Secondary malignant neoplasms after childhood cancer

Overall survival from cancer has greatly improved, although it still remains the second leading cause of mortality in the world. This result was achieved through the use of chemotherapy and radiotherapy, which are severely toxic to normal tissues. In the long-term follow-up of cancer patients, the development of secondary malignant disease is common and it is one of the most severe side effects of cancer treatment. Physicians aim to decrease this toxicity and reduce the development of secondary cancers. In this study, the epidemiology and etiology of second malignant neoplasms are reviewed.     

Second neoplasms after treatment of childhood cancer in Slovenia

BACKGROUND: The number of long time survivors of childhood cancer treatment is constantly increasing over the last decades as a result of advances in diagnosis and treatment. The occurrence of second neoplasms is one of most serious late effects observed in cancer survivors. METHODS: The risk of secondary neoplasm was studied in a cohort of 1,577 patients treated for childhood cancer registered in the Cancer Registry of Slovenia (CRS) between 1961 and 2000. The time at risk was defined from the date of diagnosis of first malignancy to the time of death or the end of the study. RESULTS: The most frequent primary malignancies were: acute leukemia 28.5%, central nervous system (CNS) tumors 21.3%, and lymphomas 16.6%. Median observation time was 7.8 years. Forty-eight patients developed second neoplasms. CNS tumors, acute leukemias, and thyroid carcinoma were most frequent second neoplasms. The cumulative risk for second neoplasm in the entire cohort was 0.06% at 5 years, 5.1% at 15 years, and 12.6% at 25 years after diagnosis of first cancer. The overall survival after second neoplasm was 65% 10 years after the diagnosis of second neoplasm. CONCLUSIONS: Patients after treatment of childhood cancer are at special risk for subsequent neoplasms and long-term follow-up is mandatory.     

Subsequent malignant neoplasms in survivors of childhood cancer: Childhood Cancer Survivor Study (CCSS) studies

Survival of children diagnosed with cancer has improved markedly, because of improvements in chemotherapy and radiation treatment protocols, better diagnosis, and risk classification and improved supportive care. Significant numbers of survivors are now entering their 30s and 40s, and data indicate that excess mortality continues in this group at least as long as 25 to 30 years after treatment. The Childhood Cancer Survivor Study (CCSS) is a large cohort study of 14,054 childhood cancer survivors who have been followed for over 13 years, with a median time from diagnosis now approaching 20 years. This cohort offers an extraordinary opportunity to study therapy-associated subsequent malignant neoplasms, and has allowed improved definition of incidence and risk factors for subsequent breast and thyroid cancer. The collection of genetic samples from members of the cohort has allowed the inclusion of studies of genetic susceptibility to subsequent malignant neoplasms in this population with a uniquely well-defined carcinogenic exposure. The planned formation of a new CCSS cohort, treated with more modern therapy, will allow the extension of these studies to younger populations and will define their experience of subsequent malignant neoplasms.     

Second malignant neoplasms after primary central nervous system malignancies of childhood and adolescence

The standardized incidence ratios (SIR) and cumulative incidence rates were determined for developing second malignant neoplasms (SMNs) after primary central nervous system (CNS) malignancies occurring during childhood using registry data. A total of 4553 cases of primary CNS malignancies were identified. Forty-six cases developed SMNs, 19 occurring in a previously radiated field. The SIRs of developing second malignant neoplasms were 6.3 and 3.1 for those cases receiving and not receiving radiation therapy, respectively. The 20-year cumulative incidences for developing SMNs were 3.3 and 1.2% for cases receiving and not receiving radiation therapy, respectively. Children surviving CNS malignancies have an increased susceptibility for SMNs.     

Second malignant neoplasms following childhood Hodgkin's disease: treatment and splenectomy as risk factors

The risk of second malignant neoplasm (SMN) was evaluated in 979 children with Hodgkin's disease. This cohort was diagnosed between 1955 and 1979 at one of the institutions of the Late Effects Study Group. Solid tumors, non-lymphocytic leukemia, and non-Hodgkin's lymphoma (NHL) developed in 18, 17, and 3 patients, respectively. The estimated cumulative probability of developing any SMN was 2% at 5 years from diagnosis, 5% at 10 years, and 9% at 15 years. The incidence is ninefold greater than the risk of acquiring cancer in 19 year-olds, the median age at which the diagnosis of SMN was made in this study population. For leukemia and NHL the corresponding probabilities were 1%, 3%, and 4% for the group as a whole but were increased (2%, 6%, and 8%) in patients who had suffered one or more recurrences. In order to analyze the risk of leukemia and NHL associated with alkylating agent chemotherapy, each patient was assigned a score of one for each alkylating agent administered for a 6-month period. Scores of 2, 4, 6, and 8 were associated with probabilities of leukemia or NHL of 2%, 3%, 6%, and 10%, respectively. In a multivariate analysis for leukemia/lymphoma that included AAD score, stage, and splenectomy, the effect of AAD score and splenectomy did not change substantially compared to the univariate results. AAD score remained statistically significant (P = .0001), and splenectomy was of borderline significance (P = .09). Of the 18 solid tumor SMNs, 15 developed within the field of radiation, and one other developed in tissue irradiated 34 years earlier for hemangioma. This study of a large and unselected group of children with Hodgkin's disease who received a variety of therapies demonstrates that children are as likely as adults to develop acute leukemia after alkylating agents and solid tumors in the field of radiation therapy.     

Second malignant neoplasms in childhood malignant brain tumour: A long‐term population‐based study

Aim: To provide a profile of second malignant neoplasms (SMN) in patients with childhood primary malignant brain tumour originating from neuroepithelial tissues with latest data in a population‐based study. Methods: Surveillance, Epidemiology, and End Results (SEER) database (1973–2007) was used to identify above‐stated patients. SMN patients were further identified, and standardised incidence ratios (SIRs) and excess absolute risks (EARs) for risk‐factor‐decided subgroups were calculated. Univariate and multivariate analyses of the association between cumulative incidence of SMN and the risk factors were performed in the whole population. Results: A total of 106 patients were identified as having SMNs. EARs peaked at age at primary diagnosis of 10–14. Males had higher SIRs and EARs than females. Both SIRs and EARs increased after 1990. Age was statistically significant in both univariable and multivariable analyses for cumulative incidence of SMN and RT was not significant in both the analyses, in the whole population of 9075 patients. After follow‐up recalculation, matched patients in the ≥1990 group had slightly shorter median interval between primary and secondary cancer than those in the <1990 group, but with no significance. Conclusion: The risk of SMN in children with primary malignant brain tumours in a more advanced treatment era might have changed. During making further advances in the treatment of these neoplasms, minimising toxicities while maintaining promising prognostic outcomes will keep being our goal.     

Second malignant tumours in childhood Hodgkin's disease

This study was undertaken to determine the treatment-specific incidence of second malignant tumours (SMT) in childhood Hodgkin's disease. The institutional databases at The Hospital for Sick Children, the Princess Margaret Hospital, and the Toronto-Bayview Regional Cancer Centre were reviewed for the years 1958–1993. Three hundred and forty-three consecutive newly diagnosed children were evaluated. The overall 30 year cumulative SMT incidence was 31%. The 20 year SMT incidence was greater for patients who relapsed (n = 129), 27%, compared with patients who remained relapse free (n = 214), 13%. For patients with stage 1–3B disease who remained relapse free, the 10 year SMT rate was 7% for patients who were surgically staged and treated with extended field radiation treatment (EF RT) (35 G), compared with 3% in clinically staged patients treated with MOPP (six cycles) and EF RT (25–30 G). To date there is no significant difference in the oncogenicity of these treatment protocols. However, EF RT alone was less effective in disease control. For stages 1–3B, 62% of patients relapsed after EF RT alone compared with 18% after bimodal treatment. Therefore treatment intensification due to relapse was more frequent in the former group. The overall 10 year SMT incidence for patients treated with these protocols was 11% and 3%, respectively. The 20 year SMT incidence following EF RT alone was 24%. We conclude that SMTs were a common late complication in childhood Hodgkin's disease and are a limiting factor in the achievement of cure. The incidence of SMTs was increased in children who required retreatment and was minimal in children who remained in a first complete remission. Therefore the initial treatment strategy in childhood Hodgkin's disease must be to minimize the risk of relapse, in order to avoid the morbidity and mortality associated with both relapse and SMT induction, and to achieve this objective with a primary treatment protocol of low oncogenicity. © 1996 Wiley-Liss, Inc.     

Second malignant tumors following treatment during childhood and adolescence for cancer

Many pediatric and adolescent cancer patients are treated with carcinogenic chemotherapeutic agents and radiation therapy to achieve permanent control of their malignancy. These modalities may induce a new cancer in the successfully treated patient. To identify disease and treatment factors which increased the risk of occurrence of a second malignant tumor following modern treatment for cancer during childhood or adolescence, we reviewed the courses of 1,406 previously untreated patients who were less than 20 years of age at diagnosis and were treated at Roswell Park Cancer Institute between January 1, 1960 and December 31, 1989. Eighteen patients developed a second malignant tumor, including two meningiomas, 2.65-25.65 years after diagnosis of the first cancer. The actuarial risk of a second malignant tumor was 5.6% at 25 years after diagnosis. Using Cox proportional hazards modelling, we identified prior therapy with BCNU (P = 0.0055) and doxorubicin (P = 0.0254) as the only factors that were significantly associated with the risk of a second malignant tumor. Three second malignant tumors of the central nervous system occurred following treatment with a nitrosourea. Successfully treated patients must be carefully followed to identify treatment related malignant tumors at an early Stage. © 1994 Wiley-Liss, Inc.     

ACTH deficiency in childhood cancer survivors

BACKGROUND: Adrenocorticotropin deficiency (ACTHD) can be clinically subtle, but life-threatening if not recognized. We assessed the prevalence of ACTHD in survivors of childhood cancer according to tumor diagnosis/therapy. PROCEDURE: Chart review of endocrine/oncology history was performed in 310 childhood cancer survivors. Patients were referred to endocrine clinic because of slow growth, fatigue, or abnormal pubertal timing. Evaluation of growth hormone (GH), thyrotropin (TSH), ACTH, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) was performed. Low response to metyrapone and/or low dose ACTH test defined ACTHD. RESULTS: ACTHD was identified in 56 (18%), [44 of 182 (24%) central nervous system (CNS) tumors, 3 of 18 (17%) non-CNS cranial tumors, 9 of 97 (9%) hematologic malignancies]. Of the 56 with ACTHD, 53 (95%) had received cranial irradiation (mean 45.5 Gy, range 14-70 Gy); three had not: one each with craniopharyngioma, hypothalamic astrocytoma, and brain stem glioma. All but one also had GH deficiency and/or central hypothyroidism. CONCLUSIONS: Childhood cancer survivors with greatest risk for ACTHD had craniopharyngioma, other suprasellar tumor, or medulloblastoma or > or =24 Gy cranial irradiation. We recommend annual testing for ACTHD for 10-15 years and continued lifelong surveillance after CNS tumor or cranial irradiation, in patients with other hypothalamic-pituitary deficiencies or symptoms of ACTHD.     

Acyclovir treatment of disseminated varicella in childhood malignant neoplasms

Primary varicella-zoster virus infection (chickenpox) in immunocompromised children is frequently associated with visceral dissemination and attendant high mortality. Eight children with malignant neoplasms and chickenpox with visceral involvement (seven with hepatitis, three with pneumonitis, two with encephalitis, and two with coagulopathy) were initially treated with intravenously (IV) administered vidarabine but demonstrated progressive visceral involvement. After three days of vidarabine treatment (two days for two patients), seven had rising serum SGPT levels, all eight had pneumonitis, seven had deteriorating mental status and/or seizure activity, and six had worsening coagulopathy. Vidarabine was replaced by IV administered acyclovir, with subsequent improvement in all but the most severely ill patient who died. Seven of eight patients recovered completely; no side effects of acyclovir were observed. This clinical experience suggests that acyclovir may be more effective than vidarabine in disseminated varicella infection; however, controlled clinical trials will be necessary to establish this.     

Educational deficits in survivors of childhood cancer

Some long-term survivors of childhood cancer experience changes in cognitive functioning and have learning difficulties in school. Psychological and educational studies of children who received cranial irradiation in treatment for acute lymphocytic leukemia or brain tumor have identified specific disabilities. A coordinated educational intervention approach is needed, using special education services available through local school districts.     

Alexithymia in long-term survivors of childhood cancer

OBJECTIVE: To investigate the incidence of alexithymia (difficulties in describing or recognizing one's own emotions, a limited fantasy life, and general constriction in the affective life) in a group of childhood cancer survivors and to explore medical determinants which predict alexithymia. METHODS: Five years after completing therapy, 72 participants were asked to complete the Bermond-Vorst Alexithymia Questionnaire (BVAQ). RESULTS: Male cancer survivors scored significantly lower on overall alexithymia compared to healthy males. They also showed higher ability to fantasize, a higher emotional arousal, and were better able to verbalize their emotional reactions. The female survivors did not show differences compared to the normal female population. No medical determinant was associated with alexithymia. CONCLUSIONS: Stress due to childhood cancer does not affect the alexithymia scores of females. However, male cancer survivors score less alexithymic than age matched controls.     

An analysis of SEER data of increasing risk of secondary malignant neoplasms among long-term survivors of childhood brain tumors

BACKGROUND: Advances made in treatment of a childhood brain cancer have extended the lives of many children and adolescents. Treatment success, however, brings the opportunity to assess late effects; most worrying among these are secondary malignant neoplasms (SMN). Even though the cumulative incidence is quite small, long-term follow-up is required because treatment-induced cancers can occur years after initial treatment. PROCEDURE: The purpose of this project was to determine what treatments and what host characteristics of children treated for a primary brain cancer are associated with an increase in the risk of a SMN in long-term survivors. Data were analyzed from 2,056 5-year survivors, of primary brain cancer in the surveillance, epidemiology, and end results (SEER) database between 1973 and 1998. Thirty-nine patients developed a SMN. Cox regression models were used to evaluate the independent contribution of a number of risk factors. RESULTS: The most important risk factor for developing a SMN in 5-year survivors was the era in which the primary cancer was treated. Compared to treatment prior to 1979, patients treated between 1979 and 1984 had a 4.7-fold increase in risk (P = 0.001), while those treated after 1985 had a 6.7-fold increase in risk. (P = 0.002). Patients treated most recently carry the greatest risk of SMN development even after controlling for radiotherapy. This could be due to the increase in intensive treatment compared to earlier years. CONCLUSION: Although the absolute excess risk of SMN remains quite low, continued surveillance is needed to evaluate long-term effects of new therapies for primary brain tumors.