Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas

Koseła-Paterczyk, Hanna; Szacht, Milena; Morysiński, Tadeusz; Ługowska, Iwona; Dziewirski, Wirginiusz; Falkowski, Sławomir; Zdzienicki, Marcin; Pieńkowski, Andrzej; Szamotulska, Katarzyna; Świtaj, Tomasz; Rutkowski, Piotr

doi:10.1016/j.ejso.2014.05.016

Cited by 81 publications

(56 citation statements)

References 35 publications

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“…More recently, a prospective study reported the results on 272 patients who were treated with an RT regimen that was similar to that in our study, with 25 Gy/5 fractions followed by immediate surgery (3 to 7 days after the end of RT) [20]. Some patients (22%) also underwent neoadjuvant chemotherapy.…”

Section: Discussionsupporting

confidence: 80%

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

et al. 2017

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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)

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Section: Discussionsupporting

confidence: 80%

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

et al. 2017

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“…However, sarcomas lacking HIF-1α in the tumor cells were more sensitive to 50 Gy of fractionated radiation therapy (10Gy x 5) in vivo . Although five fractions of radiation therapy may not recapitulate the most frequently used radiation therapy schedule for soft tissue sarcomas, it is still clinically relevant as emerging evidence suggests that hypofractionation with five fractions may have similar rates of local control and toxicity profiles [38]. Moreover, sarcoma cells lacking HIF-1α by either genomic ablation or shRNA knockdown were also sensitized to radiation in vitro by clonogenic assays.…”

Section: Discussionmentioning

confidence: 99%

HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism

Zhang

Qiu

et al. 2015

Radiation Research

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Hypoxia is a major cause of radiation resistance, which may predispose to local recurrence after radiation therapy (RT). While hypoxia increases tumor cell survival after RT because there is less oxygen to oxidize damaged DNA, whether signaling pathways triggered by hypoxia contribute to radiation resistance is poorly understood. For example, intratumoral hypoxia can increase hypoxia inducible factor 1 alpha (HIF-1α), which may regulate pathways that contribute to radiation sensitization or radiation resistance. To clarify the role of HIF-1α in regulating tumor response to radiation therapy, we generated a novel genetically engineered mouse model of soft tissue sarcoma with an intact or deleted HIF-1α. Deletion of HIF-1α sensitized primary sarcomas to RT in vivo. Moreover, cell lines derived from primary sarcomas lacking HIF-1α, or in which HIF-1α was knocked down, had decreased clonogenic survival in vitro, demonstrating that HIF-1α can promote radiation resistance in a cell autonomous manner. In HIF-1α intact and deleted sarcoma cells, radiation-induced reactive oxygen species (ROS), DNA damage repair, and activation of autophagy were similar. However, sarcoma cells lacking HIF-1α had impaired mitochondrial biogenesis and metabolic response after radiation which might contribute to radiation resistance. These results show that HIF-1α promotes radiation resistance in a cell autonomous manner.

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“…Kosela-Paterczyk and colleagues performed a prospective phase II clinical trial which accrued 272 patients and investigated a dose of 5 × 5 Gy followed by surgery three to seven days after completion of RT. After a median follow-up of 35 months, the estimated 5 year local failure rate was 19% [31], which may be on the lower level of acceptable local control.…”

Section: Methodsmentioning

confidence: 99%

“…The three lines come forth from low to high α/β ratios calculations. The grey dots numbers 1, 2 and 3 represent the three consecutive Eilber studies [26, 27], number 4 comes from the Kosela study [31], and number 5 represents Temple’s data [28]. The biological equivalent dose (BED) of these dots are calculated assuming an α/β ratio of 4 Gy (5 × 3.5 Gy equals BED of 21,875 Gy, 8 × 3.5 Gy equals a BED of 35 Gy, 10 × 3.5 Gy equals a BED of 43,75 Gy, 5 × 5 Gy equals a BED of 37,5Gy, and 10 × 3 Gy equals a BED of 35 Gy).…”

Section: Figurementioning

confidence: 99%

Preoperative radiotherapy for extremity soft tissue sarcoma; past, present and future perspectives on dose fractionation regimens and combined modality strategies

Haas

Miah

Lepéchoux

et al. 2016

Radiotherapy and Oncology

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Introduction This critical review aims to summarize published data on limb sparing surgery for extremity soft tissue sarcoma in combination with pre-operative radiotherapy (RT). Methods This review is based on peer-reviewed publications using a PubMed search on the MeSH headings “soft tissue sarcoma” AND “preoperative radiotherapy”. Titles and abstracts screened for data including “fraction size AND/OR total dose AND/OR overall treatment time”, “chemotherapy”, “targeted agents AND/OR tyrosine kinase inhibitors”, are collated. Reference lists from some articles have been studied to obtain other pertinent articles. Additional abstracts presented at international sarcoma meetings have been included as well as information on relevant clinical trials available at the ClinicalTrials.gov website. Results Data are presented for the conventional regimen of 50–50.4 Gy in 25–28 fractions in 5–6 weeks preoperative external beam RT with respect to the regimen’s local control probability compared to surgery alone, as well as acute and late toxicities. The rationale and outcome data for hypofractionated and/or reduced dose regimens are discussed. Finally, combination schedules with conventional chemotherapy and/or targeted agents are summarized. Conclusion Outside the setting of well-designed prospective clinical trials, the conventional 50 Gy in 5–6 weeks schedule should be considered as standard. However, current and future studies addressing alternative fraction size, total dose, overall treatment time and/or combination with chemotherapy or targeted agents may reveal regimens of equal or increased efficacy with reduced late morbidities.

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Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas

Cited by 81 publications

References 35 publications

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

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

HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism

Preoperative radiotherapy for extremity soft tissue sarcoma; past, present and future perspectives on dose fractionation regimens and combined modality strategies

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