Presence of Anemia and Poor Prognostic Factors in Patients with Endometrial Carcinoma

This study evaluated the relationship between pretreatment hemoglobin (Hb) and prognostic factors in Thai patients with endometrial cancer. Medical records of 228 patients who had undergone surgery between January 2005 and December 2007 were retrospectively reviewed. Associations between clinicopathological variables and pretreatment Hb levels were described using Pearson's chi square test or two-tailed Fisher's exact test. Survival analysis was performed with Kaplan-Meier estimates. Univariate and Cox-regression models were used to evaluate the prognostic impact of various factors, including Hb levels, in term of disease-free survival. The median duration of follow-up was 38.2 months. Eighty-nine patients (39%) had a preoperative Hb level of <12 g/dL, these having significantly higher rates of non-endometrioid histology, advanced FIGO stage, lymphovascular space invasion, cervical involvement, adnexal involvement, positive peritoneal cytology, and lymph node involvement than patients with Hb ≥12 g/dL. The 5-year disease-free and overall survival were significantly lower in patients with pretreatment Hb levels <12 g/dL compared with those with Hb ≥12 g/dL (79.3% vs. 89.2%, p=0.044 and 87.6% vs. 99.3%, p<0.001, respectively). In the multivariate analysis only histology, myometrial invasion, and lymphovascular invasion proved to be independent prognostic factors, whereas tumor grading, stage, cervical involvement, adnexal involvement, positive peritoneal cytology, lymph node involvement, and low Hb were not. In conclusion, presence of anemia before treatment may reflect poor prognostic factors in patients with endometrial cancer and low pretreatment hemoglobin level may have a prognostic impact on clinical outcome.


Introduction
Anemia (generally defined as Hb level below 12 g/dL) is a common condition in patients who have cancer.Its prevalence varies widely, ranging from 30% to 90% of patients with cancer, depending on the type of cancer.Gynecological malignancies are among the tumors characterized by a higher prevalence of anemia at diagnosis (Ludwig et al., 2004;Seshadri et al., 2005, Achariyapota et al., 2010).Besides worsening the quality of life, the presence of anemia itself has been found to be a poor prognostic variable and is associated with shorter survival times for several cancers (Caro et al., 2001;Van Belle et al., 2003;Alici et al., 2006).
Endometrial cancer is the most common cancer of the female genital tract in developed countries.Most patients present with postmenopausal vaginal bleeding and the majority of endometrial cancers are diagnosed while the disease is limited to the uterine corpus.Total abdominal hysterectomy and bilateral salpingo-oophorectomy is the cornerstone of treatment.In Thailand, it is the third most common gynecological malignancy after cervical and ovarian cancer with an annual incidence of 4.3 per

Presence of Anemia and Poor Prognostic Factors in Patients with Endometrial Carcinoma
Wanitchar Wilairat, Mongkol Benjapibal* data are currently available about the clinical relevance of anemia in endometrial cancer.This study was undertaken to evaluate the relationship between pretreatment Hb and prognostic factors in Thai women with endometrial cancer.

Materials and Methods
We retrospectively reviewed the hospital records of patients with with histologically confirmed endometrial cancer who underwent primary surgery at the Department of Obstetrics and Gynecology, Siriraj Hospital, between January 2005 and December 2007.Criteria for inclusion in the study were as follows: age <80 years, no past or present secondary malignancy, no other nonmalignancy-associated anemia (e.g.thalassemia or chronic iron deficiency anemia).Surgery consisted of total hysterectomy with bilateral salpingo-oophorectomy and peritoneal washing for cytology.One hundred and eight-nine patients with tumor size larger than 2 cm in greatest diameter, high grade endometrioid carcinoma (grade 2 or 3), deep myometrial invasion (≥50% of myometrial thickness), or some specific histology (serous or clear cell) underwent pelvic or pelvic and para-aortic lymphadenectomy.The tumor stage and histological diagnosis of each case were surgically determined according to the criteria of the International Federation of Gynecology and Obstetrics (FIGO staging system, 1989) and the histological classification of the World Health Organization (WHO), respectively.Endometrioid tumors were graded as well (G1), moderately (G2), or poorly (G3) differentiated.Adjuvantly, patients with high grade tumor, serous or clear cell histology, deep myometrial invasion, cervical extension, adnexal involvement, positive peritoneal cytology, and lymph node metastasis received radiotherapy, or chemotherapy, or both.Patients without these histologic factors received no adjuvant treatment.Accordingly, 93 received radiation only, 25 received chemotherapy only, 7 received both radiation and chemotherapy, and 103 received no adjuvant treatment.
Baseline hemoglobin level in each patient was determined 24-48 hours before the surgery.Patients were divided into 2 groups based on the Common Toxicity Criteria from the National Cancer Institute which were patients with normal Hb value (≥12 g/dL) and patients with anemia (<12 g/dL).Association between clinicopathological variables (histology, grading, stage, myometrial invasion, lymphovascular space invasion, cervical involvement, adnexal involvement, peritoneal cytology, and lymph node status) and pretreatment Hb levels were described using Pearson's chi square test (or two-tailed Fisher's exact test wnen appropriate).Survival analysis was performed with Kaplan-Meier estimates.Univariate and Cox-regression models were used to evaluate the prognostic impact of various factors including Hb levels in terms of disease-free survival.
A p-value of <0.05 was taken for statistical significance.Data management and statistics were performed using SPSS software for Windows version 18.The research project was approved by the ethical committee of the Siriraj Hospital, Mahidol University, and was conducted in accordance with the Declaration of Helsinki.
Correlation between anemia and baseline patients' characteristics are given in Table 1.Overall mean hemoglobin level before surgery was 12.3 g/dl (SD 1.6).After classification, 139 (61%) patients had normal Hb level (≥12 g/dL), while the remaining 89 (39%) showed some degree of anemia.These 89 patients had significant higher rates of nonendometrioid histology, advanced FIGO stage, lymphovascular space invasion, cervical involvement, adnexal involvement, positive peritoneal cytology, and lymph node involvement than patients with Hb ≥12 g/dL.The 5-year disease-free and overall survival were significantly lower in patients with pretreatment Hb levels <12 g/dL compared with those with Hb ≥12 g/ dL (79.3% vs. 89.2%,p =0.044 and 87.6% vs. 99.3%,p <0.001, respectively) (Figure 1A, 1B).Univariate analysis demonstrated a significant influence of all prognostic variables in term of 5-year disease-free survival.However in multivariate analyses, the significance prognostic factors could be determined only for histology, myometrial

Discussion
Anemia is frequently observed in cancer patients at the time of diagnosis with a prevalence of 30% to 90%, depending on the type of cancer.Gynecological malignancies are among the tumors characterized by a higher prevalence of anemia at diagnosis.According to the European Cancer Anemia Survey (ECAS), the Australian Cancer Anemia Survey (ACAS), and our 6-month survey; the percentage of patients with gynecologic malignancy who had anemia at enrollment were 49.1%, 65%, and 66%, respectively (Ludwig et al., 2004;Seshadri et al., 2005, Achariyapota et al., 2010).Our data also show a high prevalence of anemia in patients with endometrial cancer before surgery (39%).
Besides the negative effect on QoL, the presence of anemia itself has been found to be an unfavorable prognostic factor in a number of malignancies, including carcinoma of cervix (Gucer et al., 1998;Mundt et al., 1998;Logsdon et al., 1999), ovary (Obermair et al., 1998;Obermair et al., 2000;Munstedt et al., 2003;Gadducci et al., 2005;Di Maio et al., 2006;Eichbaum et al., 2009;Pongsanon et al., 2011).However, only few data are currently available concerning the correlation between anemia and prognostic factors in endometrial cancer.In the first retrospective study by Tamussino et al. 18% of 212 patients with endometrial cancer had Hb level <12 g/ dL in blood samples drawn prior to surgery.Anemia was strongly associated with other unfavorable prognostic factors and was found to be related to an impaired overall survival at univariate but not at multivariate analysis (Tamussino et al., 2001).In 2009, Metindir et al. studied retrospectively 61 endometrial cancer patients who underwent surgical treatment consisting of total abdominal hysterectomy, bilateral salpingooophorectomy, infracolic omentectomy, pelvic and paraaortic lymph node dissection, and peritoneal cytology.The author demonstrated that decreasing preoperative Hb levels reflected poor prognostic factors such as positive cytology and cervical involvement (Metindir et al., 2009).Our present data confirm the previous studies involving patients with endometrial cancer that anemia prior to surgery is associated with other poor prognostic factors and may have prognostic impact on disease-free survival and overall survival.
The etiology of cancer-related anemia is multifactorial, possibly associated with nutritional deficiencies, bleeding from tumor sites, bone marrow infiltration by the tumor, and the myelosuppressive effects of anticancer therapies.Although abnormal vaginal bleeding is the most common presenting symptom in patients with endometrial cancer, it is rarely severe enough to cause anemia.The basis for the association between low pretreatment Hb level and treatment outcome is complex and influenced by many factors.Tumor cells are known to produce and secrete several soluble cytokines (such as interleukin-1, interferon-gamma, and tumor necrosis factor) that may be able to decrease Hb levels by hemolysis, suppression of erythropoiesis, and impairment of erythropoietin response of erythroid medullary precursors.According to this hypothesis, anemia should be regarded as a paraneoplastic syndrome, a phenomenon of the biologic aggressiveness of cancer (Mercadante et al., 2000;Bron et al., 2001;Tas et al., 2002;Dicato, 2003;Weiss et al., 2005).An alternative hypothesis to explain the prognostic role of anemia is tumor hypoxia.Low Hb levels result in decreased oxygen transport capacity which causes decreased tumor oxygenation (Vaupel et al., 2003;Boogaerts et al., 2005).The effects of oxygenation on tumor biology have been long investigated.Höckel et al. measured tumor oxygenation using pO2 polarography and found that pO2 was a useful prognostic factor in patients with advanced-stage cancer of the uterine cervix (Hockel et al., 1996).Emerging evidence indicates that a hypoxic microenvironment can have a major influence on the malignant phenotype of the tumor and that oxygen may play an important role in the response to cancer treatment (Young et al., 1988;Graeber et al., 1996;Reynolds et al., 1996;Hockel et al., 2001;Vaupel et al., 2003;Van Belle et al., 2003).Previous studies involving patients with cancer have shown that non-anemic tumors are more responsive to adjuvant therapy.Both radiotherapy and chemotherapy were reported to be more effective in well oxygenated than in hypoxic conditions (Dische, 1991;Hockel et al., 1996;Liang, 1996;Eisenhauer et al., 1997;Thews et al., 1998).This could be another reason why anemic cancer patients have poor survival rates.Based on a systemic review of 19 observational studies of patients with cancer, all but one of these studies showed an association between anemia and decreased survival (Knight et al., 2004).
In conclusion, this study confirms that low pretreatment Hb level is associated with other unfavorable prognostic factors in patients with endometrial cancer.In term of disease-free survival, the presence of anemia is proved to be a prognostic factor in the univariate but not the multivariate analyses.

Figure
Figure 1.A) Disease-Free Interval.B) Overall Survival.