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Somatostatin Analogs Improve Respiratory Symptoms in Patients With Diffuse Idiopathic Neuroendocrine Cell Hyperplasia
Journal Pre-proof Somatostatin analogs (SSA) improve respiratory symptoms in patients with diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) Taymeyah Al-Toubah, MPH, Jonathan Strosberg, MD, Thor Halfdanarson, MD, Kira Oleinikov, MD, David J. Gross, MD, Mintallah Haider, MD, Mohamad Bassam Sonbol, MD, Daniel Almquist, MD, Simona Grozinsky-Glasberg, MD PII:
S0012-3692(20)30258-0
DOI:
https://doi.org/10.1016/j.chest.2020.01.031
Reference:
CHEST 2886
To appear in:
CHEST
Received Date: 22 October 2019 Revised Date:
30 December 2019
Accepted Date: 26 January 2020
Please cite this article as: Al-Toubah T, Strosberg J, Halfdanarson T, Oleinikov K, Gross DJ, Haider M, Sonbol MB, Almquist D, Grozinsky-Glasberg S, Somatostatin analogs (SSA) improve respiratory symptoms in patients with diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH), CHEST (2020), doi: https://doi.org/10.1016/j.chest.2020.01.031. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020 Published by Elsevier Inc under license from the American College of Chest Physicians.
Word count: 2299 Title: Somatostatin analogs (SSA) improve respiratory symptoms in patients with diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) Running head: Somatostatin analogs in patients with symptomatic DIPNECH Taymeyah Al-Toubah MPH1, Jonathan Strosberg MD1, Thor Halfdanarson MD2, Kira Oleinikov MD3, David J. Gross MD3, Mintallah Haider MD1, Mohamad Bassam Sonbol MD4, Daniel Almquist MD4, Simona Grozinsky-Glasberg MD3
1. H. Lee Moffitt Cancer Center and Research Institute, Department of GI Oncology, Tampa, Florida, USA 2. Mayo Clinic Cancer Center, Department of Medical Oncology, Rochester, Minnesota, USA 3. Neuroendocrine Tumor Unit, ENETS Center of Excellence, Endocrinology & Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 4. Mayo Clinic Cancer Center, Department of Hematology and Oncology, Phoenix, Arizona, USA Corresponding Author: Jonathan Strosberg, MD H. Lee Moffitt Cancer Center and Research Institute Department of Gastrointestinal Oncology P: 813-745-3636; F: 813-745-7229 Email: [email protected] Conflicts of Interest: Novartis (Consult), Ipsen and Lexicon (Speaker bureau): J. Strosberg Curium, Lexicon, Ipsen, Advanced Accelerator Applications (Consult): T. Halfdanarson None: T.Al-Toubah, K. Oleinikov, D. Gross, M. Haider, S. Grozinsky-Glasberg, M.B. Sonbol, D. Almquist
Funding: None Keywords: neuroendocrine, DIPNECH, somatostatin analog, neuroendocrine cell hyperplasia 1
Abbreviations DIPNECH
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
PFT SSA NEN 5-HIAA RECIST FEV LAR COPD
Pulmonary function tests Somatostatin analog Neuroendocrine neoplasm 5-hydroxyindoleacetic acid Response Evaluation Criteria in Solid Tumors Forced expiratory volume Long acting repeatable Chronic obstructive pulmonary disease
2
ABSTRACT Introduction: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare lung disease associated with proliferation of neuroendocrine cells in the lung and multifocal neuroendocrine tumorlets/tumors. Although usually considered an indolent condition, DIPNECH causes chronic, progressive cough and dyspnea which can adversely impact quality of life. There is very limited information on the treatment of this condition. Aims: To assess changes in symptoms as well as pulmonary function tests (PFTs) in response to somatostatin analog (SSA) treatment. Methods: Patients with clinical and/or pathological diagnosis of DIPNECH and chronic respiratory symptoms were treated with SSAs at the Moffitt Cancer Center, Hadassah Medical Center, and Mayo Clinic. Their charts were reviewed to assess changes in symptoms and pulmonary function tests. Results: 42 patients were identified who had either chronic cough or dyspnea due to proven or suspected DIPNECH and who had received treatment with an SSA. 33 patients experienced symptomatic improvement. Additionally, 14 out of 15 patients in whom PFTs were checked were noted to have an improvement in FEV1 following treatment. Conclusions: SSA treatment can improve chronic respiratory symptoms and PFTs in patients with DIPNECH.
3
INTRODUCTION Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare lung disease that was first described in the 1950s and was not fully recognized as a unique clinicopathological entity until the 1990s. Pulmonary neuroendocrine cells are present in all normal adult lung tissue and assist in repair and regeneration in response to injury.(1) Neuroendocrine cell hyperplasia can develop as a reaction to high altitude, toxic exposure, and various lung diseases. In rare cases, hyperplasia of neuroendocrine cells can occur without any clear predisposing stimulus, a condition first described by Aguayo at al. as DIPNECH.(2) In 1999 DIPNECH was added to the World Health Organization (WHO) classification of lung tumors.(3, 4) It can manifest in various ways, including development of scattered nodules or ‘tumorlets’ and may represent a preneoplastic lesion for lung neuroendocrine tumors (NETs, carcinoids). Neuroendocrine tumorlets are neoplasms smaller than 0.5cm and characterized by neuroendocrine cell invasion of peribronchiolar tissues and the development of a stroma, usually fibrotic.(5) Growth of tumorlets beyond 0.5cm and malignant transformation is quite rare. DIPNECH most commonly develops in middle-aged women, most of whom are non-smokers. Patients often present with decades of chronic cough and/or dyspnea.(6, 7) The average duration of symptoms prior to diagnosis was described in one report as 8.6 years.(3) In addition to these nonspecific symptoms, patients with the diagnosis of DIPNECH often have obstructive abnormalities on pulmonary function tests (PFTs). Radiographic imaging can reveal pulmonary nodules of different size, ground glass opacities, mosaic attenuation with air trapping, endobronchial wall thickening, and bronchiectasis.(8) The overall clinical course is often indolent and stable, however progression to respiratory failure may occur. Currently, the gold standard for diagnosis of DIPNECH is still considered a surgical lung biopsy.(6) Data on treatment of DIPNECH are exceedingly limited, and no standard of care has been described. One prior study of 11 patients with DIPNECH described six patients who were treated with somatostatin analogs (SSAs) for radiographic progression. Four patients experienced improvement in respiratory symptoms concordant with improvement in PFTs.(8) Another institutional study identified five DIPNECH patients, four of whom started an SSA and noted substantial improvement in chronic cough.(9) Based on these data as well as anecdotal experience, the National Comprehensive Cancer Network recommends observation for DIPNECH patients with non-contrast thoracic CT scans every 12-24 months, and consideration 4
of SSA therapy for patients with chronic symptoms (cough, dyspnea) and/or somatostatin receptor expressing tumors(10). In an effort to expand our understanding of this disease and the role of SSAs in symptomatic palliation, we performed a tri-institutional medical chart review to identify patients with either pathologically proven DIPNECH or lung neuroendocrine neoplasm (NEN) and suspected DIPNECH (based on clinical and radiographic findings), who were treated with SSAs for symptom control. PFT data were reviewed if available. The primary goal was to assess whether SSAs could palliate DIPNECH-associated symptoms. METHODS Study design Database analyses with chart reviews were performed at three institutions: Moffitt Cancer Center (Tampa, Florida, USA), Hadassah-Hebrew University Medical Center (Jerusalem, Israel) and Mayo Clinic (Rochester, Minnesota, USA). Patients who either had proven DIPNECH (based on lung biopsy showing neuroendocrine cell hyperplasia) or suspected DIPNECH (multifocal biopsy-proven lung NEN with chronic characteristic respiratory symptoms) were identified. Patients who had respiratory symptoms (either chronic cough or dyspnea) and were started on SSA treatment were included in the analysis. SSA type, dose and any changes in dose were documented. Institutional review board approval was obtained from each institution (Moffitt – Advarra IRB no. Pro00030613; Hadassah – Hadassah-Hebrew University Medical Centre Ethical Committee no. 0072–16; Mayo – Mayo Clinic IRB no. 18-009336) and waiver of consent was obtained due to the retrospective nature of this study. Data was analyzed using IBM SPSS® version 25. Categorical variables were analyzed using logistic regression or categorical response models. A p-value set at 0.05 was used for Pearson correlations and paired-samples ttest. Clinical assessment Chart review was used to define baseline symptoms, including cough, dyspnea, wheezing or hemoptysis. Smoking history, environmental exposure history, and any prior history of lung disease was assessed. The primary endpoint, clinical/symptomatic response to treatment, was extrapolated from chart review of progress notes by investigators in each institution and categorized as: ‘no response’, ‘mild response’, ‘moderate response’ or ‘significant response’. Duration of response was assessed. 5
Biochemical assessment Where available, urine 5-hydroxyindoleacetic acid (5-HIAA) was assessed. Radiographic assessment Scans were reviewed for evidence of progression in size/number of nodules over time, development of malignant disease (evidence of metastases) and changes in non-neoplastic lung findings (e.g. ground glass opacities). Due to lack of measurable target lesions in most patients, Response Evaluation Criteria in Solid Tumors (RECIST) analysis was not performed. Side effect assessment Treatment-related side effects (as best judged by clinicians and investigators) were documented. Pulmonary Function Tests (PFTs) When available, baseline pre-treatment PFTs were assessed, focusing on forced expiratory volume at 1 second (FEV 1). Levels ≤80% were considered abnormal. Degree of obstruction was considered mild if FEV1 was 51-80% of normal, moderate if 31-50% of normal, and severe if <30% of normal. The initial post-treatment FEV1 was recorded, if available, and compared to pretreatment values. Absolute mean changes in FEV1 were calculated.
RESULTS Clinical characteristics and patient demographics are summarized in Table 1. Forty-two consecutive patients were identified who had either chronic cough or dyspnea due to proven or suspected DIPNECH and who had received treatment with an SSA. There were two male patients and the remainder were females. Median age at diagnosis was 66 years old, with patients ranging from 44-81 years of age. Thirty-two (76.2%) of patients were non-smokers, seven (16.7%) were smokers at time of diagnosis and three (7.1%) were former smokers who quit within at least 10 years of diagnosis. Median pack year smoking history was 22.5 years (range: 10-60 years). All patients were symptomatic at baseline, with the majority experiencing cough (n=34, 81%) or dyspnea (n=27, 64%), and 19 with a combination of both. Several other baseline symptoms occurred in some patients, including fatigue (n=6), wheezing (n=5), palpitations (n=4), hot flashes/flushing (n=3), abdominal pain (n=2), diarrhea (n=1), and hirsutism (n=1). Data regarding duration of respiratory symptoms were available in 37 patients; median duration of symptoms was 5 years (mean = 10.1 years; range = 0.5 – 40 years). Twenty-eight patients underwent surgical resection of at least one tumor with only two patients 6
experiencing post-operative complications of an air leak (1) and chest pain (1). Of the 28 patients who had an initial surgical resection of disease, six underwent a subsequent surgery to further manage disease with no change in diagnosis or grade of tumor. Nine patients, who were initially diagnosed via biopsy, subsequently underwent surgical resection of dominant lesion(s) with no change in diagnosis or grade of tumor. Patients received treatment with an SSA (35 with octreotide LAR and seven with lanreotide) for an average of 38.8 months (range: 1-145 months) at the time of analysis. Twenty-five patients began treatment with octreotide LAR at a dose of 30mg every 4 weeks. Among these, two patients were eventually increased to a dose of 40mg, and one patient’s injection frequency was increased to every 2 weeks. Ten patients received treatment with octreotide 20mg, two of whom were subsequently increased to 30mg. Seven patients received lanreotide 120mg every 4 weeks without dose adjustment. Of the 42 patients studied, 15 (36%) reported mild improvement, 6 (14%) reported moderate improvement, and 11 (26%) reported significant improvement of symptoms. Ten (24%) patients reported no improvement in symptoms, four of whom reported worsening of symptoms. Thirtyone patients received concomitant medications for respiratory symptoms, including inhalers, benzonatate, and oral steroids. Most concomitant therapies had been started prior to SSA initiation and continued throughout. Three patients were documented as being able to stop their supportive medications after initiation of SSA, with no recurrence of symptoms. Sixteen patients experienced known, expected adverse effects of SSA therapy, including malabsorption, diarrhea, bloating, fatigue, and hyperglycemia. One patient developed cholelithiasis requiring cholecystectomy. Twenty-one patients carried a diagnosis of lung disease at baseline, including asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema. The most common comorbidities of patients on study were hypertension (n=24, 57.1%), diabetes (n=17, 40.4%), and arthritis (n=9, 21.4%). One patient had long-term exposure to radiation while working for several years in a nuclear reactor. There was no note of exposure to environmental toxins other than tobacco in any of the remaining patients. Out of the twenty patients who had baseline 24-hour urine 5-HIAA levels available, none had levels that were out of normal range. Since baseline values were normal, none of the patients had a subsequent 24-hour urine 5-HIAA completed for comparison. 7
CT scans and/or pathology specimens were used to determine size of dominant pulmonary lesions in all patients. Median size of dominant lesion was 15 mm (range: 3-63 mm). Thirty-two patients had innumerable other pulmonary lesions evidenced on CT scans, ranging from 1 – 32mm and ten patients had 2-8 other pulmonary lesions measuring 2-24mm in size. Relationship between dominant lesion size and symptomatic response was not statistically significant (r= 0.15, n=42, p= 0.36). On CT scans, none of the patients experienced significant changes in tumor size or number during their follow-up. One patient, who did not respond clinically to SSA, developed a new 4 mm pulmonary nodule of uncertain significance on her most recent scan, approximately 4 years after her last dose of SSA. Two other patients had minor progression (<5mm of growth) of existing disease on CT scans, without any new nodules. The remainder of patients (n=39, 92.9%) continued to have stable disease on all subsequent scans, regardless of whether or not they discontinued SSA. Of the nineteen patients who had somatostatin receptor imaging (OctreoScan or 68GaDOTATATE PET/CT), 12 had some level of positive uptake whereas 7 did not show any significant uptake (all 7 negative scans were OctreoScans, with largest tumor <2cm). The differences in the uptake between patients with positive and negative imaging, respectively, were most probably related to scan sensitivity than actual real differences in somatostatin receptor expression. Pulmonary function tests (PFTs) were assessed in 25 patients at baseline, and 15 patients had post-treatment PFTs for comparison. Among these 15 patients, 8 had mild pulmonary impairment at baseline, 3 patients had moderate impairment, 1 had severe impairment, and 3 had normal pulmonary function. Fourteen of fifteen (93%) experienced improvement in PFT value, 4 of whom also improved in the category of symptom severity (95% CI: -0.11 – 0.51, p = 0.19). Of the patients with mild pulmonary impairment at baseline, six experienced improvement in post treatment PFTs value, one demonstrated worsening in PFTs and one had no change in value (95%CI: -9.85 – -3.07, p = 0.001). All patients with moderate and severe pulmonary impairment at baseline demonstrated improvement to mild and moderate pulmonary impairment post treatment with SSA, respectively. All three patients with normal pulmonary function at baseline also experienced improvement in PFT values post treatment with SSA.
8
DISCUSSION DIPNECH is rare and poorly understood clinicopathologic entity characterized by chronic respiratory symptoms, notably cough, associated with proliferation of pulmonary neuroendocrine cells and development of lung neuroendocrine ‘tumorlets’ and/or tumors. Information on symptomatic treatment options in the literature is limited to two published case series consisting in total of 10 patients treated with SSA. To our knowledge, no other effective treatments have been described. Our multi-institutional analysis represents, by far, the largest cohort of patients with this disease treated with SSA. We have found that SSAs are highly effective at palliating chronic respiratory symptoms such as cough and dyspnea. In total, 76% of patients experienced some degree of symptom improvement, among whom 26% described significant improvement. Corroborating this evidence are results of PFTs, available in 15 patients, demonstrating improvement of PFT values in 14 patients (93%). Despite remaining on treatment for extended periods of time, only one patient discontinued SSA while the majority of patients (n=26) did not experience any significant toxicity. During this time, only one patient who initially described benefit experienced progression of symptoms. The metastatic spread potential of DIPNECH is low, and in most cases the disease has a stable or slow progressive course. Tumor size was not associated with the degree of response to treatment (p = 0.25) and among the 42 patients in this analysis, none experienced significant radiographic disease progression. The mechanisms by which SSAs exert their effects on NET cells are complex and poorly understood. Somatostatin is known to be able to inhibit different cellular functions, such as secretion, motility and proliferation, by binding to cell- and tissue-specific receptors. Somatostatin and its analogs have a paracrine (regulating adjacent cells) and/or an autocrine (self-regulatory) activity. DIPNECH and the associated NENs, as well as NENs of small intestine (SI) origin, may present with a wide range of clinical and biological behaviors, partly related to their ability to synthesize and hypersecrete a variety of peptide hormones (such as serotonin, histamine, bradykinin, prostaglandins, etc), potentially inducing reactive airway narrowing, obstruction and inflammation. The anti-secretory role of SSAs in improving these hypersecretion-related symptoms is well documented in small intestinal NETs, and can be therefore extrapolated, in our view, for DIPNECH and its related tumors.(11) 9
The limitations of this study are its retrospective design as well as the somewhat subjective categories of clinical response. Patient-reported outcomes and validated quality of life questionnaires, which could have provided more objective metrics, were not available in this analysis. Nevertheless, the consistency of findings across three, separately analyzed databases, lends credence to the finding that SSAs provide a substantial and clinically meaningful symptomatic benefit. In summary, DIPNECH is a chronic pulmonary condition that is associated with significant clinical morbidity. In DIPNECH patients who have respiratory symptoms that are uncontrolled by conventional medications, SSA treatment palliates symptoms in most cases with a relatively low rate of toxicity. SSAs should be considered a standard of care therapy in DIPNECH patients whose pulmonary symptoms are sufficiently severe to warrant treatment.
10
REFERENCES 1. Song H, Yao E, Lin C, Gacayan R, Chen MH, Chuang PT. Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis. Proc Natl Acad Sci U S A. 2012;109(43):17531-6. 2. Aguayo SM, Miller YE, Waldron JA, Jr., Bogin RM, Sunday ME, Staton GW, Jr., et al. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med. 1992;327(18):1285-8. 3. Davies SJ, Gosney JR, Hansell DM, Wells AU, du Bois RM, Burke MM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax. 2007;62(3):248-52. 4. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. Introduction to The 2015 World Health Organization Classification of Tumors of the Lung, Pleura, Thymus, and Heart. J Thorac Oncol. 2015;10(9):1240-2. 5. Gosney JR, Williams IJ, Dodson AR, Foster CS. Morphology and antigen expression profile of pulmonary neuroendocrine cells in reactive proliferations and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Histopathology. 2011;59(4):75162. 6. Nassar AA, Jaroszewski DE, Helmers RA, Colby TV, Patel BM, Mookadam F. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a systematic overview. Am J Respir Crit Care Med. 2011;184(1):8-16. 7. Almquist D, Cabrera A, Sonbol MB, Kosiorek HE, Halfdanarson TR, Ross HJ, et al. DIPNECH: The Mayo experience. Journal of Clinical Oncology. 2019;37(15_suppl):e20029-e. 8. Gorshtein A, Gross DJ, Barak D, Strenov Y, Refaeli Y, Shimon I, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors: clinical experience with a rare entity. Cancer. 2012;118(3):612-9. 9. Chauhan A, Ramirez RA. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) and the Role of Somatostatin analogs: A Case Series. Lung. 2015;193(5):653-7. 10. Shah MH, Goldner WS, Halfdanarson TR, Bergsland E, Berlin JD, Halperin D, et al. NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018. J Natl Compr Canc Netw. 2018;16(6):693-702. 11. Grozinsky-Glasberg S, Shimon I, Korbonits M, Grossman AB. Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms. Endocr Relat Cancer. 2008;15(3):701-20.
11
Table 1. Patient demographics and clinical characteristics N (%) Sex Female Male
40 (95.2) 2 (4.8)
Age < 50 50 – 59 60 – 69 70+ Ki-67% (on biopsy or surgical specimen) Not reported ≤ 2% 3-20% Smoking history Yes No Other therapies for respiratory symptoms 0 1 2-3 >3 Baseline Symptoms Cough Dyspnea Fatigue Wheezing Palpitations Chest tightness Hot flashes Hirsutism Abdominal pain
4 (9.6) 13 (30.9) 10 (23.8) 15 (35.7) 25 (59.5) 16 (38.1) 1 (2.4) 10 (23.8) 32 (76.2) 11 (26.2) 9 (21.4) 18 (42.9) 4 (9.5) 34 (80.9) 27 (64.2) 6 (14.3) 5 (11.9) 4 (9.5) 2 (4.7) 1 (2.4) 1 (2.4) 1 (2.4)
12
S0012-3692(20)30258-0
DOI:
https://doi.org/10.1016/j.chest.2020.01.031
Reference:
CHEST 2886
To appear in:
CHEST
Received Date: 22 October 2019 Revised Date:
30 December 2019
Accepted Date: 26 January 2020
Please cite this article as: Al-Toubah T, Strosberg J, Halfdanarson T, Oleinikov K, Gross DJ, Haider M, Sonbol MB, Almquist D, Grozinsky-Glasberg S, Somatostatin analogs (SSA) improve respiratory symptoms in patients with diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH), CHEST (2020), doi: https://doi.org/10.1016/j.chest.2020.01.031. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020 Published by Elsevier Inc under license from the American College of Chest Physicians.
Word count: 2299 Title: Somatostatin analogs (SSA) improve respiratory symptoms in patients with diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) Running head: Somatostatin analogs in patients with symptomatic DIPNECH Taymeyah Al-Toubah MPH1, Jonathan Strosberg MD1, Thor Halfdanarson MD2, Kira Oleinikov MD3, David J. Gross MD3, Mintallah Haider MD1, Mohamad Bassam Sonbol MD4, Daniel Almquist MD4, Simona Grozinsky-Glasberg MD3
1. H. Lee Moffitt Cancer Center and Research Institute, Department of GI Oncology, Tampa, Florida, USA 2. Mayo Clinic Cancer Center, Department of Medical Oncology, Rochester, Minnesota, USA 3. Neuroendocrine Tumor Unit, ENETS Center of Excellence, Endocrinology & Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 4. Mayo Clinic Cancer Center, Department of Hematology and Oncology, Phoenix, Arizona, USA Corresponding Author: Jonathan Strosberg, MD H. Lee Moffitt Cancer Center and Research Institute Department of Gastrointestinal Oncology P: 813-745-3636; F: 813-745-7229 Email: [email protected] Conflicts of Interest: Novartis (Consult), Ipsen and Lexicon (Speaker bureau): J. Strosberg Curium, Lexicon, Ipsen, Advanced Accelerator Applications (Consult): T. Halfdanarson None: T.Al-Toubah, K. Oleinikov, D. Gross, M. Haider, S. Grozinsky-Glasberg, M.B. Sonbol, D. Almquist
Funding: None Keywords: neuroendocrine, DIPNECH, somatostatin analog, neuroendocrine cell hyperplasia 1
Abbreviations DIPNECH
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
PFT SSA NEN 5-HIAA RECIST FEV LAR COPD
Pulmonary function tests Somatostatin analog Neuroendocrine neoplasm 5-hydroxyindoleacetic acid Response Evaluation Criteria in Solid Tumors Forced expiratory volume Long acting repeatable Chronic obstructive pulmonary disease
2
ABSTRACT Introduction: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare lung disease associated with proliferation of neuroendocrine cells in the lung and multifocal neuroendocrine tumorlets/tumors. Although usually considered an indolent condition, DIPNECH causes chronic, progressive cough and dyspnea which can adversely impact quality of life. There is very limited information on the treatment of this condition. Aims: To assess changes in symptoms as well as pulmonary function tests (PFTs) in response to somatostatin analog (SSA) treatment. Methods: Patients with clinical and/or pathological diagnosis of DIPNECH and chronic respiratory symptoms were treated with SSAs at the Moffitt Cancer Center, Hadassah Medical Center, and Mayo Clinic. Their charts were reviewed to assess changes in symptoms and pulmonary function tests. Results: 42 patients were identified who had either chronic cough or dyspnea due to proven or suspected DIPNECH and who had received treatment with an SSA. 33 patients experienced symptomatic improvement. Additionally, 14 out of 15 patients in whom PFTs were checked were noted to have an improvement in FEV1 following treatment. Conclusions: SSA treatment can improve chronic respiratory symptoms and PFTs in patients with DIPNECH.
3
INTRODUCTION Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare lung disease that was first described in the 1950s and was not fully recognized as a unique clinicopathological entity until the 1990s. Pulmonary neuroendocrine cells are present in all normal adult lung tissue and assist in repair and regeneration in response to injury.(1) Neuroendocrine cell hyperplasia can develop as a reaction to high altitude, toxic exposure, and various lung diseases. In rare cases, hyperplasia of neuroendocrine cells can occur without any clear predisposing stimulus, a condition first described by Aguayo at al. as DIPNECH.(2) In 1999 DIPNECH was added to the World Health Organization (WHO) classification of lung tumors.(3, 4) It can manifest in various ways, including development of scattered nodules or ‘tumorlets’ and may represent a preneoplastic lesion for lung neuroendocrine tumors (NETs, carcinoids). Neuroendocrine tumorlets are neoplasms smaller than 0.5cm and characterized by neuroendocrine cell invasion of peribronchiolar tissues and the development of a stroma, usually fibrotic.(5) Growth of tumorlets beyond 0.5cm and malignant transformation is quite rare. DIPNECH most commonly develops in middle-aged women, most of whom are non-smokers. Patients often present with decades of chronic cough and/or dyspnea.(6, 7) The average duration of symptoms prior to diagnosis was described in one report as 8.6 years.(3) In addition to these nonspecific symptoms, patients with the diagnosis of DIPNECH often have obstructive abnormalities on pulmonary function tests (PFTs). Radiographic imaging can reveal pulmonary nodules of different size, ground glass opacities, mosaic attenuation with air trapping, endobronchial wall thickening, and bronchiectasis.(8) The overall clinical course is often indolent and stable, however progression to respiratory failure may occur. Currently, the gold standard for diagnosis of DIPNECH is still considered a surgical lung biopsy.(6) Data on treatment of DIPNECH are exceedingly limited, and no standard of care has been described. One prior study of 11 patients with DIPNECH described six patients who were treated with somatostatin analogs (SSAs) for radiographic progression. Four patients experienced improvement in respiratory symptoms concordant with improvement in PFTs.(8) Another institutional study identified five DIPNECH patients, four of whom started an SSA and noted substantial improvement in chronic cough.(9) Based on these data as well as anecdotal experience, the National Comprehensive Cancer Network recommends observation for DIPNECH patients with non-contrast thoracic CT scans every 12-24 months, and consideration 4
of SSA therapy for patients with chronic symptoms (cough, dyspnea) and/or somatostatin receptor expressing tumors(10). In an effort to expand our understanding of this disease and the role of SSAs in symptomatic palliation, we performed a tri-institutional medical chart review to identify patients with either pathologically proven DIPNECH or lung neuroendocrine neoplasm (NEN) and suspected DIPNECH (based on clinical and radiographic findings), who were treated with SSAs for symptom control. PFT data were reviewed if available. The primary goal was to assess whether SSAs could palliate DIPNECH-associated symptoms. METHODS Study design Database analyses with chart reviews were performed at three institutions: Moffitt Cancer Center (Tampa, Florida, USA), Hadassah-Hebrew University Medical Center (Jerusalem, Israel) and Mayo Clinic (Rochester, Minnesota, USA). Patients who either had proven DIPNECH (based on lung biopsy showing neuroendocrine cell hyperplasia) or suspected DIPNECH (multifocal biopsy-proven lung NEN with chronic characteristic respiratory symptoms) were identified. Patients who had respiratory symptoms (either chronic cough or dyspnea) and were started on SSA treatment were included in the analysis. SSA type, dose and any changes in dose were documented. Institutional review board approval was obtained from each institution (Moffitt – Advarra IRB no. Pro00030613; Hadassah – Hadassah-Hebrew University Medical Centre Ethical Committee no. 0072–16; Mayo – Mayo Clinic IRB no. 18-009336) and waiver of consent was obtained due to the retrospective nature of this study. Data was analyzed using IBM SPSS® version 25. Categorical variables were analyzed using logistic regression or categorical response models. A p-value set at 0.05 was used for Pearson correlations and paired-samples ttest. Clinical assessment Chart review was used to define baseline symptoms, including cough, dyspnea, wheezing or hemoptysis. Smoking history, environmental exposure history, and any prior history of lung disease was assessed. The primary endpoint, clinical/symptomatic response to treatment, was extrapolated from chart review of progress notes by investigators in each institution and categorized as: ‘no response’, ‘mild response’, ‘moderate response’ or ‘significant response’. Duration of response was assessed. 5
Biochemical assessment Where available, urine 5-hydroxyindoleacetic acid (5-HIAA) was assessed. Radiographic assessment Scans were reviewed for evidence of progression in size/number of nodules over time, development of malignant disease (evidence of metastases) and changes in non-neoplastic lung findings (e.g. ground glass opacities). Due to lack of measurable target lesions in most patients, Response Evaluation Criteria in Solid Tumors (RECIST) analysis was not performed. Side effect assessment Treatment-related side effects (as best judged by clinicians and investigators) were documented. Pulmonary Function Tests (PFTs) When available, baseline pre-treatment PFTs were assessed, focusing on forced expiratory volume at 1 second (FEV 1). Levels ≤80% were considered abnormal. Degree of obstruction was considered mild if FEV1 was 51-80% of normal, moderate if 31-50% of normal, and severe if <30% of normal. The initial post-treatment FEV1 was recorded, if available, and compared to pretreatment values. Absolute mean changes in FEV1 were calculated.
RESULTS Clinical characteristics and patient demographics are summarized in Table 1. Forty-two consecutive patients were identified who had either chronic cough or dyspnea due to proven or suspected DIPNECH and who had received treatment with an SSA. There were two male patients and the remainder were females. Median age at diagnosis was 66 years old, with patients ranging from 44-81 years of age. Thirty-two (76.2%) of patients were non-smokers, seven (16.7%) were smokers at time of diagnosis and three (7.1%) were former smokers who quit within at least 10 years of diagnosis. Median pack year smoking history was 22.5 years (range: 10-60 years). All patients were symptomatic at baseline, with the majority experiencing cough (n=34, 81%) or dyspnea (n=27, 64%), and 19 with a combination of both. Several other baseline symptoms occurred in some patients, including fatigue (n=6), wheezing (n=5), palpitations (n=4), hot flashes/flushing (n=3), abdominal pain (n=2), diarrhea (n=1), and hirsutism (n=1). Data regarding duration of respiratory symptoms were available in 37 patients; median duration of symptoms was 5 years (mean = 10.1 years; range = 0.5 – 40 years). Twenty-eight patients underwent surgical resection of at least one tumor with only two patients 6
experiencing post-operative complications of an air leak (1) and chest pain (1). Of the 28 patients who had an initial surgical resection of disease, six underwent a subsequent surgery to further manage disease with no change in diagnosis or grade of tumor. Nine patients, who were initially diagnosed via biopsy, subsequently underwent surgical resection of dominant lesion(s) with no change in diagnosis or grade of tumor. Patients received treatment with an SSA (35 with octreotide LAR and seven with lanreotide) for an average of 38.8 months (range: 1-145 months) at the time of analysis. Twenty-five patients began treatment with octreotide LAR at a dose of 30mg every 4 weeks. Among these, two patients were eventually increased to a dose of 40mg, and one patient’s injection frequency was increased to every 2 weeks. Ten patients received treatment with octreotide 20mg, two of whom were subsequently increased to 30mg. Seven patients received lanreotide 120mg every 4 weeks without dose adjustment. Of the 42 patients studied, 15 (36%) reported mild improvement, 6 (14%) reported moderate improvement, and 11 (26%) reported significant improvement of symptoms. Ten (24%) patients reported no improvement in symptoms, four of whom reported worsening of symptoms. Thirtyone patients received concomitant medications for respiratory symptoms, including inhalers, benzonatate, and oral steroids. Most concomitant therapies had been started prior to SSA initiation and continued throughout. Three patients were documented as being able to stop their supportive medications after initiation of SSA, with no recurrence of symptoms. Sixteen patients experienced known, expected adverse effects of SSA therapy, including malabsorption, diarrhea, bloating, fatigue, and hyperglycemia. One patient developed cholelithiasis requiring cholecystectomy. Twenty-one patients carried a diagnosis of lung disease at baseline, including asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema. The most common comorbidities of patients on study were hypertension (n=24, 57.1%), diabetes (n=17, 40.4%), and arthritis (n=9, 21.4%). One patient had long-term exposure to radiation while working for several years in a nuclear reactor. There was no note of exposure to environmental toxins other than tobacco in any of the remaining patients. Out of the twenty patients who had baseline 24-hour urine 5-HIAA levels available, none had levels that were out of normal range. Since baseline values were normal, none of the patients had a subsequent 24-hour urine 5-HIAA completed for comparison. 7
CT scans and/or pathology specimens were used to determine size of dominant pulmonary lesions in all patients. Median size of dominant lesion was 15 mm (range: 3-63 mm). Thirty-two patients had innumerable other pulmonary lesions evidenced on CT scans, ranging from 1 – 32mm and ten patients had 2-8 other pulmonary lesions measuring 2-24mm in size. Relationship between dominant lesion size and symptomatic response was not statistically significant (r= 0.15, n=42, p= 0.36). On CT scans, none of the patients experienced significant changes in tumor size or number during their follow-up. One patient, who did not respond clinically to SSA, developed a new 4 mm pulmonary nodule of uncertain significance on her most recent scan, approximately 4 years after her last dose of SSA. Two other patients had minor progression (<5mm of growth) of existing disease on CT scans, without any new nodules. The remainder of patients (n=39, 92.9%) continued to have stable disease on all subsequent scans, regardless of whether or not they discontinued SSA. Of the nineteen patients who had somatostatin receptor imaging (OctreoScan or 68GaDOTATATE PET/CT), 12 had some level of positive uptake whereas 7 did not show any significant uptake (all 7 negative scans were OctreoScans, with largest tumor <2cm). The differences in the uptake between patients with positive and negative imaging, respectively, were most probably related to scan sensitivity than actual real differences in somatostatin receptor expression. Pulmonary function tests (PFTs) were assessed in 25 patients at baseline, and 15 patients had post-treatment PFTs for comparison. Among these 15 patients, 8 had mild pulmonary impairment at baseline, 3 patients had moderate impairment, 1 had severe impairment, and 3 had normal pulmonary function. Fourteen of fifteen (93%) experienced improvement in PFT value, 4 of whom also improved in the category of symptom severity (95% CI: -0.11 – 0.51, p = 0.19). Of the patients with mild pulmonary impairment at baseline, six experienced improvement in post treatment PFTs value, one demonstrated worsening in PFTs and one had no change in value (95%CI: -9.85 – -3.07, p = 0.001). All patients with moderate and severe pulmonary impairment at baseline demonstrated improvement to mild and moderate pulmonary impairment post treatment with SSA, respectively. All three patients with normal pulmonary function at baseline also experienced improvement in PFT values post treatment with SSA.
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DISCUSSION DIPNECH is rare and poorly understood clinicopathologic entity characterized by chronic respiratory symptoms, notably cough, associated with proliferation of pulmonary neuroendocrine cells and development of lung neuroendocrine ‘tumorlets’ and/or tumors. Information on symptomatic treatment options in the literature is limited to two published case series consisting in total of 10 patients treated with SSA. To our knowledge, no other effective treatments have been described. Our multi-institutional analysis represents, by far, the largest cohort of patients with this disease treated with SSA. We have found that SSAs are highly effective at palliating chronic respiratory symptoms such as cough and dyspnea. In total, 76% of patients experienced some degree of symptom improvement, among whom 26% described significant improvement. Corroborating this evidence are results of PFTs, available in 15 patients, demonstrating improvement of PFT values in 14 patients (93%). Despite remaining on treatment for extended periods of time, only one patient discontinued SSA while the majority of patients (n=26) did not experience any significant toxicity. During this time, only one patient who initially described benefit experienced progression of symptoms. The metastatic spread potential of DIPNECH is low, and in most cases the disease has a stable or slow progressive course. Tumor size was not associated with the degree of response to treatment (p = 0.25) and among the 42 patients in this analysis, none experienced significant radiographic disease progression. The mechanisms by which SSAs exert their effects on NET cells are complex and poorly understood. Somatostatin is known to be able to inhibit different cellular functions, such as secretion, motility and proliferation, by binding to cell- and tissue-specific receptors. Somatostatin and its analogs have a paracrine (regulating adjacent cells) and/or an autocrine (self-regulatory) activity. DIPNECH and the associated NENs, as well as NENs of small intestine (SI) origin, may present with a wide range of clinical and biological behaviors, partly related to their ability to synthesize and hypersecrete a variety of peptide hormones (such as serotonin, histamine, bradykinin, prostaglandins, etc), potentially inducing reactive airway narrowing, obstruction and inflammation. The anti-secretory role of SSAs in improving these hypersecretion-related symptoms is well documented in small intestinal NETs, and can be therefore extrapolated, in our view, for DIPNECH and its related tumors.(11) 9
The limitations of this study are its retrospective design as well as the somewhat subjective categories of clinical response. Patient-reported outcomes and validated quality of life questionnaires, which could have provided more objective metrics, were not available in this analysis. Nevertheless, the consistency of findings across three, separately analyzed databases, lends credence to the finding that SSAs provide a substantial and clinically meaningful symptomatic benefit. In summary, DIPNECH is a chronic pulmonary condition that is associated with significant clinical morbidity. In DIPNECH patients who have respiratory symptoms that are uncontrolled by conventional medications, SSA treatment palliates symptoms in most cases with a relatively low rate of toxicity. SSAs should be considered a standard of care therapy in DIPNECH patients whose pulmonary symptoms are sufficiently severe to warrant treatment.
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REFERENCES 1. Song H, Yao E, Lin C, Gacayan R, Chen MH, Chuang PT. Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis. Proc Natl Acad Sci U S A. 2012;109(43):17531-6. 2. Aguayo SM, Miller YE, Waldron JA, Jr., Bogin RM, Sunday ME, Staton GW, Jr., et al. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med. 1992;327(18):1285-8. 3. Davies SJ, Gosney JR, Hansell DM, Wells AU, du Bois RM, Burke MM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax. 2007;62(3):248-52. 4. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. Introduction to The 2015 World Health Organization Classification of Tumors of the Lung, Pleura, Thymus, and Heart. J Thorac Oncol. 2015;10(9):1240-2. 5. Gosney JR, Williams IJ, Dodson AR, Foster CS. Morphology and antigen expression profile of pulmonary neuroendocrine cells in reactive proliferations and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Histopathology. 2011;59(4):75162. 6. Nassar AA, Jaroszewski DE, Helmers RA, Colby TV, Patel BM, Mookadam F. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a systematic overview. Am J Respir Crit Care Med. 2011;184(1):8-16. 7. Almquist D, Cabrera A, Sonbol MB, Kosiorek HE, Halfdanarson TR, Ross HJ, et al. DIPNECH: The Mayo experience. Journal of Clinical Oncology. 2019;37(15_suppl):e20029-e. 8. Gorshtein A, Gross DJ, Barak D, Strenov Y, Refaeli Y, Shimon I, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors: clinical experience with a rare entity. Cancer. 2012;118(3):612-9. 9. Chauhan A, Ramirez RA. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) and the Role of Somatostatin analogs: A Case Series. Lung. 2015;193(5):653-7. 10. Shah MH, Goldner WS, Halfdanarson TR, Bergsland E, Berlin JD, Halperin D, et al. NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018. J Natl Compr Canc Netw. 2018;16(6):693-702. 11. Grozinsky-Glasberg S, Shimon I, Korbonits M, Grossman AB. Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms. Endocr Relat Cancer. 2008;15(3):701-20.
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Table 1. Patient demographics and clinical characteristics N (%) Sex Female Male
40 (95.2) 2 (4.8)
Age < 50 50 – 59 60 – 69 70+ Ki-67% (on biopsy or surgical specimen) Not reported ≤ 2% 3-20% Smoking history Yes No Other therapies for respiratory symptoms 0 1 2-3 >3 Baseline Symptoms Cough Dyspnea Fatigue Wheezing Palpitations Chest tightness Hot flashes Hirsutism Abdominal pain
4 (9.6) 13 (30.9) 10 (23.8) 15 (35.7) 25 (59.5) 16 (38.1) 1 (2.4) 10 (23.8) 32 (76.2) 11 (26.2) 9 (21.4) 18 (42.9) 4 (9.5) 34 (80.9) 27 (64.2) 6 (14.3) 5 (11.9) 4 (9.5) 2 (4.7) 1 (2.4) 1 (2.4) 1 (2.4)
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