Ewing sarcoma
Current standard of care for ES has evolved over decades through
randomized trials into just-tolerated, prolonged intensive chemotherapy
regimens through the addition of cytotoxic agents, (notably-
doxorubicin, ifosfamide and etoposide) to vincristine, dactinomycin and
cyclophosphamide (VAC).45-50 Randomized trials by risk
group for newly diagnosed ES are shown in Table I. More recently, the
focus has shifted to dose-intensity of the alkylating agents and through
several large, randomized trials, a clearer international consensus has
emerged. The most recent prospective COG trial randomized patients
<50years with localized ES to receive alternating vincristine,
doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) every 3
weeks (standard) compared to every 2 weeks, facilitated by the use of
granulocyte colony stimulating factor
(intensive).51,52 5y EFS was superior in the
intensified regimen compared with the standard arm, (73% vs 65%,
(P =0.048)), with no difference in toxicity (P =
0.056).52 The Euro Ewing 2012 trial demonstrated a
superior outcome for VDC/IE compared to the previous European standard,
VIDE/VAI in patients with localized and metastatic ES: a Bayesian
analysis demonstrated hazard ratios (HRs) of 0.70 for EFS and 0.64 for
overall survival and a 98% posterior probability in favor of
VDC/IE.53,54 The 3-year EFS for VIDE/ VAI was 61%
compared to 68% for VDC/IE and there was a similar difference in
overall survival, with no excess acute toxicity with
VDC/IE.54 On the basis of these results, interval
compressed VDC/IE therapy has become the international current standard
of care for localized and metastatic ES. Dexrazoxane cardioprotection
with short infusion doxorubicin allows for safe intensification of
treatment without affecting tumor response.55 The
addition of chemotherapeutic agents to VDC/IE -such as
vincristine-cyclophosphamide-topotecan in the COG trial AEWS1031 or
irinotecan temozolomide showed no survival benefit in non-metastatic
patients.56,57
Recurrent ES, which is mostly systemic relapse, occurs in 30-40% of
primary localized disease and 60-80% of metastatic
ES.58 Survival is less than 25% overall for patients
with relapsed ES, better in later relapses >2y after
treatment.59,60 The management of patients with
primary refractory or recurrent ES is less well defined with several
combinations of chemotherapy in use, largely dependent on institutional
experience. An ongoing randomized multi-arm European trial (rEECur) is
recruiting relapsed ES patients between ages 4 and 50, to multiple
chemotherapy arms to determine a standard of care. Interim analyses
suggest irinotecan plus temozolomide and gemcitabine and docetaxel are
inferior to high dose ifosfamide and cyclophosphamide/ topotecan
combination.61,62 The median PFS across all cohorts
was 4.7 months with overall survival of 13.7 months across all
therapies.61
Local management of the primary tumor in ES includes surgery or RT or a
combination of both. Complete surgical resection with clear margins (R0)
remains the most important goal for local control. 5 year local failure
rates after RT alone, surgery only, and surgery combined with RT were
15.3%, 3.9% and 6.6% respectively in 956 patients treated on COG
protocols.63 The failure rate after RT alone is higher
in pelvic and extremity tumors reflecting patients with often locally
advanced tumors unsuitable for surgery.63,64Indications for combination treatment include the expectation or
confirmation of inadequate resection margins, large tumors and poor
response to induction chemotherapy.65,66 Definitive RT
is recommended where surgery would result in unacceptable
morbidity.44,63,67-72 RT dose ranges from 45Gy to 66Gy
depending on anatomical location, tumor size and timing of RT in
relation to surgery.72,73 Whole lung RT may be used to
consolidate the response of lung metastases after chemotherapy and is
well tolerated although the benefit has not been unequivocally
demonstrated.74