- Email: [email protected]
IV thymic Epithelial Tumors
ORIGINAL ARTICLE
A Prospective Phase II Trial of Induction Chemotherapy with Docetaxel/Cisplatin for Masaoka Stage III/IV thymic Epithelial Tumors Silvia Park, MD,* Myung-ju Ahn, MD, PhD,* Jin Seok Ahn, MD, PhD,* Jong-Mu Sun, MD, PhD,* Young Mog Shim, MD, PhD,† Jhingook Kim, MD, PhD,† Yong Soo Choi, MD, PhD,† Kwhanmien Kim, MD, PhD,† Sumin Shin, MD,† Yongchan Ahn, MD, PhD,‡ O Jung Kwon, MD, PhD,§ Hojoong Kim, MD, PhD,§ Su Jin Lee, MD,* Won Jin Chang, MD,* and Keunchil Park, MD, PhD*
Background: Initial complete resection is a powerful prognostic indicator of survival in thymic epithelial tumors (TETs), but is obviously related to tumor stage. Here, we report the results of a prospective study of neoadjuvant docetaxel/cisplatin in locally advanced TETs. Methods: Patients with histologically proven, Masaoka stage III/ IV TETs at presentation were enrolled in this open-label, phase II, nonrandomized study. Patients received docetaxel 75 mg/m2 I.V, followed by cisplatin 75 mg/m2 I.V on day 1 of every 3-week cycle. After three cycles, surgical resection was performed if the tumor was considered resectable. Results: From March 2007 to July 2011, 27 patients were enrolled in the trial. Masaoka stage at presentation was III (n = 8; 29.6%), IVA (n = 17; 63.0%), and IVB (n = 2; 7.4%). Histologic types were nine thymomas (33.3%) and 18 thymic carcinomas (66.7%). After completion of neoadjuvant chemotherapy, 17 patients (63.0%) achieved partial response and 10 (37.0%) had stable disease. Nineteen patients (70.4%) underwent surgery and eight did not because of surgeons’ decision (n = 5), patient refusal (n = 2), or decision to undergo radiation therapy instead (n = 1). Fifteen among the 19 patients achieved complete resection (78.9%), which yields 55.6% of complete resection rate with intent-to-treat analysis. The most common side effects of severity greater than grade 3 were neutropenia and diarrhea. With a median follow-up of 42.6 months, 4-year overall survival, and progression-free survival in all patients was 79.4 and 40.6%, respectively. Conclusion: Neoadjuvant docetaxel/cisplatin is both feasible and well tolerated, and potentially improves surgical resectability in patients with advanced TETs. Key Words: Thymic tumor, Resectability, Preoperative chemotherapy, Docetaxel/cisplatin. Departments of Medicine, *Division of Hematology-Oncology, †Thoracic surgery, ‡Radiation Oncology, Division of §Pulmonology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Disclosure: The authors declare no conflict of interest. Address for correspondence: Keunchil Park, MD, PhD, Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135–710 Korea. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0807-0959
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
(J Thorac Oncol. 2013;8: 959-966)
A
lthough thymic epithelial tumors (TETs) are rare human neoplasms, they comprise the majority of thymic lesions, accounting for 50% of anterior mediastinal masses in adults.1,2 TETs include thymoma and thymic carcinoma3,4 and are primarily a surgical disease. Complete surgical resection is the most effective treatment modality,4–7 and the majority of patients with early-stage disease, such as Masaoka stage I tumors, have excellent prognosis, even with surgical excision alone.8–10 Initial complete resection is one of the most powerful prognostic indicators of improved outcome,7,11,12 but is obviously related to tumor stage. Patients with advanced disease whose tumors cannot be completely resected have a lower cure rate and poor prognosis.13–15 TETs are known to be sensitive to chemotherapy (CTx), and the most active single agents, include cisplatin, ifosfamide, and doxorubicin.4,16 Although single agents are active against thymic tumors, combination CTx has generally led to a better response rate (RR)17–21 and is the basis for most current regimens. The efficacy of chemotherapy, based on tumor shrinkage and palliation of symptoms, has primarily been reported in patients with inoperable advanced disease.17,18,22–24 Recently, the incorporation of induction CTx into a multidisciplinary approach for the treatment of unresectable thymic tumors has been validated, and has shown that CTx potentially converts patients with inoperable disease into surgical candidates, and contributes to improved outcome.15,25–28 Most of these protocols include anthracycline and cisplatin in the CTx regimen. Although cisplatin/anthracycline-based CTx regimens produce a RR of 50% to 100% in CTx-naive patients,15,18,19,23,25–28 anthracycline has the potential limitation of cardiotoxicity in a substantial proportion of patients, and some TET patients have pericardial involvement at the time of CTx. To date, there have been few reports of regimens incorporating newer chemotherapeutic agents, such as taxane, irinotecan, or gemcitabine in the treatment of TETs. Given that cisplatin is the most active single agent in TETs, combination CTx incorporating a drug that exhibits synergistic activity with cisplatin may be considered. Docetaxel, a third-generation
959
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
Park et al.
CTx agent, has a dramatic effect on epithelial tumors,29 and exhibits no cross-resistance with cisplatin, and no overlapping toxicities.30 In addition, in vitro data showing a synergistic effect between taxanes and platinums led to studies combining the two in patients with non–small-cell lung cancer.31,32 Recently, a few anecdotal studies have reported a substantial treatment response to paclitaxel and docetaxel monotherapy in TET patients.33,34 Here, we report the results of a prospective phase II study of neoadjuvant CTx using docetaxel/cisplatin to improve tumor resectability in patients with locally advanced TETs.
PATIENTS And Methods Study Design This was a single-center, open-label, phase II, nonrandomized study (ClinicalTrials.gov identifier NCT01312324). Patient recruitment occurred between March 2007 and July 2011. This study was approved by the Institutional Review Board of our institution, and written informed consent was obtained from all patients as per the Declaration of Helsinki. This study was sponsored by Sanofi Aventis; docetaxel was not reimbursed by insurance and the company provided a free supply of the medication.
Patient Eligibility Patients with histologically proven, Masaoka stage III/ IV TETs at presentation were eligible for this prospective study. Before treatment, thoracic surgeons determined disease resectability, and patients with inoperable disease were considered candidates for participation. All patients had tumors with definite radiologic invasion into pericardium/lung or great vessels, and had unidimensionally measurable lesion(s) by Response Evaluation Criteria In Solid Tumors criteria. Additional requirements were an age 15 years or more, Eastern Cooperative Oncology Group performance status of 0 to 2, absolute neutrophil count more than 1000/μL, platelet count more than 50,000/μL, serum creatinine less than or equal to 1.5 × the upper limit of normal (UNL) or creatinine clearance more than or equal to 50ml/min, total bilirubin less than 2 × UNL, and aspartate transaminase/alanine aminotransferase less than 3 × UNL. Patients must not have received prior CTx, radiotherapy (RTx), or any investigational therapy for TET, and could not be pregnant. Patients with prior malignancy (except for adequately-treated basal cell or squamous cell skin cancer or in situ cervical cancer) within 5 years of the study were excluded from participation. In addition, patients presenting with any of the following concomitant acute or chronic medical illness conditions were not eligible: myocardial infarction; severe or unstable angina; congestive heart failure and cerebrovascular accident in the 1 year before starting CTx; ongoing cardiac dysrhythmias of National Cancer Institute common terminology criteria for adverse events grade 2 or more; uncontrolled atrial fibrillation of any grade; uncontrolled hypertension; uncontrolled diabetes mellitus.
over 1 hour on day 1 and docetaxel 75 mg/m2 given intravenously over 1 hour on day 1, with the infusion of docetaxel scheduled to commence after administration of cisplatin. CTx was repeated at 3-week intervals. Dexamethasone (8 mg) was administered orally or intravenously as a pretreatment medication to avoid acute allergic reactions. As an antiemetic protocol, intravenous infusion of serotonin antagonists was administered before docetaxel infusion, and oral dexamethasone was administered until day 5 of each CTx cycle. After induction CTx, clinical response was assessed within 3 to 4 weeks after the last CTx cycle, and subsequent surgical resection was performed, if appropriate. After surgery, patients with incomplete resection, positive resection margin, or World Health Organization type B2-C disease received RTx within 3 to 6 weeks of surgery. If radiation was thought to be potentially harmful because of a broad radiation field, adjuvant CTx was given instead of radiation. In cases of World Health Organization type C disease, adjuvant CTx could be added before or after RTx, according to the medical oncologist’s discretion.
End points and Definitions The primary endpoint of this study was the rate of complete resection, defined as no microscopic residual tumor. Incomplete resection was defined as documented macroscopic or microscopic residual tumor. Secondary endpoints included RR, overall survival (OS), progression-free survival (PFS), and safety. Response to CTx was assessed by Response Evaluation Criteria In Solid Tumors version 1.1, OS was measured from initiation of treatment to last follow-up or death from any cause, and PFS was defined as time from initiation of treatment until documented progression or death. Toxicity during treatment was graded according to National Cancer Institute common toxicity criteria, version 3.0.
Statistical Design The exact binominal probability distribution approach as published in Gehan/Simon’s two-stage design was used. At α = 0.05 and β = 0.2, a null-hypothesized complete resection rate of 50% and expected complete resection rate of 75% were assumed. Considering a dropout rate of 10%, a total number of 27 patients were required. We planned to perform an interim analysis when the first 10 assessable patients were recruited, and if more than six responders are observed, at least 14 additional patients would have to be recruited, otherwise, the study would be terminated. Enrollment into the screening phase of the study was stopped when the anticipated number of subjects were attained. The rate of complete resection, RR, and the frequency of toxicities were demonstrated using descriptive statistics. For calculating and comparing OS and PFS, the Kaplan–Meier method was used, followed by the Log-rank test. Statistical analysis was performed using the Statistical package for the Social Sciences (SPSS) version 17.0 (SPSS Inc., Chicago, Illinois).
RESULTS
Study Treatment
Patient Characteristics
The treatment plan for all patients was three cycles of neoadjuvant CTx with docetaxel and cisplatin. The treatment regimen consisted of cisplatin 75 mg/m2 administered by infusion
A total of 27 TET patients were consecutively entered into the trial and treated with neoadjuvant docetaxel/cisplatin. Table 1 shows the baseline characteristics of these patients.
960
Copyright © 2013 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
TABLE 1. Patient Characteristics Baseline Characteristics Age, median (yr, range) Sex Male/female Masaoka stage III IVA IVB WHO histologic type B1 + B2 B2 B2 + B3 B3 C
n (%) 54 (15–68) 16 (59.3%)/11 (40.7%) 8 (29.6%) 17 (63.0%) 2 (7.4%) 1 (3.7%) 4 (14.8%) 1 (3.7%) 3 (11.1%) 18 (66.7%)
WHO. World Health Organization.
Docetaxel/Cisplatin in Thymic Epithelia Tumors
The median age was 54 years (range, 15–68 years), and 59.3% were men. The distribution of patients, according to Masaoka stage at presentation, was as follows: stage III (n = 8; 29.6%), IVA (n = 17; 63.0%), and IVB (n = 2; 7.4%). Histologic type was nine thymomas (33.3%) and 18 thymic carcinomas (66.7%), which included one thymic carcinoid and one largecell neuroendocrine carcinoma; although thymic carcinoid and large-cell neuroendocrine carcinoma can be placed in a separate category of neuroendocrine tumors of the thymus, in general, they are classified as a type of thymic carcinoma.1,35
Disease Response to Induction CTx and Toxicities All patients completed the planned induction CTx. After completion of CTx, 17 (63.0%) achieved partial response and 10 (37.0%) had stable disease (Table 2). Chemotherapeutic agents were administrated with dose modification in seven patients because of toxicity. Table 3 demonstrates the toxicities
TABLE 2. Clinical Information of Patients Treated with Neoadjuvant Chemotherapy Patient No.
Histologic Type
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Masaoka Stage
Radiologic Response
Surgerya
Complete Resection
Squamous carcinoma Squamous carcinoma Thymoma, B1 + B2 Thymoma, B2 + B3 Squamous carcinoma Squamous carcinoma Squamous carcinoma Thymoma, B2 Thymoma, B2 Squamous carcinoma Squamous carcinoma Squamous carcinoma Thymoma, B3 Adenocarcinoma Large-cell neuroendocrine carcinoma Squamous carcinoma Atypical carcinoid Squamous carcinoma Squamous carcinoma Squamous carcinoma Thymoma, B3 Squamous carcinoma Thymoma, B2 Thymoma, B1 or B2 Thymoma, B3 Thymic carcinoma
III III IVA IVA IVA IVA IVA IVA IVA IVA IVA IVA IVA III IVA III III IVA IVB IVA IVA III IVA IVA III III
PR SD PR PR PR PR PR SD PR SD PR PR PR PR SD PR SD SD PR PR SD SD SD PR SD PR
— No (R2) R0 R0 — — R0 R0 R0 R0 No (R1) — R0 — R0 R0 No (R1) R0 R0 No (R2) — R0 R0 — R0 —
Squamous carcinoma
IVB
PR
No (inoperable) Yes3 Yes1,4,6 Yes1,5 No (patient’s refusal) No (inoperable) Yes2,4,6 Yes3–6 Yes3–5 Yes3,5,6 Yes3,5 No (inoperable) Yes1,5,6 No (follow-up loss) Yes3,5,6 Yes3,6 Yes3,5,6 Yes1,5,6 Yes3,5,6 Yes3,4 No (inoperable) Yes6 Yes4,5 No (inoperable) Yes3 No (surgeon’s decision; no need for operation) Yes3,5
R0
Information on operation other than total thymectomy is addressed by suffix; 1 = extrapleuropneumonectomy, 2 = pneumonectomy, 3 = partial resection of lung, 4 = partial resection of pleural mass, 5 = partial resection of pericardium, and 6 = partial resection of vessels. SD, stable disease; PR, partial response, RTx, radiotherapy, CTx, chemotherapy. a
Copyright © 2013 by the International Association for the Study of Lung Cancer
961
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
Park et al.
TABLE 3. Toxicities
Anorexia Nausea Vomiting Diarrhea Stomatitis Mucositis Fatigue Myalgia Alopecia Fever Peripheral neuropathy Ototoxicity Leukopenia Neutropenia Anemia Thrombocytopenia
Grade 1
Grade 2
Grade 3
Grade 4
% of Patients with Toxicity ≥ Grade 3
5 5 1 2 2 2 3 4 8 2 4 1 0 1 8 3
3 1 1 2 3 1 0 2 8 0 1 0 7 4 9 0
1 2 0 3 0 0 0 0 1 0 0 0 2 5 1 1
0 0 0 0 0 0 0 0 0 0 0 0 0 3 0 0
3.7% 7.4% 0% 11.1% 0% 0% 0% 0% 3.7% 0% 0% 0% 7.4% 29.6% 3.7% 3.7%
observed during induction CTx. Major side effects of CTx included grade 3 anorexia (n = 1), nausea (n = 2), diarrhea (n = 3), and alopecia (n = 1). Major hematologic toxicities involved grade 3 leukopenia (n = 2), anemia (n = 1), thrombocytopenia (n = 1), and grades 3 to 4 neutropenia (n = 8).
(n = 2, including 1 patient who was lost to follow-up); radiation therapy alone after docetaxel/cisplatin was considered sufficient to eradicate the disease (n = 1). Of 19 patients undergoing surgical resection, 15 had complete resection, and four had incomplete resection. All four patients with incomplete resection had thymic carcinoma. Among the patients with incomplete resection, two had macroscopic residual tumor at operation field (R2 resection) and the remaining two showed microscopically positive resection margin (R1 resection). All seven patients who underwent surgery for thymoma achieved complete resection. After completion of surgical resection, subsequent therapy was performed as follows: radiotherapy (RTx; n = 8), chemotherapy (CTx; n = 7), radiotherapy with chemotherapy (RTx + CTx; n = 2), and observation (n = 2). Among the eight patients not undergoing surgery, three received definitive RT, four had palliative CTx, and one was lost to follow-up.
Overall Survival and Disease Free Survival With a median follow-up of 42.6 months, 4-year OS and PFS in all patients was 79.4 and 40.6%, respectively. When comparing OS and PFS according to achievement of complete resection after neoadjuvant docetaxel/cisplatin, patients with complete resection showed 4-year OS of 92.9% and 4-year PFS of 50.3%, compared with 62.2 and 31.2%, respectively, in patients who did not achieve complete resection (Fig. 1; OS; p = 0.19; Fig. 2, PFS, p = 0.41).
DISCUSSION
Surgery after Induction CTx and Postoperative Treatment Nineteen patients (70.4%) underwent surgical resection and eight patients did not for the following reasons: surgeon’s decision of inoperable disease (n = 5); patients’ refusal
TETs are a heterogeneous group of diseases, with a wide spectrum of morphologic appearance.3,4,36 Thymoma and thymic carcinoma are the most frequent histologic subtypes, but thymic carcinoma is a distinct entity based on its obvious cytologic atypia.12 Compared with thymoma, thymic
FIGURE 1 . Overall survival according to complete resection after induction therapy.
962
Copyright © 2013 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
Docetaxel/Cisplatin in Thymic Epithelia Tumors
FIGURE 2. Progression-free survival according to complete resection after induction therapy.
carcinoma shows more invasive and malignant behavior, and previous reports have demonstrated worse survival.12,37 Tumor stage and completeness of resection are also important factors for prognosis. OS rate is closely related to stage,1,10,13,38–41 and complete resection of thymic tumor significantly increases the survival rate, even for patients with advanced stage.4,9,13,42 Among various clinical factors, complete resection is one of the most important prognostic factors,10 therefore, all patients with thymic tumors should be evaluated by an expert thoracic surgeon for their resectability, and every effort should be made to achieve resectability in patients with initially inoperable disease. Thymic tumors are sensitive to CTx. A variety of CTx agents and combination regimens have been reported, with an objective RR between 10% to 100%, depending on the study.1 CTx regimens used in thymic tumors have been primarily cisplatin-based, and anthracycline is the most often used agent in conjunction with cisplatin,18,22,23,43 although etoposide and ifosfamide have been variably incorporated into a cisplatinbased regimen.43,44 So far, the best results in phase II studies of CTx for inoperable thymic tumors have been obtained with ADOC regimen (doxorubicin, cisplatin, vincristin, cyclophosphamide), with a 92% RR, including a 43% complete response.23 However, direct comparison between regimens is not easy1 because of the small size of the series as a result of the rarity of the disease and the heterogeneous distribution of patients with thymoma or thymic carcinoma in each series. Consequently, although it is clear that a variety of chemotherapy regimens are active against thymic tumors, we cannot definitively say which regimens offer a significant advantage for this type of tumor. The rationale for induction CTx in patients with locally advanced thymic tumor is to facilitate complete surgical resection, resulting in a higher cure rate. Successful treatment of primary disease and metastatic regional nodes is crucial,
and we conceived the idea that incorporation of docetaxel into a cisplatin regimen may be efficacious in thymic tumors. This was based on in vitro data showing collateral sensitivity and a lack of cross-resistance between taxane and platinums30 and their successful use in other epithelial tumors, such as non–small-cell lung cancer. In addition, several reports have reported antithymoma activity of taxane when used in monotherapy or combination therapy.33,34,45 In this study, we report the results of a prospective phase II study of neoadjuvant CTx using docetaxel/cisplatin in patients with locally advanced TETs. With intent-totreat analysis, 15 of 27 patients (55.6%) achieved complete resection after induction CTx. Of 26 patients whose resectability could be assessed after neoadjuvant CTx by an expert thoracic surgeon (1 of 27 patients was lost to follow-up after CTx), initially inoperable lesions were converted to resectable diseases in 21 cases (21 of 26; 80.8%). Of these 21 cases, two patients did not undergo surgical resection: one patient decided not to undergo surgery because RTx alone was considered sufficient to eradicate the residual lesion (although this case broke the protocol), and one patient refused surgery because of fear of pleuropneumonectomy. Of 19 patients who underwent surgery, 15 patients achieved R0 resection (78.9%), two achieved R1 resection (10.5%), and the remaining two had R2 resection (10.5%). Table 4 summarizes the results of previous reports of induction CTx approaches in locally advanced thymic tumors. However, although this gives a rough indication of differences in clinical outcome from each regimen, given the heterogeneous distribution of patients regarding tumor stage, histology, and postoperative treatment, direct comparison between regimens is quite limited, and deemed to be invalid. The complete resection rate with our regimen was comparable with that of other studies, but the radiologic RR was relatively low, and no patient achieved complete response. However, it should be
Copyright © 2013 by the International Association for the Study of Lung Cancer
963
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
Park et al.
TABLE 4. Induction Chemotherapy Approaches in Locally Advanced Thymic Tumors
Chemotherapy Regimen (Author, yr) Cisplatin Epirubicin Etoposide (Maccjiarini P, 1991) Cisplatin Doxorubicin Vincristine Cyclophosphamide (Rea F, 1993) Cisplatin Doxorubicin Cyclophosphamide Prednisone (Shin DM, 1998) Cisplatin Epirubicin Etoposide or Cisplatin Doxorubicin Cyclophosphamide (Loehrer PJ, 1994) Cisplatin Docetaxel (current study)
Response Ratea (CR rate)
No. of Patients with Complete Resection/No. of Surgical Resection Patients (%)
Postoperative Treatment
OS
PFS
Thymoma (4) Thymic carcinoma (3)
100% (57%)
4/7 (57.1%)
RTx
80% 2 yr
80% 2 yr
III IV
Thymoma (16)
100% (43%)
11/16 (68.8%)
CTx or RTx
70% 3 yr
NA
III IV
Thymoma (22)
77% (14%)
16/21 (76%)
RTx and CTx
95% 5 yr 79% 7-yr
77% 5 yr 77% 7-yr
66.6% (13%)c
13/15 (87%)c
RTx and CTx
78% 10 yr
53% 10 yr
63% (0%)
15/19 (78.9%)
RTx or CTx or RTx + CTx
93% 4 yr
50% 4 yr
Stage
III
III
III IV
Histology (No. of Patients)
Thymoma (34) (11)b Thymic carcinoma (11) (4)b
Thymoma (9) Thymic carcinoma (18)
*Radiologic response, Complete response. b Not all patients included in this study received induction therapy. bIndicates the number of patients who received preoperative chemotherapy. c Indicates the proportion of patients among those who received induction chemotherapy only. RTx, radiotherapy; CTx, chemotherapy; CR, complete response.
FIGURE 3. Overall survival according to histologic type.
964
Copyright © 2013 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
noted that a substantial number of patients with unfavorable features were included in the current study; there were more patients with stage IV lesions (19 of 27; 70.4%) than stage III tumors (8 of 27; 29.6%), and a large proportion of this cohort were patients with thymic carcinoma rather than thymoma (18 of 27; 66.7%). When comparing complete resection rates according to histology, the seven thymoma patients who underwent surgery obtained complete resection, whereas, four of 12 patients with thymic carcinoma had residual disease. In addition, survival curves according to pathologic subtypes showed that all patients with thymoma were alive at least until the last follow-up date, in contrast to patients with thymic carcinoma (Fig. 3), further emphasizing the adverse clinical features of thymic carcinoma. Although a relatively short follow-up period (42.6 months) can be a major limitation of this study, the overall 4-year survival rate of 79.4%, despite the substantial proportion of patients with thymic carcinoma, was not disappointing. In summary, the results of this current prospective phase II study of neoadjuvant chemotherapy using docetaxel/cisplatin suggest that this regimen is feasible and can potentially improve tumor resectability in patients with locally advanced TETs. We certify that there is no conflict of interest with any financial organization regarding the material discussed in the article. This study was sponsored by Sanofi Aventis; the company provided a free supply of the docetaxel. REFERENCES 1. Detterbeck FC, Parsons AM. Thymic tumors. Ann Thorac Surg 2004;77:1860–1869. 2. Schmidt-Wolf IG, Rockstroh JK, Schüller H, et al. Malignant thymoma: current status of classification and multimodality treatment. Ann Hematol 2003;82:69–76. 3. Suster S, Moran CA. Primary thymic epithelial neoplasms showing combined features of thymoma and thymic carcinoma. A clinicopathologic study of 22 cases. Am J Surg Pathol 1996;20:1469–1480. 4. Venuta F, Anile M, Diso D, et al. Thymoma and thymic carcinoma. Eur J Cardiothorac Surg 2010;37:13–25. 5. Rea F, Marulli G, Girardi R, et al. Long-term survival and prognostic factors in thymic epithelial tumours. Eur J Cardiothorac Surg 2004;26:412–418. 6. Moore KH, McKenzie PR, Kennedy CW, McCaughan BC. Thymoma: trends over time. Ann Thorac Surg 2001;72:203–207. 7. Lee CY, Bae MK, Park IK, Kim DJ, Lee JG, Chung KY. Early Masaoka stage and complete resection is important for prognosis of thymic carcinoma: a 20-year experience at a single institution. Eur J Cardiothorac Surg 2009;36:159–62; discussion 163. 8. Okumura M, Miyoshi S, Takeuchi Y, et al. Results of surgical treatment of thymomas with special reference to the involved organs. J Thorac Cardiovasc Surg 1999;117:605–613. 9. Wilkins KB, Sheikh E, Green R, et al. Clinical and pathologic predictors of survival in patients with thymoma. Ann Surg 1999;230:562–72; discussion 572. 10. Regnard JF, Magdeleinat P, Dromer C, et al. Prognostic factors and longterm results after thymoma resection: a series of 307 patients. J Thorac Cardiovasc Surg 1996;112:376–384. 11. Yano M, Sasaki H, Yokoyama T, et al. Thymic carcinoma: 30 cases at a single institution. J Thorac Oncol 2008;3:265–269. 12. Ogawa K, Toita T, Uno T, et al. Treatment and prognosis of thymic carcinoma: a retrospective analysis of 40 cases. Cancer 2002;94:3115–3119. 13. Blumberg D, Port JL, Weksler B, et al. Thymoma: a multivariate analysis of factors predicting survival. Ann Thorac Surg 1995;60:908–13; discussion 914.
Docetaxel/Cisplatin in Thymic Epithelia Tumors
14. McCart JA, Gaspar L, Inculet R, Casson AG. Predictors of survival following surgical resection of thymoma. J Surg Oncol 1993;54:233–238. 15. Kim ES, Putnam JB, Komaki R, et al. Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer 2004;44: 369–379. 16. Evans TL, Lynch TJ. Role of chemotherapy in the management of advanced thymic tumors. Semin Thorac Cardiovasc Surg 2005;17:41–50. 17. Giaccone G. Treatment of malignant thymoma. Curr Opin Oncol 2005;17: 140–146. 18. Loehrer PJ, Sr, Kim K, Aisner SC, et al. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 1994;12:1164–1168. 19. Loehrer PJ, Sr, Chen M, Kim K, et al. Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial. J Clin Oncol 1997;15:3093–3099. 20. Hu E, Levine J. Chemotherapy of malignant thymoma. Case report and review of the literature. Cancer 1986;57:1101–1104. 21. Hernandez-Ilizaliturri FJ, Tan D, Cipolla D, Connolly G, Debb G, Ramnath N. Multimodality therapy for thymic carcinoma (TCA): results of a 30-year single-institution experience. Am J Clin Oncol 2004;27: 68–72. 22. Kosmidis PA, Iliopoulos E, Pentea S. Combination chemotherapy with cyclophosphamide, adriamycin, and vincristine in malignant thymoma and myasthenia gravis. Cancer 1988;61:1736–1740. 23. Fornasiero A, Daniele O, Ghiotto C, et al. Chemotherapy for invasive thymoma. A 13-year experience. Cancer 1991;68:30–33. 24. Loehrer PJ, Sr, 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;91:2010–2015. 25. Macchiarini P, Chella A, Ducci F, et al. Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma. Cancer 1991;68:706–713. 26. Rea F, Sartori F, Loy M, et al. Chemotherapy and operation for invasive thymoma. J Thorac Cardiovasc Surg 1993;106:543–549. 27. Shin DM, Walsh GL, Komaki R, et al. A multidisciplinary approach to therapy for unresectable malignant thymoma. Ann Intern Med 1998;129:100–104. 28. Venuta F, Rendina EA, Longo F, et al. Long-term outcome after multimodality treatment for stage III thymic tumors. Ann Thorac Surg 2003;76:1866–72; discussion 1872. 29. Gandara DR, Vokes E, Green M, et al. Activity of docetaxel in platinumtreated non-small-cell lung cancer: results of a phase II multicenter trial. J Clin Oncol 2000;18:131–135. 30. Jensen PB, Holm B, Sorensen M, Christensen IJ, Sehested M. In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabin. Br J Cancer 1997;75: 869–877. 31. Binder D, Hackenthal M, Graseck L, et al. A phase II study of weekly docetaxel-cisplatin as first-line treatment for advanced non-small cell lung cancer. J Thorac Oncol 2009;4:1144–1147. 32. Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21:3016–3024. 33. Oguri T, Achiwa H, Kato D, et al. Efficacy of docetaxel as a second-line chemotherapy for thymic carcinoma. Chemotherapy 2004;50:279–282. 34. Umemura S, Segawa Y, Fujiwara K, et al. A case of recurrent metastatic thymoma showing a marked response to paclitaxel monotherapy. Jpn J Clin Oncol 2002;32:262–265. 35. Ogawa F, Iyoda A, Amano H, et al. Thymic large cell neuroendocrine carcinoma: report of a resected case - a case report. J Cardiothorac Surg 2010;5:115. 36. Snover DC, Levine GD, Rosai J. Thymic carcinoma. Five distinctive histological variants. Am J Surg Pathol 1982;6:451–470. 37. Blumberg D, Burt ME, Bains MS, et al. Thymic carcinoma: current staging does not predict prognosis. J Thorac Cardiovasc Surg 1998;115: 303–8; discussion 308.
Copyright © 2013 by the International Association for the Study of Lung Cancer
965
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
Park et al.
38. Verley JM, Hollmann KH. Thymoma. A comparative study of clinical stages, histologic features, and survival in 200 cases. Cancer 1985;55:1074–1086. 39. Quintanilla-Martinez L, Wilkins EW, Jr, Choi N, Efird J, Hug E, Harris NL. Thymoma. Histologic subclassification is an independent prognostic factor. Cancer 1994;74:606–617. 40. Maggi G, Casadio C, Cavallo A, Cianci R, Molinatti M, Ruffini E. Thymoma: results of 241 operated cases. Ann Thorac Surg 1991;51:152–156. 41. Elert O, Buchwald J, Wolf K. Epithelial thymus tumors–therapy and prognosis. Thorac Cardiovasc Surg 1988;36:109–113. 42. Venuta F, Rendina EA, Pescarmona EO, et al. Multimodality treatment of thymoma: a prospective study. Ann Thorac Surg 1997;64:1585–91; discussion 1591.
966
43. Oshita F, Kasai T, Kurata T, et al. Intensive chemotherapy with cisplatin, doxorubicin, cyclophosphamide, etoposide and granulocyte colonystimulating factor for advanced thymoma or thymic cancer: preliminary results. Jpn J Clin Oncol 1995;25:208–212. 44. Giaccone G, Ardizzoni A, Kirkpatrick A, Clerico M, Sahmoud T, van Zandwijk N. Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1996;14:814–820. 45. Shintani Y, Ohta M, Hazama K, Miyoshi S, Kagisaki K, Matsuda H. Thymic carcinoma successfully resected with superior vena cava after chemoradiotherapy. Jpn J Thorac Cardiovasc Surg 2001;49:717–721.
Copyright © 2013 by the International Association for the Study of Lung Cancer
A Prospective Phase II Trial of Induction Chemotherapy with Docetaxel/Cisplatin for Masaoka Stage III/IV thymic Epithelial Tumors Silvia Park, MD,* Myung-ju Ahn, MD, PhD,* Jin Seok Ahn, MD, PhD,* Jong-Mu Sun, MD, PhD,* Young Mog Shim, MD, PhD,† Jhingook Kim, MD, PhD,† Yong Soo Choi, MD, PhD,† Kwhanmien Kim, MD, PhD,† Sumin Shin, MD,† Yongchan Ahn, MD, PhD,‡ O Jung Kwon, MD, PhD,§ Hojoong Kim, MD, PhD,§ Su Jin Lee, MD,* Won Jin Chang, MD,* and Keunchil Park, MD, PhD*
Background: Initial complete resection is a powerful prognostic indicator of survival in thymic epithelial tumors (TETs), but is obviously related to tumor stage. Here, we report the results of a prospective study of neoadjuvant docetaxel/cisplatin in locally advanced TETs. Methods: Patients with histologically proven, Masaoka stage III/ IV TETs at presentation were enrolled in this open-label, phase II, nonrandomized study. Patients received docetaxel 75 mg/m2 I.V, followed by cisplatin 75 mg/m2 I.V on day 1 of every 3-week cycle. After three cycles, surgical resection was performed if the tumor was considered resectable. Results: From March 2007 to July 2011, 27 patients were enrolled in the trial. Masaoka stage at presentation was III (n = 8; 29.6%), IVA (n = 17; 63.0%), and IVB (n = 2; 7.4%). Histologic types were nine thymomas (33.3%) and 18 thymic carcinomas (66.7%). After completion of neoadjuvant chemotherapy, 17 patients (63.0%) achieved partial response and 10 (37.0%) had stable disease. Nineteen patients (70.4%) underwent surgery and eight did not because of surgeons’ decision (n = 5), patient refusal (n = 2), or decision to undergo radiation therapy instead (n = 1). Fifteen among the 19 patients achieved complete resection (78.9%), which yields 55.6% of complete resection rate with intent-to-treat analysis. The most common side effects of severity greater than grade 3 were neutropenia and diarrhea. With a median follow-up of 42.6 months, 4-year overall survival, and progression-free survival in all patients was 79.4 and 40.6%, respectively. Conclusion: Neoadjuvant docetaxel/cisplatin is both feasible and well tolerated, and potentially improves surgical resectability in patients with advanced TETs. Key Words: Thymic tumor, Resectability, Preoperative chemotherapy, Docetaxel/cisplatin. Departments of Medicine, *Division of Hematology-Oncology, †Thoracic surgery, ‡Radiation Oncology, Division of §Pulmonology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Disclosure: The authors declare no conflict of interest. Address for correspondence: Keunchil Park, MD, PhD, Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135–710 Korea. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0807-0959
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
(J Thorac Oncol. 2013;8: 959-966)
A
lthough thymic epithelial tumors (TETs) are rare human neoplasms, they comprise the majority of thymic lesions, accounting for 50% of anterior mediastinal masses in adults.1,2 TETs include thymoma and thymic carcinoma3,4 and are primarily a surgical disease. Complete surgical resection is the most effective treatment modality,4–7 and the majority of patients with early-stage disease, such as Masaoka stage I tumors, have excellent prognosis, even with surgical excision alone.8–10 Initial complete resection is one of the most powerful prognostic indicators of improved outcome,7,11,12 but is obviously related to tumor stage. Patients with advanced disease whose tumors cannot be completely resected have a lower cure rate and poor prognosis.13–15 TETs are known to be sensitive to chemotherapy (CTx), and the most active single agents, include cisplatin, ifosfamide, and doxorubicin.4,16 Although single agents are active against thymic tumors, combination CTx has generally led to a better response rate (RR)17–21 and is the basis for most current regimens. The efficacy of chemotherapy, based on tumor shrinkage and palliation of symptoms, has primarily been reported in patients with inoperable advanced disease.17,18,22–24 Recently, the incorporation of induction CTx into a multidisciplinary approach for the treatment of unresectable thymic tumors has been validated, and has shown that CTx potentially converts patients with inoperable disease into surgical candidates, and contributes to improved outcome.15,25–28 Most of these protocols include anthracycline and cisplatin in the CTx regimen. Although cisplatin/anthracycline-based CTx regimens produce a RR of 50% to 100% in CTx-naive patients,15,18,19,23,25–28 anthracycline has the potential limitation of cardiotoxicity in a substantial proportion of patients, and some TET patients have pericardial involvement at the time of CTx. To date, there have been few reports of regimens incorporating newer chemotherapeutic agents, such as taxane, irinotecan, or gemcitabine in the treatment of TETs. Given that cisplatin is the most active single agent in TETs, combination CTx incorporating a drug that exhibits synergistic activity with cisplatin may be considered. Docetaxel, a third-generation
959
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
Park et al.
CTx agent, has a dramatic effect on epithelial tumors,29 and exhibits no cross-resistance with cisplatin, and no overlapping toxicities.30 In addition, in vitro data showing a synergistic effect between taxanes and platinums led to studies combining the two in patients with non–small-cell lung cancer.31,32 Recently, a few anecdotal studies have reported a substantial treatment response to paclitaxel and docetaxel monotherapy in TET patients.33,34 Here, we report the results of a prospective phase II study of neoadjuvant CTx using docetaxel/cisplatin to improve tumor resectability in patients with locally advanced TETs.
PATIENTS And Methods Study Design This was a single-center, open-label, phase II, nonrandomized study (ClinicalTrials.gov identifier NCT01312324). Patient recruitment occurred between March 2007 and July 2011. This study was approved by the Institutional Review Board of our institution, and written informed consent was obtained from all patients as per the Declaration of Helsinki. This study was sponsored by Sanofi Aventis; docetaxel was not reimbursed by insurance and the company provided a free supply of the medication.
Patient Eligibility Patients with histologically proven, Masaoka stage III/ IV TETs at presentation were eligible for this prospective study. Before treatment, thoracic surgeons determined disease resectability, and patients with inoperable disease were considered candidates for participation. All patients had tumors with definite radiologic invasion into pericardium/lung or great vessels, and had unidimensionally measurable lesion(s) by Response Evaluation Criteria In Solid Tumors criteria. Additional requirements were an age 15 years or more, Eastern Cooperative Oncology Group performance status of 0 to 2, absolute neutrophil count more than 1000/μL, platelet count more than 50,000/μL, serum creatinine less than or equal to 1.5 × the upper limit of normal (UNL) or creatinine clearance more than or equal to 50ml/min, total bilirubin less than 2 × UNL, and aspartate transaminase/alanine aminotransferase less than 3 × UNL. Patients must not have received prior CTx, radiotherapy (RTx), or any investigational therapy for TET, and could not be pregnant. Patients with prior malignancy (except for adequately-treated basal cell or squamous cell skin cancer or in situ cervical cancer) within 5 years of the study were excluded from participation. In addition, patients presenting with any of the following concomitant acute or chronic medical illness conditions were not eligible: myocardial infarction; severe or unstable angina; congestive heart failure and cerebrovascular accident in the 1 year before starting CTx; ongoing cardiac dysrhythmias of National Cancer Institute common terminology criteria for adverse events grade 2 or more; uncontrolled atrial fibrillation of any grade; uncontrolled hypertension; uncontrolled diabetes mellitus.
over 1 hour on day 1 and docetaxel 75 mg/m2 given intravenously over 1 hour on day 1, with the infusion of docetaxel scheduled to commence after administration of cisplatin. CTx was repeated at 3-week intervals. Dexamethasone (8 mg) was administered orally or intravenously as a pretreatment medication to avoid acute allergic reactions. As an antiemetic protocol, intravenous infusion of serotonin antagonists was administered before docetaxel infusion, and oral dexamethasone was administered until day 5 of each CTx cycle. After induction CTx, clinical response was assessed within 3 to 4 weeks after the last CTx cycle, and subsequent surgical resection was performed, if appropriate. After surgery, patients with incomplete resection, positive resection margin, or World Health Organization type B2-C disease received RTx within 3 to 6 weeks of surgery. If radiation was thought to be potentially harmful because of a broad radiation field, adjuvant CTx was given instead of radiation. In cases of World Health Organization type C disease, adjuvant CTx could be added before or after RTx, according to the medical oncologist’s discretion.
End points and Definitions The primary endpoint of this study was the rate of complete resection, defined as no microscopic residual tumor. Incomplete resection was defined as documented macroscopic or microscopic residual tumor. Secondary endpoints included RR, overall survival (OS), progression-free survival (PFS), and safety. Response to CTx was assessed by Response Evaluation Criteria In Solid Tumors version 1.1, OS was measured from initiation of treatment to last follow-up or death from any cause, and PFS was defined as time from initiation of treatment until documented progression or death. Toxicity during treatment was graded according to National Cancer Institute common toxicity criteria, version 3.0.
Statistical Design The exact binominal probability distribution approach as published in Gehan/Simon’s two-stage design was used. At α = 0.05 and β = 0.2, a null-hypothesized complete resection rate of 50% and expected complete resection rate of 75% were assumed. Considering a dropout rate of 10%, a total number of 27 patients were required. We planned to perform an interim analysis when the first 10 assessable patients were recruited, and if more than six responders are observed, at least 14 additional patients would have to be recruited, otherwise, the study would be terminated. Enrollment into the screening phase of the study was stopped when the anticipated number of subjects were attained. The rate of complete resection, RR, and the frequency of toxicities were demonstrated using descriptive statistics. For calculating and comparing OS and PFS, the Kaplan–Meier method was used, followed by the Log-rank test. Statistical analysis was performed using the Statistical package for the Social Sciences (SPSS) version 17.0 (SPSS Inc., Chicago, Illinois).
RESULTS
Study Treatment
Patient Characteristics
The treatment plan for all patients was three cycles of neoadjuvant CTx with docetaxel and cisplatin. The treatment regimen consisted of cisplatin 75 mg/m2 administered by infusion
A total of 27 TET patients were consecutively entered into the trial and treated with neoadjuvant docetaxel/cisplatin. Table 1 shows the baseline characteristics of these patients.
960
Copyright © 2013 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
TABLE 1. Patient Characteristics Baseline Characteristics Age, median (yr, range) Sex Male/female Masaoka stage III IVA IVB WHO histologic type B1 + B2 B2 B2 + B3 B3 C
n (%) 54 (15–68) 16 (59.3%)/11 (40.7%) 8 (29.6%) 17 (63.0%) 2 (7.4%) 1 (3.7%) 4 (14.8%) 1 (3.7%) 3 (11.1%) 18 (66.7%)
WHO. World Health Organization.
Docetaxel/Cisplatin in Thymic Epithelia Tumors
The median age was 54 years (range, 15–68 years), and 59.3% were men. The distribution of patients, according to Masaoka stage at presentation, was as follows: stage III (n = 8; 29.6%), IVA (n = 17; 63.0%), and IVB (n = 2; 7.4%). Histologic type was nine thymomas (33.3%) and 18 thymic carcinomas (66.7%), which included one thymic carcinoid and one largecell neuroendocrine carcinoma; although thymic carcinoid and large-cell neuroendocrine carcinoma can be placed in a separate category of neuroendocrine tumors of the thymus, in general, they are classified as a type of thymic carcinoma.1,35
Disease Response to Induction CTx and Toxicities All patients completed the planned induction CTx. After completion of CTx, 17 (63.0%) achieved partial response and 10 (37.0%) had stable disease (Table 2). Chemotherapeutic agents were administrated with dose modification in seven patients because of toxicity. Table 3 demonstrates the toxicities
TABLE 2. Clinical Information of Patients Treated with Neoadjuvant Chemotherapy Patient No.
Histologic Type
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Masaoka Stage
Radiologic Response
Surgerya
Complete Resection
Squamous carcinoma Squamous carcinoma Thymoma, B1 + B2 Thymoma, B2 + B3 Squamous carcinoma Squamous carcinoma Squamous carcinoma Thymoma, B2 Thymoma, B2 Squamous carcinoma Squamous carcinoma Squamous carcinoma Thymoma, B3 Adenocarcinoma Large-cell neuroendocrine carcinoma Squamous carcinoma Atypical carcinoid Squamous carcinoma Squamous carcinoma Squamous carcinoma Thymoma, B3 Squamous carcinoma Thymoma, B2 Thymoma, B1 or B2 Thymoma, B3 Thymic carcinoma
III III IVA IVA IVA IVA IVA IVA IVA IVA IVA IVA IVA III IVA III III IVA IVB IVA IVA III IVA IVA III III
PR SD PR PR PR PR PR SD PR SD PR PR PR PR SD PR SD SD PR PR SD SD SD PR SD PR
— No (R2) R0 R0 — — R0 R0 R0 R0 No (R1) — R0 — R0 R0 No (R1) R0 R0 No (R2) — R0 R0 — R0 —
Squamous carcinoma
IVB
PR
No (inoperable) Yes3 Yes1,4,6 Yes1,5 No (patient’s refusal) No (inoperable) Yes2,4,6 Yes3–6 Yes3–5 Yes3,5,6 Yes3,5 No (inoperable) Yes1,5,6 No (follow-up loss) Yes3,5,6 Yes3,6 Yes3,5,6 Yes1,5,6 Yes3,5,6 Yes3,4 No (inoperable) Yes6 Yes4,5 No (inoperable) Yes3 No (surgeon’s decision; no need for operation) Yes3,5
R0
Information on operation other than total thymectomy is addressed by suffix; 1 = extrapleuropneumonectomy, 2 = pneumonectomy, 3 = partial resection of lung, 4 = partial resection of pleural mass, 5 = partial resection of pericardium, and 6 = partial resection of vessels. SD, stable disease; PR, partial response, RTx, radiotherapy, CTx, chemotherapy. a
Copyright © 2013 by the International Association for the Study of Lung Cancer
961
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
Park et al.
TABLE 3. Toxicities
Anorexia Nausea Vomiting Diarrhea Stomatitis Mucositis Fatigue Myalgia Alopecia Fever Peripheral neuropathy Ototoxicity Leukopenia Neutropenia Anemia Thrombocytopenia
Grade 1
Grade 2
Grade 3
Grade 4
% of Patients with Toxicity ≥ Grade 3
5 5 1 2 2 2 3 4 8 2 4 1 0 1 8 3
3 1 1 2 3 1 0 2 8 0 1 0 7 4 9 0
1 2 0 3 0 0 0 0 1 0 0 0 2 5 1 1
0 0 0 0 0 0 0 0 0 0 0 0 0 3 0 0
3.7% 7.4% 0% 11.1% 0% 0% 0% 0% 3.7% 0% 0% 0% 7.4% 29.6% 3.7% 3.7%
observed during induction CTx. Major side effects of CTx included grade 3 anorexia (n = 1), nausea (n = 2), diarrhea (n = 3), and alopecia (n = 1). Major hematologic toxicities involved grade 3 leukopenia (n = 2), anemia (n = 1), thrombocytopenia (n = 1), and grades 3 to 4 neutropenia (n = 8).
(n = 2, including 1 patient who was lost to follow-up); radiation therapy alone after docetaxel/cisplatin was considered sufficient to eradicate the disease (n = 1). Of 19 patients undergoing surgical resection, 15 had complete resection, and four had incomplete resection. All four patients with incomplete resection had thymic carcinoma. Among the patients with incomplete resection, two had macroscopic residual tumor at operation field (R2 resection) and the remaining two showed microscopically positive resection margin (R1 resection). All seven patients who underwent surgery for thymoma achieved complete resection. After completion of surgical resection, subsequent therapy was performed as follows: radiotherapy (RTx; n = 8), chemotherapy (CTx; n = 7), radiotherapy with chemotherapy (RTx + CTx; n = 2), and observation (n = 2). Among the eight patients not undergoing surgery, three received definitive RT, four had palliative CTx, and one was lost to follow-up.
Overall Survival and Disease Free Survival With a median follow-up of 42.6 months, 4-year OS and PFS in all patients was 79.4 and 40.6%, respectively. When comparing OS and PFS according to achievement of complete resection after neoadjuvant docetaxel/cisplatin, patients with complete resection showed 4-year OS of 92.9% and 4-year PFS of 50.3%, compared with 62.2 and 31.2%, respectively, in patients who did not achieve complete resection (Fig. 1; OS; p = 0.19; Fig. 2, PFS, p = 0.41).
DISCUSSION
Surgery after Induction CTx and Postoperative Treatment Nineteen patients (70.4%) underwent surgical resection and eight patients did not for the following reasons: surgeon’s decision of inoperable disease (n = 5); patients’ refusal
TETs are a heterogeneous group of diseases, with a wide spectrum of morphologic appearance.3,4,36 Thymoma and thymic carcinoma are the most frequent histologic subtypes, but thymic carcinoma is a distinct entity based on its obvious cytologic atypia.12 Compared with thymoma, thymic
FIGURE 1 . Overall survival according to complete resection after induction therapy.
962
Copyright © 2013 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
Docetaxel/Cisplatin in Thymic Epithelia Tumors
FIGURE 2. Progression-free survival according to complete resection after induction therapy.
carcinoma shows more invasive and malignant behavior, and previous reports have demonstrated worse survival.12,37 Tumor stage and completeness of resection are also important factors for prognosis. OS rate is closely related to stage,1,10,13,38–41 and complete resection of thymic tumor significantly increases the survival rate, even for patients with advanced stage.4,9,13,42 Among various clinical factors, complete resection is one of the most important prognostic factors,10 therefore, all patients with thymic tumors should be evaluated by an expert thoracic surgeon for their resectability, and every effort should be made to achieve resectability in patients with initially inoperable disease. Thymic tumors are sensitive to CTx. A variety of CTx agents and combination regimens have been reported, with an objective RR between 10% to 100%, depending on the study.1 CTx regimens used in thymic tumors have been primarily cisplatin-based, and anthracycline is the most often used agent in conjunction with cisplatin,18,22,23,43 although etoposide and ifosfamide have been variably incorporated into a cisplatinbased regimen.43,44 So far, the best results in phase II studies of CTx for inoperable thymic tumors have been obtained with ADOC regimen (doxorubicin, cisplatin, vincristin, cyclophosphamide), with a 92% RR, including a 43% complete response.23 However, direct comparison between regimens is not easy1 because of the small size of the series as a result of the rarity of the disease and the heterogeneous distribution of patients with thymoma or thymic carcinoma in each series. Consequently, although it is clear that a variety of chemotherapy regimens are active against thymic tumors, we cannot definitively say which regimens offer a significant advantage for this type of tumor. The rationale for induction CTx in patients with locally advanced thymic tumor is to facilitate complete surgical resection, resulting in a higher cure rate. Successful treatment of primary disease and metastatic regional nodes is crucial,
and we conceived the idea that incorporation of docetaxel into a cisplatin regimen may be efficacious in thymic tumors. This was based on in vitro data showing collateral sensitivity and a lack of cross-resistance between taxane and platinums30 and their successful use in other epithelial tumors, such as non–small-cell lung cancer. In addition, several reports have reported antithymoma activity of taxane when used in monotherapy or combination therapy.33,34,45 In this study, we report the results of a prospective phase II study of neoadjuvant CTx using docetaxel/cisplatin in patients with locally advanced TETs. With intent-totreat analysis, 15 of 27 patients (55.6%) achieved complete resection after induction CTx. Of 26 patients whose resectability could be assessed after neoadjuvant CTx by an expert thoracic surgeon (1 of 27 patients was lost to follow-up after CTx), initially inoperable lesions were converted to resectable diseases in 21 cases (21 of 26; 80.8%). Of these 21 cases, two patients did not undergo surgical resection: one patient decided not to undergo surgery because RTx alone was considered sufficient to eradicate the residual lesion (although this case broke the protocol), and one patient refused surgery because of fear of pleuropneumonectomy. Of 19 patients who underwent surgery, 15 patients achieved R0 resection (78.9%), two achieved R1 resection (10.5%), and the remaining two had R2 resection (10.5%). Table 4 summarizes the results of previous reports of induction CTx approaches in locally advanced thymic tumors. However, although this gives a rough indication of differences in clinical outcome from each regimen, given the heterogeneous distribution of patients regarding tumor stage, histology, and postoperative treatment, direct comparison between regimens is quite limited, and deemed to be invalid. The complete resection rate with our regimen was comparable with that of other studies, but the radiologic RR was relatively low, and no patient achieved complete response. However, it should be
Copyright © 2013 by the International Association for the Study of Lung Cancer
963
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
Park et al.
TABLE 4. Induction Chemotherapy Approaches in Locally Advanced Thymic Tumors
Chemotherapy Regimen (Author, yr) Cisplatin Epirubicin Etoposide (Maccjiarini P, 1991) Cisplatin Doxorubicin Vincristine Cyclophosphamide (Rea F, 1993) Cisplatin Doxorubicin Cyclophosphamide Prednisone (Shin DM, 1998) Cisplatin Epirubicin Etoposide or Cisplatin Doxorubicin Cyclophosphamide (Loehrer PJ, 1994) Cisplatin Docetaxel (current study)
Response Ratea (CR rate)
No. of Patients with Complete Resection/No. of Surgical Resection Patients (%)
Postoperative Treatment
OS
PFS
Thymoma (4) Thymic carcinoma (3)
100% (57%)
4/7 (57.1%)
RTx
80% 2 yr
80% 2 yr
III IV
Thymoma (16)
100% (43%)
11/16 (68.8%)
CTx or RTx
70% 3 yr
NA
III IV
Thymoma (22)
77% (14%)
16/21 (76%)
RTx and CTx
95% 5 yr 79% 7-yr
77% 5 yr 77% 7-yr
66.6% (13%)c
13/15 (87%)c
RTx and CTx
78% 10 yr
53% 10 yr
63% (0%)
15/19 (78.9%)
RTx or CTx or RTx + CTx
93% 4 yr
50% 4 yr
Stage
III
III
III IV
Histology (No. of Patients)
Thymoma (34) (11)b Thymic carcinoma (11) (4)b
Thymoma (9) Thymic carcinoma (18)
*Radiologic response, Complete response. b Not all patients included in this study received induction therapy. bIndicates the number of patients who received preoperative chemotherapy. c Indicates the proportion of patients among those who received induction chemotherapy only. RTx, radiotherapy; CTx, chemotherapy; CR, complete response.
FIGURE 3. Overall survival according to histologic type.
964
Copyright © 2013 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
noted that a substantial number of patients with unfavorable features were included in the current study; there were more patients with stage IV lesions (19 of 27; 70.4%) than stage III tumors (8 of 27; 29.6%), and a large proportion of this cohort were patients with thymic carcinoma rather than thymoma (18 of 27; 66.7%). When comparing complete resection rates according to histology, the seven thymoma patients who underwent surgery obtained complete resection, whereas, four of 12 patients with thymic carcinoma had residual disease. In addition, survival curves according to pathologic subtypes showed that all patients with thymoma were alive at least until the last follow-up date, in contrast to patients with thymic carcinoma (Fig. 3), further emphasizing the adverse clinical features of thymic carcinoma. Although a relatively short follow-up period (42.6 months) can be a major limitation of this study, the overall 4-year survival rate of 79.4%, despite the substantial proportion of patients with thymic carcinoma, was not disappointing. In summary, the results of this current prospective phase II study of neoadjuvant chemotherapy using docetaxel/cisplatin suggest that this regimen is feasible and can potentially improve tumor resectability in patients with locally advanced TETs. We certify that there is no conflict of interest with any financial organization regarding the material discussed in the article. This study was sponsored by Sanofi Aventis; the company provided a free supply of the docetaxel. REFERENCES 1. Detterbeck FC, Parsons AM. Thymic tumors. Ann Thorac Surg 2004;77:1860–1869. 2. Schmidt-Wolf IG, Rockstroh JK, Schüller H, et al. Malignant thymoma: current status of classification and multimodality treatment. Ann Hematol 2003;82:69–76. 3. Suster S, Moran CA. Primary thymic epithelial neoplasms showing combined features of thymoma and thymic carcinoma. A clinicopathologic study of 22 cases. Am J Surg Pathol 1996;20:1469–1480. 4. Venuta F, Anile M, Diso D, et al. Thymoma and thymic carcinoma. Eur J Cardiothorac Surg 2010;37:13–25. 5. Rea F, Marulli G, Girardi R, et al. Long-term survival and prognostic factors in thymic epithelial tumours. Eur J Cardiothorac Surg 2004;26:412–418. 6. Moore KH, McKenzie PR, Kennedy CW, McCaughan BC. Thymoma: trends over time. Ann Thorac Surg 2001;72:203–207. 7. Lee CY, Bae MK, Park IK, Kim DJ, Lee JG, Chung KY. Early Masaoka stage and complete resection is important for prognosis of thymic carcinoma: a 20-year experience at a single institution. Eur J Cardiothorac Surg 2009;36:159–62; discussion 163. 8. Okumura M, Miyoshi S, Takeuchi Y, et al. Results of surgical treatment of thymomas with special reference to the involved organs. J Thorac Cardiovasc Surg 1999;117:605–613. 9. Wilkins KB, Sheikh E, Green R, et al. Clinical and pathologic predictors of survival in patients with thymoma. Ann Surg 1999;230:562–72; discussion 572. 10. Regnard JF, Magdeleinat P, Dromer C, et al. Prognostic factors and longterm results after thymoma resection: a series of 307 patients. J Thorac Cardiovasc Surg 1996;112:376–384. 11. Yano M, Sasaki H, Yokoyama T, et al. Thymic carcinoma: 30 cases at a single institution. J Thorac Oncol 2008;3:265–269. 12. Ogawa K, Toita T, Uno T, et al. Treatment and prognosis of thymic carcinoma: a retrospective analysis of 40 cases. Cancer 2002;94:3115–3119. 13. Blumberg D, Port JL, Weksler B, et al. Thymoma: a multivariate analysis of factors predicting survival. Ann Thorac Surg 1995;60:908–13; discussion 914.
Docetaxel/Cisplatin in Thymic Epithelia Tumors
14. McCart JA, Gaspar L, Inculet R, Casson AG. Predictors of survival following surgical resection of thymoma. J Surg Oncol 1993;54:233–238. 15. Kim ES, Putnam JB, Komaki R, et al. Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer 2004;44: 369–379. 16. Evans TL, Lynch TJ. Role of chemotherapy in the management of advanced thymic tumors. Semin Thorac Cardiovasc Surg 2005;17:41–50. 17. Giaccone G. Treatment of malignant thymoma. Curr Opin Oncol 2005;17: 140–146. 18. Loehrer PJ, Sr, Kim K, Aisner SC, et al. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 1994;12:1164–1168. 19. Loehrer PJ, Sr, Chen M, Kim K, et al. Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial. J Clin Oncol 1997;15:3093–3099. 20. Hu E, Levine J. Chemotherapy of malignant thymoma. Case report and review of the literature. Cancer 1986;57:1101–1104. 21. Hernandez-Ilizaliturri FJ, Tan D, Cipolla D, Connolly G, Debb G, Ramnath N. Multimodality therapy for thymic carcinoma (TCA): results of a 30-year single-institution experience. Am J Clin Oncol 2004;27: 68–72. 22. Kosmidis PA, Iliopoulos E, Pentea S. Combination chemotherapy with cyclophosphamide, adriamycin, and vincristine in malignant thymoma and myasthenia gravis. Cancer 1988;61:1736–1740. 23. Fornasiero A, Daniele O, Ghiotto C, et al. Chemotherapy for invasive thymoma. A 13-year experience. Cancer 1991;68:30–33. 24. Loehrer PJ, Sr, 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;91:2010–2015. 25. Macchiarini P, Chella A, Ducci F, et al. Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma. Cancer 1991;68:706–713. 26. Rea F, Sartori F, Loy M, et al. Chemotherapy and operation for invasive thymoma. J Thorac Cardiovasc Surg 1993;106:543–549. 27. Shin DM, Walsh GL, Komaki R, et al. A multidisciplinary approach to therapy for unresectable malignant thymoma. Ann Intern Med 1998;129:100–104. 28. Venuta F, Rendina EA, Longo F, et al. Long-term outcome after multimodality treatment for stage III thymic tumors. Ann Thorac Surg 2003;76:1866–72; discussion 1872. 29. Gandara DR, Vokes E, Green M, et al. Activity of docetaxel in platinumtreated non-small-cell lung cancer: results of a phase II multicenter trial. J Clin Oncol 2000;18:131–135. 30. Jensen PB, Holm B, Sorensen M, Christensen IJ, Sehested M. In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabin. Br J Cancer 1997;75: 869–877. 31. Binder D, Hackenthal M, Graseck L, et al. A phase II study of weekly docetaxel-cisplatin as first-line treatment for advanced non-small cell lung cancer. J Thorac Oncol 2009;4:1144–1147. 32. Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21:3016–3024. 33. Oguri T, Achiwa H, Kato D, et al. Efficacy of docetaxel as a second-line chemotherapy for thymic carcinoma. Chemotherapy 2004;50:279–282. 34. Umemura S, Segawa Y, Fujiwara K, et al. A case of recurrent metastatic thymoma showing a marked response to paclitaxel monotherapy. Jpn J Clin Oncol 2002;32:262–265. 35. Ogawa F, Iyoda A, Amano H, et al. Thymic large cell neuroendocrine carcinoma: report of a resected case - a case report. J Cardiothorac Surg 2010;5:115. 36. Snover DC, Levine GD, Rosai J. Thymic carcinoma. Five distinctive histological variants. Am J Surg Pathol 1982;6:451–470. 37. Blumberg D, Burt ME, Bains MS, et al. Thymic carcinoma: current staging does not predict prognosis. J Thorac Cardiovasc Surg 1998;115: 303–8; discussion 308.
Copyright © 2013 by the International Association for the Study of Lung Cancer
965
Journal of Thoracic Oncology® • Volume 8, Number 7, July 2013
Park et al.
38. Verley JM, Hollmann KH. Thymoma. A comparative study of clinical stages, histologic features, and survival in 200 cases. Cancer 1985;55:1074–1086. 39. Quintanilla-Martinez L, Wilkins EW, Jr, Choi N, Efird J, Hug E, Harris NL. Thymoma. Histologic subclassification is an independent prognostic factor. Cancer 1994;74:606–617. 40. Maggi G, Casadio C, Cavallo A, Cianci R, Molinatti M, Ruffini E. Thymoma: results of 241 operated cases. Ann Thorac Surg 1991;51:152–156. 41. Elert O, Buchwald J, Wolf K. Epithelial thymus tumors–therapy and prognosis. Thorac Cardiovasc Surg 1988;36:109–113. 42. Venuta F, Rendina EA, Pescarmona EO, et al. Multimodality treatment of thymoma: a prospective study. Ann Thorac Surg 1997;64:1585–91; discussion 1591.
966
43. Oshita F, Kasai T, Kurata T, et al. Intensive chemotherapy with cisplatin, doxorubicin, cyclophosphamide, etoposide and granulocyte colonystimulating factor for advanced thymoma or thymic cancer: preliminary results. Jpn J Clin Oncol 1995;25:208–212. 44. Giaccone G, Ardizzoni A, Kirkpatrick A, Clerico M, Sahmoud T, van Zandwijk N. Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1996;14:814–820. 45. Shintani Y, Ohta M, Hazama K, Miyoshi S, Kagisaki K, Matsuda H. Thymic carcinoma successfully resected with superior vena cava after chemoradiotherapy. Jpn J Thorac Cardiovasc Surg 2001;49:717–721.
Copyright © 2013 by the International Association for the Study of Lung Cancer