A scoring system for the effectiveness of Hepatitis-B vaccination in children receiving treatment for cancer

Transcription

1 Turkish Journal of Cancer Vol.3/ No. 4/2 A scoring system for the effectiveness of Hepatitis-B vaccination in children receiving treatment for cancer FUNDA ÇORAPÇIOĞLU, FAİK SARIALİOĞLU, NUR OLGUN, KAMER MUTAFOĞLU UYSAL Department of Pediatric Oncology, Dokuz Eylül University, Institute of Oncology, İzmir-Turkey The purpose of this study was to determine the variables that may influence the outcome of a Hepatitis-B (HBV) vaccination program in children who were receiving treatment for cancer. This study was performed retrospectively using hospital records belonging to the children with cancer who received HBV vaccine in our center between January 993 and June 998. Only patients who received three doses of HBV vaccine for three consecutive months and whose antibody titers were determined at least once within the first six months after the last dose of vaccination were included in this study. The effect of patients age, sex, tumor type and vaccine type on the outcome of vaccine response were evaluated. To assess the effect of combined modality treatment on the vaccine response, a risk factor scoring was calculated for each patient. In addition, possible relationship between the vaccination response and the lowest blood lymphocyte concentration during the vaccination period was also evaluated. A total of 52 patients were studied. The rate of seroconversion was 65% in the overall group. No significant effects of patients age, sex, tumor type and vaccine type on the vaccine response were seen. When surgery, radiotherapy, chemotherapy and infectious complications are accepted as risk factors, the total risk factor score showed significant difference among the groups according to anti-hbs titers. The anti-hbs titers showed a significant correlation with the lowest concentration of blood lymphocytes during the vaccination period. The total risk factor scoring and blood lymphocyte concentration helped to predict the response to immunization in children with cancer. [Turk J Cancer 2;3(4):5-57] Key words: Hepatitis-B vaccination, childhood cancer, anticancer therapy 5

2 ÇORAPÇIOĞLU et al. 5 Hepatitis-B virus (HBV) infection, with the characteristics of fulminant course and high rate of progression to the chronic phase, is a serious clinical problem for children with cancer who receive anticancer treatment. Immunization plays a vital role in prophylaxis but insufficient antibody response is a major problem (,2). Multimodal anticancer therapy protocols, that include surgery, chemotherapy (CT) (with different drugs, doses and schedules) and radiotherapy (RT) affect and impair the immune response in a complex manner (3). Thus several variables may influence the antibody response to vaccination in children with cancer and whole consequences are not clear at present. Our aim in this study was to determine correlates of the antibody response in the vaccinated children receiving anticancer treatment. We also wanted to develop a scoring system for predicting the antibody response in these children. Materials and Methods We included in our study, 52 of the children admitted to our center between January 993 and June 998 whose cancer diagnosis became certain and have been included in the vaccination program after the HBV serology was determined as negative. Basic inclusion criteria was that the patient should have had the Hepatitis-B vaccination with a 2 nd (Engerix B; Smith Kline Beecham) or 3 rd (GenHevac B; Pasteur Mérieux) generation vaccine type and having the vaccine response evaluated at least once by anti-hbs assessment, between 3 rd and 6 th months of the initial vaccine dose. Any one of the mentioned types of Hepatitis-B vaccine was given as a 4 µg intramuscular dose to the left deltoid muscle based on, and 2 months schedule. Dosage depended on neither age nor the body weight of patient (4,5). The study design was retrospective and non-interventional. All data were collected from the charts of patients. Patients age, sex, tumor type, vaccine type and the values of total lymphocyte counts (TLC) during vaccination period were noted. Major surgery (except biopsy), RT, CT and infections are all known to cause decreased responsiveness to vaccination when they expose during critical periods prior to or after vaccination (3,5). Treatment modalities listed below were defined as immunosuppressive: surgery, performed within the period of one month before and three months after the first dose vaccination; RT given within the period of two months before and three months after the first dose of vaccination and CT given within the period of one month before and three months after the first dose of vaccination (3,6,7). Treatment modalities used out of these intervals, were accounted as treatment periods at which immunosuppressive effect was not expected. We determined the immunosuppressive effect of the anticancer treatment taking into account the following features: The type of the surgical intervention, RT site (patients who had received RT were grouped according to the site as primary tumor site, mediastinal and craniospinal) and CT intensity (patients received CT were grouped according to CT doses and immunosuppressive effects of chemotherapeutic agents). Chemotherapy protocols were grouped according to the post-therapeutic myelosuppression rate observed in the patients: mild if the rate was less than 5%; moderate, if it was between 5% and 2% and severe, if the rate was more than 2%. The immunosuppressive effects of CT and/or RT

3 52 HBV VACCINATION in CHILDREN with CANCER obviously continued for more than three months. The first three months were the focus of interest because this was the time of evaluation of the first antibody titer. In addition, patients were evaluated for having any episode of local or systemic infection during the study period. According to definitions given above, we developed a scoring system (Table ). The total risk factor scores of each patient were calculated. Table Scoring system for oncological therapy-induced immunosuppression Risk factor Surgery (except biopsy) Radiotherapy Chemotherapy Infection No immunosuppressive surgery Immunosuppressive surgery No immunosuppressive radiotherapy Local immunosuppressive radiotherapy (except mediastinum) Mediastinal immunosuppressive radiotherapy Craniospinal immunosuppressive radiotherapy No immunosuppressive chemotherapy Mild immunosuppressive chemotherapy Moderate immunosuppressive chemotherapy Severe immunosuppressive chemotherapy No infection for at least three months after the first dose of vaccine One or more infectious episodes within three months after the first dose of vaccine Point Quantification of the antibodies against the HBsAg was done by enzyme immunoassay (Cobas Core; Anti-HBs Quant. EIA-Roche) using serum prepared from venous blood samples taken within the first six months after the last dose (8). Concentration below miu/ml were considered seronegative and above values were accepted as seropositive. Titers between and miu/ml were regarded as low and those above miu/ml as high antibody response (4, 9). Statistical analyses: The SPSS 6. program were used for data analysis. We used chi-square test to evaluate the effects of age, sex, tumor and vaccine types on vaccine response; Kruskal-Wallis test to determine the relationship between anti-hbs titers of risk factor groups and the least lymphocyte counts; Spearman correlation analysis to assess the correlation between TLC and anti- HBs titers.

4 ÇORAPÇIOĞLU et al. 53 Results The study group included 52 patients. Some of the important characteristics of study group are given in Table 2. Table 2 Characteristics of the study group Total number of patients Observation period (months), mean±sd (range) Age (years), mean±sd (range) Age groups years > years Sex Male Female Patients with lymphoproliferative tumors Patients with solid tumors Vaccine type 2 nd generation 3 rd generation ±6.2 (6-66) 9.9±5. (9 months-8 years) The first anti-hbs titers taken into account were evaluated 5.±2. months after the first dose of vaccine. Patients having > miu/l anti-hbs titers (low and high antibody response, 29% and 36% of patients respectively) were accepted as seropositive and the seroconversion rate was 65% in the whole group. The antibody titer was between and in 4% of the patients and 3% of the patients antibody titer was miu/l. The antibody titer was assessed only once in 3 patients, twice in 2 patients and three times for two patients after vaccination. Detailed time dependent analysis of vaccine responses in this group could not be performed because of the insufficiency of the number of patients and heterogeneity of patients' properties. No significant relationship was found between the antibody response and the patients' age, sex and tumor type (p=.23,.322,.43 respectively). Twenty nine patients received 2 nd generation and 23 patients received 3 rd generation vaccine. Type of the vaccine had also no significant effect on antibody response (p=.236) (Data not shown). Total risk factors score calculated for each patient showed significant difference among the groups according to anti-hbs titers (p=.36) (Table 3). During the vaccination period, blood lymphocyte counts of 4 patients were obtained more than once. Significant correlation was identified between anti- HBs titers and the lowest TLC in this group (p<., r=,57) (Figure ). There was also a significant relationship between total risk factor score and TLC (p=.3). None of the patients developed Hepatitis-B infection during the study period

5 54 HBV VACCINATION in CHILDREN with CANCER Table 3 Relationship between seroconversion rates and the risk factor scores According to each score According to the grouping of scores *Anti-HBs titer > mlu/l Total risk score n Seroconversion* rate 5 4/5 7 7/ / /5 4 4/ 5 4 /4 6-7 / % % Anti-HBs titer (miu/l) The lowest lymphocyte number Fig. Relationship of the lowest total lymphocyte number with vaccine response

6 ÇORAPÇIOĞLU et al. 55 Discussion It is well known that multimodal anticancer therapy leads to immune system dysfunction (,3). Studies regarding Hepatitis-B vaccination in children with cancer have observed the effects of age, sex, tumor and vaccine type on antibody response. This response has been reported to be better in children younger than years and in girls (4,9). Studies searching the efficacy of the 3 rd generation vaccines containing pre-s2 protein showed that this type of vaccine is more effective to reach the seroconversion in the patient groups with immunosuppression, but the issue is still subject to discuss (,2). Different studies stated that the highest antibody responses were obtained in solid tumor groups since impaired number and functions of lymphocytes cause poor vaccine response in lymphoreticular malignancies (2,3,3). On the contrary Hovi et al. (4) reported lower vaccine response in patients with solid tumors. This study emphasized that the treatment for solid tumors consisted mostly of courses with intensive multiagent CT. In our study, no significant effect of age, sex, vaccine type and tumor type on seroconversion rate was found. These results may be affected by the small number of patients in our study. Each of all components of anticancer treatment is a cause of immunosuppression. In surgery disturbance of tissue integrity, releasing of stress hormones and cytokines contribute to immunosuppresion (5). In experimental models, RT causes suppression of cellular immunity for 3 weeks to 4 months period if applied in high doses and wide areas (3,6). Chemotherapeutic agents affect many steps of cellular and humoral immunity. They cause disorders in both number and function of phagocytic cells, T cell lines and antibody production. Intensity of CT protocol is an important factor that influence vaccine response of the patients (3,7,6). Even though the negative effects of anticancer treatment on vaccine response are known, widely used combined treatment protocols and impossibility of elimination of other contributing factors lead to difficulty on making comment on the effects of each treatment modality. Infections occurring as a complication of these modalities also contribute to immune system dysfunction (3). In this study, each of the factors like surgery, RT, CT and infections have been accounted as risk factors and a risk factor scoring for each patient was calculated. We determined that vaccine responses of the patients whose total risk factor score are high, were considerably low. Regarding this, in children with cancer, treatment modalities form a complex model. Thus, risk factor scoring is a realistic model and we stated that vaccine response should be taken under close observation in patients with high risk factor scores. The amount and the function of phagocytic cells and T lymphocytes, which are activated in the first steps of vaccine response, show same changes due to anti-cancer therapy; this is an issue emphasized in recent studies. CD4(+) T cells are known to be affected relatively more than CD8(+) cells. In these patients, antibody response is also suppressed. In children whose treatment is over, disorder of cellular and humoral immune system may still be present until 9 to 2 months after the treatment (5,6,7). Since we studied retrospectively, T cell subgroups and immunoglobulin levels of the patients could not be obtained.

7 56 HBV VACCINATION in CHILDREN with CANCER However we found that the lowest TLC, measured during vaccination period, is a parameter that significantly affects the antibody titer level. On the other hand, Hepatitis-B infection is not detected in patients who could not provide seroconversion in vaccination period. Although it may not be easy to make further comments because of the small number of patients in the group, studies regarding the question like "Is anti-body titer, a real indicator for protectiveness in children with cancer?" should be conducted in the future. References. Akyol H, Sarıalioğlu F, Büyükpamukçu M. Hepatitis-B virus infections in pediatric patients receiving anti-cancer chemotherapy. Turk J Cancer 99;2: Meral A, Sevinir B, Günay Ü. Efficacy of immunization against Hepatitis-B virus infection in children with cancer. Med Pediatr Oncol 2;35: Lehrnbecher T, Foster C, Vazquez N, et al. Therapy-induced alterations in host defense in children receiving therapy for cancer. J Pediatr Hematol-Oncol 997;9: Berberoğlu S, Büyükpamukçu M, Sarıalioğlu F, et al. Hepatitis-B vaccination in children with cancer. Pediatr Hematol Oncol 995;2: Weitberg AB, Weizman SA, Watkins E, et al. Immunogenicity of Hepatitis-B vaccine in oncology patients receiving chemotherapy. J Clin Oncol 985;3: Hall EJ, Cox JD. Lymphoma and leukemia. In: Moss WT, Cox JD, editors. Radition Oncology: Rationale, Technique, Results, Physical and Biologic Basis of Radiation Therapy. 7 th ed. St. Louis, Baltimore: Toronto,989; Ridgway D, Woff LJ. Active immunization of children with leukemia and other malignancies. Leuk Lymphoma 993;9: Ostrow DH, Edwards B, Kimes D, et al. Quantitation of hepatitis B surface antibody by an automated microparticle enzyme immunoassay. J Virol Methods 99;32: Hollinger BF. Factors influencing the immune response to hepatitis-b vaccine, booster dose guidelines and vaccine protocol recommendations. Am J Med 989;87: Wood RC, MacDonald KL, White KE, et al. Risk factors for lack of detectable antibody following Hepatitis-B vaccination of Minnesota health care workers, JAMA Korea 994: Trépo C, Rougier P, Gassin M. Preliminary results of a randomised comparative immunogenecity study of three recombinant HBV vaccines in healthy medical personnel: confirmation in man of the enhancement of anti- HBs response by pre-s2. Progress in Hepatitis-B Immunization. Ed & P Coursaget 99;9: Coursaget P, Bringer L, Sarr G, et al. Comparative immunogenicity in children of mammalian cell-derived recombinant Hepatitis-B vaccine and plasma derived Hepatitis-B vaccine. Vaccine 992;: Entacher U, Jürgenssen O, Thun-Hohenstein L, et al. Hepatitis-B vaccination and immune response in children with malignant disease. Eur J Pediatr 985;44:6-3.

8 ÇORAPÇIOĞLU et al Hovi L, Valle M, Siimes MA, et al. Impaired response to hepatitis-b vaccine in children receiving anticancer chemotherapy. Pediatr Infect Dis J 995;4: Wilmore DW. Homeostasis: Bodily changes in trauma and surgery. In: Sabiston DC Jr, editor. Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 5 th ed. WB Saunders Company, 997; Mustafa MM, Buchanan GR, Winick NJ, et al. Immune recovery in children with malignancy after cessation of chemotherapy. J Pediatr Hematol Oncol 998;2: Alanko S, Perlliniemi TT, Salmi TT. Recovery of blood lymphocytes and serum immunoglobulins after treatment of solid tumors in children. Pediatr Hematol Oncol 994;:33-45.