|Ahead of print
The prognostic value of decrease in prognostic nutritional index in stage III non-small cell lung cancer patients during curative thoracic radiotherapy
Zumrut Arda Kaymak, Emine Elif Ozkan
Department of Radiation Oncology, Suleyman Demirel University Faculty of Medicine, Isparta, Turkey
|Date of Submission||07-Jan-2020|
|Date of Decision||10-Jun-2020|
|Date of Acceptance||18-Sep-2020|
|Date of Web Publication||21-Jun-2021|
Zumrut Arda Kaymak,
Department of Radiation Oncology, Suleyman Demirel University Faculty of Medicine, Isparta
Source of Support: None, Conflict of Interest: None
Background: Curative thoracic radiotherapy (CTRT) with concurrent chemotherapy has been considered as standard treatment approach for stage-III non-small cell lung cancer (NSCLC). The hematological and esophageal toxicities that have been encountered during CTRT would affect the immunonutritional status of the patients. The aim of this study is to evaluate the prognostic value of the change in pre- and post-treatment prognostic nutritional index (PNI) in stage-III NSCLC patients.
Methods: Eighty seven consecutive stage III NSCLC patients' data were collected. Pre-radiotherapy (RT) and post-RT PNI values were calculated and the impact of prognostic value of PNI change on overall survival (OS) was evaluated by univariate and multivariate Cox regression analyses. A cutoff value of PNI change was obtained by receiver operator characteristic (ROC) curve analysis.
Results: The cutoff value was found to be a 22% decrease in PNI by ROC curve analysis in terms of effect on OS. The median OS of low and high PNI decrease groups were 22.5 and 16.5 months respectively (P = 0,001). In univariate and multivariate analyses PNI decrease of ≥ 22% was found to be an independent poor prognostic factor for OS (P = 0.012) and hazard ratio (95% confidence interval)= 2.05 (1.16–3.62).
Conclusion: The PNI change would be a convenient parameter to assess the immunonutritional status of the patient at the end of CTRT. A decrease of more than 22% of PNI value may predict poor prognosis.
Keywords: Prognostic factor, prognostic nutritional index decrease, stage-III non-small cell lung cancer (NSCLC), survival, thoracic radiotherapy
Key Message: Impairment of immunonutritional status is a common toxicity in curative definitive chemoradiotherapy of stage III non-small cell lung cancer patients. The decrease in the prognostic nutritional index during chemoradiotherapy is associated with a poor prognosis
|How to cite this URL:|
Kaymak ZA, Ozkan EE. The prognostic value of decrease in prognostic nutritional index in stage III non-small cell lung cancer patients during curative thoracic radiotherapy. Indian J Cancer [Epub ahead of print] [cited 2021 Oct 28]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=318895
| » Introduction|| |
Despite recent advances in cancer treatment, lung cancer is still the leading cause of cancer-related mortality, worldwide. Approximately 80% of lung cancer cases are non-small cell lung cancer (NSCLC) histologically, and one fourth of them are diagnosed to be locally advanced. Definitive thoracic radiotherapy (RT) with concurrent chemotherapy (CT) has been considered as a standard care for stage III NSCLC, but according to the results of studies in the past two decades, the therapeutic landscape has broadened to include induction CT, immunotherapy, and even surgery in cases with good response.,,
Since 5-year survival for all stages of lung cancer is less than 15%, it is important to identify poor prognostic patients. Several prognostic factors have been identified in patients with NSCLC. The most important one is, TNM stage, where clinical factors (e.g., age, gender, or performance status), smoking, histologic features (e.g., lymphovascular invasion),, carcinoembryonic antigen levels, and molecular markers have also been indicated as prognostic factors for patients with NSCLC. Laboratory parameters were evaluated in terms of prognostic value for cancer by many researchers because of being inexpensive, reproducible, and easily accessible. Inflammatory markers and malnutrition are reported to have a correlation with poor survival. Glasgow prognostic score, C-reactive protein/albumin ratio, neutrophil/lymphocyte ratio, and platelet/lymphocyte ratio are some of the nutrition/inflammation-based hematological biomarkers that have been reported to predict the prognosis of lung cancer.
Prognostic nutritional index (PNI), being calculated by serum albumin concentration and total peripheral blood lymphocyte count, was initially used to determine the immunonutritional status of patients who underwent gastrointestinal surgery. Prognostic significance of PNI has been reported in colorectal, gastric, esophagus, pancreas malignancies, and pleural mesothelioma,,,, which confirms that PNI can be used to assess prognosis in cancer patients regardless of primary.
The prognostic significance of PNI in lung cancer has been severally evaluated in small-cell lung cancer (SCLC) or NSCLC patients. In stage I–IV NCSLC patients, the cutoff value for the pretreatment PNI was reported to be 45–51.15., However, lack of a definite cutoff value leads to uncertainty to predict prognosis via PNI in clinical practice. The aim of this study was to investigate the prognostic significance of the change in PNI during definitive thoracic RT in patients with stage-III NSCLC in order to facilitate individual assessment of patients in radiation oncology department.
| » Subjects and Methods|| |
Patients and treatment modality
Patients with a histopathologicaily confirmed NSCLC who underwent thoracic RT with a curative intend in Suleyman Demirel University Hospital, Radiation Oncology department between November 2011 and August 2018 were enrolled in the study. The electronic files of the patients and data from our clinical archive system were reviewed. Stage III patients, according to AJCC Cancer Staging Manual eight edition (2017) with accessible pre-radiotherapy and post-radiotherapy laboratory data in terms of serum albumin concentration and total peripheral blood lymphocyte count, were enrolled in this study. Patients who were given palliative radiotherapy or lost to follow-up were excluded. Clinicopathological features of the patients, which were investigated for their prognostic significance, were obtained from hospital database.
The primary tumor and the involved lymph node regions were delineated as gross tumor volume. Clinical target volume was formed with a margin of 6–8 mm to the primary tumor and 5–7 mm to the involved nodes. In order to determine planned target volume (PTV), 1–1.5 cm was added to clinical target volume. RT was planned via 3-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) and delivered with 1.8–2 Gy daily fraction to a median total dose of 66 Gy (range: 60 - 66Gy) by a linear accelerator producing 6–18 MV photons. Weekly platinum-based concurrent chemotherapy (CT) up to 6 cycles was applied to 72 patients where the remaining 15 patients were not suitable for CT due to comorbidities.
Pre-radiotherapy and post-radiotherapy PNI values were calculated for each patient with the formula of [10 × serum albumin level (g/dL) + 0.005 × peripheral lymphocyte count (per mm3). Percentage difference between the two PNI values was obtained.
The protocol of this study was approved by the institutional ethics committee (protocol no: 46-05/02/2019) and conducted in accordance with World's Medical Association's Declaration of Helsinki.
All statistical analysis were performed by the Statistical Package for the Social Sciences software program version 21.0 (SPSS Inc., Chicago, IL, USA). The continuous variables are evaluated for normal distribution by normality tests. Normally distributed data are presented as either mean [±standard deviation(SD), range] or median (range). A receiver operator characteristic (ROC) curve was constructed to reveal an association between difference in PNI and overall survival. According to the ROC curve the best cutoff value for PNI change that can predict survival was determined. The patients were separated into two groups as high and low PNI difference according to the cutoff value. The clinicopathological characteristics of two groups were analyzed by Fisher's exact test, the Chi-square test, or the unpaired t-test, as appropriate. The survivals of the groups were compared with log-rank test and the survival curves were created by Kaplan-Meier method. A Cox regression model was used to analyze independent prognostic significance of the change in PNI value and other clinicopathological features. A P value <0.05 was considered as statistically significant.
| » Results|| |
A total of 87 patients (80 men and 7 women) were evaluated in this study with a median follow-up period of 19.3 months (range 1.5–60.1 months). Twenty-two (25.3%) patients were alive, 59 (67.8%) patients had distant metastasis and/or local recurrence. For the entire group, median overall survival (OS) and progression-free survival (PFS) were 18.7 (95% confidence interval (CI): 15.3–22.16), and 13.4 (95% CI: 12.07–14.8) months, respectively. 2-year OS was found as 38.2%.
Mean pre and post-treatment PNI values were 48.11(SD: ±6.84, range: 31.5 - 69) and 38.91(SD: ±6.79, range: 19.3-54.8), respectively. A median 17% decrease (ranging between 16.9% increase and 65.1% decrease) was found between pre and post-treatment PNI values.
The predictive cutoff value of PNI change for OS via ROC curve was 22% of decrease in PNI (sensitivity 63.07%; specificity 86.36%) [Figure 1].
|Figure 1: Receiver operating characteristics (ROC) curve analysis for change in the prognostic nutritional index (PNI) during thoracic radiotherapy. Area under the curve (AUC) = 0.627, P = 0.016, 95% CI: 0.549–0.796|
Click here to view
Clinicopathologic features evaluated for low and high PNI change groups were age, histopathology, ECOG performance status, T stage, N stage, concurrent chemotherapy, and thoracic RT dose. No statistically significant difference was found between two groups [Table 1].
The median OS of 31 patients who had a PNI decrease less than 22% was 22.5 months, where median OS of remaining 56 patients who had a decrease in PNI more than 22% was 16.5 months which was statistically significant (P = 0,001) [Figure 2]. PFS of low and high PNI decrease-groups were 13.4 months and 12.8 months, respectively. However, the difference was not statistically significant (P = 0.632).
|Figure 2: Kaplan Meier Curve showing median overall survival; PNI: prognostic nutritional index|
Click here to view
In univariate analysis; ECOG performance status and PNI change were identified as significant factors for OS (P = 0.004 and 0.002, respectively). The result of multivariate analysis revealed PNI change only as an independent prognostic factor for OS (P = 0.012 and HR (95% CI) = 2.05 (1.16–3.62)) [Table 2].
|Table 2: Results of univariate and multivariate Cox regression analysis for overall survival|
Click here to view
| » Discussion|| |
PNI is calculated with a formula including serum albumin level and peripheral lymphocyte count. Serum albumin level has already been demonstrated as a parameter for nutritional status and it is known to be inversely correlated with poor prognosis in NSCLC. It has been advocated that peripheral blood lymphocyte count, one of the basic constituents of cellular immunity, may also predict survival in NSCLC. PNI, calculated with serum albumin level and peripheral lymphocyte count, is considered to be an effective prognostic index and many studies have been conducted on this subject. PNI is identified as a prognostic factor for OS and postoperative complications in several cancer types but not for cancer-specific survival. Wang et al. published a meta-analysis of 21 studies (17 NSCLC and 4 SCLC) which demonstrated that low PNI predicts poor survival in lung cancer patients. In another review study on the prognostic value of PNI for lung cancer patients, as a result of subgroup analysis, low PNI was found to be more predictive for OS in NSCLC than in SCLC.
PNI has also been shown to be a possible predictive factor for postoperative complications in NSCLC patients who were candidates for surgery. The cutoff value for preoperative PNI value was determined as 48 which was identified as an independent prognostic factor both for OS and recurrence-free survival.
It should be mentioned that stage I–IV patients were included in the study samples of the previous studies focusing on prognostic significance of pretreatment PNI in NSCLC cases., The majority of NSCLC cases referred for concurrent chemoradiotherapy with curative intend have stage-III disease since it is considered as standard of care for such cases. In our study only patients with stage-III disease were included, which would provide more specific outcomes for the clinical practice. Similar to our study sample, Li et al. have evaluated the prognostic impact of PNI in stage IIIB-IV NSCLC patients who had received CT or epidermal growth factor receptor–tyrosine kinase inhibitors. As a conclusion, the authors indicated that the cases with a low PNI value (<50) had poorer survival results.
Coping with esophageal toxicity would have primary importance for compliance to curative thoracic radiotherapy (CTRT) and subsequent CT. Especially, in stage-III patients, due to the mediastinal LN irradiation, esophagus is exposed to higher doses leading to mild acute esophagitis up to 70% and severe esophagitis up to 26% of patients., Depending on its severity; acute esophagitis may cause malnutrition and decrease in serum albumin levels in patients. With the additional toxicity of concomitant CT in terms of nausea, vomiting and consequent loss of appetite; a decrease in PNI is expected. In another research Shimizu et al. evaluated the predictive value of pre-treatment PNI on CT compliance and survival among NSCLC patients and they concluded that PNI may influence the treatment compliance with oral tegafur agent but not with the platinum based CT. Based on the hypothesis and results of above mentioned studies we planned to evaluate the importance of PNI change during thoracic RT.
However, no study on predictive feature of PNI change during CTRT was encountered in the literature research which makes our study distinctive. We found that a decrease of >22% between pre- and post-treatment PNI values was the only independent factor for OS in multivariate analysis. Therefore, to our concern, change in PNI value may enhance the clinical utility of PNI for individual assessment as a new approach. On the other hand, it provides a method to evaluate RT process in term of patients' immunonutritional status.
Although there was a noteworthy difference between the PFS values of low and high PNI decrease-groups (13.4 months and 12.8 months, respectively), the difference was not statistically significant (P = 0.632). This might be resulting from the insufficient number of patients to attain significance.
The other clinicopathologic features evaluated such as age, histopathology, T stage, N stage, concurrent CT, and thoracic RT dose were not found to effect prognosis significantly. This result which is somehow in controversy with previous studies can be attributed to limited number of patients.
There are still some limitations of this study among which the retrospective design and the limited sample size due to a single center data are the two major ones. The patients with missing data were excluded from the study. Moreover, only the patients who completed CTRT were assigned to be valid for the evaluation in terms of 22% PNI decrease.
| » Conclusion|| |
CTRT is the encouraged initial treatment modality for stage III NSCLC patients. Acute esophagitis is one of the main issues that can affect the immunonutritional status of the patients during treatment. PNI would be a convenient parameter to assess the nutritional status during CTRT process. As a result of our study, it is concluded that in addition to the previously mentioned pretreatment value of PNI, a decrease of more than 22% between pre-treatment and post-treatment values of PNI is significantly associated with poor prognosis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Siegel RL, Miller KD, Jema A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30.
Dillman RO, Herndon J, Seagren SL, Eaton WL, Green MR. Improved survival in stage III non-small-cell lung cancer: Seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst 1996;88:1210-5.
Watanabe SI, Nakagawa K, Suzuki K, Takamochi K, Ito H, Okami J, et al
. Neoadjuvant and adjuvant therapy for Stage III non-small cell lung cancer. Jpn J Clin Oncol 2017;47:1112-8.
Deslypere G, Gullentops D, Wauters E, Vansteenkiste J. Immunotherapy in non-metastatic non-small cell lung cancer: Can the benefits of stage IV therapy be translated into earlier stages? Ther Adv Med Oncol. 2018;4;10:1758835918772810
Crinò L, Weder W, van Meerbeeck J, Felip E. ESMO Guidelines Working Group: Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21:103-15.
Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al
. The IASLC lung cancer staging project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007;2:706-14.
Thunnissen E, van der Oord K, den Bakker M. Prognostic and predictive biomarkers in lung cancer. A review. Virchows Arch 2014;464:347-58.
Shiono S, Katahira M, Abiko M, Sato T. Smoking is a perioperative risk factor and prognostic factor for lung cancer surgery. Gen Thorac Cardiovasc Surg 2015;63:93-8.
Inoue M, Minami M, Sawabata N, Takamochi K, Ito H, Okami J, et al
. Clinical outcome of resected solid-type small-sized c-stage IA non-small cell lung cancer. Eur J Cardiothorac Surg 2010;37:1445-9.
Higgins KA, Chino JP, Ready N, D'Amico TA, Berry MF, Sporn T, et al
. Lymphovascular invasion in non-small-cell lung cancer: Implications for staging and adjuvant therapy. J Thorac Oncol 2012;7:1141-7.
Matsuoka K, Sumitomo S, Nakashima N, Nakajima D, Misaki N. Prognostic value of carcinoembryonic antigen and CYFRA21-1 in patients with pathological stage I non-small cell lung cancer. Eur J Cardiothorac Surg 2007;32:435-9.
Starnes SL, Pathrose P, Wang J, D'Amico TA, Berry MF, Sporn T, et al
. Clinical and molecular predictors of recurrence in stage I non-small cell lung cancer. Ann Thorac Surg 2012;93:1606-12.
Kovarik M, Hronek M, Zadak Z. Clinically relevant determinants of body composition, function and nutritional status as mortality predictors in lung cancer patients, Lung Cancer 2014;84:1-6.
Yotsukura M, Ohtsuka T, Kaseda K, Kamiyama I, Hayashi Y, Asamura H. Value of the glasgow prognostic score as a prognostic factor in resectable non-Small cell lung cancer. J Thorac Oncol 2016;11:1311-8.
Zhou T, Zhan J, Hong S, Hu Z, Fang W, Qin T, et al
. Ratio of C-reactive protein/abumin is an inflammatory prognostic score for predicting overall survival of patients with small-cell lung cancer. Sci Rep 2015;18:10481.
Takahashi Y, Kawamura M, Hato T, Harada M, Matsutani N, Horio H. Neutrophil-lymphocyte ratio as a prognostic marker for lung adenocarcinoma after complete resection. World J Surg 2016;40:365-72.
Sanchez-Salcedo P, De-Torres JP, Martinez-Urbistondo D, Gonzalez-Gutierrez J, Berto J, Campo A, et al
. The neutrophil to lymphocyte and platelet to lymphocyte ratios as biomarkers for lung cancer development. Lung Cancer 2016;97:28-34.
Onodera T, Goseki N, Kosaki G. Prognostic nutritional index in gastrointestinal surgery of malnourished cancer patients. Nihon Geka Gakkai Zasshi 1984;85:1001-5.
Nozoe T, Kimura Y, Ishida M, Saeki H, Korenaga D, Sugimachi K. Correlation of pre-operative nutritional condition with post-operative complications in surgical treatment for oesophageal carcinoma. Eur J Surg Oncol 2002;28:396-400.
Migita K, Takayama T, Saeki K, Matsumoto S, Wakatsuki K, Enomoto K, et al
. The prognostic nutritional index predicts long-term outcomes of gastric cancer patients independent of tumor stage. Ann Surg Oncol 2013;20:2647-54.
Nozoe T, Kohno M, Iguchi T, Mori E, Maeda T, Matsukuma A, et al
. The prognostic nutritional index can be a prognostic indicator in colorectal carcinoma. Surg Today 2012;42:532-5.
Kanda M, Fujii T, Kodera Y, Nagai S, Takeda S, Nakao A. Nutritional predictors of postoperative outcome in pancreatic cancer. Br J Surg 2011;98:268-74.
Yao ZH, Tian GY, Wan YY, Kang YM, Guo HS, Liu QH, et al
. Prognostic nutritional index predicts outcomes of malignant pleural mesothelioma. J Cancer Res Clin Oncol 2013;139:2117-23.
Li D, Yuan X, Liu J, Li C, Li W. Prognostic value of prognostic nutritional index in lung cancer: A meta-analysis. J Thorac Dis 2018;10:5298-307.
Wang Z, Wang Y, Zhang X, Zhang T. Pretreatment prognostic nutritional index as a prognostic factor in lung cancer: Review and meta-analysis. Clin Chim Acta 2018;486:303-10.
Gupta D, Lis CG. Pretreatment serum albumin as a predictor of cancer survival: A systematic review of the epidemiological literature. Nutr J 2010;9:69.
Zhang J, Huang SH, Li H, Li Y, Chen XL, Zhang WQ, et al
. Preoperative lymphocyte count is a favorable prognostic factor of disease-free survival in non-small-cell lung cancer. Med Oncol 2013;30:352.
Sun K, Chen S, Xu J, Li G, He Y. The prognostic significance of the prognostic nutritional index in cancer: A systematic review and meta-analysis. J Cancer Res Clin Oncol 2014;140:1537-49.
Okada S, Shimada J, Kato D, Tsunezuka H, Teramukai S, Inoue M. Clinical significance of prognostic nutritional index after surgical treatment in lung cancer. Ann Thorac Surg 2017;104:296-302.
Kim TH, Cho KH, Pyo HR, Lee JS, Han JY, Zo JI, et al
. Dose-volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:995-1002.
Li XL, Yao ZH, Wan YY, Mou XY, Ni YH, Sun EL, et al
. Prognostic impact of prognostic nutritional index in advanced (stage IIIB/IV) non-small cell lung cancer patients. Neoplasma 2019;66:971-7.
Takeda K, Nemoto K, Saito H, Ogawa Y, Takai Y, Yamada S. Dosimetric correlations of acute esophagitis in lung cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:626-9.
Rodríguez N, Algara M, Foro P, Lacruz M, Reig A, Membrive I, et al
. Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimensional conformal radiotherapy and chemotherapy. Int J Radiat Oncol Biol Phys 2009;73:810-7.
Shimizu K, Okita R, Saisho S, Yukawa T, Maeda A, Nojima Y, Nakata M. Prognostic nutritional index before adjuvant chemotherapy predicts chemotherapy compliance and survival among patients with non-small-cell lung cancer. Ther Clin Risk Manag 2015;11:1555.
[Figure 1], [Figure 2]
[Table 1], [Table 2]