NcXHF

PAOLO G. CASALI
institution to another, with a view toward local cytoreduction,
in addition to its possible systemic effects.
In conclusion, there is a huge need for effective adjuvant
and/or neoadjuvant treatments in STS. The proportion of
potentially amenable patients may roughly amount to onehalf
of cases. This applies to adult-type STS, because extraskeletal
Ewing sarcomas and embryonal or alveolar
rhabdomyosarcoma fall in a distinct group of sarcomas, even
when they occur in the adult, which deserves chemotherapy
in all cases as a key component of the standard treatment.
AVAILABLE EVIDENCE
Several randomized, controlled trials have been performed
with adjuvant chemotherapy for STS, starting from the
1970s, when chemotherapy was shown to be crucial in revolutionizing
the prognosis of childhood sarcomas, (i.e., osteosarcoma,
Ewing sarcoma, and rhabdomyosarcoma). Trials
performed in STS can be divided into two generations. Firstgeneration
trials used anthracycline-based regimens—that
is, either doxorubicin alone or combinations that today
would be regarded as exploiting doxorubicin as virtually the
only, or nearly only, active drug. Second-generation trials
have been based on combinations of anthracyclines and ifosfamide.
Doses varied substantially, but at least the two main
active drugs in STS were incorporated. A high degree of heterogeneity
can be found in all these studies also, as far as the
patient populations are concerned, and the number of patients
ranged from a few dozens to hundreds.
A meta-analysis of these randomized clinical trials, published
in 2008, confırmed the benefıt that a previous metaanalysis,
done on individual patient data, had already shown
in terms of local and distant relapse rate; the 2008 publication
also noted a statistically signifıcant benefıt in terms of overall
KEY POINTS
Adjuvant chemotherapy is not standard treatment in soft
tissue sarcoma (STS), but it is an option to share with the
patient in conditions of uncertainty when the risk of
relapse is high.
Controlled evidence is available, and was also pooled in
meta-analyses, but its weakness is that studies have been
conflicting.
If the decision is to resort to chemotherapy in the patient
with localized high-risk STS, chemotherapy can be
administered preoperatively if cytoreduction is felt to help
improve the quality of surgical margins and/or sequelae.
Personalization of adjuvant chemotherapy across diverse
STS subgroups is worth testing in clinical research as a
way forward, to improve its efficacy.
Personalized, rational decision making in conditions of
uncertainty on adjuvant treatment for patients with STS is
the every-day challenge that multidisciplinary tumor boards
face at reference sarcoma centers or within sarcoma
networks.
survival for doxorubicin plus ifosfamide (p 0.01). 7,8 The
magnitude of benefıt was in the 5% to 10% range. Although
small, this could well justify the choice of using chemotherapy
in high-risk patients, and a meta-analysis of several randomized
clinical trials could be regarded as suffıcient evidence to back
this choice. Methodologically, the last meta-analysis was not
done on individual patient data. However, the main limitation
of any meta-analysis of adjuvant chemotherapy in STS is
that the pooled trials are conflicting, and the largest trials
point to a lack of benefıt. Clearly, this substantially undermines
any positive conclusion. Conversely, small trials were
less heterogeneous in their patient population and/or were
carried out by single institutions with more expertise with the
disease. In rare cancers, large trials enrolling patients from a
variety of institutions with different expertise levels may pose
substantial problems in terms of quality of care. Random assignment
is not a guarantee that this clinical bias is offset just
because it is operating in both arms, because the most effective
treatment may be more penalized by shortcomings in
quality of care (e.g., in the adjuvant setting, by surgical treatment).
In 2012, a large, randomized trial was published by the European
Organization for Research and Treatment of Cancer
(EORTC) Soft Tissue and Bone Sarcoma Group, which provided
a negative result by using a regimen of doxorubicin
plus ifosfamide at full doses, though the latter was given at 5
g/m 2 in 24 hours. 9 The relapse rate of the study patient population
was in the 50% range; thus, it was at a level that may be
slightly lower than the one selected by some positive studies.
By updating the meta-analysis using aggregate data for overall
survival of this and other new studies, a statistically significant
benefıt was still apparent in terms of survival in favor of
chemotherapy (p 0.02).
A randomized trial performed by the Italian Sarcoma
Group (ISG) and the Spanish Sarcoma Group (GEIS), published
in 2008, compared fıve cycles (three preoperatively
and two postoperatively) of full-dose epirubicin (an analog of
doxorubicin) plus ifosfamide with 3 preoperative cycles of
the same regimen. 10 Both relapse-free survival and overall
survival were superimposable, but they also were superimposable
to the treatment arm (fıve postoperative cycles of the
same regimen) of a previous randomized trial carried out by
ISG that had a no-chemotherapy control arm. 11 That trial
had been closed in advance because of an early major benefıt
in survival in favor of the adjuvant treatment arm. With a longer
follow-up time, the statistical signifıcance was lost, though a
trend was preserved. 12 The patient population of the ISG trials
was defınitely in the high-risk group, and it was calculated that
the prognosis expected without chemotherapy for patients enrolled
on the most recent trial, estimated through available nomograms,
was compatible with the performance of the control
group in the fırst study. This may be taken as indirect evidence
that three courses of a full-dose regimen of anthracycline plus
ifosfamide can give some prognostic benefıt in a truly high-risk
STS patient population.
It is interesting that several trials on adjuvant chemotherapy
in STS detected some benefıt in terms of local relapses. 8,13
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