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Study of Association between RDW and Tumour Stage in Patients with Pancreatic Cancer

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Abstract

Introduction

Predicting the clinical outcome in pancreatic cancer is often challenging due to the lack of reliable and cost-effective prognostic parameters. Red Cell Distribution Width (RDW), an index of the variability in the size of the circulating RBCs has been reported to have prognostic significance in some malignancies. However, there is a scarcity of literature supporting its relevance in pancreatic cancer.

Objective

  1. To study the association between RDW and tumour stage in patients with pancreatic cancer attending a tertiary care hospital in South India.
  2. To correlate study the association between RDW and duration of survival among them after surgery for pancreatic cancer.

Methods

Retrospective data of 254 pancreatic cancer patients, who had undergone surgery at a tertiary care centre between 2002 and 2015, was obtained from digital medical records. This was supplemented with data obtained from telephone conversations with the patients and/or their next of kin. Data analysis was performed using SPSS version 20.

Results

Higher RDW values were associated with advanced tumour stages- 84.2% of patients with stage 3 cancer and 92.3% with stage 4 cancer had high RDW values. The mean RDW value for stage 1 patients was 14.93, while that for patients with tumour stages 2, 3, and 4 was 16.14, 17.51, and 18.68 respectively. High RDW values were also significantly associated with lower survival. The mean duration of survival for people with normal RDW values was 83 months while that for patients with higher values was significantly lower at 72 months. This difference was proven to be statistically significant by a log-rank test, which showed a p-value of 0.015. RDW values were found to be independent of age and gender.

Conclusion

There is appears to be a significant association between RDW and tumour stage in pancreatic cancer. RDW also correlates with the duration of survival in pancreatic cancer patients. Thus it may be of considerable useful in predicting the clinical outcome in pancreatic cancer.

Introduction

Pancreatic cancer is a malignant neoplasm of the pancreatic tissue. Although infrequent it is one of the most rapidly lethal cancers with a 5-year survival rate of less than 7 percent [1], causing more than 331,000 deaths per year[2]. Predicting the clinical outcome of pancreatic cancer is often very challenging. Although CA 19-9 levels have increasingly been used as a diagnostic as well as prognostic tool for pancreatic cancer, several some studies have emerged proving its inadequacy show no correlation [3][4]. The American Society of Clinical Oncology does not recommend using CS CA19-9 as a standalone diagnostic and prognostic tool for pancreatic cancer[5].In such a scenario, identification of additional parameters that are reliable, reproducible, and cost-effective could prove to be of substantial help in predicting disease outcomes in pancreatic cancer patients.

Red Cell Distribution Width (RDW) is an index of the variability in the size of the circulating Red Blood Corpuscles. RDW values are widely available to clinicians as a part of routine haemograms, but it is rarely used except to distinguish different types of anemia. Recent research, however, has furnished mounting evidence that a high RDW value is linked to several cardiovascular diseases, sepsis, COPD, and hepatitis [6][7]. Reports indicating that an increase in RDW values correlates with tumour stage and prognosis in lung cancers (Koma et al) [8] and tumour stage and grade in renal cell carcinoma (Wang et al)[9]have garnered considerable attention. There is, however, a deficiency paucity of literature focusing on RDW in the setting of pancreatic cancer. ????[10].The present study attempts to gain insight into the prognostic value of RDW in pancreatic cancer by looking into theat its association between RDW and with tumour stage as well as the impact of RDW values on survival.

Methodology

In this study, we retrospectively analyzed the data of 254 consecutive patients (where Follow up was possible) who had undergone potentially curative resectional surgery for pancreatic cancer at a tertiary referral centre between 2002 and 2015. Data regarding the patients demographics, tumour stage, RDW value, and treatment details were obtained from the digital records. Patients(or their next of kin) were then contacted by telephone and the nature of the study was explained to them. A total of eg 280 pts were operated on  26 patients either had not followed up and could not be contacted telephonically either. They were also informed that their participation in the study was solely on a voluntary basis and not mandatory, however, no one declined. All data (including life status) was entered into a Microsoft Excel spreadsheet. Based on the standard lab reference values for RDW at our centre (11.6 to 14.8) a cutoff value of 14.8 was taken and the patients were divided into two categories those with high RDW values (more than 14.8) and those with low or normal RDW values(less than or equal to 14.8). Patients were also grouped based on their AJCC tumour stage. The data was then analyzed using SPSS version 20 to look for any association between RDW and tumour stage, variation in RDW values with age and sex, and the impact of RDW on survival using Kaplan Meir survival analysis

Results

The mean age of study participants was 63.69 years. The majority of the patients were in the age group of 60 to 69years (31.88%), followed by 50 to 59 years (28.74%). 64.96% of the study participants were males and 35.04% were females. Out of the 254 cases, the majority (60.2%) were diagnosed with stage 2 cancer.[Table 1]

Table 1

Sociodemographics

Tumour stage number percentagenumber percentage

  1. Stage 1 56 22%
  2. Stage 2 153 60.2%
  3. Stage 3 19 7.5%
  4. Stage 4 26 10.2%
  • Total 254 100%

Out of 254 patients, 177 (69.8%) had high RDW values (more than 14.8) while remaining 77 (30.31%) had RDW values less than or equal to 14.8.[Table 2]

As the tumour stage advanced, the number of individuals in the high RDW category showed a progressive increase from 48.2% of stage one individuals to 99.3% of stage 4 individuals. (Table 2).

Table 2

Distribution of individuals based on tumour stage and RDW category

Tumour stage low RDW HIGH RDW

  1. Stage 1 (56) 29(51.8%) 27(48.2%)
  2. Stage 2 (153) 43(28.2%) 110(71.8%)
  3. Stage 3 (19) 3(15.8%) 16(84.2%)
  4. Stage 4 (26) 2 (0.7%) 24(99.3%)
  • Total 77 177

The mean RDW value was found to progressively increase from stage 1 to stage 4. Stage 1 had a mean of 14.9, Stage 2 had a mean of 16.1, stage 3 had a mean of 17.5, and stage 4 had a mean of 18.7. RDW values were found to be independent of age and gender.

The mean duration of survival for people with low RDW values(less than or equal to 14.8) was 83 months while those with RDW values above 14.8 had lower mean duration of survival, 72 months. This is depicted in the Kaplan Meir survival analysis curve in Figure 1. This difference was proven to be statistically significant by a log-rank test, which obtained a p-value of 0.015. The median duration of survival could not be calculated as close to 15% of the individuals who were followed up were still alive.

FIGURE 1

Kaplan Meir survival analysis curve for pancreatic cancer patients with respect to their RDW values

Discussion

RDW definition

Start a short para on RDW

In the current study, RDW values were positively correlated positively with the stage of pancreatic cancer, with a higher RDW value correlating with a more advanced tumour stage. This finding concurs with the results of a previously Studies correlating RDW to tumour stage in other cancers conducted as well as the only study found in English indexed literature by Yilmaz et al in pancreatic cancer [10] which reported a strong association between tumour stage and RDW value among pancreatic cancer patients. Studies correlating RDW to tumour stage in other cancers also showed similar results [8] [9]. The precise mechanism of the association between RDW and tumour stage is unknown. Several factors affecting RDW values such as RBC circulation half-life and membrane deformability can be affected by inflammation [11] which is recognized as a hallmark of tumour development. Research studies point toward a possible correlation between RDW and C-reactive protein (CRP) values [12]. Neote et al [13]detected several receptors for inflammatory factors on the RBC surface and hypothesized that RBCs are involved in the inflammatory process. Forhecz et al[14] found that inflammatory factors potentially affect iron metabolism, and RBC life span, and cause the release of immature red blood cells into circulation causing an increase in the RDW. Inflammatory factors have also been hypothesized to suppress the action of erythropoietin on erythroid stem cells and prevent the antiapoptotic effect of erythropoietin on maturating RBCs. [14]

The current study also showed that the mean duration of survival for patients with low RDW values(less than or equal to 14.8) was significantly higher than those with high RDW values (above 14.8). This result is in agreement with several previously published studies. Podhorecka et al showed that elevated RDW was associated with shorter survival time in patients with chronic lymphocytic leukemia [15]. A metanalysis by Ai et al indicated that increased pretreatment RDW predicted poorer overall survival, progress-free survival, and event-free survival in patients suffering from hematological malignancies [16]. The reason for this association too remains unknown. A possible explanation is that RDW has correlated with several circulating cytokines such as Il-6, tumor necrosis factor-alpha, and hepcidin that can affect the biological behavior of tumor cells [17, 18].

While the finding of the current study that RDW was found to be independent of sex gender is in agreement with studies such as that by Hoffman et al[19], our finding that RDWhowever unlike them we was also found to be independent of no correlation with age differs from the conclusions arrived at by Hoffman et al[19] who found that RDW increases with age. While the possible as the aforementioned study was conducted among presumably healthy individuals. It is likely that the present study was conducted in individuals with malignancies, a condition associated with there could be increased signaling along the IGFs/mTOR pathway. Persistent IGF-1/mTOR signaling enhances erythropoiesis by activating erythropoietin [20] [21] resulting in heterogeneity of RBC size due to a high turnover rates. So the RDW becomes affected by the metabolically driven (growth factor – IGF-1/mTOR) signaling rather than chronological aging.

While the present study shows that RDW has a strong association with tumour stage and survival rate, many of our study subjects(53% )were lost to follow up and this may have led to attrition bias.

In conclusion, there is appears to be a significant association between RDW and tumour stage in pancreatic cancer patients.RDW also correlates with duration of survival in these patients. It is a simple and easily available parameter, obtained at no additional cost incurred to the patient. Therefore RDW may be of considerable use in predicting the clinical outcome in pancreatic cancer patients.

However, in view of the limitations of the present study, larger-scale prospective studies be would be required to confirm these results.

References

  1. Michaud D.S. (2017) Epidemiology of Pancreatic Cancer. In: Loda M., Mucci L., Mittelstadt M., Van Hemelrijck M., Cotter M. (eds) Pathology and Epidemiology of Cancer. Springer, Cham DOI https://doi.org/10.1007/978-3-319-35153-7_25Publisher Name Springer, Cham Print ISBN 978-3-319-35151-3 Online ISBN978-3-319-35153-7
  2. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 2012 v1.0, Cancer Incidence and 2.Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer; 2013. Accessed 2016-03-04.
  3. Wu Z, Kuntz A, Wadleigh RG. CA 19-9 tumor marker: is it reliable? A case report in a patient with pancreatic cancer. ClinAdvHematolOncol. 2013;11:5052.
  4. Howaizi M, Abboura M, Krespine C, Sbai-Idrissi MS, Marty O, Djabbari-Sobhani M. A new cause for CA19.9 elevation: heavy tea consumption. Gut. 2003;52:913914.
  5. Locker GY, Hamilton S, Harris J, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J ClinOncol. 2006;24:53135327.
  6. Ye Z, Smith C, Kullo IJ. Usefulness of red cell distribution width to predict mortality in patients with peripheral artery disease. Am J Cardiol. 2011;107:12411245.
  7. Patel KV, Semba RD, Ferrucci L, Newman AB, Fried LP, Wallace RB, Bandinelli S, Phillips CS, Yu B, Connelly S, Shlipak MG, Chaves PH, Launer LJ, Ershler WB, Harris TB, Longo DL, Guralnik JM. Red cell distribution width and mortality in older adults: a meta-analysis. J Gerontol A BiolSci Med Sci. 2010;65:258265
  8. Increased red blood cell distribution width is associated with cancer stage and prognosis in patients with lung cancer. Koma Y, Onishi A, Matsuoka H, Oda N, Yokota N, Matsumoto Y, et al. (2013)
  9. Red Cell Distribution Width Is Associated with Presence, Stage, and Grade in Patients with Renal Cell Carcinoma Fang-Ming Wang, 1 Gongjun Xu, 2 Yan Zhang, 3 and Lu-Lin Ma
  10. Effect of pre-operative red blood cell distribution on cancer stage and morbidity rate in patients with pancreatic cancer. A Yilmaz,1 FU Malya,2 G Ozturk,1 B Citgez,2 Y Ozdenkaya,1 C Ersavas,1 AF Agan,3 H Senturk,4 and O Karatepe1
  11. Weiss G, Goodnough LT. Anemia of Chronic Disease. N Engl J Med. 2005;35210:101123.
  12. Lippi G, Plebani M. Red blood cell distribution width (RDW) and human pathology. One size fits all. ClinChem Lab Med 2014;52:12479.
  13. Neote K, Darbonne W, Ogez J, et al.Identification of a promiscuous inflammatory peptide receptor on the surface of red blood cells. J Biol Chem1993;268:122479.
  14. Forhecz Z, Gombos T, Borgulya G, et al. Red cell distribution width in heart failure: Prediction of clinical events and relationship with markers of ineffective erythropoiesis, inflammation, renal function, and nutritional state. J Am Heart Assoc2009;158:65966.
  15. Podhorecka M, Halicka D, Szymczyk A, Macheta A, Chocholska S, Hus M, Darzynkiewicz Z. Assessment of red blood cell distribution width as a prognostic marker in chronic lymphocytic leukemia. Oncotarget. 2016;7:3284653. doi: 10.18632/oncotarget.9055.
  16. Prognostic role of RDW in hematological malignancies: a systematic review and meta-analysis Lisha Ai , Shidai Mu , Yu HuCancer Cell International201818:61https://doi.org/10.1186/s12935-018-0558-3
  17. Rhodes CJ, Howard LS, Busbridge M, Ashby D, Kondili E, Gibbs JS, Wharton J, Wilkins MR. Iron deficiency and raised hepcidin in idiopathic pulmonary arterial hypertension: clinical prevalence, outcomes, and mechanistic insights. J Am CollCardiol. 2011;58:3009. DOI: 10.1016/j.jacc.2011.02.057.
  18. de Gonzalo-Calvo D, de Luxan-Delgado B, Rodriguez-Gonzalez S, Garcia-Macia M, Suarez FM, Solano JJ, Rodriguez-Colunga MJ, Coto-Montes A. Interleukin 6, soluble tumor necrosis factor receptor I and red blood cell distribution width as biological markers of functional dependence in an elderly population: a translational approach. Cytokine. 2012;58:1938. doi: 10.1016/j.cyto.2012.01.005.
  19. Hoffmann JJ, Nabbe KC, van den Broek NM. Effect of age and gender on reference intervals of red blood cell distribution width (RDW) and mean red cell volume (MCV).Clin Chem Lab Med. 2015 Nov;53(12):2015-9. doi: 10.1515/cclm-2015-0155.
  20. Kim I, Kim CH, Yim YS, Ahn YS. Autocrine function of erythropoietin in IGF-1-induced erythropoietin biosynthesis. Neuroreport. 2008;9:16991703.
  21. Kling PJ, Taing KM, Dvorak B, Woodward SS, Philipps AF. Insulin-like growth factor-I stimulates erythropoiesis when administered enterally. Growth Factors. 2006;24:218223.

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