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 considered , 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 patient’s 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 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 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 individual’s 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 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 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 secondary 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 effective 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, Hodgkin’s 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.

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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	VCR 18 mg Procarbazine 5040 mg CCNU X Temozolomide 6 gr	54 Gy
VCR: Vincristine; IF: Ifosfamide; ADR: doxorubicin; CPA: Cyclophosphamide; VP16: Etopside; CCNU: Lomustine.

 

Table 2- Secondary malignancies, administered cytotoxic drugs ,radiation therapies and outcome of therapies among patients .
Patient No.	Primary malignancy	Age at diagnosis	Treatment duration	Chemotherapy (cumulative doses)	Radiotherapy (cumulative doses)	Outcome
1	ALL (B pre-crusor)	6	3 years	VCR 27.9 mg Laspar 319.5 mg DNR 60 mg Ara-c 440 mg CPA 3.6 gr	30 Gy	Remission
2	ALL(L1)	6	40 months	Laspar 98.4 mg CPA 2.5 gr Ara-c 490 mg VCR 27 mg DNR 60 mg MTX 6712 mg ADR 80 mg	–	Remission
3	AML (non-M3)	12	12 days	Ara-c 915 mg Idarubicin 40.5 mg VP16 510 mg	–	Expired
4	AML	13	3 months	Ara-c 3.2 gr VCR 8 mg CPA 2.6 gr ADR 120 mg	–	Expired
5	AML(M1)	15	N/A	Ara-c 8060 mg DNR 120 mg VP16 910 mg ADR 250 mg CPA 600 mg	–	N/A
6	Osteosarcoma	11	40 weeks	MTX 160 gr ADR 400 mg Cisplatin 720 mg IF 20 gr VP16 675 mg	–	Remission
7	Gliosarcoma	12 months	X	X	Ongoing treatment
VCR: Vincristine; IF: Ifosfamide; ADR: doxorubicin; CPA: Cyclophosphamide; VP16: Etopside; CCNU: DNR: Daunorubicin; Ara-c: Cytarabine; MTX: Methotrexate.