Neoadjuvant Hypofractionated Radiotherapy and Chemotherapy in High-Grade Extremity Soft Tissue Sarcomas: Phase 2 Clinical Trial Protocol

Abstract

BackgroundNeoadjuvant radiotherapy (RT) and chemotherapy are applied to large, high-grade extremity soft tissue sarcomas to treat metastatic disease earlier and sterilize margins to perform R0 surgery. However, preoperative RT increases wound complication rates (rWC), delaying adjuvant chemotherapy or preventing it from being administered altogether. Hypofractionated neoadjuvant RT can be offered in this situation, concomitant to chemotherapy, allowing patients to receive chemotherapy as a preoperative treatment in less time with an acceptable rWC.ObjectiveThe objectives of this protocol are to maintain low rates of morbidity and mortality compared to literature data, improving survival rates and avoiding poor responders from receiving unnecessary adjuvant chemotherapy.MethodsThis noncontrolled, single-arm, phase 2 clinical trial recruited patients aged over 18 years with high-grade soft tissue sarcomas in the girdles or extremities. Three neoadjuvant chemotherapy (ifosfamide and doxorubicin) cycles were administered with 5 days of hypofractionated RT (25 Gy in 5 fractions) in the second cycle of doxorubicin only. Viable cell counts in the surgical specimen were measured, and patients in whom this value was less than 30% continued to receive an additional 3 full chemotherapy cycles as adjuvant treatment.ResultsPrimary endpoint will be disease-specific survival measured by the evaluation of local and distant recurrence after neoadjuvant treatment. The secondary endpoints will be wound complication and amputation rates and chemotherapy toxicity. We also will record the viable cell rates after the schema and correlate this with survival.ConclusionsAs seems with other solid tumors, hypofractionated RT has comparable efficacy and safety as conventional fractionation. This modality of treatment combined with chemotherapy could increase the pathological response rates and improve the outcomes of select patients.Trial RegistrationClinicalTrials.gov NCT02812654; https://clinicaltrials.gov/ct2/show/NCT02812654 (Archived by WebCite at http://www.webcitation.org/6qC3puBOy)

Clinically relevant radioresistant rhabdomyosarcoma cell lines: functional, molecular and immune-related characterization

“…The literature presents RR cell lines generated by using different irradiation schemes [6,9,[27][28][29][30][31][32]. Herein, we took inspiration from the hypo-fractionated program used for sarcoma patients, irradiating cells with 6 Gy 6 times [18] that, considering the low α/β ratio of RMS [20], permit us to reach radiobiologically equivalent dose of 66 Gy, equal to that clinically delivered with conventional schedule [2]. It should be noted that fractions were not delivered daily but when cells restarted to growth, as used in other studies [9,27] that consider tumor cells in 2D more sensitive to treatments [15].…”

“…RT for RMS tumors usually provides 50/66 Gy in fractions of 2 Gy [2]. However, hypofractioned programs, single higher doses for a reduced number of fractions, are used to overcome the intrinsic radioresistance of RMS [18]. In order to generate clinically relevant radioresistant (RR) RMS cell lines, RD and RH30 cells were subjected to hypo-fractionated schedule based on the use of 6 fractions, each at 6 Gy.…”

Neoadjuvant Radiotherapy for Soft Tissue Sarcoma

“…However, there are extensive disputes and challenges regarding the use of chemotherapy and radiotherapy in these patients. Some studies have adopted optional chemotherapy treatment as an adjunct to increase the chance of preserving a limb, but the use of this method has not had a significant effect on overall survival [4].…”

“…Other studies have suggested that in patients for whom the tumor cannot be removed completely by surgery, to increase the chance of tumor necrosis considering its high survival, a neoadjuvant chemotherapy treatment with hypofractionated radiotherapy or in some cases adjuvant chemotherapy, depending on the living cells, has been recommended. These methods have been able to improve patient complications and induce a pathologic response [4]. Various protocols have been proposed for radiotherapy of these patients.…”

Hypofractionated preoperative radiotherapy for high risk soft tissue sarcomas in a geriatric patient population

“… 13 25 Gy in 5 fractions in combination with chemotherapy has been reported as a phase 2 trial protocol. 14 The advantage for geriatric patients is the significantly reduced overall treatment time and the limited daily visits to the radiation oncology department making it more feasible as an outpatient treatment. Thus, radiotherapy is an option even in frail geriatric patients who otherwise would undergo surgery alone due to the high burden of daily visits to radiation treatment units over several weeks.…”