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How Do I Treat…?

Practical perspectives on cancer treatment by thought leaders, explaining how they would approach the treatment of a patient in their area of expertise.

Saturday, November 17, 2012
ONLINE FIRST: ROBERT MAKI: How I Treat Patients with Metastatic Soft Tissue Sarcoma

 

ROBERT G. MAKI, MD, PhD, is Professor of Pediatrics, Hematology/Oncology; Professor of Medicine, Hematology, and Medical Oncology; and Professor of Orthopaedics at Mount Sinai School of Medicine in New York City

 

The management of soft tissue sarcoma is made difficult by the relative rarity of this family of tumors and the heterogeneity of the diagnosis, in which more than 50 types are recognized; an updated accounting from expert pathologists is expected in 2013. However, knowledge of just a few of the major subtypes can go a long way towards insuring the best management for patients. Not discussed here is the management of GIST, which is the most common sarcoma by some accounts, and is treated with tyrosine kinase inhibitors imatinib, sunitinib, regorafenib, and possibly others.

 

As for soft tissue sarcoma, since large tumors (over 5 cm) have a significant risk of metastatic disease, consideration is given to adjuvant therapy. The benefit of chemotherapy, typically doxorubicin-ifosfamide, is small, if any, with the strongest data being the results of a meta-analysis of patients treated with chemotherapy or not in randomized studies,1 and the strongest counterargument from the largest single study of adjuvant chemotherapy, which showed no improvement in survival.2

 

The most common sarcoma subtypes otherwise are undifferentiated pleomorphic sarcoma (UPS, formerly termed malignant fibrous histiocytoma, MFH), leiomyosarcoma, and liposarcoma, which comes in three distinct genetic subtypes, well differentiated/dedifferentiated, myxoid-round cell, and pleomorphic. In patients who have metastases and are treatment naïve, doxorubicin, ifosfamide, or both are most commonly used.

 

The recently presented data at ESMO on the simple question of doxorubicin +/- ifosfamide at high doses and effects on clinical parameters underscores trials done in a similar fashion over the last 20 to 25 years.3

 

AIM (doxorubicin-ifosfamide-mesna) demonstrated a response rate of 26 percent compared with doxorubicin alone (13%), and an improvement in progression-free survival of approximately three months was observed with the combination, without an overall survival advantage, although there was a modest trend towards improved survival with the combination.

 

These data reinforce the idea that doxorubicin and ifosfamide are additive in benefit but not synergistic, and thus can be used in sequence in most patients, avoiding unnecessary toxicity. For those patients with aggressive and symptomatic disease, AIM is a good option. It is worth noting that there are certain diagnoses in which AIM is not recommended, such as extraskeletal myxoid chondrosarcoma or alveolar soft part sarcoma, in which the response rate to chemotherapy is negligible, and consideration for other therapy is appropriate.

 

In further advanced disease, I look more to tumor biology to guide therapy, and occasionally use these data for clinical treatment choices. Gemcitabine-based therapy is active in UPS and leiomyosarcoma specifically (as well as some other subtypes).4-6 Two randomized studies showed the improved survival with combinations of chemotherapy over gemcitabine monotherapy (specifically gemcitabine with either docetaxel or with dacarbazine), but for any specific histology, we do not have definitive proof that use of two drugs is better than one.4,6

 

It is reasonable to state that in aggregate, combination therapy appears superior to monotherapy, although smaller studies refute this concept.7

 

In advanced disease, taxanes are active in angiosarcoma specifically, and dacarbazine has specific activity in leiomyosarcoma, as two simple drug-histology pairings. Pazopanib was recently FDA approved for recurrent/metastatic sarcomas failing on other therapy by virtue of improved progression-free survival on therapy in a randomized phase III clinical trial.8 The RECIST response rate was below 10 percent, and there was a modest trend towards improved overall survival. 

 

Other drugs of note include trabectedin, which is approved in Europe for advanced soft tissue sarcomas.9 The data leading to EMA approval were not sufficient for FDA approval in the U.S., but the drug is available on expanded access at more than 30 centers across the United States.

 

Myxoid-round cell liposarcoma is specifically sensitive to trabectedin, and efforts continue in the U.S. to obtain FDA approval. The ifosfamide-like agents palifosfamide and TH302 are undergoing phase III trials in first-line therapy for patients with metastatic sarcoma; outcomes data will dictate if they are approved for use in sarcoma patients.

 

Clinical trials are a good option for patients whenever available; these studies oftentimes provide new options for therapy before or after exhaustion of standard agents.

 

At the end of the day, if there are questions on specific therapeutic options for a particular sarcoma of soft tissue or bone, discussion with someone who treats these cancers every day will help insure the best possible care for a patient. These health care providers are generally very approachable as they as much as anyone recognize the complexity of these diagnoses.

 

 

REFERENCES

           1.  Pervaiz N, Colterjohn N, et al: A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma.  Cancer 2008;113:573-581.

2.  Woll PJ, van Glabbeke M, et al: Adjuvant chemotherapy (CT) with doxorubicin and ifosfamide in resected soft tissue sarcoma (STS): Interim analysis of a randomised phase III trial. Proc ASCO 2007; 25(18S):10008.

3.  van der Graaf WTA, Judson I, et al: Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced or metastatic soft tissue sarcoma. Presented at: 37th European Society for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA7.

4.  García Del Muro X, López-Pousa A, et al: Spanish Group for Research on Sarcomas. Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. JCO 2011; 29:2528-2533.

5.  Hensley ML, Blessing JA, et al: Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma. Gynecol Oncol 2008;109:323-328.

6.  Maki RG, Wathen JK, et al: Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas. JCO 2007;25:2755-2563.

7.  Pautier P, Floquet A, et al: Randomized Multicenter and Stratified Phase II Study of Gemcitabine Alone Versus Gemcitabine and Docetaxel in Patients with Metastatic or Relapsed Leiomyosarcomas. Oncologist. 2012; 17:1213-1220.

8.  van der Graaf WT, Blay JY, et al: Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012;379:1879-1886.

9.  Demetri GD, Chawla SP, 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. JCO 2009;27:4188-4196.   

About this Blog

Editor

Practical perspectives on cancer treatment by thought leaders, explaining how they approach the treatment of a patient in their area of expertise.

As the blog’s Editor, RAMASWAMY GOVINDAN, MD, OT’s Clinical Advisory Editor for Oncology -- Co-Director of the Section of Medical Oncology and Professor of Medicine at Washington University School of Medicine, Alvin J. Siteman Cancer Center -- notes, “While all of us want to see more patients enrolled in well-designed clinical trials, this series is all about how one treats patients “off-protocol” in routine clinical practice. Practice patterns vary, since we do not always have firm data for every single clinical scenario.”

Let us know what you think! Add your comments, both about individual treatment scenarios as well as to suggest future questions.