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Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide followed by surgery for thymic carcinoma H. Kawasaki*, N. Taira, T. Ichi, T. Yohena, T. Kawabata, K. Ishikawa Department of Surgery, National Hospital Organization Okinawa Hospital, Okinawa, Japan Accepted 9 March 2014 Available online - - -

Abstract Objective: We present our experience treating the patients with thymic carcinoma using induction chemotherapy according to weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide (CODE) followed by surgery. Patients and methods: From January 2001 to December 2010, 17 patients were diagnosed as having thymic carcinoma at our hospital. We performed CODE chemotherapy for induction treatment followed by surgical resection in 7 of these patients. Results: Seven patients consisted of 6 men and 1 woman, with an average age of 47.3 years (range 25e67 years). Five patients were clinically staged as Masaoka Stage III, and 2 were Stage IVa. A partial response was identified in 5 patients, and stable disease was observed in 2 patients. No cases of progressive disease were seen. Surgical resection was performed in all the patients: 6 underwent an R0 resection and 1 underwent an R1 resection. The estimated overall survival rates at 5 and 10 years were both 80%, and the relapse-free survival rates at 5 and 10 years were 68.6% and 53.6% respectively. Conclusions: Induction chemotherapy using the CODE regimen, followed by a complete surgical resection can be performed with a promising survival outcome for patients with thymic carcinoma with borderline resectable lesions. Ó 2014 Elsevier Ltd. All rights reserved. Keywords: Thymic carcinoma; Weekly chemotherapy; Induction chemotherapy

Introduction Thymic carcinoma is a relatively rare malignant tumor derived from thymic epithelium, with a reported incidence of 5e36% of all thymic epithelial tumors.1e4 The clinical course of thymic carcinoma is characterized by early and frequent metastasis and a poor prognosis. The tumors have an aggressive histopathological appearance and have often invaded neighboring organs or disseminated throughout the thoracic cavity at the time of diagnosis.1,5,6 Although some reports have suggested that tumor resectability, tumor stage, or tumor histology grading influence the outcome, a standard treatment for thymic carcinoma has not yet been established.7,8 Several reports have stated

that thymic carcinomas respond to cisplatin-based combined chemotherapy6,9e11; however, the optimal chemotherapy regimen for thymic carcinoma remains uncertain. Yoh et al.12 reported that the CODE regimen, which includes the combination of cisplatin, vincristine, doxorubicin and etoposide, demonstrated a good response and was well tolerated in patients with advanced thymoma and thymic carcinoma. Here we present our experience treating 7 patients with thymic carcinoma, who underwent induction chemotherapy according to the CODE regimen, followed by surgery. Patients and methods Patients and pretreatment evaluation

Abbreviations: CODE, cisplatin, vincristine, doxorubicin, and etoposide; CT, computed tomography; MRI, magnetic resonance imaging. * Corresponding author. Department of Surgery, National Hospital Organization Okinawa Hospital, 3-20-14 Ganeko, Ginowan, Okinawa 9012214, Japan. Tel.: þ81 98 898 2121; fax: þ81 98 897 9838. E-mail address: [email protected] (H. Kawasaki).

We retrospectively reviewed patients with thymic carcinoma who had been treated at the National Hospital Organization Okinawa Hospital, Okinawa, between January 2001 and December 2010. The histological diagnosis of thymic carcinoma was diagnosed based on the WHO criteria.13

0748-7983/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2014.03.006 Please cite this article in press as: Kawasaki H, et al., Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide followed by surgery for thymic carcinoma, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.006

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H. Kawasaki et al. / EJSO xx (2014) 1e5

The clinical stage of thymic carcinoma was assessed according to the criteria proposed by Masaoka et al.14 A clinical evaluation, including a medical history and physical examination, blood examination, chest roentgenogram and CT, and an examination for extrathoracic metastasis, involving an abdominal CT, brain MRI, and bone scintigram, was performed for each patient. Borderline resectable patients with a good performance status were selected as candidates for induction CODE chemotherapy if an incomplete resection had been deemed likely if they were to undergo initial surgery alone. Candidates were also required to have good organ function. Patient selection was decided at a case conference, and each patient provided informed consent. Induction chemotherapy regimens The selected patients underwent CODE chemotherapy on a preoperative basis. Briefly, the CODE regimen consisted of a weekly dose of cisplatin (25 mg/m2, intravenously [i.v.]), vincristine (1 mg/m2, i.v.) during weeks 1, 2, 4, 6, and 8, doxorubicin (40 mg/m2, i.v.) during weeks 1, 3, 5, 7, and 9, and etoposide (80 mg/m2, i.v.) for 3 days during weeks 1, 3, 5, 7, and 9. Prophylactic recombinant human granulocyte colony-stimulating factor (G-CSF; 50 mg/m2) was administered subcutaneously on the days when the cytotoxic drugs were not given. Each treatment cycle was repeated at 1-week intervals. If the toxicities were acceptable and the tumor responded to the treatment, the patient was expected to complete a maximum of nine cycles of chemotherapy.12 Toxicities and response Toxicities associated with chemotherapy were evaluated using with National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2. Objective response was evaluated using a computed tomography scan according to the guidelines set forth by the Response Evaluation Criteria in Solid Tumors15 and were classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). The pathologic effect of the induction therapy was determined using resected specimens according to the General Rule for Clinical and Pathological Record of Lung Cancer, 6th edition, as described below.16 A complete response (Ef.3) was defined as pathologically complete cancer cell death. A major response (Ef.2) was defined as viability in lesser than one-third of the cancer cells. A moderate response (Ef.1b) was defined as viability in more than one-third but less than two-thirds of the cancer cells. A minor response (Ef.1a) was defined as viability in more than two-thirds of the cancer cells. Adjuvant treatment and follow-up Postoperative irradiation therapy was added in patients with an incomplete resection, and was performed in an

adjuvant setting for patients with a complete resection. Postoperative chemotherapy was planned for patients with incomplete resections and was performed as adjuvant in patients who were deemed capable of tolerating the treatment. Statistical analysis Categorical data were analyzed using the Chi-square analysis, while continuous variables were examined using the Student t-test. The survival duration was defined as the time from the day of first treatment (or the visiting day for those who did not receive any treatment) until the day of death or the last follow-up contact. The survival curves were estimated using the KaplaneMeier method, and comparisons among the survival curves were made using the log-rank test. Differences were considered statistically significant when the P value was less than 0.05. Results Patients’ characteristics From January 2001 to December 2010, 68 thymic epithelial tumor patients were admitted and underwent treatment at the National Hospital Organization Okinawa Hospital. During the same period, 17 patients were diagnosed as having thymic carcinoma. The patients consisted of 15 men and 2 women with an average age of 54.6 years (renege, 25e67 years). We performed CODE therapy for induction treatment in 7 of these patients (Table 1). The candidate for induction CODE chemotherapy were mainly selected because of good performance status and tended to be younger, although a significant relation was not seen. Tables 1 and 2 show the characteristics of the patient who underwent induction CODE chemotherapy. Six men and 1 woman, with an average age of 47.3 years (range 25e67 years) underwent treatment. Among these 7 patients, 5 had a history of smoking. Four patients had some complaints, such as coughing, dyspnea, and chest pain. Three patients were asymptomatic, and their tumor was detected incidentally on a chest roentgenogram performed as part of an annual health examination. Six patients had squamous cell carcinoma, and one patient had adenosquamous cell carcinoma. According to the clinical staging system described by Masaoka et al., five patients had Stage III disease and two patients had Stage IVa disease. Treatment outcomes and prognoses Table 3 shows the treatment outcomes and prognoses of 7 patients who received induction CODE chemotherapy. Three patients received 6 weeks of CODE chemotherapy, 2 patients received 4 weeks, and 1 received 3 weeks, and 1 received 7 weeks. The average number of chemotherapy weeks was 5.1. Among the 7 patients, 5 patients

Please cite this article in press as: Kawasaki H, et al., Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide followed by surgery for thymic carcinoma, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.006

H. Kawasaki et al. / EJSO xx (2014) 1e5 Table 1 Characteristics of patients who did or did not receive induction CODE.

Age Range (year) Average  SD Sex Male Female Symptom Yes No Performance status 0 1 2 3 4 Average  SD Masaoka Stage III IVa IVb Histology Sq Ad Adsq

Patients with CODE 7

Patients without CODE 10

25e67 47.29  18.025

50e81 57.9  9.032

6 1

8 2

4 3

9 1

3 3 1 0 0 0.714  0.756

1 3 3 1 2 2.000  1.333

5 2 0

4 0 6

6 0 1

9 1 0

P value P ¼ 0.1282 P ¼ 0.7610 P ¼ 0.1160 P ¼ 0.0368

carcinoma,

experienced grade 3/4 neutropenia; these complications were generally transient, and no complication from infection/fever occurred. A partial response was identified in 5 cases (71%), and stable disease was identified in 2 cases. None of the cases exhibited progressive disease. After re-evaluation, surgical resection could be performed in all the patients in this series; 6 had an R0 resection, and 1 had an R1 resection. Two patients required superior vena cava resection and reconstruction using a polytetrafluoroethylene (PTFE) graft. Two patients required a pleurectomy for pleural metastases. Other resected structures included the pericardium (n ¼ 6), lung (n ¼ 5), and phrenic nerve Table 2 Characteristics of 7 patients who received induction CODE chemotherapy. No Age Sex Smoking Symptoms Histology Masaoka Invaded stage organ 1

67

M

Never

2

30

M

Never

3 4 5 6 7

25 56 69 33 51

M M M M F

Smoker Smoker Smoker Smoker Smoker

Cough, Dyspnea Cough, Dyspnea Non Non Non Cough Chest pain

(n ¼ 4). One patient had an incomplete resection, because of aortic arch invasion. In this patient, most of the gross tumor was resected, and an R1 resection was thought to have been achieved. No perioperative adverse events or postoperative deaths occurred in this series. The pathological response to the induction therapy was evaluated using resected specimens. A major response (Ef.2) was achieved in 3 cases, a moderate response (Ef.1b) was achieved in 2 cases, and a minor response (Ef.1a) was achieved in 2 cases. Six patients underwent postoperative irradiation therapy, but one patient refused such treatment. One patient who had an R1 resection underwent postoperative chemotherapy using the CODE regimen. All the cases were followed in our hospital outpatient clinic. The median observation time was 90 months. Survival

P ¼ 0.0200

P ¼ 0.3776

SD ¼ standard deviation, Sq ¼ squamous cell Ad ¼ adenocarcinoma, Adsq ¼ adenosquamous carcinoma.

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Adsq

III

PC, L

Sq

III

INV

Sq Sq Sq Sq Sq

III IVa IVa III III

SVC, PC, L SVC, PC, PL PC, L, PL R, PL PC, L

Adsq ¼ adenosquamous carcinoma, Sq ¼ squamous cell carcinoma, PC ¼ pericardium, L ¼ lung, INV ¼ innominate vein, SVC ¼ superior vena cava, PL ¼ pleura, R ¼ rib.

Table 3 and Fig. 1 show the prognosis and the survival curve for patients who were treated with induction CODE. One patient who had an R1 resections died of tumor progression 54 months after surgery. Two patients were alive with recurrences at 103 months and 31 months after surgery. Four patients with a complete resection were alive without recurrence; the periods since surgery were 135 months, 123 months, 113 months, and 24 months, respectively. The estimated relapse-free survival rates at 5 and 10 years were 68.6% and 53.6% respectively, and the estimated overall survival rates at 5 and 10 years were both 80%. Characteristics of 10 patients who did not received induction CODE chemotherapy Of the 10 patients who did not receive CODE induction chemotherapy, 1 with Stage III thymic carcinoma initially underwent surgery; however, he relapsed and died from distant metastasis at 28 months after surgery. Another patient with Stage IVb thymic carcinoma with single lung metastasis received induction chemotherapy with cisplatin and doxorubicin followed by surgery; however, the disease metastasized to the lung and bone and he died at 36 months after surgery. Two patients who received irradiation therapy with curative intent relapsed and died at 39 and 46 months, respectively, after radiotherapy. Three patients who received palliative irradiation therapy died at 5, 23 and 31 months, respectively, after treatment. Three patients received best supportive care because of poor performance status and severe complications. There were no 5-year survivors in these 10 patients with more advanced stage disease and poor performance status. Discussion Surgical resection of the tumor is the first choice for the treatment of resectable cases of thymic carcinoma.2,7,8

Please cite this article in press as: Kawasaki H, et al., Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide followed by surgery for thymic carcinoma, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.006

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H. Kawasaki et al. / EJSO xx (2014) 1e5

Table 3 Treatment outcomes and prognoses of 7 patients who received induction CODE chemotherapy. No

CODE weeks

Toxicity

Radiological effect

Resectability

Pathological effect

PostRT

PostCT

Relapse site

Time to relapse (month)

Prognosis

Overall survival (month)

1 2 3 4

6 4 6 7

PR PR PR PR

R0 R0 R0 R1

Ef.1b Ef.2 Ef.2 Ef.1b

Yes Yes No Yes

No No Yes No

Non Non Non PL, LV

e e e 15

A without R A without R A without R D with R

135 123 113 54

5 6

4 3

SD PR

R0 R0

Ef.2 Ef.1a

Yes Yes

Yes No

PL PL, B

78 20

A with R A with R

103 31

7

6

G4 G4 G3 G4 G3 G3 G3 G3 G2

SD

R0

Ef.1a

Yes

No

Non

e

A without R

Neut Neut Emesis Neut Anemia Neut Neut GTP GTP

24

RT ¼ radiotherapy, CT ¼ chemotherapy, G ¼ grade, Neut ¼ neutropenia, PR ¼ partial response, SD ¼ stable disease, PL ¼ pleura, LV ¼ liver, B ¼ bone, A without R ¼ alive without relapse, D with R ¼ dead with relapse, A with R ¼ alive with relapse.

However, most of the tumors have invaded neighboring organs or have disseminated throughout the thoracic cavity at the time of diagnosis.1,5,6 Kondo et al. reported that among 186 cases of thymic carcinoma, 39% (74/186) were Stage III and 46.8% (87/186) were Stage IV. They also commented that for the treatment of thymic carcinoma, surgery alone is rare and that most cases require adjuvant therapy.17 Resectability is reportedly a prognostic factor for the thymic carcinoma.7,8 To improve the resectability, multimodality treatment, including induction chemotherapy, radical surgery and/or irradiation, has been reported as an adequate treatment choice for patients with advanced thymic carcinoma.6,10 Theoretically, induction chemotherapy not only eradicates micrometastases, but it can also decrease the tumor size and improve the resectability, and survival rate. Recent studies have shown some encouraging results for the use of platinum-based chemotherapy in patients with thymic carcinoma.9e11 However, the optimal chemotherapy regimen for thymic carcinoma remains uncertain. CODE chemotherapy, which consists of cisplatin, vincristine, doxorubicin, and etoposide administered

Figure 1. Overall and relapse-free survival of patients treated with induction CODE chemotherapy.

according to an intensive weekly schedule, has been used for the treatment of small cell lung cancer.18,19 Yoh at al.12 reported that the CODE regimen produced a good response and was well tolerated by patients with advanced thymoma and thymic carcinoma. We presented here our experience treating 7 cases of thymic carcinoma using induction chemotherapy according to the CODE regimen, followed by surgery. The overall response rate after induction CODE chemotherapy was 71%, and no cases of progressive disease occurred. After re-evaluation, surgical resection was feasible in all the patients in this series. Complete resections were performed in 6 of the 7 cases. A good therapeutic effect was pathologically confirmed, with the majority of tumor cells exhibiting necrosis. The estimated overall survival rates at 5 and 10 years were both 80%, and the relapse-free survival rates at 5 and 10 years were 71.4% and 53.6% respectively. We recognize that the observed results could be due to selection bias because the patient population was selected for good performance status and had lower disease stages than all thymic carcinoma patients. Although the small number of selected patients in this study, the progression and survival results were quite favorable in comparison to historical single institute surgical series data for advanced thymic carcinoma.3,4,8 A relatively high rate of hematological toxicity has been reported for the CODE regimen.18e20 Kunitoh et al.20 reported the results of the JCOG 9606 study that evaluated the safety and efficacy of CODE followed by resection and/ or thoracic radiotherapy for patients with localized thymoma. Although the JCOG 9606 study showed that CODE chemotherapy combined with local therapy could be safely administered to thymoma patients, compliance to chemotherapy was poor; the main toxicities were hematological toxicities, only 57% of the patients completed the planned 9-week schedule. To avoid hematological toxicity, we administered G-CSF, but grade 3/4 hematological toxicity occurred at a relatively high rate during the late stage of treatment. However, the hematological toxicity was generally transient, and no complications arising

Please cite this article in press as: Kawasaki H, et al., Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide followed by surgery for thymic carcinoma, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.006

H. Kawasaki et al. / EJSO xx (2014) 1e5

from infection/fever occurred. One case of grade 3 emesis was seen. Other grade 3/4 toxicities were not observed. Although most of the treatments were ended after an average 5.1 weeks because of toxicity, the radiological and histological treatment results showed a remarkable efficacy. Conclusion In conclusion, induction chemotherapy using the CODE regimen followed by complete surgical resection can be performed with an acceptable morbidity and a promising survival outcome for thymic carcinoma patients who have borderline resectable lesions and good performance status. Source of funding None. Conflict of interest statement None declared.

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7. Ogawa K, Toita T, Uno T, et al. Treatment and prognosis of thymic carcinoma: a retrospective analysis of 40 cases. Cancer 2002;94: 3115–9. 8. Yano M, Sasaki H, Yokoyama T, et al. Thymic carcinoma: 30 cases at a single institution. J Thorac Oncol 2008;3:265–9. 9. Loehrer Sr PJ, Jiroutek M, Aisner S, et al. Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 2001;91: 2010–5. 10. Lucchi M, Mussi A, Ambrogi M, et al. Thymic carcinoma: a report of 13 cases. Eur J Surg Oncol 2001;27:636–40. 11. Koizumi T, Takabayashi Y, Yamagishi S, et al. Chemotherapy for advanced thymic carcinoma: clinical response to cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC chemotherapy). Am J Clin Oncol 2002;25:266–8. 12. Yoh K, Goto K, Ishii G, et al. Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide is an effective treatment for advanced thymic carcinoma. Cancer 2003;98:926–31. 13. Rosai J. Histological typing of tumours of the thymus. 2nd ed. New York: Springer-Verlag; 1999, p. 13–5. 14. Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48:2485–92. 15. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–16. 16. The Japan Lung Cancer Society, editor. Role for clinical and pathological record of lung cancer. 6th ed. Tokyo: Kanehara; 2003, p. 168–9. 17. Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 2003;76:878–84. 18. Murray N, Shah A, Osoba D, et al. Intensive weekly chemotherapy for the treatment of extensive-stage small-cell lung cancer. J Clin Oncol 1991;9:1632–8. 19. Furuse K, Fukuoka M, Nishiwaki Y, et al. Phase III study of intensive weekly chemotherapy with recombinant human granulocyte colonystimulating factor versus standard chemotherapy in extensive-disease small-cell lung cancer. The Japan Clinical Oncology Group. J Clin Oncol 1998;16:2126–32. 20. Kunitoh H, Tamura T, Shibata T, et al. JCOG Lung Cancer Study Group. A phase II trial of dose-dense chemotherapy, followed by surgical resection and/or thoracic radiotherapy, in locally advanced thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9606). Br J Cancer 2010;103:6–11.

Please cite this article in press as: Kawasaki H, et al., Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide followed by surgery for thymic carcinoma, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.006

Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide followed by surgery for thymic carcinoma.

We present our experience treating the patients with thymic carcinoma using induction chemotherapy according to weekly chemotherapy with cisplatin, vi...
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