NcXHF

ADJUVANT/NEOADJUVANT MEDICAL THERAPY OF ADULT SOFT TISSUE SARCOMAS
This observation is diffıcult to explain, especially in the presence
of a questionable benefıt for distant relapse. However,
one should recall that the local control in some patients with
high-risk STS may be challenging. In addition, some local relapses
in STS may well lead to death. This might explain the
differences in survival in the absence of comparable differences
in distant relapses. In addition, this could add to the
rationale of placing chemotherapy preoperatively, as long as
the decision has been made in the single case to use it as an
adjunct to surgery. The ISG trial allowed the combination of
neoadjuvant chemotherapy with preoperative radiation
therapy, and this proved to be tolerable in the proportion of
patients in whom it was used.
With an incidence in the range of 0.5 per 100,000 per year,
uterine sarcomas are a relevant subgroup in the STS family.
They entail a signifıcant risk of relapse. Leiomyosarcoma is
the main subgroup, if one excludes mixed mullerian tumors
(carcinosarcomas), which are currently held to be epithelial
in nature. Other highly malignant subgroups are high-grade
endometrial stromal sarcomas and undifferentiated uterine
sarcomas. Recent, uncontrolled evidence was provided on a
regimen employing four cycles of gemcitabine plus docetaxel
and another that was based on four cycles of the same chemotherapy
followed by four cycles of doxorubicin. 14,15 The
latter regimen was associated with an interesting relapse-free
survival rate compared with external controls, though the
rate decreased with a longer follow-up time. A randomized
trial is ongoing to compare this regimen to a nochemotherapy
arm in uterine leiomyosarcomas.
CURRENT RECOMMENDATIONS
The 2014 National Comprehensive Cancer Network (NCCN)
clinical practice guidelines state that adjuvant chemotherapy
for STS greater than 5 cm and intermediate to high grade in
the extremities, superfıcial trunk, or head and neck, can be
viewed as an appropriate intervention on the basis of lowerlevel
evidence marked by limited and conflicting data. 16
Thus, adjuvant chemotherapy is a legitimate option, but is
not standard. In essence, the same applies to uterine leiomyosarcomas
or undifferentiated sarcomas.
The 2015 European Society for Medical Oncology (ESMO)
clinical practice guidelines state that chemotherapy can be
regarded as an option for patients with high-grade, deep STS
that is greater than 5 cm as adjuvant or neoadjuvant treatment,
but they acknowledge no consensus on its role, given
the conflicting results of available studies. 17 In uterine leiomyosarcomas,
the value of adjuvant chemotherapy also is
said to be undetermined.
In brief, clinical practice guidelines must take into account
that some evidence was provided on the potential value of
adjuvant chemotherapy in STS but that this evidence is insuffıcient
to make chemotherapy standard practice. Thus, a
clinical decision shared with the patient to resort to adjuvant
chemotherapy in the presence of a high risk of relapse is
fully justifıed according to current consensus recommendations,
provided that the patient is aware that it is not
standard treatment.
ISSUES
Available studies mainly refer to the most typical presentations,
that is, limb and superfıcial trunk STS. Their results are
conflicting, and uncertainty has not been settled, but at least
they can help by providing direct evidence. In clinical practice,
one may be challenged by patients with STS who fall outside
the average STS patient. In general, the primary site can
be regarded as a minor source of discrepancy for the effıcacy
of systemic therapy, because there is no major reason, ultimately,
why the same histology should benefıt differently depending
on the primary site. Sometimes, an atypical site
entails an additional risk of relapse. For example, a pleural
synovial sarcoma is likely to entail a higher risk than a limb
synovial sarcoma because of the additional locoregional risk
of pleural spread. Thus, one may estimate that an additional
reason for selecting adjuvant chemotherapy is in place. It
goes without saying that the reverse may be true as well; that
is, the additional risk is even less likely to be covered by available
adjuvant treatments.
Some rare histologies may pose further uncertainty, because
their behavior may be less known and, most important,
their chemotherapy sensitivity may deviate from that of
average STS. Indeed, some histologies (e.g., epithelioid sarcoma,
or alveolar soft part sarcoma) are less sensitive to standard
chemotherapy for STS, and this may be a good reason to
refrain from using adjuvant chemotherapy for them, when
the lack of any tumor lesion prevents one from the opportunity
to check tumor response (i.e., tumor sensitivity). In these
cases, delaying chemotherapy to the time of relapse may be a
reasonable choice, though the pursued effect of chemotherapy
as an adjuvant would be different by defınition. Sometimes,
these histologies are less sensitive to anthracyclines
plus ifosfamide but may be sensitive to other agents (e.g.,
leiomyosarcoma is less sensitive to ifosfamide and more sensitive
to dacarbazine). In these cases, one may try to personalize
the choice of the medical therapy. Of course, this adds to
the uncertainty of adjuvant chemotherapy in STS, and the
patient needs to be informed accordingly within a deeply
shared decision-making process. In general, because the approach
to the medical therapy of STS is increasingly histology
driven, the assessment of whether an histology-driven approach
to the adjuvant therapy of STS may improve its effectiveness
is a priority for clinical research. However, when
single histologies are considered, the number of eligible patients
for clinical studies further diminishes, and conventional
statistics faces major challenges.
With regard to the regimen choice in the adjuvant setting,
aside from the possible role of histology-driven options, fulldose
anthracycline-plus-ifosfamide combinations should
be regarded as standard. Certainly, this conclusion may be
challenged by the unclear superiority of the combination of
these two drugs over single-agent doxorubicin in advanced
disease, as recently suggested by a randomized trial. 18 How-
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
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