Studies

This is a multi-centre, open label, randomized phase 3 selection study (1:2:2 randomization). After confirmation of the eligibility criteria, 185 patients will be randomized 1:2:2 to either the control arm (doxorubicin 60-75 mg/m² IV every 3 weeks) or experimental arm 1 (doxorubicin 12 mg/m2 IV every week) or experimental arm 2 (cyclophosphamide 100 mg orally BD plus prednisolone 10-20 mg orally on day 1 to day 7 of each 14 day cycle). Health-related quality of life (HRQoL) assessment will be performed every 3 weeks during the first 12 weeks and every 12 weeks thereafter until month 12 after start of treatment. Disease evaluation will be performed every 12 weeks until progression. The primary endpoint of the study is difference among the study arms in physical and role functioning at 12 weeks.

Histologically proven advanced unresectable or metastatic soft tissue sarcoma Representative formalin fixed, paraffin embedded tumor blocks or a minimum of 10 unstained tissue slides, either from the primary tumor or a metastatic lesion, must be available for histological central review. Histological central review is not required before treatment start but it is mandatory to send at least 10 unstained tumor slides (blocks optional) at time of study entry. Local histopathological diagnosis will be accepted for entry into this trial. Age ≥ 65 years of age (patients between 65 and 69 years old are eligible if G8 score ≤ 14; patients ≥ 70 years old are eligible independent of G8 score) WHO performance status 0 – 2 Life expectancy based on other significant morbidity of ≥ 6 months Presence of measurable disease (according to RECIST 1.1), as confirmed by imaging within the 28 days prior to randomization. CT with IV contrast is the preferred imaging modality. In case of any contra-indications (medical or regulatory), it is allowed to perform a non-contrast CT + MRI. Progressive disease at entry based on RECIST 1.1 Patients amenable to receive doxorubicin according to investigator’s assessment Adequate haematological and organ function assessed prior to randomization: Haematological function: Haemoglobin ≥ 9.0 g/dL or 5.6 mmol/L Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Coagulation: partial thromboplastin time (PTT) ≤ 1.0 times upper limit of normal (1.0 x ULN) of institutional limits and prothrombin time (PT) ≤ 1.0 x ULN of institutional limits 11. Renal function: estimated glomerular filtration rate (eGFR) > 50 ml/min/m2 (calculated by the MDRD formula in appendix E); no proteinuria ≥ grade 2 (CTCAE version 5.0); 12. Hepatic function: bilirubin ≤ 1.0 x ULN of institutional limits, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤1.5 x ULN. If isolated elevated bilirubin <2 x ULN and Gilberts syndrome suspected, suggest repeating bloods after food. If bilirubin improves to meet the criteria above this is acceptable. More severe persistent hepatic impairment of whatever cause would exclude the patient from treatment till resolved. 13. Cardiac function: clinically normal function based on the institutional lower limit of normal for left ventricular ejection fraction (LVEF) as assessed either by multi-gated acquisition scan (MUGA) or cardiac ultrasound and 12 lead electrocardiogram (ECG) without clinically relevant abnormalities. Measurement should include investigator assessment of a potential participant’s risk for heart failure with a validated clinical classification system, i.e. the New York Heart Association Functional Classification. Only patients with NYHA class 1 and 2 according to appendix D are eligible. 13. Completion of EORTC QLQ-C30 and EORTC QLQ-ELD14 at baseline. 14. Assessment of G8 geriatric screening tool 15. Assessment of Katz Index of Independence in Activities of Daily Living (ADL) 16. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: 17. With female partners of childbearing potential, men must remain abstinent or use a condom during the treatment period and for a period of 6 months after the last dose of doxorubicin-based chemotherapy and for a period of 12 months after the last dose of cyclophosphamide-based chemotherapy. Men must refrain from donating sperm during this same period. Contraception should be considered for the female partners of childbearing potential as well. 18. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for a period of 6 months after the last dose of doxorubicin-based chemotherapy and for a period of 12 months after the last dose of cyclophosphamide-based chemotherapy to avoid exposing the embryo. 19.Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations including commitment to completing questionnaires during the course of the study.

Symptomatic or known brain metastasis Any prior treatment with anthracyclines Any prior systemic treatment for metastatic STS Inability to swallow and/ or retain oral tablets Rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption Hypersensitivity to doxorubicin, cyclophosphamide, prednisolone or to any of their metabolites or to any of their excipients Uncontrolled severe illness, including but not limited to: Congestive heart failure Angina pectoris Acute inflammatory heart disease Myocardial infarction within 1 year before randomization Arterial hypertension defined as blood pressure ≥ 150/100 mm Hg despite optimal medical therapy Uncontrolled cardiac arrhythmia Increased haemorragic tendency Uncontrolled diabetes Bone marrow aplasia Psychosis Active or uncontrolled infections among which those requiring systemic antibiotics or antimicrobial therapy. Inflammation of the urinary bladder (interstitial cystitis) and/or obstructions of the urine flow. Vaccination with live vaccines within 30 days prior to study entry Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are not eligible for this trial. Known contraindication to imaging tracer or contrast medium and contraindication to MRI Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and its active requirements (including completion of questionnaires) and follow-up schedule; those conditions should be discussed with the patient before randomization in the trial

Currently, there is no consensus about the optimal treatment for patients with high grade soft tissue sarcomas (STS) which are localized in the extremities. To ensure overall survival, there is a tendency to operate with wide resection margins, but this has a high impact on quality of life especially when limb function must be sacrificed. (Neo)adjuvant radiotherapy allows for narrower surgical margins but is associated with significant short -and long-term side-effects. As evidence on the best treatment is lacking, treatment choice for individual patients should be driven by their weighing of the benefits and harms of the treatment options in light of their personal situation. However, current treatment decision-making in STS care is one-size fits all, and not informed by individualized risks of treatment options and patients’ preferences. Consequently, there is no guarantee that patients with STS will receive treatment that is appropriate for their situation, and patients experience uncertainty about which treatment is best for their personal situation (decisional conflict). From literature it is known that decision supporting interventions contribute to a better informed choice and less decisional conflict. Therefore, our research group developed a validated personalized risk assessment tool (Personalised Sarcoma Care: PERSARC) which provides patients and STS professionals insight into the personalized risks and benefits of each treatment option based on patient’s age, tumor size, tumor depth and histology in their decision-making process. It is hypothesized that use of PERSARC leads to significantly less decisional conflict in patients and more informed decisions compared to usual care (treatment decisions without use of PERSARC) by reducing the uncertainty regarding risks and benefits of treatment options in high-grade extremity STS patients.

Patients (>= 18 years) with primarily diagnosed (histologically confirmed) grade 2-3 extremity STS, who do not have a treatment plan yet and will be treated with curative intent. Patients with sarcoma subtypes or treatment options other than those mentioned in the PERSARC app are unable to participate. Furthermore, patients need to be Dutch fluency and literacy and mentally competent.

Patient that are treated without curative intent Patient that needs to be treated with chemotherapy or isolated limb perfusion Patients were surgery is not indicated Sarcoma subtypes not mentioned in the PERSARC app

Name: Anouk Kruiswijk Email: a.a.kruiswijk@lumc.nl Phone: 0631974532

The investigators will follow the EORTC QLG questionnaire development guidelines. First, a computerized search of the academic literature will be performed to identify all relevant HRQoL issues for and existing HRQoL questionnaires currently used among patients with sarcoma. In parallel, semi-structured interviews will be conducted worldwide with patients with sarcoma(N=179) and health care professionals (HCPs; N=35; phase 1a). The patient sample will be stratified to capture diversity across the sarcoma population tumour location (extremities, axial, head and neck, thorax, retroperitoneal/intra-abdominal and gynecological), stage (localized vs. metastatic disease ) and type or lines of treatment. This list of HRQoL issues generated by the a) literature search, b) relevant items from the Item Library, and c) semi-structured patient and HCP interviews, and will be consolidated into a comprehensive list of issues for all languages of collaborating countries. In phase 1b, the new list of HRQoL issues will be presented to another group of patients with sarcoma(N=475) and HCPs (N=72). Patients and HCPs will be asked to rate the HRQoL issues on relevance (4point Likert scale) and to prioritize the 10 most important issues.

Age at diagnosis 18 years or older Having a confirmed diagnosis of sarcoma

Having any psychiatric condition or cognitive impairment that would hamper participation in interview/completion of self-reported questionnaires. Patients with a Gastrointestinal Stroma Tumour (GIST) diagnosis, as they are quite unique in terms of type of disease and treatment. Patients with Kaposi sarcoma, as this disease occurs quite often in people with AIDS Patients with Carcinosarcoma as this disease is generally seen as a carcinoma

Currently, soft tissue sarcomas (STS) are preoperatively irradiated in a conventionally fractionated regimen of 25 x 2 Gy in five weeks. Recent radiobiological investigations, however, suggest sensitivity to (modest) hypofractionation. Within this study, patients will be randomized to receive either the conventional schedule of 25 x 2 Gy or a shorter preoperative regimen of 14 x 3 Gy, in the hypothesis that both the postoperative wound complication rate until 30 days after surgery, as well as the local control probability at two years are comparable in both arms.

Histologically confirmed newly diagnosed intermediate to high grade soft tissue sarcoma localized to the extremities, trunk and chest wall or the head and neck area, for which the standard treatment is a combination of and radiotherapy and surgery (deep seated and/or > 5cm in largest tumor diameter and/or an anticipated close resection margin and/or grade II/III according to the FNCLCC definition) Absence of regional and/or distant disease. Patients staged by at least a CT scan of the chest (. Staging may also be performed by FDG-PET scanning and or total body MRI scans. Patients with an uncertain metastatic status (e.g. small indifferent lung nodules) and patients with a low metastatic burden not precluding the application of both preoperative radiotherapy and definitive surgery, are allowed to participate WHO Performance Status ≤ 2 Able and willing to undergo preoperative radiotherapy Able and willing to undergo definitive surgery Able and willing to comply with regular follow-up visits Able and willing to complete patient reported outcome questionnaires (health-related quality of life and cost effectiveness) Able and willing to undergo randomization Age ≥ 18 years  

Prior malignancies; except another malignancy and disease-free for ≥ 5 years, or completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma Patients with recurrent sarcomas who underwent prior radiotherapy to the target lesion (if the primary sarcoma was managed by surgery only and no perioperative RT, patients are eligible) Ewing sarcoma and other PNET family tumors, rhabdomyosarcomas (both pediatric and adult), osteosarcomas Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial Female patients who are pregnant Intention to perform an isolated limb perfusion, instead of a tumor resection Neoadjuvant chemotherapy to be scheduled between end of radiotherapy and definitive surgery (neoadjuvant chemotherapy before radiotherapy is allowed)

To prospectively and retrospectively collect data of patients with bone or soft tissue sarcoma in the Netherlands to improve the knowledge and therefore the treatment care. Besides to create a continuous basis for a large variety of research purposes including prognostic and predictive research, health care policies and cost-effectiveness studies.

Age ≥ 18 years Histologically proven bone or soft tissue sarcoma, excluding Gastrointestinal Stromal Tumours

Altered mental status that would prohibit the understanding of any giving of informed consent

Radboudumc Radiotherapiegroep

Name: dr. P.M. Braam E-mail: p.braam@radboudumc.nl Phone: +31-243614515 Address: Radboudumc, Geert Grooteplein Zuid 32, 6525 GA Nijmegen