Secondary Malignancies in Pediatric Population

Secondary Malignancies in Pediatric Population Secondary malignancies in pediatric population: a case series and literature review Introduction Advances in medical care therapies and early diagnosis has fulfilled the hope for normal life expectancy in many cancerous patients with a 5 year survival rate for at least 75% in childhood (1). Although expecting 70% long-term survive in children with diagnosed cancer, 60-70% of them will develop a consequential disability by the primary cancer treatment as a cost(2). Development of second cancer (a new cancer following the first after a complete treatment , whether the onset is in childhood or as an adult, however 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 effects of chemotherapy drugs and radiation on both normal and cancerous cells (4). When major risk factors for developing the secondary malignancies in childhood survivors such as the primary origin, early diagnosis , onset age, duration of therapy , dose received and familial history of the cancer are c onsidered , radiation associated solid tumors as well as hematologic malignancies account for the most probable types in secondary cancers (5-8). Despite the excellent prognosis for long-term survival in childhood acute 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 after 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 researchers, data regarding this topic is rather inconclusive because of variety of factors involved (12, 13). In present case series study, a series of pediatric secondary malignancies with different primary cancers and subsequent treatment protocol are presented. Methods: In this case series study, 11 samples were selected retrospectively from patients attending at Mahak Pediatric Cancer 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 method of diagnosis, cumulative doses of cytotoxic drugs and treatment outcome was extracted. In case of any missing records, patients were contacted to acquire required data. 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 in formation 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 mean  ± standard deviation and frequency (percentage). Case history Patients primary malignancies type and administered therapy are shown in Table 1. Patients Secondary cancer type and features of therapy administered is shown in Table 2. Patients No.1 was a 15 years old girl, who presented with pain in buttocks when she was 4 years old, then following bone marrow biopsy. She was first diagnosed with Ewing sarcoma. During 1 year of treatment, She underwent VAC/IE (vincristine (VCR) + doxorubicin (ADR) + cyclophosphamide (CPA) alternating with ifosfamide (IF) + etoposide) regimen. This treatment protocol led to complete remission. After 1 year, during a routine laboratory test, elevated levels of white blood cell was detected. Following flow-cytometry and cytogenetic 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 CNS prophylaxis protocol was also administered. Complete remission was confirmed for her after treatment. During 6 years of follow-up, she has not 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, etoposide and cyclophosphamide) and daunorubicin, which led to remission. When he was 6 years old, in a routine laboratory test, elevated white blood 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. After 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 pulmonary 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 CNS 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, due 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 retinoblastoma 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 still going through chemotherapy. Based on the literature review, Discussion Based 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. Cancer and the administered treatment (including radiation, chemotherapy, surgery, hormonal therapy, and newer drug therapies) can affect 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 destroying cancerous cells by affecting their genetic structures, but in therapy process normal cell are also involved just as malignant cells. This involvement will consequently lead to a poptosis, 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 newly established malignancy 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 cyclophosphamide 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 development of secondary malignancies as they increase in the relative risk for a secondary malignancy 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 se condary malignancy. In a study by Bhatia et al. investigating Therapy-related 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 another well-known chemotherapeutic 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 eff ective agents against secondary hematologic malignancies due to 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 Survivor 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). Common 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 component 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 fossa 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. Conclusion Present case series study, presented a series of patients with secondary neoplasms with their administered 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. References: 1.Bhatia S, Sklar C. Second cancers in survivors of childhood cancer. Nature Reviews Cancer. 2002;2(2):124-32. 2.Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. International Journal of Radiation Oncology* Biology* Physics. 2006;65(1):1-7. 3.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: a cancer journal for clinicians. 2015;65(1):5-29. 4.Schneider U, Lomax A, Lombriser N. Comparative risk assessment of secondary cancer incidence after treatment of Hodgkins disease with photon and proton radiation. Radiation research. 2000;154(4):382-8. 5.Henderson TO, Rajaraman P, Stovall M, Constine LS, Olive A, Smith SA, et al. Risk factors associated with secondary sarcomas in childhood cancer survivors: a report from the childhood cancer survivor study. International Journal of Radiation Oncology* Biology* Physics. 2012;84(1):224-30. 6.Ng AK, Bernardo MP, Weller E, Backstrand K, Silver B, Marcus KC, et al. Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: long-term risks and risk factors. Blood. 2002;100(6):1989-96. 7.Tarella C, Passera R, Magni M, Benedetti F, Rossi A, Gueli A, et al. Risk factors for the development of secondary malignancy after high-dose chemotherapy and autograft, with or without rituximab: a 20-year retrospective follow-up study in patients with lymphoma. Journal of Clinical Oncology. 2010:JCO. 2010.28. 9777. 8.Neglia JP, Friedman DL, Yasui Y, Mertens AC, Hammond S, Stovall M, et al. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. Journal of the National Cancer Institute. 2001;93(8):618-29. 9.Kleinerman RA, Tucker MA, Tarone RE, Abramson DH, Seddon JM, Stovall M, et al. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. Journal of Clinical Oncology. 2005;23(10):2272-9. 10.Miralbell R, Lomax A, Cella L, Schneider U. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. International Journal of Radiation Oncology* Biology* Physics. 2002;54(3):824-9. 11.Tward JD, Wendland MM, Shrieve DC, Szabo A, Gaffney DK. The risk of secondary malignancies over 30 years after the treatment of nonà ¢Ã¢â€š ¬Ã‚ Hodgkin lymphoma. Cancer. 2006;107(1):108-15. 12.Travis LB, Gospodarowicz M, Curtis RE, Aileen Clarke E, Andersson M, Glimelius B, et al. Lung Cancer Following Chemotherapy and Radiotherapy for Hodgkins Disease. Journal of the National Cancer Institute. 2002;94(3):182-92. 13.Veiga LHS, Bhatti P, Ronckers CM, Sigurdson AJ, Stovall M, Smith SA, et al. Chemotherapy and Thyroid Cancer Risk: A Report from the Childhood Cancer Survivor Study. Cancer Epidemiology Biomarkers & Prevention. 2012;21(1):92-101. 14.Andrykowski MA. Physical and mental health status of survivors of multiple cancer diagnoses. Cancer. 2012;118(14):3645-53. 15.Boffetta P, Kaldor JM. Secondary malignancies following cancer chemotherapy. Acta Oncologica. 1994;33(6):591-8. 16.Obeid M, Panaretakis T, Tesniere A, Joza N, Tufi R, Apetoh L, et al. Leveraging the immune system during chemotherapy: moving calreticulin to the cell surface converts apoptotic death from silent to immunogenic. Cancer Research. 2007;67(17):7941-4. 17.Mertens AC, Liu Q, Neglia JP, Wasilewski K, Leisenring W, Armstrong GT, et al. Cause-Specific Late Mortality Among 5-Year Survivors of Childhood Cancer: The Childhood Cancer Survivor Study. Journal of the National Cancer Institute. 2008;100(19):1368-79. 18.Hawkins MM, Wilson LMK, Burton HS, Potok MH, Winter DL, Marsden HB, et al. Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. Journal of the National Cancer Institute. 1996;88(5):270-8. 19.Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation. Blood. 2004;104(5):1474-81. 20.Davies SM. Therapyà ¢Ã¢â€š ¬Ã‚ related leukemia associated with alkylating agents. Medical and pediatric oncology. 2001;36(5):536-40. 21.Pedersen-Bjergaard J. Insights into leukemogenesis from therapy-related leukemia. New England Journal of Medicine. 2005;352(15):1591-4. 22.Schoch C, Kern W, Schnittger S, Hiddemann W, Haferlach T. Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML. Leukemia. 2004;18(1):120-5. 23.Linassier C, Barin C, Calais G, Letortorec S, Bremond J-L, Delain M, et al. Early secondary acute myelogenous leukemia in breast cancer patients after treatment with mitoxantrone, cyclophosphamide, fluorouracil and radiation therapy. Annals of oncology. 2000;11(10):1289-94. 24.Hijiya N, Ness KK, Ribeiro RC, Hudson MM. Acute leukemia as a secondary malignancy in children and adolescents: current findings and issues. Cancer. 2009;115(1):23-35. 25.Bhatia S, Krailo MD, Chen Z, Burden L, Askin FB, Dickman PS, et al. Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: a report from the Childrens Oncology Group. Blood. 2007;109(1):46-51. 26.Hande KR. Topoisomerase II inhibitors. update on cancer therapeutics. 2008;3(1):13-26. 27.Hijiya N, Hudson MM, Lensing S, Zacher M, Onciu M, Behm FG, et al. Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. Jama. 2007;297(11):1207-15. 28.Pui CH, Relling MV. Topoisomerase II inhibitorà ¢Ã¢â€š ¬Ã‚ related acute myeloid leukaemia. British journal of haematology. 2000;109(1):13-23. 29.Ezoe S. Secondary leukemia associated with the anti-cancer agent, etoposide, a topoisomerase II inhibitor. International journal of environmental research and public health. 2012;9(7):2444-53. 30.Hoeksema KA, Jayanthan A, Cooper T, Gore L, Trippett T, Boklan J, et al. Systematic in-vitro evaluation of the NCI/NIH Developmental Therapeutics Program Approved Oncology Drug Set for the identification of a candidate drug repertoire for MLL-rearranged leukemia. Onco Targets Ther. 2011;4:149-68. 31.De Boer J, Walf-Vorderwà ¼lbecke V, Williams O. In focus: MLL-rearranged leukemia. Leukemia. 2013;27(6):1224-8. 32.Bernt KM, Armstrong SA. Targeting epigenetic programs in MLL-rearranged leukemias. ASH Education Program Book. 2011;2011(1):354-60. 33.Brenner DJ, Doll R, Goodhead DT, Hall EJ, Land CE, Little JB, et al. Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. Proceedings of the National Academy of Sciences. 2003;100(24):13761-6. 34.Friedman DL, Whitton J, Leisenring W, Mertens AC, Hammond S, Stovall M, et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. Journal of the National Cancer Institute. 2010;102(14):1083-95. 35.Kaatsch P, Reinisch I, Spix C, Berthold F, Janka-Schaub G, Mergenthaler A, et al. Case-control study on the therapy of childhood cancer and the occurrence of second malignant neoplasms in Germany. Cancer causes control. 2009;20(6):965-80. 36.Goldsby R, Burke C, Nagarajan R, Zhou T, Chen Z, Marina N, et al. Second solid malignancies among children, adolescents, and young adults diagnosed with malignant bone tumors after 1976. Cancer. 2008;113(9):2597-604. 37.Constine LS, Tarbell N, Hudson MM, Schwartz C, Fisher SG, Muhs AG, et al. Subsequent malignancies in children treated for Hodgkins disease: associations with gender and radiation dose. International Journal of Radiation Oncology* Biology* Physics. 2008;72(1):24-33. 38.Kry SF, Salehpour M, Followill DS, Stovall M, Kuban DA, White RA, et al. The calculated risk of fatal secondary malignancies from intensity-modulated radiation therapy. International Journal of Radiation Oncology* Biology* Physics. 2005;62(4):1195-203. 39.Werner-Wasik M, Swann RS, Bradley J, Graham M, Emami B, Purdy J, et al. Increasing tumor volume is predictive of poor overall and progression-free survival: Secondary analysis of the Radiation Therapy Oncology Group 93-11 phase I-II radiation dose-escalation study in patients with inoperable non-small-cell lung cancer. International Journal of Radiation Oncology* Biology* Physics. 2008;70(2):385-90. 40.Soussain C, Ricard D, Fike JR, Mazeron J-J, Psimaras D, Delattre J-Y. CNS complications of radiotherapy and chemotherapy. The Lancet. 2009;374(9701):1639-51. 41.Packer RJ, Zhou T, Holmes E, Vezina G, Gajjar A. 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 malignancy Age at diagnosis Treatment duration Chemotherapy (cumulative doses) Radiotherapy (cumulative doses) 1 Ewing sarcoma 4 y/o 1 year VCR 9.9 mg VP16 3630 mg IF 55 gr ADR 140 mg CPA 7 gr 2 Neuroblastoma 18 mo. 22 mo. VCR 9 mg CPA 3.5 gr VP16 400 mg ADR 60 mg Cisplatin 160 mg 3 Meduloblastoma 10 10 months VCR 24 mg CCNU 320 mg 360 Gy and 180 Gy (posterior fossa) 4 Small round cell tumor 12 4 months VCR 12 mg IF 60 gr VP16 3.9 gr 8 Gy 5 Histiocytosis X 12 1 year Vinblastine 135 mg 6 Retinoblastoma 4 mo. 14 months VCR 14 mg VP16 700 mg Carboplatin 3.5 gr 60 Gy 7 Astrocytoma 2 months 6 months months<