Volume 34, Issue 2, April 2024, Pages 172-179Author links open overlay panel, , ,

There is a misconception that sarcomas are resistant to radiotherapy. This manuscript summarizes available (pre-) clinical data on the radiosensitivity of soft tissue sarcomas. Currently, clinical practice guidelines suggest irradiating sarcomas in 1.8-2 Gy once daily fractions. Careful observation of myxoid liposarcomas patients during preoperative radiotherapy led to the discovery of this subtype's remarkable radiosensitivity. It resulted subsequently in an international prospective clinical trial demonstrating the safety of a reduced total dose, yet still delivered with conventional 1.8-2 Gy fractions. In several areas of oncology, especially for tumors of epithelial origin where radiotherapy plays a curative role, the concurrent application of systemic compounds aiming for radiosensitization has been incorporated into routine clinical practice. This approach has also been investigated in sarcomas and is summarized in this manuscript. Observing relatively low α/β ratios after preclinical cellular investigations, investigators have explored hypofractionation with daily doses ranging from 2.85-8.0 Gy per day in prospective clinical studies, and the data are presented. Finally, we summarize work with mouse models and genomic investigations to predict observed responses to radiotherapy in sarcoma patients. Taken together, these data indicate that sarcomas are not resistant to radiation therapy.

Section snippetsRoutine Clinical Practice, the Paradigm of 1.8-2 Gy Fractions

As a single modality, radiotherapy (RT) can be applied with curative intent in many epithelial malignancies (like inoperable cervical cancer, non-small cell lung cancer, and head-and-neck cancers, to name a few). Similarly, in the setting of hematologic malignancies, RT can be applied with curative intent given the high response rates of malignant lymphomas to RT. For the management of soft tissue sarcomas (STS), RT is usually prescribed in close conjunction with surgery, either pre- or

Radiotherapy Improves Local Control When Added to Surgery: Implications for Radiosensitivity of STS

It is a common perception that carcinomas as a group are radiosensitive compared to sarcomas. However, a comparison of randomized trials of surgery with or without radiotherapy for carcinomas and sarcomas demonstrates that these data do not support this perception. Over the past decades, results from clinical trials in breast cancer patients have shown that radiotherapy in addition to breast conserving surgery can replace the need for mastectomy. Nomograms like the “IBTR!”4 can estimate the

Radiation Sensitivity of Myxoid Liposarcomas

While the average radiosensitivity of STS may be similar to epithelial cancers, some subtypes of STS can have exquisite radiosensitivity. For example, in several clinical patient cohorts,10, 11, 12, 13 the subtype of myxoid liposarcomas (MLS) was shown to be highly radiosensitive as a marked volume shrinkage14 as well as an early histological response15 could be readily observed during RT.

These clinical observations led to the hypothesis that a conventionally fractionated RT dose of 50 Gy in 5

Past and Current Experience With Radiation Sensitizers

In the past, several studies have been published on systemic therapies given concurrently with RT, and such trials are currently recruiting participants. Several classes of drugs have been tested for radiosensitization of STS.17 Table 1 provides examples of investigations of concurrently applied systemic agents in the preoperative phase (sequential designs and interdigitation of drugs and RT are left out of consideration).

Several arguments for pursuing this approach include:

Cellular Radiobiology of Sarcomas

The paradigm of 1.8-2.0 Gy fraction sizes in daily clinical practice has been alluded to above. Given the wide variety of histological subtypes, all being an STS,20 it may easily be questioned whether this “one size fits all” approach is justified. Moreover, prescribing RT for STS in conventional fraction sizes is based on the assumption that the α/β ratio is high, for example, 10 Gy or above. However, until recently there was only very limited radiobiological data available to substantiate

Translational Radiobiology

The challenge in determining response to radiation therapy lies in the numerous histological subtypes, intratumoral and interpatient heterogeneity within and between these subtypes, and the rarity of each subtype. Beyond cell lines evaluating SF which reports limited outcome data, there is an inherent need to evaluate tumor heterogeneity, intrinsic radiosensitivity, and immunogenicity to refine the understanding of the biological effect of radiation on the variety of soft tissue sarcomas. Soft

Paving the Way to Hypofractionation for Sarcomas

Hypofractionation has already been widely adopted in daily clinical practice to treat prostate and breast cancer patients. Hypofractionation offers several advantages. For patients, the shorter overall treatment time might be associated with a lower treatment-related burden. Approximately 40% of all sarcoma patients are 70 years of age and above. A meaningful reduction in treatment burden will not only benefit elderly patients themselves but will also have an impact on society, including

Definitive RT for STS (Without Surgery)

Definitive RT is well described in the literature in several indication areas, for instance as local management in localized Ewing sarcoma, in desmoid type fibromatosis, and even in angiosarcomas of the scalp. Far less clear is the role of definitive RT in large, deep-seated, and/or high grade STS where the patient is inoperable based on size and site or where the patient is medically inoperable or both. In this setting, Allignet et al.39 have recently performed a meta-analysis. Summarizing 29

Conclusions and Future Perspective

When radiotherapy is to be applied to sarcoma patients in routine daily practice, these regimens should be delivered in 1.8-2.0 Gy once-daily fractions. This prescription is based on decades of clinical experience and is thereby described in several clinical practice guidelines around the globe. However, until recently, such regimens are not so much based upon thorough scientific investigations, in part due to the rarity and heterogeneity of the disease. Nevertheless, deviations from these

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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