Childhood Cancer Survivors Risk Developing Second Malignant Neoplasms Biology Essay

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Abstract

Introduction: Childhood cancer survivors were at risk of development of second malignant neoplasms. The aim of this study is to evaluate the incidence, risk factors and outcome of second malignant neoplasms in childhood cancer survivors in a tertiary pediatric oncology center in Hong Kong.

Methods: Retrospective review of patients with childhood cancer treated in Children's Cancer Center in Prince of Wales Hospital between May 1984 and June 2009. Cumulative incidence of second malignant neoplasms was calculated. Case records of patients who developed second malignant neoplasms were reviewed. Treatment related data including chemotherapy and radiotherapy for primary cancer were collected. We also looked at the effect of radiotherapy on second malignant neoplasms in survivors of acute lymphoblastic leukemia.

Results: Total 1374 new cases aged less than 21 years old were treated in our center in this 25-year study period. Median follow up time was 5.3 years (range 0-26.1 years). Median age of primary diagnosis was 6.3 years (range 0-20.1 years). Twelve cases developed second malignant neoplasms with 10-year and 20-year cumulative incidence of 1.3% (95% confidence interval 0.3-2.3%) and 2.9% (95% confidence interval 1.1-4.7%) respectively. Another 4 cases were referred to us from other centers for the management of second malignant neoplasms. In this cohort of 16 children with second malignant neoplasms, the median age of second malignancies was 12.9 years (range 5.5 - 21 years). The most common primary diagnosis was acute lymphoblastic leukemia (n=6). The most frequent second malignant neoplasms were acute leukemia or myelodysplastic syndrome (n=6) and central nervous system tumor (n=4). Median interval between diagnosis of primary and second malignant neoplasms was 7.4 years (range 2.1-13.3 years). Median interval was shorter for second leukemia or myelodysplastic syndrome of 4.2 years compared to second solid tumor of 9.1 years (t-test for mean P=0.046). Nine patients died of progression of second malignant neoplasms, mainly resulted from second central nervous system tumor and osteosarcoma. Seven out of 16 patients who developed second malignant neoplasms had a family history of cancer among the first or second-degree relatives. All patients who developed acute leukemia or myelodysplastic syndrome as second malignant neoplasms had prior use of chemotherapy with alkylating agents, topoisomerase II inhibitors or platinum compounds. Eight patients developed second solid tumor within the previous irradiated field. Radiotherapy significantly increased the risk of development of second solid tumor in patients with acute lymphoblastic leukemia (P=0.027). Conclusion: Childhood cancer survivors were at risk of development of second malignant neoplasms. Cumulative incidence of second cancer in our center was comparable to western countries. Radiotherapy was associated with second solid tumour among patients with acute lymphoblastic leukemia which could occur up to 12.3 years after completion of treatment. Patients who developed second brain tumor and osteosarcoma had poor outcome.

Introduction

With the advancement in diagnosis and treatment of childhood cancer over the past decades, overall survival of pediatric patients with various neoplasms improved significantly with 5-year survival rates increased from 50-60% in the 1970s to 70-80% in recent decade (1). Though a majority of children with cancer have achieved a cure, many of them suffer from long-term effects of cancer therapy. One of the most serious late sequelae is the development of second malignant neoplasms (SMNs). Several large cohort studies showed there were 3 to 6-folds increase in the occurrence of SMNs among childhood cancer survivors compared to the general population (2-4). SMNs were associated with poor outcome. Childhood Cancer Survivor Study has assembled the largest cohort in the assessment of the late mortality among 5-year survivors of childhood cancer. Recurrence or progressive disease of primary cancer accounted for 58% of death while subsequent neoplasms attributed up to 18.5% of death which was the second most common cause of late mortality. At 20 years from diagnosis, death related to SMNs even exceeded death from primary cancers and other causes (5).

There is increasing evidence that certain types of SMNs are therapy-related or associated with genetic predisposition. Radiotherapy is an important risk factor for the development of SMNs, especially solid tumors and carcinoma within the radiation field (6-9). Younger age at radiation exposure (9) and higher cumulative doses were associated with greater risk. Second acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been related to chemotherapeutic agents such as alkylating agents (9;10), epipodophyllotoxins (11;12), anthracyclines (12) and platinum compounds (13). There were two types of therapy-related leukemia. The first type resulted from the use of alkylating agents. It occurred after a latency period of 5 to 7 years and was often preceded by a preleukemic phase of myelodysplasia. Monosomy or deletions on chromosome 5 or 7 were commonly seen in this type of therapy-related leukemia. The second type was related to topoisomerase II inhibitors including epipodophyllotoxins and anthracyclines. It usually developed early with a median interval of 2 years from initial therapy and was not preceded by MDS. It was associated with cytogenetic abnormalities involving the mixed-lineage leukemia (MLL) gene at chromosome band 11q23. Therapy-related AML/MDS is rapidly progressive and relatively resistant to treatment (14). Patients with cancer predisposition syndrome e.g. genetic form of retinoblastoma, neurofibromatosis, Li-Fraumeni syndrome, familial polyposis coli were known to have greater risk of development of SMNs.

Racial and ethnic differences were shown to be important determinants of disease survival in cancer patients (15). Data about second malignant neoplasms in the Chinese population is scarce. The aim of this retrospective review is to evaluate the incidence, risk factors and outcome of second malignant neoplasms in long-term cancer survivors in a tertiary pediatric oncology center in Hong Kong.

Patients and Methods

Lady Pao Children's Cancer Centre at Prince of Wales Hospital is a tertiary referral center for pediatric oncology in Hong Kong. Cases were retrieved from our center computer database including all patients who were diagnosed a primary cancer before 21 years of age between 1st May 1984 and 30th June 2009. Patients who were lost to follow-up were excluded from the study. Duration of follow up was counted from the date of diagnosis of primary neoplasm to the date of death or the study end date on 30th June 2010. Long-term survivors were followed up at least annually in the outpatient clinic.

SMN is defined as a histologically distinct cancer that develops after the first cancer. Case records of all patients who developed SMNs were reviewed. Treatment related data of the primary malignancies, relapses, and conditioning for stem cell transplantations up to the event of SMNs were collected. Use of chemotherapy was reviewed with cumulative doses of alkylating agents, anthracyclines, epipodophyllotoxins and platinum compounds calculated. Data on radiation dose and radiation field were collected for all patients with SMNs who received radiotherapy.

We chose to look at the effect of radiotherapy in the largest patient cohort with acute lymphoblastic leukemia (ALL). From observation in previous studies, there was a long latency between the exposure to radiotherapy and development of second malignant neoplasms. Hence, we only included patients with primary acute lymphoblastic leukemia treated in our center who survived for 5 years or more in the analysis of risk of SMNs with radiotherapy.

Primary outcome is to calculate the cumulative incidence of SMNs among children treated for primary cancer in our center. Secondary outcome is to identify risk factors for development of SMNs and to evaluate the patients' outcome.

Statistical analysis:

Cumulative incidence of SMN was calculated by Kaplan-Meier method with SPSS version 16.0. Ninety-five percent confidence interval (CI) was calculated from the standard error. Patients with primary cancers treated in other oncology centers and referred to us for the management of second malignant neoplasms were excluded from the calculation of cumulative incidence. Time to an event was calculated from the date of primary diagnosis to the date of SMNs, date of death, or date of end of study, whichever occurred first. Fisher's exact test was used to compare categorical variables. Student's t-test was used to compare means. Statistical significance was defined as P value of less than 0.05.

Results

Patient characteristics

Total 1374 patients were diagnosed with primary cancer in the study period. One hundred and forty-one patients were lost to follow up leaving 1233 patients eligible for this retrospective study. Eight hundred and two patients were alive at the time of analysis. The 5-year overall survival was 66.7%. Median age at diagnosis was 6.3 years (range 0-20.1 years). Median duration of follow up was 5.3 years (range 0-26.1 years). The most common primary malignant neoplasm was leukemia (44.6%), followed by central nervous system tumor (12.9%) and bone tumor (8.2%). Table 1 summarizes the distribution of primary and second malignant neoplasms during the 25-year study period.

Second malignant neoplasms

Sixteen patients who developed SMNs were identified. Among them, 4 patients were referred from other hospitals for the management of SMNs. Median age at primary diagnosis and second malignant neoplasms were 5.0 years (Range 0.8 - 12.7) and 12.9 years (Range 5.5-21 years) respectively. The most frequent primary diagnosis was acute lymphoblastic leukemia (n=6); the other diagnoses included peripheral T-cell lymphoma (n=2), intracranial germ cell tumor (n=2) and 1 case each of medulloblastoma, osteosarcoma, neuroblastoma, extracranial germ cell tumor, retinoblastoma and Langerhans cell histiocytosis. The most frequent SMNs were acute leukemia or myelodysplastic syndrome (n=6) and central nervous system (CNS) tumor (n=4). The most common combination was central nervous system tumor after cranial or total body irradiation for acute lymphoblastic leukemia (n=4). Median interval between diagnosis of primary and second malignant neoplasms was shown in Table 2. Mean interval was shorter for second leukemia compared to second solid tumor (t-test for mean P=0.046). Excluding the 4 patients who were referred from other hospitals, the 10-year and 20-year cumulative incidence of SMNs was 1.3% (95% CI 0.3-2.3%) and 2.9% (95% CI 1.1-4.7%) respectively. Seven patients had family history of cancer in the first-degree or second-degree relatives.

Table 3 summarized the type and treatment regimens of primary malignancies, type of SMNs and patients' outcome of these 16 patients. Nine patients died of progression of SMNs, mainly resulted from second central nervous system tumor (n=4), osteosarcoma (n=3) and therapy-related acute leukemia (n=2).

Cumulative doses of chemotherapy with alkylating agents, epipodophylloxins, anthracyclines and platinum compounds in the 6 patients with second acute leukemia or MDS were summarized in Table 4. Five of them demonstrated cytogenetics abnormalities. Four of the patients were classified as therapy-related AML/MDS in view of the presence of chromosomal abnormalities involving chromosome 7. All patients had received alkylating agents and most of them were also given platinum compounds, epipodophyllotoxins or anthracyclines.

Among the 10 patients who developed second solid tumor, 9 of them had received radiotherapy with 8 patients developed tumor within the previous irradiated field. In our cohort of 234 five-year survivors of primary acute lymphoblastic leukemia, 4 patients developed second brain cancer and one developed parotid acinic cell adenocarcinoma. Four had history of cranial irradiation and one had total body irradiation during stem cell transplantation. Radiotherapy significantly increased the risk of development of second solid tumor within the radiation field in patients with acute lymphoblastic leukemia compared to those without prior history of radiotherapy (P=0.027). Results were shown in Table 5.

Discussion

Over the past decades, there was increasing interest in the late complications of cancer therapy. Second malignant neoplasms posed significant morbidity and mortality on childhood cancer survivors. A population-based cohort study of 30,880 childhood cancer survivors from Nordic cancer registries showed that the 20-year cumulative risk of SMNs was 2.6% (3); while another cohort of 16,541 3-year childhood cancer survivors in Britain showed the cumulative incidence of 3.1% (2). Childhood Cancer Survivor Study, included patients in United States and Canada, reported the cumulative risk of SMNs to be 3.2% after 20 years (4). Several other cohort studies in western countries also showed similar results with 10-year cumulative incidence of SMNs of 1-1.6% and 20-year cumulative incidence up to 3.6-4.4% (16-18). The risk continued to rise with time. This was shown in the Childhood Cancer Survivor Study in which the cumulative incidence of SMNs increased from 3.2% at 20-year to 9.3% at 30-year, with elevated standardized incidence ratios compared to the general population (19). However, there is paucity of data in Asian countries. This retrospective study aims to review the experience in a tertiary oncology center in Hong Kong with predominant Chinese population. In our cohort, the 10-year and 20-year cumulative incidence was comparable to Western populations.

The distribution of primary neoplasm in our cohort was similar to other registries. Leukemia was the most common primary neoplasm, followed by central nervous system tumor. Hodgkin's disease was less commonly seen in Chinese, which only accounted for 1.3% of our study population. In our cohort, the most frequent SMNs were acute leukemia or myelodysplastic syndrome and central nervous system tumor. Central nervous system tumor and breast cancer were frequently reported as SMNs in other studies. Breast cancer mainly developed in female survivors of Hodgkin's disease with history of chest irradiation. The lack of patient developing second breast cancer was probably due to the small number of female patients with Hodgkin's disease in our study, and also because radiotherapy was less commonly given. In previous studies, median time from the diagnosis of primary cancer to the occurrence of SMNs ranged from 5 years to 12 years (4;9;20). Second leukemia usually developed early after primary cancer, therefore, the reported incidence of SMNs would be low in studies that only included 5-year survivors.

Radiotherapy was an important risk factor for the development of second malignant neoplasms. We have eight cases of second solid tumor developed within the radiation field. Radiotherapy associated solid tumor typically occur after a long latency period with a median of 9.1 years in our study, probably due to longer time required for accumulation of mutations. Among patients with acute lymphoblastic leukemia, the risk of developing SMNs was significantly higher in those with history of radiation therapy compared with non-irradiated patients. Greater risk was observed with increasing radiotherapy dose (21). This association was also observed in our study with statistical significant difference noted between the two groups with or without history of radiotherapy. In our study, brain tumors developed in 4 patients including 2 with glioblastoma multiforme, 1 with anaplastic astrocytoma and 1 with medulloblastoma. All four patients with second brain tumors after ALL have received radiotherapy within the field with dose ranging from 12 to 41.4 Gy. Three patients received cranial radiotherapy for CNS relapses and one received total body irradiation during stem cell transplantation. No second brain tumor was observed among patients without prior history of radiotherapy. Radiation posed significant risk on second brain tumor even at a relative low dose of 12 Gy. The more frequently encountered radiation-induced intracranial tumors included gliomas and meningiomas. Medulloblastoma, which occurred in one of our patients, was only rarely reported (22). Radiation associated brain tumor tends to be aggressive with poor response to therapy. All our patients died of progressive disease. Cranial irradiation is an effective CNS-directed therapy in ALL to prevent CNS relapse, but it carries significant risk of neuropsychological sequelae and development of second brain tumor. So the current trend is to avoid the use of prophylactic cranial irradiation except in selected high-risk cases or in patients with CNS leukemia. Instead, intrathecal chemotherapy and high dose methotrexate are used as CNS prophylaxis. Parotid tumor as second malignant neoplasm had been described in long-term survivors of childhood acute lymphoblastic leukemia, particularly in children who have received cranial irradiation. The majority of cases were mucoepidermoid carcinoma of parotid gland while acinic cell carcinoma was rare. Most of the cases developed parotid tumour after a long latency period of more than 10 years. It is important to be aware of the risk of second malignant neoplasm in cancer survivors with history of cranial radiotherapy presenting with parotid swelling. Early detection with surgical resection is associated with better prognosis.

Second acute myeloid leukemia and myelodysplastic syndrome have been described in patients receiving chemotherapeutic agents such as alkylating agents, topoisomerase II inhibitors and platinum compounds. Treatment with alkylating agents was associated with elevated risk of leukemia with dose-response effect. Four of our patients who developed therapy-related AML/MDS demonstrated deletions in chromosome 7. All of them had received alkylating agents including cyclophosphamide, ifosfamide or lomustine. Exposure to moderate cumulative dose of epipodophyllotoxins (>1000mg/m2) (4) or anthracyclines (170mg/m2) (12) were found be associated with increased risk of second leukemia. However, dose-response relationship was not consistently shown in different studies (23). Five of our patients with second leukemia had received epipodophyllotoxins with cumulative doses ranging from 500 to 4000mg/m2 and anthracyclines with dose of 225 to 420mg/m2. Platinum-based chemotherapy was shown to be associated with second leukemia when cumulative dose was greater than 750mg/m2 and duration of treatment was more than 6 months (13). Risk was even higher when used with radiotherapy. We have one patient with cerebellar medulloblastoma who developed second AML. He had received radiotherapy followed by lomustine and cisplatin of 600mg/m2 over 11 months. It was difficult to determine the risk of second leukemia associated with individual drug as most patients received combination treatment. Current available evidence was still limited in addressing the leukemic potential regarding each chemotherapeutic agent, threshold cumulative dose, schedule of administration and interaction of different drugs.

Metaiodobenzylguanidine (MIBG) is a radioisotope selectively taken up by cells of neural origin including neuroblastoma cells. It can deliver targeted radiation to tumor while sparing the normal tissues. It provides additional benefits in treatment of neuroblastoma but may also be associated with complication of acute leukemia or myelodysplastic syndrome as second malignant neoplasms (24). One of our patients who had received combined treatment with chemotherapy, local radiotherapy, immunotherapy, MIBG treatment and autologous stem cell transplantation developed therapy-related AML. He subsequently died of disease progression. While MIBG therapy improves disease control, the associated risk of second malignant neoplasm may compromise survival and monitoring of this complication is indicated.

Patients with cancer predisposition syndrome e.g. genetic form of retinoblastoma, neurofibromatosis, Li-Fraumeni syndrome, familial polyposis coli are known to have greater risk in development of SMNs. Survivors with heritable or bilateral retinoblastoma are at increased risk of developing SMNs due to both genetic and treatment factors. They are susceptible to carcinogenic effect of radiation, especially over the head and neck region in the previously irradiated field. One study reported that the 30-year cumulative incidence of SMNs was up to 35% among patients with bilateral retinoblastoma who received radiotherapy, compared to 5.8% who did not (25). Common SMNs that developed in this group of patients are osteosarcoma, fibrosarcoma and squamous cell carcinoma. One of our patients with bilateral retinoblastoma developed osteosarcoma within the irradiation field as a result of both genetics predisposition and effect of radiotherapy. One case-control study showed that childhood cancer survivors with early onset cancer in one or more first-degree or second-degree family member had greater risk of developing SMNs (8). Seven out of the 16 patients who developed SMNs in our study had a family history of cancer among the first or second-degree relatives. Hence, vigilant follow up is required especially for those childhood cancer survivors with cancer predisposition syndrome or family history of early onset cancer.

In our center, yearly follow up is offered for long-term cancer survivors. The high follow-up rate of 90% in the current study gave an accurate estimation of the risk of development of second cancer. However, there were several limitations of our study. First, the number of cases that developed second malignant neoplasm was small which made detailed evaluation on the effect of chemotherapy and radiotherapy on second cancer difficult. Second, overall follow-up period was relatively short with median follow up period of 5.3 year and only 70 patients (5.7%) were followed up for more than 20 years. Evidence from Childhood Cancer Survivor Study showed that there was a 2.3-fold increase in the number of SMNs 7 years later. Ongoing surveillance is required to identify further cases of SMNs and to obtain information on the lifetime risk. Third, the data was based on a single center which limited its generalization. Collaboration in multicenter study with longer follow up will give more representative information of the population.

We believed the pathogenesis of second malignant neoplasms was multifactorial, with the combined effect from genetic risk factors together with carcinogenic effects of cancer treatment. More studies are required to understand the carcinogenic mechanism, which is essential for clinicians to modify treatment protocols for selected low-risk patients to be treated with less intensive therapy in order to minimize risk without compromising cure. Cranial irradiation is now seldom given to ALL patients as CNS prophylactic treatment, and there is a trend of decreased second brain tumors. Second malignant neoplasms may take a decade to develop. Long term structured medical follow-up care is required for early detection and treatment. For example, to monitor blood counts to look for second leukemia or myelodysplastic syndrome especially during the early follow up period in patients who had received carcinogenic chemotherapy; to look for symptoms and signs of second solid tumor over the previous irradiated field. More vigilant follow up is required for patients with family history of early onset cancer or familial cancer predisposition syndromes. Patients and parents should be educated on the long-term complications of cancer therapy and to seek early medical advice for symptoms. It is also important for primary health care workers to be aware of the risks because these life-threatening SMNs may first present to them with non-specific symptoms. Proper evaluation on early signs and symptoms, and timely referral to oncologists for further management would be essential to decrease morbidity and mortality.

Conclusion

Childhood cancer survivors are at risk of development of second malignant neoplasms related to cancer treatment or genetic factors. The risk is similar between patients of different population. As second malignant neoplasm is associated with poor outcome, physicians should take great effort in minimizing the risk to improve long-term survival and quality of life.

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