Adjuvant Chemotherapy for Soft Tissue Sarcoma: Is It Indicated?

Jul 02, 2012


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

Sarcoma makes up a true minority of malignancies.In adults, sarcomasmake up only 1% to 2% of all cancers; in children, sarcomas account forapproximately 7% of all of pediatric malignancies. There are alsoapproximately 60 different diseases that are included under thisdiagnosis of sarcoma. The large high-grade sarcomas have a poor curerate with surgery alone. Metastatic soft tissue sarcoma is rarelycured. Taking all of the facts together, you can see why effectiveadjuvant chemotherapy is indicated for a large high-grade sarcoma.

The rarity of sarcomas and the great variation of the diseases includedunder this diagnosis would predict that well-designed studies would bedifficult to enroll sufficient numbers of patients to give results thatreach significance. This has been the case. The pediatric populationhas fared better than the adults, since they have at least onedisease—rhabdomyosarcoma—for which clearly designedstudies1 have been completed, demonstrating the clear-cut benefit foradjuvant chemotherapy. In 1997, the first meta-analysis was published,which showed an advantage for adjuvant chemotherapy for largehigh-grade soft tissue sarcomas.2 This analysis was updated in 20083and showed that soft tissue sarcomas treated with adjuvant chemotherapyhad 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% foradjuvant chemotherapy (95% CI 2%-11%: p=0.003), or 40% versus 46%. Theassumption is that the major advantage for adjuvant chemotherapy is forlarge, high-grade sarcomas of the extremities, although specific datapoints were not included in the studies to allow an accurate subgroupanalysis to answer this point.

In this issue of ASCO Connection, Dr. Alberto Pappo and Dr.Margaret von Mehren outline these studies and enumerate the difficultythat the clinician caring for a patient with a soft tissue sarcomafaces in making a decision about employing adjuvant chemotherapy. Theyalso discuss the hope for the future, namely definable targets that canbe exploited for higher cure rates in our patients with largehigh-grade sarcomas. They allude to the problem that this hoped-fortherapy has to confront, namely a very disrupted genome in soft tissuesarcomas.4 This genomic disaster may make the discovery of theimportant targets very difficult. When new agents are found to targetthese important pathways, the paucity of patients will make the studyof these agents using the randomized trial model very difficult.Therefore, in soft tissue sarcomas, should we perform different typesof studies to prove the effectiveness of these new drugs?

Dr.Mennel is a medical oncologist and hematologist at TexasOncology-Baylor Charles A. Sammons Cancer Center. He currently serveson ASCO’s Cancer Education Committee, Integrated Media andTechnology Committee, and the ASCOConnection EditorialBoard.

1. Raney RB, Anderson JR, Barr FG, et al.JPediatr 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 TissueSarcomas

AlbertoS. Pappo, MD
St.Jude Children’s Research Hospital

Soft tissue sarcomas account for about 7% of all cancers in patientsunder age 20, and rhabdomyosarcoma is the most common histologicdiagnosis in this population, with an expected 350 cases per year inthe United States. Historically, when treated with local measures alone(such as surgery and radiotherapy), rhabdomyosarcoma was curable inless than 30% of cases.1,2 The observations that selected chemotherapyagents were active against this disease3,4 prompted the formation ofthe Intergroup Rhabdomyosarcoma Study Group in 1972 (IRSG; now known asthe Soft Tissue Sarcoma Committee of the Children’s OncologyGroup [COG]). Since its inception, more than 5,000 patients have beentreated in a series of prospective randomized trials. These trials haveincreased cure rates to over 70% and have identified clinical andbiological factors that accurately predict outcome, facilitating thedevelopment of risk-based therapies (see Table 1).5,6 Patients withhigh-risk disease, as well as some patients with intermediate-riskdisease, continue to fare poorly. Novel therapies are desperatelyneeded 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 tissuesarcomas in pediatrics, known as nonrhabdomyosarcoma soft tissuesarcomas, are more prevalent in older patients, and, prior to 2007,only three prospective trials that accrued fewer than 200 patients hadbeen conducted in the U.S.7-9 Since then, however, COG has developedand completed a prospective trial (ARST0332) that will provide the mostcomprehensive information to date regarding the biology, clinicalcourse, and treatment of these patients.

The unprecedented progress that we have witnessed in the past 30 yearsreinforces the importance of enrolling patients in well-designedprospective clinical trials. Current efforts to better understand thegenetic features that drive tumor growth of soft tissue sarcomas areexpected to lead to studies that explore novel targeted agents incombination with standard therapies for these diseases.

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

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5. Pappo AS, Shapiro DN, Crist WM. Pediatr Clin North Am.1997;44:953-72.
6. Raney RB, Anderson JR, Barr FG, et al.JPediatr Hematol Oncol.2001;23:215-20.
7. Pappo AS, Devidas M, Jenkins J, et al.JClin 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.MedPediatr Oncol. 1998;30:201-9.

The Role of Adjuvant Chemotherapy in the Treatment of Adult Soft TissueSarcomas

Margaretvon Mehren, MD
FoxChase Cancer Center

Soft tissue sarcomas (STS) account for about 1% of all cancers inadults, with an annual incidence of 11,280 for all age groups.1 Unlikepediatric sarcomas, in which rhabdomyosarcoma accounts for the majorityof cases, there is a tremendous heterogeneity of histologies diagnosedin adult patients. Increasingly, differences in tumor biology are beingelucidated, challenging our practice of grouping these tumors as oneentity when evaluating therapeutic agents. Gastrointestinal stromaltumor (GIST) is the clearest example of biologic data leading to acompletely different treatment paradigm; the use of tyrosine kinaseinhibitors targeting KIT and PGFRA has resulted in improved overallsurvival in the adjuvant and metastatic disease settings.2,3

Trials testing the benefit of chemotherapy in patients with metastaticsarcoma have demonstrated some evidence for tumor response andprogression-free survival benefit. The highest response rates have beenachieved with doxorubicin and ifosfamide,4 and thus these agents havebeen utilized in trials assessing therapy in the adjuvant setting.5Unlike the outcomes in rhabdomyosarcoma, trials evaluating the benefitof adjuvant treatment have had varying results for progression-free andoverall survival. Meta-analyses have been performed to betterunderstand outcomes. An analysis published in 2008 included 1,953patients from published clinical trials.6 This study documentedstatistically significant odds ratios (OR) in favor of adjuvantchemotherapy 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 statisticallysignificant (OR 0.84 [95% CI 0.68-1.03; p=0.09]) but doxorubicincombined with ifosfamide was (OR 0.56 [95% CI 0.36-0.85; p=0.01]). Thisstudy did not include the most recent adjuvant study completed by theEORTC evaluating doxorubicin and ifosfamide versus observation inresected grade 2 and 3 extremity tumors. When included in ameta-analysis by other investigators, the analysis identified only arecurrence-free survival benefit at 10 years, but no benefit foroverall survival.7 Finally, a meta-analysis of retrospective data fromthe French Sarcoma Group, which included histologic grade as a variablein the analysis, identified a significant benefit for adjuvantchemotherapy for improved metastasis-free and overall survival at fiveyears (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 grade3 tumors.8

Trying to make a clinical judgment on the benefits of adjuvantchemotherapy using evidence-based clinical trial results ischallenging. The trials analyzed have used varying regimens and dosesof chemotherapies and have enrolled different patient populations.

Increasingly, biologic data is underscoring that these diseases we havelabeled soft tissue sarcoma are a very heterogeneous group, and it isnot feasible to conduct individual trials for each individualhistology. Smaller histology-specific international trials are neededin the metastatic disease setting to provide information for potentialtherapies that might be considered in the adjuvant setting. To date,our studies have demonstrated that 1) the benefit of adjuvant therapyfor intra-abdominal tumors other than GIST is very limited and notrecommended, and 2) for extremity and trunk tumors, factors suggestinga poorer prognosis should be considered on an individual basis, such assize 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 membersince 1995, she has previously served on the Scientific ProgramCommittee.

1. American Cancer Society. Cancer Facts & Figures 2012.Atlanta: American Cancer Society, 4 May 2012.
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3. Caram MV, Schuetze SM. J Surg Oncol.2011;104:888-95.
4. Singer S, Maki RG. O’Sullivan B. “SoftTissue Sarcomas,” in DeVita, Hellman, andRosenberg’s Cancer: Principles and Practice of Oncology, 8thEdition, edited by DeVita VT,Lawrence TS, and Rosenberg SA.Philadelphia: Lippincott Williams & Wilkins, 2011.
5. Patrikidou A, Domont J, Cioffi A, et al.CurrTreat Options Oncol.2011;12:21-31.
6. Pervaiz N, Colterjohn N, Farrokhyar F, etal. Cancer.2008;113:573-81.
7. O’Connor JM, Chacón M, Petracci FE, etal.J Clin Oncol. 2008;26(May 20suppl; abstr 10526).
8. Italiano A, Delva F, Mathoulin-Pelissier S,et al. AnnOncol. 2010;21:2436-41.



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