Soft tissue sarcomas (STSs) are rare cancers with a 5-year survival rate of 60%, and there is no standard treatment for high-risk extremity and trunk STSs (eSTS). A phase III trial suggests that adding moderate regional hyperthermia (HT) to anthracycline-based chemotherapy, followed by surgery and radiotherapy (RT), can improve 10-year overall survival by 10%. This trial aims to optimize treatment by combining the most effective regimens from chemotherapy, HT, RT, and surgery, and will evaluate the feasibility of this new total neoadjuvant treatment (TNT) approach.
Histologically confirmed primary high-risk Soft tissue sarcoma (STS) of extremity or trunk.
High-risk according to the prognostic Sarculator tool: 10-year OS probability < 60%5.
Resectable tumor: resectability is based on pre-operative imaging and has to be defined by the local treating sarcoma team. A patient is not considered resectable when the expectation is that only a R2 resection is feasible.
Measurable disease per RECIST v1.1.
Metastatic disease.
Previous Whoops resection.
Ex-ulcerating tumors or tumors infiltrating the skin.
Other invasive malignancy within 5 years, with the exception of adequately treated non melanoma skin cancer, localized cervical cancer, localized and Gleason ≤ 6 prostate cancer.
Single group
Doxorubicin
DrugTrial treatment consists of 3 neoadjuvant cycles of doxorubicin with either ifosfamide or dacarbazine (the latter only in case of leiomyosarcoma). Doxorubicin will be given at a dose of 75 mg/m2 Body surface area (BSA) on day 1 of each cycle as a intravenous infusion over 15 minutes.
Ifosfamide
DrugTrial treatment consists of 3 neoadjuvant cycles of doxorubicin with either ifosfamide or dacarbazine (the latter only in case of leiomyosarcoma). Ifosfamide will be given at a dose of 3 g/m2 BSA on days 1 to 3 of each cycle, for a total dose per cycle of 9 g/m2 BSA, as an intravenous infusion of 3 g/m2 daily over 4 hours.
Dacarbazine
DrugTrial treatment consists of 3 neoadjuvant cycles of doxorubicin with either ifosfamide or dacarbazine (the latter only in case of leiomyosarcoma). Dacarbazine will be given at a daily dose of 300 mg/m2 BSA on days 1 to 3 of each cycle, for a total dose per cycle of 900 mg/m2 BSA, as an intravenous infusion over 30 minutes.
Hyperthermia
Other interventionHyperthermia (HT) sessions are scheduled on days 1 and 3 of each chemotherapy cycle. The duration of the preheating phase is always 30 minutes. Together with the treatment phase of 60 minutes, the duration of a HT session is uniformly 90 minutes (Total treatment time). On days 2, chemotherapy will be applied without HT.
Radiotherapy
RadiationRadiotherapy (RT) treatment should start ideally 19 days after last chemotherapy dose received (range -4 / +7), preferably on a Monday to omit that the last RT fractions will be applied directly after the weekend. Start of RT can be postponed up to 14 days due to medical reasons without violating treatment protocol. Patients will preferably receive normofractionated RT to a total dose of 50 Gy in 25 fractions of 2 Gy over 5 weeks23. Alternatively, patients can receive a moderate hypofractionated RT to either a total dose of 42.75 Gy in 15 fractions of 2.85 Gy over 3 weeks or a total dose of 42 Gy in 14 fractions of 3 Gy over 2 weeks and four days41. The respective total treatment time changes respectively. The RT treatment should be delivered once daily except on weekends.
Surgery
Procedure/SurgeryStandard of care surgical resection must be done by an experienced sarcoma surgeon. All lesions of the trunk and extremities will be resected after total neoadjuvant treatment with chemotherapy, HT and RT. Surgery will take place preferentially 6 weeks (+/- 2 weeks) after end of radiation.
Protocol feasibility rate
PFR defined as percentage of patients who are able to finish the following planned trial treatment parts according to protocol
Disease-free survival (DFS)
DFS defined as * time from registration until local or distant relapse, * or, if tumor has not been operated, time from registration until progression according to RECIST v1.1, * or death from any cause, whichever occurs first.
Objective response rate (ORR)
ORR assessed by the independent response reviewer and defined as proportion of patients achieving complete response (CR) or partial response (PR) according to RECIST v1.1 during trial treatment and before surgery.
Pathologic complete response (pCR)
pCR rate, assessed by the central pathologist and defined as proportion of patients with ≤ 10% viable cells (equivalent to EORTC-STBSG response grade A-C43) in the resection specimen. pCR rate will be evaluated in resected patients only.
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