Study IDs Effective Risk-Stratification System for Pediatric Sarcomas

A new risk-stratification system for pediatric and young adult patients with non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS) was able to effectively classify patients for the appropriate therapy. Treatment arms in the study showed that patients classified as low risk may be able to undergo surgery alone, and that certain patients who are intermediate- or high-risk can undergo radiotherapy after surgery in lower doses than previously studied.

The results of the COG ARST0332 study were presented by Sheri L. Spunt, MD, MBA, of Lucile Packard Children’s Hospital Stanford, at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.

“The risk stratification scheme that was used in this study effectively separated patients into distinct prognostic groups,” Spunt said. “Overall outcomes in this study were similar to or better than retrospective studies despite lower dose of radiotherapy.”

NRSTS account for about 4% of childhood cancer. These cancers have been very poorly studied over the last 4 decades, according to Spunt, with only three prospective clinical trials being conducted in North America.

“As a result there is no clear standard of care for these patients,” Spunt said.

This COG study was designed to evaluate patient outcomes when they are stratified by a risk-based strategy. Patients had to be younger than 30 years and have a new diagnosis of a WHO intermediate or malignant soft-tissue tumor.

Most patients underwent gross total tumor resection prior to enrollment except those with non-metastatic, high-grade tumors expected to have at least microscopic residual disease after resection, those whose tumor could not be excised without unacceptable morbidity, and those with high-grade tumors with metastases.

During her presentation, Spunt explained the three risk-based groups established by the study and the four treatment arms examined:

• Low-risk patients were those with tumors that were low-grade non-metastatic, grossly resected tumors or high-grade non-metastatic grossly resected tumors of 5 cm or less in diameter. These patients were observed (Arm A) or received adjuvant radiotherapy at a dose of 55.8 Gy (Arm B).

• Intermediate-risk patients had high-grade non-metastatic grossly resected tumors and had a maximal tumor diameter of 5 cm or more. They underwent treatment with adjuvant chemotherapy with ifosfamide/doxorubicin and radiotherapy at 55.8 Gy (Arm C). The intermediate-risk group also included patients with non-metastatic tumors that were not resected at study entry. This group underwent neoadjuvant chemoradiotherapy with ifosfamide/doxorubicin and 45 Gy preoperative radiation with a 10.8 Gy boost at first resection and a 19.8 Gy boost at second resection (Arm D).

• High-risk patients were those with metastatic disease. All of the patients were allocated to Arm C (adjuvant chemotherapy plus radiotherapy) if they had complete resection or Arm D (neoadjuvant chemoradiotherapy) if they had unresected disease.

Overall about 40% of the patients were in the low-risk groups (212 in surgery alone, 19 in adjuvant radiotherapy) and 60% were in the high-risk groups (120 in adjuvant chemotherapy/radiotherapy and 200 in the neoadjuvant chemoradiotherapy). There were 551 patients in the study. The median age of patients was 13.7 years.

“The outcomes for patients of the low-dose treatment arms were excellent, but outcomes for patients on the intermediate- and high-risk arms, as expected, were less favorable,” Spunt said.

Patients in Arm A had a 4-year event-free survival of 91% and an overall survival of 97%; Arm B had an event-free survival of 73% and overall survival of 100%; Arm C, 64% and 80%; and Arm D, 49% and 63%.

According to Spunt, there was a statistically significant difference in outcomes for event-free survival for each of the four treatment arms. In addition, patients in the low-risk arm had significantly improved overall survival compared with the intermediate- and high-risk treatment groups (P < .001).

The researchers also looked at subgroups of patients within Arm A. Those patients with low-grade, margin-negative tumors had a cumulative incidence of local failure of 2.5% and no distant recurrences. Patients with low-grade tumors and positive margins had a cumulative incidence of local failure of 14.5%, “suggesting that observation in these patients may be warranted,” Spunt said. However, there were not enough patients in that arm to draw definitive conclusions. 

Finally, the last group of patients in the Arm A observation arm were those with high-grade tumors of 5 cm or less with negative margins. This group of patients had a cumulative incidence of local failure of 7.5%.

“Patients with less than 5-cm high-grade tumors can be safely managed with wide resection alone,” Spunt said.

There were no deaths due to toxicity and only 10 patients had unexpected grade 4 adverse events.