Patterns of Failure Following Postoperative Radiation Therapy Based on “Tumor Bed With Margin” for Stage II to IV Type C Thymic Epithelial Tumor

International Journal of

Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation

Patterns of Failure Following Postoperative Radiation Therapy Based on “Tumor Bed With Margin” for Stage II to IV Type C Thymic Epithelial Tumor Kyung Hwa Lee, MD,* Jae Myoung Noh, MD, PhD,* Yong Chan Ahn, MD, PhD,* Dongryul Oh, MD, PhD,* Jhingook Kim, MD, PhD,y Young Mog Shim, MD, PhD,y and Jung-ho Han, MD, PhDz Departments of *Radiation Oncology, yThoracic and Cardiovascular Surgery, and zPathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Received Mar 7, 2018, and in revised form Jun 12, 2018. Accepted for publication Jul 30, 2018.

Summary This retrospective study, performed to report failure patterns and evaluate the suitability of radiation target volume of the “tumor bed only with margin” in Masaoka-Koga stage II to IV type C thymic epithelial tumor after postoperative radiation therapy, indicated that most failures occurred out of the radiation field, mostly in the pleura, not the regional lymph nodes. The policy of using a target

Purpose: The study purpose was to report failure patterns in Masaoka-Koga stage II to IV type C thymic epithelial tumor (TET) after postoperative radiation therapy (PORT) and to evaluate the suitability of PORT target volume confined to the “tumor bed only with margin.” Methods and Materials: A retrospective review of 53 patients with stage II to IV type C TET was performed. The clinical outcomes, failure patterns in relation to PORT target volume, and prognostic factors were analyzed. Results: During a median follow-up period of 69 months, 14 deaths and 25 recurrences were observed. The 5-year rates of overall survival, disease-specific survival, and freedom from recurrence were 81.0%, 91.5%, and 49.7%, respectively. The failure patterns in relation to PORT target volume were in-field failure in 2 patients (3.8%), marginal in 2 (3.8%), and out of field in 23 (43.4%), respectively. The most common failure site was the pleura (12 patients), followed by the lung parenchyma (8 patients). Relapse involving the regional lymph nodes was observed in 6 patients, of whom 4 had synchronous distant failure and only 2 had isolated ipsilateral supraclavicular lymph node failure.

Reprint requests to: Yong Chan Ahn, MD, PhD, Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-gu, Seoul 06351, Republic of Korea. Tel: þ82-2-3410-2602; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 102, No. 5, pp. 1505e1513, 2018 0360-3016/$ - see front matter Ó 2018 Published by Elsevier Inc. https://doi.org/10.1016/j.ijrobp.2018.07.2022

K.H.L. and J.M.N. contributed equally to this work. Conflict of interest: none.

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1506 Lee et al. volume confined to only the tumor bed seems reasonable in treating these patients, although the development of a more effective systemic therapy regimen is warranted.

Conclusions: The policy of PORT target volume confined to only the tumor bed seems reasonable in treating patients with stage II to IV type C TET. The development of a more effective systemic therapy regimen is warranted. Ó 2018 Published by Elsevier Inc.

Introduction Type C thymic epithelial tumor (TET) is a rare malignancy that usually follows an aggressive clinical course, leading to poor clinical outcomes.1 Although an aggressive multimodality approach, usually including surgical resection, radiation therapy (RT), and chemotherapy, has been preferred in treating patients with type C TET, the optimal treatment strategy still needs to be determined mainly because of the paucity of prospective clinical trials.2 Postoperative RT (PORT) has been generally recommended to eradicate the potential residual tumor burden after surgery in treating patients with type A to B3 TET,3-7 but its role in type C histology has not been extensively studied. Moreover, it is still unclear whether the PORT target volume could be confined to the “tumor bed only (with margin)” or should be expanded to include the adjacent lymph node (LN) regions electively. In addition, no study has addressed the failure pattern regarding the PORT target volume in type C TET. We report our clinical experiences including failure patterns in relation to the PORT target volume in stage II to IV type C TET.

Methods and Materials Patients and treatment After receiving approval by the institutional review board (2017-11-128), we retrospectively reviewed the medical records of patients who received PORT for histopathologically confirmed Masaoka-Koga stage II to IV type C TET from 2002 until 2014. PORT was to start within 4 to 6 weeks of surgery, and the target volume was confined to the tumor bed including involved pleura, according to our policy. The tumor bed was defined based on the initial tumor extent, surgical findings, and postsurgical pathologic reports. The surgeons were asked to place metal clips at the resection bed for future guidance on PORT target delineation if they were not confident in the adequacy of the resection margins. Uninvolved regional LN regions were not electively covered unless involved as in Masaoka-Koga stage IVB. Figure 1 shows an example of our target volume delineation in a 75-year-old male patient with stage III thymic squamous cell carcinoma who underwent extended total thymectomy and chest wall reconstruction followed by PORT. All patients were treated with 3-dimensional conformal RT using 3 anteriorly located beams (anterior and both

anterior obliques), which was almost the same protocol as in our previous report on treating patients with type A to B3 TET.8 The median total dose was 54 Gy (range, 46-64 Gy), given at 2 Gy per fraction. Chemotherapy was delivered to 28 patients (52.8%): 4 before surgery, 9 after surgery but before PORT, 14 after PORT, and 1 both before surgery and after PORT. The most commonly used combination of chemotherapy was cisplatin, adriamycin (doxorubicin), and cyclophosphamide, followed by etoposide and cisplatin.

Definitions of endpoints and statistical analysis The endpoints included the rates of overall survival (OS), disease-specific survival (DSS), and freedom from recurrence (FFR). The failure pattern was subdivided into local, regional, and distant according to the International Thymic Malignancy Interest Group (ITMIG) guidelines9: Local failure was defined as failure within or around the primary tumor bed; regional failure, as intrathoracic failure not contiguous with the primary tumor bed including pleuropericardial seeding; and distant failure, as extrathoracic failure including parenchymal pulmonary metastasis. In addition, all treatment failures were categorized with respect to the PORT target volume according to the ITMIG guidelines10: In-field failure was defined as failure within 100% of the isodose line (IDL); marginal failure, as failure outside 100% but within 50% or more of the IDL; and out-of-field failure, as failure outside 50% of the IDL. The durations of OS and DSS were calculated from the date of initial histopathologic diagnosis until the date of the last follow-up or death, and the duration of FFR was calculated from the date of completion of PORT until the date of the last follow-up or recurrence. The c2 test and t test were used to analyze the distributions of categorical and continuous variables, respectively. The Kaplan-Meier method was used to determine the survival rate. The log-rank test was used to compare differences between groups. Multivariate analysis was not performed because of the small number of patients. P < .05 was considered statistically significant, and SPSS software (version 23.0; IBM, Armonk, NY) was used for statistical analysis.

Results Patient characteristics Patient characteristics are summarized in Table 1. A total of 53 patients with stage II to IV type C TET underwent

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Failure patterns of type C TET 1507

Fig. 1. A 75-year-old male patient underwent extended total thymectomy and chest wall reconstruction followed by postoperative radiation therapy for stage III thymic squamous cell carcinoma. (A) Preoperative computed tomography shows anterior chest wall invasion (arrow). (B) The clinical target volume (light blue line) is confined to the tumor bed. (A color version of this figure is available at https://doi.org/10.1016/j.ijrobp.2018.07.2022.) PORT after curative resection. The median age was 54 years (range, 20-81 years), and 69.8% of patients were men. The median greatest tumor dimension at diagnosis was 6.5 cm (range, 0.8-12 cm). The postsurgical residual tumor burdens were R0 (no macroscopic or microscopic residual) in 44 patients (83.0%), R1 (microscopic residual) in 5 (9.4%), and R2 (macroscopic residual) in 2 (3.8%). The postsurgical Masaoka-Koga stages were II in 22 patients (41.5%), III in 22 (41.5%), and IV in 9 (17.0%). The American Joint Committee on Cancer stages (eighth edition), proposed by the International Association for the Study of Lung Cancer and ITMIG,11 were I in 22 patients (41.5%), II in 2 (3.8%), III in 20 (37.7%), IVA in 7 (13.2%), and IVB in 2 (3.8%). Among all patients, 43 (81.1%) had thymic carcinoma (TC) whereas 10 (18.9%) had thymic neuroendocrine tumor (TNET). The most common histologic type among patients with TC was squamous cell carcinoma, occurring in 38 patients (88.4%); other types included mucoepidermoid carcinoma, clear cell carcinoma, sarcomatoid carcinoma, lymphoepithelioma-like carcinoma, and carcinoma not otherwise specified. Among the 10 patients with TNET, 6 (60.0%) had atypical carcinoid and 4 (40.0%) had large cell neuroendocrine carcinoma. The median age of patients with TC was greater than that of patients with TNET (55 years vs 51 years, P Z .025).

OS, DSS, and FFR During the median follow-up period of 69 months (range, 6-160 months), 14 patients (26.4%) died, of whom 8 (15.1%) died of disease, and 25 (47.2%) experienced recurrence. The median durations of OS and DSS were not reached yet, and that of FFR was 54 months (range, 1151 months). The 5-year rates of OS, DSS, and FFR were 81.0%, 91.5%, and 49.7%, respectively (Fig. 2).

Patterns of failure Local, regional, and distant failures occurred in 2 patients (3.8%), 17 patients (32.1%), and 10 patients (18.9%), respectively (Table 2). The first failure patterns were categorized in relation to the PORT target volume: In-field, marginal, and out-of-field failures occurred in 2 patients (3.8%), 2 patients (3.8%), and 23 patients (43.4%), respectively. Table 3 summarizes the detailed information on the failure patterns and consequent outcomes after salvage treatment efforts. One patient in whom isolated local and in-field failure developed underwent successful salvage after reoperation after 102 months. Exclusive regional failure was observed in 13 patients, among whom 7 with 1 to 3 lesions

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1508 Lee et al. Table 1

Patient characteristics

Median age (range), y Sex, n Male Female ECOG PS, n 0 1 Median greatest tumor dimension (range), cm Surgical margin status, n R0 R1 R2 Unknown Masaoka-Koga stage, n 2 3 4 AJCC stage (eighth edition), n I: T1N0M0 II: T2N0M0 III: T3N0M0 IVA T1N1M0 T2N1M0 T3N1M0 IVB T2N2M0 T2N0M1 Chemotherapy, n Yes No Median RT dose (range), Gy

Total (N Z 53)

TC (n Z 43)

TNET (n Z 10)

P value

54 (20-81)

55 (38-81)

51 (20-62)

.025 .988

37 (69.8%) 16 (30.2%)

30 (69.8%) 13 (30.2%)

7 (70.0%) 3 (30.0%)

23 (43.4%) 30 (56.6%) 6.5 (0.8-12)

20 (46.5%) 23 (53.5%) 6.5 (0.8-12)

3 (30.0%) 7 (70.0%) 6.5 (1.8-10)

44 5 2 2

38 4 1 0

.484

(83.0%) (9.4%) (3.8%) (3.8%)

(88.4%) (9.3%) (2.3%) (0.0%)

6 1 1 2

.883 .370

(60.0%) (10.0%) (10.0%) (20.0%) .714

22 (41.5%) 22 (41.5%) 9 (17.0%)

17 (39.5%) 19 (44.2%) 7 (16.3%)

5 (50.0%) 3 (30.0%) 2 (20.0%)

22 (41.5%) 2 (3.8%) 20 (37.7%)

17 (39.5%) 2 (4.7%) 17 (39.5%)

5 (50.0%) 3 (30.0%)

1 (1.9%) 1 (1.9%) 5 (9.4%)

1 (2.3%) 5 (11.6%)

1 (10.0%) -

1 (1.9%) 1 (1.9%)

1 (2.3%)

1 (10.0%) -

28 (52.8%) 25 (47.2%) 54 (46-64)

22 (51.2%) 21 (48.8%) 54 (50-64)

6 (60.0%) 4 (40.0%) 54 (46-54)

.736

.614

.114

Abbreviations: AJCC Z American Joint Committee on Cancer; ECOG PS Z Eastern Cooperative Oncology Group performance status; RT Z radiation therapy; TC Z thymic carcinoma; TNET Z thymic neuroendocrine tumor.

underwent a salvage local therapy effort with either surgery or high-dose RT; salvage was successful in only 1. Relapse involving the regional LNs was observed in 6 patients (11.3%), of whom 4 had synchronous distant or regional failures, including lung metastases in 2 and pleural metastases in 2; only 2 had isolated lower neck LN failures. Of the 6 patients with LN failures, 5 had out-of-field failures whereas only 1 had marginal failure accompanied by synchronous parenchymal lung metastasis. Among the 10 patients in whom a distant failure component developed, 9 presented with parenchymal lung metastases (2 with and 7 without synchronous LN metastases) whereas 1 had multiple skeletal metastases with synchronous pleural seeding. Six patients presented with a single lung metastasis at a median of 36 months (range, 15-70 months), and in 3 of 4 patients who underwent either salvage surgery or stereotactic body RT, salvage was successful. Exclusively out-of-field failure was observed in 21 patients. The most common failure site was the pleura (12 patients), followed by the lung parenchyma (8 patients).

Prognostic factors The significance of several potential prognostic factors regarding the 5-year rates of OS, DSS, and FFR was tested using univariate analysis (Table 4). The unfavorable factor for OS was age of 60 years or older (56.7% vs 93.4%, P Z .002); the unfavorable factors for DSS were Eastern Cooperative Oncology Group performance status of 1 or higher (85.3% vs 100%, P Z .030), greatest tumor dimension of 9 cm or more (85.7% vs 92.4%, P Z .022), and TNET histology (77.1% vs 95.2%, P Z .027); and the unfavorable factors for FFR were higher Masaoka-Koga stage (11.1% vs 43.4% vs 72.9%, P Z .002) and American Joint Committee on Cancer stage (eighth edition) (0% vs 14.3% vs 45.3% vs 69.9%, P Z .010). There was a tendency toward an inferior 5-year FFR rate in patients with TNET compared with patients with TC (24.0% vs 56.4%, P Z .120). No incidence of grade 3 or higher toxicity related to PORT was observed (Table 5).

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Failure patterns of type C TET 1509

A

B 81.0%

80% 60% 40% 20% 0% 0

12

24

36

48

60

91.5%

100%

Disease-specific survival

Overall survival

100%

72

80% 60% 40% 20% 0% 0

12

24

36

48

60

72

38

33

26

Months

Months Number at risk

Number at risk 53

50

48

44

38

33

53

26

50

48

44

web 4C=FPO

Freedom-from-recurrence

C 100% 80%

49.7%

60% 40% 20% 0% 0

12

24

36

48

60

72

23

19

13

Months Number at risk 52

Fig. 2.

42

38

29

Kaplan-Meier plots of overall survival (A), disease-specific survival (B), and freedom from recurrence (C).

Discussion

explained by a few factors: (1) a relatively higher proportion of patients underwent R0 to R1 resection, (2) all patients received PORT, (3) a lower proportion of patients had Masaoka-Koga stage IV, and (4) the aggressive salvage local therapy effort resulted in a successful second cure. Of 25 patients with 1 to 3 recurrent lesions including a single lung metastasis in this study, 12 were treated with salvage local therapy, either surgery or high-dose RT, which resulted in successful salvage in 5. A few studies addressed the failure patterns among patients with type A to B3 TET after PORT.20-22 Rimner et al22 reported the failure pattern in relation to the RT target volume among patients with stage II to IV thymoma, excluding type C. They observed frequent recurrences involving the pleura followed by the LNs, which were mostly intrathoracic but out-of-field failures in relation to

Type C TET is known to be associated with more aggressive clinical behavior and a poorer prognosis than type A to B3 TET. TNET used to be a subtype of type C TET according to the third edition of the World Health Organization classification proposed in 2004 12 and was separated from type C in the revised World Health Organization classification proposed in 2015.13 Several recent population-based studies, some of which did not include TNET, showed that the addition of PORT was beneficial with respect to OS and/or recurrence-free survival.14-17 The 5-year OS rate in our study was 81.0%, which was favorable compared with recent population-based studies (61%-63%),15,17 as well as other retrospective studies (53%-68%).18,19 This favorable outcome could be Table 2

Failure pattern according to ITMIG guidelines

Failure pattern, n In field In field þ out of field Marginal Marginal þ out of field Out of field Total, n

Local

Local þ regional

Regional

Regional þ distant

Distant

1 (1.9%) 1 (1.9%)

1 (1.9%) 1 (1.9%)

1 (1.9%) 12 (22.2%) 13 (24.1%)

1 (1.9%) 2 (3.7%) 3 (5.6%)

7 (13.0%) 7 (13.0%)

Abbreviation: ITMIG Z International Thymic Malignancy Interest Group.

Total 1 1 1 1 21 25

(1.9%) (1.9%) (1.9%) (1.9%) (38.9%) (46.5%)

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1510 Lee et al. Table 3

Detailed information on failure patterns and salvage treatment efforts

Case Age, y/ No. Sex Histology 1 2

50/F 52/M

TC TNET

3

63/M

4

MasaokaPORT Koga dose, stage Residual Gy 3 4B

R2 R0

64 54

TC

3

R0

54

41/M

TNET

2

R0

54

5

68/M

TC

2

R0

54

6

39/M

TC

4B

R0

54

7

51/M

TC

4B

R0

54

8

62/F

TC

4B

R0

54

9

62/F

TNET

4B

R2

46

10

43/M

TNET

3

R0

54

11

65/M

TC

4B

R0

54

12

45/M

TC

3

R1

60

13

49/F

TC

2

R0

54

14

48/F

TC

3

R0

54

15

52/M

TNET

2

Unknown

54

16

68/M

TC

4B

R0

54

17

66/M

TC

3

R0

54

18

60/M

TNET

3

R0

54

19

20/F

TNET

2

R0

54

20

75/M

TC

3

R0

54

21

51/M

TC

3

R0

54

22

63/M

TC

3

R0

54

23

61/M

TC

4B

R0

54

24

56/F

TC

3

R0

54

25

45/M

TC

2

R0

54

Failure site Local at 30 mo Local þ regional (pleura) at 37 mo Regional (pleura) at 1 mo Regional (mediastinum) at 5 mo Regional (pleura) at 9 mo Regional (pleura and LN) at 9 mo Regional (LN) at 10 mo Regional (pleura and LN) at 12 mo Regional (pleura) at 15 mo Regional (LN) at 21 mo Regional (pleura) at 31 mo Regional (pleura) at 35 mo Regional (pleura) at 37 mo Regional (pleura) at 53 mo Regional (pleura) at 54 mo Regional (LN) þ distant (lung) at 2 mo Regional (LN) þ distant (lung) at 26 mo Regional (pleura) þ distant (bone) at 32 mo Distant (lung) at 1 mo Distant (lung) at 4 mo Distant (lung) at 6 mo Distant (lung) at 15 mo Distant (lung) at 31 mo Distant (lung) at 41 mo Distant (lung) at 70 mo

Relation to PORT target

Salvage treatment

Follow-up status after recurrence

In field Surgery In þ out of field Observation

NED at 99 mo AWD at 3 mo

Out of field

Palliative CTx

DOD at 5 mo

Marginal

Palliative CTx

DOD at 15 mo

Out of field

Palliative CTx

DOD at 48 mo

Out of field

Surgery

AWD at 69 mo

Out of field

RT

DOD at 50 mo

Out of field

Palliative CTx

AWD at 51 mo

Out of field

Observation

DOD at 35 mo

Out of field

CCRT

AWD at 34 mo

Out of field

Surgery þ PORT

NED at 53 mo

Out of field Out of field

Surgery followed by NED at 122 mo surgery þ PORT Palliative CTx AWD at 45 mo

Out of field

Surgery

AWD at 38 mo

Out of field

Surgery

AWD at 53 mo

Out of field

Palliative CTx

DOD at 2 mo

Marginal þ out Observation of field

AWD at 17 mo

Out of field

Palliative CTx

DOD at 48 mo

Out of field

Palliative CTx

DOD at 75 mo

Out of field

Palliative CTx

DOD at 4 mo

Out of field

Palliative CTx

DOD at 67 mo

Out of field

NED at 49 mo

Out of field

Surgery followed by RT Surgery

NED at 13 mo

Out of field

SBRT

NED at 22 mo

Out of field

Surgery

NED at 68 mo

Abbreviations: AWD Z alive with disease; CCRT Z concurrent chemoradiation therapy; CTx Z chemotherapy; DOD Z dead of disease; F Z female; LN Z lymph node; M Z male; NED Z no evidence of disease; PORT Z postoperative radiation therapy; SBRT Z stereotactic body radiation therapy; TC Z thymic carcinoma; TNET Z thymic neuroendocrine tumor.

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Failure patterns of type C TET 1511

Prognostic factors for 5-year rates of OS, DSS, and FFR by univariate analysis 5-y OS

Age 60 y <60 y Sex Female Male ECOG performance status 0 1 Greatest tumor dimension <9 cm 9 cm Histology Carcinoma Neuroendocrine tumor Postsurgical residual R0 R1-R2 Masaoka-Koga stage II III IV AJCC stage (eighth edition) I-II III IVA IVB Chemotherapy No Yes

5-y DSS

5-y FFR

n

%

P value

%

P value

%

P value

21 32

56.7 93.4

.002

81.0 96.8

.112

42.0 56.0

.164

16 37

80 83.3

.555

93.3 91.5

.506

55.6 47.8

.425

23 30

88.4 75.4

.163

100.0 85.3

.030

55.3 45.4

.318

46 7

83.2 64.3

.052

92.4 85.7

.022

54.2 19.0

.075

43 10

82.1 77.1

.330

95.2 77.1

.027

56.4 24.0

.120

44 7

85.3 57.1

.523

93.1 83.3

.766

51.3 50.0

.893

22 22 9

78.4 86.4 74.1

.692

95.5 95.2 74.1

.099

72.9 43.4 11.1

.002

24 20 7 2

72.7 85.0 85.7 0.0

.525

95.7 94.7 95.7 0.0

.063

69.9 45.3 14.3 0.0

.010

25 28

73.9 87.8

.445

95.8 87.8

.221

54.2 45.4

.534

Abbreviations: AJCC Z American Joint Committee on Cancer; DSS Z disease-specific survival; ECOG Z Eastern Cooperative Oncology Group; FFR Z freedom from recurrence; OS Z overall survival.

the RT target volume. The failure pattern after PORT in type C TET (including or excluding TNET) has not been studied previously. In our study the major failure pattern in relation to the PORT target volume was out-of-field failure, which was observed in 21 patients (84.0%) among 25 who had any type of failure. Although failures occurred more frequently in type C TET than in type A to B3, the failure pattern was more or less similar. We observed 6 patients (11.3%) in whom regional LN failure developed, of whom 4 had synchronous distant failures and only 2 had isolated

Table 5

Treatment-related toxicity

Adverse event Acute irradiation-induced esophagitis Radiation pneumonitis Fatigue Breast pain

Grade 1, n

Grade 2, n

Grade 3-5, n

12 (22.6%)

3 (5.7%)

0 (0%)

4 (7.5%) 2 (3.8%) 1 (1.9%)

1 (1.9%) 0 (0%) 0 (0%)

0 (0%) 0 (0%) 0 (0%)

ipsilateral supraclavicular LN failures. Moreover, in 2 patients with isolated LN failures, multiorgan systemic metastases eventually developed after high-dose salvage RT with or without concurrent chemotherapy. On the basis of our observation, electively enlarging the PORT target volume to include the uninvolved deep mediastinal and/or low neck LN regions would not be justified when considering RT-related toxicity risk. Longer-term follow-up including a larger number of patients, however, might be warranted. Very few studies have compared the clinical outcomes of patients with TC and TNET, mainly because of rarity and heterogeneity. Moreover, TNET has recently been separated from type C TET. Some retrospective studies, which focused on only TNET, reported frequent metastases to the mediastinal LNs and distant organs, resulting in a generally poor prognosis.23-27 However, Filosso et al,19 in their largest clinical series, showed that the patients with TC and TNET, after surgery, showed a similar median OS (6.6 years vs 7.5 years, P Z .79) and 5-year recurrence-free survival rate (35% vs 34%, P Z .59) on multivariate analysis. Weksler et al25 also reported no significant difference in OS rates

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between patients with TC and those with TNET (117 months vs 85 months, P Z .794). In our study the patients with TC and TNET showed similar failure patterns, but those with TNET tended to undergo a more aggressive course with inferior DSS and FFR than those with TC. Because of the small number of patients, our study might not be confirmative to characterize the differences between TC and TNET, and more studies are warranted. A few factors were shown to be prognostic in this study: A higher Eastern Cooperative Oncology Group status, larger greatest dimension of tumor, and a histology of TNET were associated with poorer DSS; advanced Masaoka-Koga stage and advanced new TNM stage were associated with poorer FFR, but not OS or DSS. The prognostic implication of the newly proposed TNM system in terms of FFR was affirmed in this study. In our study 28 patients (52.8%) received systemic chemotherapy: as adjuvant therapy in 23, neoadjuvant therapy in 4, and both in 1. The most commonly used adjuvant chemotherapy regimen was cisplatin, adriamycin, and cyclophosphamide (18 patients), followed by etoposide and cisplatin (3 patients). In the neoadjuvant setting, docetaxel and cisplatin were used in 3 patients. In fact, the role of chemotherapy in TC regarding clinical outcomes still is less clear, except in patients with inoperable disease. Wei et al28 mentioned in their review article that the treatment of TC was based more on expert opinion or experience than on the evidence after randomized controlled trials (mainly because of its rarity) and that a cisplatin-based chemotherapy regimen was the usual choice in current practice. However, despite the difficulty of performing prospective clinical trials, recent data from phase 2 trials that evaluated carboplatin and/or paclitaxel, as well as capecitabine and/or gemcitabine, showed favorable outcomes.29-31 The role of molecular targeted therapy in the treatment of unresectable TC has also been evaluated in a phase 2 clinical trial.32 In addition, recent studies on immunotherapeutic target molecules in TET showed frequent expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) in TET and an association of PD-L1 with improved survival, suggesting the potential for development of antiePD-1/ePD-L1 therapies.33,34 Although most patients in these studies had unresectable or metastatic disease, continuous efforts to develop a more effective systemic therapy regimen would potentially improve FFR in TC patients.

References

Conclusions The current PORT target volume, which was confined to only the tumor bed in treating patients with Masaoka-Koga stage II to IV type C TET, seems reasonable, considering the failure pattern and minimal RT-related morbidity profile. However, the development of a more effective systemic therapy regimen to deal with rather frequent pleuropericardial seeding and distant metastases is warranted.

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