Harmonizing adult and pediatric approaches to the treatment of soft-tissue sarcoma

Soft-tissue sarcomas (STSs) constitute a miscellaneous set of mesenchymal extraskeletal malignant tumors that affect pediatric and adult age groups (accounting for approximately 8% of all pediatric cancers but less than 1% of all adult malignancies).

Soft-tissue sarcomas vary in terms of their biology, their natural history and how they respond to treatment, and their epidemiological features differ considerably between adults and children, although all the histotypes can be seen at any age. Rhabdomyosarcoma accounts for more than half of the cases seen in the pediatric population, but can also occur in adults (and more than 1000 such adults are listed in the North American Surveillance Epidemiology and End Results [SEER] database) [1]. Liposarcoma and leiomyosarcoma are typically adult diseases, but they can also be found in children and adolescents, just like all the other histotypes forming the group of so-called ‘adult-type non-rhabdomyosarcoma STSs’. Synovial sarcoma has a peak incidence in the third decade of life, but this particular subtype is relatively common in all age groups [2].

What remains to be established is whether the clinical behavior of a given STS is the same in patients of different ages. This is by no means a pointless question because, until recently (and sometimes even now), entirely different therapeutic strategies have been adopted for pediatric and adult oncology protocols to deal with STS (e.g., regarding the use of systemic therapy). Furthermore, different overall outcomes have been reported in pediatric and adult groups. Nobody knows whether the less satisfactory global results documented in many adult series are due to differences in the tumors’ clinical prognostic features and biology or, to some degree at least, the different treatment strategies used. A couple of interesting studies recently focused on comparing adult and pediatric patients with synovial sarcoma and rhabdomyosarcoma, and they came to the conclusion that factors other than an unfavorable clinical presentation might be involved in the generally worse outcome for adult patients [1,2]. No final data are available as yet, but it has been suggested that the different intensity of the treatment delivered might have a part to play [3,4]. This may have to do with adults being less able to tolerate intensive treatments than children, or with physicians dealing with adult or pediatric disease having a different attitude to the use of intensive treatments and, for example, the suitability of chemotherapy.

A major problem is that STSs are rare tumors so, as in the case of other rare diseases, the clinical and biological details available on them are scanty and it is often difficult to conduct clinical trials sufficient to arrive at evidence-based, or even shared, treatment guidelines. It is nonetheless hard to believe that a given STS histotype in a child or adolescent is fundamentally different from the same tumor in an adult, so it would seem reasonable for patients with the same disease to be treated with the same therapeutic strategies, regardless of age.

However, this is easier said than done and the two worlds of pediatric oncology and adult medical oncology sometimes appear to be streets apart (or so it seems in Italy, at least), even when they are dealing with the same diseases. To give an example, pediatric and adult oncologists often adopt different classification, staging and grading systems (e.g., depending on the surgical margins, the same case would be called Intergroup Rhabdomyosarcoma Study group I, II or III by the former, but R0, R1 or R2 by the latter). They also have different methods of data collection, for instance, and this consequently makes it difficult to share what they know. In some cases, there even seems to be a sort of reluctance to cooperate: oncologists from the two groups appear diffident and rather inclined to defend their own background and strategies, possibly because they fear their role will become less important.

Of course, the people who pay the heaviest price (in terms of the quality of their professional care) for these shortcomings in communication between pediatric and adult medical oncologists are the adolescent and young adult patients; the age group in a sort of ‘no-man’s land’, midway between the two different worlds. Several studies and publications have emphasized that these patients have been clearly under-represented in clinical trials, and that this situation has coincided with this particular age group’s survival rates failing to improve over the last few years [5].

More generally, it is evident that getting adult and pediatric oncologists to cooperate poses a challenge, entailing numerous potential cultural and logistic problems for these two groups, which come from different backgrounds and have different priorities and goals. The target of healthcare delivery differs considerably in pediatric and medical oncology. The pediatric model is family-focused, and based on multidisciplinary teams with a high staff/patient ratio, while the adult model is more disease-focused, with programs for dealing with specific types of tumor. Pediatric oncologists have been outstandingly successful in promoting national and international, multicenter collaborative networks (in spite of the small numbers of cases involved), and in focusing on Phase III (randomized or risk-based) trials, whereas adult oncologists put a great deal of effort into Phase I–II trials and research on new treatments, while their randomized Phase III trials usually deal only with the most common cancers.

Intergroup trials with no age limits (e.g., the European and American Osteosarcoma Study Group [EURAMOS] protocol for osteosarcoma, or the Italian Sarcoma Group protocols for bone sarcomas) have demonstrated, however, that successful cooperation is possible.

If we take the case of STS, until recently, a 15-year-old with synovial sarcoma was treated very differently from a 22-year-old with the same disease, even if they were treated at the same experienced institution (the former would receive chemotherapy whatever the stage of his/her disease, the latter probably would not – because synovial sarcoma was considered scarcely responsive to chemotherapy by adult oncologists and chemotherapy was therefore only administered in a few, selected cases) [2]. This is probably still happening in some European countries. However, the most important issue is not just a matter of standardizing the treatment of adolescents and young adults with STS, it is the challenge to see pediatric and adult oncologists pooling their resources. Both would have much to gain from cooperating with one another, and sharing their experiences and expertise would have synergistic effects. For example, the pediatric oncologists’ experience of developing multidisciplinary cooperative protocols and their established national and international networks could prove very helpful for adult oncologists, while the experience adult oncologists have gained of novel therapies may help pediatric oncologists to gain access to new drugs and participate in Phase I–II trials.

Cooperative studies across age groups may be the way to pool enough cases to find answers to important questions. As an example, it is worth mentioning the European pediatric Soft Tissue Sarcoma Study Group’s protocol, developed in 2005 specifically for pediatric non-rhabdomyosarcoma STS (which had previously been treated according to protocols for rhabdomyosarcoma): this protocol drew more from adult experiences than from the pediatric literature in an effort to find common ground for future cooperation with adult groups and thereby genuinely harmonize the pediatric and adult treatment approaches. Although it covered most of Europe, this protocol was still unable to reach the numbers required to plan randomized therapeutic arms [6].

In the near future, new therapies suitable for targeting specific STS histotypes – other than the ifosfamide–doxorubicin combination – may well become available. We already have taxanes for angiosarcoma, gemcitabine (possibly associated with docetaxel) for leiomyosarcoma, trabectedine for myxoid/round cell liposarcoma and new molecular-targeted therapies, such as imatinib, for dermatofibrosarcoma protuberans [7]. In times of histology-driven therapies, STSs might no longer be treated and studied together as a group, but focusing separately on single histotypes. Pediatric oncologists must be aware that this will only be feasible if they succeed in establishing close forms of cooperation between international groups and active exchanges with adult medical oncology groups.

Finally, cooperation between adult and pediatric experts on STS may facilitate the procurement of tumor samples and, thus, further our understanding of the biology of these malignancies, enabling us to identify molecular targets for novel therapeutic approaches and to ascertain whether differences really exist between these diseases in different age groups.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.