Second malignancy	e.g. leukaemia, sarcoma
Chronic health conditions	e.g. breathlessness, fatigue
Cardiological	e.g. arrhythmias
Neurological	e.g. peripheral neuropathy
Pulmonary	e.g. fibrosis
Endocrine	e.g. GH deficiency
Fertility	e.g. premature ovarian failure
Bone	e.g. osteoporosis
Renal	e.g. hypomagnesaemia

Second malignancy

Second malignancies are the second most common cause of death (after the primary cancer) in those diagnosed with cancer, and can either be a solid tumour or haematological (leukaemia or myelodysplastic syndromes). The risk of second malignancy is increased with combinations of chemotherapy and radiotherapy but is also dependent upon the underlying genetics of the individual and the sensitivity of the tissue irradiated (Table 6.1).

Table 6.1 The most common second malignancy after treatment for cancer and some of the identified or proposed causative agents

Type of secondary malignancy	Identified or potential risk factors
Leukaemia	Chemotherapy, e.g. etoposide, anthracyclines
Sarcoma	Radiotherapy for e.g. previous sarcoma or retroperitoneal lymph nodes Genetics, e.g. Li–Fraumeni, hereditary retinoblastoma

Lung

Radiotherapy especially in smokers

Potential risk from multiple CT scans for follow-up

Breast Radiotherapy, e.g. mantle or hemithorax especially if given in late teens or early twenties (up to 4–7 times the standardized mortality ratio) Uterine Tamoxifen (risk 1 in 100,000), increased in those with HNPCC Colorectal Pelvic or abdominal radiotherapy Bladder

Pelvic radiotherapy

Possibly some alkylating agents (with radiotherapy)

In general secondary solid tumours arise in sites of previous radiotherapy, especially if chemotherapy was also given. The total dose of radiotherapy delivered as well as the type and energy of the treatment and treated volume determine the risk. The tissues most likely to give rise to a secondary malignancy following radiotherapy are bone marrow, thyroid, breast and soft tissues (sarcomas) (Box 6.2).

Box 6.2
Learning points

• Secondary tumours are often very aggressive and do not respond as well to treatment as primary tumours of the same histology.

• In Ewing’s sarcoma, radiotherapy with greater than 54 Gy is associated with second malignancy but treatment with less than 45 Gy is associated with local recurrence.

Leukaemias and myelodysplastic syndromes have been found to relate to previous chemotherapy treatment, especially with etoposide, anthracyclines and alkylating agents. These leukaemias are characterized by a chromosomal abnormality at 11q23, tend to occur within 2 years of primary treatment and have a poor prognosis. Intensive regimens for Ewing’s sarcoma or rhabdomyosarcoma have a risk of up to 20% at 20 years of secondary haematological malignancy. Myelodysplastic syndromes have been associated with previous alkylating agents.

The cumulative incidence of any second malignancy increases with time from primary treatment, e.g. from 10.6% at 20 years to 26.3% at 30 years following treatment for Hodgkin’s disease. The increased risk of breast cancer in patients treated with mantle radiotherapy for Hodgkin’s disease led to the removal of radiotherapy in the treatment of the majority of cases. The relative risk of second malignancy is greatest when treated at a younger age at time of diagnosis and decreases with older age at the time of treatment. In another study, the 15-year cumulative risk of a second malignancy was 11.2% overall, with the greatest number of cases in lung cancer (2.8%), leukaemia (1.5%), colorectal cancer (1.5%) and breast cancer (1.2%).

Example box 6.1

A 21-year-old woman was treated for Ewing’s sarcoma of the right pelvis with neoadjuvant chemotherapy, debulking surgery, radiotherapy and further chemotherapy. She had a good response to treatment with only a small mass remaining which remained stable on CT scans for 5 years. With increasing symptoms of pelvic and groin pain at 8 years an X-ray then MRI was performed which showed a mass in the left acetabulum (Figure 6.1). The appearance of the mass was not typical for a Ewing’s sarcoma and a biopsy was performed. The pathology showed an osteosarcoma. Despite staging showing no distant disease and treatment with chemotherapy, the tumour progressed rapidly, lung metastases developed and the patient died within a year.