Girard, Nicolas MD*; Lal, Rohit MD†; Wakelee, Heather MD‡; Riely, Gregory J. MD§; Loehrer, Patrick J. MD∥
Thymic malignancies are rare epithelial tumors that may be aggressive and difficult to treat.1 Thymomas are usually localized to the anterior mediastinum and are frequently eligible for upfront surgical resection, which is the mainstay of the curative-intent treatment.1 However, approximately 30% of patients present with an advanced tumor at the time of diagnosis, with invasion of neighboring organs, dissemination to the pleura, the pericardium, or less frequently extrathoracic organs. In such cases, chemotherapy has been used both to reduce the tumor burden—possibly allowing subsequent surgery or radiotherapy—and to achieve prolonged disease control. Recurrence after resection may be similarly treated with chemotherapy. Thymic carcinomas, although rare, are usually already advanced at the time of presentation, and systemic therapy is important for almost all of these patients.
Knowledge regarding chemotherapy for thymic tumors has mainly been based on retrospective series, 2–9 although several prospective trials have also been conducted.10–21 These studies have clearly demonstrated the chemosensitivity of thymoma, and to a lesser extent thymic carcinoma, to various cytotoxic agents and combinations. However, details of patient selection are often lacking (either disease extent or general condition), and the intent of the treatment sequence is often vague.
Adoption of a common language and definition of terms is crucial for the International Thymic Malignancies Interest Group (ITMIG) effort to develop a international prospective database of thymic tumors. The article by Huang et al.22 provides definitions for survival and endpoints for recurrences assessment and discusses how to measure response to treatment. Herein, we discuss additional points with regard to chemotherapy, including treatment sequence, general modalities, and impact of corticosteroids.
This article represents a broad consensus within the ITMIG community, based on available underlying evidence. A core workgroup assembled data for discussion based on a literature review and formulated proposed definitions for data elements (N.G., G.J.R., P.J.L., R.L., and H.W.). These proposals were discussed at the ITMIG Definitions and Terminology workshop on November 16, 2010, which was supported by the International Association for the Study of Lung Cancer. Subsequent review with an extended workgroup including radiation oncologists led to refinement of these definitions. The manuscript was distributed to all ITMIG members for further comment, and ultimately the refined article was approved and adopted by ITMIG members.
CHEMOTHERAPY IN THYMIC MALIGNANCIES
Intent of Treatment
Chemotherapy is used in various clinical scenarios for thymic malignancies (Table 1). First, chemotherapy may constitute part of curative-intent treatment for locally advanced tumors. The objective of the treatment strategy is to achieve long-term survival with no evidence of recurrence. In this setting, chemotherapy is combined with local treatment (e.g., preoperative and postoperative chemotherapy and surgery, or chemoradiotherapy).
Chemotherapy may also be delivered as palliative-intent treatment in advanced or metastatic thymic tumors to improve tumor-related symptoms. Despite a reasonable hope for prolonged disease control, eradication of the tumor is not expected. In this setting, chemotherapy is typically delivered as the sole treatment modality.
The response and survival rates may significantly differ depending on the clinical context for which chemotherapy is delivered. Our first recommendation is that before beginning chemotherapy, the intent of treatment is clearly stated (Table 1; Figure 1): (1) is chemotherapy delivered as curative or palliative-intent treatment? (2) For curative-intent primary chemotherapy, is subsequent surgery or radiotherapy or both planned? Obviously the final treatment strategy may change depending on tumor response and other criteria. Investigators should indicate which treatments the patient ultimately received. A prospective database with such information will allow meaningful integration of reports from different institutions.
The wide variation in the number of patients treated with surgery or radiotherapy after primary chemotherapy suggests significant heterogeneity in the inclusion criteria among studies (Table 2). This highlights the need to clearly state the inclusion criteria, the treatment intent and plan, and the treatment that was eventually delivered.
General Reporting Guidelines for Chemotherapy
When reporting on primary, postoperative, and palliative chemotherapy, investigators should clearly indicate: (1) the cytotoxic agents used, (2) the number of cycles, and (3) whether more than 70% of the planned dose intensity was eventually delivered.23 This threshold is usually chosen in chemotherapy phase II trials to define the feasibility of a proposed treatment.
Acute and late toxicity of chemotherapy should be carefully and systematically evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4 system.24 Grade 3 to 5 and dose-limiting toxicities should be documented. Investigators should pay special attention to the accurate assessment of late and chronic toxicities, because patients with thymoma live longer than patients with other types of cancers. In particular, there may be an underestimated increased risk of cardiac toxicity because of repeated use of anthracyclines, often combined with radiotherapy and surgery, and possibly development of paraneoplastic myocarditis.25
Response assessment recommendations for thymic malignancies are described in a previous ITMIG article.22 The results for thymoma and thymic carcinoma should be reported separately. The main imaging study used for tumor response assessment is computed tomography (CT) scan. In patients receiving octreotide, octreoscan results should be documented before therapy.26 We also recommend systematic documentation of the effect of antitumor treatment on associated paraneoplastic syndromes (if present), 27 which should include documentation of any concurrent specific therapies (e.g., symptom-palliation or immunosuppressive drugs).
Curative-intent chemotherapy may be delivered either before surgery or radiotherapy (primary chemotherapy), concurrent with radiotherapy, or after surgery (postoperative chemotherapy; Table 1, Figure 1).
Primary chemotherapy is a chemotherapy delivered as first treatment in case of locally advanced nonmetastatic thymic tumor (Masaoka-Koga stage III or IVA28). The chemosensitivity of thymoma provides a strong rationale to use chemotherapy in this setting. The main objective of primary chemotherapy is to make feasible subsequent R0 resection, which is the most significant prognostic factor on survival in thymic malignancies.29
Several chemotherapy regimens have been used in this setting (Table 2). Usually two to four cycles of primary chemotherapy are administered. Imaging reassessment with contrast-enhanced CT scan is usually performed 3 to 4 weeks after the last chemotherapy injection. If surgical resection is the objective of the therapeutic strategy for locally advanced thymic tumors, the final treatment plan may change depending on tumor response to primary chemotherapy (Figure 1). A response is observed in approximately 70 to 80% of cases in the largest studies (Table 2). Patients for whom R0 resection is thought to be feasible undergo surgery. A time interval longer than 8 weeks between the last cycle of chemotherapy and surgery is not considered appropriate. In the largest reported series, surgery was performed in the majority of patients, and complete resection was achieved in approximately 50% of cases. For those cases, the final treatment strategy is “primary preoperative chemotherapy followed by surgery.”
When the patient is not deemed to be a surgical candidate—either because R0 resection is not believed to be achievable or because of poor performance status or coexistent medical condition (“medically inoperable” patient)—curative-intent, definitive radiotherapy may be delivered (Figure 1).30 The curative value of radiotherapy in this setting has to be evaluated in further studies. In the literature, radiotherapy is ultimately delivered in 0 to 50% of patients receiving primary chemotherapy (Table 2). The final treatment strategy is “definitive chemoradiotherapy.” A time interval longer than 6 weeks between the last chemotherapy cycle and the delivery of the first radiation fraction is not considered appropriate. Chemotherapy may be given concurrently with the radiation therapy.
If radiotherapy is not feasible, either because of a large tumor burden that precludes safe delivery of appropriate doses or because of comorbidities increasing the risks of radiation-induced toxicity, treatment consists of chemotherapy alone. Treatment with chemotherapy alone is a strategy that is ultimately palliative (Figure 1, see below). In the reported literature, 0 to 21% of patients with locally advanced thymic tumors receiving primary chemotherapy cannot receive surgery or radiation therapy or other local treatment (Table 2). The final treatment strategy is “palliative chemotherapy” (see below).
Our recommendations for reporting on curative-intent chemotherapy for locally advanced thymic tumors are the following (Table 1): (1) the terms “induction chemotherapy” and “neoadjuvant chemotherapy” should be replaced by the term “primary chemotherapy”; (2) the terms “marginally resectable,” “potentially respectable,” and “unresectable” tumors should be avoided; instead, investigators should indicate tumor stage28; (3) intent of primary chemotherapy, that is, before surgery or radiotherapy; and (4) final treatment strategy have to be detailed for all patients: preoperative chemotherapy followed by surgery, definitive chemoradiotherapy, or palliative chemotherapy; and (5) thymomas and thymic carcinomas should be analyzed separately. Of note, some series including patients with locally advanced thymic tumors reported on the use of primary chemotherapy associated with sequential or concurrent radiotherapy in a preoperative intent (Table 2). Such strategy should be referred to as “preoperative chemoradiotherapy.”
Postoperative chemotherapy is defined as a chemotherapy delivered after surgery (Table 1). Only sparse evidence exists in the literature regarding postoperative chemotherapy in thymic malignancies. The rationale is limited in thymomas given the low incidence of systemic recurrences after definitive surgery.29 Adjuvant chemotherapy regimens are similar to those of primary chemotherapy. Postoperative chemotherapy consisted of cyclophosphamide, doxorubicin, cisplatin in a French series of 21 stage III-IVA thymoma patients, 31 and cyclophosphamide, doxorubicin, and cisplatin plus prednisone were used in two prospective MD Anderson Cancer Center trials of postoperative radiotherapy followed by chemotherapy.15,32 Current guidelines do not recommend the use of postoperative chemotherapy in thymoma.
However, thymic carcinomas often exhibit frequent and early locoregional and systemic recurrences after surgery.33 In a large series that included 92 thymic carcinomas, 5-year survival was 82% with postoperative chemotherapy (n = 12), 47% with postoperative chemoradiation (n = 24), 74% with postoperative radiotherapy (n = 33), and 72% with no postoperative treatment (n = 16).29 However, the number of patients is small, and they were selected for a particular treatment approach, highlighting the need for collaborative, well-defined research.
Our recommendations for reporting on postoperative chemotherapy for thymic malignancies are as follows: (1) use the term “postoperative chemotherapy” instead of “adjuvant chemotherapy” or “consolidation chemotherapy”; it is self-explanatory and is consistent with reporting guidelines for radiotherapy30; (2) thymomas and thymic carcinomas should be analyzed separately; and (3) the completeness of the resection should be indicated (i.e., complete resection [R0], microscopic residual disease [R1], or gross residual disease [R2]).
Chemotherapy after R2 resection is considered as postoperative chemotherapy, provided surgery is performed with curative intent (not simply for diagnosis)—this definition maintains consistency with that recommended for postoperative radiotherapy.30 After an R2 resection, postoperative radiotherapy may be combined sequentially or concurrently with chemotherapy (this latter instance is referred to as postoperative chemoradiotherapy).
Postoperative chemotherapy should be initiated within 12 weeks after surgery. The term postoperative chemotherapy is still appropriate after more than 12 weeks when both chemotherapy and radiotherapy are planned, and the radiotherapy was initiated within 12 weeks, provided no tumor recurrence is observed. Chemotherapy that is initiated postoperatively because imaging reveals recurrence or progression of disease should be labeled as “chemotherapy for recurrent disease” not postoperative chemotherapy.
Palliative chemotherapy is given as the sole treatment modality, with no plan for surgery or radiotherapy, for example, in patients with metastatic disease (Table 1). Palliative chemotherapy may also ultimately be the treatment given in patients with locally advanced tumors which do not respond sufficiently to be eligible for subsequent surgery or radiotherapy (Figure 1). The objectives of palliative-intent chemotherapy are to improve potential tumor-related symptoms and to achieve tumor response. Prolonged disease control is possible, but tumor eradication is not expected.
Several prospective and retrospective studies have reported on palliative chemotherapy regimens (Table 3), but because there are no randomized studies, it is unclear which regimen is best; however, anthracycline-based regimens seem to have improved response rates. In general, a combination regimen is recommended, for at least three and no more than six cycles.
In the palliative-intent setting, several consecutive lines of chemotherapy may be administered when the patient presents with tumor progression. We recommend the use of the standard terms “first-line,” “second-line,” and “third-line” chemotherapy, etc.
Chemotherapy for Recurrence
Chemotherapy for recurrence refers to chemotherapy delivered for tumor recurrence appearing after previous curative-intent treatment, which results in complete disappearance of tumor. This term should not be used for tumor progression after palliative-intent chemotherapy without a complete response. In this scenario, chemotherapy is referred to as second-line or third-line chemotherapy.
Similar to what is done for initial management, the treatment of thymic tumor recurrences are typically palliative intent but may be curative intent; in this latter situation, treatment may include chemotherapy, surgery, or radiotherapy. As for radiotherapy, our recommendation is to use the same terms and policies as for initial treatment, but stating that this is for recurrence.
CORTICOSTEROIDS IN THYMIC MALIGNANCIES
Impact on Response Assessment
Corticosteroids have been known for a long time to have a “lympholytic” effect.35,36 The thymuses of patients receiving corticosteroids have significantly increased fat and connective tissue, decreased germinal centers, and resulted in poorer corticomedullary differentiation than those of untreated patients not receiving steroids. The changes after corticosteroid treatment mimic those after aging or acute stress, with retention of the myoepithelial stroma but depletion of thymic lymphoid elements. In lymphocytic thymomas (type AB, B1, and B2), corticosteroids may then produce a significant reduction of lesion size at imaging studies through lymphocytic depletion, with no antitumor effect.
Only limited data are available regarding the significance of this phenomenon in a clinical setting. In the Eastern Cooperative Oncology Group phase II trial evaluating the combination of octreotide and corticosteroids (prednisone at a dose of 0.6 mg/kg/d) versus octreotide alone, higher response rates were observed in patients receiving corticosteroids (38 versus 11% in patients treated with octreotide alone).26
Given the possible impact of corticosteroids on response assessment, our recommendation is to document whether the patient has received corticosteroids at a dose higher than 0.5 mg/kg/d of prednisone (or a correspondingly equivalent dose of another steroid) and the duration of corticosteroids treatment. The 0.5 mg/kg/d cutoff is chosen based on the dose delivered in the Eastern Cooperative Oncology Group trial and to avoid complex reporting of temporary administration of corticosteroids at low doses to control chemotherapy side effects. We recommend that response rates be reported and analyzed separately for patients receiving or not receiving steroids at this dose or higher. Ultimately, whether response criteria should be modified for thymomas with a substantial lymphocytic component versus other thymic malignancies when corticosteroids are given is currently unknown and calls for prospective studies.
Impact on Definition of Recurrence/Progression
The thymus may enlarge in various circumstances, including infections, burns, and corticosteroid or chemotherapy cessation (especially after an intensive regimen given to infants and young adults).37–39 This phenomenon is referred as “rebound thymic hyperplasia.” Rebound hyperplasia has been reported to occur 2 to 14 months after cessation of corticosteroids and may persist for 2 to 45 months. Histologically, it corresponds to a true thymic hyperplasia, with enlargement of the thymus, and no increase in the number of lymphoid follicles.40
Rebound hyperplasia has not been reported to occur in patients with thymic tumors but needs to be discussed given the potential implication on outcome assessment. Given the reported timeframe of this phenomenon, our recommendation is to consider rebound hyperplasia as in patients presenting with a potential local recurrence who stopped chemotherapy or corticosteroids within 15 months of regrowth of the thymic lesion.
Certain imaging characteristics may help to distinguish thymic hyperplasia and tumor recurrence. Typically, thymic hyperplasia results in a symmetric, nonfocal enlargement of the thymus on a CT scan. Both thymic hyperplasia and thymoma may be intimately related to the vessels (without invasion).40 Fluorodeoxyglucose positron emission tomography is not useful in this setting because both entities exhibit similar degrees of increased fluorodeoxyglucose uptake.41 Chemical shift magnetic resonance imaging has also been evaluated to distinguish thymoma and thymic hyperplasia.42 If the nature of thymic enlargement occurring within 15 months of treatment cessation is unclear based on imaging tissue, biopsy is recommended.
Chemotherapy is a major treatment modality for thymoma and thymic carcinoma. This article defines terms and policies, so that outcomes after chemotherapy can be reported in a consistent manner. These measures represent a consensus of the ITMIG community and will be used in ITMIG collaborative projects. Adopting these definitions will allow ITMIG members and others interested in the field to compare results and conduct collaborative investigations. The definitions may be updated in the future as new information comes to light. For example, the curative value of surgery or radiotherapy in specific clinical settings, such as stage IVA disease, should be evaluated in further studies.
A major impediment to progress is the limited number of patients in studies to date (Tables 1 and 2). The ITMIG prospective international database together with consistently defined terms will allow analysis of much larger patient cohorts over shorter period of time. Many questions regarding chemotherapy for thymic malignancies remain unanswered; however, the consistency afforded by the consensus definitions in this article and the collaborative spirit of ITMIG provide a framework, so that they can be addressed.
The authors thank Andrea Bezjak, Conrad Falkson, and Daniel Gomez for their contributions to development of the definitions and policies in this article.
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