Journal of Thoracic Oncology:
A Prospective Phase II Trial of Induction Chemotherapy with Docetaxel/Cisplatin for Masaoka Stage III/IV thymic Epithelial Tumors
Park, Silvia MD*; Ahn, Myung-ju MD, PhD*; Ahn, Jin Seok MD, PhD*; Sun, Jong-Mu MD, PhD*; Shim, Young Mog MD, PhD†; Kim, Jhingook MD, PhD†; Choi, Yong Soo MD, PhD†; Kim, Kwhanmien MD, PhD†; Shin, Sumin MD†; Ahn, Yongchan MD, PhD‡; Kwon, O Jung MD, PhD§; Kim, Hojoong MD, PhD§; Lee, Su Jin MD*; Chang, Won Jin MD*; Park, Keunchil MD, PhD*
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@example.com
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.
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.
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.
Neoadjuvant docetaxel/cisplatin is both feasible and well tolerated, and potentially improves surgical resectability in patients with advanced TETs.
Although 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 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
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.
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.
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 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.
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).
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. 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 large-cell 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 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).
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 (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).
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 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 cisplatin-based 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-to-treat 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 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.
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Thymic tumor; Resectability; Preoperative chemotherapy; Docetaxel/cisplatin
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