Journal of Thoracic Oncology:
Malignancies of the Thymus Supplement
The Role of Chemotherapy in Advanced Thymoma
Schmitt, Jordan MD*; Loehrer, Patrick J. Sr. MD*
*Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
Disclosure: The authors declare no conflicts of interest.
Address for correspondence: Jordan Schmitt, MD, IU Simon Cancer Center, Indiana Cancer Pavilion, 535 Barnhill Drive, Room 473, Indianapolis, IN 46202. E-mail: email@example.com
Background: Thymoma and thymic carcinomas are rare malignancies. Most thymomas and about one-third of thymic carcinomas can be cured with local therapy. The remainder of will be candidates for systemic therapy. Numerous retrospective trials confirm objective responses to a variety of single-agent and combination chemotherapeutic regimens.
Methods: No prospective randomized comparison of regimens has been performed because of the rarity of the disease. This paper reviewed the literature of chemotherapy in advanced thymic malignancies.
Results: Existing data suggest that anthracycline plus cisplatin regimens seem to demonstrate higher response rates and perhaps longer median survival times compared with nonanthracycline-containing regimens.
Discussion: Thymic malignancies are sensitive to a broad spectrum of systemic agents. Thymic carcinoma has a distinct clinical presentation and worse therapeutic outcomes than thymoma. Despite reproducible high response rates in thymoma, durable complete remissions are rare. Thus, novel new therapeutic targets need to be identified and appropriate agents developed to have further impact on this disease.
Approximately one third of patients with thymoma will have invasive or advanced unresectable disease at the time of diagnosis.1–3 These patients often have either local invasion into neighboring organs, pleural, or pericardial dissemination or less commonly extrathoracic metastasis to the liver, bone, brain, or kidney.4 According to Masaoka et al.,5 those with invasive disease and those with metastatic disease have 5-year overall survivals estimated at 67% and 50%, respectively. Because of the rarity of thymomas, the published experience with chemotherapy has been limited, but there have been numerous case reports and small prospective trials documenting that thymomas are a chemotherapy-sensitive disease and that systemic chemotherapy is capable of producing durable remissions in those patients with advanced or metastatic thymoma.
Historically, various chemotherapy agents have demonstrated activity as single agents in thymoma (Figure 1). There have been only a few small phase II trials looking at single-agent chemotherapy for advanced thymoma. These include cisplatin, interleukin-2, pemetrexed, and ifosfamide. All trials included patients who had been previously treated with chemotherapy. This article will review the salient articles evaluating the role of chemotherapy or thymic tumors. The role of targeted agents will be discussed elsewhere in this issue.
As mentioned, much of the published experiences of single agents in thymic malignancies have focused on case reports in small retrospective series. In most of these, the predominant histology studied has been thymoma. In the 1970s and early 1980s, a number of case reports suggested activity with cisplatin or doxorubicin-based therapy. One of the first articles described a complete remission in a patient with renal metastases from thymoma who was treated with cisplatin.6 This was followed shortly thereafter by the earliest published prospective phase II trial in thymoma, which was conducted by the Eastern Cooperative Oncology Group (ECOG) and evaluated cisplatin (50 mg/m2 every 3 weeks) in patients with advanced/metastatic thymoma.7 In this study, 21 patients were eligible for assessment, and two (10%) demonstrated a partial remission. No complete remissions were noted. Median survival was reported as 76 weeks for all patients on the study with a 2-year survival estimated at 39%.
From 1984 to 1996, several British investigators looked at ifosfamide as single-agent therapy in invasive thymoma.8 Two different regimens of ifosfamide plus mesna were used. The most common toxicities were nausea, vomiting, and leucopenia. Five complete responses and one partial response were noted in the 13 (overall response, 46.2%) assessable patients. Two of the patients had thymic carcinoma and had stable disease as the best response to therapy. The median duration of complete response was 66+ months, and the estimated survival rate 5 years after ifosfamide therapy was 57%.
Based on both a case report showing complete response and the lymphocytic effect of interleukin (IL)-2 (activation of cytolytic T-lymphocytes),9 IL-2 for the treatment of thymoma was further investigated in a 14-patient phase II clinical trial performed at Indiana University.10 This trial enrolled previously treated patients with thymoma between 1992 and 1994. Eligible patients were treated with IL-2 at 12 × 106 IU/m2/d subcutaneously daily for 5 days for 4 weeks followed by 2 weeks of rest. The median number of cycles received was two. Five of the 14 patients required dose reductions for grade 3 toxicities. Two patients developed new signs of myasthenia gravis while on study. Results of the trial revealed no objective responses.
Twenty-seven previously treated patients (16 thymoma and 11 thymic carcinoma) were treated with single-agent pemetrexed. Toxicity was mild with no patient experiencing grade IV toxicity. Two complete and two partial responses (RECIST criteria) were observed among the patients with thymoma, and one partial response in a patient with thymic carcinoma was noted. The median overall survival was 29 months for all patients.
A case report by Palmieri et al.11 reported a complete response and resolution of pure red cell aplasia in a patient treated with high-dosage octreotide (1.5 mg/d/subcutaneously) plus prednisone (0.6 mg/kg/d). The report was followed by a trial conducted through ECOG, which evaluated octreotide alone for two cycles and if no objective response was seen, prednisone was added to regimen.12 In this trial, 32 patients with thymoma and six patients with thymic carcinoma or carcinoid were evaluable. Eight patients had grade 4 or 5 toxicity including one death secondary to grade 5 infection without neutropenia. Of 38 patients treated with octreotide alone, four (10.5%) had an objective response. For the 21 patients in whom prednisone was added to octreotide, there were two complete and six partial responses noted. The objective response rate for all patients was 30.3%.
Other case reports have demonstrated response to rarely of agents including 5-fluorouracil, gemcitabine, paclitaxel, navelbine, maytansine, suranim, and gallium nitrate.13–15 Several phase II trials with targeted agents such as gefitinib, imatinib, and erlotinib plus bevacizumab have been conducted and have shown no significant activity in patients with thymic carcinoma or thymoma. These will be discussed elsewhere in this monography.
In the 1980s and early 1990s, combination chemotherapy in advanced thymic malignancies became more popular. Hu et al. published a review of trials and case reports in 1986, which concluded that thymoma seems to be sensitive to corticosteroids (11/13 patients with documented response) and to platinum-based combination chemotherapy (84% response rate [10/25 with complete response and 11/25 with partial response]). They also speculated that the response seen in nonplatinum-based chemotherapy was likely related to the concurrent use of corticosteroids and not to the chemotherapeutic agents themselves.16 Multiple phase II trials and case series have been published to evaluate various combinations. The majority of clinical trials focused on platinum-based combination chemotherapy (Table 1). Most of these regimens containing both cisplatin and doxorubicin have reported objective response rates ranging from 50 to 92%.17
One of the first prospective phase II trials with combination chemotherapy was completed by the ECOG. In 30 patients with stage IV thymoma or thymic carcinoma, 15 had an objective response to cisplatin (50 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) (PAC) administered every 3 weeks. The median duration of response was 12 months, and the 5-year overall survival was 32%.18
In patients with limited, unresected thymoma, treatment consisting of PAC for 2 to 4 cycles followed by radiotherapy to the involved field (54 Gy). Among 23 fully evaluable patients, five complete and 11 partial responses were observed. The median time to treatment failure was 93 months, and the median overall survival was 93 months (range, 1–110 months). The 5-year survival was 52%.19
Similar results of high-degree activity were reported by Kim et al.,20 in which they used a regimen of cisplatin, doxorubicin, cyclophosphamide plus prednisone (CAPP). In this series largely composed of patients with locally advanced thymoma, 17 of 22 (77%) patients had an objective response to therapy. Three patients had a complete response to therapy. Responding patients underwent surgical resection followed by radiation therapy. The median survival time of the group of patients was not reached at the time of the publication.
Fornasiero et al.21 used the doxorubicin, cisplatin, vincristine, cyclophosphamide regimen (cisplatin, vincristine, doxorubicin, and cyclophosphamide). In these retrospective analyses, 34 of 37 patients achieved a partial (48%) or complete (43%) response. The median survival, however, was only 15 months, which questions the value of the addition of vincristine to the PAC regimen.
Several regimens have evaluated combinations which exclude anthracycline. The first prospective trial of this nature was led by Giaccone et al.,22 for the European Organization for Research and Treatment of Cancer. In the trial, 16 previously untreated patients with advanced thymoma were treated with cisplatin plus etoposide. Five complete and four partial responses were noted for an overall response rate of 56%. The median survival time was 51.6 months.
Attempting to build on this experience, the ECOG conducted a prospective trial in thymic malignancies (thymoma and thymic carcinoma) using cisplatin plus etoposide with the addition of ifosfamide (VIP).17 In 28 evaluable patients, only nine (32%) had an objective response. The median survival time was 31.6 months. This trial that used a drug with single-agent activity, ifosfamide, seemed to question the backbone of a cisplatin, etoposide regimen as standard frontline therapy.
Further evidence against nonanthracycline-containing regimens as part of first-line therapy came from another ECOG trial. In this trial by Lemma et al.,23 45 patients with thymoma (N = 24) or thymic carcinoma (N = 21) were treated with carboplatin (area under the curve = 6) plus paclitaxel (225 mg/m2) every 3 weeks. Overall, a 28.6% objective response rate was observed for patients with thymic carcinoma and a 34.8% for those with thymoma. The progression-free survival was 5.0 and 16.8 months, respectively.
The role of high-dose chemotherapy followed by autologous stem-cell transplant has not yet been established. Iwasaki et al. published a report of two cases of advanced thymoma who received standard chemotherapy (ADOC) followed by high-dose ifosfamide, carboplatin, and etoposide with autologous stem-cell rescue. They observed one pathologic CR and one pathologic PR.24 Another study looking at the role of autologous transplantation in poor-risk malignancies included two patients with relapsed thymoma. In this series, both patients achieved a CR after high-dose chemotherapy with BEAM (semustine, etoposide, cytarabine, and melphalan) and autologous stem-cell transplant.25 Finally, a series from Indiana University was reported on four patients with platinum-sensitive, relapsed thymoma who underwent salvage therapy with high-dose carboplatin and etoposide followed by autologous stem-cell transplant. They noted that three patients maintained the PR achieved after initial chemotherapy, and the fourth patient maintained the previously achieved CR with acceptable toxicity.26 No durable responses were noted.
With the role of transplantation not yet clearly defined, salvage therapy with targeted agents has been the focus of ongoing research. Other combination therapies include targeted agents, which are discussed in another chapter. A trial with erlotinib plus bevacizumab failed to demonstrate meaningful activity. As mentioned in the chapter by Rajun and Giaccone in this journal, the histone deacetylase inhibitor, belinostat, demonstrated single-agent activity in recurrent thymic tumors. As such, belinostat plus PAC is currently being evaluated in previously untreated patients with advanced thymoma through an ongoing trial at the National Cancer Institute and the Indiana University Melvin and Bren Simon Cancer Center.
Supported in part by Grant CA-P30CA082709-11, awarded by the National Cancer Institute Support Grant.
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Thymoma; Anthracycline; Cisplatin; Thymic carcinoma; Single agent therapy; Combination chemotherapy
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