G. Mennel, MD, FACP
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
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
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?
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
1. Raney RB, Anderson JR, Barr FG, et al.
Pediatr Hematol Oncol.
2. Sarcoma Meta-Analysis Collaboration.
3. Pervaiz N, Colterjohn N, Farrokhyar F, et al. Cancer.
4. Helman LJ, Meltzer P. Nat Rev Cancer.
Role of Chemotherapy in the Treatment of Pediatric Soft Tissue
S. Pappo, MD
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 disease3,4
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
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
V, vincristine; A, actinomycin D; C, cyclophosphamide; I, ifosfamide; D, doxorubicin, E, etoposide; Ir, irinotecan; RT, radiotherapy
| Risk Group (Percent of cases)
|| Expected 5-year failure-free survival
| Low (35%)
|| Embryonal tumors
Localized disease at favorable sites
and grossly resected disease at unfavorable sites
| Intermediate (50%)
|| Embryonal tumors
Unresected disease at unfavorable sites
All localized disease
| VAC± an experimental arm±RT
| High (15%)
|| Embryonal and alveolar tumors
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.
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
Clinical Oncology and Cancer.Net.
1. Flamant F, Hill C. Cancer.
2. Neifeld JP, Maurer HM, Godwin D, et al.
Pediatr Surg. 1979;14:699-703
3. Wilbur J. Cancer Chemother Rep.
4. Pratt CB, Hustu HO, Fleming ID, et al.
5. Pappo AS, Shapiro DN, Crist WM. Pediatr Clin North Am.
6. Raney RB, Anderson JR, Barr FG, et al.
Pediatr Hematol Oncol.
7. Pappo AS, Devidas M, Jenkins J, et al.
Clin Oncol. 2005;23:4031-8
8. Pratt CB, Pappo AS, Gieser P, et al. J Clin Oncol.
9. Pratt CB, Maurer HM, Gieser P, et al.
Pediatr Oncol. 1998;30:201-9
Role of Adjuvant Chemotherapy in the Treatment of Adult Soft Tissue
von Mehren, MD
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
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
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
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.
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
1. American Cancer Society. Cancer Facts & Figures 2012.
Atlanta: American Cancer Society, 2012.
Accessed 4 May 2012.
2. Pisters PW, Colombo C. J Surg Oncol.
3. Caram MV, Schuetze SM. J Surg Oncol.
4. Singer S, Maki RG. O’Sullivan B. “Soft
Tissue Sarcomas,” in DeVita, Hellman, and
Rosenberg’s Cancer: Principles and Practice of Oncology, 8th
, edited by DeVita VT,
Lawrence TS, and Rosenberg SA.
Philadelphia: Lippincott Williams & Wilkins, 2011.
5. Patrikidou A, Domont J, Cioffi A, et al.
Treat Options Oncol.
6. Pervaiz N, Colterjohn N, Farrokhyar F, et
7. O’Connor JM, Chacón M, Petracci FE, et
J Clin Oncol. 2008;26(May 20
suppl; abstr 10526)
8. Italiano A, Delva F, Mathoulin-Pelissier S,
et al. Ann