Neoadjuvant Therapy for Soft-Tissue Sarcomas-One Size Does Not Fit All

January 15, 2016
Arun S. Singh, MD
Arun S. Singh, MD

,
Fritz C. Eilber, MD
Fritz C. Eilber, MD

Volume 30, Issue 1

Improvements in neoadjuvant therapy for soft-tissue sarcomas will require the development of more efficacious systemic therapies and, if possible, the performance of histology-specific, prospective, randomized clinical trials to advance the field.

Surgery continues to be the cornerstone of the treatment plan for patients with soft-tissue sarcomas. The exact contribution of chemotherapy, radiation therapy, and combined chemoradiation therapy in the management of soft-tissue sarcomas is not as well defined due to a lack of level 1 evidence of the benefit of these modalities, particularly chemotherapy. The genesis of this impediment stems from the rarity and pathologic heterogeneity of soft-tissue sarcomas, which has made it difficult to sufficiently power clinical trials. As such, most of the data for neoadjuvant chemoradiation therapy stem from studies that group together multiple different histologies that can exhibit very different clinical behaviors and responses to systemic therapy. Attempts at assessing the histology-specific impact of systemic therapy have been retrospective in nature, employing historical controls or contemporary cohorts.

In this issue of ONCOLOGY, Fairweather et al review several important studies and the rationale for the use of neoadjuvant chemotherapy, radiation therapy, and chemoradiation therapy in the treatment of soft-tissue sarcomas.[1] Neoadjuvant therapy is thought to be important because it can downstage tumors; offers earlier treatment of micrometastatic disease; and can serve as an in vivo test of chemotherapy and/or radiation therapy, allowing early treatment modifications such as stopping or changing chemotherapy and decreasing the dose or field of radiation. But these benefits must be weighed with the risks of delaying surgery and the wound-healing complications that can occur from neoadjuvant therapy. The authors have highlighted several studies that, while not level 1 clinical evidence, demonstrate a benefit from neoadjuvant therapy for soft-tissue sarcomas. In these instances where there are ample observational data, we feel that staunchly supporting the dogma of the randomized controlled trial may not be beneficial to patients. These observational studies are still important in forming treatment decisions, since the rarity of some types of sarcomas will preclude high-powered studies from ever being done.[2]

The first randomized trial to show a survival benefit of adjuvant chemotherapy for osteosarcoma was completed in an era where a standard of care was lacking, despite studies from large-volume sarcoma institutions such as Memorial Sloan Kettering Cancer Center (MSKCC), MD Anderson Cancer Center, and the Mayo Clinic, which supported the use of chemotherapy as an adjunct to surgery for osteosarcoma.[3] Further, it was the addition of neoadjuvant and adjuvant chemotherapy that radically improved the outcome of patients with both bony and soft-tissue Ewing sarcoma and increased survival rates from approximately 15% with definitive surgery and radiation (or amputation) to nearly 70% today.[4] These cases illustrated that the availability of effective systemic therapy can change the course of chemoresponsive sarcomas with high metastatic potential.

Looking closer, we see that outcomes of individual chemoresponsive histologies can be improved with systemic therapy. Eilber et al demonstrated that patients with synovial sarcoma who were treated with an ifosfamide-based regimen had improved distal relapse–free survival-from 46% to 74% at 4 years compared with patients who were treated with localized therapy alone.[5] At the University of California, Los Angeles and MSKCC, 245 patients with high-risk liposarcoma of the extremities were treated with neoadjuvant or adjuvant chemotherapy and, on multivariate analysis, treatment with ifosfamide was independently associated with improved disease-specific survival compared with no chemotherapy (hazard ratio, 0.3; P = .01).[6] On the other hand, regardless of histology, attempts have been made to select patients who will achieve the greatest benefit from neoadjuvant/adjuvant therapy by looking at the pathologic response to neoadjuvant therapy. However, the results from these studies have been variable,[7-9] with no clear consensus on how to grade pathologic response in soft-tissue sarcomas. Some researchers have started to investigate the use of tumor standard uptake value changes with fluorodeoxyglucose positron emission tomography imaging as a possible prognostic biomarker for response to therapy/improved outcomes.[10,11]

As with other malignancies, neoadjuvant treatment has impacted sarcoma therapy by fostering a movement away from morbid amputations and toward functional limb-sparing approaches.[12] Neoadjuvant therapy has also changed the standard of care in osteosarcoma and Ewing sarcoma, demonstrating a role for its use in sarcoma subtypes for which sufficiently powered randomized clinical trials may never be done.

Fairweather et al highlight the important topic of neoadjuvant therapy for the management of soft-tissue sarcoma and the lack of level 1 clinical data in this area. They also highlight several informative observational studies that clinicians can use to counsel patients with large, high-grade sarcomas who have a ≥ 50% likelihood of developing systemic disease.[13] As such, it is critical for these patients to be evaluated and treated by an experienced multidisciplinary sarcoma program. Improvements in neoadjuvant therapy for soft-tissue sarcomas will require the development of more efficacious systemic therapies and, if possible, the performance of histology-specific, prospective, randomized clinical trials to advance the field.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Fairweather M, Keung E, Raut CP. Neoadjuvant therapy for soft-tissue sarcomas. Oncology (Williston Park). 2016;30:99-106.

2. Concato J. Is it time for medicine-based evidence? JAMA. 2012;307:1641-3.

3. Eilber F, Giuliano A, Eckardt J, et al. Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol. 1987;5:21-6.

4. Balamuth NJ, Womer RB. Ewing’s sarcoma. Lancet Oncol. 2010;11:184-92.

5. Eilber FC, Brennan MF, Eilber FR, et al. Chemotherapy is associated with improved survival in adult patients with primary extremity synovial sarcoma. Ann Surg. 2007;246:105-13.

6. Eilber FC, Eilber FR, Eckardt J, et al. The impact of chemotherapy on the survival of patients with high-grade primary extremity liposarcoma. Ann Surg. 2004;240:686-95; discussion 95-7.

7. Eilber FC, Rosen G, Eckardt J, et al. Treatment-induced pathologic necrosis: a predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas. J Clin Oncol. 2001;19:3203-9.

8. Mullen JT, Hornicek FJ, Harmon DC, et al. Prognostic significance of treatment-induced pathologic necrosis in extremity and truncal soft tissue sarcoma after neoadjuvant chemoradiotherapy. Cancer. 2014;120:3676-82.

9. Ryan CW, Montag AG, Hosenpud JR, et al. Histologic response of dose-intense chemotherapy with preoperative hypofractionated radiotherapy for patients with high-risk soft tissue sarcomas. Cancer. 2008;112:2432-9.

10. Herrmann K, Benz MR, Czernin J, et al. 18F-FDG-PET/CT imaging as an early survival predictor in patients with primary high-grade soft tissue sarcomas undergoing neoadjuvant therapy. Clin Cancer Res. 2012;18:2024-31.

11. Schuetze SM, Rubin BP, Vernon C, et al. Use of positron emission tomography in localized extremity soft tissue sarcoma treated with neoadjuvant chemotherapy. Cancer. 2005;103:339-48.

12. Gronchi A, Colombo C, Raut CP. Surgical management of localized soft tissue tumors. Cancer. 2014;120:2638-48.

13. Eilber FC, Brennan MF, Eilber FR, et al. Validation of the postoperative nomogram for 12-year sarcoma-specific mortality. Cancer. 2004;101:2270-5.