Individualizing the use/non‐use of radiation therapy (RT) in soft tissue sarcoma (STS): When abstention is better than care

In soft tissue sarcoma (STS)management, limb-sparing surgery relies on the complementary administration of radiation therapy (RT), to minimize the risk of local recurrence, as demonstrated a couple of decades ago by two pivotal trials, one employing brachytherapy (BRT) [1] and one post-operative external beam RT (EBRT) [2]. They both reported a risk reduction of local recurrence from greater than 30%with surgery alone to less than 10%with surgery and radiation, but neither found any impact on distant failure or overall survival. Thanks to these 2 trials and somewhat consistently with the approach to other diseases (i.e., mastectomy vs. breast preserving surgery and radiation therapy), since then most STS of the extremities and torso were routinely treated by the combination. Nevertheless, in spite of the convincing evidence favoring such an approach, we did realize in the recent years how the majority of the treated patients got only its side effects, as 70% of them wouldn’t have recurred and 10% did recur anyway. Most importantly, none derived a survival benefit, while many experienced a profound impact by such an approach in quality of life (i.e., chronic pain, stiffness of the limb, bone fractures, etc.). The administration of pre-operative RT was later shown to be associated to less long-term side effects [3]. Although no differences in the overall local control rate were seen between the administration of preor post-operative RT, an uncontrolled retrospective evidence favors the use of preoperative RT (alone or in combination with chemotherapy) whenever surgery is expected to be marginal and/or the tumor has a high risk of relapse [4,5]. Indeed, nowadays several groups have shifted from the initial paradigm, offering the same local therapy (surgeryþ post-operative RT) to all comers, to a tailored approach, selecting patients for preor post-operative RT, based on the expected local recurrence risk, location and histology of the tumor, age of the patient, etc. Moreover, several patients are also now treated by surgery alone and this has been accommodated in the European and American guidelines, although no prospective controlled study have been performed or planned to back this up [6,7]. One of the most important factors to individualize STS treatment is indeed histology, as STS is a family made up by 50 plus different subtypes, with different biology, natural history, and sensitivity to treatments. Myxoid liposarcomas (MLS), either the pure (low grade) and the cellular (high grade) variants, are known to be the most RT sensitive STS subtypes, with greater than 50% major response rate to preoperative RT documented in uncontrolled series [8]. Pure MLS is also known to have a very limited tendency to local recurrence, as clearly shown in this paper by Baxter and colleagues [9] and by others [10]. So its sensitivity to RT should be factored into decision making but in light of its favorable natural history. This study shows how several MLS patients may be treated by surgery alone, even when their tumor is large and deeply located. An easy conclusion would be that patients with easily resectable MLS can be safely treated by surgery alone, while RT may be reserved to those with borderline resectable ones or when function preservation is a goal (Fig. 1). Then the question to address is which quality of evidence we need, to make these recommendations in general and specifically in MLS. We are dealing with a subgroup (MLS) within a relatively rare group of tumors (adult STS). Fifty plus different histologies do exist in adult STS, as mentioned above. The task of studying these tumors by means of prospective randomized trials is challenging, especially when subgroups need to be considered. The incidence of MLS is <0.5/ 100,000/year. We may discuss how ‘standard treatment’ can be defined in rare tumors, particularly ‘very rare’ ones. Clearly, we must take most profit from ‘any’ evidence we have in our hands, by fairly balancing it by consensus within the medical community. Then, we must go the patient’s bedside. We will have been left with a degree of uncertainty, and our task is to share it with our patients. The problem of rare cancers is infact one of a higher uncertainty. By nomeans does this imply that decision-making in rare cancers should be conceptually different from that in more frequent conditions. As usual, it is crucial for the clinician to address decision-making rationally. National, international, even global collaborations should be pursued to make more studies possible. They are vital to assess the value of new treatment strategies, with special regard to multidisciplinary approaches. Prospectively maintained data bases and biobanks for medical research are one of the cornerstones to make progress in rare cancers. As amatter of facts, all cases may be useful to advance science. Thus, prospective clinical data bases, registries and connection of electronic patient records on a network basis should be encouraged. Retrospective and observational clinical studies on selected patient subgroups are as important as prospective controlled studies, because