Original Study

Thymic Epithelial Neoplasms: A 12-Year Canadian Regional Cancer Program Experience Paul Wheatley-Price,1,4 Hannah Jonker,1 Derek Jonker,1,4 Farid Shamji,2,4 Marcio M. Gomes3,4 Abstract Thymoma and thymic carcinoma are uncommon neoplasms. In this review of 12 years of cases at a single institution, 76 patients were identified and surgery was performed in 64 of them, with complete resection in 83% of these patients. Although only 14 patients received chemotherapy, the initial response rate was > 50%, with no patients experiencing primary disease progression. Background: Thymic epithelial neoplasms are rare, with little prospective research to guide management. Surgery is the primary treatment modality for localized disease, but chemotherapy may be indicated in advanced disease. We performed a retrospective chart review of all cases over a 12-year period at our institution. Patients and Methods: With ethics approval, data collected included patient characteristics, histologic type (World Health Organization [WHO] criteria), staging (Masaoka system), paraneoplastic syndromes, treatment details, and outcomes. The primary analysis is descriptive. Results: Thymic epithelial neoplasms were identified in 76 patients: 46% women with a median age 60 years (range, 25-89 years), 93% with Eastern Cooperative Oncology Group performance status of 0 to 1. Myasthenia gravis was present in 21%. The distribution by WHO histologic classification was A, 15%; AB, 30%; B1, 16%; B2, 13%; B3, 17%; C, 7%; neuroendocrine thymic tumor (NETT), 1%; and unclassified, 1%. Of 64 patients who underwent operation, 53 underwent R0 resection. Eleven surgical patients received chemotherapy (induction, n ¼ 6; adjuvant, n ¼ 4; both, n ¼ 1) and 27 received radiotherapy (induction, n ¼ 2; adjuvant, n ¼ 25). Twelve patients were not considered for surgery, and 3 patients received no therapy at all. Chemotherapy was received at some point in the disease course in 14 patients. Common first-line regimens were platinum/etoposide (n ¼ 8), carboplatin/paclitaxel (n ¼ 3), and CAP (cyclophosphamide, doxorubicin [Adriamycin], cisplatin [n ¼ 2]). The first-line response rate (Response Evaluation in Solid Tumors [RECIST]) was 55%. After a median follow-up of 45 months, 59 (78%) patients remain alive. Thymoma was associated with superior overall survival compared with thymic carcinoma (P < .0001). Conclusion: Although surgical resection is the mainstay of treatment for thymic epithelial neoplasms, it remains clear that these are chemosensitive diseases. Clinical Lung Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Chemotherapy, Thymic carcinoma, Thymoma

Introduction Thymic epithelial neoplasms, primarily thymoma and thymic carcinoma, are uncommon, with the incidence in the United States being approximately 0.15 per 100,000 person years.1 The PWP and HJ contributed equally to this work. 1 Ottawa Hospital Research Institute and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada 2 Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada 3 Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada 4 The Ottawa Hospital, Ottawa, Ontario, Canada

Submitted: Oct 10, 2013; Accepted: Dec 2, 2013 Address for correspondence: Paul Wheatley-Price, MBChB, MRCP, MD, Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, ON, K1H 8L6 Fax: 613-247 3511; e-mail contact: [email protected]

1525-7304/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2013.12.003

infrequent presentation of this disease in clinical practice has hindered both clinical research and the development of proper guidelines for management. With these challenges for research, evidence for best practice has been based primarily on small case series of individual institutional experiences.2,3 More recently there have been several prospective studies looking at the effect of adjuvant radiotherapy after surgical resection4 or various forms of chemotherapy for unresectable thymoma,5-13 a multimodality approach,14-16 or studies of biological or targeted agents,17-22 but all of these generally have small numbers of patients. Advances have been made in understanding the biological behavior of the tumor from the surgical pathologic staging system of Masaoka and the histologic descriptors in the WHO classification. Diligent application of this knowledge should foster development of targeted therapy.

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Thymic Epithelial Neoplasms: A Case Series The strict terms reserved for the most common tumors of the thymus gland originating from the endodermal thymic epithelial cells are thymoma and thymic carcinoma. The neuroendocrine carcinoid tumor of the thymus gland has a different embryologic origin from the neural crest cell and are extremely rare. The clinical presentation varies from incidental findings on imaging studies to symptoms of local invasion, mediastinal compression, or varied systemic paraneoplastic manifestations. A number of patients with thymoma are identified after evaluation for a diagnosis of myasthenia gravis (MG), with about 10% to 15% of patients with MG subsequently diagnosed with thymoma.1 Other autoimmune disorders such as red cell aplasia are associated with thymoma. We undertook a retrospective review of patients seen at our tertiary hospital to advance knowledge in the management of thymic epithelial neoplasms. The Ottawa Hospital Cancer Program is the only referral center for radiation, medical oncology, and thoracic surgery services in the Champlain region of Eastern Ontario, serving a population of approaching 1.5 million.

Patients and Methods After ethics board approval, a search was undertaken for all patients with a diagnosis of thymoma, thymic carcinoma, and other epithelial thymic malignancies seen at our institution from January 1, 2000 until December 31, 2012. Patients were included if they were referred from outside centers but excluded if on review of the chart the diagnosis could not be confirmed. In eligible patients, a retrospective chart review was performed, collecting 74 data points. Data points included baseline patient demographics, histologic type using the World Health Organization (WHO) classification,23 staging using the Masaoka system,24 presence or absence of paraneoplastic syndromes such as MG and red cell aplasia, treatment types, patient outcome, and additional information on systemic therapy and response rates. When the histologic report did not clearly indicate a WHO classification, the report was reviewed by an investigator (MMG [a thoracic pathologist]). When there was uncertainty between classifications (eg, B2 or B3), the worse classification was reported for the purpose of analysis.

The primary analysis was descriptive. End points of interest included overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, overall survival for all patients, and disease-free survival for patients with surgically resected thymic tumors. In addition, exploratory analyses were undertaken to determine the impact of certain factors on survival, including age, sex, performance status, disease stage, histologic features, resection status, chemotherapy, and radiation. Statistical analysis was undertaken using descriptive statistics. Comparison of baseline characteristics between thymic carcinoma and thymoma was done using the Fisher exact test or the t test. Overall survival was defined as the time from histologic diagnosis to death, with patients alive at last follow-up censored at last point they were known to be alive. Disease-free survival was defined as the time from surgery to recurrence or death. Time-to-event outcomes were compared using the Kaplan-Meier method, with log-rank testing and calculation of hazard ratio (HR) with 95% confidence interval (CI). When data collection was complete, a basic statistical analysis was carried out to determine the patient characteristics. KaplanMeier survival analysis was carried out for survival by thymic tumor type, survival by thymoma histologic subtype, outcome by sex, and survival by age. Statistical analyses were conducted using MedCalc, version 12.7.0 (MedCalc Software, Ostend, Belgium).

Results The initial medical record search identified 90 patients with a diagnosis of thymic neoplasm. Of these, 14 were excluded because the diagnosis could not be confirmed. Of the remaining 76 patients, 70 (92%) had thymoma, 5 (6.6%) were diagnosed with thymic carcinoma, and 1 (1.3%) had a neuroendocrine tumor, specifically a thymic carcinoid. Baseline characteristics and histologic features are shown in Table 1. Overall, there were 35 female patients (46%) and 41 male patients (54%). There was no sex preponderance in the 70 patients with thymoma, with 34 women (49%); however, 80% (4 of 5) of the thymic carcinoma cases were men. The median age at diagnosis was 61 years for thymoma (range, 25-89 years), and 52 years (range, 41-73) in thymic

Table 1 Baseline Patient and Tumor Characteristics by Thymic Cancer Type Variable Age (years), mean (range) Sex: M(%)/F(%) Myasthenia Gravis (%) Histologic Type

Masaoka Stage

Size (cm), mean (range)

Thymoma (n [ 70)

Thymic Carcinoma (n [ 5)

NETT (n [ 1)

P Valuea

61 (25-89) 36 (51)/34 (49) 16 (23) A 11 AB 23 B1 12 B2 10 B3 13 Unclassified 1 I 28 IIa 16 IIb 8 III 8 IVa 8 Unclassified 2 6.2 (1.9-18)

52 (41-73) 4 (80%)/1 (20%)

46 Male

.225 .361

Squamous 2 Unclassified 3

Moderately-differentiated (atypical carcinoid)

IVa 3 IVb 1 Unclassified 1

IVb 1

6.3 (4.7-7.7)

14

Abbreviation: NETT ¼ neuroendocrine thymic tumor. a Denotes comparison of thymoma versus thymic carcinoma.

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Paul Wheatley-Price et al Figure 1 Waterfall Plot of Tumor Response in Patients Receiving First-line Chemotherapy (Excluding Patients Receiving Adjuvant Therapy)

Abbreviations: ADOC ¼ doxorubicin (Adriamycin), vincristine (Oncovin), cyclophosphamide; CAP ¼ cyclophosphamide, doxorubicin (Adriamycin), cisplatin; CP ¼ carboplatin/paclitaxel; PE ¼ platinum/etoposide; RECIST ¼ Response Evaluation Criteria in Solid Tumors.

carcinoma. Of all the patients, 71 (93%) had a good baseline performance status (Eastern Cooperative Oncology Group, 0-1). MG was present in 16 (21%) patients, all of whom had thymoma (9 women; 7 men). There were no other autoimmune or paraneoplastic syndromes diagnosed. Among the 16 patients with a diagnosis of MG, the Myasthenia Gravis Foundation of America initial classification25 was as follows: class I (ocular muscle weakness only), n ¼ 4; class II (mild weakness of extraocular muscles), n ¼ 6; class III (moderate weakness of extraocular muscles), n ¼ 3; class IV (severe weakness of extraocular muscles), n ¼ 2; and class V (requiring intubation), n ¼ 1.

The WHO histologic classification was A (n ¼ 11, 15%), AB (n ¼ 23, 30%), B1 (n ¼ 12, 16%), B2 (n ¼ 10, 13%), B3 (n ¼ 13, 17%), C (n ¼ 5, 7%), neuroendocrine thymic tumor (NETT) (n ¼ 1, 1%), and unclassified (n ¼ 1, 1%). The average tumor size was 6.2 cm for thymoma (range, 1.9-18 cm) and 6.3 cm for thymic carcinoma (range, 4.7-7.7 cm). Definitive surgery was performed in 64 patients (84%), with 53 patients undergoing R0 resection. For those who had surgery, 11 also received chemotherapy as induction (n ¼ 6), adjuvant (n ¼ 4), or both (n ¼ 1). Radiotherapy was received by 27 patients, either as induction (n ¼ 2) or adjuvant therapy (n ¼ 25). Of the 25 patients who received adjuvant radiotherapy, the surgical resection status was R0 in 15 patients, R1 in 9 patients, and R2 in just 1 patient. The pathologic Masaoka stage was IIa (n ¼ 6), IIb (n ¼ 6), III (n ¼ 8), IVa (n ¼ 4), and IVb (n ¼ 1). Alternatively, of the 64 surgical patients, 0 of 26 patients with stage I disease received radiotherapy, 12 of 24 (50%) of patients with stage II disease received radiotherapy, and 13 of 14 (93%) patients with stage III or IV disease received radiotherapy. Of the surgical patients, 7 (11%) had a recurrence, and treatment for the recurrence was surgery (n ¼ 2), chemotherapy plus radiotherapy (n ¼ 4) or chemotherapy, or radiotherapy plus surgery (n ¼ 1). Twelve patients (16%) were not treated surgically, with their primary treatment being radiotherapy (n ¼ 5) or chemotherapy plus radiotherapy (n ¼ 4). Three patients did not receive active treatment of any modality (surgery, chemotherapy, or radiotherapy) over the course of their illness. In total, only 14 patients (18%) received systemic therapy in any setting. When evaluable, the first-line response rate (by RECIST) was 55%, but no patients had progressive disease (Fig. 1). Common first-line regimens were platinum/etoposide (n ¼ 7), carboplatin/ paclitaxel (n ¼ 3), and CAP (cyclophosphamide, doxorubicin

Figure 2 Overall Survival (OS) by Thymic Tumor Type

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Thymic Epithelial Neoplasms: A Case Series Table 2 Phase II Trials of Systemic Therapy in Unresectable Thymic Cancers Overall Survival Regimen

Patients

ORR (%)

Median (Months)

Carboplatin AUC 6 i.v. Paclitaxel 225 mg/m2q3w Cisplatin 25 mg/m2/wk, wk 1-9 Vincristine 1 mg/m2/wk, wk 1, 2, 4, 6, 8 Doxorubicin 40 mg/m2, d 1-3, wk 1, 3, 5, 7, 9 Etoposide 80 mg/m2, d 1-3, wk 1, 3, 5, 7, 9 (Followed by surgery þ postoperative RT) Etoposide 100 mg/m2, d 1-3 Ifosfamide 1500 mg/m2, d 1-3 Cisplatin 30 mg/m2, d 1-3, q3w Cisplatin 25 mg/m2, wk 1-9 Vincristine 1 mg/m2 wk 1, 2, 4, 6, 8 Doxorubicin 40 mg/m2, d 1-3, wk 1, 3, 5, 7, 9 Etoposide 80 mg/m2, d 1-3, wk 1, 3, 5, 7, 9 Cyclophosphamide 50 mg/m2, d 1 Doxorubicin 60 mg/m2, civ over 72 h Cisplatin 90 mg/m2, civ over 72 h Prednisone 100 mg, d 1-5, q3-4 wk (Followed by surgery þ postoperative RT) Carboplatin 700 mg/m2 Etoposide 750 mg/m2d e5 to e3 (Followed by bone marrow transplantation) Cisplatin 50 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2, d 1, q3-4 wk (Followed by surgery þ postoperative RT) Etoposide 75 mg/m2, d 1-4 Ifosfamide 1200 mg/m2, d 1-4 Cisplatin 20 mg/m2, d 1-4, q3w Cisplatin 60 mg/m2, d 1 Etoposide 120 mg/m2, d 1-3, q3w Cisplatin 80 mg/m2, d 1 Doxorubicin 45 mg/m2, d 1 Cyclophosphamide 800 mg/m2, d 1 Etoposide 80 mg/m2, d 1-3 G-CSF 90 mg/m2, s.c., d 5-18, q3-4 wk Cisplatin 50 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2, d1, q3w Cisplatin 50 mg/m2, d 1, q3w

Thymoma n ¼ 21 TC n ¼ 23 Locally advanced thymoma N ¼ 21

42.9 21.7 61.9

59.4 20 NR

Thymoma N ¼ 16

25

NR

78.1

Disseminated thymoma N ¼ 27

59

NR

89

Thymoma N ¼ 22

77.3

NR

95

NR

60

Study 10

Lemma et al

2011

Kunitoh et al15 2010

Grassin et al7 2010

Kunitoh et al9 2009

Kim et al14 2004

Hanna et al8 2001

Loehrer et al16 1997

Loehrer et al11 2001

Giaccone et al6 1996 Oshita et al13 1995

Loehrer et al12 1994

Bonomi et al5 1993

Thymoma n ¼ 4 TC n ¼ 1

100

2 Years (%) 80 47 100

Thymoma N ¼ 23

69.6

NR

72

Thymoma n ¼ 20 TC n ¼ 8

32.1 (all)

31.6 (all)

70 (all)

N ¼ 16 Thymoma

56.3

52

80

Thymoma n ¼ 7 TC n ¼ 7

42.9

14.7

50

Thymoma n ¼ 29 TC n ¼ 1

50

37.7

64.5

Thymoma N ¼ 21

10

17.5

39

37.5 0 0 37.5 (all)

NR 23.4 UNK 18

75% (all)

8 0 0

NR 12.4 4

66 0 NR

0

NR

UNK

0

UNK

UNK

Nonchemotherapy Systemic Therapy Trials Loehrer et al19 2004

Octreotide 0.5 mg, s.c. t.i.d.

Palmieri et al21 2002

Giaccone17, 2011

Octreotide 0.5mg/kg, s.c. t.i.d. þ prednisone 0.6 mg/kg p.o. daily  3 mo then prednisone 0.2 mg/kg p.o. daily Belinostat 1g/m2

Giaccone et al18 2009

Imatinib 600 mg p.o. daily

Palmieri et al20 2012

Imatinib 400 mg p.o. daily

Gordon et al22 1995

Interleukin-2

Thymoma n ¼ 32 TC n ¼ 5 NETT n ¼ 1 Thymoma n ¼ 10 TC n ¼ 3 NETT n¼3 Thymoma n ¼ 25 TC n ¼ 16 Thymoma, B3 n ¼ 2 TC n ¼ 5 Thymoma and TC N ¼ 15 Thymoma N ¼ 14

32

Abbreviations: AUC ¼ area under the curve; G-CSF ¼ granulocyte colony-stimulating factor; i.v. ¼ intravenously; NETT ¼ neuroendocrine thymic tumor; NR ¼ not reached; ORR ¼ overall response rate; q3w ¼ every 3 weeks; RT ¼ radiotherapy; s.c. ¼ subcutaneously; TC ¼ thymic carcinoma; t.i.d. ¼ 3 times/day; UNK ¼ not reported.

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[Adriamycin], cisplatin [n ¼ 2]). Only 3 patients received further chemotherapy in a second-line setting or beyond (3 patients received 3 more lines of treatment).

Clinical Lung Cancer Month 2014

The median follow-up for all patients was 45 months, and 59 (78%) remain alive. Of the 5 patients with thymic carcinoma, 4 of 5 have died, resulting in a median survival of 10 months.

Paul Wheatley-Price et al Of the patients with thymoma, 1-, 2-, and 5-year survivals were 94%, 93%, and 83%, respectively (Fig. 2). Median overall survival for patients with thymoma was 11.8 years. Thymoma was associated with superior overall survival (HR, 0.05; 95% CI, 0.013-0.21; P < .0001) compared with thymic carcinoma. In evaluating the impact of baseline factors on overall survival, none achieved statistical significance, although there was a trend toward worse survival with age  65 years (HR, 2.13; 95% CI, 0.79-5.8; P ¼ .089). There was no significant impact on survival for male sex (HR, 1.5; 95% CI, 0.58-3.89; P ¼ .38), Masaoka stage, thymoma histologic subtype, presence of MG, or performance status. However, the small sample size may have limited the capacity to detect these differences.

Discussion Thymic epithelial neoplasms are uncommon. The type of treatment is determined more by the local behavior of invasion in the mediastinum than it is by the presence of associated paraneoplastic systemic effects, and surgery remains the primary modality of therapy. This study was conducted in a sole-provider regional cancer referral center that covers a region of 1.5 million. With an approximate yearly incidence of 6.3 cases, this would be equivalent to 1 case per 186,000 population. Despite the small cohort size, we were able to demonstrate that survival for thymic carcinoma was significantly worse than that for thymoma, which is well reported and to a degree validates our data set. Seventy-eight percent of patients included in this study are still living, giving a median follow-up of 45 months and an estimated median survival of nearly 12 years. However, median survival for patients with thymic carcinoma was only 10 months. For all thymic epithelial neoplasms, surgical resection is the mainstay of treatment. The role of adjuvant radiotherapy after surgery is debated, particularly for stage II disease. Although overall survival has been reported with the use of adjuvant radiotherapy, these studies have combined stage II and stage III, and there is a suggestion that there may be little benefit in stage II given the low recurrence rate in this group.26,27 This equipoise in the literature is reflected in the results from our cohort, in which radiotherapy was not given at all in stage I disease, was given almost universally (> 90%) in stage III/IV disease, but was given only 50% of the time in the debated stage II group. A prospective randomized study to investigate the role of adjuvant radiotherapy in this group of patients is planned through the International Thymic Malignancy Interest Group (ITMIG). Our case series demonstrated again that thymic malignancies are chemosensitive. In our study, the overall response rate was 55% with combination chemotherapy but, as demonstrated in Figure 1, no patients had primary progression of disease while receiving therapy. A systematic review of the literature identified 11 published phase II trials of chemotherapy (Table 2). For thymoma, response rates with combination chemotherapy (excluding single-agent cisplatin and high-dose chemotherapy as part of stem cell transplantation) ranged from 25% to 77.3%.5-16 Highest response rates were present in those studies that used a combination chemotherapy regimen of cisplatin, cyclophosphamide, and doxorubicin.14,16

For thymic carcinoma, response rates were generally lower (eg, 21.7% with carboplatin plus paclitaxel),10 but many of these studies did not report the response rate separately because of the smaller sample size.8,11-13 Clearly, thymic carcinoma is a much more aggressive disease than thymoma. With a median survival of only 10 months in our series, better treatments are needed. As our understanding of the biological characteristics of this tumor increases, newer agents may become available for evaluation. Thymic carcinomas frequently have c-kit mutations (consistently not seen in thymoma), CD70, and upregulation of cyclooxygenase 2.28-32 The insulin-like growth factor-1 receptor has also been reported to have high expression in thymic tumors (more commonly thymic carcinoma than thymoma) and insulin-like growth factor receptor inhibitors are being tested in this disease (clinicaltrials.gov ID NCT00965250).33 In addition, epidermal growth factor receptor is overexpressed in many thymic epithelial neoplasms, although epidermal growth factor receptor mutations are rare.34-36 Although there are case reports of the efficacy of erlotinib,37 a trial of gefitinib in 26 patients with advanced thymoma or thymic carcinoma demonstrated little clinical activity.36 A “gatekeeper” tumor suppressor gene, as yet undiscovered, has been hypothesized after observations of common genetic alterations on chromosome 6q25 across thymoma subtypes and thymic carcinoma.38-40 Ultimately, given the rarity of these cancers, coordinated multinational trials will need to be undertaken to make advances for thymic malignancies. ITMIG, founded in 2010, is leading the international community in such a coordinated approach.41 ITMIG has now completed a large international retrospective database of thymic malignancies (including the data from this series) and has started collecting data in a prospective manner. ITMIG also seeks to coordinate research and collaboration in areas such as staging, classification, radiotherapy, and systemic therapy trials.

Conclusion In summary, surgery clearly remains the central pillar in the increasingly multidisciplinary management of thymic epithelial neoplasms. Despite the identification of molecular signals in thymoma and thymic carcinoma, no targeted therapies have yet demonstrated proven efficacy; therefore, traditional cytotoxic agents remain the standard of care in cases in which systemic therapy is indicated.

Clinical Practice Points  Thymic epithelial neoplasms are rare tumors of the anterior

mediastinum.  The majority of patients are treated surgically, with the option of

induction chemotherapy, adjuvant radiotherapy, or both in more locally advanced cases.  In advanced disease, these neoplasms are demonstrated to be chemosensitive.  The overall survival for thymoma is generally good, but median survival for patients with thymic carcinoma is significantly shorter.  ITMIG is leading efforts in collaboration for developing guidelines and leading research in these tumors.

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Thymic Epithelial Neoplasms: A Case Series Acknowledgments The authors would like to thank The Ottawa Hospital Cancer Centre clinical trials office for their support of this research and Gillian Gresham for assisting with biostatistics.

Disclosure The authors have stated that they have no conflicts of interest.

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