Chemotherapy in Soft-Tissue Sarcoma: Where Do We Go From Here?

Cytotoxic chemotherapy has been one of the therapeutic cornerstones in the management of soft-tissue sarcoma for decades. The current armamentarium, however, is limited by the number and efficacy of available agents. Dr. Ravi and colleagues should be congratulated on their thorough review of chemotherapy use in soft-tissue sarcoma, as well as their wonderful summary of the relevant data on patients with advanced disease, and of the controversial data regarding the role of chemotherapy in the adjuvant setting.[1]

The development and approval of new agents in soft-tissue sarcoma has been slow, and new strategies are needed to take advantage of the underlying molecular and biological heterogeneity inherent to this group of rare mesenchymal neoplasms. Recently, targeted therapy has made inroads into the management of advanced (non–gastrointestinal stromal tumors) soft-tissue sarcoma, with the US Food and Drug Administration (FDA) approval of pazopanib.[2] There are also increasing efforts to explore the potential role of immunotherapeutics in soft-tissue sarcomas.[3,4] While exciting and eagerly anticipated, it is unclear whether these novel therapies will eventually supplant conventional chemotherapy from its current stronghold, particularly for patients with advanced disease.

In many respects, we have become victims of our own designs. Clinical trials exploring novel cytotoxic chemotherapeutic agents have traditionally enrolled a broad, unselected, and heterogeneous soft-tissue sarcoma patient population. In the setting of less than compelling results, and in the absence of embedded correlatives, investigators have been left scrambling to determine which subgroups will most likely benefit from a particular therapy. Recent examples of novel cytotoxic chemotherapeutics that have been explored in unselected patient populations with advanced soft-tissue sarcoma include palifosfamide, TH-302, and aldoxorubicin.

Palifosfamide, a novel cytotoxic designed to contain the active metabolite of ifosfamide, without the significant neurologic or genitourinary side effects, showed very promising activity in preclinical and early-phase clinical trials. The randomized, phase II PICASSO study, comparing doxorubicin vs doxorubicin + palifosfamide, showed that patients treated with the combination had an improved median progression-free survival (PFS) (7.8 mo) compared with those who received doxorubicin alone (4.4 mo).[5] Results from the subsequent randomized, phase III PICASSO 3 study, however, failed to confirm the benefit, resulting in the sponsor’s decision to halt further development of the agent for use in soft-tissue sarcoma.[6]

TH-302, a novel hypoxia-activated prodrug of bromo-isophosphoramide mustard, has yielded very exciting results in early-phase clinical trials as well. In an open-label phase II study, administration of TH-302 in combination with doxorubicin in patients with advanced soft-tissue sarcoma resulted in a median PFS of 6.5 months (95% confidence interval [CI], 5.8–7.7 mo) and a median overall survival of 21.5 months (95% CI, 16–26.2 mo).[7] An ongoing phase III, randomized, open-label study comparing doxorubicin with the combination of doxorubicin + TH-302 has completed accrual, and results are eagerly anticipated.

In a multicenter, phase II study, aldoxorubicin, a novel formulation of doxorubicin attached to a linker that covalently binds to albumin, was compared with doxorubicin alone in an unselected population of patients with advanced soft-tissue sarcoma.[8] Median PFS was 5.7 months for patients randomized to aldoxorubicin vs 4.7 months for those who received doxorubicin (P = .0002), with an overall response rate of 24% vs 5.3% for the aldoxorubicin and doxorubicin arms, respectively. The safety profile appeared to be acceptable. While these results are encouraging, they need to be confirmed, and a phase III trial to evaluate aldoxorubicin further has recently been initiated.

Reflecting the marked heterogeneity and molecular diversity of soft-tissue sarcoma, these tumors demonstrate a spectrum of responsiveness to systemic cytotoxic chemotherapy. Synovial sarcoma and myxoid/round-cell liposarcoma (MRCLS) appear to be among the most chemotherapy-sensitive soft-tissue sarcoma subtypes. Synovial sarcoma has shown responsiveness to ifosfamide-containing chemotherapeutic regimens, and MRCLS has shown marked sensitivity to trabectedin, an agent not currently FDA-approved in the United States.[9-11] Uterine leiomyosarcoma appears to have greater response rates than other soft-tissue sarcomas to the combination of gemcitabine + docetaxel, while paclitaxel has yielded impressive response rates in scalp angiosarcomas.[12-14]

With regard to histology-specific cytotoxic chemotherapeutics, eribulin and trabectedin have both shown promising activity. A nonrandomized, multicenter phase II study of eribulin, a nontaxane microtubule inhibitor, in patients with advanced soft-tissue sarcoma showed the agent to be associated with favorable 12-week PFS rates, specifically in leiomyosarcoma and liposarcoma cohorts.[15] Similarly, trabectedin, a marine-derived antineoplastic alkylating agent approved outside of the United States for patients with advanced soft-tissue sarcoma, has shown activity in a number of phase II soft-tissue sarcoma studies, with particular activity in liposarcoma and leiomyosarcoma.[16] The results from these studies have led to two separate randomized, open-label, multicenter, phase III trials of eribulin vs dacarbazine and of trabectedin vs dacarbazine, in the third-line soft-tissue sarcoma setting. Both trials have completed accrual and results are anticipated.

While the future is bright for the development and investigation of novel chemotherapeutics for treatment of soft-tissue sarcoma, investigators will need to gain better insight into the molecular drivers of pathogenesis, and give continued thoughtful consideration to clinical trial design. Critical to the success of novel chemotherapeutics will be embedded biologic correlatives, which will make it possible to assess for biomarkers of response, and thus to enrich for clinical response in those individuals most likely to benefit from a specific therapy. The “one size fits all” mentality, which has permeated the field of soft-tissue sarcoma management for decades, has resulted in a paucity of new agents over the years. The recent evolution towards a histology-driven therapeutic approach is encouraging, but the future of “precision medicine” will require us to delve deeper at the individual patient level.

Financial Disclosure:Dr. Riedel receives clinical trial research support from ARIAD, Astex, EISAI, Novartis, Tracon, and Ziopharm; consulting fees from CytRx and Morphotek for participation on Data and Safety Monitoring Boards; honoraria from GlaxoSmithKline for educational initiatives; and honoraria from Novartis for serving on a sarcoma advisory board. Dr. Gwin has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Ravi V, Patel S, Benjamin RS. Chemotherapy for soft-tissue sarcomas. Oncology (Williston Park). 2015;29:43-50.

2. van der Graaf WT, Blay JY, Chawla SP, et al; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379:1879-86.

3. Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29:917-24.

4. D’Angelo SP, Tap WD, Schwartz GK, Carvajal RD. Sarcoma immunotherapy: past approaches and future directions. Sarcoma. 2014;2014:391967.

5. Verschraegen CF, Chawla SP, Mita MM, et al; PICASSO Study Investigators. A phase II, randomized, controlled trial of palifosfamide plus doxorubicin versus doxorubicin in patients with soft tissue sarcoma (PICASSO). J Clin Oncol. 2010;28(15s):abstr 10004.

6. Ryan CW, Schoffski P, Merimsky O, et al. PICASSO 3: a phase 3 international, randomized, double-blind, placebo-controlled study of doxorubicin (dox) plus palifosfamide (pali) vs. dox plus placebo for patients (pts) in first-line for metastatic soft tissue sarcoma (mSTS). Presented at the European Cancer Congress; September 27 - October 1, 2013; Amsterdam, Netherlands. abstr 3802.

7. Chawla SP, Cranmer LD, Van Tine BA, et al. Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. J Clin Oncol. 2014;32:3299-306.

8. Chawla SP, Papai Z, Sankhala K, et al. Randomized phase 2b trial comparing first-line treatment with aldoxorubicin versus doxorubicin in patients with advanced soft tissue sarcomas. J Clin Oncol. 2014;32(suppl 5s): abstr 10502.

9. Rosen G, Forscher C, Lowenbraun S, et al. Synovial sarcoma. Uniform response of metastases to high dose ifosfamide. Cancer. 1994;73:2506-11.

10. Spillane AJ, A’Hern R, Judson IR, et al. Synovial sarcoma: a clinicopathologic, staging, and prognostic assessment. J Clin Oncol. 2000;18:3794-803.

11. Jones RL, Fisher C, Al-Muderis O, Judson IR. Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur J Cancer. 2005;41:2853-60.

12. Hensley ML, Blessing JA, Mannel R, Rose PG. Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial. Gynecol Oncol. 2008;109:329-34.

13. Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of Sarcoma Alliance for Research Through Collaboration study 002 [corrected]. J Clin Oncol. 2007;25:2755-63. Erratum in: J Clin Oncol. 2007;25:3790.

14. Penel N, Bui BN, Bay JO, et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol. 2008;26:5269-74.

15. Schöffski P, Ray-Coquard IL, Cioffi A, et al. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol. 2011;12:1045-52.

16. Demetri GD, Chawla SP, von Mehren M, et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol. 2009;27:4188-96.