Secondary Malignancies in Pediatric Population

Secondary Malignancies in pediatric PopulationSecondary malignancies in pediatric population a case series and literature reviewIntroductionAdvances in checkup c atomic number 18 therapies and archaeozoic diagnosis has fulfilled the hope for normal life foresight in many cancerous perseverings with a 5 class survival rate for at least 75% in childhood (1). Although expecting 70% long-term survive in children with described cancer, 60-70% of them will develop a consequential disability by the primary(a) cancer word as a cost(2). Development of mo cancer (a new cancer following the first aft(prenominal) a transact treatment , whether the onset is in childhood or as an adult, except histologically different from the origin) is a grieving expected side- effect embracing 6% of all diagnosed cancers in Unites states (3), as a result of the carcinogenic cause of chemotherapy drugs and shaft on both normal and cancerous cellular phones (4). When major risk factors for dev eloping the alternate malignancies in childhood survivors such as the primary origin, early diagnosis , onset age, duration of therapy , dose authorized and familial history of the cancer are considered , radiation associated solid tumors as well as hematological malignancies account for the most probable types in secondary cancers (5-8). in spite of the excellent prognosis for long-term survival in childhood nifty lymphoblastic leukemia, retinoblastoma and Hodgkin lymphoma , radiation associated secondary solid tumors almost covers two-thirds of all cases in long term (4, 9, 10). The increased risk of the incidence persists for at least 30 years aft(prenominal) the primary treatment of Hodgkin lymphoma (11). Chemotherapy agents, such as alkylating agents have been proposed to play role in secondary cancers incidence. Although studies in field of secondary cancers and their relationship with administered treatment protocols have been a field of interest for queryers, data re garding this topic is rather inconclusive because of variety of factors involved (12, 13).In familiarize case series weigh, a series of pediatric secondary malignancies with different primary cancers and subsequent treatment protocol are presented.MethodsIn this case series deliberate, 11 samples were selected retrospectively from patients attending at Mahak Pediatric cancerous neoplastic disease Treatment and Research Center (Tehran, Iran) from 2007 to 2016, who were diagnosed with a secondary cancer. All a patients had been already diagnosed with a primary cancer and had received standard treatment protocol of primary cancer. Clinical information was obtained by the authors or provided by referring physicians. Using patients records, past medical history, type of primary and secondary cancer including regularity of diagnosis, cumulative doses of cytotoxic drugs and treatment outcome was extracted. In case of any missing records, patients were contacted to acquire required dat a. All patients had already undergone required diagnostic modalities to diagnose malignancies properly. A literature search in Ovid, Medline and PubMed was carried out using the terms secondary cancer, chemotherapy and radiotherapy to provide enough material to discuss findings. A medical information scientist performed the literature retrieval and the initial screening of relevant studies.Statistical analysis was performed using SPSS version 16. Quantitative data was expressed as stringent standard deviation and frequency (percentage).Case historyPatients primary malignancies type and administered therapy are shown in give in 1. Patients Secondary cancer type and features of therapy administered is shown in Table 2.Patients zero(prenominal)1 was a 15 years overaged girl, who presented with pain in only whentocks when she was 4 years old, then following devise marrow biopsy. She was first diagnosed with Ewing sarcoma. During 1 year of treatment, She underwent VAC/IE (vincrist ine (videocassette recorder) + doxorubicin (ADR) + cyclophosphamide (CPA) alternating with ifosfamide (IF) + etoposide) regimen. This treatment protocol led to finish remission. later on 1 year, during a routine laboratory test, elevated levels of white profligate cell was detected. Following flow-cytometry and cyto hereditary studies, pre-B cell precursor ALL diagnosis was confirmed, which was associated with central nervous system involvement according to lumbar puncture examination. During 3 years, she was administered with X regimen. Also, complete systema nervosum centrale prophylaxis protocol was also administered. Complete remission was confirmed for her later treatment. During 6 years of implement, she has non had any signs of relapse.Patient No.2 was a 12 years old boy, who attended clinic presenting with balance disorder. Following 24-hour urine catecholamine test and MIBG scan neuroblastoma diagnosis was made. He underwent OPEC regimen (vincristine, cisplatin, etopo side and cyclophosphamide) and daunorubicin, which led to remission. When he was 6 years old, in a routine laboratory test, elevated white rakehell cells were detected. Flow-cytometry studies indicated ALL(L1), so the patient was administered with standard regimen and intrathecal chemotherapy. This treatment led to complete remission. During 2 years of follow-up patients has no sign of relapse.Patient No.3 was a 14 year old, who had first presented with headache. Following imaging, meduloblastoma diagnosis was made. later 10 months of chemotherapy and radiation, patient had complete remission. Patient had a history of heart failure. Two years later, an elevated white blood cells were detected in complete blood count. Flow-cytometry studies revealed non-M3 AML. Despite chemotherapy, patient was expired after 12 days of treatment initiation.Patients No.4 was 12 years old girl, who presented with intermittent coughs. So, bronchoscopy was performed, which revealed small cell lung tumor . She underwent 4 months of chemotherapy , radiotherapy and pulmonic lobectomy. During this period, when she had been receiving chemotherapy for 3 months, she presented altered level of consciousness. Following lumbar puncture and cerebrospinal fluid flowcytometry AML diagnosis was made. She underwent central nervous system prophylaxis. Despite 3 months of treatment, patient was expired.Patient No.5 is a 21 year old girl, who first presented with right sided pre-orbital swelling when she was 12 years old. Following biopsy, histiocytosis X diagnosis was made. After treatment she was in complete remission, but two years later a brain CT scan revealed signs of disease relapse. when 15 years old, delinquent to the elevated white blood cells count and flow-cytometry AML(M1) diagnosis was made. Although patient underwent 2 years of chemotherapy, she did not continue the treatment process, so she was lost to follow-up.Patient No.6 is a 13 year old girl, who was first diagnosed with reti noblastoma when she was 4 months old. She underwent VEC (vincristine+etoposide+carboplatin) chemotherapy protocol and radiotherapy. Enucleation was performed for both eyes when she was 2 years old. At last, patient had complete remission. When she was 11 years old, she attended clinic with right-sided face pain. After biopsy, osteosarcoma diagnosis was made. She underwent MAP protocol (High-dose methotrexate, cisplatin, and doxorubicin), ifosfamide and etoposide for 40 weeks. After complete remission, she has had no sign of relapse so far.Patient No.7 is a 12 years old boy, who was first diagnosed with actrocytoma grade II-III shown as a supratentorial mass in brain imaging which was confirmed by biopsy. Then, patient underwent PCV (lomustine + procarbazine + vincristine) plus temozolomide protocol and radiotherapy. After 6 courses of chemotherapy, patients underwent gross total resection of tumor. One year after complete remission, patient presented with backache. Biopsy indicated gliosarcoma. So far patient has undergone radiotherapy and surgery, also he is dummy up going through chemotherapy.Based on the literature review,DiscussionBased on information from the U.S. Surveillance Epidemiology, about 16 percent of cancers are in persons with a prior history of cancer. It is thought that the main point behind this phenomenon is that patients after treatment of cancer, patients live long enough to have second cancer (14). But as matter of fact, the cancer experience does not finish as treatment does. malignant neoplastic disease and the administered treatment (including radiation, chemotherapy, surgery, hormonal therapy, and newer drug therapies) can yarn-dye almost every aspect of an individuals life. Besides, not considering the secondary cancers as a part of natural incidences of time course, secondary cancers might be due to the treatments received by the patients at time of primary cancer treatment (15). Most of the therapies used in cancer, aim at dest roying cancerous cells by affecting their genetic structures, but in therapy process normal cell are also involved just as malignant cells. This involvement will consequently have to apoptosis, mutation or recovery. Mutations are tried to be minimized by the corrective mechanisms defined in cells and immune system (16). When these mechanisms fail a impertinently established malignity is unavoidable.Current study presents 7 patients with secondary cancers (5 hematological malignancies, 1 osteosarcoma and 1 gliosarcoma). All secondary malignancies in current study had mesanchymal components, also both localized secondary malignancies (gliosarcoma and osteosarcoma) were in previous radiotherapy field. Vincristine, etopside and alkylating agents (such as ifosfamide and cyclophosphamide) were the most used cytotoxic drugs. Both patients No.3 and 4 who were expired, had undergone chemotherapy and radiotherapy.Based on the literature review, alkylating agents such as ifosfamide and cycl ophosphamide are know of mainstays of treatments for hematologic malignancies, solid tumors and preconditioning regiments for hematologic stem cell transplantation, but it has been shown that they are important risk factors for schooling of secondary malignancies as they increase in the relative risk for a secondary malevolence of 1.5-2.5 (17-21). Especially, exposure to alkylating agents has been associated with an increased risk hematologic malignancies development, often referred to as therapy-related acute myelogenous leukemia (22, 23). Therapy-related AML seems to have an onset within 5-7 years after therapy for primary cancer, and this risk appears to increase further with the concomitant use of epipodophyllotoxins such as etopside (24). In present case series, patients No. 1,2 and 4 had also received a combination of alkylating agents and etopside, which could have been a major risk factor for the secondary malignancy.In a study by Bhatia et al. investigating Therapy-relate d myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone, it was concluded that exposure to ifosfamide from 90 to 140 g/m2, cyclophosphamide from 9.6 to 17.6 g/m2, and doxorubicin from 375 to 450 mg/m2 increased the risk of tharapy related myelodysplasia and acute myeloid leukemia significantly (25). Patient No. 1 had also received doxorubicin, ifosfamide and cyclophosphamide , but the cumulative doses were not that much of what Bhatia et al.(25) mentioned. In a study by Granowetter et al. about comparing dose-Intensified with standard chemotherapy for non-metastatic Ewing sarcoma, it was concluded that dose escalation of alkylating agents do not improve the outcome for patients with Ewing sarcoma of bone or soft tissue (25). So, by taking this into account, more cautious approaches should be chosen when deciding about chemotherapy doses, especially alkylating agents.Topoisomerase II inhibitors as some other well-known chemo altera tive agents are widely used treatment of pediatric malignancies. This category includes anthracyclines (e.g. doxorubicin) , anthracenediones as well as epipodophyllotoxins (e.g. etoposide and tenoposide)(26). Therapy related AMLs due to topoisomerase II inhibitors are known as an entity of therapy and incidence varies in literature, but has been reported as high as 9% (27-29). In contrast to the latency period after exposure to alkylating agents which was about 5-7 years, therapy related AMLs after topoisomerase II exposures have a more early onset, usually within 2-3 years after primary malignancy chemotherapy (24). In present case series, the time interval between secondary AMLs and primary therapy were less than 2 years, which is less than what mentioned for alkylating agents and topoisomerase II inhibitors this might be due to the combination of these categories in our therapy protocols. Based on studies, the most effective agents against secondary hematologic malignancies due t o top topoisomerase II inhibitors are cytarabine, dactinomycin, daunorubicin, docetazel, mitoxantrone, gemcitabine, mitomycin C, etoposide, teniposide, topotecan, triethylnemelamine, and vinblastine (30-32). Also, in present case series, following agents were used for secondary malignancy chemotherapy.Ionizing radiation as a standard of care for many pediatric malignancies is used in many conditions such as CNS malignancies, Hodgkins lymphoma, solid tumors and as part of preconditioning regimens for hematologic stem cell transplantation (33). Carcinogen role of ionizing radiation is reported in detail in the literature. According to The Childhood Cancer subsister Study, ionizing radiation exposure was accompanied with a relative risk of developing secondary malignancy of 2.7, and was also the strongest independent risk factor for secondary malignancy development (34). In a study based on German Childhood Cancer Registry, it was concluded that ionizing radiation after adjustment for various chemotherapy was associated with an odds ratio of developing a secondary malignancy at 2.05 (35). For the development of secondary malignancy after radiation the latency period is typically 10-15 years after primary treatment is typically 10-15 years after primary treatment (36). mutual secondary malignancies seen in pediatric population with prior cancer history include bone tumors, breast and thyroid carcinoma, non-melanoma skin cancer and benign CNS tumors. These tumors are often associated with previously irradiated treatment region (4, 37-39) in present case series, patients No. 3, 4, 6 and 7 had received radiotherapy, and in patients No. 6 and 7 had the secondary malignancies where the prior field of radiotherapy was, although incidence of these malignancies are far less than the latency period mentioned.Radiotherapy is the most important therapeutic modality in the treatment of many primary CNS tumors, so this have brought secondary malignancies as an undeniable com ponent of this modality (40). In a study by Packer et al. studying survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy, reported on 359 children with medulloblastoma treated with 2,340 cGy of craniospinal radiation with 5,580 cGy of posterior pitfall radiotherapy and chemotherapy, also it was reported that 5 percent of patients developed a secondary malignancy, with a majority of them being highly aggressive gliomas. The median time to a secondary malignancy was 5.8 years, with an estimated cumulative incidence rate at 5 and 10 years of 1.1 percent and 4.2% percent, respectively (41) similar to this study, in present case series, patient No. 7 who had undergone radiotherapy due to astrocytoma, developed gliosarcoma as the secondary tumor. Fortunately this patients is currently under treatment and his condition is improving. closePresent case series study, presented a series of patients with secondary neoplasms with their a dministered cumulative doses of chemotherapy and radiotherapy. Considering this , these information might lead to a more cautious approach in selecting chemotherapy and radiotherapy protocols. Further studies should focus on comparing different treatment protocols with adequate follow-up period not also to evaluate treatment efficacy, but to assess long term consequences. Also, studies with more detailed treatment protocol of patients with secondary malignancies should be performed to make a more precise conclusion.References1.Bhatia S, Sklar C. Second cancers in survivors of childhood cancer. Nature Reviews Cancer. 20022(2)124-32.2.Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. 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Survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy results of Childrens Oncology Group trial A9961. Neuro-Oncology. 2012.Table 1- Primary malignancies, administered cytotoxic and radiation therapies administered to patients .Patient No.Primary malignancyAge at diagnosisTreatment durationChemotherapy(cumulative doses)Radiotherapy(cumulative doses)1Ewing sarcoma4 y/o1 yearVCR 9.9 mgVP16 3630 mgIF 55 grADR 140 mgCPA 7 gr2Neuroblastoma18 mo.22 mo.VCR 9 mgCPA 3.5 grVP16 cd mgADR 60 mgCisplatin 160 mg3Meduloblastoma1010 monthsVCR 24 mgCCNU 320 mg360 Gy and180 Gy (posterior fossa)4 slim round cell tumor124 monthsVCR 12 mgIF 60 grVP16 3.9 gr8 Gy5Histiocytosis X121 yearVinblastine 135 mg6Retinoblastoma4 mo.14 monthsVCR 14 mgVP16 700 mgCarboplatin 3.5 gr60 Gy7Astrocytoma2 months6 months months