Long-term treatment of metastatic adenoid cystic carcinoma with sequential brachytherapy and stereotactic body radiotherapy

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Radiat Oncol J. 2024;42(3):237-243

Publication date (electronic) : 2024 August 14

doi : https://doi.org/10.3857/roj.2024.00325

Allison Y. Zhong¹, Sangwoo S. Kim¹, Austin Hopper¹, Greg White¹, Sayuri Miyauchi¹, Riley N. Jones¹, Dan Scanderbeg¹, Loren K. Mell¹, Elizabeth Weihe², Nathalie Boutros¹, Stephen W. Doggett³, Andrew B. Sharabi^,1

¹Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA

²Department of Radiology, University of California San Diego, La Jolla, CA, USA

³Department of Radiation Oncology, Providence Mission Hospital, Mission Viejo, CA, USA

Correspondence: Andrew B. Sharabi Department of Radiation Medicine and Applied Sciences, Moores Cancer Center, University of California San Diego, 3855 Health Sciences Drive, MC 0843, La Jolla, CA 92093, USA. Tel: +1-858-822-6040 E-mail: ansharabi@health.ucsd.edu

Received 2024 April 20; Revised 2024 June 18; Accepted 2024 June 18.

Abstract

Introduction

Adenoid cystic carcinoma (ACC) is a malignancy that typically arises from glandular tissues in the head and neck region, most commonly the major and minor salivary glands [1]. It is relatively rare, with a yearly incidence of approximately 3–4.5 cases per million [2]. ACC is known for its prolonged clinical course with delayed recurrences and poor long-term prognosis. The 5-year survival rate ranges from 55%–89%, while the 15- and 20-year survival rates are much less favorable at approximately 23%–40% [3]. About half of patients with ACC develop distant metastases [1,4]. Survival rates drop dramatically in patients with distant metastases, with some studies reporting 5-year survival rates as low as 15.5% and other studies reporting no surviving ACC patients 14–16 years after surgical resection of distant metastases. Metastases most commonly involve the lungs, although other reported sites include bone, liver, kidney, and prostate [1,5].

Standard treatment for ACC is surgical resection when possible. However, ACC tumors are often difficult to resect completely, and positive margins are common [6]. For this reason, along with ACC's propensity for infiltrative growth and perineural invasion, adjuvant radiotherapy has emerged as a major treatment modality to improve local control of ACC [7,8]. Treatment of disseminated disease is especially challenging due to the lack of effective systemic therapies [9]. Stereotactic body radiotherapy (SBRT) can be used to deliver a high dose of radiation to lung metastases while sparing the surrounding tissue, leading to favorable local control [10]. Brachytherapy is also a viable option in this setting. A recent retrospective small-cohort study showed that computed tomography (CT)-guided palladium-103 permanent seed brachytherapy can effectively treat multiple ACC pulmonary metastases with minimal complications [2]. Another retrospective study suggested that iodine-125 seed brachytherapy can be repeated multiple times for different lung sites while maintaining safety and efficacy [11].

In this case report, we document the clinical course of an ACC patient with lung and liver metastases who has survived for approximately 12 years since diagnosis and for whom disease progression was controlled primarily with brachytherapy and SBRT.

Case Report

A 45-year-old man in the United States with no significant past medical history developed left ear pain in December 2010. He was treated for sinusitis, but the pain persisted. Eventually, a magnetic resonance imaging in May 2012 revealed a 5.5-cm tumor at the base of the tongue. A staging positron emission tomography/CT (PET/CT) scan showed a hypermetabolic lesion in the left tongue base and no gross evidence of distant metastases. He subsequently underwent partial glossectomy with bilateral neck dissection at University of California Los Angeles in July 2012. Pathology revealed ACC consistent with pT3N1 disease, with one positive right lymph node.

From August to October 2012, the patient received concomitant chemoradiation therapy involving seven cycles of carboplatin/taxol and 60 Gy in 30 fractions of simultaneous integrated boost-intensity-modulated radiotherapy. Follow-up PET/CT scans in November 2012 and July 2013 were negative. Then, a repeat PET/CT scan in July 2014 showed two new sub-centimeter nodules in the right lung concerning for metastatic disease. Pulmonary function tests (PFTs) performed in August 2014 demonstrated a forced expiratory volume in 1 second (FEV1) of 100% of the predicted value, a forced vital capacity (FVC) of 113% of the predicted value, and a normal FEV1/FVC ratio. In September 2014, the patient underwent placement of brachytherapy seeds within these two lesions at Providence Mission Hospital. During this time, he also self-referred to University of California San Diego for further evaluation.

Surgical procedures for implantation of brachytherapy seeds were conducted on an outpatient basis as previously described [12]. Briefly, the patient was sedated and continuous blood pressure, electrocardiogram, and oxygen saturation by pulse oximetry were continually monitored. All seeds were implanted percutaneously under CT guidance. The patient was placed on the CT-guided fluoroscopic imaging device (Siemens SOMATOM CT fluoroscopic scanner; Siemens, Munchen, Germany) and target sites were scanned at 3 mm intervals. The resulting images were reviewed by the interventional radiologist to identify target lesions. An 18-gauge 20-cm needle was placed into or adjacent to each target lesion and images were once again reviewed to ensure ideal needle position. Adjustments of needle position were made as necessary with multiple episodes of CT-guided fluoroscopic imaging. Images of the implanted needle/applicator and of the immediately implanted seeds were captured, printed, and filed, and seeds were implanted according to preplan. Initially, a portion of the seeds were implanted and seed position was monitored with multiple episodes of CT-guided fluoroscopic scanning to ensure that seed deposition closely matched simulated preplan seed positions prior to implanting the remaining planned seeds. Multiple manual needle adjustments and episodes of CT-guided fluoroscopic scanning were carried out during seed placement to prevent overdosage of adjacent structures and to ensure correct dosage of the target lesion.

As the size and number of pulmonary nodules increased, repeat brachytherapy was performed in November 2014 to one lesion in the left apex, and again in March 2015 to lesions in the left apex and right paradiaphragm. By this point, the patient had received five brachytherapy treatments in total, with no reported side effects. Chest CT scans during this time demonstrated enlargement of all lesions not containing brachytherapy seeds, while treated lesions were stable or had decreased in size.

After molecular findings revealed an activating AKT1 mutation, and as his pulmonary disease continued to worsen, the patient enrolled in a phase I trial with MSC2363318A, a dual AKT inhibitor. Though he initially tolerated the starting dose of 320 mg orally once daily, the patient eventually required multiple dose reductions due to worsening side effects including tremor, fatigue, myalgias, gastrointestinal upset, and xerostomia. In October 2016, after six months on the medication, a chest CT scan showed further progression of his pulmonary disease. The decision was made to discontinue the study medication.

After consulting with the Radiation Medicine department at University of California San Diego, the patient agreed to participate in a randomized phase II study of checkpoint blockade immunotherapy combined with SBRT in advanced metastatic disease (Clinical Trial.gov identifier: NCT02843165). He was started on pembrolizumab 200 mg every 3 weeks, which he tolerated well. He received 28.5 Gy in 3 fractions of SBRT to each lung from October 31, 2016 to November 3, 2016. An interval CT scan showed that the lesions treated with SBRT decreased in size, while other lesions increased in size. PFTs performed in February 2017 demonstrated an FEV1 of 97% of the predicted value, an FVC of 108% of the predicted value, and a normal FEV1/FVC ratio. Because the patient responded well to SBRT previously, he received an additional 28.5 Gy in 3 fractions of SBRT to each lung from February 14, 2017 to February 16, 2017, while continuing to receive pembrolizumab.

In May 2017, the patient began to develop respiratory symptoms including cough, shortness of breath, and dyspnea on exertion. A chest CT scan showed evidence of pneumonitis likely related to therapy as well as growth of untreated lung lesions, so pembrolizumab was discontinued. He was started on a slow taper of prednisone, which led to improvement of his respiratory symptoms. With no other treatment options available, the patient was put on active surveillance, with serial chest CT scans notable for resolving drug toxicity but slow progression of pulmonary nodules. He reported feeling well during this time, aside from persistent xerostomia and dysphagia. Additional brachytherapy was performed to the bilateral lungs in November 2019, which led to an iatrogenic pneumothorax in the left lung requiring chest tube placement in September 2020, when the patient was also restarted on pembrolizumab; and again in November 2020.

In February 2021, the patient reported 1 month of worsening fatigue, shortness of breath, dyspnea on exertion, left upper back pain, and constant pressure in the left upper quadrant below the ribcage. A PET/CT scan revealed new hypermetabolic lesions in the liver concerning for hepatic metastases. Pathology from liver biopsy was consistent with metastatic ACC. In May 2021, the patient received brachytherapy to lesions in the left lung and liver. A follow-up PET/CT scan on August 16, 2021 demonstrated remarkable response to the treated liver lesions but the development of new lesions in the liver, lung, and left 12th rib. During this time, the patient developed a COVID-19 infection that was complicated by shingles in his left torso and post-herpetic neuralgia. PFTs performed in December 2021 showed a marked decline in lung function, with an FEV1 of 74% of the predicted value, an FVC of 71% of the predicted value, and a normal FEV1/FVC ratio.

Additional brachytherapy was performed in February 2022, with additional implants placed in the left lung and liver. PFTs performed two months later showed an FEV1 of 63% of the predicted value, an FVC of 70% of the predicted value, and a normal FEV1/FVC ratio. In June 2022, a chest CT showed increased metastatic disease burden in both the lungs and liver. The patient continued to experience shortness of breath and dyspnea on exertion, which were believed to be sequelae of the numerous ablative interventions in his lungs. He also reported severe pleuritic pain in the left chest wall. He received brachytherapy again to the left lung and liver in January 2023. PFTs performed immediately prior to treatment demonstrated an FEV1 of 63% of the predicted value, an FVC of 59% of the predicted value, and a normal FEV1/FVC ratio. He then received 20 Gy in 5 fractions of SBRT to the left ribs from January 30, 2023 to February 3, 2023 for pain control.

At follow-up in May 2023, the patient reported significant pain relief from the latest radiation course in the nodular areas on the anterior chest wall. However, he continued to have pain in his left torso and back that had not improved despite numerous pain interventions. The most recent PET/CT scan in June 2023 showed progression of disease in both the lungs and liver. He underwent palliative SBRT again from August 4, 2023 to August 9, 2023, receiving 24 Gy in 3 fractions to the left anterior chest wall, 24 Gy in 3 fractions to the left posterior medial chest wall, and 30 Gy in 3 fractions to the left medial liver lesion. He additionally received brachytherapy to the bilateral lungs, liver, and intrathoracic soft tissue later that month, complicated by right-sided pneumothorax requiring chest tube placement. PFTs performed immediately prior to treatment demonstrated an FEV1 and FVC of 57% of the predicted values, and a normal FEV1/FVC ratio. At follow-up in September 2023, he reported significant reduction of pain in the chest wall, with PET imaging showing stable-to-decreased hypermetabolic uptake in treated sites particularly in the liver.

Over the years, the patient has received four courses of radiotherapy and approximately 85 brachytherapy implantations. Over 950 seeds of Theragenics (Theragenics Corp., Buford, GA, USA) palladium-103 and Isoray (GT Medical Technologies Inc., Tempe, AZ, USA) cesium-131 have been implanted to his lungs and liver, to prescription doses ranging from 85 to 100 Gy. Each brachytherapy treatment was performed under general anesthesia with percutaneous CT fluoroscopy-guided placement of an 18-gauge needle, and each site of metastasis was typically treated with 5–25 seeds. Fig. 1 presents the sequence of all procedures that the patient underwent including surgeries, chemotherapies, and radiotherapies (both SBRT and brachytherapy). Fig. 2 illustrates various locations of unique brachytherapy implant sites within the patient's lung interstitium and includes recent chest X-rays which clearly delineate the extent and location of individual brachytherapy seeds and implants. The dosimetry and plan sum of his radiotherapy treatments are provided in Fig. 3 and Table 1. In total, he has had nearly 100 different metastases treated with both brachytherapy and SBRT. Adverse effects of seed insertion were minimal. The patient experienced occasional mild thoracic pain from needle punctures, which was resolved with acetaminophen. The patient also experienced a small pneumothorax which was treated intraoperatively with a blood patch, and a second small pneumothorax that was observed without treatment. There were no bleeding events. His excellent response to these treatments is demonstrated in Fig. 4. As of the most recent follow-up, the patient has survived approximately 12 years since his diagnosis of ACC.

Fig. 1.

Sequence of all interventions from July 2012 to August 2023. IMRT, intensity-modulated radiotherapy; R, Right; L, Left; SBRT, stereotactic body radiotherapy.

Fig. 2.

Extensive interstitial lung brachytherapy treatment. (A) Chest X-ray posteroanterior (left) and lateral (right) images showing the extent of brachytherapy treatment implant sites. (B) Series of coronal images with anterior/posterior reference plane indicated in green line on corresponding sagittal reference image. Red arrows indicate locations of unique and separate brachytherapy treatment implant sites over multiple years. In total, approximately 70 sites were treated with over 850 seeds.

Fig. 3.

Dosimetry and plan sum of external beam and SBRT treatments. (A) Plan sum with isodose lines and 3-dimensional representation of external beam and SBRT treatment sites. (B) Coronal images with isodose lines for external beam and SBRT treatments. SBRT, stereotactic body radiotherapy.

Table 1.

OAR dose constraints with EQD₂ conversions of plan sum delivered external beam doses

Fig. 4.

Responses to (A) brachytherapy and (B) SBRT. (A) Axial images of lung nodules pre- and post-brachytherapy treatment (Tx) demonstrating complete response. (B) Axial images of lung nodules pre- and post-SBRT treatment demonstrating complete response. SBRT, stereotactic body radiotherapy.

Discussion

Oligometastatic disease is a state in which metastases are limited in number and location and tend to be amenable to local treatment [13]. Ablative local therapy to oligometastases with surgery or radiotherapy is becoming increasingly common [14]. Evidence supporting the use of brachytherapy in the oligometastatic setting, however, is sparse. In this case, although this patient did not have oligometastatic disease, we continued to deliver local therapies in an attempt to provide durable control and limit morbidity from metastatic progression. From a radiotherapy perspective, brachytherapy offers advantages over external beam techniques, including more favorable dose distribution and the ability to spare normal tissue. A retrospective analysis of patients with unresectable liver metastases found that interstitial brachytherapy was a safe and effective treatment option with good local control rates and low toxicity [15]. A systematic review suggested that brachytherapy can lead to excellent local control and quality of life in patients with brain metastases [16]. Brachytherapy has also demonstrated consistent benefit in treating spinal metastases, leading to improvements in function, pain, local recurrence rate, and overall survival, with a favorable complication profile [17]. In patients with metastatic lung cancer, brachytherapy can be used either alone or as a boost to external beam radiotherapy to improve local tumor control and survival [18].

For ACC, interstitial brachytherapy has been shown to be an effective and safe option for both primary locally advanced tumors and pulmonary metastases [2,19]. As expected for ACC, this patient has had an indolent clinical course with high frequency of metastases to the lungs and liver. Since 2014, he has undergone numerous brachytherapy interventions primarily for his pulmonary metastases, with the most recent procedure in January 2023. In fact, this case represents the most brachytherapy treatments reported in a single patient that we are aware of. Lesions treated with brachytherapy tended to remain stable or even decrease in size, whereas untreated lesions were more likely to progress. Brachytherapy appeared to contribute to improved pain control in this patient, who reported minimal pain until recent years despite the presence of multiple lung lesions. At his most recent follow-up, he endorsed ongoing pain in his left torso and back; we suspect this is most likely related to his history of post-herpetic neuralgia versus post-treatment scarring.

The application of brachytherapy likely contributed to greater preservation of lung function in this patient, as it has been shown to cause less damage to healthy lung tissue compared to SBRT [20]. Other treatments for pulmonary metastases include surgery and radiofrequency ablation; however, it is unlikely that these modalities would have been feasible or effective for this patient given the large number of pulmonary sites involved. Moreover, systemic therapies were not effective in reducing disease progression, nor were they well-tolerated in this patient.

In conclusion, ACC is a rare malignancy characterized by indolent disease course, late recurrences and metastases, and poor long-term prognosis. In patients with pulmonary metastases, brachytherapy is a feasible option to improve local tumor control and help preserve lung function. Thus, sequential brachytherapy represents an enabling technology that is particularly beneficial in patients with extensive pulmonary involvement, where other modalities such as multisite SBRT or surgical resection of all disease may not feasible.

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