2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

SYSTEMIC TREATMENT OF THYMOMA
Study
Table 2. Landmark Studies Reporting on Palliative Chemotherapy Regimens in Advanced Thymic Malignancies
No. of
Patients
Period of
Accrual
(years)
Palliative-Intent, Definitive Chemotherapy
Palliative chemotherapy is administered as the sole treatment
modality for thymic tumors, with no plan for surgery
or radiotherapy (e.g., in patients with metastatic or recurrent
disease, or with locally advanced tumors that did not
sufficiently shrink after primary chemotherapy to be eligible
for subsequent focal treatment). 6 The main objectives of
palliative-intent chemotherapy are to improve potential
tumor-related symptoms and to achieve tumor response.
Prolonged disease control is possible, but tumor eradication
is not expected. Several studies—both prospective and retrospective—described
several regimens for definitive chemotherapy
(Table 2), but because there are no randomized
studies, it is unclear which cytotoxic agents are best; multiagent
combination regimens and anthracycline-based regimens
appear to have improved response rates compared
with others. In general, a combination regimen is recommended,
for at least three and no more than six cycles.
Overall, response rates are 20% to 40%, lower than those
observed in the preoperative setting.
In the palliative-intent setting, several consecutive lines
of chemotherapy may be administered when patients present
with tumor progression. Delay of progression ranges
from 4 to 80 months in the literature. It is estimated that
50% to 70% of patients with thymoma recurrence receive
chemotherapy, while some recurrences may be eligible for
surgery and/or radiotherapy. 7 Strategy may consist of the
readministration of a previously effective regimen, 37 as well
as the use of less toxic agents, including paclitaxel or
pemetrexed (Table 2). The repeated use of anthracyclines is
limited by potential cardiac toxicity, which may be even
more relevant in the recurrence setting, in case of combination
with radiotherapy and surgery, and given the possible
development of paraneoplastic myocarditis. Specific to recur-
Tumor
Type Design Regimen Agents Doses
Single-agent chemotherapy
Bonomi et al 1993 27 21 4 T/TC Phase II Cisplatin 50 mg/m 2 /3 weeks 10
Highley et al 1999 28 15 12 T/TC Retrosp Ifosfamide 1.5g/m 2 � 5 days/3 weeks 46
Loehrer et al 2006 29 27 1 T/TC Phase II Pemetrexed 500 mg/m 2 /3 weeks 17
Combination chemotherapy
Fornasiero et al 1990 30 32 11 T Retrosp ADOC Doxorubicin 40 mg/m 2 /3 weeks 91
Cisplatin 50 mg/m 2 /3 weeks
Vincristin 0.6 mg/m 2 /3 weeks
Cyclophosphamide 700 mg/m 2 /3 weeks
Loehrer et al 1994 31 30 9 T/TC Phase II CAP Cisplatin 50 mg/m 2 /3 weeks 51
Doxorubicin 50 mg/m 2 /3 weeks
Cyclophosphamide 500 mg/m 2 /3 weeks
Giaccone et al 1996 32 16 6 T Phase II PE Cisplatin 60 mg/m 2 /3 weeks 56
Etoposide 120 mg/m 2 � 3/3 weeks
Loehrer et al 2001 33 34 2 T/TC Phase II VIP Etoposide 75 mg/m 2 � 4 days/3 weeks 32
Ifosfamide 1.2 g/m 2 � 4 days/3 weeks
Cisplatin 20 mg/m 2 � 4 days/3 weeks
Lemma et al 2011 34 46 7 T/TC Phase II Carbo-Px Carboplatin AUC 5/3 weeks 43
Paclitaxel 225 mg/m 2 /3 weeks
Palmieri et al 2011 35 15 3 T/TC Phase II CAP-GEM Capecitabine 650 mg/m 2 bid � 14 days/3 weeks 40
Gemcitabine 1000 mg/m 2 � 2 days/3 weeks
Okuma et al 2011 36 9 8 TC Retrosp Cisplatin-Irinotecan Cisplatin 80 mg/m 2 /4 weeks 56
Irinotecan 60 mg/m 2 � 3 days/4 weeks
Abbreviations: T, thymoma; TC, thymic carcinoma; Retrosp, retrospective.
rent thymic tumors after first course of treatment with definitive
chemotherapy is the use of octreotide, which as single
agent produced objective tumor responses rates ranging from
10% to 37% in tumors showing increased uptake at OctreoScan
(Indium-111 pentetreotide; Covidien; Dublin, Ireland) scintigraphy.
38 Of note, objective responses to octreotide have
been reported only in thymomas, not in thymic carcinomas.
Overall, given the modest results of chemotherapy in the
palliative-intent setting, novel strategies are needed. In this
way, amrubicin, a new generation anthracycline, is currently
investigated in refractory thymic tumors (clinicaltrials.gov
ID: NCT01364727).
Targeted Therapy for Thymic Malignancies
Response
Rate (%)
Despite the rarity of thymic tumors, substantial efforts
have been made to dissect the molecular pathways involved
in thymus carcinogenesis. 3,10-13 The main signaling pathways
with potential druggable targets that have been explored
in thymic tumors are the epidermal growth factor
receptor (EGFR), the KIT/mast/stem-cell growth factor receptor
(KIT/SCFR), and the insulin-like growth factor-1
receptor (IGF-1R) pathways. Antiangiogenic agents may
also be of interest.
EGFR Pathway Inhibitors
Overall, EGFR is overexpressed in approximately 70% of
thymomas and 50% of thymic carcinomas. 3,10,11 EGFR expression,
as well as EGFR gene amplification, was shown to
be higher in stage III to IV tumors. However, EGFR mutations
are rare in thymic malignancies. 3,10 Thus far, only two
cases of thymomas harboring EGFR mutations have been
found of a total of 158 tumors collectively analyzed. The
mutations were L858R in one case and G863D in the other
case, both of which are associated with response to EGFR
477