extremity and trunk wall STS patients receiving pre- or postoperative RT.
Methods
In this retrospective study, LR rates and patterns in 91 adult patients with primary diagnosis of localized high-grade STS of the extremities and trunk wall treated with pre- or postoperative RT at our institution between 2004 and 2021 were analyzed. Radiation treatment plans and imaging data sets at diagnosis and LR were compared.
Results
Seventeen out of 91 (18.7 %) patients developed a LR after a median time to LR of 12.7 months. In 10 out of 13 LRs (76.9%) with available treatment plans and radiographic imaging data at the time of recurrence, the LR occurred within the planned target volume (PTV), two LRs were marginal (15.4%, at the edge of the PTV volume), and one relapsed out-of-field (7.7%, outside the PTV volume). Positive surgical margins (microscopic or macroscopic) were found in 5 out of 91 patients (5.5%), one of which was found in the 17 patients with LRs (5.9%). Eleven of 13 LR patients (84.6%) with available treatment plans and radiographic imaging data received postoperative RT; the median total RT dose was 60 Gy. Volumetric-modulated arc therapy was used in 10 (76.9%), intensity-modulated radiotherapy in two (15.4%) and three-dimensional conformal radiation therapy in 1 (7.7%) of 13 LRs.
Conclusions
The majority of LRs occurred within the PTV suggesting that LR is most likely not a consequence of inadequate target volume definition, but rather of radioresistant tumor biology. To further improve local tumor control, future research on the potential of dose escalation with normal tissue sparing, STS subtype-specific tumor biology, radiosensitivity, and surgical technique is indicated.
Pre- or postoperative radiotherapy (RT) is a mainstay of local therapy for high-grade soft tissue sarcomas (STS) and does improve local tumor control (LC) [1-5]. Positive surgical margins and high-grade histology are the most important risk factors for local recurrence (LR) [6-11]. Defining appropriate target volume is crucial in RT as insufficient tumor coverage may increase the risk of LR while large RT volumes increase the risk of late morbidity (e.g. lymphedema, immobilizing fibrosis and joint stiffness), particularly when RT is administered postoperatively [12, 13]. Current target delineation guidelines for extremity or truncal STS recommend a preoperative dose of 2 to 50 Gy to a gross tumor volume (GTV) plus 1.5 cm radial and 3-4 cm longitudinal (parallel to the muscle fibers) anatomically constrained expansion with inclusion of peritumoral edema and biopsy tract (when feasible) for the clinical target volume (CTV) [2]. In the postoperative setting, a sequential boost plan of 1.8-2 to 50-50.4 Gy to a larger CTV1 followed by 2 to 10 Gy (clear surgical margins) or 2 to 16 Gy (positive surgical margins) to a smaller CTV2 is applied [2]. CTV1 encompasses the tumor bed (defined by clips and preoperative magnetic resonance imaging (MRI)) plus 1.5 cm radial and 3-4 cm longitudinal anatomically constrained expansion including the operative field, surgical scar and drain sites. The sequential boost to CTV2 is applied to the tumor bed plus 1.5 cm radial and 2 cm longitudinal expansion [2]. The planned target volume (PTV) expansion is 1 cm, except if daily image guidance is applied where it may be reduced to 0.5 cm. The target volume delineation recommendations have not changed substantially from previous guidelines according to which the cases in this study were delineated [2, 14].
Analyzing the pattern of LR relative to the delineation volume is critical. A relevant number of LR outside or at the margin of the treatment volume would suggest inadequate safety margins provoking a change in delineation guidelines. However, a relevant number of LR inside of the treatment volume would suggest aggressive, radioresistant tumor biology, insufficient dosing (limited by normal tissue tolerance) or problems related to the surgical technique. Advancing RT techniques such as intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) play another important role on LC for STS. IMRT and VMAT improve conformity and IMRT studies have shown promising effects on LC compared to three-dimensional conformal radiation therapy (3D-CRT), although no prospective comparative trials with the primary outcome on LC have been published yet [15, 16].
In previous retrospective studies mostly applying 3D-CRT, the majority of LR were found within the radiation volume [17-20]. This study analyzed LRs in pre- or postoperative RT (mostly IMRT and VMAT) and the location of LR with regard to the target volume to assess the adequacy of RT volume definition.
Methods
This single-center retrospective study included patients with the primary diagnosis of localized high-grade STS (G2+G3) of the extremities and trunk wall who developed local recurrent disease after pre- or postoperative RT or radiochemotherapy (RCT) between 2004 and 2021. The inclusion criteria were: primarily diagnosed, histopathologically confirmed and resected high-grade STS with pre- or postoperative RT or RCT, tumors located in the extremities or trunk wall. Exclusion criteria were metastatic or recurrent disease at the time of diagnosis, other tumor locations, age < 18 years, low-grade (G1) histology, the most common STS of childhood and adolescence (rhabdomyosarcoma, Ewing sarcoma) and sarcoma-like lesions (desmoid fibromatosis or dermatofibrosarcoma protuberans)
The study was approved by the institutional review board. We reviewed radiation treatment plans, medical records, pathology reports, and radiological images of eligible patients. We assessed LR evident in computed tomography (CT), positron emission tomography CT (PET-CT) or MRI by co-registering the images to the planning CT images from the initial RT treatment
All treatment plans and details on RT planning were created and analyzed in Varian Eclipse Version 15.1 (Palo Alto, CA, United States). Target volumes were delineated on planning CT and MRI according to departmental guidelines and valid delineation guidelines at that time [14]: In the preoperative setting, the GTV encompassed the tumor on contrast-enhanced T1-weighted MRI image. The GTV was then expanded 3 cm longitudinally, 1.5 cm radially and included edema visible on T2-weighted MRI while being constrained for anatomical structures (e.g. bones, fasciae) to obtain the CTV. For postoperative RT, the CTV1 included the tumor expansion visible on preoperative MRI and surgical clips plus 3-4 cm longitudinal and 1-2 cm radial expansion. A sequential boost radiation was applied to the CTV2 encompassing the tumor bed with a 1-2 cm radial and 2 cm longitudinal expansion. The PTV encompassed the CTV +1 cm margin in all directions. A LR was defined by the first clear radiographic evidence of disease recurrence in MRI, CT or PET-CT within the same anatomical region where the STS was found and treated initially. Subsequently, the radiographic images of disease recurrence were co-registered with the former radiation plans. A recurrence within the PTV volume was defined as an in-field LR. A LR outside of the PTV was defined as out-of-field. If the LR reaches the PTV border or crosses the PTV field on both sides, the recurrence was defined as marginal.
Two patients with LR received preoperative RT with 1.8-2 to 50.4-56 Gy. In all other LR, cases the RT was administered postoperatively with 1.5-2 to 56-66 Gy depending on surgical margin status and individual case discussion in the interdisciplinary tumor boards (see table 1). In selected patients, a simultaneous integrated boost of 2.15-2.2 Gy to a cumulative dose of 60.5-61.6 Gy to the region of high risk for disease recurrence on individual clinical case discussion was applied postoperatively
Table 1Patient, tumor and treatment characteristics. The table summarizes the patient, tumor and treatment characteristics, oncological outcomes, and patterns of failure in all 13 patients with local disease recurrence.
After surgery and RT, patient follow-up, including physical examination and imaging, were conducted in case of suspected disease recurrence and regularly every three months for the first two years and extended to larger intervals thereafter. Statistical analysis was performed using IBM SPSS Statistics 29 (Chicago, IL, United States).
Results
Patient, tumor, and treatment characteristics are shown in table 1. Out of 204 initially identified STS patients, 91 met the eligibility criteria. After a median follow-up time of 46 months (range, 3-155 months), 17 of 91 (18.7%) patients developed a LR. In four patients, the radiological images showing local recurrences were not available for analysis.
Mean age at first diagnosis was 58.9 years, with more male than female patients (8:5). The majority of LR occurred within the PTV (10/13, (76.9%)), followed by marginal recurrences (2/13, (15.4%)) and out-of-field recurrences (1/13, (7.7%)). When the LR were analyzed relative to the CTV volume, one more patient developed the LR marginally instead of in-field and one LR occurred out-of-field instead of marginal. In all 13 patients, surgical margins were clear after resection (R0). Mean time to LR was 17.7 months. RT was performed as follows: Apart from two large undifferentiated pleomorphic sarcomas (UPS) cases receiving preoperative RCT, all other patients were treated postoperatively. The most common dose regimen was 2-60 Gy (median dose: 60 Gy) to a median PTV volume of 1,442 cm³. One patient (patient 4) with a relatively small myxofibrosarcoma of the left calf was treated with 3D-CRT. In all other cases IMRT or VMAT were used. Representative radiographic images for in-field (patient 6), marginal (patient 12), and out-of-field recurrences (patient 13) are shown in figure 1.
Figure 1Planning CT overlaid by T1-weighted, contrast-enhanced MRI images or contrast enhanced CT and topograms showing LRs. Red line: PTV contour; purple line: LR. Patient 7 Right thigh of a 74 year-old female patient with radiographic evidence of a relapsing myxofibrosarcoma 39.4 month after postoperative RT. The LR is located within the PTV. Patient 12 Left trunk wall/shoulder girdle of a 58 year-old male patient, who developed a local relapsing myxofibrosarcoma 4.1 months after R0 resection and postoperative RT. The LR is crossing the PTV borders and extending further caudally . Patient 13 Recurrent malignant peripheral nerve sheath tumor in the paravertebral mediastinum of a 32 year-old male patient 6.6 months after postoperative RT. The recurrence is located outside of the large PTV.
Herein, we describe our single-institutional data of 13 patients with locally recurrent high-grade STS treated between 2004 and 2021 to analyze the pattern of failure after RT. Previous large retrospective studies have all found that LRs mostly occur within the treatment volume. The Norwegian study by Jebsen et al. from 2013 found 32 out of 49 (65%) in-field LRs, while the Princess Margaret Hospital (PMH) study from Toronto, Canada, by Dickie et al. from 2012 found 49 out of 60 (82%) LRs to occur in-field (table 2) [17, 19].
Table 2Study characteristics of previous and the present study analyzing the pattern of local recurrence in STS after pre- or postoperative RT.
Our data support these findings with 76.9% of LRs found within the PTV (table 1). Also, the proportion of out-of-field- (7.7%) and marginal recurrences (15.4%) were similar to the Norwegian study (65% in-field, 14% out-of-field and 20% marginal) [19]. In the PMH study, the in-field proportion was even larger with 82% in-field, 15% out-of-field and 4% marginal recurrences, even though the applied delineation guidelines did not differ substantially to the present study (table 2). Important underlying differences explaining these variations may be the definition of in-field, marginal and out-of-field recurrences: In the study from the PMH recurrences within the PTV were defined as in-field; recurrences outside of the PTV, but within the 50% isodose line, were considered marginal [17]. However, there was no clear definition on how a LR within the 50% isodose volume crossing the PTV volume line was classified. These cases were considered marginal in the present study. Assuming that these cases were also defined as in-field in the PMH study, it may explain the large proportion of 82% in-field recurrences [17]. Moreover, some cases of the PMH cohort were treated using two-dimensional RT techniques limiting the possibility of precise analysis.
The out-of-field recurrence in the present study (patient 13) was clearly more than 2 cm away from the PTV volume suggesting that the CTV and PTV margins are inadequate in these cases. In this patient a large postoperative volume covering the left trunk wall was irradiated (figure 1). The patient developed LR in the left paravertebral mediastinum and distant metastasis in the right lung. Despite the large preoperative tumor volume and the young age of the patient, a PTV extension to the left paravertebral muscles and the left mediastinum would not have been indicated postoperatively. While this may be considered an atypical LR pattern, the distant metastasis to the right lung does reflect the characteristic aggressive biology of malignant peripheral nerve sheath tumors (MPNST) that are known for their high risk of distant spread and poor oncological outcomes [11, 21-23].
Another difference in the present study is the overall higher LR rate of 18.7% (17/91 patients) compared to 55/462 (11.9%) in the Norwegian study, 60/768 (7.8%) in the PMH study or 5-year LC rates of over 90% in large randomized trials [13, 17, 19, 24]. The rate of positive surgical margins (R1/R2), as the single most important risk factor for LR, in the present study cohort was comparably low (5/91, (5.5%)); (165/768, (21.5%) in the PMH study [6-8, 10]. Importantly, the authors did not find significant differences in the rate of R1/R2 resections among the in-field, out-of-field, and marginal recurrences. In the present study, no positive surgical margins were found in any locally recurrent STS. Notably, the locally-recurrent STS consisted mostly of histological subtypes with unfavorable prognoses, high morbidity and disease recurrence such as UPS (4/17, (23.5%)) or MPNST (3/17, (17,6%)) [11, 22, 23].
The majority of patients in the present study cohort from 2004-2021 received IMRT or VMAT as advanced RT techniques. No firm conclusions can be drawn due to the small number of patients. Large cohort studies suggest IMRT to be an independent favorable predictor for LC in comparison to 3D-CRT, although no prospective trials have been conducted [15]. For VMAT, the increase in conformity and normal tissue sparing has shown limited local toxicity compared to 3D-CRT in patients with extremity STS [16].
A list of previous studies analyzing the patterns of recurrence in STS after pre- or postoperative RT are summarized in table 2. The previous studies summarize large datasets overlooking many years of experience from high-volume facilities such as the PMH in Toronto, Canada, the Massachusetts General Hospital in Boston, United States, and multiple European centers [17, 19, 20]. While there are numerous ongoing prospective trials investigating different dosing, RT timing (pre- and postoperative) and techniques (e.g., proton irradiation) for different STS subtypes and locations, there are currently no registered prospective trials comparing different delineation plans for STS [25-33].
Our study is limited by the small number of LR cases that preclude inferential statistical analysis. The retrospective nature and the single-institutional data are further important factors introducing bias. Moreover, the exact reproducibility of RT plans and data that have been collected more than a decade ago is restricted. Another essential limitation inherent to most studies on STS including the present is the significant heterogeneity and rarity of these malignancies, making prospective trials or subtype-specific studies particularly challenging.
Conclusions
This retrospective analysis found the majority of LRs in high-grade STS to occur within the PTV, thereby confirming previous studies on this topic. Despite no existing prospective comparative trials on safety margins for STS, our study and the literature consistently suggest that RT volume definition is adequate. To further improve LC in high-grade STS patients, more emphasis should therefore be put on subtype-specific or even case-specific tumor biology, including radiosensitivity and molecular targets, normal tissue sparing, which allows increased dose delivery to the tumor, and optimization of surgical techniques. Future studies on these fields are awaited with great interest.
Ethics approval and consent to participate
Approved by the local institutional review board
Consent for publication
Not applicable
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
Individual author contributions were anonymized for review. All authors have read and agreed to the published version of the manuscript.
Funding
None
Data Availability
The research datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
Felix Ehret is a participant in the BIH Charité Junior Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and Berlin Institute of Health at Charité (BIH).
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