Novel strategies in radiation therapy: high-dose radiotherapy for oligometastatic/oligo-progressive thymic tumors

Abstract

Oligometastatic and oligoprogressive thymic tumors are unique clinical presentations that are generally rare, yet occur with some regularity, especially in large volume centers. Close observation is often a viable option at first. Surgical resection is usually the primary local therapy approach whenever possible based on technical resectability and patient’s medical operability. High-dose radiation therapy has opened more opportunities for patients who may need adjuvant radiation therapy to further optimize local tumor control in addition to surgery or definitive therapy, or in place of surgical resection when surgery may be difficult or impossible due to tumor- or patient-related factors, with high local control rates in appropriately selected patients. Especially in the metastatic setting, long-term effects of therapy and quality of life need to be balanced against local tumor control and survival endpoints. The excellent ratio of high efficacy and low risk of adverse events with high-dose stereotactic body radiation therapy and intensity-modulated radiation therapy make this radiation technique a particularly attractive treatment approach for optimizing local control and quality of life. A deep understanding of the strengths and weaknesses of each treatment modality are critical to allow for optimal use and integration of local and systemic treatment options. Here, we review the newest data for the role of local therapies in oligometastatic, oligoresidual and oligoprogressive thymic tumors with a focus on the development of high-dose radiation therapy techniques.

Introduction

Oligometastatic thymic tumors are a special clinical scenario presenting a challenge to specialists treating patients with thymic malignancies. Within metastatic thymic disease, distinct clinical states can be identified, including oligometastatic, oligoresidual, and oligoprogressive disease, which may represent different phases of the same disease continuum (1-3). The treatment options include close observation, systemic therapies and local ablative therapies (LATs) including surgical resection and radiation therapy (RT) techniques. Systemic therapy remains a key component of standard-of-care management in metastatic thymic tumors and is often combined with local treatment approaches, particularly in multimodality strategies (4,5). When to select which modality and in what combination with other modalities depends on the perceived biology, location, extent and growth rate of the tumor. The optimal use of each modality also depends on the institutional expertise with these modalities.

Oligometastatic thymic malignancies

Pleural dissemination is the most common presentation of metastatic disease from thymic primary tumors (6). While pleural disease may present in a diffuse pattern that does not fit classical oligometastatic definitions, selected patients may still exhibit limited-volume pleural or extrapleural metastatic disease that is clinically managed within an oligometastatic framework. We and others previously described that patients may present with de novo stage IVA disease with pleural or pericardial involvement at presentation or with pleural recurrences as the most common site of disease progression after initial curative treatment for localized thymic primary tumors (6-9). Between 24 and 38% of patients recur in the pleura after an R0 resection and postoperative RT to the mediastinal tumor bed. Thymic carcinomas metastasize more commonly to distant extrathoracic organs compared to thymomas (7). Thymomas can have a prolonged disease course even after presentation with pleural or distant metastases, and it is apparent that some patients present with an oligometastatic picture (10). Even patients with de novo stage IVA thymic malignancies can have a median overall survival (OS) of 11 years and a median time to progression of 2.2. years (n=72) (10). Patients frequently experience multiple episodes of progression (median =3). The longest observed disease-free interval was 12.4 years in our dataset and 18% remained long-term disease free despite having initially presented with metastases.

To describe and categorize a specific oligometastatic M1 category has proven to be challenging. Part of the challenge in defining an oligometastatic category in thymic malignancies is the fact that pleural or pericardial involvement can present itself in a localized or diffuse, even miliary, distribution. For localized presentations there are the possibilities of a single implant, multiple ipsilateral implants or multiple or bilateral implants. These different scenarios illustrate the heterogeneity of the M1a category, yet they have significant implications on the potential management options which may not be the same for the various clinical presentations. The 9^th edition of the International Association for the Study of Lung Cancer/American Joint Committee on Cancer (IASLC/AJCC) staging system defines metastatic spread of thymic tumors as M1a when presenting with pleural or pericardial nodules and M1b when presenting with intraparenchymal pulmonary nodules or distant metastases (11). Unfortunately, the database for the 9^th edition of the staging system revision had many patients with missing details of their M-status (12). Consequently, the ability to identify new subsets of patients such as oligometastatic, oligoresidual or oligoprogressive patients within the M-category was hampered by small numbers.

When discussing oligometastatic disease presentations it is important to clearly define the various states that may occur throughout the course of the disease. Most commonly the term “oligometastatic” is somewhat arbitrarily defined as less than 3 or 5 macroscopically detectable metastases at a given assessment (13,14). Some patients present at initial presentation with de novo oligometastases; others may present with an oligoresidual pattern where there may have been more than 5 metastases at presentations, but only a few metastases persist after initial systemic therapy; yet another frequently observed pattern is an oligoprogressive picture where only some metastases progress after an initial course of systemic therapy or local therapy such as surgical resection with or without RT (1). For the oligometastatic or oligoresidual scenarios the therapeutic goal in general should be the removal of all macroscopically visible gross disease by means of local therapies, e.g., surgical resection, RT or a combination of both. In the oligoresidual and especially in the oligoprogressive scenario, the therapeutic approach with local therapies should be carefully evaluated in the context of the availability and effectiveness of systemic therapies and may vary depending on the development of novel systemic therapies.

LAT options

LATs include surgical resection, RT, interventional radiology ablative techniques such as radiofrequency, microwave or cryoablation. The indication and usefulness of LATs in the metastatic setting depends on the organ site that is involved, the extent and volume of metastatic disease as well as the patient’s functional status and comorbidities. In general, surgical resection is the preferred option for any operable patient with technically resectable disease. Since many patients with thymic tumors are diagnosed at a younger age, surgical options are usually available to them, at least for the first interventions for pleural or pericardial oligometastases. With repeated surgical interventions further surgical resection may become increasingly difficult, thus making nonsurgical treatment options more attractive and reasonable alternatives to surgical resection with potentially better tolerance.

High-dose radiotherapy

From a radiation oncology perspective, ablative therapy has become possible through the development and implementation of stereotactic body radiation therapy (SBRT) (Figure 1). SBRT allows the delivery of ultrahigh doses per fraction using highly conformal radiation fields guided by on-board two-dimensional (2D) and now routinely three-dimensional (3D) imaging using so called cone-beam computed tomography (CBCT) images that allow direct visualization of the target tumor in the treatment position. Historically limited to brain metastases and known as stereotactic radiosurgery (SRS), the ability of CBCT imaging, four-dimensional (4D) imaging to allow assessment of respiratory tumor motion, and ultraprecise delivery using (micro-)multileaf collimators have expanded the use of SBRT to extracranial sites. SBRT has become the standard of care for inoperable early-stage lung cancers given impressive long-term local control rates of over 90% (15-19). It has also proven to be highly effective as LAT for oligometastatic disease of various histologies, even historically radioresistant histologies such as melanoma, renal cell cancer or sarcomas (20-22). Even larger tumors can be controlled long-term using SBRT, when an adequate ablative dose is delivered (23,24). In thymic malignancies, although data remain limited, emerging case reports suggest that SBRT is feasible for isolated metastatic lesions, including rare sites such as sacral bone metastases, with durable local control and symptom relief described in individual cases (25).

Figure 1.

SBRT example. Axial (A), coronal (B), and sagittal (C) CT images demonstrate SBRT treatment planning. The GTV is contoured in red (red arrows). CT, computed tomography; GTV, gross tumor volume; SBRT, stereotactic body radiation therapy.

For pleural disease there is some data from patients with malignant pleural mesothelioma that SBRT, even at just moderately high doses can be effectively used to treat pleural disease with 2-year local control rates of over 90% (26-28). Some studies on LAT for oligometastatic disease have shown progression-free survival (PFS) and even OS benefits in patients with lung cancer.

Specifically in patients with thymic tumors, there is currently limited data available for the role of RT in oligometastatic disease (29-32). In a single institution prospective study on 32 patients, the response rates of SBRT to intermediate doses were reported to be 96.9% with a local control rate of 81%. The doses used in this study were a median dose to the gross tumor volume of 56 Gy (range, 49–70 Gy) in 10 fractions prescribed to the 50% isodose line covering the planning target volume (PTV) (29). Pasquini et al. reported on 22 patients who were treated with a median dose of 30 Gy in 3 fractions using SBRT, prescribed to the 80% isodose (30). The 1- and 2-year-local control rate was reported to be 92% and 78%, and no grade 3–4 adverse events (AEs) were observed.

One of the largest series on the role of RT in stage IV thymic tumors was reported by Jackson et al. at ASTRO 2022 (32). This study included 48 patients treated with a range of doses with a median biologically effective dose of 51 Gy. It included patients with pleural disease (27%), bone metastases (41%) and others. While histology and disease site were not significant factors, a biological effective dose (BED) of >60 Gy was associated with better PFS and OS, likely reflecting a more limited disease extent amenable to a higher radiation dose. However, it may also indicate that thymic tumors may not be as radiosensitive as previously assumed, at least not in the metastatic setting. Therefore, there may be a role for high-dose ablative SBRT or at least some moderate dose escalation when local control must be prioritized. Core characteristics of the included studies are summarized in Table 1.

Table 1. Clinical studies of radiotherapy in metastatic thymic tumors.

Study	Sample size (n)	Histology	Clinical setting	RT technique	Dose/fractionation	BED₁₀ (Gy)†	Median follow-up	Oncologic outcomes	AEs
Hao et al., 2017 (29)	32	Thymoma, thymic carcinoma	Stage II–IV disease (primary or recurrent)	SBRT	56 Gy (49–70 Gy) in 10 fractions (median)	73–119	54 months	ORR 96.9%; LC 81.3%; median tumor shrinkage 62.2%; in-field failure 4; out-of-field failure 2; median PFS 28 months (subgroup)	Mostly G1 to G2; oesophagitis (G1 25%, G2 9.4%), pneumonitis 15.6%; no ≥ G3 AE
Pasquini et al., 2021 (30)	22	Thymoma	Pleural metastatic disease	SBRT	30 Gy (24–40 Gy) in 3 fractions (median)	NR	33.2 months	LC 92% (1 year), 78% (2 years), 71% (3 years); DCR decreased over time; median PFS 20.4 months	Mostly G1 to G2 respiratory symptoms; one rib fracture; no ≥ G3 AE
Xu et al., 2021 (31)	12	Thymic epithelial tumors (histology not specified)	Stage II–IV disease (primary or recurrent)	CyberKnife SBRT	40–50 Gy in 5 to 10 fractions (mean 45 Gy in 6 fractions)	65–100 (median 85.5 for GTV)	69.3 months	5-year OS 68.2%; 10-year OS 45.5%; LRFS 90.9%; DMFS 58.7%	Mostly G1 to G2; no ≥ G3 AE or treatment related death
Jackson et al., 2022 (32)	48	Thymoma, thymic carcinoma, atypical thymic carcinoid	Stage IV oligometastatic (≤5 lesions) or oligoprogressive disease	Hypofractionated RT or SBRT	Not specified; median BED₁₀ 51 Gy (38–106 Gy)	51 (median)	36 months	Median OS 50 months; median PFS 6.5 months; BED >60 Gy associated with improved outcomes, Thymoma was associated with better PFS than TC or ATC, with no difference in OS or LF	Low AEs; no ≥ G3 AE

^†, BED calculated using α/β =10 Gy. AE, adverse event; ATC, atypical thymic carcinoid; BED, biological effective dose; CI, confidence interval; DCR, disease control rate; DMFS, distant metastasis-free survival; G, grade; GTV, gross tumor volume; LC, local control; LF, local failure; LRFS, local recurrence-free survival; NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RT, radiation therapy; SBRT, stereotactic body radiation therapy; TC, thymic carcinoma.

Pleural RT options

When pleural metastases present themselves in a more diffuse pattern growing as a rind in the pleural space surrounding the lung, there are situations where in adequately young and fit patients there may be a role for surgical resection by pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP). There is some data to support the idea that multimodality therapy, ideally trimodality therapy, has the best chances for long-term local control and outcomes even in stage IV thymic tumors (33). Depending on the type of surgery, adjuvant RT may be offered to the ipsilateral thorax after EPP using hemithoracic RT or the ipsilateral pleura after P/D using hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) (Figure 2). These radiation techniques were initially developed for patients with malignant pleural mesothelioma, where they have been shown to be feasible and safe. A single institution phase III trial in patients with mesothelioma demonstrated an OS benefit (34). A multi-institutional cooperative group trial unfortunately did not complete accrual due to the coronavirus disease (COVID) pandemic (NRG-LU006, clinicaltrials.gov: NCT04158141). There may be a subset of patients with thymic tumors that could potentially benefit from a similar approach. However, given the much longer prognosis and life expectancy of patients with thymic tumors, one must be cautious with extrapolation from patients with a much more aggressive disease such as mesothelioma. Patients with thymic cancer are on average significantly younger and healthier, have a much better prognosis, longer natural history of their disease and therefore longer life expectancy when compared to patients with pleural mesothelioma. Therefore, especially the long-term AEs of IMPRINT need to be carefully evaluated in the thymic patient population. A phase II study was initiated at the New York Proton Center to study the potential role of IMPRINT in patients with pleural metastases from thymic tumors to prospectively define the risk for AEs, failure patterns and PFS and OS using proton-based hemithoracic IMPRINT (clinicaltrials.gov: NCT05354570). The primary endpoint of this study will be the incidence of grade 3 pneumonitis. It will provide critical, high-quality data on the outcomes and AEs of this comprehensive pleural radiation approach, specifically in patients with thymic cancers.

Figure 2.

Hemithoracic IMPRINT field examples. Axial (A,B), coronal (C,D), and sagittal (E,F) CT images demonstrate treatment planning for left-sided (A,C,E) and right-sided (B,D,F) hemithoracic pleural radiotherapy fields. CT, computed tomography; IMPRINT, intensity-modulated pleural radiation therapy.

Close observation and palliative RT options

While palliative considerations are less common in oligometastatic settings, they should always be considered. It is important to distinguish palliative radiotherapy for symptom control in diffuse or high-volume metastatic disease from metastasis-directed therapy used in oligometastatic, oligoresidual, or oligoprogressive settings. Preservation of quality of life is particularly relevant in patients who have metastastic disease and may not be curable in the long-term. Frequently, close observation of a slow-growing oligometastatic site is a very reasonable option to consider as opposed to surgical intervention or immediate use of local ablative RT options. The decision of intervening early versus observing at first depends on multiple factors, such as the anticipated growth rate, location and distribution pattern of recurrent disease, impact and AEs of intervention on quality of life, and technical resectability of the tumor and medical operability of the patient for surgical interventions, and potential contraindications for RT for local ablative RT.

Palliative RT should be considered when the disease is not amenable for local ablative RT, e.g., if the disease is too large or too diffuse for a high dose RT approach. Nevertheless, palliative RT is a very important option to treat thoracic lesions that are causing pain, e.g. because of chest wall, brachial plexus or neuroforaminal invasion, lesions causing vascular compression, e.g., superior vena cava syndrome, or invading great vessels, lesions causing airway compression or hemoptysis in the hilum or trachea, or lesions causing dysphagia from esophageal compression. Even in palliative settings, advanced conformal radiation techniques such as three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) can help minimize side effects and optimize quality of life in addition to achieving local tumor control (Figure 3). Distant metastases to organs outside the thorax may be amenable to palliative RT as a standard indication for palliative RT. In some situations, it may be worthwhile considering prophylactic treatment of a lesion if further progression would be expected to cause significant harm to the patient’s quality of life or make it significantly harder to treat with reasonable side effects. There is some data for bone metastases that prophylactic treatment decreases the risk of bone fractures (35).

Figure 3.

IMRT plan for a pleural lesion. Axial CT image demonstrating treatment planning for a left-sided pleural lesion treated with palliative IMRT. The target volume is contoured in red, and the radiation dose distribution is displayed in color. CT, computed tomography; IMRT, intensity-modulated radiotherapy.

Conclusions

Metastatic thymic tumors encompass a spectrum of disease states, including oligometastatic, oligoresidual, and oligoprogressive patterns, which may be amenable to aggressive local therapies. Local therapy options such as surgical resection, including minimally invasive and robotic approaches, as well as SBRT, are very effective and result in high local control rates with minimal side effects. Trimodality therapy, incorporating systemic therapy in combination with surgery and/or RT, may also be appropriate in selected patients who are amenable. Systemic therapy remains a key component of management in metastatic thymic carcinoma and is commonly integrated into multimodality treatment strategies; however, in selected patients with limited-volume or indolent disease, immediate systemic therapy may not always be required. The key to optimally select patients for local therapies will be our ability to understand and predict tumor biology and clinical behavior. The use of RT, as well as other local therapies, needs to be carefully weighed against close observation, systemic treatment options and quality of life considerations.

Supplementary

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