Introduction
Robert G. Mennel, MD, FACP
Texas Oncology–Baylor Charles A. Sammons Cancer Center

Sarcoma makes up a true minority of malignancies. In adults, sarcomas make up only 1% to 2% of all cancers; in children, sarcomas account for approximately 7% of all of pediatric malignancies. There are also approximately 60 different diseases that are included under this diagnosis of sarcoma. The large high-grade sarcomas have a poor cure rate with surgery alone. Metastatic soft tissue sarcoma is rarely cured. Taking all of the facts together, you can see why effective adjuvant chemotherapy is indicated for a large high-grade sarcoma.

The rarity of sarcomas and the great variation of the diseases included under this diagnosis would predict that well-designed studies would be difficult to enroll sufficient numbers of patients to give results that reach significance. This has been the case. The pediatric population has fared better than the adults, since they have at least one disease—rhabdomyosarcoma—for which clearly designed studies¹ have been completed, demonstrating the clear-cut benefit for adjuvant chemotherapy. In 1997, the first meta-analysis was published, which showed an advantage for adjuvant chemotherapy for large high-grade soft tissue sarcomas.² This analysis was updated in 20083 and showed that soft tissue sarcomas treated with adjuvant chemotherapy had a reduction in the risk of death with a hazard ratio of 0.77 (95% CI 0.64-0.93; p=0.01). The absolute risk reduction of death was 6% for adjuvant chemotherapy (95% CI 2%-11%: p=0.003), or 40% versus 46%. The assumption is that the major advantage for adjuvant chemotherapy is for large, high-grade sarcomas of the extremities, although specific data points were not included in the studies to allow an accurate subgroup analysis to answer this point.

In this issue of ASCO Connection, Dr. Alberto Pappo and Dr. Margaret von Mehren outline these studies and enumerate the difficulty that the clinician caring for a patient with a soft tissue sarcoma faces in making a decision about employing adjuvant chemotherapy. They also discuss the hope for the future, namely definable targets that can be exploited for higher cure rates in our patients with large high-grade sarcomas. They allude to the problem that this hoped-for therapy has to confront, namely a very disrupted genome in soft tissue sarcomas.⁴ This genomic disaster may make the discovery of the important targets very difficult. When new agents are found to target these important pathways, the paucity of patients will make the study of these agents using the randomized trial model very difficult. Therefore, in soft tissue sarcomas, should we perform different types of studies to prove the effectiveness of these new drugs?

Dr. Mennel is a medical oncologist and hematologist at Texas Oncology-Baylor Charles A. Sammons Cancer Center. He currently serves on ASCO’s Cancer Education Committee, Integrated Media and Technology Committee, and the ASCO Connection Editorial Board.

References
1. Raney RB, Anderson JR, Barr FG, et al. J Pediatr Hematol Oncol. 2001;23:215-20.
2. Sarcoma Meta-Analysis Collaboration. Lancet. 1997;350:1647-54.
3. Pervaiz N, Colterjohn N, Farrokhyar F, et al. Cancer. 2008;113:573-81.
4. Helman LJ, Meltzer P. Nat Rev Cancer. 2003;3:685-94.


The Role of Chemotherapy in the Treatment of Pediatric Soft Tissue Sarcomas
Alberto S. Pappo, MD
St. Jude Children’s Research Hospital

Soft tissue sarcomas account for about 7% of all cancers in patients under age 20, and rhabdomyosarcoma is the most common histologic diagnosis in this population, with an expected 350 cases per year in the United States. Historically, when treated with local measures alone (such as surgery and radiotherapy), rhabdomyosarcoma was curable in less than 30% of cases.^1,2 The observations that selected chemotherapy agents were active against this disease^3,4 prompted the formation of the Intergroup Rhabdomyosarcoma Study Group in 1972 (IRSG; now known as the Soft Tissue Sarcoma Committee of the Children’s Oncology Group [COG]). Since its inception, more than 5,000 patients have been treated in a series of prospective randomized trials. These trials have increased cure rates to over 70% and have identified clinical and biological factors that accurately predict outcome, facilitating the development of risk-based therapies (see Table 1).^5,6 Patients with high-risk disease, as well as some patients with intermediate-risk disease, continue to fare poorly. Novel therapies are desperately needed for these patients.

TABLE 1. Therapeutic Regimens for Pediatric Soft Tissue Rhabdomyosarcoma, According to Risk Group

Risk Group (Percent of cases)	Characteristics	Therapy	Expected 5-year failure-free survival
Low (35%)	Embryonal tumors Localized disease at favorable sites and grossly resected disease at unfavorable sites	VA±C±RT	95%
Intermediate (50%)	Embryonal tumors Unresected disease at unfavorable sites Alveolar tumors All localized disease	VAC± an experimental arm±RT	65%
High (15%)	Embryonal and alveolar tumors Metastatic disease	VAC±I,D,E,V,Ir±RT	30%

V, vincristine; A, actinomycin D; C, cyclophosphamide; I, ifosfamide; D, doxorubicin, E, etoposide; Ir, irinotecan; RT, radiotherapy

In contrast to rhabdomyosarcoma, the remaining 60% of soft tissue sarcomas in pediatrics, known as nonrhabdomyosarcoma soft tissue sarcomas, are more prevalent in older patients, and, prior to 2007, only three prospective trials that accrued fewer than 200 patients had been conducted in the U.S.^7-9 Since then, however, COG has developed and completed a prospective trial (ARST0332) that will provide the most comprehensive information to date regarding the biology, clinical course, and treatment of these patients.

The unprecedented progress that we have witnessed in the past 30 years reinforces the importance of enrolling patients in well-designed prospective clinical trials. Current efforts to better understand the genetic features that drive tumor growth of soft tissue sarcomas are expected to lead to studies that explore novel targeted agents in combination with standard therapies for these diseases.

Dr. Pappo, of St. Jude Children’s Research Hospital, specializes in pediatric melanoma, soft tissue sarcomas, and pediatric gastrointestinal stromal tumors. He currently serves on the Editorial Boards of the Journal of Clinical Oncology and Cancer.Net.

References
1. Flamant F, Hill C. Cancer. 1984;53:2417-21.
2. Neifeld JP, Maurer HM, Godwin D, et al. J Pediatr Surg. 1979;14:699-703.
3. Wilbur J. Cancer Chemother Rep. 1974;58:281-4.
4. Pratt CB, Hustu HO, Fleming ID, et al. Cancer Res. 1972;32:606-10.
5. Pappo AS, Shapiro DN, Crist WM. Pediatr Clin North Am. 1997;44:953-72.
6. Raney RB, Anderson JR, Barr FG, et al. J Pediatr Hematol Oncol. 2001;23:215-20.
7. Pappo AS, Devidas M, Jenkins J, et al. J Clin Oncol. 2005;23:4031-8.
8. Pratt CB, Pappo AS, Gieser P, et al. J Clin Oncol. 1999;17:1219.
9. Pratt CB, Maurer HM, Gieser P, et al. Med Pediatr Oncol. 1998;30:201-9.


The Role of Adjuvant Chemotherapy in the Treatment of Adult Soft Tissue Sarcomas
Margaret von Mehren, MD
Fox Chase Cancer Center

Soft tissue sarcomas (STS) account for about 1% of all cancers in adults, with an annual incidence of 11,280 for all age groups.¹ Unlike pediatric sarcomas, in which rhabdomyosarcoma accounts for the majority of cases, there is a tremendous heterogeneity of histologies diagnosed in adult patients. Increasingly, differences in tumor biology are being elucidated, challenging our practice of grouping these tumors as one entity when evaluating therapeutic agents. Gastrointestinal stromal tumor (GIST) is the clearest example of biologic data leading to a completely different treatment paradigm; the use of tyrosine kinase inhibitors targeting KIT and PGFRA has resulted in improved overall survival in the adjuvant and metastatic disease settings.^2,3

Trials testing the benefit of chemotherapy in patients with metastatic sarcoma have demonstrated some evidence for tumor response and progression-free survival benefit. The highest response rates have been achieved with doxorubicin and ifosfamide,⁴ and thus these agents have been utilized in trials assessing therapy in the adjuvant setting.⁵ Unlike the outcomes in rhabdomyosarcoma, trials evaluating the benefit of adjuvant treatment have had varying results for progression-free and overall survival. Meta-analyses have been performed to better understand outcomes. An analysis published in 2008 included 1,953 patients from published clinical trials.⁶ This study documented statistically significant odds ratios (OR) in favor of adjuvant chemotherapy for local recurrence (OR 0.73 [95% CI 0.56-0.94; p=0.02]), distant and overall recurrence (OR 0.67 [95% CI 0.56-0.82; p=0.0001]). When analyzing survival, doxorubicin alone was not statistically significant (OR 0.84 [95% CI 0.68-1.03; p=0.09]) but doxorubicin combined with ifosfamide was (OR 0.56 [95% CI 0.36-0.85; p=0.01]). This study did not include the most recent adjuvant study completed by the EORTC evaluating doxorubicin and ifosfamide versus observation in resected grade 2 and 3 extremity tumors. When included in a meta-analysis by other investigators, the analysis identified only a recurrence-free survival benefit at 10 years, but no benefit for overall survival.⁷ Finally, a meta-analysis of retrospective data from the French Sarcoma Group, which included histologic grade as a variable in the analysis, identified a significant benefit for adjuvant chemotherapy for improved metastasis-free and overall survival at five years (HR 0.7 [95% CI 0.6-0.9; p=0.01] and HR 0.6 [95% CI 0.5-0.8; p=0.0002], respectively) was observed, but only in patients with grade 3 tumors.⁸

Trying to make a clinical judgment on the benefits of adjuvant chemotherapy using evidence-based clinical trial results is challenging. The trials analyzed have used varying regimens and doses of chemotherapies and have enrolled different patient populations.

Increasingly, biologic data is underscoring that these diseases we have labeled soft tissue sarcoma are a very heterogeneous group, and it is not feasible to conduct individual trials for each individual histology. Smaller histology-specific international trials are needed in the metastatic disease setting to provide information for potential therapies that might be considered in the adjuvant setting. To date, our studies have demonstrated that 1) the benefit of adjuvant therapy for intra-abdominal tumors other than GIST is very limited and not recommended, and 2) for extremity and trunk tumors, factors suggesting a poorer prognosis should be considered on an individual basis, such as size and histologic grade.

Dr. von Mehren is a medical oncologist at Fox Chase Cancer Center, where she serves as the Director of Sarcoma Oncology. An ASCO member since 1995, she has previously served on the Scientific Program Committee.

References
1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer Society, 2012. www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf. Accessed 4 May 2012.
2. Pisters PW, Colombo C. J Surg Oncol. 2011;104:896-900.
3. Caram MV, Schuetze SM. J Surg Oncol. 2011;104:888-95.
4. Singer S, Maki RG. O’Sullivan B. “Soft Tissue Sarcomas,” in DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology, 8th Edition, edited by DeVita VT, Lawrence TS, and Rosenberg SA. Philadelphia: Lippincott Williams & Wilkins, 2011.
5. Patrikidou A, Domont J, Cioffi A, et al. Curr Treat Options Oncol. 2011;12:21-31.
6. Pervaiz N, Colterjohn N, Farrokhyar F, et al. Cancer. 2008;113:573-81.
7. O’Connor JM, Chacón M, Petracci FE, et al. J Clin Oncol. 2008;26(May 20 suppl; abstr 10526).
8. Italiano A, Delva F, Mathoulin-Pelissier S, et al. Ann Oncol. 2010;21:2436-41.