Introduction
Dear Editor,
Thymoma is the most common type of thymic tumors,
whereas thymic carcinomas are very rare tumors with
poor prognosis and an incidence of 0.05% and were first
reported by Shimosato et al.[] in 1977. Surgery is the
mainstay of therapy in resectable cases. Multimodal approach
plays a crucial role in partially resectable or nonresectable
cases. However, due to the rare nature of these
tumors, there have been no extensive studies on pre- and
post-operative chemoradiotherapy and dose selection
for chemotherapy regimens and radiotherapy. Here, we
describe the case of a patient with partially resectable locally
advanced thymic carcinoma in whom 40% reduction
was achieved after concurrent chemoradiotherapy.
A 35-year-old male patient presented to the clinic
with chest pain that had persisted for 1 month. Posteroanterior
chest radiography result revealed a mass
in the middle mediastinum. Pre-operative magnetic
resonance imaging (MRI) results revealed the soft-tissue
density mass lesion, with a few millimetric calcification
foci (approximately 84×75 mm), adjacent to
the left upper lobe paramediastinal area in the anterior
mediastinum (Fig. 1). Partial resection of the mediastinal
mass was performed with the left thoracotomy. On
gross pathological examination, the tumor was a 3 cm
diameter, non-encapsulated solid mass lacking broad
fibrous septae on the cut surface. Surgical margin was
positive because of incomplete resection due to proximity
to the big vessels. Microscopically, the tumor was
composed of sheets of cohesive non-keratinizing squamous
cells displaying invasion to the lungs. Immunohistochemical
studies support the diagnosis of thymic
carcinoma with positive CD5, CD117, CK5/6, and P63 staining. Positive CD5 and CD117 indicate a thymic
origin. Negative TTF-1, CK7, and CK20 ruled out
metastasis. No lymphovascular or perineural invasion
was observed (Fig. 2a-d). The Masaoka stage was identified
as IVa. There was no evidence to indicate myasthenia
gravis. Following partial resection, chemoradiotherapy
was administered. Cisplatin 50 mg/m2 on days
1, 8, 29, and 36; etoposide 50 mg/m2 on days 1-5 and
29-33; and radiotherapy at a total dose of 59.4 Gy at
1.8 Gy/fraction helical tomotherapy for 33 days were
planned. When the mass shrank at 39.6 Gy, adaptive
planning was applied, and the radiotherapy doses administered
to the lung and heart were reduced. Chest MRI performed 2 months after the chemoradiotherapy
revealed that the mass had shrunk by 40% (Fig. 3). The
patient is stable at the 6th year follow-up.
Fig 1: Pre operative magnetic resonance imaging.
Fig 2: (a) Sheets of non-keratinising malignant squamous cells with infiltrative growth pattern (hematoxylin and eosin
×100), (b) Positive CD5 staining (×400), (c) Positive CK5/6 (×400), (d) Positive CD117 staining (×400).
Fig 3: After chemoradiotherapy magnetic resonance imaging.
Thymic carcinoma is a rare aggressive neoplasm.
It is usually diagnosed at the advanced stage of III or
IV according to the Masaoka staging system. Although
complete surgical resection is the main treatment
modality, it is not always feasible due to invasion of
the neighboring vessels, lung tissues, pericardium,
and pleura. Alternatively, several treatment modalities,
such as surgery following induction chemotherapy and
surgery following chemoradiotherapy, are available.
There is no standard treatment due to the uncommon
nature of the disease. Some studies have shed light on
the use of induction chemotherapy regimen.[-] In a
study that reported an overall survival rate of 78% with surgery following induction chemotherapy followed by
radiotherapy, the neoadjuvant chemotherapy setting for
eight patients consisted of cisplatin (75 mg/m2 on day
1), epirubicin hydrochloride (100 mg/m2 on day 1), and
etoposide (120 mg/m2 on days 1, 3, and 5) repeated 3
times every 3 weeks; the induction chemotherapy regimen
for the remaining patients consisted of cisplatin
(50 mg/m2), adriblastin (50 mg/m2), and cyclophosphamide
(500 mg/m2) repeated 3 times every 3 weeks.
A dose of 40 Gy was usually administered to patients
undergoing complete resection and 50-60 Gy to those
undergoing partial resection; the mediastinum or residual
tumor areas were irradiated in 3-5 weeks with five
fractions per week.[] In a majority of reported cases,
cisplatin is a key agent for chemotherapy against thymic
tumors and was included in all of the reported regimens: Adriamycin/cisplatin/vincristine/cyclophosphamide or
cisplatin/etoposide,[] cisplatin/epirubicin/etoposide
or cisplatin/adriamycin/cyclophosphamide, and adriamycin/
cisplatin/cyclophosphamide/prednisone.[]
Theoretically, induction chemotherapy with concurrent
radiotherapy seems to be ideal for these cases similar to
that for other malignancies; however, limited prospective
or retrospective studies and case reports are available.
Therefore, we selected cisplatin 50 mg/m2 on days
1, 8, 29, and 36 and etoposide 50 mg/m2 on days 1-5 and
29-33 with concurrent radiotherapy for induction treatment,
although the supporting evidence is currently
limited. In our case, as only partial resection was possible
due to vascular invasion, concurrent chemoradiotherapy
was actually planned for induction purposes.
Therefore, the initial planned dose of radiotherapy was
59 Gy. We reassessed the possibility of surgery with
chest MRI at 50.4 Gy (day 28 of radiotherapy). Since it
was considered unresectable based on the decision of
the chest surgery clinic, we completed radiotherapy at
a dose of 59 Gy concurrently with chemotherapy. Thus,
we demonstrated the efficacy of chemoradiotherapy
with the use of cisplatin and etoposide in our case.
Paclitaxel is another preferred induction chemotherapy
agent. It is a new agent that induces excessive
polymerization of tubulin and has demonstrated clinical
activity in a wide variety of malignancies, including
ovarian, breast, head-and-neck, and lung cancers.
Morio et al.[] reported a case of Stage IVb thymic
carcinoma with lymph node metastasis and achieved
complete resection after induction therapy with weekly
paclitaxel plus cisplatin and concurrent radiotherapy (total dose 40 Gy). Another case of advanced thymic
carcinoma treated with induction docetaxel, which is
also a new agent classified as a taxan-like paclitaxel,
plus cisplatin, and concurrent radiotherapy (total dose
40 Gy) also achieved complete resection.[]
Although systemic workups did not detect any distant
metastases, the patient was diagnosed as Stage IVb
according to the Masaoka staging system[] because
of mediastinal lymph node metastasis. Two cycles of
chemotherapy consisting of paclitaxel (180 mg/m2, 3 h)
and cisplatin (80 mg/m2, 1 h) on day 1 were administered
every 3 weeks.
Anthracycline-based regimens are the current standard
of care for thymic carcinomas according to the
results of various Phase II clinical trials, but they have
not been tested in a Phase III study. Fornasiero et al.[]
reported their 13 years of experience in treating 37 patients
with Stages III and IV thymic carcinoma with cisplatin,
doxorubicin, vincristine, and cyclophosphamide
combination. The ORR was 91.8%; with 43% achieving
CR, but the median survival time was only 15 months.
Loehrer et al.[] reported a 50% ORR with 10% of patients
achieving CR and a median survival patient with
thymic carcinoma with metastatic or locally progressive
recurrent disease were treated with paclitaxel. There is
another Phase II study using a multidisciplinary approach
with induction chemotherapy followed by surgical
resection, radiation therapy, and consolidation
chemotherapy for unresectable thymoma. In this Phase
II study; 22 patients received induction chemotherapy
with PAC plus prednisone for three cycles. The authors
reported that induction chemotherapy resulted in a 14%
CR and a 63% PR rate. However, anthracyclines are
known to be associated with cardiomyopathy, especially
when combined with radiotherapy. Therefore, non-anthracycline
regimens may be preferable for patients
treated with chemoradiotherapy.[]
The European Organization for Research and Treatment
of Cancer conducted a study in which 16 patients
with advanced or recurrent thymoma were treated
with cisplatin and etoposide. In this trial, five patients
achieved CR and four achieved PR (ORR, 56%).[]
On the basis of a single agent activity of ifosfamide in
thymoma, 20 patients with advanced thymoma and
eight patients with thymic carcinoma were treated with
etoposide, ifosfamide, and cisplatin in an intergroup
trial conducted by ECOG. An ORR of 35% and 25%
was reported in patients with thymoma and thymic
carcinoma, respectively.[] Grassin et al.[] reported
similar poor results (PR, 25%) in a study of 16 patients
treated with etoposide, ifosfamide, and cisplatin. These
cisplatin plus etoposide-based regimens produced
apparently inferior response rates to those previously reported for anthracycline-based regimens.[] As
anthracycline-based chemotherapy can cause cardiac
toxicities and cardiomyopathy, etoposide plus cisplatin
is a potential alternative if radiotherapy is also to be
administered. Furthermore, etoposide plus cisplatin
combined with radiotherapy is the standard treatment
for patients with localized advanced non-small-cell
lung cancer[,] and local small-cell lung cancer[]
and has generally been well-tolerated by such patients.
In summary, combined cisplatin plus etoposide for
thymic carcinoma is effective and reasonably well-tolerated,
particularly with concurrent radiotherapy. Despite
the limited evidence to support the use of cisplatin plus
etoposide as a treatment for advanced thymic carcinoma,
it is an alternative chemotherapy when anthracycline-
based regimens cannot be used. Given the rarity of
this tumor, prospective randomized trials are unlikely.
Cumulative data, however, suggest that anthracyclinebased
regimens should remain the standard of care for
these patients. However, for patients who can be treated
with concurrent radiotherapy, etoposide plus cisplatin is
a potential chemotherapy regimen for this malignancy.
