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Neoadjuvant Chemotherapy in High-Risk Soft-Tissue Sarcoma: A New Standard?



Standard chemotherapy as neoadjuvant therapy is effective in these patients at high risk of relapse and is feasible in 90% of patients. These results may change the treatment of soft-tissue sarcoma of the extremities and trunk wall.
— Alessandro Gronchi, MD

For the first time, a randomized trial has provided good evidence to support the use of neoadjuvant chemotherapy for treatment of high-risk soft-tissue sarcoma of the extremities or trunk wall.1 But the findings of the study were surprising, because neoadjuvant chemotherapy with one-size-fits-all anthracycline/ifosfamide was superior to chemotherapy individually tailored to each of the five most common types of soft-tissue sarcoma of the extremities or trunk wall.

“This is a negative study, but it provides strong support for the first time ever for neoadjuvant chemotherapy in the treatment of soft-tissue sarcoma and for the efficacy of standard chemotherapy. Short-course full-dose anthracycline/ifosfamide increased recurrence-free survival and overall survival by more than 20% at 46 months,” stated lead author Alessandro Gronchi, MD, Chair of Sarcoma Surgery at the National Cancer Institute, Milan, Italy.

“Standard chemotherapy as neoadjuvant therapy is effective in these patients at high risk of relapse and is feasible in 90% of patients,” he told listeners at the Presidential Symposium held during the 2016 European Congress for Medical Oncology (ESMO). “These results may change the treatment of soft-tissue sarcoma of the extremities and trunk wall,” Dr. Gronchi stated.

Thomas Brodowicz, MD

Thomas Brodowicz, MD

Not all experts were convinced by these data. “What we can conclude out of this is that neoadjuvant anthracycline plus ifosfamide is better than the histology-driven regimens, but the question still is, is it better in comparison to no treatment?” said Thomas Brodowicz, MD, Program Director of the Bone and Soft Tissue-Sarcoma Unit at the Medical University of Vienna, Austria. “Furthermore, are three cycles of histology-driven treatment enough, and is the neoadjuvant approach the right approach for all high-risk patients?” he asked.

Soft-tissue sarcomas are rare and heterogeneous, comprising different diseases, each with a distinct histologic profile. Adjuvant therapy for soft-tissue sarcoma is controversial, with contradictory results in previous studies, including a meta-analysis.

Study Details

In a previous study with 10-year follow-up,2 Dr. Gronchi and co-investigators found that three courses of intensive anthracycline/ifosfamide were as effective as five courses given in the perioperative setting, so they designed the present study to compare three courses of this regimen vs histology-tailored chemotherapy in five common histologies of soft-tissue sarcoma. The five histology-tailored regimens were based on previously published data on metastatic disease to identify drugs that had the best activity in these five distinct subtypes:

  • High-grade myxoid liposarcoma: trabectedin (n = 65)
  • Undifferentiated pleomorphic sarcoma: gemcitabine plus docetaxel (n = 97)
  • Synovial sarcoma: high-dose prolonged-infusion ifosfamide (n = 70)
  • Malignant peripheral nerve sheath tumors: etoposide plus ifosfamide (n = 27)
  • Leiomyosarcoma: gemcitabine plus dacarbazine (n = 28).

From May 2011 to May 2016, the study recruited 435 patients with localized, high-risk (50%–70% risk of relapse at 5 years), chemotherapy-naive soft-tissue sarcoma of the extremities or trunk wall, with a grade 3 malignancy of 5 cm or greater. Of them, 287 patients were randomized to three courses of full-dose anthracycline/ifosfamide vs three courses of a histology-driven regimen. The primary endpoint was relapse-free survival, and secondary endpoints were overall survival and response rate. Patients were randomized 1:1 to standard chemotherapy vs histology-tailored chemotherapy. Median age was 50 years, and median tumor size was 10 cm.

The study was closed to recruitment at the third futility analysis, when it became evident the standard regimen was achieving better outcomes.

Key Findings

At a median follow-up of 12.3 months, patients who received neoadjuvant anthracycline/ifosfamide showed a significantly higher probability of relapse-free survival at 46 months compared with those who received histology-driven individualized chemotherapy (62% vs 38%, respectively, P = .004) as well as a probability of improved overall survival (89% vs 64%, respectively, P = .033).

Neoadjuvant Therapy for Soft-Tissue Sarcoma

  • Surgery is the cornerstone of treatment of soft-tissue sarcoma, but a subgroup of patients are at high risk of relapse.
  • The role of adjuvant chemotherapy is a hotly debated issue, and studies have shown conflicting outcomes in the overall population.
  • The first evidence from a randomized trial in support of adjuvant therapy for soft-tissue sarcoma suggests that standard anthracycline/ifosfamide is superior to histology-driven tailored chemotherapy, if given to patients with soft-tissue sarcoma subtypes at high risk of relapse, with the exception of myxoid liposarcoma.

Only one of the subtypes, myxoid liposarcoma, had similar rates of relapse-free and overall survival for trabectedin (a histology-driven regimen) compared with standard chemotherapy, and that subgroup will be expanded to assess any differences in outcomes, Dr. Gronchi said. “Trabectedin is far less toxic than chemotherapy,” he noted. ■

Disclosure: Dr. Gronchi reported no potential conflicts of interest. Dr. Brodowicz has received lecture fees from Roche, Amgen, Bayer, Novartis, PharmaMar, and Eisai and is on the advisory boards of Amgen, Bayer, Novartis, and Eisai.

References

1. Gronchi A, Ferrari S, Quagliuolo V, et al: Full-dose neoadjuvant anthracycline + ifosfamide chemotherapy is associated with a relapse free survival and overall survival benefit in localized high-risk adult soft tissue sarcomas of the extremities and trunk wall: Interim analysis of a prospective trial. 2016 ESMO Congress. Abstract LBA6_PR. Presented October 10, 2016.

2. Gronchi A, Stacchiotti S, Verderio P, et al: Short, full-dose adjuvant chemotherapy in high-risk soft tissue sarcomas: Long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. Ann Oncol. October 11, 2016 (early release online).


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