Management of stage IVA (M1a) thymoma: observation versus chemotherapy versus surgery versus radiation therapy?—extended abstract

The treatment of tumor, node, metastasis (TNM) stage IVA thymoma due to M1a disease (pleural/pericardial metastases) is challenging mainly due to several factors which preclude establishing high-level recommendations. Stage IVA thymoma is a rare stage of a rare tumor. It is estimated that only 7% of thymoma patients present with de novo stage IVA disease and 15% of patients develop pleural/pericardial metastases after previously treated early-stage disease (1). Additionally, it has been suggested that de novo disease is associated with a worse prognosis as compared to patients who relapse with pleural/pericardial metastases after initial therapy consequentially may require a more aggressive treatment approach (2). The current 8^th edition staging system does not account for the number of pleural/pericardial metastases, the size of metastases, or invasion into any local organ therefore lacks granularity. Most deaths following treatment of other solid neoplasms are due to recurrent disease which is not necessarily the case with thymoma. Due to mainly indolent biology, thymoma patients with recurrent pleural/pericardial disease typically experience extended survival. In addition, late deaths are not infrequently due to other conditions such as secondary malignancies. Finally, thymoma patients present with wide range of ages and comorbidities which can contribute to non-thymoma mortality. When critically analyzing outcomes of any treatment approach to stage IVA thymoma, disease-free and disease-specific survival analyses thus become important, however these variables are not uniformly available. Collectively, these factors not only make randomized trials very difficult to conduct but also may confound individual treatment approaches.

Several treatment options for stage IVA thymoma, either alone or in combination, are currently worthy of consideration. First, given the typically indolent biology and absence of a randomized study demonstrating that any treatment improves overall survival as compared to “doing nothing”, observation, at least initially, becomes not unreasonable particularly for patients with high comorbidities. Initial observation could also be considered for patients with relapsed pleural/pericardial disease after remote surgery for early-stage thymoma.

There are a growing number of systemic options available including combination and single-agent chemotherapy. Immunotherapy and targeted agents are emerging and may hold promise. Platinum-based chemotherapy regimens typically result in a moderate response although a wide range of responses from none to complete are observed. Induction chemotherapy followed by surgery appears to be most productive of R0 resections therefore constitutes National Comprehensive Cancer Network/European Society for Medical Oncology (NCCN/ESMO) guidelines for potentially operable patients (3). A review of published series treating stage IVA thymoma patients with induction therapy followed by surgery, found an 81% average response rate to therapy and an impressive 59% average 10-year survival (4). Studies included in this review were however small and mainly retrospective involving select patients. Additionally, as disease-free survival was not provided for most of these reports, it is reasonable to speculate that many patients in these series relapsed and were “alive with disease” at last follow-up. There is currently no randomized study demonstrating that induction chemotherapy provides an overall survival benefit, therefore upfront surgery is also a reasonable option in select cases and constitutes an alternative treatment per NCCN/ESMO guidelines (2).

From a surgical standpoint, there are three general approaches, all with distinct advantages and disadvantages. A discrete pleural metastatectomy is probably reasonable for a limited number of pleural/pericardial metastases and associated with low morbidity. Total pleurectomy/decortication (with or without intrathoracic heated chemotherapy) has been proposed as a more aggressive approach while sparing lung parenchyma for stage IVA disease although an improvement in disease-free survival as compared to discrete metastatectomy has not been demonstrated to date. Extrapleural pneumonectomy has traditionally been reserved as a “last ditch” procedure for patients with bulky pleural disease. Arguably however of all the surgical approaches, extrapleural pneumonectomy has the best potential to remove all microscopic pleural disease with the obvious downside of significantly higher morbidity and mortality. A literature review identified six published series reporting on outcomes of patients undergoing either pleural metastatectomy or extrapleural pneumonectomy for stage IVA disease (5-10). Not surprisingly, most patients in these series underwent pleural metastatectomy but on average, 70% to 80% of these patients had relapsed at last follow-up. There was a distinct trend of patients undergoing extrapleural pneumonectomy in these series having improved disease-free survival which is noteworthy as extrapleural pneumonectomy is usually reserved for patients with a larger burden of pleural disease.

Finally, radiation therapy is typically used in the adjuvant setting after R1 and R2 resections. To date, no benefit of adjuvant radiation therapy has been demonstrated after R0 resections. For therapeutic purposes standard external beam radiation therapy to large areas of pleural disease is believed to present prohibitive lung toxicity, therefore intensity modulated radiation therapy is currently being evaluated for non-surgical patients in conjunction with chemotherapy. For treatment of isolated areas of pleural disease, focused radiation therapy utilizing stereotactic body radiation therapy or proton beam radiation appear to be reasonable considerations.

In summary, stage IV thymoma is heterogeneous from disease severity and patient demographic standpoints. For most patients, an individualized multidisciplinary approach is therefore needed keeping all options in mind. Neoadjuvant chemotherapy followed by surgery or surgery alone as per NCCN/ESMO guidelines, is reasonable for select patients but doesn’t rise to a high evidence level. There are a wide range of surgical approaches which can be utilized however the optimal approach is unknow and needs further study. Unfortunately, for most stage IVA thymoma patients, this will ultimately become a chronic disease to greater or lesser extents regardless of treatment approach and future intervention may be required. Accordingly at Indiana University, we have trended to use a “one bullet at a time” approach with the aim of minimizing morbidity, particularly for patients with preexisting comorbidities or minimal symptomology. This approach involves beginning with first line platinum-based chemotherapy. If a good response is achieved, then the patient is observed. When there is disease progression, this process is repeated with second and even third line systemic therapy keeping surgery as a salvage option. This approach also needs further study. Given the poor ability to conduct randomized studies, mining large databases and performing single-arm clinical trials will hopefully refine staging and improve treatment recommendations for stage IVA thymoma patients.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Malgorzata Szolkowska, Chul Kim, Mohammad Ashraghi, and Claudio Silva) for “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” published in Mediastinum. The article has undergone external peer review.

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-23-63/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-23-63/coif). “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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