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

Intensity-Modulated and Image-Guided Radiotherapy in Patients with Locally Advanced Inoperable Pancreatic Cancer after Preradiation Chemotherapy

Background. Radiotherapy (RT) in patients with pancreatic cancer is still a controversial subject and its benefit in inoperable stages of locally advanced pancreatic cancer (LAPC), even after induction chemotherapy, remains unclear. Modern radiation techniques such as image-guided radiotherapy (IGRT) and intensity-modulated radiotherapy (IMRT) may improve effectiveness and reduce radiotherapy-related toxicities. Methods. Patients with LAPC who underwent radiotherapy after chemotherapy between 09/2004 and 05/2013 were retrospectively analyzed with regard to preradiation chemotherapy (PRCT), modalities of radiotherapy, and toxicities. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier curves. Results. 15 (68%) women and 7 men (median age 64 years; range 40–77) were identified. Median duration of PRCT was 11.1 months (range 4.3–33.0). Six patients (27%) underwent conventional RT and 16 patients (73%) advanced IMRT and IGRT; median dosage was 50.4 (range 9–54) Gray. No grade III or IV toxicities occurred. Median PFS (estimated from the beginning of RT) was 5.8 months, 2.6 months in the conventional RT group (conv-RT), and 7.1 months in the IMRT/IGRT group (P=0.029); median OS was 11.0 months, 4.2 months (conv-RT), and 14.0 months (IMRT/IGRT); P=0.141. Median RT-specific PFS for patients with prolonged PRCT > 9 months was 8.5 months compared to 5.6 months for PRCT < 9 months (P=0.293). This effect was translated into a significantly better median RT-specific overall survival of patients in the PRCT > 9 months group, with 19.0 months compared to 8.5 months in the PRCT  <  9 months group (P=0.049). Conclusions. IGRT and IMRT after PRCT are feasible and effective options for patients with LAPC after prolonged preradiation chemotherapy

Surgical Margins in Soft Tissue Sarcoma Management and Corresponding Local and Systemic Recurrence Rates: A Retrospective Study Covering 11 Years and 169 Patients in a Single Institution

Soft tissue sarcomas (STSs) are a diverse group of rare malignant soft tissue tumors with a high disease burden. Treatment protocols are complex and, to this day, a precise recommendation for the surgical margin width is lacking. The present study aims to analyze the width of the surgical margins in STS resection specimens and analyze them for local and systemic disease-free survival as well as for most frequent histologic STS subtypes. A total of 169 consecutive patients diagnosed and treated in curative intent in our institution following a primary and localized STS of the extremities or trunk from January 2010 to December 2020 were included in this study regardless of age. Our data reveal that low-grade STSs are best controlled locally by a surgical margin >= 2 mm and in this way also preventing distant metastases effectively. Local recurrence-free survival and metastasis-free survival in high-grade STS were improved by intact muscle fascia or periosteum at the margin when compared only to soft tissue. However, the outcome was independent of the surgical margin width, suggesting a close but negative margin may be safe in high-grade STS subtypes with less invasive growth patterns when combined with adjunct radiochemotherapy

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

Comorbidities rather than older age define outcome in adult patients with tumors of the Ewing sarcoma family

BACKGROUND: Ewing family of tumors (EFT) is rarely diagnosed in patients (pts) over the age of 18 years (years), and data on the clinical course and the outcome of adult EFT pts is sparse. METHODS: In this retrospective analysis, we summarize our experience with adult EFT pts. From 2002 to 2020, we identified 71 pts of whom 58 were evaluable for the final analysis. RESULTS: Median age was 31 years (18-90 years). Pts presented with skeletal (n = 26), and extra-skeletal primary disease (n =32). Tumor size was ≥8 cm in 20 pts and 19 pts were metastasized at first diagnosis. Between the age groups (≤25 vs. 26-40 vs. ≥41 years) we observed differences of Charlson comorbidity index (CCI), tumor origin, as well as type and number of therapy cycles. Overall, median overall survival (OS) was 79 months (95% confidence interval, CI; 28.5-131.4 months), and median progression-free survival (PFS) 34 months (95% CI; 21.4-45.8 months). We observed a poorer outcome (OS, PFS) in older pts. This could be in part due to differences in treatment intensity and the CCI (<3 vs. ≥3; hazard ratio, HR 0.334, 95% CI 0.15-0.72, p = 0.006). In addition, tumor stage had a significant impact on PFS (localized vs. metastasized stage: HR 0.403, 95% CI 0.18-0.87, p = 0.021). CONCLUSIONS: Our data confirms the feasibility of intensive treatment regimens in adult EFT pts. While in our cohort outcome was influenced by age, due to differences in treatment intensity, CCI, and tumor stage, larger studies are warranted to further explore optimized treatment protocols in adult EFT pts

Combination therapy with Olaratumab/doxorubicin in advanced or metastatic soft tissue sarcoma -a single-Centre experience

BACKGROUND: The antibody targeting platelet-derived growth factor receptor alpha (PDGFRA), olaratumab, was approved in 2016 for metastatic soft tissue sarcoma (STS) in combination with doxorubicin based on promising results of a phase Ib/II trial by the Food and Drug Administration (FDA). However, recently the phase III ANNOUNCE trial could not confirm the additional value of olaratumab in this context. METHODS: Here, in a retrospective analysis we share our single-centre experience with olaratumab/doxorubicin in STS by including n = 32 patients treated with olaratumab/doxorubicin between 2016 and 2019. RESULTS: Median progression-free survival (PFS) in the overall cohort was 3.1 months (range 0.6-16.2). A response [complete remission (CR), partial remission (PR) or stable disease (SD)] was seen in n = 11 (34%) cases, whereas n = 21 (66%) patients showed progressive disease (PD). In n = 9 patients surgery was performed subsequently in an individual therapeutic approach. Out of n = 5 patients receiving additional regional hyperthermia, n = 3 achieved PR or SD. CONCLUSIONS: This single-centre experience does also not support the promising phase Ib/II results for olaratumab/doxorubicin in STS. However, our findings do not preclude that olaratumab combination therapy could be valuable in a neoadjuvant setting. This warrants further exploration also taking into account the heterogeneous nature of STS

Impact of a specialised palliative care intervention in patients with advanced soft tissue sarcoma - a single-centre retrospective analysis

BACKGROUND: Soft tissue sarcomas (STS) account for less than 1% of all malignancies. Approximately 50% of the patients develop metastases with limited survival in the course of their disease. For those patients, palliative treatment aiming at symptom relief and improvement of quality of life is most important. However, data on symptom burden and palliative intervention are limited in STS patients. AIM: Our study evaluates the effectiveness of a palliative care intervention on symptom relief and quality of life in STS patients. DESIGN/SETTING: We retrospectively analysed 53 inpatient visits of 34 patients with advanced STS, admitted to our palliative care unit between 2012 and 2018. Symptom burden was measured with a standardised base assessment questionnaire at admission and discharge. RESULTS: Median disease duration before admission was 24 months, 85% of patients had metastases. The predominant indication for admission was pain, weakness and fatigue. Palliative care intervention led to a significant reduction of pain: median NRS for acute pain was reduced from 3 to 1 (p < 0.001), pain within the last 24 h from 5 to 2 (p < 0.001) and of the median MIDOS symptom score: 18 to 13 (p < 0.001). Also, the median stress level, according to the distress thermometer, was reduced significantly: 7.5 to 5 (p = 0.027). CONCLUSIONS: Our data underline that specialised palliative care intervention leads to significant symptom relief in patients with advanced STS. Further efforts should aim for an early integration of palliative care in these patients focusing primarily on the identification of subjects at high risk for severe symptomatic disease