It is well recognised that the intense treatments used to treat paediatric cancers increase the patient’s risk of developing another cancer in later life. Deaths from
subsequent malignant neoplasms are one of the leading causes of late mortality in childhood cancer survivors [31, 81, 160, 161].
A primary cancer is one that originates in a primary site or tissue and is not an extension, nor a recurrence, nor a metastasis [165]. A second cancer is defined as a new primary cancer that occurs in a person who has had cancer in the past, this may also be described as a subsequent primary cancer, second primary cancer, subsequent malignant neoplasm or a second malignant
neoplasm [166]. Throughout the rest of this thesis the abbreviation SMN is used to define subsequent malignant neoplasm unless otherwise stated. The
International Agency for Research on Cancer (IARC), the International
Association of Cancer Registries (IACR), World Health Organisation (WHO) and the European Network of Cancer Registries have published rules for defining and recording multiple primary tumours in cancer registries where the
recognition and existence of two or more primary cancers does not depend on time [165]. Neoplasms of different morphology should be regarded as multiple cancers even if diagnosed simultaneously in the same site [165]. Studies may use different follow-up periods and eligibility criteria to examine SMNs.
Studies based on the CCSS, BCCSS and TYACSS only include 5-year survivors of childhood cancer and examine all new neoplasms recorded after this date [35, 82, 167, 168]. Several studies have based their definition of SMNs on the IARC and IACR rules for defining multiple primaries irrespective of the time elapsed since the primary neoplasm was diagnosed; including in a large study of SMNs after childhood non-CNS solid tumours based on data from 13 cancer registries [169], a Canadian study focussing on SMNs developing in the first 5 years following diagnosis [170], and a large study based in the Nordic countries [34]. While other studies have examined SMNs in patients who survived a minimum of two months [171], three months [172], three years [173] or five years [174] following diagnosis of a primary cancer.
For childhood cancer survivors the risk of developing a SMN was between 3 – 10 times higher than that of the general population [34, 35, 167, 170, 171]. These studies differed in terms of inclusion criteria of childhood cancer
survivors and the definitions used to define the SMN making direct comparison between studies difficult. However, all found a substantial increased risk
compared to the general population. Pole et al showed that 40% of SMNs in childhood cancer survivors occurred in the first 5 years following diagnosis [170]
therefore comparisons between studies including all cancer survivors and those only containing 5-year survivors may vary substantially in the number of SMNs reported. The magnitude of excess risks and specific types of second cancer vary widely with type of first cancer and also in length of follow-up. In the CCSS the median time to first occurrence of subsequent malignant neoplasm was 18 years and was shortest for development of leukaemia at 9 years and longest for small intestine and colorectal cancer at 23 years [167].
The cumulative incidence for a SMN continues to increase across the life- course; 25-30 years after diagnosis of a childhood cancer the cumulative incidence of developing a SMN ranged from 4-8% [167, 170, 171, 173, 174]. Long-term childhood cancer survivors from the CCSS had a cumulative incidence of a SMN by age 55 of 16% [168], similar results were also found in the BCCSS where the cumulative incidence by age 55 was 14% [35]. Findings based on the CCSS have shown that the cumulative incidence of SMNs
decreased for those diagnosed in the 1990s compared to those diagnosed 1970s [164, 175].
All types of childhood cancer are associated with an increased risk of SMN however several studies have shown that the standardised incidence ratios (SIR) are highest for a primary diagnosis of Hodgkin lymphoma (SIRs range from 6-16 [35, 167, 170, 171, 173]), retinoblastoma (SIRs range from 13-15 [35, 171]) and bone tumours (SIR range from 4-18 [35, 170, 173]) and in particular Ewings sarcoma (SIRs range from 9-13 [167, 171]). The highest cumulative incidence of second malignancy following a non-CNS solid primary tumour occurred after retinoblastoma reaching 18% 50 years after the diagnosis of the primary cancer [169].
A range of SMNs are diagnosed in long-term childhood cancer survivors, studies reporting these have used different coding and groupings of SMN and have different periods of follow-up but the most common sites and types of SMN include female breast cancer, CNS tumours, bone tumours, soft tissue sarcomas, melanoma, thyroid, digestive tumours, genitourinary tumours and endocrine tumours [35, 167-170, 173]. The incidence and range of subsequent neoplasms change over follow-up. Pole et al examined SMN in the first 5-years from diagnosis of a childhood cancer and found early SMNs (those developing within 5 years of diagnosis) were more likely to be leukaemia, lymphoma or sympathetic nervous system tumours and around one third of early SMNs were
solid tumours [170]. The site distribution of second cancers changes over the life-course. In the Nordic countries CNS tumours accounted for 39% of SMN diagnosed in 0-14 years olds but only 9% of SMNs in 60+ years where breast cancers were the most common SMN comprising 32% of all SMNs [34]. In the BCCSS bone tumours and glioma accounted for 50% of the excess risk for patients aged <20 years at diagnosis of a SMN, whereas digestive and
genitourinary tumours accounted for 36% of the excess risk in those aged over 40 [35].
An increased risk of SMNs in those who received radiotherapy or chemotherapy has been reported in several studies [35, 167, 168, 170, 173], with the greatest excess risk for those that received both treatment modalities [173]. The risk of developing a colorectal cancer for childhood cancer survivors treated with abdominopelvic radiation is similar to that of individuals with a strong family history of colorectal cancer; cumulative incidence by age 50 is 1.4% for childhood cancer survivors compared to 1.2% those with a family history of colorectal cancer [35].
Other risk factors associated with an increased risk of SMN were female sex [167, 168], age at diagnosis, although Friedman et al [167] reported that older age at diagnosis increased the risk of SMN while Pole et al [170] reported younger age at diagnosis increased the risk, attained age [35] and treatment era [34, 167].
Several studies based on pooled European data on almost 70,000 5-year survivors of childhood cancer have examined the risk of diagnosis of specific subsequent tumours including leukaemia and soft-tissue sarcomas and bone tumours [176-178]. Compared to the general population childhood cancer survivors had 4-times the expected risk of leukaemia [176], 16-times the expected risk of soft tissue sarcoma [177] and 22-times the expected risk of bone tumours [178]. The large sample size of these studies enabled a detailed examination of risks for specific subtypes of these diagnostic groups.
Studies on SMNs in TYA are limited. The TYACSS study examined SMNs in a cohort of 200,000 5-year survivors diagnosed aged 15-39 years in England and Wales and reported the risk of SMNs after each specific AYA cancer type [82]. SMNs were most frequently diagnosed in survivors of breast cancer, cervical
cancer, testicular cancer and Hodgkin lymphoma with the cumulative incidence 35-years post-diagnosis of all SMNs ranging from 12% for breast cancer
survivors, to 27% in female survivors of Hodgkin Lymphoma. Lung cancers accounted for a substantial proportion of the excess number of SMNs
diagnosed within these groups [82]. A study based on SEER data reported on SMNs diagnosed in a cohort of 150,000 AYAs (aged 15-39 years) in the US after specific AYA cancer types and reported an SIR of 1.6, compared to an SIR of 4.3 or children and 1.1 for older adults [174]. Higher risks of SMNs were observed for patients with a primary diagnosis of AML, Hodgkin lymphoma, NHL, testicular cancer, melanoma, breast cancer and sarcoma, with the highest SIRs for survivors of Hodgkin lymphoma (SIR=3) [174]. For those aged 15-39 years at diagnosis of primary cancer the 30-year cumulative incidence was 18% for those who received radiation compared to 12% for those that did not [174]. A further US study based on two-year survivors aged 15-39 years at diagnosis estimated the incidence of SMNs were 2.6 time higher than matched controls with a cumulative incidence of 13% twenty-years post diagnosis [179]. Older age at primary diagnosis, female sex, ethnic group, advanced stage of disease and radiotherapy exposure were all associated with an increased risk of SMN, although these risk factors varied by first cancer type [179].
In childhood cancer survivors it is estimated that 40% of SMNs are diagnosed within 5-years from primary tumour [170] and in the US, a study of 15-39 year olds estimated that 73% of SMNs were diagnosed 1-5 years from primary diagnosis [180]. There are differences in the types of SMNs diagnosed by latency period: early onset SMNs are more likely to be leukaemias and
lymphomas [181]. Few studies have assessed the impact of latency on survival. In AYA aged 15-39 years, the risk of death doubled for those with a latency period of 1-5 years compared to those with a latency period of 6 years or more [180]. While in Canada childhood cancer survivors with early onset SMNs were 1.8 times more likely to die that those who developed an SMN after 5-years [170]. Another US study of SMNs developing before the age of 20 found those with a latency of less than 5-years had lower survival, but this study only included primary solid tumours [182].
Survival from SMNs is lower in children and AYAs compared to survival rates for the same type of primary tumour; 5-year survival in children was 80% for primary tumours compared to 47% for SMNs and in AYA 81% for primary
survivors reported an increased risk of death for those with a SMN compared to those diagnosed with a first cancer after adjustment for potential confounders including sex, age at diagnosis, decade of diagnosis, ethnicity and diagnostic group [184]. An increased risk of death was found across several diagnostic groups: breast cancer, thyroid cancer, AML, CNS tumours, melanoma, bone cancers and soft tissue sarcomas [184]. A Dutch study found survival from sarcoma SMNs was worse than for patients with a first primary sarcoma, and there were no survival differences between primary tumours and SMNs for breast cancer or melanoma. However, this study was based on a small number of long-term survivors (45 sarcoma, 41 breast cancer and 17 melanoma
survivors) [185].
To summarise, the risk of developing a SMN continues to increase throughout follow-up and varies by type of primary cancer and other risk factors such as sex, age at diagnosis, length of follow-up and treatment received for primary cancer. A range of different types of SMN are diagnosed and these vary across the life course. Studies based on the TYA age range are more limited.
Prognosis following SMN diagnosis is an important area for further research.