Chemoradiation is a common treatment for inoperable locally advanced non-small cell lung cancers (1). The treatment involves radiation over 6-7 weeks with concurrent chemotherapy. Side effects can include fatigue, esophagitis, and radiation pneumonitis (RP), with the risk being roughly proportional to the extent of normal tissue exposure (2, 3). In the clinical trials that established chemoradiation as the standard of care, RP was observed in 5-20% of patients and was associated with advanced age or pre-existing lung conditions including chronic obstructive pulmonary lung disease or interstitial lung disease (3–8). At a cellular level, radiation causes several effects including edema, epithelial changes, disruption of the microvasculature, and atelectasis that lead to inflammatory changes resulting in RP (3, 4). Clinically, RP presents weeks to months following treatment, manifesting as fever, cough, shortness of breath, and ground-glass opacities (3, 4). RP can have significant negative impacts on quality of life (4, 9, 10). Severe RP is often treatable with corticosteroids with symptom improvement in 75-93% of patients, but some patients are refractory (3, 11, 12). Androgens are also well known to have anti-inflammatory properties, but have not been studied as a remedy for RP. Older studies have shown that androgen therapy can reduce the risk of exacerbations of asthma and COPD, but given the potential risks of androgen therapy including adverse cardiovascular events and increased risks of malignancy, these medications have not been implemented. In this case report, we present a patient with corticosteroid-refractory RP that responded favorably to androgen-based therapy.

A 62-year-old male body builder with a 20-pack year smoking history and surgical history of repaired inguinal hernia and appendectomy presented to his PCP with cough, fatigue, and weight loss. CT of the chest showed a 7 cm mass in the right lower lobe of the lung with enlarged subcarinal lymph nodes ( Figure 1A ). Subsequent PET/CT showed FDG uptake in the lung mass and right hilar and subcarinal lymph nodes ( Figure 2 ), but no evidence of metastatic disease. Pre-treatment pulmonary function tests revealed a FVC of 66% and FEV1 of 59%. Biopsy of the right lung mass confirmed poorly-differentiated squamous cell carcinoma of pulmonary origin. Nodal involvement was confirmed by endobronchial ultrasound guided sampling of mediastinal lymph nodes. He was treated with chemoradiation to a dose of 6000 cGy in 30 fractions ( Figure 3 ) with 6 cycles of carboplatin and paclitaxel given weekly. Of note, the lung V20 for his radiation plan was 31%. Two cycles of consolidative carboplatin and paclitaxel were also given.

CT Chest 2 months post radiation completion showed shrinkage of the primary mass to 4.4 cm, reduction in the size of involved lymph nodes and associated radiation changes in the surrounding lung ( Figure 1B ). However, by 3 months, he developed malaise and a persistent cough, so an empiric 1 week course of azithromycin and prednisone were prescribed for pneumonia. His symptoms persisted despite therapy and repeat imaging 3 months later showed opacities within the high and intermediate areas of radiation dose consistent with pneumonitis ( Figure 1C ). A 5 week prednisone taper with a starting dose of 25 mg was prescribed. Symptoms improved with therapy but returned as he tapered to 5 mg so the dose was increased to 20 mg and additional course of azithromycin was prescribed. Repeat pulmonary function tests showed had slightly worsened with a FVC of 57% and FEV1 of 63%. Further attempts over the next 4 months to wean from prednisone failed. After 9 months of collective prednisone therapy, he noted abdominal fullness and was found to have elevated ALT and AST of 114 and 53, respectively. On CT imaging he was noted to have hepatic steatosis. Evaluation with colonoscopy, abdominal US, and CT enterography were unremarkable leading to the conclusion that his liver dysfunction was a sequela of steroid therapy. Based on his understanding that androgens can have anti-inflammatory effects, the patient elected to taper prednisone and self-prescribed the androgen-based regimen shown in Table 1 .

Within two weeks of initiating therapy, the patient experienced a reduction in abdominal fullness, resolution of cough and improved energy. By eight weeks, he felt fully recovered and was able to return to full workouts lifting weights. During androgen therapy, no other significant changes in medical therapy, diet or lifestyle were noted that could be linked to his improvement. CT of the chest 17 months post radiation therapy showed consolidation of the treated lobe and resolution of pneumonitis elsewhere in the lung ( Figure 1F ). As of most recent follow up, 5 years post treatment, the patient had no clinically significant deficits related to cancer therapy and no evidence of active disease. The patient's treatment course is summarized as as e timeline in the supplementary materials.

To our knowledge, this is the first case report of using androgen and HGH-based therapy to treat radiation pneumonitis. However, the concept of treating inflammatory pulmonary disease with androgen or HGH therapy has substantial precedent. The idea that androgens are important regulators of pulmonary inflammation originated with a number of clinical observations. It is well documented that men and women show differences in lung pathology. For example, female neonates produce surfactants earlier in development when compared to male neonates and are at lower risk for respiratory distress syndrome or asthma (13, 14). Also, patients with Klinefelter syndrome, the most common cause of hypogonadism, are 69% more likely to be hospitalized with pulmonary diseases like COPD or pneumonia (15). Additionally, men treated with anti-androgens experience a higher rate of interstitial lung disease with a reported odds ratio up to 6.6 (16). There is also rationale for using HGH to address lung injury. Laboratory studies have shown that HGH may participate in lung development, growth, and repair (17). Additionally, several studies on animal models of acute lung injury have shown dramatic attenuation of lung injury by recombinant HGH (18, 19).

Collectively, these observations have led to prospective studies of androgen therapy and HGH. A study on women with asthma showed that administration of testosterone decreased risks of hospitalizations from asthma attacks by 9.1% in older patients (20).. A meta-analysis from China found that androgens improved body weight, fat-free mass, and symptoms in patients with chronic obstructive pulmonary disease. These changes, however, did not translate into changes in pulmonary function or muscle strength (21). Similarly, another retrospective study of middle-aged men with COPD who received testosterone replacement therapy showed lower rates of respiratory-related hospitalizations (22). A study of HGH in patients with COPD showed improvements in pulmonary function of 27% (23).

The regimen used by the patient in this case report is complex, making it difficult to interpret which agents provided the benefits observed. Nevertheless, the dosages used can be placed into context. The testosterone regimen of 600 mg of testosterone weekly is substantially higher than doses typically used in testosterone replacement therapy (100-200 mg weekly), and has been shown to improve strength and muscle size in healthy men (24). Similarly, doses of nandrolone around 200 mg weekly improved body mass and fat-free mass over the course of 8 weeks (25). This dose was significantly lower than the dose our patient used. The HGH dose of 0.08 mg biweekly is lower than the dose used in the previously cited COPD trial where 0.05 mg/kg was given daily (23). The mesterolone dose of 50 mg BID is similar to the dose used in men with oligospermia and improved sperm counts and mobility who received 100 – 150 mg daily (26). The stanozolol dose of 10 mg TID is lower than the doses used in a recently published trial (2 mg TID) that found improved progression-free survival for patients with high-risk myelodysplastic syndrome (27). In mouse studies, anastrazole was delivered to mice and showed decrease radiation induced lung fibrosis. These mice were given doses equivalent to 1 mg given to an adult daily (28). Although our patients regimen varies from doses reported in literature, there are clear connections between anabolic steroids and beneficial clinical outcomes (29).

In this case, androgen and HGH therapy provided a clear benefit for RP and did not cause cancer recurrence. However, extending this regimen, or a portion of this regimen, to other patients would entail risks, especially within the cancer population. Testosterone or androgen precursors can also increase cardiovascular events, produce neuropsychiatric problems and alter reproductive capacity. Additionally, testosterone has been shown to increase the risk of prostate and testicular cancer and linked to increased risks of breast and liver cancer (30–33). HGH can induce tumor formation in animal models and is associated with increased risk of thyroid and colorectal cancer in patients with acromegaly. However, studies of children and adult cancer survivors who received HGH have not shown an increased risk of cancer progression (34, 35). Clearly, additional prospective studies would be necessary to establish efficacy, dosing and other guidelines for HGH or androgen therapies for RP.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Written informed consent was obtained from the individual (s) for the publication of any potentially identifiable images or data included in this article.

AY and KW were responsible for the concept of the case report. AY drafted the manuscript and KW critically revised the manuscript. All authors contributed to the article and approved the submitted version.

This work was funded by the Department of Radiation Oncology at UT Southwestern.

We would like to acknowledge the patient presented in this case report for his willingness to assist us with this manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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