Sarcoma

Background

Sarcomas are rare mesenchymal tumours representing <1% of all adults cancers. Although rare, sarcomas cause a substantial loss of years of life, because of their predilection to affect adolescents, and young adults (1).

Surgical excision is used in almost all cases of localized sarcoma (2). In selected cases, radical radiotherapy (RT) can be effectively used instead (3). For the majority of patients. However, conservative surgery is combined with pre- or post-operative radiotherapy (4). Randomized controlled studies have shown that combined treatment leads to higher rates of local control than surgery alone (5). Most centers report local control rates of approximately 90% with the combination of margin-negative limb-sparing surgery and RT for high-grade extremity soft tissue sarcomas (STS) (6). This good local control, are associated with known complications including wound healing, fibrosis, telangiectasia, joint stiffness, oedema and stress fractures of bones (7).

The major therapeutic goals in the treatment of sarcomas, therefore, are not only to obtain the highest survival and local tumor control probabilities but also, the lowest achievable morbidity. For extremity lesions, another important goal is optimal limb function.

In an attempt to reduce late effects, the VORTEX study is testing the possibility of reducing the radiotherapy margin to clinical target volume (CTV) from 4 to 2 cm (https://clinicaltrials.gov/ct2/show/NCT00423618?term=radiotherapy&cond=Sarcoma&cntry=GB&rank=5). Meanwhile, it is suggested by various studies that the use of IMRT would most probably reduce the incidence and severity of radiation late effects (8). No study has yet gathered enough data to confirm this assumption.

Because of the rarity of the disease and because sarcomas constitute various histopathological subtypes affecting the whole body and not restricted to one anatomical site or organ, it is difficult to report on large cohorts of homogenous patients. Literature data, therefore, are mostly single institution retrospective reports with small number of patients in each study. Moreover, there is a great deal of variation in radiotherapy practice between reports, being the use of pre-operative versus post-operative radiotherapy or applying various total dose, dose/fraction, radiation technique, time interval between radiotherapy and surgery or various margins needed to CTV.

These factors blurs our knowledge and emphasize the need for more prospectively collected data on late effects after sarcoma radiotherapy.

Aims

This is a national project under the umbrella of the Danish Sarcoma Group (DSG) that should include all adult patients with sarcomas of the extremities that will be treated in the two sarcoma centers in Denmark with radically intended dose of external beam radiotherapy with photons and/or protons. The project should last for 3 years and aims at:

• Clarifying the prevalence and severity of late radiation effects in the Danish patients with sarcomas of the extremities.
• Cast a light on the impact of these effects on the quality of life using a patient-reported outcome measure.
• Guide the optimization of radiotherapy in a way that reduces late effects without compromising local control.

Methods

Acute and late radiation effects will be systematically and prospectively registered in the National Sarcoma Database during routine follow-up visits. The National sarcoma database has been recently modified to include prospective registration of acute and late toxicity after radiotherapy. Local relapses will also be recorded.

Toronto Extremity Salvage Score (TESS) is a patient-reported outcome measure that is recently validated by Aarhus sarcoma center in Danish patients (9). The patients will be asked to report outcome using TESS in relation to their regular follow-up visits through internet-based medium (for example Ambu-Flex system). The system should be able to link, patient- and doctor-reported outcome measures.

All radiation dose plans of included patients will be stored centrally in the Danish Radiotherapy Dose-Plan Bank. Late toxicities will be correlated with selected radiation parameters from dose-volume data in an attempt to reveal/create constraints for endpoints such as oedema of the extremity by relating the incidence and severity of the endpoint to a specific dose-volume parameter such as “the volume of the limb cross-section irradiated to a certain dose (30 Gy)”.

Local failures will be also be correlated to radiation dose as well as to tumor characteristics including molecular markers related to radiation resistance such as hypoxia.

Certain late effects such as telangiectasia and fibrosis are difficult to quantify. In an attempt to uniformly quantify these effects, an attempt will be made to link late toxicity data to clinical photos and may be a representative MR imaging. Separate studies on inter and intra-observer variability will be performed for more accurate and objective registration of these toxicities.

Expected results

This project will generate a unique population-based, prospectively collected set of data on late radiation effects in sarcoma patients and their effects on the patients quality of life as reported by the patients. To the best of our knowledge, no similar set of data is present elsewhere in the world. This comprehensive and systematic data registry and its coupling with the dose plans would enable us to set evidence-based constraints for the various relevant endpoints.

Expected impact

Reducing the incidence and severity of radiation-induced toxicities, while maintaining optimal control rate after radiotherapy.