Therapieoptimierung bei Weichgewebssarkomen

Hintergrund: Sarkome treten im Erwachsenenalter sehr selten auf und sind gleichzeitig sehr heterogen in ihrem biologischen Verhalten. Systematische retrospektive Auswertungen sind darum von elementarer Bedeutung für das Erzielen eines besseren Krankheitsverständnisses und Grundlage der Therapieoptimierung bei Weichgewebssarkomen, welche das Thema der vorliegenden Habilitationsschrift ist. Methoden: Es werden fünf Originalarbeiten zusammengefasst und diskutiert, in welchen retrospektiv einfach zu erhebende klinische Charakteristika untersucht, die Ergebnisse multimodaler Therapiestrategien analysiert und die positiven Effekte supportiver Maßnahmen demonstriert wurden. Eine weitere Originalarbeit hat systematisch die verfügbare Evidenz zu hypofraktionierter Bestrahlung ausgewertet. Ergebnisse: Das mediane progressionsfreie Überleben bei älteren Patient:innen mit Tumoren der Ewingsarkom-Familie wird durch Komorbiditäten und das Tumorstadium beeinflusst. Bei intensivmedizinisch betreuten Sarkompatient:innen haben etablierte Sepsis- und Performance-Scores und allgemeine Charakteristika (Geschlecht, Tumorlokalisation, Therapieintention) prognostische Aussagekraft. Die Hinzunahme von Olaratumab zu Doxorubin führt nicht zu einer signifikanten Verbesserung des Überlebens. Durch die kombinierte Radiochemotherapie wird bei Patient:innen mit high grade lokalisierten Weichgewebssarkomen im Vergleich zur alleinigen Strahlentherapie sowohl die lokale Kontrolle als auch die Verhinderung von Fernmetastasen verbessert. Die präoperative hypofraktionierte Radiatio ist der normofaktionierten Bestrahlung nicht unterlegen und somit eine gute Behandlungsoption für Patient:innen mit Weichgewebssarkomen. Eine spezialisierte palliativmedizinische Intervention bei Patient:innen mit fortgeschrittenem Weichgewebssarkom führt zu einer signifikanten Abnahme der Symptomlast (Schmerzen, allgemeine Symptome und Stresslevel). Schlussfolgerungen: Die dargestellten Innovationen der Sarkomtherapie lassen sich drei unterschiedlichen Bereichen zuordnen. Beginnend bei der Identifizierung von in der klinischen Routine einfach zu erhebenden Biomarkern zur präziseren Patient:innenselektion werden Beispiele für die Optimierung der Therapie selbst gegeben: dazu gehören der Einsatz zielgerichteter Substanzen insbesondere im Rahmen multimodaler Strategien und relevante technische Fortschritte in der Strahlentherapie. Abschließend wird am Beispiel der Integration palliativmedizinischer Interventionen in die Tumorbehandlung die Bedeutung des frühzeitigen Einsatzes supportiver Maßnahmen gezeigt.Background: Sarcoma is very rare in adults and comprises a large number of different subentities, who are heterogenous in their biological behavior. Systematic retrospective analyses are elementary for improving understanding of sarcoma diseases as well as their diagnosis and therapy, though. Methods: Six original works analyzing retrospectively or by literature review prognostic clinical characteristics in sarcoma patients, efficacy of multimodal therapeutic strategies, and the positive impact of supportive therapy are summarized and discussed. Results: Median progression free survival in adult patients diagnosed with Ewing family of tumors is influenced by comorbidities and tumor stage. Well-established sepsis and performance scores such as SAPS II and SOFA as well as general characteristics (gender, tumor location, therapeutic intention) have prognostic impact on survival of patients with soft tissue sarcoma admitted to the intensive care unit. Addition of olaratumab to doxorubicin does not improve survival in sarcoma patients. Combined chemoradiation results in better local control rate as well as in reduction of distant metastasis compared to any other therapeutic strategy. Preoperative hypofractionated radiation is shorter, often less toxic and at least as efficient as normofractionated radiotherapy. Specialized palliative care intervention in patients with advanced sarcoma significantly reduces symptom burden (pain, general symptoms, and distress). Conclusion: Innovation of sarcoma management starts with identification of biomarkers enabling more precise patient selection. Therapeutic efficacy is improved by including targeted substances as well as individualized multimodal strategies and technical progress in radiotherapy. Additionally, early inclusion of palliative medicine decreases symptom burden and improves quality of life in advanced disease

The role of neoadjuvant radiochemotherapy in the management of localized high-grade soft tissue sarcoma

Background: Standard treatment of soft tissue sarcoma (STS) of the extremities includes limb-sparing surgery combined with pre- or postoperative radiotherapy (RT). The role of perioperative chemotherapy (CTX) remains uncertain. STS patients with high-risk features for local recurrence, distant metastases, and increased mortality may require additional systemic therapy. The objective of this study was to evaluate predictors of outcome regarding local control (LC), overall survival (OS), and freedom from distant metastases (FFDM) in a large single-center cohort of patients suffering from localized high-grade STS (grade 2/3, G2/G3). Special emphasis was put on a subgroup of patients who received combined neoadjuvant radiochemotherapy (RCT). Methods: Overall, 115 adult STS patients were included in this retrospective study. The median follow-up was 34 months. Twenty-three patients (20.0%) were treated with neoadjuvant RCT, 92 (80.0%) received other therapies (adjuvant RT alone (n = 58); neoadjuvant CTX + adjuvant RT (n = 17); adjuvant RCT (n = 10), neoadjuvant RT alone (n = 7)). To assess potential prognostic factors on LC, OS, and FFDM, univariate (UVA) and multivariable (MVA) Cox proportional hazards models were applied. Results: UVA showed significantly better LC rates in the neoadjuvant RCT group (p = 0.025), with trends in MVA (p = 0.057). The 3-year LC rate was 89.7% in the neoadjuvant RCT group vs. 75.6% in the "other therapies" group. UVA also showed significantly better OS rates in the neoadjuvant RCT group (p = 0.049), however, this was not confirmed in MVA (p = 0.205), the 3-year OS rate was 85.8% for patients treated with neoadjuvant RCT compared to 73.5% in the "other therapies" group. UVA showed significantly better FFDM rates in (p = 0.018) and a trend towards better FFDM rates in MVA (p = 0.059). The 3-year FFDM rate was 89.7% for patients treated with neoadjuvant RCT compared to 65.9% in the "other therapies" group. In the subgroup of patients with G3 STS, neoadjuvant RCT was a significant positive predictor of LC and FFDM in MVA (p = 0.047, p = 0.027) but not for OS. Overall grade 3 and 4 toxicities were significantly higher (p = 0.019) in the neoadjuvant RCT group and occurred in 73.9% vs. 38.0% in patients receiving other therapies. Conclusions: The results suggest that neoadjuvant RCT might improve LC and FFDM in patients with localized G3 STS while also being associated with increased acute complication rates. Further prospective research is warranted to confirm these findings

Preoperative hypofractionated radiotherapy for soft tissue sarcomas: a systematic review

Background: Soft tissue sarcomas (STS) represent a diverse group of rare malignant tumors. Currently, five to six weeks of preoperative radiotherapy (RT) combined with surgery constitute the mainstay of therapy for localized high-grade sarcomas (G2-G3). Growing evidence suggests that shortening preoperative RT courses by hypofractionation neither increases toxicity rates nor impairs oncological outcomes. Instead, shortening RT courses may improve therapy adherence, raise cost-effectiveness, and provide more treatment opportunities for a wider range of patients. Presumed higher rates of adverse effects and worse outcomes are concerns about hypofractionated RT (HFRT) for STS. This systematic review summarizes the current evidence on preoperative HFRT for the treatment of STS and discusses toxicity and oncological outcomes compared to normofractionated RT. Methods: We conducted a systematic review of clinical trials describing outcomes for preoperative HFRT in the management of STS using PubMed, the Cochrane library, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Embase, and Ovid Medline. We followed the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Trials on retroperitoneal sarcomas, postoperative RT, and hyperthermia were excluded. Articles published until November 30th, 2021, were included. Results: Initial search yielded 94 articles. After removal of duplicate and ineligible articles, 13 articles qualified for analysis. Eight phase II trials and five retrospective analyses were reviewed. Most trials applied 5 x 5 Gy preoperatively in patients with high-grade STS. HFRT courses did not show increased rates of adverse events compared to historical trials of normofractionated RT. Toxicity rates were mostly comparable or lower than in trials of normofractionated RT. Moreover, HFRT achieved comparable local control rates with shorter duration of therapy. Currently, more than 15 prospective studies on HFRT + / - chemotherapy are ongoing. Conclusions: Retrospective data and phase II trials suggest preoperative HFRT to be a reasonable treatment modality for STS. Oncological outcomes and toxicity profiles were favorable. To date, our knowledge is mostly derived from phase II data. No randomized phase III trial comparing normofractionated and HFRT in STS has been published yet. Multiple ongoing phase II trials applying HFRT to investigate acute and late toxicity will hopefully bring forth valuable findings

TFE3 activation in a TSC1‐altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms

Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options