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  • Review Article
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Second cancers in survivors of childhood cancer

Nature Reviews Cancer volume 2, pages 124–132 (2002)Cite this article

Key Points

  • Survivors of childhood cancer are at a 3–6-fold increased risk of developing a second cancer, compared with the general population. Although second cancers are a comparatively rare complication in cancer survivors, they are associated with significant morbidity and mortality.

  • For most second cancers, the risk decreases with increasing age of diagnosis of the first cancer; female gender is also associated with an increased risk of second cancers.

  • Radiation therapy increases the risk of several second cancers in a dose-dependent manner. Most second cancers associated with radiotherapy occur in or near the area that was irradiated, and most have a long latency.

  • Certain chemotherapeutic agents, particularly alkylating agents and topoisomerase II inhibitors, increase the risk of developing a second cancer. In some cases, specific genetic changes caused by these agents explain the increased risk of particular second cancers.

  • Emerging risk factors for second cancers include familial cancer syndromes, gene–environment interactions, lifestyle choices and other medical complications associated with treatment for the primary cancer.

  • By understanding the factors that increase risk of second cancers, we might be able to implement strategies to prevent them. For example, individuals known to be at increased risk of therapy-induced cancers can be treated with modified regimens that reduce this risk.

Abstract

More than 70% of children diagnosed with cancer can now be expected to be long-term survivors. However, the consequences of 'cure' might be considerable for the survivors of cancer: 60–70% of young adults who have survived childhood cancer will develop at least one medical disability as a result of their cancer or, more commonly, as a result of their therapy. Of these, the most devastating is a second cancer.

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Figure 1: Cancer incidence in childhood cancer survivors.
Figure 2: Risk factors for subsequent cancers.
Figure 3: Second cancers in survivors of Hodgkin's disease.

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Authors and Affiliations

  1. City of Hope National Medical Center, Duarte, 91010, California, USA

    Smita Bhatia

  2. Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Charles Sklar

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  1. Smita Bhatia
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retinoblastoma

soft-tissue carcinomas

uterine cervical cancer

 LocusLink:

ATM

CYP3A

GSTM1

GSTP1

GSTT1

IGF1

MLL

NQO1

TP53

 Medscape DrugInfo:

cisplatin

doxorubicin

etoposide

mechlorethamine

melphalan

teniposide

 OMIM:

Li–Fraumeni syndrome

Glossary

MYELODYSPLASIA

A syndrome that is characterized by ineffective haematopoiesis. Morphological abnormalities occur in at least one, and often several, types of haematopoietic cell, particularly erythrocytes. Secondary myelodysplasia is characterized by progression to acute myeloid leukaemia after a variable length of time.

CYTOCHROME P450

A family of enzymes, most abundant in the hepatic endoplasmic reticulum, that are responsible for the metabolism of various chemicals, including carcinogens.

DNA ADDUCT

A DNA adduct forms as a result of DNA binding to a genotoxic chemical. It reflects exposure to specific carcinogens, and is a marker of cumulative unrepaired DNA damage.

ALKYLATING AGENTS

An important group of anticancer drugs that exert their cytotoxic effect through the alkylation of DNA, resulting in inhibition of DNA replication and transcription. Examples include mechlorethamine, cyclophosphamide, melphalan, busulphan and cisplatin.

TOPOISOMERASE II INHIBITORS

Topoisomerase II inhibitors block the unwinding of supercoiled DNA during DNA cleavage by forming a complex between the enzyme and DNA. Those that are used as chemotherapeutic agents include epipodophyllotoxins, anthracyclines, acridine, anthracenedione and doxorubicin.

ATAXIA TELANGIECTASIA

An autosomal recessive genetic disorder that is characterized by cerebellar ataxia, oculocutaneous telangiectasia and immunodeficiency.

PRIMARY PREVENTION

Prevention of disease by altering susceptibility or reducing exposure for susceptible individuals.

SECONDARY PREVENTION

The early detection and treatment of disease.

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Bhatia, S., Sklar, C. Second cancers in survivors of childhood cancer. Nat Rev Cancer 2, 124–132 (2002). https://doi.org/10.1038/nrc722

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