Division of Hematology/Oncology and Palliative Care, Department of Internal Medicine (M.P., L.J.L.); and Division of Pulmonary and Critical Care (R.W.S.), Virginia Commonwealth University, Richmond, Virginia, USA
Address correspondence to: Meera Pahuja, MD, MSc, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, P.O. Box 980230, Richmond, VA 23298, USA. ude.ucv-hvcm
Octreotide, a synthetic analogue of the hormone somatostatin, is primarily used in palliative medicine because of its antisecretory effect and has been shown to be effective in the management of bowel obstruction, nausea, and diarrhea. Octreotide also has been successfully used for the management of bronchorrhea in both inpatient and outpatient settings. We report the case of a 47-year-old female with a history of bronchioloalveolar cell carcinoma whose copious bronchial secretions were controlled with octreotide. Octreotide should be further evaluated as a first-line treatment for bronchorrhea.
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Keywords: Bronchorrhea, octreotide, bronchioloalveolar carcinoma
Bronchorrhea is arbitrarily defined as the production of more than 100 mL of watery sputum per day.1 It is typically associated with malignancy, specifically bronchioloalveolar cell carcinoma (BAC) and pulmonary metastases. The BAC is a subtype of pulmonary adenocarcinoma, which is further subdivided into mucinous, nonmucinous, and an intermediate form. The mucinous form arises from mucinous metaplasia of bronchiolar cells and is associated with mucosecretion. Rates of BAC are increasing and it accounts for 3–9% of new lung cancer diagnoses, of which 20–25% are the mucinous form.2 Although uncommon, bronchorrhea also is associated with nonmalignant processes such as chronic bronchitis, asthma, tuberculosis, and scorpion stings.
Excess sputum production in patients with BAC is thought to be caused by a few different mechanisms. First, inflammatory stimuli are thought to cause hypersecretion of mucous glycoprotein. Takeyama et al.3 suggested linkage to an epidermal growth factor receptor (EGFR) pathway in which stimulation of EGFR causes MUC5AC expression in airway epithelial cells in vivo and in vitro. The MUC5AC is a major component of the mucus matrix forming a family of mucins in the airways.4 Bronchorrhea also is thought to be caused by increased trans-epithelial chloride secretion, which in turn is associated with the excretion of water. Finally, it is thought to be related to excessive transudation of plasma products into airways.5 The true incidence of bronchorrhea in patients with BAC is not known; but one review found that it occurs in 6% of the cases.6
Despite its rare occurrence, when bronchorrhea does occur, it causes significant morbidity for patients and may lead to excessive coughing, dyspnea, and exhaustion. In addition to the physical symptoms, the profuse sputum production can cause difficulties with social integration. Also, there have been reports of increased sputum production causing electrolyte imbalances, dehydration, and even respiratory failure.7
We report here the successful treatment of bronchorrhea using octreotide in a 47-year-old female with BAC. The patient presented to pulmonary clinic in July 2011 with a chief complaint of “coughing up too much sputum” for two months and producing about 1 L of sputum per day. She also noted significant dyspnea, chest pressure, and pain associated with the chronic cough. She was diagnosed with BAC in 2004 and initially had a left lung lobectomy. She underwent a right lung wedge resection in 2006, and also received radiation and chemotherapy.
Despite treatment, the cancer progressed and she noted increasing watery sputum production starting in 2009. At presentation to pulmonary clinic, her symptoms had significantly impaired her quality of life. She had been managed with levalbuterol, glycopyrrolate, guaifenesin, orally inhaled tiotropium, salmeterol, opioids, and prednisone, without reduction in sputum quantity. A computed tomography scan of the chest on admission showed marked progression of disease in the parenchyma of both lungs, with increasing left lung consolidations, multiple cavitating pulmonary nodules, and new diffuse consolidations of the right lung.
Case reports suggest that subcutaneous (SC) octreotide has been used successfully to treat bronchorrhea; however, the patient was fearful of SC injections. She was admitted to the inpatient palliative care unit for a trial of intravenous (IV) octreotide at 12.5 μg/hour. After 24 hours, her secretions had decreased to 150 mL/day; and by 72 hours, she had produced a total of 500 mL of sputum. On hospital Day 4, the octreotide was discontinued and her secretions remained minimal. She was discharged with a plan for SC administration of octreotide; however, the patient opted instead to receive daily IV infusions of octreotide in the outpatient clinic.
Five days after discharge, she noted that her sputum production increased to unacceptable levels within 12 hours of the IV infusion. One week after discharge, she was readmitted to the inpatient palliative care unit for the management of bronchorrhea and started again on IV octreotide with reduction in her sputum to 100 mL/day. She was discharged on 200 μg octreotide administered through SC route twice a day.
When the patient was evaluated in the outpatient clinic four weeks later, it was noted that her secretions diminished with SC administration of octreotide, and her symptoms of dyspnea, chest pressure, and cough had improved. Of note, there were no other medications that were adjusted to account for the marked improvement in symptoms.
This case describes the management of a rare yet very burdensome symptom frequently associated with BAC. Managing the symptoms related to bronchorrhea can be difficult, although there are a few case reports in the literature suggesting the success of various treatments. Macrolide antibiotics and steroids have been shown to reduce sputum volume production in patients with BAC secondary to the anti-inflammatory effect of these drugs, which act as immunomodulators and reduce mucin gene expression. Hiratsuka et al.8 found that clarithromycin treatment in conjunction with inhaled beclomethasone reduced sputum volume from 900 to 300 mL a day in a patient with bronchorrhea secondary to BAC. Furthermore, they found that after stopping the clarithromycin and continuing inhaled beclomethasone alone, the bronchorrhea was controlled for four more months. There also are case reports of successful treatment of bronchorrhea with corticosteroids alone in patients with BAC. Nakajima et al.9 described the successful treatment of bronchorrhea in a patient with BAC with high-dose pulse methylprednisolone 1000 mg/day followed by oral prednisolone 60 mg/day. The patient’s sputum volume was controlled at 10 mL/day after four weeks of treatment.
There have been case reports about the successful use of inhaled indomethacin for the management of bronchorrhea. Increased transepithelial chloride transport can be promoted by prostaglandins, which are inhibited by indomethacin. Inhaled indomethacin was reported to be effective for severe refractory bronchorrhea in two patients with BAC, not only reducing sputum volume but also improving quality of life.10
There also have been promising reports of the use of gefitinib in the management of bronchorrhea. Gefitnib is an oral selective EGFR-tyrosine kinase inhibitor. It is thought that EGFR expression and activation causes goblet cell metaplasia from Clara cells and mucus hypersecretion in the airway.11 Takao et al.12 reported successful treatment of bronchorrhea in a 63-year-old female with BAC after two weeks of gefitinib therapy. She was maintained on gefitinib for nine months without symptoms and without radiologic evidence of recurrence of disease. A recent case report by Popat et al.5 also showed the successful use of gefitinib in a 46-year-old man with BAC despite his negative EGFR mutation status. The authors suggest that successful use of gefitinib for bronchorrhea is independent of its antiproliferative effect and likely secondary to the role of EGFR in regulating mucin production.5
There also are case reports of treatment of bronchorrhea with octreotide in patients with BAC. Hudson et al.13 described the successful use of octreotide through SC route to manage the symptoms of bronchorrhea in a 74-year-old female with BAC. The patient was producing more than 1 L of sputum per day; and after two days of octreotide therapy, sputum production subsided completely.
Octreotide is a synthetic analogue of the hormone somatostatin; and although the exact mechanism of action is unknown, it is thought to act on the same receptors as somatostatin. Octreotide inhibits the secretion of many hormones including gastrin, cholecystokinin, glucagon, growth hormone, insulin, secretin, pancreatic polypeptide, thyroid-stimulating hormone, and vasoactive intestinal peptide. Because of this antisecretoy effect, octreotide reduces gastrointestinal motility, inhibits gall-bladder contraction, reduces secretion of fluids by the intestine and pancreas, and has even been shown to have an analgesic effect.14
Octreotide has long been used by palliative care practitioners to manage symptoms, including malignant bowel obstruction,15 ascites,16 nausea,17 and gastrointestinal hemorrhage.18 It also has been used to manage excessive secretions related to fistulae.19 As a result of its antisecretory effect, octreotide is a potent antidiarrheal agent and has been used to manage diarrhea related to carcinoid syndrome20 and human immunodeficiency virus–related diarrhea.21
Common side effects of octreotide include headache; gastrointestinal reactions including cramps, nausea, vomiting, diarrhea, and constipation; gallstones; hyperglycemia; hypoglycemia; and transient injection site reactions. Octreotide also is listed among drugs that can prolong the QT interval; however, studies are inconclusive as to whether the prolonged QT interval is the result of octreotide or directly related to the offending illness that required octreotide management, such as acromegaly.22 It is important to note that the patient in our report did not suffer any known side effects related to the octreotide during both the IV and SC administration of the drug. She did have pain related to the SC injections; however, no injection site reaction was noted.
It is thought that bronchorrhea is caused by increased transepithelial chloride secretion in the lungs. Octreotide lowers plasma levels of the hormone secretin and there are secretin receptors present on the human lung.12 Secretin is a potent stimulant of electrolyte and water movement, and it has been suggested that inhibiting secretin reduces chloride and water efflux from bronchial epithelial cells, thereby reducing sputum production.13
As demonstrated in this case report, there are many ways to administer octreotide. In addition to the IV and SC routes, there also is an intramuscular depot injection. One intramuscular depot injection may manage symptoms for up to four weeks. However, the intramuscular depot injection can be cost prohibitive. In one large U.S. academic medical center, the cost of a 20 mg depot injection is $2319, versus IV and SC administration, each of which only cost about $10 per day. Given the added cost of administering octreotide daily by the IV or SC routes, further studies are warranted to establish if it is cost-effective to use the intramuscular depot injection in patients who have known improvement of symptoms with octreotide. In addition to the costs, one must take into account the added burden to patients that is associated with daily IV or SC administration.
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This case report highlights the use of octreotide to successfully manage bronchorrhea in various health care settings, such as inpatient palliative care units, outpatient clinics, and home-based therapy. The report also touches on the various administration modalities of octreotide that can be used for symptom management across these settings. Octreotide has been successfully used for the management of bronchorrhea and should be further studied and considered as first-line treatment.