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Proposing the use of hyponatremia as a marker to help identify high risk individuals for lung cancer
Medical Hypotheses 79 (2012) 327–328
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Proposing the use of hyponatremia as a marker to help identify high risk individuals for lung cancer Pashtoon Murtaza Kasi ⇑ International Scholars Program, Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15213, USA
a r t i c l e
i n f o
Article history: Received 15 March 2012 Accepted 13 May 2012
a b s t r a c t The use of computerized tomography (CT) scans has been recently brought into attention to help screen high risk individuals for lung cancer. Even though they are highly sensitive, their cost seems to be the main hindrance. Our hypothesis is to see if other factors could help identify a subset amongst the high risk individuals. Our focus specifically is on hyponatremia. It is well known that patients with lung cancer can have associated hyponatremia and multiple mechanisms have been put forward. Our hypothesis is that the degree of hyponatremia can be correlated with size or aggressiveness of the tumor and if true, then screening high risk individuals with hyponatremia can yield more patients with possible lung cancer. This, therefore, may help decrease the associated costs as compared to imaging/screening everyone with a CT scan for lung cancer and have a major impact at the public health level. Ó 2012 Elsevier Ltd. All rights reserved.
Background Lung cancer and screening ‘Long-term survival is quite uncommon in refractory small cell lung cancer (SCLC) patients, with less than 25% of patients with limited-stage disease and 1–2% of patients with extensive-stage disease remaining alive at 5 years’ [1]. In another series of 114 patients, metastases were present in 49.1% of patients at presentation [2]. Such numbers highlight the need for screening tools that can help catch the disease early. The use of computerized tomography (CT) scans (more specifically the low-dose CT scans) has been recently brought into attention to help screen high risk individuals for lung cancer and also has been shown to decrease mortality [3]. This argument is supported by the fact that routine chest X-rays (CXR) for surveillance purposes cannot catch nodules or tumors till they are much larger in size and identifying lung cancer early in these individuals may help prevent morbidity, mortality and overall healthcare associated costs. On the other hand, CT scans are not a cheap modality. Even though they are highly sensitive as well as specific to an extent, their cost seems to be the main hindrance and the argument put forward by those against the use of routine CT scans for
Abbreviations: ANP, atrial natriuretic peptide; CI, confidence interval; CT, computerized tomography; OR, odds ratio; Na+, sodium; NSCLC, non small cell lung cancer; SIADH, syndrome of inappropriate anti diuretic hormone secretion; SCLC, small cell lung cancer. ⇑ Tel.: +1 412 897 2301. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2012.05.023
surveillance in these individuals. Insurance agencies currently would not approve the use of CT scans as a surveillance strategy for lung cancer in patients with a significant smoking history. Our hypothesis is to see if other factors could be brought into the equation to further identify a subset amongst the high risk individuals (essentially smokers). The specific factor that that we think may be very useful in helping identify individuals with lung cancer is serum sodium levels/hyponatremia. Hyponatremia and lung cancer Serum sodium levels are very cheap and are essentially part of any basic or comprehensive metabolic panel. It is well known that patients with lung cancer can have associated hyponatremia (more common with small cell lung cancer) [4]. The mechanisms put forward for hyponatremia are outlined as follows: (1) Syndrome of Inappropriate Anti Diuretic Hormone secretion (SIADH): either directly from the mass being within the lungs or from ectopic release of ADH from tumor cells. SIADH as noted above is a common paraneoplastic syndrome caused by small cell carcinoma (SCC) [5]. (2) Raised levels of atrial natriuretic peptides (ANPs) through ‘persistent natriuresis and inappropriately low aldosterone levels’ [6,7]. (3) Involvement of adrenal or brain through metastases further contributing to the degree of hyponatremia [8]. Hyponatremia in some case reports has been attributed to other causes as well [9].
328
P.M. Kasi / Medical Hypotheses 79 (2012) 327–328
Prevalence Evidence supporting the use of serum sodium as a good screening tool is evidenced by the fact in that some series abnormal serum sodium (defined by Na+ < 130 mmol/L) was seen in about 56.1% of patients with lung cancer [2]. Our review of literature reveals that even though it is fairly prevalent, it is under recognized. Although, hyponatremia has been characteristically associated with small cell lung cancer, clinical studies interestingly show that it is also seen in conjunction with other histopathological types of lung cancer (in some studies even more so than small lung cancer) [2]. Contrary to literature, ‘hyponatremia was mainly associated with adenocarcinoma and to a lesser extent with small cell carcinoma’ in the aforementioned series. In another series of 453 patients with Small Cell Lung Cancer (SCLC): – Plasma Na+ was <125 mEq/L in 47 patients (11%) – 126–135 mEq/L in 151 (33%) and – 255 patients (56%) showed normal values [10]. Other reports talk about hyponatremia in up to a third of patients with SCLC and to varying degrees in NSCLC [7]. Mortality In a study focusing on treatment associated deaths in a total of 1225 (222 small cell and 1003 non-small cell lung cancers), the incidence of chemotherapy associated death correlated with hyponatremia (OR: 45.5, CI: 13.4–154) [11]. Similarly, in 453 patients with SCLC, ‘the median survival was 11.2 months in patients with normal plasma Na+, and 7.1 months in patients with subnormal values (p = 0.0001)’ [6]. Hyponatremia has also been used as part of some prognostic scoring systems and has been shown to be independent predictors of a poor survival [12,13]. Implications It can therefore, be postulated, that the degree of hyponatremia can be correlated with size or aggressiveness of the tumor. If true, then screening high risk individuals with hyponatremia can yield more patients with possible lung cancer and may help decrease the associated costs as compared to imaging from screening everyone with a CT scan. Also of note is that fact that although paraneoplastic syndromes manifest in advanced stages, they do occur early on as well [14]. In some reports, asymptomatic hyponatremia was noted to be the only manifestation of lung cancer [15]. Evaluation of the hypothesis/idea The approach to testing the hypothesis would be to: (a) Either study the databases of cohorts employing the use of computerized tomography (CT) scans and identify how many patients were noted to have hyponatremia on presentation and studying if increases the yield for screening patients for lung cancer. (b) Prospectively follow high risk patients and monitor their serum sodium levels closely (e.g. every 3 months or so); and offer CT scanning if patients’ sodium levels significantly decrease from their baseline. Most of the studies on hyponatremia and lung cancer only mention the metabolic derangement once it was very significant (e.g. <120 mmol/L versus others employing an arbitrary number of <130 mmol/L). Our suggestion would be to study not only just abnormal values of sodium but also those in whom serum sodium levels of
patients were significantly lower than their baseline, i.e. the trend of their serum sodium levels. Outcome here would be to see if this helps in identifying patients with lung cancer early and also help reduce costs by scanning only those who have a derangement of sodium level rather than everyone. (c) Employing sodium level into a scoring system to help identify which patients should get an imaging study. For example, the use of Alvarado scoring system in appendicitis helps guide in which subset of patients should a CT scan be performed. Serum sodium levels and other predictors of lung cancer, e.g. pack years of smoking, symptoms such as cough and weightloss; would be useful to develop and would have major clinical as well as economic implications on the public health level. Conflict of interest statement The author declares that he has no conflict of interest. No sources of funding were used. Access to articles was obtained through the department/university’s library database. Acknowledgement The author is deeply indebted to the Department of Internal Medicine, University of Pittsburgh Medical Center, for their constant support and encouragement. References [1] Ogawara D, Fukuda M, Nakamura Y, Kohno S. Efficacy and safety of amrubicin hydrochloride for treatment of relapsed small cell lung cancer. Cancer Manag Res 2010;2:191–5. [2] Alamoudi OS. Lung cancer at a University Hospital in Saudi Arabia: a four-year prospective study of clinical, pathological, radiological, bronchoscopic, and biochemical parameters. Ann Thorac Med 2010;5(1):30–6. [3] National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365(5):395– 409. [4] Vantyghem MC, Balavoine AS, Wémeau JL, Douillard C. Hyponatremia and antidiuresis syndrome. Ann Endocrinol (Paris) 2011;72(6):500–12 [Epub 2011 Nov 25]. [5] Tantisattamo E, Ng RC. Dual paraneoplastic syndromes: small cell lungcarcinoma-related oncogenic osteomalacia and syndrome of inappropriate antidiuretic hormone secretion: report of a case and review of the literature. Hawaii Med J 2011;70(7):139–43. [6] Radulescu D, Bunea D, Pripon S, Duncea C, Radulescu L. Severe paraneoplastic hyponatremia and hypoosmolality in a patient with small-cell lung carcinoma:syndrome of inappropriate antidiuretic hormone secretion versus atrialnatriuretic peptide or both? Clin Lung Cancer 2007;8(6):392–5. [7] Chute JP, Taylor E, Williams J, Kaye F, Venzon D, Johnson BE. A metabolic study of patients with lung cancer and hyponatremia of malignancy. Clin Cancer Res 2006;12(3 Pt 1):888–96. [8] Yokosuka K, Kawashima T, Okada N, Wakabayashi T, Kawashima S, Kuroda T, et al. Impaired consciousness caused by a metastatic adrenal tumor of pulmonary adenocarcinoma. Intern Med 2008;47(2):109–12. [9] Barton JC, Barton JC, Bertoli LF. Recurrent acute kidney injury associated with metastatic bronchial carcinoid. Am J Med Sci 2012;343(1):106–8. [10] Hansen O, Sørensen P, Hansen KH. The occurrence of hyponatremia in SCLC and the influence on prognosis: a retrospective study of 453 patients treated in a single institution in a 10-year period. Lung Cancer 2010;68(1):111–4. [11] Minami-Shimmyo Y, Ohe Y, Yamamoto S, Sumi M, Nokihara H, Horinouchi H, et al. Risk factors for treatment-related death associated with chemotherapy and thoracic radiotherapy for lung cancer. J Thorac Oncol 2012;7(1):177–82. [12] Jacot W, Colinet B, Bertrand D, Lacombe S, Bozonnat MC, Daurès JP. OncoLR health network. Quality of life and comorbidity score as prognostic determinants in non-small-cell lung cancer patients. Ann Oncol 2008;19(8):1458–64. [13] Kimura T, Kudoh S, Hirata K, Takifuji N, Negoro S, Yoshikawa J. Prognostic factors in elderly patients with unresectable non-small cell lung cancer. Anticancer Res 2001;21(2B):1379–83. [14] Thomas L, Kwok Y, Edelman MJ. Management of paraneoplastic syndromes in lung cancer. Curr Treat Options Oncol 2004;5(1):51–62. [15] Kamoi K, Kurokawa I, Kasai H, Mizusawa A, Ebe T, Sasaki H, et al. Asymptomatic hyponatremia due to inappropriate secretion of antidiuretic hormone as the first sign of a small cell lung cancer in an elderly man. Intern Med 1998;37(11):950–4.
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Proposing the use of hyponatremia as a marker to help identify high risk individuals for lung cancer Pashtoon Murtaza Kasi ⇑ International Scholars Program, Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15213, USA
a r t i c l e
i n f o
Article history: Received 15 March 2012 Accepted 13 May 2012
a b s t r a c t The use of computerized tomography (CT) scans has been recently brought into attention to help screen high risk individuals for lung cancer. Even though they are highly sensitive, their cost seems to be the main hindrance. Our hypothesis is to see if other factors could help identify a subset amongst the high risk individuals. Our focus specifically is on hyponatremia. It is well known that patients with lung cancer can have associated hyponatremia and multiple mechanisms have been put forward. Our hypothesis is that the degree of hyponatremia can be correlated with size or aggressiveness of the tumor and if true, then screening high risk individuals with hyponatremia can yield more patients with possible lung cancer. This, therefore, may help decrease the associated costs as compared to imaging/screening everyone with a CT scan for lung cancer and have a major impact at the public health level. Ó 2012 Elsevier Ltd. All rights reserved.
Background Lung cancer and screening ‘Long-term survival is quite uncommon in refractory small cell lung cancer (SCLC) patients, with less than 25% of patients with limited-stage disease and 1–2% of patients with extensive-stage disease remaining alive at 5 years’ [1]. In another series of 114 patients, metastases were present in 49.1% of patients at presentation [2]. Such numbers highlight the need for screening tools that can help catch the disease early. The use of computerized tomography (CT) scans (more specifically the low-dose CT scans) has been recently brought into attention to help screen high risk individuals for lung cancer and also has been shown to decrease mortality [3]. This argument is supported by the fact that routine chest X-rays (CXR) for surveillance purposes cannot catch nodules or tumors till they are much larger in size and identifying lung cancer early in these individuals may help prevent morbidity, mortality and overall healthcare associated costs. On the other hand, CT scans are not a cheap modality. Even though they are highly sensitive as well as specific to an extent, their cost seems to be the main hindrance and the argument put forward by those against the use of routine CT scans for
Abbreviations: ANP, atrial natriuretic peptide; CI, confidence interval; CT, computerized tomography; OR, odds ratio; Na+, sodium; NSCLC, non small cell lung cancer; SIADH, syndrome of inappropriate anti diuretic hormone secretion; SCLC, small cell lung cancer. ⇑ Tel.: +1 412 897 2301. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2012.05.023
surveillance in these individuals. Insurance agencies currently would not approve the use of CT scans as a surveillance strategy for lung cancer in patients with a significant smoking history. Our hypothesis is to see if other factors could be brought into the equation to further identify a subset amongst the high risk individuals (essentially smokers). The specific factor that that we think may be very useful in helping identify individuals with lung cancer is serum sodium levels/hyponatremia. Hyponatremia and lung cancer Serum sodium levels are very cheap and are essentially part of any basic or comprehensive metabolic panel. It is well known that patients with lung cancer can have associated hyponatremia (more common with small cell lung cancer) [4]. The mechanisms put forward for hyponatremia are outlined as follows: (1) Syndrome of Inappropriate Anti Diuretic Hormone secretion (SIADH): either directly from the mass being within the lungs or from ectopic release of ADH from tumor cells. SIADH as noted above is a common paraneoplastic syndrome caused by small cell carcinoma (SCC) [5]. (2) Raised levels of atrial natriuretic peptides (ANPs) through ‘persistent natriuresis and inappropriately low aldosterone levels’ [6,7]. (3) Involvement of adrenal or brain through metastases further contributing to the degree of hyponatremia [8]. Hyponatremia in some case reports has been attributed to other causes as well [9].
328
P.M. Kasi / Medical Hypotheses 79 (2012) 327–328
Prevalence Evidence supporting the use of serum sodium as a good screening tool is evidenced by the fact in that some series abnormal serum sodium (defined by Na+ < 130 mmol/L) was seen in about 56.1% of patients with lung cancer [2]. Our review of literature reveals that even though it is fairly prevalent, it is under recognized. Although, hyponatremia has been characteristically associated with small cell lung cancer, clinical studies interestingly show that it is also seen in conjunction with other histopathological types of lung cancer (in some studies even more so than small lung cancer) [2]. Contrary to literature, ‘hyponatremia was mainly associated with adenocarcinoma and to a lesser extent with small cell carcinoma’ in the aforementioned series. In another series of 453 patients with Small Cell Lung Cancer (SCLC): – Plasma Na+ was <125 mEq/L in 47 patients (11%) – 126–135 mEq/L in 151 (33%) and – 255 patients (56%) showed normal values [10]. Other reports talk about hyponatremia in up to a third of patients with SCLC and to varying degrees in NSCLC [7]. Mortality In a study focusing on treatment associated deaths in a total of 1225 (222 small cell and 1003 non-small cell lung cancers), the incidence of chemotherapy associated death correlated with hyponatremia (OR: 45.5, CI: 13.4–154) [11]. Similarly, in 453 patients with SCLC, ‘the median survival was 11.2 months in patients with normal plasma Na+, and 7.1 months in patients with subnormal values (p = 0.0001)’ [6]. Hyponatremia has also been used as part of some prognostic scoring systems and has been shown to be independent predictors of a poor survival [12,13]. Implications It can therefore, be postulated, that the degree of hyponatremia can be correlated with size or aggressiveness of the tumor. If true, then screening high risk individuals with hyponatremia can yield more patients with possible lung cancer and may help decrease the associated costs as compared to imaging from screening everyone with a CT scan. Also of note is that fact that although paraneoplastic syndromes manifest in advanced stages, they do occur early on as well [14]. In some reports, asymptomatic hyponatremia was noted to be the only manifestation of lung cancer [15]. Evaluation of the hypothesis/idea The approach to testing the hypothesis would be to: (a) Either study the databases of cohorts employing the use of computerized tomography (CT) scans and identify how many patients were noted to have hyponatremia on presentation and studying if increases the yield for screening patients for lung cancer. (b) Prospectively follow high risk patients and monitor their serum sodium levels closely (e.g. every 3 months or so); and offer CT scanning if patients’ sodium levels significantly decrease from their baseline. Most of the studies on hyponatremia and lung cancer only mention the metabolic derangement once it was very significant (e.g. <120 mmol/L versus others employing an arbitrary number of <130 mmol/L). Our suggestion would be to study not only just abnormal values of sodium but also those in whom serum sodium levels of
patients were significantly lower than their baseline, i.e. the trend of their serum sodium levels. Outcome here would be to see if this helps in identifying patients with lung cancer early and also help reduce costs by scanning only those who have a derangement of sodium level rather than everyone. (c) Employing sodium level into a scoring system to help identify which patients should get an imaging study. For example, the use of Alvarado scoring system in appendicitis helps guide in which subset of patients should a CT scan be performed. Serum sodium levels and other predictors of lung cancer, e.g. pack years of smoking, symptoms such as cough and weightloss; would be useful to develop and would have major clinical as well as economic implications on the public health level. Conflict of interest statement The author declares that he has no conflict of interest. No sources of funding were used. Access to articles was obtained through the department/university’s library database. Acknowledgement The author is deeply indebted to the Department of Internal Medicine, University of Pittsburgh Medical Center, for their constant support and encouragement. References [1] Ogawara D, Fukuda M, Nakamura Y, Kohno S. Efficacy and safety of amrubicin hydrochloride for treatment of relapsed small cell lung cancer. Cancer Manag Res 2010;2:191–5. [2] Alamoudi OS. Lung cancer at a University Hospital in Saudi Arabia: a four-year prospective study of clinical, pathological, radiological, bronchoscopic, and biochemical parameters. Ann Thorac Med 2010;5(1):30–6. [3] National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365(5):395– 409. [4] Vantyghem MC, Balavoine AS, Wémeau JL, Douillard C. Hyponatremia and antidiuresis syndrome. Ann Endocrinol (Paris) 2011;72(6):500–12 [Epub 2011 Nov 25]. [5] Tantisattamo E, Ng RC. Dual paraneoplastic syndromes: small cell lungcarcinoma-related oncogenic osteomalacia and syndrome of inappropriate antidiuretic hormone secretion: report of a case and review of the literature. Hawaii Med J 2011;70(7):139–43. [6] Radulescu D, Bunea D, Pripon S, Duncea C, Radulescu L. Severe paraneoplastic hyponatremia and hypoosmolality in a patient with small-cell lung carcinoma:syndrome of inappropriate antidiuretic hormone secretion versus atrialnatriuretic peptide or both? Clin Lung Cancer 2007;8(6):392–5. [7] Chute JP, Taylor E, Williams J, Kaye F, Venzon D, Johnson BE. A metabolic study of patients with lung cancer and hyponatremia of malignancy. Clin Cancer Res 2006;12(3 Pt 1):888–96. [8] Yokosuka K, Kawashima T, Okada N, Wakabayashi T, Kawashima S, Kuroda T, et al. Impaired consciousness caused by a metastatic adrenal tumor of pulmonary adenocarcinoma. Intern Med 2008;47(2):109–12. [9] Barton JC, Barton JC, Bertoli LF. Recurrent acute kidney injury associated with metastatic bronchial carcinoid. Am J Med Sci 2012;343(1):106–8. [10] Hansen O, Sørensen P, Hansen KH. The occurrence of hyponatremia in SCLC and the influence on prognosis: a retrospective study of 453 patients treated in a single institution in a 10-year period. Lung Cancer 2010;68(1):111–4. [11] Minami-Shimmyo Y, Ohe Y, Yamamoto S, Sumi M, Nokihara H, Horinouchi H, et al. Risk factors for treatment-related death associated with chemotherapy and thoracic radiotherapy for lung cancer. J Thorac Oncol 2012;7(1):177–82. [12] Jacot W, Colinet B, Bertrand D, Lacombe S, Bozonnat MC, Daurès JP. OncoLR health network. Quality of life and comorbidity score as prognostic determinants in non-small-cell lung cancer patients. Ann Oncol 2008;19(8):1458–64. [13] Kimura T, Kudoh S, Hirata K, Takifuji N, Negoro S, Yoshikawa J. Prognostic factors in elderly patients with unresectable non-small cell lung cancer. Anticancer Res 2001;21(2B):1379–83. [14] Thomas L, Kwok Y, Edelman MJ. Management of paraneoplastic syndromes in lung cancer. Curr Treat Options Oncol 2004;5(1):51–62. [15] Kamoi K, Kurokawa I, Kasai H, Mizusawa A, Ebe T, Sasaki H, et al. Asymptomatic hyponatremia due to inappropriate secretion of antidiuretic hormone as the first sign of a small cell lung cancer in an elderly man. Intern Med 1998;37(11):950–4.