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Liddy Shriver Sarcoma Initiative

Chemotherapy for Non-Rhabdomyosarcoma Soft Tissue Sarcomas of Childhood: To Treat or Not to Treat?

An ESUN Article

Crystal Mackall, MD
Pediatric Oncology Branch
National Cancer Institute

The approach to the treatment of sarcomas in children vs. adults varies substantially. This is primarily due to the fact that most sarcomas occurring in childhood arise from primitive tissues and are highly sensitive to chemotherapy (e.g. Ewing’s sarcoma family of tumor, rhabdomyosarcoma and osteosarcoma). In contrast, adult sarcomas typically arise from more mature tissues (e.g. synovial sarcoma, leiomyosarcoma, and liposarcoma) and they are generally less sensitive to chemotherapy. The clear benefits that chemotherapy provide for patients with the pediatric-type sarcomas has led to universal acceptance that all patients with these diseases receive chemotherapy as part of their treatment regimen. However, the role that chemotherapy plays in treating adults with sarcomas continues to be an area of substantial controversy. 

There are many confounding reasons that contribute to the difficulty in discerning whether chemotherapy improves outcome for patients with adult-type sarcomas. First, since the ability for chemotherapy agents to kill sarcomas varies greatly among different types of adult-type sarcomas, and since studies typically include all comers without specifically selecting for sarcoma subtype, beneficial results seen in one study might not be seen in other studies. For example, synovial sarcomas are typically sensitive to chemotherapy whereas alveolar soft part sarcomas typically show little if any sensitivity (Ref. 1). Results between studies therefore may vary greatly depending upon the individual subtypes of sarcomas included in the study. Second, sound local therapies which span the gamut from imaging of the tumor, surgical technique, and radiation therapy (in select cases) are also essential components of a good treatment outcome. Each of these modalities has evolved over the last two decades, resulting in a moving target when one compared results of local therapy alone with the combination of local therapy plus chemotherapy. For this reason, studies that use historical controls instead of randomizing patients to different treatment regimens might mistakenly conclude that chemotherapy improved results when in fact other advances in the treatment regimen might also have played a role. A third major issue is that fact that chemotherapy regimens are not all equal so that studies which show no benefit from adding one particular regimen do not necessarily rule out that a different regimen or a regimen with the same drugs given at higher doses might show benefit. Thus, the role that chemotherapy plays in the management of adults with soft tissue sarcomas remains a matter of debate. As evidence for this, two recent studies using state of the art chemotherapy regimens came to differing conclusions about the role for adding chemotherapy for soft tissue sarcomas in adults (Refs. 2-4).

With this as a background, three recent studies have focused on this issue as it pertains to adult-like soft-tissue sarcomas when they occur in children. As noted above, most pediatric sarcomas can be grouped into “childhood-type” sarcomas, which are sensitive to chemotherapy. However, children also sometimes develop adult-type sarcomas, which in these cases appear to be derived from the same, mature tissues from which they are derived in adults. Not surprising, the difficulties in ascertaining a role for chemotherapy is these tumors in adults are only amplified to the rarity of the tumors overall in children. Nonetheless, three of these recent studies suggest that there may be some benefit from administering chemotherapy to select groups of children with “adult-type” sarcomas (e.g. non-rhabdomyosarcoma soft tissue sarcomas or NR-STS). The first study was led by Italian researchers, who performed a retrospective review of clinical outcomes in children with NR-STS treated by the Italian Cooperative Group for Soft Tissue Sarcoma (Ref. 5). Outcomes were reviewed in 182 patients, and the researchers were careful to exclude the pediatric-type sarcomas, as well as excluding tumors which were not clearly malignant tumors or which are unique to early childhood such as infantile fibrosarcoma. By doing this, the investigators had carved out a group of children who had histologic diagnoses that were essentially indistinguishable from a usual cohort of adults with soft tissue sarcomas. The childhood cohort did show a predominance of synovial cell sarcomas, with 32% of the entire cohort comprising this subtype. This is important, as mentioned above, since synovial sarcomas tend to respond better to chemotherapy than other adult-sarcoma subtypes. Most of these patients did not have metastatic disease, and with regard to overall outcome, the reflected previous studies which show that overall survival is most dependent upon the ability to accomplish a complete surgical resection. Overall survival was 89% in patients who underwent complete surgical resection, 79% in patients who underwent marginal surgical resection, 52% in patients who presented with disease that was unresectable but non-metastatic and 17% for patients who presented with metastatic disease. Importantly, the reliability of the survival outcomes for the last two groups is probably not high since they comprised very low numbers of patients (only 13 of 182 patients were unresectable and 6 of 182 patients had metastatic disease in this cohort). Of the overall cohort, 114 of 182 patients received chemotherapy and in general, it was administered to three groups of patients: those with high grade tumors which were > 5 cm, those with unresectable disease at the time of presentation, and those with metastatic disease. While not conclusive, the results suggested that chemotherapy provided some benefit both for patients with large high grade tumors as described above, and for patients with unresectable disease. For instance, for the patients who presented with disease that was initially unresectable, chemotherapy led to a tumor response in 58% and ultimately rendered 70% of those patients able to subsequently undergo complete surgical resection.

Synovial sarcoma was the most common histology contained in this study, comprising 32% of the entire cohort. As noted above, synovial sarcoma is generally sensitive to chemotherapy and therefore the large proportion of patients with this tumor in this study might account for the favorable results in patients who received chemotherapy. To address this, the same group combined their results with another cohort (German Soft-tissue Sarcoma Cooperative Group) in a second study and purposely evaluated effects of chemotherapy in children with NR-STS, excluding synovial sarcoma (Ref. 6). They restricted this retrospective analysis to the group of patients noted above who appeared most likely to benefit from chemotherapy, namely those with large aggressive primary tumors (e.g. tumor diameter >5 cm and Grade III). They identified 36 patients who met these criteria, of which 21 received chemotherapy and 15 did not. Comparing results in patients who received chemotherapy vs. those who did not: event free survival was 37% vs. 0%, local recurrence free survival was 57% vs. 33%, metastasis free survival was 49% vs. 0% and overall survival was 41% vs. 23.8%. Although the results showed marginal statistical significance at best due to low numbers of patients, they suggested that chemotherapy may benefit some children with NR-STS, even when synovial sarcoma is excluded.

In both of the studies noted above, the emphasis was on adjuvant chemotherapy, which is defined as therapy given after surgical resection, when there is no evidence for persistent disease. The logic behind such therapy is that chemotherapy may be able to eradicate microscopic residual disease at the site of the primary tumor or in metastatic sites and therefore improve overall survival. A third retrospective study, performed by investigators at the National Cancer Institute, reviewed experience in treating children with multiagent chemotherapy for NR-STS (Ref. 7). The cohort was comprised entirely of patients with metastatic disease (15 of 25 patients) and patients with unresectable, non-metastatic disease (10 of 25 patients). Thus, none of these patients received chemotherapy in the adjuvant setting, but rather received chemotherapy at a time when disease could be evaluated for response using imaging. Overall 80% of patients showed evidence for tumor shrinkage (complete and/or partial response) following chemotherapy with a 50% overall survival and 34% event free survival five years. While a cohort of patients who did not receive chemotherapy was not included in this study, the high response rate and the substantial survival rate at 5 years for this very high risk group of patients strongly suggested that chemotherapy provided some benefit.

In summary, while the central role that chemotherapy plays in treating patients with classic pediatric sarcomas is clear, the role for chemotherapy in adult-type soft tissue sarcomas of childhood is continuing to be elucidated. There is a general consensus that tumors < 5cm and/or those which are low grade (Grade I or II) are best treated with local measures alone. However, three recent studies provide data that suggests that modern chemotherapy regimens, incorporating ifosfamide and adriamycin, can provide substantial benefit to children with NR-STS who have locally aggressive tumors (> 5 cm and Grade III) or to children who have unresectable or metastatic disease. Ultimately, firm conclusions cannot be drawn without randomized controlled studies which stratify individual histologic subtypes, however patients suffering from these diseases and their treating teams must make decisions based upon information which is available now. These recent studies suggest that children with high risk, non-rhabdomyosarcoma soft tissue sarcomas may benefit from a multimodality treatment regimen that adds chemotherapy to sound local therapies.

References

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