ABSTRACT

Objective:

To evaluate different weight loss (WL) cut-off points as prognostic markers of 3-month survival after diagnosis of stage IV non-small cell lung cancer (NSCLC).

Methods:

This was a prospective study involving 104 patients with metastatic (stage IV) NSCLC who were admitted to a cancer treatment center in southern Brazil between January of 2014 and November of 2016. We evaluated total WL and WL per month, as well as WL and WL per month in the 6 months preceding the diagnosis. The patients were followed for 3 months after diagnosis. A Cox proportional hazards regression model and Kaplan-Meier curves were used in order to evaluate 3-month survival.

Results:

The median WL in the 6 months preceding the diagnosis was 6% (interquartile range, 0.0-12.9%). Patients with WL ≥ 5% had a median survival of 78 days, compared with 85 days for those with WL < 5% (p = 0.047). Survival at 3 months was 72% for the patients with WL ≥ 5% (p = 0.047), 61% for those with WL ≥ 10% (p < 0.001), and 45% for those with WL ≥ 15% (p < 0.001). In the multivariate analysis, the hazard ratio for risk of death was 4.51 (95% CI: 1.32-15.39) for the patients with WL ≥ 5%, 6.34 (95% CI: 2.31-17.40) for those with WL ≥ 10%, and 14.17 (95% CI: 5.06-39.65) for those with WL ≥ 15%.

Conclusions:

WL in the 6 months preceding the diagnosis of NSCLC is a relevant prognostic factor and appears to be directly proportional to the rate of survival at 3 months.

Keywords:
Weight loss; Carcinoma, non-small-cell lung; Prognosis

RESUMO

Objetivo:

Avaliar diferentes pontos de corte da perda de peso (PP) como marcadores prognósticos de sobrevida em 3 meses após o diagnóstico de câncer de pulmão de células não pequenas estádio IV (CPCNP).

Métodos:

Estudo prospectivo envolvendo 104 pacientes com CPCNP metastático (estádio IV) que foram internados em um centro de tratamento de câncer no sul do Brasil entre janeiro de 2014 e novembro de 2016. Avaliamos a PP total e PP por mês, bem como PP e PP por mês nos 6 meses anteriores ao diagnóstico. Os pacientes foram acompanhados por 3 meses após o diagnóstico. Um modelo de regressão de riscos proporcionais de Cox e curvas de Kaplan-Meier foram utilizados para avaliar a sobrevida em 3 meses.

Resultados:

A mediana da PP nos 6 meses anteriores ao diagnóstico foi de 6% (intervalo interquartil, 0,0-12,9%). Pacientes com PP ≥ 5% tiveram uma sobrevida mediana de 78 dias, comparados a 85 dias para aqueles com PP < 5% (p = 0,047). A sobrevida em 3 meses foi de 72% para os pacientes com PP ≥ 5% (p = 0,047), 61% para aqueles com PP ≥ 10% (p < 0,001) e 45% para aqueles com PP ≥ 15% (p < 0,001). Na análise multivariada, a taxa de risco para óbito foi de 4,51 (IC95%: 1,32-15,39) para os pacientes com PP ≥ 5%, 6,34 (IC95%: 2,31-17,40) para aqueles com PP ≥ 10%, e 14,17 (IC95%: 5,06-39,65) para aqueles com PP ≥ 15%.

Conclusões:

A PP nos 6 meses anteriores ao diagnóstico de CPCNP é um fator prognóstico relevante e parece ser diretamente proporcional à taxa de sobrevida em 3 meses.

Descritores:
Perda de peso; Carcinoma pulmonar de células não pequenas; Prognóstico

INTRODUCTION

Weight loss (WL) is a common complaint of patients with lung cancer and a common reason for patient referral to a specialist.¹1 Ross PJ, Ashley S, Norton A, Priest K, Waters JS, Eisen T, et al. Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers? Br J Cancer. 2004;90(10):1905-11. https://doi.org/10.1038/sj.bjc.6601781
https://doi.org/10.1038/sj.bjc.6601781...

2 Jeremic B, Milicic B, Milisavljevic S. Clinical prognostic factors in patients with locally advanced (stage III) non-small cell lung cancer treated with hyperfractionated radiation therapy with and without concurrent chemotherapy: single-Institution Experience in 600 Patients. Cancer. 2011;117(13):2995-3003. https://doi.org/10.1002/cncr.25910
https://doi.org/10.1002/cncr.25910... ^-33 Martin L, Birdsell L, Macdonald N, Reiman T, Clandinin MT, McCargar LJ, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol. 2013;31(12):1539-47. https://doi.org/10.1200/JCO.2012.45.2722
https://doi.org/10.1200/JCO.2012.45.2722... Cancer cachexia, resulting from an imbalance between energy intake and consumption, is associated with a combination of poor caloric intake and increased resting energy expenditure, probably due to a cytokine-induced systemic inflammatory response.⁴4 Fredrix EW, Wouters EF, Soeters PB, van der Aalst AC, Kester AD, von Meyenfeldt MF, et al. Resting energy expenditure in patients with non-small cell lung cancer. Cancer. 1991;68(7):1616-21. https://doi.org/10.1002/1097-0142(19911001)68:7&lt;1616::AID-CNCR2820680725&gt;3.0.CO;2-3
https://doi.org/10.1002/1097-0142(199110...

5 Hyltander A, Drott C, Körner U, Sandström R, Lundholm K. Elevated energy expenditure in cancer patients with solid tumours. Eur J Cancer. 1991;27(1):9-15. https://doi.org/10.1016/0277-5379(91)90050-N
https://doi.org/10.1016/0277-5379(91)900...

6 Staal-van den Brekel A, Schols A, ten Velde G, Buurman WA, Wouters EF. Analysis of energy balance in lung cancer patients. Cancer Res. 1994;54(24):6430-3.^-77 Staal-van den Brekel A, Dentener MA, Schols AM, Buurman WA, Wouters EF. Increased resting energy expenditure and weight loss are related to a systemic inflammatory response in lung cancer patients. J Clin Oncol. 1995;13(10):2600-5. https://doi.org/10.1200/JCO.1995.13.10.2600
https://doi.org/10.1200/JCO.1995.13.10.2... Some studies have demonstrated that this increase in resting energy expenditure can also vary depending on the type of tumor.⁸8 Melville S, McNurlan MA, Calder AG, Garlick PJ. Increased protein turnover despite normal energy metabolism and responses to feeding in patients with lung cancer. Cancer Res. 1990;50(4):1125-31.^,99 Jatoi A, Daly BD, Hughes V, Dallal GE, Roubenoff R. The prognostic effect of increased energy expenditure prior to treatment for lung cancer. Lung Cancer. 1999;23(2):153-8. https://doi.org/10.1016/S0169-5002(99)00008-2
https://doi.org/10.1016/S0169-5002(99)00... Other factors that contribute to cancer cachexia include nausea, vomiting, constipation, diarrhea, pain, altered taste perception, and depression.¹1 Ross PJ, Ashley S, Norton A, Priest K, Waters JS, Eisen T, et al. Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers? Br J Cancer. 2004;90(10):1905-11. https://doi.org/10.1038/sj.bjc.6601781
https://doi.org/10.1038/sj.bjc.6601781...

Despite its potential benefit for the clinical evaluation of patients with non-small cell lung cancer (NSCLC), the definition of cachexia varies significantly across studies and many WL cut-off points have been proposed in the attempt to classify the syndrome in an objective manner.¹⁰10 Buccheri G, Ferrigno D. Importance of weight loss definition in the prognostic evaluation of non-small-cell lung cancer. Lung Cancer. 2001;34(3):433-40. https://doi.org/10.1016/S0169-5002(01)00273-2
https://doi.org/10.1016/S0169-5002(01)00...

11 Tartari RF, Ulbrich-Kulczynski JM, Filho AF. Measurement of mid-arm muscle circumference and prognosis in stage IV non-small cell lung cancer patients. Oncol Lett. 2013;5(3):1063-1067. https://doi.org/10.3892/ol.2013.1128
https://doi.org/10.3892/ol.2013.1128...

12 Kimura M, Naito T, Kenmotsu H, Taira T, Wakuda K, Oyakawa T, et al. Prognostic impact of cancer cachexia in patients with advanced non-small cell lung cancer. Support Care Cancer. 2015;23(6):1699-708. https://doi.org/10.1007/s00520-014-2534-3
https://doi.org/10.1007/s00520-014-2534-...

13 Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489-95. https://doi.org/10.1016/S1470-2045(10)70218-7
https://doi.org/10.1016/S1470-2045(10)70... ^-1414 Aapro M, Arends J, Bozzetti F, Fearon K, Grunberg SM, Herrstedt J, et al. (2014) Early recognition of malnutrition and cachexia in the cancer patient: a position paper of a European School of Oncology Task Force. Ann Oncol. 2014;25(8):1492-9. https://doi.org/10.1093/annonc/mdu085
https://doi.org/10.1093/annonc/mdu085... A recent consensus suggested that WL be defined as any decrease greater than 5% in relation to the usual weight or greater than 2% in individuals with a body mass index < 20 kg/m².¹³13 Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489-95. https://doi.org/10.1016/S1470-2045(10)70218-7
https://doi.org/10.1016/S1470-2045(10)70... However, setting up a single cut-off point to classify cachexia can underestimate its real prognostic value. Different levels of cachexia severity can have various effects on the prognosis of cancer and could serve as a valuable clinical indicator.

The objective of this study was to evaluate 3-month survival in a population of patients with stage IV NSCLC. We also tested the prognostic value of different WL cut-off points.

METHODS

Study population

This prospective cohort study was conducted at Santa Rita Hospital, an oncology referral center and part of the Santa Casa de Misericórdia de Porto Alegre Hospital Complex, in the city of Porto Alegre, located in southern Brazil. We included consecutive patients newly diagnosed with metastatic (stage IV) NSCLC and admitted to Santa Rita Hospital between January of 2014 and November of 2016. Patients were treated at the discretion of the attending physician. All patients received a nutritional consultation at admission, regularly received high-calorie meals, and were instructed to rest before meals. However, they did not receive any type of nutritional supplementation as part of the palliative care or during chemotherapy. The follow-up period was ≤ 3 months after the diagnosis of cancer, as confirmed by reviews of medical records, hospital records, and phone calls. All diagnoses required clinical, radiological, and histological confirmation. Patients who had previously undergone antineoplastic treatment were excluded, as were those who were under 18 years of age. Survival and mortality rates were calculated from the time of the histological diagnosis until death or until the end of the third month of follow-up. Patient charts were reviewed, and tumor-node-metastasis variables were upgraded in accordance with the revised stage groupings established by the International Association for the Study of Lung Cancer.¹⁵15 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(8):706-14. Erratum in: J Thorac Oncol. 2007;2(10):985. https://doi.org/10.1097/JTO.0b013e31812f3c1a
https://doi.org/10.1097/JTO.0b013e31812f... Performance status was assessed with the Eastern Cooperative Oncology Group scale.¹⁶16 Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. https://doi.org/10.1097/00000421-198212000-00014
https://doi.org/10.1097/00000421-1982120... ⁾ The study was approved by the local institutional review board. All participating patients gave written informed consent.

WL classification

Each patient was prospectively evaluated following the standards established in previous reports.¹⁷17 Centers for Disease Control and Prevention--CDC [homepage in the internet]. Atlanta (GA): CDC; [updated 2017 Jan; cited 2017 Jul 29]. National Health and Nutrition Examination Survey (NHANES)--Anthropometry Procedures Manual. [Adobe Acrobat document, 102p.]. Available from: http://www.cdc.gov/nchs/data/nhanes/nhanes_07_08/manual_an.pdf
http://www.cdc.gov/nchs/data/nhanes/nhan... Definitions of WL-related variables were also based on those established in other studies¹⁰10 Buccheri G, Ferrigno D. Importance of weight loss definition in the prognostic evaluation of non-small-cell lung cancer. Lung Cancer. 2001;34(3):433-40. https://doi.org/10.1016/S0169-5002(01)00273-2
https://doi.org/10.1016/S0169-5002(01)00... : total WL-the difference between weight at the time of diagnosis and usual weight; WL per month-total WL divided by the number of months of WL; and WL per month in 6 months-total difference between weight at the time of diagnosis and weight in the preceding 6 months. Patients were also subjectively evaluated in terms of their self-awareness of WL at the time of NSCLC diagnosis in relation to their usual weight. Different WL cut-off points (5%, 10%, and 15%) were tested in order to classify cachexia and to correlate the different degrees of cachexia with the survival rates.

Statistical analysis

Continuous variables are expressed as medians and interquartile range (IQR). Univariate analyses of survival were based on the Kaplan-Meier method.¹⁸18 Altman DG. Practical statistics for medical research, 1st ed. London: Chapman & Hall; 1991. Survival was calculated by Cox proportional hazards regression model in a multivariate analysis.¹⁹19 Cox DR. Regression models and life-tables. J Royal Statistical Soc. Series B (Methodological) 1972;34:187-220. The Wald test was used in order to calculate significance for each factor. All parameters associated with mortality (p < 0.1) in the univariate analysis were included in a multivariate model, in which values of p < 0.05 were considered statistically significant. All tests were two-tailed, with the level of significance set at 0.05. All results were analyzed with the SPSS Statistics software package, version 20.0 (IBM Corporation, Armonk, NY, USA).

RESULTS

Patient characteristics are summarized in Table 1. The median age was 63 years (IQR, 52.5-69.0 years). Of a total of 104 patients evaluated, 63 (60.6%) were male. The most prevalent histological type of NSCLC was adenocarcinoma, which was seen in 57 (54.7%) of the patients, followed by squamous cell carcinoma, seen in 36 (34.6%), and mixed/undefined, seen in 11 (10.6%). The median Eastern Cooperative Oncology Group performance status was 2 (IQR, 1-3). Most (60.6%) of the patients underwent chemotherapy after diagnosis. Of the 104 patients, 44 (42.3%) underwent radiation therapy and 10 (9.6%) received supportive care exclusively. The 3-month mortality rate was 20.1% (95% CI: 12.9-29.1), 21 patients dying within the first 3 months after being diagnosed with cancer. The median WL in 6 months was 6% (IQR, 0.0-12.9%).

Patient outcomes, stratified by WL cut-off points, are summarized in Table 2. All cut-off points for WL in 6 months were statistically associated with a poorer prognosis as assessed by mean days of survival in 3 months. Patients with WL ≥ 5% had a mean survival of 78 days, compared with 85 days for those with WL < 5% (p = 0.047). When the WL cut-off points of ≥ 10% and ≥ 15% were applied, the mean survival decreased to 73 days and 66 days, respectively (p < 0.001 for both). However, there was no statistically significant difference between the patients who were aware of their WL and those who were not in terms of the 3-month survival rate (p = 0.081).

Kaplan-Meier survival curves for the first 3 months after diagnosis are shown in Figure 1. We observed a direct linear trend between the proportional WL and mortality. Event-free survival at 3 months was 88% for the patients with WL < 5%, compared with 72% for those with WL ≥ 5% (p = 0.047), 61% for those with WL ≥ 10% (p < 0.001), and 45% for those with WL ≥ 15% (p < 0.001).

The outcomes of the Cox proportional hazards regression model are summarized in Table 3. The univariate and multivariate (adjusted) analyses both demonstrated that the risk of death during the 3-month follow-up period was higher when the higher WL cut-off points were applied. The adjusted multivariate analysis showed that the risk of death increases exponentially as the cut-off points of WL increase, the hazard ratios for the 5%, 10%, and 15% cut-off points being 4.51 (95% CI: 1.32-15.39), 6.34 (95% CI: 2.31-17.40), and 14.17 (95% CI: 5.06-39.65), respectively.

DISCUSSION

In the present study, our aim was to determine the value of WL as a prognostic factor in patients with NSCLC, as well as whether that association differs among four WL cut-off points. We have shown that greater WL translates to shorter overall survival for patients with NSCLC. We found that, among patients with advanced NSCLC, the 3-month mortality rate was almost two times higher for those with WL ≥ 15% than for those with WL < 5%. Our results suggest that pre-treatment WL is an important clinical parameter with relevant prognostic value in patients with advanced NSCLC.

Our findings are consistent with those of previous studies that evaluated survival and WL in populations of lung cancer patients that were more heterogeneous, including patients in different stages of the disease.¹1 Ross PJ, Ashley S, Norton A, Priest K, Waters JS, Eisen T, et al. Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers? Br J Cancer. 2004;90(10):1905-11. https://doi.org/10.1038/sj.bjc.6601781
https://doi.org/10.1038/sj.bjc.6601781...

2 Jeremic B, Milicic B, Milisavljevic S. Clinical prognostic factors in patients with locally advanced (stage III) non-small cell lung cancer treated with hyperfractionated radiation therapy with and without concurrent chemotherapy: single-Institution Experience in 600 Patients. Cancer. 2011;117(13):2995-3003. https://doi.org/10.1002/cncr.25910
https://doi.org/10.1002/cncr.25910... ^-33 Martin L, Birdsell L, Macdonald N, Reiman T, Clandinin MT, McCargar LJ, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol. 2013;31(12):1539-47. https://doi.org/10.1200/JCO.2012.45.2722
https://doi.org/10.1200/JCO.2012.45.2722... ^,1010 Buccheri G, Ferrigno D. Importance of weight loss definition in the prognostic evaluation of non-small-cell lung cancer. Lung Cancer. 2001;34(3):433-40. https://doi.org/10.1016/S0169-5002(01)00273-2
https://doi.org/10.1016/S0169-5002(01)00...

11 Tartari RF, Ulbrich-Kulczynski JM, Filho AF. Measurement of mid-arm muscle circumference and prognosis in stage IV non-small cell lung cancer patients. Oncol Lett. 2013;5(3):1063-1067. https://doi.org/10.3892/ol.2013.1128
https://doi.org/10.3892/ol.2013.1128... ^-1212 Kimura M, Naito T, Kenmotsu H, Taira T, Wakuda K, Oyakawa T, et al. Prognostic impact of cancer cachexia in patients with advanced non-small cell lung cancer. Support Care Cancer. 2015;23(6):1699-708. https://doi.org/10.1007/s00520-014-2534-3
https://doi.org/10.1007/s00520-014-2534-... ^,2020 Buccheri G, Ferrigno D, Tamburini M. Karnofsky and ECOG performance status scoring in lung cancer: a prospective, longitudinal study of 536 patients from a single institution. Eur J Cancer. 1996;32A(7):1135-41. https://doi.org/10.1016/0959-8049(95)00664-8
https://doi.org/10.1016/0959-8049(95)006...

21 Paralkar VR, Li T, Langer CJ. Population characteristics and prognostic factors in metastatic non-small-cell lung cancer: a Fox Chase Cancer Center retrospective. Clin Lung Cancer. 2008;9(2):116-21. https://doi.org/10.3816/CLC.2008.n.018
https://doi.org/10.3816/CLC.2008.n.018... ^-2222 Blanchon F, Grivaux M, Asselain B, Lebas FX, Orlando JP, Piquet J, et al. 4-year mortality in patients with non-small-cell lung cancer: development and validation of a prognostic index. Lancet Oncol. 2006;7(10):829-36. https://doi.org/10.1016/S1470-2045(06)70868-3
https://doi.org/10.1016/S1470-2045(06)70... The prognostic significance of WL in stage IV NSCLC could be attributed to the potential link to cachexia. Defined as a multifactorial syndrome of progressive loss of skeletal muscle mass that cannot be completely reversed, cachexia has a heterogeneous clinical presentation that varies according to tumor type, site, and stage.¹³13 Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489-95. https://doi.org/10.1016/S1470-2045(10)70218-7
https://doi.org/10.1016/S1470-2045(10)70... ^,2121 Paralkar VR, Li T, Langer CJ. Population characteristics and prognostic factors in metastatic non-small-cell lung cancer: a Fox Chase Cancer Center retrospective. Clin Lung Cancer. 2008;9(2):116-21. https://doi.org/10.3816/CLC.2008.n.018
https://doi.org/10.3816/CLC.2008.n.018... Lung cancer is often accompanied by malnutrition, sarcopenia, and cachexia. Following the cancer-specific cachexia classifications, van der Meij et al.²³23 van der Meij BS, Schoonbeek CP, Smit EF, Muscaritoli M, van Leeuwen PA, Langius JA. Pre-cachexia and cachexia at diagnosis of stage III non-small-cell lung carcinoma: an exploratory study comparing two consensus-based frameworks. Br J Nutr. 2013;109(12):2231-9. https://doi.org/10.1017/S0007114512004527
https://doi.org/10.1017/S000711451200452... demonstrated that, at the time of diagnosis, approximately 18% and 23% of stage III NSCLC patients had cachexia or were in a state of pre-cachexia, respectively. However, the exact basis of these prognostic differences remains unknown.

Several hypotheses have been proposed to explain the association between cachexia and poorer prognosis. Some authors have suggested that the survival advantage associated with obesity is due to the relatively large energy stores.²¹21 Paralkar VR, Li T, Langer CJ. Population characteristics and prognostic factors in metastatic non-small-cell lung cancer: a Fox Chase Cancer Center retrospective. Clin Lung Cancer. 2008;9(2):116-21. https://doi.org/10.3816/CLC.2008.n.018
https://doi.org/10.3816/CLC.2008.n.018...

22 Blanchon F, Grivaux M, Asselain B, Lebas FX, Orlando JP, Piquet J, et al. 4-year mortality in patients with non-small-cell lung cancer: development and validation of a prognostic index. Lancet Oncol. 2006;7(10):829-36. https://doi.org/10.1016/S1470-2045(06)70868-3
https://doi.org/10.1016/S1470-2045(06)70... ^-2323 van der Meij BS, Schoonbeek CP, Smit EF, Muscaritoli M, van Leeuwen PA, Langius JA. Pre-cachexia and cachexia at diagnosis of stage III non-small-cell lung carcinoma: an exploratory study comparing two consensus-based frameworks. Br J Nutr. 2013;109(12):2231-9. https://doi.org/10.1017/S0007114512004527
https://doi.org/10.1017/S000711451200452... Conversely, when the stores are depleted, the energy balance is negative.²¹21 Paralkar VR, Li T, Langer CJ. Population characteristics and prognostic factors in metastatic non-small-cell lung cancer: a Fox Chase Cancer Center retrospective. Clin Lung Cancer. 2008;9(2):116-21. https://doi.org/10.3816/CLC.2008.n.018
https://doi.org/10.3816/CLC.2008.n.018...

22 Blanchon F, Grivaux M, Asselain B, Lebas FX, Orlando JP, Piquet J, et al. 4-year mortality in patients with non-small-cell lung cancer: development and validation of a prognostic index. Lancet Oncol. 2006;7(10):829-36. https://doi.org/10.1016/S1470-2045(06)70868-3
https://doi.org/10.1016/S1470-2045(06)70... ^-2323 van der Meij BS, Schoonbeek CP, Smit EF, Muscaritoli M, van Leeuwen PA, Langius JA. Pre-cachexia and cachexia at diagnosis of stage III non-small-cell lung carcinoma: an exploratory study comparing two consensus-based frameworks. Br J Nutr. 2013;109(12):2231-9. https://doi.org/10.1017/S0007114512004527
https://doi.org/10.1017/S000711451200452... Cachexia and a loss of skeletal muscle mass are associated with poor prognosis in patients with advanced NSCLC who are receiving chemotherapy.¹⁰10 Buccheri G, Ferrigno D. Importance of weight loss definition in the prognostic evaluation of non-small-cell lung cancer. Lung Cancer. 2001;34(3):433-40. https://doi.org/10.1016/S0169-5002(01)00273-2
https://doi.org/10.1016/S0169-5002(01)00... ^,2424 Goldstraw P, Ball D, Jett JR, Le Chevalier T, Lim E, Nicholson AG, et al. Non-small-cell lung cancer. Lancet. 2011;378(9804):1727-40. https://doi.org/10.1016/S0140-6736(10)62101-0
https://doi.org/10.1016/S0140-6736(10)62... Another hypothesis is that individuals with sarcopenia are susceptible to infections during hospitalization and residence in nursing homes, where such infections and premature termination of treatment are both possible contributors to shortened survival.²⁵25 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):1-6. https://doi.org/10.1016/j.lungcan.2014.01.020
https://doi.org/10.1016/j.lungcan.2014.0... Accordingly, the well-recognized poor prognosis in advanced lung cancer masks some heterogeneity that could be partially explained by WL stratification and other, as yet unconfirmed, biological factors.

Cachexia is a multifactorial syndrome with a complex pathogenesis. Therefore, multimodal interventions should be used in order to prevent WL among patients with cachexia.²⁶26 Aversa Z, Costelli P, Muscaritoli M. Cancer-induced muscle wasting: latest findings in prevention and treatment. Ther Adv Med Oncol. 2017;9(5):369-382. https://doi.org/10.1177/1758834017698643
https://doi.org/10.1177/1758834017698643... Frequent high-calorie meals and rest before meals are recommended. Currently, there is little evidence that nutritional supplementation is efficacious.²⁷27 Koretz RL, Lipman TO, Klein S; American Gastroenterological Association. AGA technical review on parenteral nutrition. Gastroenterology. 2001;121(4):970-1001. https://doi.org/10.1053/gast.2001.28031
https://doi.org/10.1053/gast.2001.28031... Physical activity has an anti-inflammatory effect and is effective in reducing muscle catabolism, increasing protein synthesis, and reversing protein degradation.²⁸28 Gould DW, Lahart I, Carmichael AR, Koutedakis Y, Metsios GS. Cancer cachexia prevention via physical exercise: molecular mechanisms. J Cachexia Sarcopenia Muscle. 2013;4(2):111-24. https://doi.org/10.1007/s13539-012-0096-0
https://doi.org/10.1007/s13539-012-0096-... Pharmacological treatment can also be used to prevent cachexia. Corticosteroids and progesterone analogs have been shown to increase appetite, thus resulting in modest weight gain. However, such drugs do not improve survival or quality of life.²⁹29 Ruiz Garcia V, López-Briz E, Carbonell Sanchis R, Gonzalvez Perales JL, Bort-Marti S. Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database Syst Rev. 2013;(3):CD004310. https://doi.org/10.1002/14651858.CD004310.pub3
https://doi.org/10.1002/14651858.CD00431...

Our study has some limitations, not the least of which is the small sample size. In addition, there are many confounding variables that could influence the analysis of 3-month survival of patients with advanced NSCLC. One such variable is the main treatment adopted, which, in our sample. was quite heterogeneous, therefore potentially affecting the prognosis. However, we believe that using a Cox proportional hazards regression model was an effective strategy to reduce the influence of those confounders, and the associations detected retained their significance even after the multivariate analyses. Studies including larger patient samples are needed in order to corroborate our findings. Further studies should also include biomarkers linked to aggressive behavior of lung cancer, such as circulating tumor cells and circulating cell-free nucleic acids, which could also affect survival rates, and patients who have such biomarkers might show different rates of WL.³⁰30 Matikas A, Syrigos KN, Agelaki S. Circulating Biomarkers in Non-Small-Cell Lung Cancer: Current Status and Future Challenges. Clin Lung Cancer. 2016;17(6):507-516. https://doi.org/10.1016/j.cllc.2016.05.021
https://doi.org/10.1016/j.cllc.2016.05.0...

Although increased efforts have been directed toward the identification of biological markers as prognostic indicators of lung cancer, there are some important clinical indices that should be also considered more thoroughly. In conclusion, our results indicate that proportional WL is an important prognostic factor for 3-month survival after diagnosis in patients with stage IV NSCLC.

REFERENCES

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