J Cancer Res Clin Oncol (2013) 139:2117–2123 DOI 10.1007/s00432-013-1523-0
ORIGINAL PAPER
Prognostic nutritional index predicts outcomes of malignant pleural mesothelioma Zhou-Hong Yao • Guang-Yan Tian • Yun-Yan Wan • Yan-Meng Kang • Hai-Sheng Guo Qing-Hua Liu • Dian-Jie Lin
•
Received: 22 June 2013 / Accepted: 6 September 2013 / Published online: 23 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose Nutritional status has been associated with longtime outcomes in cancer patients. We investigated whether the prognostic nutritional index (PNI), an indicator of nutritional status, affects overall survival in patients with malignant pleural mesothelioma (MPM). Methods We enrolled 121 patients with histologically confirmed MPM, who had successfully undergone biopsy by medical thoracoscopy in this study. Demographic, clinical and laboratory data were collected retrospectively. The PNI was calculated as 109 serum albumin value (g/ dl) ? 0.005 9 total lymphocyte count (per mm3) in peripheral blood. Univariate and multivariate analyses were used to identify prognostic factors.
Results Mean pretreatment PNI was 44.6. PNI was significantly associated with age (P = 0.031), smoking habits (P = 0.039) and weight loss (P = 0.029). Survival analysis showed PNI to be an independent prognostic factor in MPM. Patients with lower PNIs (PNI \ 44.6) had greater risk of death than those with higher PNIs (PNI C 44.6; hazard ratio: 2.290; 95 % confidence interval: 1.415–3.706; P = 0.001). These analyses were adjusted for patient age, gender, smoking habits, dyspnea, chest pain, weight loss, primary site of tumor, histology, platinum-based systemic chemotherapy, hospital and stage. Conclusions Pretreatment PNI is a novel independent prognostic factor in MPM. Keywords Prognostic nutritional index Malignant pleural mesothelioma Survival Prognosis
Z.-H. Yao Y.-Y. Wan Q.-H. Liu (&) D.-J. Lin (&) Department of Respiratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, No. 324 Jingwuweiqi Road, Jinan 250021, Shandong Province, People’s Republic of China e-mail: [email protected] D.-J. Lin e-mail: [email protected] G.-Y. Tian Department of Neurology, Jinan Children’s Hospital, Jinan 250021, Shandong Province, People’s Republic of China Y.-M. Kang Department of Respiratory Medicine, Shandong Provincial Qianfoshan Hospital, Jinan 250021, Shandong Province, People’s Republic of China H.-S. Guo Department of Respiratory Medicine, Dongying People’s Hospital, Dongying 257000, Shandong Province, People’s Republic of China
Introduction Malignant pleural mesothelioma (MPM) is an asbestosrelated fatal malignancy, the incidence of which is still expected to increase over the next few decades because of its long latency period (20–40 years), although world-wide use of asbestos has decreased in recent decades (Hodgson et al. 2005). Although detection and therapeutic technologies have improved greatly, MPM remains difficult to treat, and standard therapies are still in flux. Though some authors suggest that antifolate agents and trimodality therapy (surgery, radiotherapy and chemotherapy) can improve the survival of MPM patients (Vogelzang et al. 2003; de Perrot et al. 2009), overall survival (OS) for MPM is still poor, with median OS at approximately 12 months (van Meerbeeck et al. 2005). Therefore, accurately predicting the prognosis of MPM patients is important in improving their survival.
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Nutritional condition and immunological status are important both in avoiding postoperative complication and in improving long-term outcomes of patients with malignant cancers (Nozoe et al. 2002; Morgan et al. 2011; Benizri et al. 2013; Ray-Coquard et al. 2009). The prognostic nutritional index (PNI), which is calculated by combining the serum albumin concentration with total peripheral blood lymphocyte count, was initially used to assess immune-nutritional status of patients who underwent gastrointestinal surgery (Onodera et al. 1984). Recently, lower PNI has been shown to be a prognostic marker in patients with various carcinomas including esophageal (Nozoe et al. 2002), colorectal (Nozoe et al. 2012), liver (Pinato et al. 2012), pancreas (Kanda et al. 2011) and stomach (Migita et al. 2013) cancers. A large recent study has shown that PNI could predict prognosis in malignancy regardless of the site of origin (Proctor et al. 2011). However, to our knowledge, PNI has not been investigated in MPM patients. Therefore, we retrospectively studied the relationship between PNI and clinicopathological characteristics and OS in MPM patients.
Materials and methods Patients This study enlisted 134 consecutive patients diagnosed with MPM who underwent biopsy by medical thoracoscopy in three hospitals (Shandong Provincial Hospital Affiliated to Shandong University, Qilu Hospital and Shandong Provincial Chest Hospital, China) from October 2001 to January 2013. All patients were newly confirmed to have MPM and had not yet received treatment. Patients with previous or coexisting cancers other than MPM and those with insufficient laboratory data were excluded from this study, leaving a total of 121 subjects. Their histological diagnoses were based on 2004 World Health Organization (WHO) classification criteria for pleural tumors (Travis et al. 2004). MPM staging was based on the International Mesothelioma Interest Group (IMIG) guidelines (Rusch 1995). All patients provided informed consent prior to this study. The Ethics Committee of Shandong University approved the study protocol. All patients were followed up until May 31, 2013, or death.
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methods, and pathological stage. Each patient had a clinical thoracic computed tomography examination (CT) before biopsy. Abdominal ultrasound, cranial CT, magnetic resonance imaging and emission CT were carried out when necessary. A total of 62 patients (51.2 %) received platinumbased systemic chemotherapy for at least two cycles. These included pemetrexed ? cisplatin/carboplatin in 44 patients; gemcitabine ? cisplatin/carboplatin in 6 patients; docetaxel ? cisplatin in 6 patients; mitomycin ? vindesine ? cisplatin in 2 patients; cyclophosphamide ? doxorubicin ? cisplatin in 2 patients; mitomycin ? cisplatin ? 5-fluorouracil in 1 patient; and vinorelbine ? cisplatin in 1 patient. All of the remaining 59 patients accepted nonsystemic chemotherapy. These included best supportive care in 47 patients; local cisplatin in thoracic cavity in 7 patients; and radiotherapy in 5 patients. Stages I–II and stages III–IV were grouped together. Nutritional and immunological assessment We obtained data from pretreatment blood tests, including serum albumin and total peripheral lymphocyte count from the patients’ medical records. PNI was then calculated with the following formula: 109 serum albumin value (g/ dl) ? 0.005 9 peripheral lymphocyte count (per mm3), according to a previous study (Migita et al. 2013). Statistical analysis The OS was calculated as the time from the date of the biopsy through medical thoracoscopy to that of death or last followup. Patients who were still alive or lost to follow-up were censored at final follow-up. Statistical analysis was carried out using SPSS 19.0 statistical software (SPSS Inc., Chicago, IL, USA). Continuous variables with normal distribution were described as means and standard deviations (SD). Means were compared using t test, t0 test or F test. The Kaplan–Meier method was used to calculate survival curves. The log-rank test was used to analyze statistical significance. The proportional hazard (PH) assumption for all variables was tested using time-dependent Cox model. The timedependent Cox model was carried out to identify independent prognostic factors, while the PH assumption was violated. P \ 0.05 was considered significant. Confidence intervals (CI) were calculated at 95 %.
Data Results The clinical characteristics of patients in our study were collected retrospectively from medical records and evaluated as prognostic factors. These data included the patient’s age, gender, smoking habits, chest pain, dyspnea, sudden weight loss, primary site of MPM, histology type, therapeutic
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Characteristics of patients A total of 121 patients were analyzed in this study (Table 1). The median age for the patients was 57 (range:
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Table 1 Relationship between the clinicopathological characteristics and the PNI Variables
N (%)
PNI
P value
\57
57 (47.1)
45.9 ± 5.7
0.031
C57
64 (52.9)
43.4 ± 6.6
Male
65 (53.7)
43.8 ± 6.3
Female
56 (46.3)
45.5 ± 6.2
75 (62.0)
45.5 ± 5.7
46 (38.0)
43.0 ± 6.9
No
62 (51.2)
44.0 ± 6.7
Yes
59 (48.8)
45.1 ± 5.8
No
29 (24.0)
45.5 ± 6.7
Yes
92 (76.0)
44.3 ± 6.2
No
86 (71.1)
45.4 ± 5.9
Yes
35 (28.9)
42.6 ± 6.9
Performed
62 (51.2)
45.0 ± 6.1
Not performed
59 (48.8)
44.1 ± 6.5
75 (62.0)
45.2 ± 5.4
46 (38.0)
43.6 ± 7.5
Age (years)
Gender
Smoking habits No Yes
0.151
platinum-based systemic chemotherapy and 59 (48.8 %) nonsystemic chemotherapy (see ‘‘Materials and methods’’ section for details). By the 2004 WHO classification criteria for pleural tumor, 62 % (75/121) of the tumors were epithelioid cell type and 38 % (46/121) nonepithelioid cell type. By IMIG guidelines, 72 patients (59.5 %) were classified as stages I–II and 49 patients (40.5 %) as stages III–IV. A total of 70 patients (57.8 %) were diagnosed in Shandong Provincial Hospital Affiliated to Shandong University, 18 patients (14.9 %) in Qilu Hospital and 33 patients (27.3 %) in Shandong Provincial Chest Hospital.
0.039*
PNI and characteristics of patients
Chest pain 0.354
Dyspnea 0.360
Weight loss 0.029
PBSC
Histology Epithelioid Nonepithelioid
0.420
0.218*
PNI value and survival
IMIG stage I–II
72 (59.5)
44.4 ± 6.0
III–IV
49 (40.5)
44.8 ± 6.8
Right
67 (55.4)
44.1 ± 6.2
Left
54 (44.6)
45.1 ± 6.5
Hospital 1
70 (57.8)
44.5 ± 6.1
Hospital 2
18 (14.9)
45.2 ± 6.3
Hospital 3
33 (27.3)
44.3 ± 6.9
0.773
Primary site of tumor 0.365
Hospital 0.876#
PNI prognostic nutritional index, PBSC platinum-based systemic chemotherapy, IMIG International Mesothelioma Interest Group, Hospital 1 Shandong Provincial Hospital Affiliated to Shandong University, Hospital 2 Qilu Hospital, Hospital 3 Shandong Provincial Chest Hospital * t’ test,
#
Mean PNI before treatment was 44.6 (SD = 6.3). PNI was significantly associated with age, smoking habits and weight loss (Table 1). Mean PNI in patients aged C57 years old was significantly lower than in patients aged \57 years old (43.4 vs. 45.9, P = 0.031). Mean PNI was lower in smokers than in nonsmokers (43.0 vs. 45.5, P = 0.039). Mean PNI significantly differed in patients who presented with weight loss at diagnosis compared with patients who had maintained their weight (42.6 vs. 45.4, P = 0.029). No relation was observed between PNI and gender, chest pain, dyspnea, platinum-based systemic chemotherapy, histological type, IMIG stage, hospital, or primary site of tumor (P [ 0.05).
F test
18–81) years old. Patients comprised 65 males (53.7 %) and 56 females (46.3 %; male/female ratio: 1/0.86). A total of 46 patients (38 %) smoked. Main symptoms were dyspnea (76 %), chest pain (48.8 %) and weight loss (28.9 %). Among these patients, 55.4 % (67/121) patients had a primary tumor site in right thoracic cavity and 44.6 % in left. A total of 62 patients (51.2 %) received
Mean PNI (44.6) in our study cohort was used to divide patients into the PNI-low group (60 patients [49.6 %] with PNI \ 44.6) and the PNI-high group (61 patients [50.4 %] with PNI C 44.6). As of the last follow-up, 77 patients (63.6 %) had died—31 patients in the PNI-high group and 46 patients in the PNI-low group. Median OS of all patients was 15 months (range: 0.3–86 months). The Kaplan–Meier method and log-rank test indicated that the lower PNI value was associated with shorter OS (P = 0.003; Fig. 1). Median OS of patients in the PNI-high and PNI-low group was 18 and 11 months, respectively (Table 2); 1-year OS rates were 72.3 and 45.5 % in PNI-high group and PNI-low group, respectively; and the 2-year OS rate was 38.7 % for PNI-high group and 18.4 % for PNI-low group (Fig. 1). In univariate analysis of OS, low PNI (P = 0.003), nonepithelial type (P \ 0.001), male gender (P = 0.005) and the presence of chest pain (P = 0.025) were associated with significantly worse outcomes (Table 2). In testing PH assumption, PH assumptions for all prognostic factors except ‘‘histology’’ were not violated (P = 0.023). Therefore, the multivariate analysis was performed using the time-dependent Cox model, which
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J Cancer Res Clin Oncol (2013) 139:2117–2123 Table 2 Univariate analysis of prognostic factors of overall survival Variables
MOS (months) \57
15
C57
14
Gender
Male
11
Female
19
Smoking habits
No
15
Yes
14
No
16
Age (years)
Chest pain
0.005 0.309
Yes
12
No
11
Yes
15
0.071
Weight loss
No Yes
14 16
0.374
PBSC
Performed
16
Not performed
13
Epithelioid
16
Nonepithelioid IMIG stage Primary site of tumor Hospital
showed PNI to be an independent prognostic factor in MPM. Patients with lower PNIs had elevated risk of death compared with those with higher PNIs (HR: 2.290; 95 % CI, 1.415–3.706; P = 0.001; Table 3). These analyses were adjusted for patient age, gender, smoking habits, dyspnea, chest pain, weight loss, primary tumor site, histology, platinum-based systemic chemotherapy, hospital and stage.
0.502
Dyspnea
Histology Fig. 1 Kaplan–Meier survival curves evaluate the overall survival (OS) according to the prognostic nutritional index (PNI) value. The OS rate of the PNI-low group (PNI \ 44.6) was significantly lower than that of the PNI-high group (PNI C 44.6) (P = 0.003)
P value
PNI
9
I–II
15
III–IV
11
Right
14
Left
16
Hospital 1
14
Hospital 2
20
Hospital 3
14
PNI-high
18
PNI-low
11
0.025
0.141 \0.001 0.061 0.567
0.621 0.003
MOS median overall survival, HR hazard ratio, CI confidence interval, PBSC platinum-based systemic chemotherapy, IMIG International Mesothelioma Interest Group, Hospital 1 Shandong Provincial Hospital Affiliated to Shandong University, Hospital 2 Qilu Hospital, Hospital 3 Shandong Provincial Chest Hospital, PNI prognostic nutritional index
Discussion
Table 3 Multivariate survival analysis for various potential prognostic factors of overall survival
Nutritional status is the condition of the body, resulting from intake, absorption and use of nutrients, and is particularly influenced by physiological and pathological status (Andreoli et al. 2011). Cancer is a cause of malnutrition. A large multicenter study in Cuba (Barreto Penie 2005) found that the diagnosis of cancer was one of the common clinical variables associated with increased malnutrition rates, and patients’ nutritional status was significantly related to the presence of cancer. Malnutrition was highly prevalent among patients with cancer, regardless of the stage of medical or surgical treatment (Barreto Penie 2005). Malnutrition plays an important role in the incidence of postoperative complications, length of hospital stay, short OS, quality of life and increased mortality of malignant tumors (Morgan et al. 2011; Nozoe et al. 2002; Ryan et al. 2012; Van Cutsem and Arends 2005; Tong et al.
Variables
HR
95 % CI
PNI
2.290
1.415–3.706
0.001
Histology# Chest pain
3.049 1.649
1.855–5.011 1.041–2.611
\0.001 0.033
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P value
Multivariate analysis was assessed using time-dependent Cox model HR hazard ratio, CI confidence interval, PNI prognostic nutritional index #
The proportional hazard assumption for ‘‘histology’’ was violated
2009; Lee et al. 2013). PNI was presented by Smale et al. (1981) to predict the risk of operative morbidity and mortality after gastrointestinal surgery. However, their formula was complicated to apply. The simplified PNI used in our study was presented by Onodera et al. (1984). It is based on two simple laboratory parameters, albumin and
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absolute lymphocyte count, which are measured routinely in clinical practice. The PNI was initially designed to assess the nutritional and immunological status of patients who underwent gastrointestinal surgery. More recently, a large study by Proctor et al. reported that PNI can predict the prognosis of malignancy regardless of the site of origin (Proctor et al. 2011). Pinato et al. found PNI to be useful for assessing survival in patients with hepatocellular cancer (Pinato et al. 2012). Similar results were reported for patients receiving chemotherapy for advanced colorectal cancer (Okada et al. 2012). MPM is also frequently associated with malnutrition (Khalid et al. 2007), possibly due to tumor progression and decreased oral intake as a result of chest pain or dyspnea due to pleural effusion. However, to our knowledge, there is no such study regarding PNI in MPM. We are the first time to evaluate the prognostic role of PNI in MPM. In our present study, PNI was shown to be an independent predictor of OS in patients with MPM. The OS of the PNI-low group was significantly lower than that of PNI-high group (P = 0.003). These results are consistent with several previous studies evaluating the predictive role of PNI in malignancies (Nozoe et al. 2002, 2012; Benizri et al. 2013; Pinato et al. 2012; Kanda et al. 2011; Migita et al. 2013). We saw a close correlation between PNI and age, which was consistent with the finding by Watanabe et al. who studied elderly patients who underwent gastrectomies and observed that PNI in younger patients is significantly higher than that in older patients (Watanabe et al. 2012). In our study, in which median age was 57 years old, mean PNI was higher in older patients than in younger patients (P = 0.031). Advanced age is an independent adverse predictor of survival for MPM patients (Bagheri et al. 2011; Borasio et al. 2008), but we failed to find the relationship between prognosis and age in our study cohort. Interestingly, in our present study, we found that the PNI was related with smoking and mean PNI in patients with smoking history was significantly lower than in nonsmokers. Smoking can induce anoxia and decrease food intake (Wager-Srdar et al. 1984). A study by Chen et al. showed that chronic cigarette smoke exposure to male Balb/C mice can both induce anoxia and reduce the plasma leptin and insulin (Chen et al. 2008). A large anonymous questionnaire indicated that among some women, smoking is specially used to lose or control weight (Fulkerson and French 2003). MPM is classified into three main histological subtypes: epithelioid, sarcomatoid and biphasic. Of these, epithelioid is the most common; 75 patients (62 %) in our study were diagnosed as having the epithelioid subtype. Median OS in patients with nonepithelioid MPM was
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clearly shorter than for patients with epithelioid MPM. Multivariate analysis showed that the nonepithelioid type was an independent adverse prognostic factor. The prognostic significance of histology type for MPM has been validated in many studies (Borasio et al. 2008; Kao et al. 2013; Flores et al. 2007). The most frequent symptoms of MPM in our study cohort were dyspnea, chest pain and weight loss. The prognostic roles of weight loss and chest pain for MPM are controversial (Baldwin et al. 2011; Herndon et al. 1998; Tanrikulu et al. 2010; Flores et al. 2007). We found that median OS in patients with chest pain was shorter than the patients without chest pain; it was an independent prognostic factor. However, we found no significant relationship between prognosis and weight loss or dyspnea. Previous studies reported that male gender, smoking habits, therapeutic method, advanced stage and left-sided tumor affected OS in MPM (Edwards et al. 2000; Flores et al. 2007; Kao et al. 2013; Gemba et al. 2013). Only male gender in our study was found to be a significant prognostic factor in univariate analysis; disappointingly, however, multivariate analysis did not associate male gender or the above factors with survival. The three hospitals were located in the same province and had similar diagnostic and treatment practices, and similar sources of patients. No difference of PNI or median OS was found between the hospitals. The variable ‘‘hospital’’ was not an independent prognostic factor for MPM patients in the present study. As our study was limited by its retrospective nature and small number of patients, a larger, prospective, randomized controlled research is needed to validate our results. In conclusion, the present study showed that PNI—an indicator of nutritional status that is simple to construct from laboratory parameters—is a useful predictor of the long-term outcome of MPM. Acknowledgments We thank the staff at the Department of Respiratory Medicine of Shandong Provincial Hospital Affiliated to Shandong University and Qilu Hospital of Shandong University as well as the staff at the Department of Tuberculosis Medicine of Shandong Provincial Chest Hospital for their assistance in collecting the clinical data. Conflict of interest
We declare that we have no conflict of interest.
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2123 Giaccone G (2005) Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol Off J Am Soc Clin Oncol 23(28):6881–6889. doi:10.1200/JCO.20005.14.589 Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol Off J Am Soc Clin Oncol 21(14):2636–2644. doi:10.1200/JCO.2003.11.136 Wager-Srdar SA, Levine AS, Morley JE, Hoidal JR, Niewoehner DE (1984) Effects of cigarette smoke and nicotine on feeding and energy. Physiol Behav 32(3):389–395 Watanabe M, Iwatsuki M, Iwagami S, Ishimoto T, Baba Y, Baba H (2012) Prognostic nutritional index predicts outcomes of gastrectomy in the elderly. World J Surg 36(7):1632–1639. doi:10.1007/s00268-012-1526-z
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ORIGINAL PAPER
Prognostic nutritional index predicts outcomes of malignant pleural mesothelioma Zhou-Hong Yao • Guang-Yan Tian • Yun-Yan Wan • Yan-Meng Kang • Hai-Sheng Guo Qing-Hua Liu • Dian-Jie Lin
•
Received: 22 June 2013 / Accepted: 6 September 2013 / Published online: 23 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose Nutritional status has been associated with longtime outcomes in cancer patients. We investigated whether the prognostic nutritional index (PNI), an indicator of nutritional status, affects overall survival in patients with malignant pleural mesothelioma (MPM). Methods We enrolled 121 patients with histologically confirmed MPM, who had successfully undergone biopsy by medical thoracoscopy in this study. Demographic, clinical and laboratory data were collected retrospectively. The PNI was calculated as 109 serum albumin value (g/ dl) ? 0.005 9 total lymphocyte count (per mm3) in peripheral blood. Univariate and multivariate analyses were used to identify prognostic factors.
Results Mean pretreatment PNI was 44.6. PNI was significantly associated with age (P = 0.031), smoking habits (P = 0.039) and weight loss (P = 0.029). Survival analysis showed PNI to be an independent prognostic factor in MPM. Patients with lower PNIs (PNI \ 44.6) had greater risk of death than those with higher PNIs (PNI C 44.6; hazard ratio: 2.290; 95 % confidence interval: 1.415–3.706; P = 0.001). These analyses were adjusted for patient age, gender, smoking habits, dyspnea, chest pain, weight loss, primary site of tumor, histology, platinum-based systemic chemotherapy, hospital and stage. Conclusions Pretreatment PNI is a novel independent prognostic factor in MPM. Keywords Prognostic nutritional index Malignant pleural mesothelioma Survival Prognosis
Z.-H. Yao Y.-Y. Wan Q.-H. Liu (&) D.-J. Lin (&) Department of Respiratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, No. 324 Jingwuweiqi Road, Jinan 250021, Shandong Province, People’s Republic of China e-mail: [email protected] D.-J. Lin e-mail: [email protected] G.-Y. Tian Department of Neurology, Jinan Children’s Hospital, Jinan 250021, Shandong Province, People’s Republic of China Y.-M. Kang Department of Respiratory Medicine, Shandong Provincial Qianfoshan Hospital, Jinan 250021, Shandong Province, People’s Republic of China H.-S. Guo Department of Respiratory Medicine, Dongying People’s Hospital, Dongying 257000, Shandong Province, People’s Republic of China
Introduction Malignant pleural mesothelioma (MPM) is an asbestosrelated fatal malignancy, the incidence of which is still expected to increase over the next few decades because of its long latency period (20–40 years), although world-wide use of asbestos has decreased in recent decades (Hodgson et al. 2005). Although detection and therapeutic technologies have improved greatly, MPM remains difficult to treat, and standard therapies are still in flux. Though some authors suggest that antifolate agents and trimodality therapy (surgery, radiotherapy and chemotherapy) can improve the survival of MPM patients (Vogelzang et al. 2003; de Perrot et al. 2009), overall survival (OS) for MPM is still poor, with median OS at approximately 12 months (van Meerbeeck et al. 2005). Therefore, accurately predicting the prognosis of MPM patients is important in improving their survival.
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Nutritional condition and immunological status are important both in avoiding postoperative complication and in improving long-term outcomes of patients with malignant cancers (Nozoe et al. 2002; Morgan et al. 2011; Benizri et al. 2013; Ray-Coquard et al. 2009). The prognostic nutritional index (PNI), which is calculated by combining the serum albumin concentration with total peripheral blood lymphocyte count, was initially used to assess immune-nutritional status of patients who underwent gastrointestinal surgery (Onodera et al. 1984). Recently, lower PNI has been shown to be a prognostic marker in patients with various carcinomas including esophageal (Nozoe et al. 2002), colorectal (Nozoe et al. 2012), liver (Pinato et al. 2012), pancreas (Kanda et al. 2011) and stomach (Migita et al. 2013) cancers. A large recent study has shown that PNI could predict prognosis in malignancy regardless of the site of origin (Proctor et al. 2011). However, to our knowledge, PNI has not been investigated in MPM patients. Therefore, we retrospectively studied the relationship between PNI and clinicopathological characteristics and OS in MPM patients.
Materials and methods Patients This study enlisted 134 consecutive patients diagnosed with MPM who underwent biopsy by medical thoracoscopy in three hospitals (Shandong Provincial Hospital Affiliated to Shandong University, Qilu Hospital and Shandong Provincial Chest Hospital, China) from October 2001 to January 2013. All patients were newly confirmed to have MPM and had not yet received treatment. Patients with previous or coexisting cancers other than MPM and those with insufficient laboratory data were excluded from this study, leaving a total of 121 subjects. Their histological diagnoses were based on 2004 World Health Organization (WHO) classification criteria for pleural tumors (Travis et al. 2004). MPM staging was based on the International Mesothelioma Interest Group (IMIG) guidelines (Rusch 1995). All patients provided informed consent prior to this study. The Ethics Committee of Shandong University approved the study protocol. All patients were followed up until May 31, 2013, or death.
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methods, and pathological stage. Each patient had a clinical thoracic computed tomography examination (CT) before biopsy. Abdominal ultrasound, cranial CT, magnetic resonance imaging and emission CT were carried out when necessary. A total of 62 patients (51.2 %) received platinumbased systemic chemotherapy for at least two cycles. These included pemetrexed ? cisplatin/carboplatin in 44 patients; gemcitabine ? cisplatin/carboplatin in 6 patients; docetaxel ? cisplatin in 6 patients; mitomycin ? vindesine ? cisplatin in 2 patients; cyclophosphamide ? doxorubicin ? cisplatin in 2 patients; mitomycin ? cisplatin ? 5-fluorouracil in 1 patient; and vinorelbine ? cisplatin in 1 patient. All of the remaining 59 patients accepted nonsystemic chemotherapy. These included best supportive care in 47 patients; local cisplatin in thoracic cavity in 7 patients; and radiotherapy in 5 patients. Stages I–II and stages III–IV were grouped together. Nutritional and immunological assessment We obtained data from pretreatment blood tests, including serum albumin and total peripheral lymphocyte count from the patients’ medical records. PNI was then calculated with the following formula: 109 serum albumin value (g/ dl) ? 0.005 9 peripheral lymphocyte count (per mm3), according to a previous study (Migita et al. 2013). Statistical analysis The OS was calculated as the time from the date of the biopsy through medical thoracoscopy to that of death or last followup. Patients who were still alive or lost to follow-up were censored at final follow-up. Statistical analysis was carried out using SPSS 19.0 statistical software (SPSS Inc., Chicago, IL, USA). Continuous variables with normal distribution were described as means and standard deviations (SD). Means were compared using t test, t0 test or F test. The Kaplan–Meier method was used to calculate survival curves. The log-rank test was used to analyze statistical significance. The proportional hazard (PH) assumption for all variables was tested using time-dependent Cox model. The timedependent Cox model was carried out to identify independent prognostic factors, while the PH assumption was violated. P \ 0.05 was considered significant. Confidence intervals (CI) were calculated at 95 %.
Data Results The clinical characteristics of patients in our study were collected retrospectively from medical records and evaluated as prognostic factors. These data included the patient’s age, gender, smoking habits, chest pain, dyspnea, sudden weight loss, primary site of MPM, histology type, therapeutic
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Characteristics of patients A total of 121 patients were analyzed in this study (Table 1). The median age for the patients was 57 (range:
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2119
Table 1 Relationship between the clinicopathological characteristics and the PNI Variables
N (%)
PNI
P value
\57
57 (47.1)
45.9 ± 5.7
0.031
C57
64 (52.9)
43.4 ± 6.6
Male
65 (53.7)
43.8 ± 6.3
Female
56 (46.3)
45.5 ± 6.2
75 (62.0)
45.5 ± 5.7
46 (38.0)
43.0 ± 6.9
No
62 (51.2)
44.0 ± 6.7
Yes
59 (48.8)
45.1 ± 5.8
No
29 (24.0)
45.5 ± 6.7
Yes
92 (76.0)
44.3 ± 6.2
No
86 (71.1)
45.4 ± 5.9
Yes
35 (28.9)
42.6 ± 6.9
Performed
62 (51.2)
45.0 ± 6.1
Not performed
59 (48.8)
44.1 ± 6.5
75 (62.0)
45.2 ± 5.4
46 (38.0)
43.6 ± 7.5
Age (years)
Gender
Smoking habits No Yes
0.151
platinum-based systemic chemotherapy and 59 (48.8 %) nonsystemic chemotherapy (see ‘‘Materials and methods’’ section for details). By the 2004 WHO classification criteria for pleural tumor, 62 % (75/121) of the tumors were epithelioid cell type and 38 % (46/121) nonepithelioid cell type. By IMIG guidelines, 72 patients (59.5 %) were classified as stages I–II and 49 patients (40.5 %) as stages III–IV. A total of 70 patients (57.8 %) were diagnosed in Shandong Provincial Hospital Affiliated to Shandong University, 18 patients (14.9 %) in Qilu Hospital and 33 patients (27.3 %) in Shandong Provincial Chest Hospital.
0.039*
PNI and characteristics of patients
Chest pain 0.354
Dyspnea 0.360
Weight loss 0.029
PBSC
Histology Epithelioid Nonepithelioid
0.420
0.218*
PNI value and survival
IMIG stage I–II
72 (59.5)
44.4 ± 6.0
III–IV
49 (40.5)
44.8 ± 6.8
Right
67 (55.4)
44.1 ± 6.2
Left
54 (44.6)
45.1 ± 6.5
Hospital 1
70 (57.8)
44.5 ± 6.1
Hospital 2
18 (14.9)
45.2 ± 6.3
Hospital 3
33 (27.3)
44.3 ± 6.9
0.773
Primary site of tumor 0.365
Hospital 0.876#
PNI prognostic nutritional index, PBSC platinum-based systemic chemotherapy, IMIG International Mesothelioma Interest Group, Hospital 1 Shandong Provincial Hospital Affiliated to Shandong University, Hospital 2 Qilu Hospital, Hospital 3 Shandong Provincial Chest Hospital * t’ test,
#
Mean PNI before treatment was 44.6 (SD = 6.3). PNI was significantly associated with age, smoking habits and weight loss (Table 1). Mean PNI in patients aged C57 years old was significantly lower than in patients aged \57 years old (43.4 vs. 45.9, P = 0.031). Mean PNI was lower in smokers than in nonsmokers (43.0 vs. 45.5, P = 0.039). Mean PNI significantly differed in patients who presented with weight loss at diagnosis compared with patients who had maintained their weight (42.6 vs. 45.4, P = 0.029). No relation was observed between PNI and gender, chest pain, dyspnea, platinum-based systemic chemotherapy, histological type, IMIG stage, hospital, or primary site of tumor (P [ 0.05).
F test
18–81) years old. Patients comprised 65 males (53.7 %) and 56 females (46.3 %; male/female ratio: 1/0.86). A total of 46 patients (38 %) smoked. Main symptoms were dyspnea (76 %), chest pain (48.8 %) and weight loss (28.9 %). Among these patients, 55.4 % (67/121) patients had a primary tumor site in right thoracic cavity and 44.6 % in left. A total of 62 patients (51.2 %) received
Mean PNI (44.6) in our study cohort was used to divide patients into the PNI-low group (60 patients [49.6 %] with PNI \ 44.6) and the PNI-high group (61 patients [50.4 %] with PNI C 44.6). As of the last follow-up, 77 patients (63.6 %) had died—31 patients in the PNI-high group and 46 patients in the PNI-low group. Median OS of all patients was 15 months (range: 0.3–86 months). The Kaplan–Meier method and log-rank test indicated that the lower PNI value was associated with shorter OS (P = 0.003; Fig. 1). Median OS of patients in the PNI-high and PNI-low group was 18 and 11 months, respectively (Table 2); 1-year OS rates were 72.3 and 45.5 % in PNI-high group and PNI-low group, respectively; and the 2-year OS rate was 38.7 % for PNI-high group and 18.4 % for PNI-low group (Fig. 1). In univariate analysis of OS, low PNI (P = 0.003), nonepithelial type (P \ 0.001), male gender (P = 0.005) and the presence of chest pain (P = 0.025) were associated with significantly worse outcomes (Table 2). In testing PH assumption, PH assumptions for all prognostic factors except ‘‘histology’’ were not violated (P = 0.023). Therefore, the multivariate analysis was performed using the time-dependent Cox model, which
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J Cancer Res Clin Oncol (2013) 139:2117–2123 Table 2 Univariate analysis of prognostic factors of overall survival Variables
MOS (months) \57
15
C57
14
Gender
Male
11
Female
19
Smoking habits
No
15
Yes
14
No
16
Age (years)
Chest pain
0.005 0.309
Yes
12
No
11
Yes
15
0.071
Weight loss
No Yes
14 16
0.374
PBSC
Performed
16
Not performed
13
Epithelioid
16
Nonepithelioid IMIG stage Primary site of tumor Hospital
showed PNI to be an independent prognostic factor in MPM. Patients with lower PNIs had elevated risk of death compared with those with higher PNIs (HR: 2.290; 95 % CI, 1.415–3.706; P = 0.001; Table 3). These analyses were adjusted for patient age, gender, smoking habits, dyspnea, chest pain, weight loss, primary tumor site, histology, platinum-based systemic chemotherapy, hospital and stage.
0.502
Dyspnea
Histology Fig. 1 Kaplan–Meier survival curves evaluate the overall survival (OS) according to the prognostic nutritional index (PNI) value. The OS rate of the PNI-low group (PNI \ 44.6) was significantly lower than that of the PNI-high group (PNI C 44.6) (P = 0.003)
P value
PNI
9
I–II
15
III–IV
11
Right
14
Left
16
Hospital 1
14
Hospital 2
20
Hospital 3
14
PNI-high
18
PNI-low
11
0.025
0.141 \0.001 0.061 0.567
0.621 0.003
MOS median overall survival, HR hazard ratio, CI confidence interval, PBSC platinum-based systemic chemotherapy, IMIG International Mesothelioma Interest Group, Hospital 1 Shandong Provincial Hospital Affiliated to Shandong University, Hospital 2 Qilu Hospital, Hospital 3 Shandong Provincial Chest Hospital, PNI prognostic nutritional index
Discussion
Table 3 Multivariate survival analysis for various potential prognostic factors of overall survival
Nutritional status is the condition of the body, resulting from intake, absorption and use of nutrients, and is particularly influenced by physiological and pathological status (Andreoli et al. 2011). Cancer is a cause of malnutrition. A large multicenter study in Cuba (Barreto Penie 2005) found that the diagnosis of cancer was one of the common clinical variables associated with increased malnutrition rates, and patients’ nutritional status was significantly related to the presence of cancer. Malnutrition was highly prevalent among patients with cancer, regardless of the stage of medical or surgical treatment (Barreto Penie 2005). Malnutrition plays an important role in the incidence of postoperative complications, length of hospital stay, short OS, quality of life and increased mortality of malignant tumors (Morgan et al. 2011; Nozoe et al. 2002; Ryan et al. 2012; Van Cutsem and Arends 2005; Tong et al.
Variables
HR
95 % CI
PNI
2.290
1.415–3.706
0.001
Histology# Chest pain
3.049 1.649
1.855–5.011 1.041–2.611
\0.001 0.033
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P value
Multivariate analysis was assessed using time-dependent Cox model HR hazard ratio, CI confidence interval, PNI prognostic nutritional index #
The proportional hazard assumption for ‘‘histology’’ was violated
2009; Lee et al. 2013). PNI was presented by Smale et al. (1981) to predict the risk of operative morbidity and mortality after gastrointestinal surgery. However, their formula was complicated to apply. The simplified PNI used in our study was presented by Onodera et al. (1984). It is based on two simple laboratory parameters, albumin and
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absolute lymphocyte count, which are measured routinely in clinical practice. The PNI was initially designed to assess the nutritional and immunological status of patients who underwent gastrointestinal surgery. More recently, a large study by Proctor et al. reported that PNI can predict the prognosis of malignancy regardless of the site of origin (Proctor et al. 2011). Pinato et al. found PNI to be useful for assessing survival in patients with hepatocellular cancer (Pinato et al. 2012). Similar results were reported for patients receiving chemotherapy for advanced colorectal cancer (Okada et al. 2012). MPM is also frequently associated with malnutrition (Khalid et al. 2007), possibly due to tumor progression and decreased oral intake as a result of chest pain or dyspnea due to pleural effusion. However, to our knowledge, there is no such study regarding PNI in MPM. We are the first time to evaluate the prognostic role of PNI in MPM. In our present study, PNI was shown to be an independent predictor of OS in patients with MPM. The OS of the PNI-low group was significantly lower than that of PNI-high group (P = 0.003). These results are consistent with several previous studies evaluating the predictive role of PNI in malignancies (Nozoe et al. 2002, 2012; Benizri et al. 2013; Pinato et al. 2012; Kanda et al. 2011; Migita et al. 2013). We saw a close correlation between PNI and age, which was consistent with the finding by Watanabe et al. who studied elderly patients who underwent gastrectomies and observed that PNI in younger patients is significantly higher than that in older patients (Watanabe et al. 2012). In our study, in which median age was 57 years old, mean PNI was higher in older patients than in younger patients (P = 0.031). Advanced age is an independent adverse predictor of survival for MPM patients (Bagheri et al. 2011; Borasio et al. 2008), but we failed to find the relationship between prognosis and age in our study cohort. Interestingly, in our present study, we found that the PNI was related with smoking and mean PNI in patients with smoking history was significantly lower than in nonsmokers. Smoking can induce anoxia and decrease food intake (Wager-Srdar et al. 1984). A study by Chen et al. showed that chronic cigarette smoke exposure to male Balb/C mice can both induce anoxia and reduce the plasma leptin and insulin (Chen et al. 2008). A large anonymous questionnaire indicated that among some women, smoking is specially used to lose or control weight (Fulkerson and French 2003). MPM is classified into three main histological subtypes: epithelioid, sarcomatoid and biphasic. Of these, epithelioid is the most common; 75 patients (62 %) in our study were diagnosed as having the epithelioid subtype. Median OS in patients with nonepithelioid MPM was
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clearly shorter than for patients with epithelioid MPM. Multivariate analysis showed that the nonepithelioid type was an independent adverse prognostic factor. The prognostic significance of histology type for MPM has been validated in many studies (Borasio et al. 2008; Kao et al. 2013; Flores et al. 2007). The most frequent symptoms of MPM in our study cohort were dyspnea, chest pain and weight loss. The prognostic roles of weight loss and chest pain for MPM are controversial (Baldwin et al. 2011; Herndon et al. 1998; Tanrikulu et al. 2010; Flores et al. 2007). We found that median OS in patients with chest pain was shorter than the patients without chest pain; it was an independent prognostic factor. However, we found no significant relationship between prognosis and weight loss or dyspnea. Previous studies reported that male gender, smoking habits, therapeutic method, advanced stage and left-sided tumor affected OS in MPM (Edwards et al. 2000; Flores et al. 2007; Kao et al. 2013; Gemba et al. 2013). Only male gender in our study was found to be a significant prognostic factor in univariate analysis; disappointingly, however, multivariate analysis did not associate male gender or the above factors with survival. The three hospitals were located in the same province and had similar diagnostic and treatment practices, and similar sources of patients. No difference of PNI or median OS was found between the hospitals. The variable ‘‘hospital’’ was not an independent prognostic factor for MPM patients in the present study. As our study was limited by its retrospective nature and small number of patients, a larger, prospective, randomized controlled research is needed to validate our results. In conclusion, the present study showed that PNI—an indicator of nutritional status that is simple to construct from laboratory parameters—is a useful predictor of the long-term outcome of MPM. Acknowledgments We thank the staff at the Department of Respiratory Medicine of Shandong Provincial Hospital Affiliated to Shandong University and Qilu Hospital of Shandong University as well as the staff at the Department of Tuberculosis Medicine of Shandong Provincial Chest Hospital for their assistance in collecting the clinical data. Conflict of interest
We declare that we have no conflict of interest.
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