"Very well done and exciting. Congratulations."
Adult soft-tissue sarcomas (STS) are rare. Their incidence is around four per 100,000 annually. They are essentially curable through surgery in around 50% of cases.1 Surgery is the mainstay of treatment in localised disease. Radiation therapy complements surgery in several cases, adding to local control of the disease. Surgery also plays a role in the metastatic setting when metastases are confined to the lungs, which is the case in roughly half of metastatic first presentations. Chemotherapy is used in the advanced setting, mainly with a palliative intent. Its value in the adjuvant setting is still to be proved. Therefore, its effect on survival (as assessed by clinical trials) is at best limited.
The treatment of adult sarcomas stands in sharp contrast to childhood sarcomas. In the 1970s, the introduction of chemotherapy made a big difference in the prognosis of rhabdomyosarcoma, Ewing’s sarcoma and osteosarcoma, raising their cure rate from less than 20% to more than 60%.2 The chemosensitivity of adult STS is too low to have a similar effect on survival. Interestingly, the benefit seen in childhood sarcomas has largely been due to the introduction of chemotherapy itself, mainly based on a few active drugs, since subsequent improvements in chemotherapy have brought limited progress. Cytotoxic chemotherapy has made a prognostic difference in childhood sarcomas because these are chemosensitive, while it has not had any effect on adult STS because these are much less chemosensitive.
Doxorubicin was introduced into the treatment regime for STS in the 1970s, and ifosfamide followed in the 1980s. This led to combination regimens, the antitumour activity of which seemed higher than that of doxorubicin alone or doxorubicin-based combination regimens (e.g. cyclophosphamide, vincristine, doxorubicin and dacarbazine [CYVADIC]).
The benefit of these regimens was clearly shown by well conducted phase II studies;3 however, phase III randomised trials failed to confirm any survival benefits. The response rate for combination therapy was only marginally higher in two trials and equal in another compared with doxorubicin alone.4–6 Many factors may explain these results. The most important is probably the different patient selection criteria of phase II and III studies. The latter need a higher number of patients (thus these are less selected) and involve a higher number of centres. This probably dilutes any advantage of chemotherapy regimens, which would be limited in any case. The main proof of this is the lower response rate of phase III trials compared with phase II studies.
The patient populations enrolled by the two different kinds of study are evidently different. Conceptually, this leaves room for the possibility that there are some patients in advanced stages of the illness who may benefit from intense chemotherapy. Indeed, this is a possibility, although it is difficult to prove. For example, some patients have isolated lung metastases that are amenable to surgery, but also have unfavourable prognostic factors (e.g. a significant number of lesions). They may experience benefits from chemotherapy if an active regimen is administered. This is just a possibility, because there are no clinical trials addressing the issue. Indeed, a recent retrospective analysis does not suggest such a benefit for chemotherapy ‘adjuvant’ to surgery of lung metastases.7 However, there are hints that lung metastases may respond better than lesions to other sites, although this may be just a consequence of the fact that they are more amenable to being measured.