2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Thymoma: From Chemotherapy to
Targeted Therapy
Overview: Thymic malignancies are rare epithelial tumors
that may be aggressive and difficult to treat. Thymomas are
frequently eligible for upfront surgical resection. However,
nearly 30% of patients present with locally advanced tumor at
time of diagnosis, and chemotherapy is then used to reduce
the tumor burden—possibly allowing subsequent surgery
THYMIC MALIGNANCIES represent a wide range of
clinical, histologic, and radiologic entities, which may
be aggressive and difficult to treat. 1-3 The current histopathologic
classification distinguishes thymomas from thymic
carcinomas; thymomas are further subdivided into
different types (types A, AB, B1, B2, and B3), according to
the morphology of epithelial tumor cells (with an increasing
degree of atypia from type A to type B3), the relative
proportion of the nontumoral lymphocytic component (decreasing
from types B1 to B3), and the resemblance to
normal thymic architecture. 2 More than 25% of thymomas
actually exhibit morphologic heterogeneity, whereas 10% to
15% combine different histologic types. Tumor invasiveness,
as evaluated by the Masaoka staging system, is a major
predictor of outcome. 4,5
Surgery is the mainstay of the curative-intent treatment
of thymic tumors, 1 and complete resection represents the
most noteworthy favorable prognostic factor. 1,5 Contrary to
thymic carcinomas, recurrences after complete surgical
resection of thymomas are rare and mostly occur locoregionally,
5 which limits the rationale for postoperative chemotherapy.
Nearly 30% of patients present with locally
advanced tumor at time of diagnosis, with invasion of
intrathoracic neighboring structures, and/or dissemination
to the pleura and the pericardium. In such cases, primary
chemotherapy has been used both to reduce the tumor
burden—possibly allowing subsequent surgery and/or radiotherapy—and
to achieve prolonged disease control. 1,6
Finally, chemotherapy is also the palliative-intent treatment
for unresectable, metastatic, and recurrent thymic
tumors. 1,6
As a consequence of the rarity of thymomas, our knowledge
regarding chemotherapy in this setting has mainly
been based on retrospective series, most of which were
published years ago. Only a few prospective trials have been
conducted. Most studies included both thymomas and thymic
carcinomas, and did not report detailed results by
histologic type. Taken together, these studies, despite recruiting
limited numbers of patients over extended period of
times and being heterogeneous with regard to patient selection
criteria, therapeutic sequence, and intent of the treatment,
demonstrated the chemosensitivity of thymoma to
various cytotoxic agent combinations. 1,6 Interpretation of
outcomes data, especially overall survival and response
rates, should integrate 1) the fact that only half of patients
with thymoma actually die as a result of tumor progression,
whereas 25% of deaths are related to thymoma-associated
immunologic manifestations, including myasthenia 7 ;2)the
correlation between histology and stage, considering that
type A to B1 thymomas more frequently present as stage I to
By Nicolas Girard, MD, PhD
and/or radiotherapy. Metastatic and recurrent thymic malignancies
may be similarly treated with chemotherapy. More
recently, the molecular characterization of thymoma led to the
identification of potentially druggable targets, laying the foundation
to implement personalized medicine for patients.
II disease, whereas type B2 to B3 thymomas are usually
diagnosed as stage III to IV disease 8 ; this specific feature
may potentially confound the prognostic or predictive value
of these variables; and 3) the potential effect on lymphocytic
thymomas (types AB, B1, and B2) of corticosteroids, which
are usually delivered concurrently with chemotherapy, and
may produce a substantial reduction of lesion size at imaging
studies through lymphocytic depletion, with no antitumor
effect. 9
Novel strategies are still needed, especially for type B3
thymomas, which, similarly to thymic carcinomas, carry
a poor prognosis despite multimodal treatment. 5 In the
past, insights in the biology of thymic tumors were originally
made after anecdotal clinical responses to targeted
therapies, 3 and substantial efforts were subsequently conducted
to dissect the molecular pathways involved in carcinogenesis.
3,10-13 Research is hampered by the rarity of
these tumors, evolution of histopathologic concepts, and a
lack of established cell lines and animal models. However,
these studies led to the identification of potentially druggable
targets, laying the foundations to implement personalized
medicine in the field.
Chemotherapy for Thymoma
Curative-Intent, Preoperative Chemotherapy
In locally advanced thymic malignancies (i.e., unresectable
Masaoka stage III and IVA disease at time of diagnosis),
chemotherapy aims at making feasible subsequent R0
resection to achieve long-term survival. 1,6 Several chemotherapy
regimens have been used in this setting, mostly
consisting of doxorubicin- and/or platinum-based multiagent
combinations (Table 1). Usually two to four cycles of chemotherapy
are administered before imaging reassessment. In
this setting, response rates to chemotherapy ranged from
70% to 80% in the largest studies (Table 1). Patients for
whom R0 resection was thought to be feasible underwent
surgery, and complete resection was achieved in approximately
50% of cases (Table 1).
In those studies, when the patient was not deemed to be a
From the Department of Respiratory Medicine, Pilot Unit for the Management of Rare
Intrathoracic Tumors, National Expert Center for Thymic Malignancies, Louis Pradel
Hospital, Hospices Civils de Lyon; and UMR 754 “Retrovirus and Compared Pathology,”
Claude Bernard University, Lyon, France.
Author’s disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Nicolas Girard, Service de Pneumologie, Hôpital Louis
Pradel, 28, Avenue Doyen Lépine, 69677 Lyon (Bron), France; email: nicolas.girard@chulyon.fr.
© 2012 by American Society of Clinical Oncology.
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