Chemotherapy Definitions and Policies for Thymic Malignancies
2011; Elsevier BV; Volume: 6; Issue: 7 Linguagem: Inglês
10.1097/jto.0b013e31821ea5f7
ISSN1556-1380
AutoresNicolas Girard, Rohit Lal, Heather A. Wakelee, Gregory J. Riely, Patrick J. Loehrer,
Tópico(s)Pituitary Gland Disorders and Treatments
ResumoThymic malignancies are rare epithelial tumors that may be aggressive and difficult to treat.1Girard N Mornex F Van Houtte P et al.Thymoma: a focus on current therapeutic management.J Thorac Oncol. 2009; 4: 119-126Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar 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.1Girard N Mornex F Van Houtte P et al.Thymoma: a focus on current therapeutic management.J Thorac Oncol. 2009; 4: 119-126Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar 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, 2Fornasiero A Daniele O Ghiotto C et al.Chemotherapy of invasive thymoma.J Clin Oncol. 1990; 8: 1419-1423PubMed Google Scholar, 3Venuta F Rendina EA Longo F et al.Long-term outcome after multimodality treatment for stage III thymic tumors.Ann Thorac Surg. 2003; 76: 1866-1872Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 4Lucchi M Ambrogi MC Duranti L et al.Advanced stage thymomas and thymic carcinomas: results of multimodality treatments.Ann Thorac Surg. 2005; 79: 1840-1844Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 5Jacot W Quantin X Valette S et al.Multimodality treatment program in invasive thymic epithelial tumor.Am J Clin Oncol. 2005; 28: 5-7Crossref PubMed Scopus (26) Google Scholar, 6Rea F Sartori F Loy M et al.Chemotherapy and operation for invasive thymoma.J Thorac Cardiovasc Surg. 1993; 106: 543-549PubMed Google Scholar, 7Bretti S Berruti A Loddo C et al.Multimodal management of stages III-IVa malignant thymoma.Lung Cancer. 2004; 44: 69-77Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 8Yokoi K Matsuguma H Nakahara R et al.Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone.J Thorac Oncol. 2007; 2: 73-78Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 9Wright CD Choi NC Wain JC et al.Induction chemoradiotherapy followed by resection for locally advanced Masaoka stage III and IVA thymic tumors.Ann Thorac Surg. 2008; 85: 385-389Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar although several prospective trials have also been conducted.10Loehrer Sr, PJ 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: 1164-1168PubMed Google Scholar, 11Giaccone G Ardizzoni A Kirkpatrick A et al.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: 814-820Crossref PubMed Scopus (177) Google Scholar, 12Loehrer Sr, PJ Jiroutek M Aisner S et al.Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial.Cancer. 2001; 91: 2010-2015Crossref PubMed Scopus (159) Google Scholar, 13Lemma GL Loehrer PJ Lee JW et al.A phase II study of carboplatin plus paclitaxel in advanced thymoma or thymic carcinoma: E1C99.J Clin Oncol. 2008; 26: 8018Google Scholar, 14Macchiarini P Chella A Ducci F et al.Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma.Cancer. 1991; 68: 706-713Crossref PubMed Scopus (165) Google Scholar, 15Kim 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: 369-379Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 16Berruti A Borasio P Roncari A et al.Neoadjuvant chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide (ADOC) in invasive thymomas: results in six patients.Ann Oncol. 1993; 4: 429-431PubMed Scopus (41) Google Scholar, 17Kunitoh H Tamura T Shibata T et al.A phase II trial of dose-dense chemotherapy, followed by surgical resection and/or thoracic radiotherapy, in locally advanced thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9606).Br J Cancer. 2010; 103: 6-11Crossref PubMed Scopus (52) Google Scholar, 18Loehrer Sr, PJ 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: 3093-3099PubMed Google Scholar, 19Berruti A Borasio P Gerbino A et al.Primary chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide in locally advanced thymomas: a single institution experience.Br J Cancer. 1999; 81: 841-845Crossref PubMed Scopus (72) Google Scholar, 20Bonomi PD Finkelstein D Aisner S Ettinger D EST 2582 phase II trial of cisplatin in metastatic or recurrent thymoma.Am J Clin Oncol. 1993; 16: 342-345Crossref PubMed Scopus (58) Google Scholar, 21Highley MS Underhill CR Parnis FX et al.Treatment of invasive thymoma with single-agent ifosfamide.J Clin Oncol. 1999; 17: 2737-2744PubMed Google Scholar 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.22Huang J Detterbeck F Wang Z et al.Standard outcome measures for thymic malignancies.J Thorac Oncol. 2010; 5: 2017-2023Crossref PubMed Scopus (107) Google Scholar 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 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).TABLE 1Summary of Reporting Guidelines and Data Fields for Thymic Malignancies Treated with ChemotherapyChemotherapy strategies Initial treatment Curative intent Primary chemotherapyChemotherapy delivered before another focal treatment—surgery or radiotherapy.Intent of the treatment has to be documented, i.e., primary chemotherapy before surgery or primary chemotherapy before radiotherapy.Final strategy has to be indicated for all patients: primary preoperative chemotherapy or primary chemoradiotherapy. Postoperative chemotherapy Chemotherapy delivered after surgery.Completeness of the resection (R0, R1, or R2) should be indicated. Palliative intent Palliative chemotherapyChemotherapy delivered alone in cases for which there is no plan for surgery or radiotherapy. Chemotherapy for recurrenceChemotherapy delivered for tumor recurrence appearing after previous curative-intent treatment.Chemotherapy for recurrence may be curative intent (primary preoperative/chemoradiation, postoperative) or palliative intent (chemotherapy alone).Intent of the treatment and final strategy have to be documented as for initial treatment.Chemotherapy general reporting guidelines ModalitiesChemotherapy regimenNumber of cycles administeredDose intensity: > or <70% of the planned dose intensity AnalysisTreatment outcome has to be evaluated separately for thymoma and thymic carcinoma. ToxicitiesGrade 3–5 and dose-limiting toxicities (acute and late) of the treatment may be reported using the National Cancer Institute Common Terminology Criteria for Adverse Events v4 system.Acute and late toxicities have to be reported. Special attention has to be paid to late and chronic toxicities of the treatment, such as cardiac toxicities. ResponseAssessment of tumor response has been described in a previous article.22Huang J Detterbeck F Wang Z et al.Standard outcome measures for thymic malignancies.J Thorac Oncol. 2010; 5: 2017-2023Crossref PubMed Scopus (107) Google ScholarOctreoscan results should be reported for patients treated with octreotide.Effect of antitumor treatment on associated paraneoplastic manifestations has to be documented.Corticosteroid treatment doses (equivalent prednisone doses above 0.5 mg/kg/d) and durations should be reported. RecurrenceRebound hyperplasia has to be considered as a differential diagnosis for local recurrence when tumor regrowth occurs within the 15 months after treatment cessation. Open table in a new tab 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.TABLE 2Primary Chemotherapy or Chemoradiation for Locally Advanced Thymic MalignanciesReferencePrimary Chemotherapy RegimennPeriod of Accrual (yr)Subsequent Treatment (%)TumorResponse Rate (%)SurgeryComplete ResectionRT (Definitive ChemoRT)Palliative ChemotherapyTypeStageStudyChemotherapy Macchiarini14Macchiarini P Chella A Ducci F et al.Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma.Cancer. 1991; 68: 706-713Crossref PubMed Scopus (165) Google ScholarCEE72T/TCIIIPhase II1001005700 Berruti16Berruti A Borasio P Roncari A et al.Neoadjuvant chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide (ADOC) in invasive thymomas: results in six patients.Ann Oncol. 1993; 4: 429-431PubMed Scopus (41) Google ScholarADOC62TIII-IVAPhase II83?17?? Rea6Rea F Sartori F Loy M et al.Chemotherapy and operation for invasive thymoma.J Thorac Cardiovasc Surg. 1993; 106: 543-549PubMed Google ScholarADOC166TIII-IVARetrospective1001006900 Venuta3Venuta F Rendina EA Longo F et al.Long-term outcome after multimodality treatment for stage III thymic tumors.Ann Thorac Surg. 2003; 76: 1866-1872Abstract Full Text Full Text PDF PubMed Scopus (169) Google ScholarCEE1514T/TCIIIRetrospective66100??? Bretti7Bretti S Berruti A Loddo C et al.Multimodal management of stages III-IVa malignant thymoma.Lung Cancer. 2004; 44: 69-77Abstract Full Text Full Text PDF PubMed Scopus (84) Google ScholarADOC/PE2511T/TCIII-IVARetrospective726844?? Kim15Kim 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: 369-379Abstract Full Text Full Text PDF PubMed Scopus (226) Google ScholarCAPP2210TPhase II771007200 Lucchi4Lucchi M Ambrogi MC Duranti L et al.Advanced stage thymomas and thymic carcinomas: results of multimodality treatments.Ann Thorac Surg. 2005; 79: 1840-1844Abstract Full Text Full Text PDF PubMed Scopus (105) Google ScholarCEE3627T/TCIII-IVARetrospective676978193 Jacot5Jacot W Quantin X Valette S et al.Multimodality treatment program in invasive thymic epithelial tumor.Am J Clin Oncol. 2005; 28: 5-7Crossref PubMed Scopus (26) Google ScholarCAP56T/TCIII-IVARetrospective7538255012 Yokoi8Yokoi K Matsuguma H Nakahara R et al.Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone.J Thorac Oncol. 2007; 2: 73-78Abstract Full Text Full Text PDF PubMed Scopus (73) Google ScholarCAMP1415T/TCIII, IVA-BRetrospective9364141421 Kunitoh17Kunitoh H Tamura T Shibata T et al.A phase II trial of dose-dense chemotherapy, followed by surgical resection and/or thoracic radiotherapy, in locally advanced thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9606).Br J Cancer. 2010; 103: 6-11Crossref PubMed Scopus (52) Google ScholarCODE218TIIIPhase II6262432414Chemoradiation Loehrer18Loehrer Sr, PJ 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: 3093-3099PubMed Google ScholarCAP2312T/TCIII-IVAphase II701507015 Berruti19Berruti A Borasio P Gerbino A et al.Primary chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide in locally advanced thymomas: a single institution experience.Br J Cancer. 1999; 81: 841-845Crossref PubMed Scopus (72) Google ScholarADOC167TIII-IVAphase II8156563113 Wright9Wright CD Choi NC Wain JC et al.Induction chemoradiotherapy followed by resection for locally advanced Masaoka stage III and IVA thymic tumors.Ann Thorac Surg. 2008; 85: 385-389Abstract Full Text Full Text PDF PubMed Scopus (113) Google ScholarPE, ADOC, CAP, CEE109T/TCIII-IVARetrospective401008000The CAP, ADOC, and PE regimen are described in Table 1. The CODE regimen consists of cisplatin (25 mg/m2/wk), vincristin (1 mg/m2/wk), adriamycin (40 mg/m2/wk), and etoposide (80 mg/m2×3 d/wk), the CEE regimen of cisplatin (75 mg/m2/3 wk), epirubicin (100 mg/m2/3 wk), etoposide (120 mg/m2×3 d/ 3 wk), and the CAMP regimen of CAP with prednisolone (1000 mg/m2×4 d and 500 mg/m2×2 d/3 wk).T, thymoma; TC, thymic carcinoma; RT, radiotherapy. Open table in a new tab The CAP, ADOC, and PE regimen are described in Table 1. The CODE regimen consists of cisplatin (25 mg/m2/wk), vincristin (1 mg/m2/wk), adriamycin (40 mg/m2/wk), and etoposide (80 mg/m2×3 d/wk), the CEE regimen of cisplatin (75 mg/m2/3 wk), epirubicin (100 mg/m2/3 wk), etoposide (120 mg/m2×3 d/ 3 wk), and the CAMP regimen of CAP with prednisolone (1000 mg/m2×4 d and 500 mg/m2×2 d/3 wk). T, thymoma; TC, thymic carcinoma; RT, radiotherapy. 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.23Hryniuk W Bush H The importance of dose intensity in chemotherapy of metastatic breast cancer.J Clin Oncol. 1984; 2: 1281-1288Crossref PubMed Scopus (749) Google Scholar 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.24http://evs.nci.nih.gov/ftp1/CTCAEGoogle Scholar 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.25Mygland A Vincent A Newsom-Davis J et al.Autoantibodies in thymoma-associated myasthenia gravis with myositis or neuromyotonia.Arch Neurol. 2000; 57: 527-531Crossref PubMed Scopus (88) Google Scholar Response assessment recommendations for thymic malignancies are described in a previous ITMIG article.22Huang J Detterbeck F Wang Z et al.Standard outcome measures for thymic malignancies.J Thorac Oncol. 2010; 5: 2017-2023Crossref PubMed Scopus (107) Google Scholar 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.26Loehrer Sr, PJ Wang W Johnson DH Eastern Cooperative Oncology Group Phase II Trial et al.Octreotide alone or with prednisone in patients with advanced thymoma and thymic carcinoma: an Eastern Cooperative Oncology Group Phase II Trial.J Clin Oncol. 2004; 22: 293-299Crossref PubMed Scopus (150) Google Scholar We also recommend systematic documentation of the effect of antitumor treatment on associated paraneoplastic syndromes (if present), 27Tormoehlen LM Pascuzzi RM Thymoma, myasthenia gravis, and other paraneoplastic syndromes.Hematol Oncol Clin North Am. 2008; 22: 509-526Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar 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 IVA28Detterbeck F Nicholson AG Kondo K et al.The Masaoka-Koga Stage Classification for thymic malignancies: clarification and definition of terms.J Thorac Oncol. 2011; 6: S1710-S1716Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). 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.29Kondo K Monden Y Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan.Ann Thorac Surg. 2003; 76: 878-884Abstract Full Text Full Text PDF PubMed Scopus (534) Google Scholar 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).30Gomez D Komaki R Yu J et al.Radiation therapy definitions and reporting guidelines for thymic malignancies.J Thoracic Oncol. 2011; 6: S1743-S1748Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar 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 stage28Detterbeck F Nicholson AG Kondo K et al.The Masaoka-Koga Stage Classification for thymic malignancies: clarification and definition of terms.J Thorac Oncol. 2011; 6: S1710-S1716Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar; (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.29Kondo K Monden Y Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan.Ann Thorac Surg. 2003; 76: 878-884Abstract Full Text Full Text PDF PubMed Scopus (534) Google Scholar 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, 31Cowen D Richaud P Mornex F et al.Thymoma: results of a multicentric retrospective series of 149 non-metastatic irradiated patients and review of the literature. FNCLCC trialists. Fédération Nationale des Centres de Lutte Contre le Cancer.Radiother Oncol. 1995; 34: 9-16Abstract Full Text PDF PubMed Scopus (123) Google Scholar and cyclophosphamide, doxorubicin, and cisplatin plus prednisone were used in two prospective MD Anderson Cancer Center trials of postoperative radiotherapy followed by chemotherapy.15Kim 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: 369-379Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 32Shin DM Walsh GL Komaki R et al.A multidisciplinary approach to therapy for unresectable malignant thymoma.Ann Intern Med. 1998; 129: 100-104Crossref PubMed Scopus (123) Google Scholar 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.33Eng TY Fuller CD Jagirdar J et al.Thymic carcinoma: state of the art review.Int J Radiat Oncol Biol Phys. 2004; 59: 654-664Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar 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).29Kondo K Monden Y Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan.Ann Thorac Surg. 2003; 76: 878-884Abstract Full Text Full Text PDF PubMed Scopus (534) Google Scholar 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 radiotherapy30Gomez D Komaki R Yu J et al.Radiation therapy definitions and reporting guidelines for thymic malignancies.J Thoracic Oncol. 2011; 6: S1743-S1748Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar; (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.30Gomez D Komaki R Yu J et al.Radiation therapy definitions and reporting guidelines for thymic malignancies.J Thoracic Oncol. 2011; 6: S1743-S1748Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar 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. T, thymoma; TC, thymic carcinoma. 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 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 have been known for a long time to have a "lympholytic" effect.35Kirkove C Berghmans J Noel H et al.Dramatic response of recurrent invasive thymoma to high doses of corticosteroids.Clin Oncol (R Coll Radiol). 1992; 4: 64-66Abstract Full Text PDF PubMed Scopus (51) Google Scholar, 36Craven C Reddy PK Ringel SP et al.Effect of corticosteroids on the thymus in myasthenia gravis.Muscle Nerve. 1981; 4: 425-428Crossref PubMed Scopus (13) Google Scholar 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).26Loehrer Sr, PJ Wang W Johnson DH Eastern Cooperative Oncology Group Phase II Trial et al.Octreotide alone or with prednisone in patients with advanced thymoma and thymic carcinoma: an Eastern Cooperative Oncology Group Phase II Trial.J Clin Oncol. 2004; 22: 293-299Crossref PubMed Scopus (150) Google Scholar 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. 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).37Gerhardt S Gehling G Schuster P Rebound hyperplasia of the thymus with secondary intrathymic bleeding. Rare differential diagnosis of acute chest pain.Dtsch Med Wochenschr. 2004; 129: 1916-1918Crossref PubMed Scopus (4) Google Scholar, 38Miniero R Busca A Leonardo E et al.Rebound thymic hyperplasia following high dose chemotherapy and allogeneic BMT.Bone Marrow Transplant. 1993; 11: 67-70PubMed Google Scholar, 39Hendrickx P Döhring W Computed tomographic detection of chemotherapy-induced thymus changes in patients with metastatic testicular tumors.Rofo. 1989; 150: 268-273Crossref PubMed Google Scholar 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.40Nishino M Ashiku S Kocher ON et al.The thymus: a comprehensive review.Radiographics. 2005; 26: 325-348Google Scholar 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).40Nishino M Ashiku S Kocher ON et al.The thymus: a comprehensive review.Radiographics. 2005; 26: 325-348Google Scholar Fluorodeoxyglucose positron emission tomography is not useful in this setting because both entities exhibit similar degrees of increased fluorodeoxyglucose uptake.41Kumar A Regmi SK Dutta R et al.Characterization of thymic masses using (18)F-FDG PET-CT.Ann Nucl Med. 2009; 23: 569-577Crossref PubMed Scopus (65) Google Scholar Chemical shift magnetic resonance imaging has also been evaluated to distinguish thymoma and thymic hyperplasia.42Takahashi K Inaoka T Murakami N et al.Characterization of the normal and hyperplastic thymus on chemical-shift MR imaging.AJR Am J Roentgenol. 2003; 180: 1265-1269Crossref PubMed Scopus (55) Google Scholar 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 (TABLE 1, TABLE 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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