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ORIGINAL ARTICLE
Year : 2015  |  Volume : 11  |  Issue : 8  |  Page : 275-279

Clinical analysis of 64 patients with lung-cancer-associated hypercalcemia


Department of Oncology, Beijing Hospital, Beijing 100730, China

Date of Web Publication26-Nov-2015

Correspondence Address:
Bin Ai
Department of Oncology, Beijing Hospital, Beijing 100730
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.170539

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 > Abstract 

Objective: This study investigated the factors influencing survival time of patients with lung-cancer-associated hypercalcemia.
Data and Methods: A total of 64 pathologically confirmed patients with Stage IV lung-cancer-associated hypercalcemia were enrolled from Beijing Hospitals between August 2010 and July 2015. Clinical materials included patients' gender, age, pathological type, highest albumin-corrected calcium level, serum alkaline phosphatase level, creatinine clearance rate, organ (bone, liver, brain, and adrenal gland) metastasis, number of distal metastatic sites, and survival time after diagnosis of hypercalcemia. Univariate and multivariate analyses were performed to screen the risk factors affecting patients' survival.
Results: Albumin-corrected calcium levels of the 64 patients ranged from 2.56 to 4.57 mmol/L, and the median value was 2.76 mmol/L. Survival time after diagnosis of hypercalcemia varied from 1 to 1340 days, and the median survival time was 104 days. Univariate analysis showed that gender, age (>60-year-old), albumin-corrected calcium levels, elevation of alkaline phosphatases, brain metastasis, and number of distal metastatic sites were predictors for poor survival (P = 0.026, P = 0.022, P < 0.001, P = 0.043, P = 0.041, P = 0.003). In Cox proportional hazard model analysis, corrected hypercalcemia levels and alkaline phosphatase levels were determined to be risk factors affecting patients' survival time (hazard ratio [HR] = 6.828, P = 0.000; HR = 1.957, P = 0.026).
Conclusions: Patients with Stage IV lung-cancer-associated moderate and severe hypercalcemia exhibited shorter survival time and poor prognosis. After correction, moderate and severe elevations of hypercalcemia and abnormal elevation of alkaline phosphatase levels were shown to be significant factors shortening patients' survival time.

Keywords: Hypercalcemia, lung cancer, survival time


How to cite this article:
Li X, Bie Z, Zhang Z, Li Y, Hu X, Liu W, Zhang S, Cheng G, Ai B. Clinical analysis of 64 patients with lung-cancer-associated hypercalcemia. J Can Res Ther 2015;11, Suppl S4:275-9

How to cite this URL:
Li X, Bie Z, Zhang Z, Li Y, Hu X, Liu W, Zhang S, Cheng G, Ai B. Clinical analysis of 64 patients with lung-cancer-associated hypercalcemia. J Can Res Ther [serial online] 2015 [cited 2020 Aug 10];11:275-9. Available from: http://www.cancerjournal.net/text.asp?2015/11/8/275/170539


 > Introduction Top


Nearly 20–30% of patients with malignant hypercalcemia will suffer from hypercalcemia at some time during the disease,[1],[2],[3],[4] which is a common complication of cancer. Patients with hypercalcemia exhibit poor prognosis, and hypercalcemia mostly affected patients in progressive stages and shortened survival times.[5] Hypercalcemia may produce many nonspecific symptoms, and severe hypercalcemia can lead to coma and aggravate renal damage. Hypercalcemia can be associated with any malignant tumor but is more common in lung cancer, breast cancer, and multiple myeloma. In the present study, clinical materials were collected from 64 patients with lung-cancer-associated hypercalcemia in Beijing hospitals from January 2001 to December 2011 to investigate the influence of various factors on prognosis and survival time of patients with different calcium levels.


 > Data and Methods Top


Clinical data

To retrospectively analyze the clinical materials of 64 patients with lung-cancer-associated hypercalcemia in Beijing hospitals from August 2010 to July 2015, the following were used as inclusion criteria: Pathological diagnosis of lung cancer and hypercalcemia level in clinical Stage IV: According to references, calcium level >2.54 mmol/L (10.2 mg/dl).[6] To correct serum albumin levels below 40 mg/d, the following correction formula was used: Corrected calcium (mmol/L) = measured calcium (mmol/L) + (40− serum albumin mg/dl) ×0.02.[7] Patients' gender, age, pathological type, corrected calcium maximum value in the course of disease, serum alkaline phosphatase level, creatinine clearance rate, organ (bone, liver, brain, and adrenal gland) metastasis, number of distal metastatic sites, and time of death after diagnosis of hypercalcemia were recorded. Serum creatinine clearance rate was calculated using Cockcroft–Gault formula as follows: Creatinine clearance rate = (140− age) × weight/72 × serum creatinine (mg/dl) (*0.85 if female patients). Primary endpoint was survival time after diagnosis of hypercalcemia. In retrospective analysis, the last follow-up deadline was July 01, 2015.

Statistical processing

Statistical analysis was performed using SPSS version 17 (IBM Corp., Chicago, USA). Univariate analysis was conducted first. Afterward, a stepwise selection method was used to conduct multivariate Cox regressive analysis of related factors that can affect survival time with inclusion criteria of influence factors set at 0.05 and exclusion level at 0.1. A value of P < 0.05 showed that the difference was statistically significant. In survival analysis, log-rank test was used to create Kaplan–Meier survival curves.


 > Results Top


Clinical data

Maximum blood calcium density ranged from 2.56 to 4.41 mmol/L among the 64 patients. Serum albumin below 50 mg/dl should be corrected, and 46 patients needed correction (71.9%). Albumin-corrected calcium levels ranged from 2.56 to 4.57 mmol/L, with median value at 2.76 mmol/L. Mild elevation was observed in 46 cases, moderate elevation in 10 cases, and severe elevation in 8 cases. In terms of blood calcium level, hypercalcemia can be divided into the following three types: Mild elevation (blood calcium density ranged from 2.55 to 3.0 mmol/L), moderate elevation (3.0 to 3.4 mmol/L), and severe elevation (>3.4 mmol/L).[8],[9] A total of 43 patients were male and 21 were female. Age ranged from 37 to 90 years, and the median age was 67 years with 46 patients over 60-year-old (73%). Twenty-two cases of adenocarcinoma (34%), 30 cases of nonadenocarcinoma (47%), and 12 cases of small cell carcinoma (19%) were recorded. Twenty-six cases of abnormally elevated alkaline phosphatase (41%) were observed. Thirty-six cases with serum creatinine clearance below normal value (56%), 29 cases of bone metastases of (45%), 21 cases of liver metastasis (33%), 15 cases of brain metastasis (23%), and 9 cases of adrenal metastasis (14%) were also recorded. In terms of the number of organ metastasis sites, 17 cases exhibited 1 metastasis site, 19 cases showed 2, and 27 cases showed more than 3.

Survival time after hypercalcemia

Mild elevation of blood calcium was recorded in 64 cases (71.8%), moderate elevation in 10 cases (15.7%), and severe elevation in 8 cases (12.5%). After hypercalcemia, survival time ranged from 1 to 1340 days, and the median survival time was 104 days. After mild, moderate, and severe elevation, the median survival time was 186, 14, and 10 days, respectively [Figure 1] and Table 1].
Figure 1: Survival in 64 lung cancer patients complicated with malignancy-associated hypercalcemia

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Table 1: The median survival time of 64 lung cancer patients complicated with malignancy-associated hypercalcemia according to the albumin-corrected calcium level

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Analysis of prognostic factors

Univariate analysis of gender, age, pathological type, blood calcium maximum value after correction, serum alkaline phosphatase level, creatinine clearance rate, and organ (bone, liver, brain, adrenal gland) metastasis showed a total of 11 organ metastasis sites that can potentially affect patients' survival time [Table 2]. Males showed poorer prognosis than females (median survival time was 90 days vs. 225 days, P = 0.026). Patients at or over 60-year-old exhibited poorer prognosis than patients <60-year-old (median survival time was 66 days vs. 246 days, P = 0.022). After correction, patients with moderate and severe elevations of blood calcium showed poorer prognosis than patients with mild elevation (median survival time was 14 days vs. 186 days, P < 0.001). Patients with abnormal elevation of serum alkaline phosphatase exhibited poorer prognosis than patients with normal elevation (median survival time was 36 days vs. 182 days, P = 0.043). Patients with brain metastasis exhibited poorer prognosis (median survival time was 66 days vs. 135 days, P = 0.041). Higher number of organs transferred also translated to poorer prognosis (median survival time was 562 days vs. 58 days, P = 0.003) [Table 2]. Univariate analyses of factors influencing survival time of patients with lung-cancer-associated hypercalcemia. Six potential influencing factors were subjected to Cox proportional hazards model. Stepwise screening method was used to perform multivariate analysis, and the results showed that the maximum values of blood calcium after correction (mild, moderate, and severe elevations) and serum alkaline phosphatase levels (normal and abnormal) were found to be the risk factors affecting the survival time of hypercalcemia patients (hazard ratio [HR] = 6.828, P = 6.828; HR = 1.957, P = 0.026) [Table 3]. Through stratification according to the abovementioned factors and construction of survival curves, the results indicated that the survival curves did not cross for patients with different levels of various factors, which confirmed that the two abovementioned factors satisfied the premise of the Cox proportional hazards model and verified the correctness of Cox regression analysis.
Table 2: Cox univariate analysis of the prognostic factors for median survival time of the 64 lung cancer patients complicated with malignancy-associated hypercalcemia

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Table 3: Cox multivariate analysis of the prognostic factors of the 64 lung cancer patients complicated with malignancy-associated hypercalcemia

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 > Discussion Top


For hypercalcemia, serum calcium ion concentration abnormally elevated over 2.54 mmo1/L (10.2 mg/dl).[6] Given that the levels of serum calcium ion are usually measured, and serum total calcium levels will change because of the changes of the serum albumin level, the blood calcium level should be corrected using the correction formula (corrected calcium value [mmol/L] = total serum calcium measurement value [mmol/L] + [40− serum albumin measurement value] × 0.02 mmol/L)[7] when the serum albumin level is <40 g/L. The present study included a total of 64 patients, in which 46 patients needed to be corrected (71.9%), and blood calcium values after correction were higher than the actual measured values, indicating that for patients with Stage IV tumor, most of the serum albumin levels were lower than 40 mg/dL in various cases. To obtain more accurate values, correction must be conducted using the abovementioned conditions to avoid ignoring patients with seemingly normal but abnormal elevation of blood calcium after correction. Although patients with mild hypercalcemia may not show symptoms, moderate and severe hypercalcemia can cause a series of symptoms, such as correlated nerve mental symptoms, which can gradually deteriorate with the aggravation of hypercalcemia and may also affect the kidneys and the cardiovascular system.

Tumor-associated hypercalcemia can be divided into three types, namely, partial soluble osseous hypercalcemia, which is a type of cancer causing increase of bone destruction absorption and is the most common condition in multiple myeloma and breast cancer; glucocorticoid-induced hypercalcemia, which refers to the increase in malignant tumor-causing parathyroid-related protein (PTHrP) secretion (PTHrP can increase bone absorption and reduce kidney calcium excretion); and PTHrP-mediated glucocorticoid-induced hypercalcemia, which is common in squamous-cell carcinomas, including lung squamous carcinoma, head and neck squamous-cell carcinomas, and esophageal squamous-cell carcinomas. Other types of lymphoma can secrete 1, 25-2 hydroxyl Vitamin D (1, 25 [OH]2D) and increase bone resorption and intestinal absorption of calcium. Ectopic parathyroid hormone secretion is also a rare cause of hypercalcemia. Furthermore, several tumors secrete cytokines, such as interleukin-1 (IL-1), IL-6, transforming growth factors-β, and tumor necrosis factor-α to cause hypercalcemia.[5],[10]

Tumor-associated hypercalcemia exhibits poorer prognosis, and approximately 50% of patients died within 30 days.[5] In the present study, the overall median survival time was 104 days, mildly elevated blood calcium median survival time was 186 days, and severely elevated blood calcium median survival time was only 14 days. Mild elevation showed no significant effect on survival time, but moderate and severe elevations seriously shortened the survival time of patients (P < 0.001), which represents a life-threatening complication needing active treatment.

Univariate Cox regression analysis showed that gender, age, blood calcium level after correction, alkaline phosphatase level, existence of brain metastases, and number of organ metastasis influenced the survival time of patients. In this study, 73% of the patients were over 60-year-old, and univariate analysis indicated that patients equal to or over 60-year-old showed statistically significant poorer prognosis than those <60-year-old, with median survival time of 66 days versus 246 days, respectively (P = 0.022). The obtained results may be explained by the fact that patients over 60-year-old exhibited more basic diseases compared with younger patients. In particular, the main visceral organ function of patients over 60-year-old is easier to be affected compared with younger patients when suffering from hypercalcemia, which is also the reason for shorter survival time. In the present study, bone metastasis showed no clear effect on survival time (median survival time was 55 days vs. 182 days, P = 0.026), which also indirectly showed that lung-cancer-associated hypercalcemia is not only related to bone metastases. Lung cancer hypercalcemia can be caused by various mechanisms, such as cancer leading to an increased secretion of PTHrP, which is also an important consideration, especially in lung squamous carcinoma. In the present study, patients with abnormal elevation of serum alkaline phosphatase showed poorer prognosis than those with normal elevation (median survival time was 36 days vs. 182 days, P = 0.043). Alkaline phosphatase level was observed to be closely related to bone destruction; therefore, abnormal elevation is a better indicator of existence of bone destruction than bone metastasis, and future studies must focus more on this research area. In the present study, patients with brain metastases exhibited poorer prognosis (66 days vs. 135 days, P = 0.041), and brain metastasis-associated hypercalcemia may worsen nerve mental symptoms, leading to rapid deterioration and death. The results also suggested that patients with more organ metastasis showed poorer prognosis, and the median times in 1, 2, and equal to or over 3 metastasis sites were 562, 58, and 42 days, respectively (P = 0.003); the number of organ metastasis indirectly indicated tumor load and tumor progression. Thus, survival time of patients with organ metastasis number equal to or over 2 was significantly shortened. Recent studies suggest that tumor hypercalcemia is found in patients with squamous-cell carcinomas.[11],[12],[13] In the present study, patients with nonadenocarcinoma accounted for 47% of the total number, which is significantly higher than those with adenocarcinoma and small cell carcinoma, thereby providing evidence that patients with adenocarcinoma were more likely to suffer from hypercalcemia. Univariate analysis indicated that patients with small-cell lung cancer showed the shortest survival periods, and those with no adenocarcinoma exhibited the longest survival times (52 days vs. 90 days vs. 132 days, respectively); however, the difference was not statistically significant (P = 0.32). Multivariate Cox regression analysis of the six potential factors affecting survival time showed that blood calcium and serum alkaline phosphatase levels after correction significantly influenced the survival time of patients (HR = 6.828, P = 6.828; HR = 1.957, P = 0.026).

In recent years, some studies have investigated the prognosis of tumor-associated hypercalcemia in China. However, the number of reports on lung-cancer-associated hypercalcemia has been decreasing, and the number of cases is limited. Research objectives are limited to patients with Stage IV lung cancer, and the number of clinical cases was relatively higher. Certain limitations to retrospective analysis exist, but based on research of relative single disease and relatively more cases, the present study exhibits certain reference value for clinical treatment and prognosis of lung-cancer-associated hypercalcemia.


 > Summary Top


Lung-cancer-associated hypercalcemia shows low incidence rate but poor prognosis. Patients with lung-cancer-associated moderate and severe elevations of blood calcium exhibit the poorest prognosis with median survival time of only 14 days, and patients with abnormal elevation of serum alkaline phosphatase show poorer prognosis than those with normal elevation. Therefore, for patients with moderate and severe elevations of blood calcium and abnormal elevation of serum alkaline phosphatase, early treatments, such as reduction of blood calcium, should be actively taken. Changes in the disease condition must be closely observed, and blood calcium levels should be monitored to improve the survival time of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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Horwitz MJ, Stewart AF. Humoral hypercalcemia of malignancy. In: Favus MF, editor. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. Washington, D.C: American Society for Bone and Mineral Research; 2003. p. 246-50.  Back to cited text no. 2
    
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Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350:1655-64.  Back to cited text no. 3
    
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Clines GA, Guise TA. Hypercalcemia in hematologic malignancies and in solid tumors associated with extensive localized bone destruction. In: Favus MJ, editor. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. Washington, D.C: American Society for Bone and Mineral Research; 2003. p. 251-6.  Back to cited text no. 4
    
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Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 2005;352:373-9.  Back to cited text no. 5
    
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Hiraki A, Ueoka H, Takata I, Gemba K, Bessho A, Segawa Y, et al. Hypercalcemia-leukocytosis syndrome associated with lung cancer. Lung Cancer 2004;43:301-7.  Back to cited text no. 6
    
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Zhang J, Wang H, Tian W, He Q, Zhu M. Brown tumor of the rib as a first presentation of primary hyperparathyroidism: Report of three cases and literature review. Thorac Cancer 2013;4:474-8.  Back to cited text no. 7
    
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Ye W, Yang Y, Wang J, Kadziola Z, Rajan N, Qin S. Prognostic factors for patients with advanced non-small cell lung cancer treated with gemcitabine-platinum as first-line therapy in an observational setting in China. Thorac Cancer 2014;5:319-24.  Back to cited text no. 8
    
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Bedard G, Zeng L, Poon M, Lam H, Lauzon N, Chow E. Comparison of the EORTC QLQ-BM22 and the BOMET-QOL quality of life questionnaires in patients with bone metastases. Asia-Pacific Journal of Clinical Oncology 2014;10:118-23.   Back to cited text no. 9
    
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Santarpia L, Koch CA, Sarlis NJ. Hypercalcemia in cancer patients: Pathobiology and management. Horm Metab Res 2010;42:153-64.  Back to cited text no. 10
    
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Iwase M, Takemi T, Manabe M, Nagumo M. Hypercalcemic complication in patients with oral squamous cell carcinoma. Int J Oral Maxillofac Surg 2003;32:174-80.  Back to cited text no. 11
    
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Bradley PJ, Hoskin D. Hyercalcaemia in head and neck squamous cell carcinoma. Curr Opin Otolaryngol Head Neck Surg 2006;14:51-4.  Back to cited text no. 12
    
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Kato N, Yasukawa K, Onozuka T, Kimura K. Paraneoplastic syndromes of leukocytosis, thrombocytosis, and hypercalcemia associated with squamous cell carcinoma. J Dermatol 1999;26:352-8.  Back to cited text no. 13
    


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    Tables

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