AUTHORS:

Freddy Lynn Jade P. Moog M.D.(1), Angela D. Gaerlan, M.D.(1), Michael Vincent C. Saniel M.D (1), Miriam Joy C. Calaguas M.D. (1) and Luisito O. Llido M.D.* (2)

*Corresponding author; Email: llido2001@gmail.com

INSTITUTION WHERE RESEARCH WAS CONDUCTED:

1. Department of Radiation Oncology, St. Luke’s Medical Center, Metro Manila, Philippines
2. Clinical Nutrition Services, St. Luke’s Medical Center, Metro Manila, Philippines

ABSTRACT: | Back

Bacground: Radiation therapy in cancer patients causes hematologic abnormalities like decrease in hemoglobin, white blood cells, and platelets which affect wound healing, immune defense, and quality of life. The current availability of pharmaconutrients holds promise of modulating these adverse effects.

Objective: To determine the effect of oral supplementation with pharmaconutrients on patients with cancer undergoing radiation therapy on the following hematologic indices: hemoglobin, total WBC, neutrophil, lymphocyte, and platelet counts.

Methodology: Cancer patients who underwent radiotherapy from year 2007 to 2009 were grouped according to their diet: Study Group (n=24) which received standard diet plus oral nutritional supplements supplemented with pharmaconutrients and a Control Group (n= 32) which only had standard diet. The oral supplement is a 200 ml drink given twice per day providing 600 kcal, 40 g protein, 40% fat for energy, MCT=6.4 g, EPA (eicosapentanoic acid)=2 g, antioxidants (Vit A=600 ug, Vit C=75.2mg, Vit E=15 mg, B-carotene=1500 ug), zinc=8 mg, selenium=54 ug, and Fiber=6 g). The hematologic data: hemoglobin, total WBC count, neutrophil count, lymphocyte count, and platelet count, were taken at the start and after the completion of the prescribed radiation dose. The results were analyzed using paired t-test.

Results: In the study group the following blood indices were higher compared to the control group at the end of radiation therapy: hemoglobin in gm% (12.8 > 11.8, p=0.002), total WBC (7276 > 4877, p=0.0005), and neutrophil count (5363 > 3315, p=0.0007). The platelet pattern in the control group showed a significant decreasing pattern (265 → 231, p=0.003) while in the study group the decrease was not significant (278 →254 p=0.098). There was no difference in the lymphocyte count.

Conclusion: Oral supplementation with pharmaconutrients in cancer patients undergoing radiation therapy resulted to lesser hematologic toxic changes in hemoglobin, total WBC, neutrophil, and platelet counts.

KEYWORDS: radio-oncology, immuno-nutrition, blood indices, fish oils (EPA/DHA), antioxidants

INTRODUCTION | Back

Cancer is associated with metabolic and neuro-chemical modifications leading to poor intake and weight loss which have a negative impact on the nutritional status of cancer patients. Nutritional status is usually poor before any therapy starts and may even get worse through the side effects of chemotherapy and radiation therapy. The incidence of malnutrition in patients with cancer ranges from 40 to 80% (1) and frequently occurs in patients with cancer of the gastrointestinal or head and neck area (2,3). Malnutrition increases the risk of infections, treatment toxicity and health-care costs and decreases response to treatment, quality of life (QoL) and life expectancy (4).  

Numerous studies have been published evaluating the value of nutritional support in cancer patients, however, these often focus on the association between nutritional status and outcomes such as survival rate and the treatment response. Few studies concentrated on the benefits of nutrition on treatment side effects. One such study showed that adequate nutrition support during radiotherapy can decrease the impact of side effects, minimize weight loss, improve quality of life and help patients recover from the radiotherapy more quickly (5).

Radiotherapy treatment is associated with undesirable side effects including cells of the hematopoietic system are notably radiosensitive. Cell death may occur in the first or subsequent division following irradiation resulting in the common side effect of bone marrow toxicity. The complications of cytotoxic cancer therapy (i.e. chemotherapy and radiotherapy) have led physicians to investigate adjunctive treatments in alleviating cancer treatment-related side effects. Currently the roles of pharmaconutrients such as omega-3 fatty acids and antioxidants in lessening these side effects have been raised. (6) It is, therefore, the aim of this study to determine the effect of using oral nutritional formulas supplemented with pharmaconutrients on the hematologic profile specifically on hemoglobin, total WBC, neutrophil, lymphocyte, and platelet counts for patients with cancer undergoing radiation therapy.

METHODOLOGY | Back

Patients who underwent radiotherapy (RT) at the Department of Radiation Oncology-St. Luke’s Medical Center were block-randomized to be either in the Study Group or the Control Group. All patients from year 2007 to 2009 were included in this study. Inclusion criteria were out-patients having at least 20 fractions of radiotherapy to the head and neck, chest and abdomen/pelvis. Patients were deemed ineligible if they were hospital inpatients for greater than 5 days and receiving enteral or parenteral nutrition.

In all, 56 patients were eligible for inclusion (31 males, 25 females; mean age 54 to 60 years) and were grouped to those who were given standard diet plus oral nutritional supplements composed of a micronutrient fortified beverage (n= 24) and those on standard diet alone (n= 32).

A total of 43 % of subjects were receiving radiotherapy to the head and neck, 39 % of patients were receiving radiotherapy to the abdominal and pelvic area and 18 % were receiving radiotherapy to the chest and mediastinum area. Subject characteristics at baseline are presented in Table 1.

Oral Supplementation with Immunonutrients
The micronutrient supplement was developed and produced by Fresenius Kabi as a cappucino-flavored micronutrient-fortified beverage drink. Each serving contained 630 kJ of energy, with two servings providing 1260 kJ to each participating patient. The supplement is unique in that it is rich in fish oil (EPA + DHA), high in energy, high in protein and high in fat including MCT, high in antioxidant vitamins and contains fiber and other micronutrients (Table2). Each study participant consumed the beverage drink twice a day in between meals daily during the course of the radiation treatment. 

Data collection and Statistical Analysis
All subjects had complete blood count (CBC) during the first week and at the end of RT. The following parameters: hemoglobin, total WBC, neutrophil, lymphocyte, and platelet counts were compared during the first week of radiotherapy and after completion. The results were analyzed using paired t-test. Significance was pegged at < 0.05 (9). The NCSS 2004/PASS 2002 software was used in the statistical analysis of the data (© 2004 Jerry Hintze, McGraw-Hill Companies).

RESULTS | Back

In the study group the following blood indices were higher compared to the control group at the end of radiation therapy: hemoglobin in gm% (12.8 > 11.8, p=0.002), total WBC (7276 > 4877, p=0.0005), and neutrophil count (5363 > 3315, p=0.0007) as shown in Figure 1. The platelet pattern in the control group showed a significant decreasing pattern (265 → 231, p=0.003) while in the study group the decrease was not significant (278 →254 p=0.098). There was no difference in the lymphocyte count and the lymphocyte pattern showed that the decrease was significant in both groups (Table 3).

DISCUSSION: | Back

The most common form of cell death in radiotherapy is mitotic death. In tissues with a rapid turnover rate such as the hematopoietic system, the change can be seen immediately. The stem cells of the hematopoietic system are radiosensitive; the different cell types display an extensive range of radiosensitivities. For instance there are types of lymphocytes that are very radiosensitive while plasma cells and macrophages are very resistant. These differences are most likely owing to the degree of differentiation and maturation of the cell type and also if cell division is required for participation in the response. The transit time from stem cell to fully functioning cell that differs for the various circulatory blood elements and these differences may account for the complex changes in blood count seen after irradiation.

Figure 2 shows a diagram of the time course after exposure for the peripheral blood lymphocyte count from persons involved in radiation accidents (5). Data are also provided for neutrophils and platelets for comparison (6). As seen in the graphs, the lymphocytes reached its lowest level more rapidly as compared to the neutrophils for the same dose. This difference could be due to what is called the interphase death. While most cells die attempting to divide, some types of lymphocytes die immediately and this nonmitotic form of death is called interphase death and the mechanism to this is still not clear. There are three components in the cell killing as shown in Figure 2 when lymphocyte count is plotted against time: an acute phase in which nadir levels are reached in a matter of hours; a dose-dependent plateau that persists for -45 days; a slow recovery that lasts for several months before normal values are reached. As can be seen, the recovery of normal lymphocyte count was reached more slowly than the recovery of normal platelet or neutrophil count. This distinction probably illustrates that lymphocyte maturation occurs more slowly than the maturation of platelets and neutrophils since the improvement of all three cell types is dependent on the pluripotential stem cells.

Stem cells of the hematopoietic tissues are located primarily in the bone marrow, with 60% located in the pelvis and proximal sections of the femur and humerus. Bone marrow toxicity can lead to neutropenia and lymphophenia increasing the risk for infection, thrombocytopenia and its association with increase risk for bleeding and anemia with its multiple consequences including fatigue and hypoxemia.  After large doses of radiation, number of blood cells is altered lymphophenia is followed by granulopenia, then thrombopenia and finally anemia.   

Omega-3 fatty acids (also referred to as ω−3 fatty acids or n−3 fatty acids) are a family of unsaturated fatty acids  that the human body cannot synthesize de novo. Nutritionally important omega fatty acids include α-linolenic acid (ALA), eicosapentanoic acid (EPA), and docosahexaenoic acid (DHA), all of which are polyunsaturated fatty acids (PUFA). The omega-3 PUFA have been given interest with regard to their effects in reducing tumor growth and metastasis. A number of reports have described their beneficial effects in decreasing the incidence of carcinogen-induced tumors and also in decreasing tumor growth rates and spread in animal models (7-8).  Aside from these effects there are other reported benefits of omega-3 PUFA dietary supplements given before or during any cytotoxic cancer therapy (i.e. chemotherapy and radiation therapy) including: reversing tumor cell drug resistance in chemotherapy (9); reducing the gastrointestinal, hematological, or cardiac side effects of various chemotherapeutic treatments (10-12); and decreasing cancer cachexia (13-15).  Likewise, antioxidants have their role in decreasing the adverse effects of cytotoxic cancer therapy and the evident mechanism is due to the fact that antioxidants bind to free radicals thus preventing oxidative damage, and it is well known that radiation as well as many chemotherapeutic agents kills cells by generating very high levels of free radicals.

In the current study we focused on the effect of omega-3 PUFA and antioxidants on the hematological side effects of radiation therapy.  As seen in the results, the study group had significantly higher blood counts as compared to the control group at the end of the study specifically the hemoglobin, WBC and neutrophils parameters. The platelet count although it showed no significant difference in the study group as compared to the control group at the end of the study the decreasing pattern is  significantly lower in the control group. The lymphocyte pattern showed that in both groups it was significantly decreased by the end of the study, probably due to the premise mentioned earlier that lymphocytes are extremely radiosensitive because of interphase death.

A number of studies are in support of the potential effects of omega 3-fatty acids and antioxidants in minimizing the side effects of cytotoxic cancer therapy.  In a study done by Hardman (16) bone marrow cellularity was increased when omega-3 fatty acids and PUFA were included in the diet of rats treated by doxorubicin. According to their findings the possible explanation for the higher erythrocyte counts is the decreased osmotic fragility of the erythrocytes because of incorporation of omega-3 fatty acids in the erythrocyte membrane. In a similar study (17) it was reported that the erythrocytes of mice given 12% fish oil had higher levels of omega-3 fatty acids and their erythrocytes were also less osmotically fragile. Frenoux et al. (18) report that a diet rich in g-linolenic acid (18:3n-6), EPA, and DHA increased the antioxidant status of rats, defined as the ability of RBC to withstand free radical-induced hemolysis. This could result in a longer life span for individual erythrocytes, a reduced need for new erythrocytes, and a reduced need for proliferation of erythroblasts to maintain RBC counts in the peripheral blood. Atkinson et al. (19) reported that the cellularity and the number of granulocyte- macrophage colony-forming units were higher in bone marrow of rats fed DHA. It seems likely that the EPA and DHA in the fish oil consumed by mice should have a similar effect to purified DHA on the bone marrow and that increased bone marrow cellularity would result in higher peripheral blood counts as was observed. Also In a study done by Youssef Al-Tonbary (20) oxidative stress was found to be increased during cytotoxic treatments and antioxidant status decreased in a group of children with Acute Lymphoblastic Leukemia.  In the group that received Vitamin E and N-Acetylcysteine there were reduced chemotherapy and radiotherapy toxicity and decreased occurrence of toxic hepatitis, hematological complications, and need for blood and platelet transfusions.

Aside from omega 3-fatty acids and antioxidants, the beverage is also rich in other vitamins and minerals known to help increase hemoglobin levels. The effect on hemoglobin increase could be due not only to increased iron status as provided by the supplement, but also to vitamin A, folate, vitamin B12, zinc and other immunonutrients essential to normal erythropoiesis (21). Furthermore, in addition to these independent effects of various immunonutrients, the existence of interactions between nutrients is another argument for supplementing with multiple instead of single micronutrients. For example, vitamin C increases the absorption of iron, copper deficiency may lead to iron deficiency anemia (22), and zinc is involved in the conversion of β-carotene to vitamin A (23).

CONCLUSION: | Back

In this study it was found that oral supplementation with immunonutrients in cancer patients undergoing radiation therapy resulted to lesser hematologic toxic changes in hemoglobin, total WBC, and neutrophil count. This advantage is possibly due to the high calorie, high protein, high fat (omega 3-fatty acids) and low carbohydrate diet together with the antioxidants and vitamins and minerals known to help increase these blood components.

IMPLICATIONS FOR PRACTICE

Patients at risk for hematologic toxicity, such as those undergoing radiotherapy and even chemotherapy, should receive an additional oral supplementation to lessen the need for blood transfusions, avoid treatment stoppage and even to improve post-radiation outcomes.

REFERENCES: | Back

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Abstract | Introduction | Methodology | Results | Discussion | References | Back to Total Names Codes