Introduction

In the UK the estimated numbers of people living after a cancer diagnosis range from 1–1.5 million. With increasing cancer incidence and survival it is thought that this will rise to represent 1.5–2.5% of the adult population. The 5-year survival for children diagnosed with cancer is now 79% and for adult cancers is 64%. There are a number of medical, psychological, social and economic issues which can significantly contribute to a patient’s morbidity and mortality after a diagnosis of cancer. This chapter aims to overview these issues.

Paediatric oncology and the history of survivorship

The median age of diagnosis of cancer in the general population is 70 years but the most significant increase in survival rates in the past 30 years has been in the area of paediatric oncology. Many children were treated in a clinical trial such that the initial survivorship data was gained from paediatric patients. The medical sequelae of cancer treatment as a child have profound consequences due to the current average life expectancy.

Given the dependence of children upon their parents and the developmental needs of a growing child some of their psychosocial survivorship issues are different to those of adults. In addition the families of children treated for cancer are significantly affected and many parents or siblings of childhood survivors suffer long-lasting psychological and social consequences even when the clinical outcome has been good.

Medical late effects

Late effects are dependent upon the original cancer, its treatment, the family genetics and the developmental stage of the individual when treated for cancer. Box 6.1 lists some of the major effects that can occur.

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

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).

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%).

Infertility

Infertility as a consequence of cancer or its treatment remains a significant issue for young people who have not yet completed their families (Figure 6.2). The risk depends on the gender of the patient and the type of therapy administered as well as the type of cancer (Box 6.3). Overall the fertility of childhood cancer survivors when compared with their siblings is 0.76 for men and 0.93 for women.

In the UK, guidelines have been developed by a working party to highlight possible management strategies and risks of infertility with different cancer treatments (Box 6.4). These are available from the Royal College of Radiologist website (http://www.rcr.ac.uk/publications.aspx?PageID=149&PublicationID=269).

Infertility in men commonly occurs after alkylating agents or radiotherapy to the gonadal region or after total body irradiation. For this reason all men who are capable of producing sperm should be offered sperm banking. Sperm aspiration may be considered for those unable to ejaculate e.g. pelvic Ewing’s which has affected the sacral nerves. Some men will retain their fertility. This can occur up to 2 years after treatment is completed. Retrograde ejaculation can occur in men who have had bilateral retroperitoneal lymph node dissection e.g. following chemotherapy for a testicular tumour with residual lymph node masses.

Fibrosis of the uterus can occur following pelvic radiotherapy and may cause growth restriction of a developing foetus even if the patient becomes pregnant.

Premature ovarian failure can occur in response to pelvic (or spinal) radiotherapy or certain (but not all) chemotherapy agents. The risk of menopause is associated with the type of therapy rather than the type of cancer. The highest risk for women is those who had radiotherapy below the diaphragm combined with alkylating agents. High-dose treatments (including total body irradiation) and alkylating agents will usually render a woman infertile. Even in those cases where fertility is preserved after treatment, the timing of the menopause is likely to be several years earlier than the patient’s peers.

Treatment with anthracyclines as a young adult may require an echocardiogram during pregnancy as cardiac function may be impaired with increased cardiac output requirements due to the developing foetus.

There appears to be no significant increase in congenital abnormalities in the offspring of survivors, nor any increase in childhood cancers in the offspring, including after bone marrow transplantation (Box 6.5).

Bone late effects

Bone growth is affected by steroids, chemotherapy or radiotherapy (Box 6.6). In addition hormonal manipulation with aromatase inhibitors or anti androgen therapy can have profound consequences on bone loss. Osteopenia occurs frequently at the end of treatment with combination chemotherapy. In ER positive breast cancer where patients may have chemotherapy followed by an aromatase inhibitor, the hormonal treatment compounds the osteoporotic effect of the chemotherapy such that calcium supplementation or bisphosphonates are frequently required to prevent fractures. To minimize the risk of fractures from significant osteoporosis patients should be screened for osteoporosis prior to commencing hormonal treatment using a risk assessment and bone mineral density scan. Patients should be reassessed after 6–12 months on hormonal therapy. Those at significant risk should be advised about calcium in their diet and/or prescribed calcium supplements. At very high risk or after a fracture, bisphosphonates (orally or intravenously) should be prescribed.

Osteoradionecrosis can occur after high-dose radiotherapy particularly to the head and neck region. Pre-treatment dental assessment and corrective procedures are important in preventing this side effect.

Osteonecrosis is a known complication of treatment for leukaemia, lymphoma or bone marrow transplantation and is thought to be due to high-dose steroids. It tends to occur most in weight bearing bones e.g. femur such that arthroplasty of the hip joint may be carried out in up to 20% patients with femoral head osteonecrosis. Osteonecrosis of the jaw is a recognized complication of treatment with zolendronic acid. Patients should see a dental surgeon prior to starting treatment and zolendronic acid should be stopped and further dental assessments made if there is any suspicion of dental abscess.

Neurological

Neurological damage can occur either centrally to the brain itself or to the peripheral or autonomic nerves depending on the tumour and treatment given. For those with CNS tumours, cranial radiotherapy may be given in combination with chemotherapy which can produce combined peripheral and central neurological deficits.

Certain chemotherapeutic agents are known to be neurotoxic such as platinums and vinca alkaloids. The risk is greater with increasing age, particularly over the age of 50 and unless specifically assessed during treatment, the damage may be permanent and debilitating. Painful peripheral neuropathies are most commonly associated with these drugs, especially vincristine. For cisplatin, the symptoms and signs of peripheral neuropathy can progress even after treatment has finished which highlights the importance of detecting deterioration.

Hearing loss due to damage to the auditory nerve can occur with platinums, especially cisplatin, so that audiometry should be performed prior to and after treatment.

Neurocognitive impairment can also occur and the risk is greatest amongst survivors of ALL and CNS tumours. Many of these patients are treated at a young age so the impact of neurocognitive impairment reduces their chance of further education or employment. The effects are worse in those treated under the age of 5 and in females.

Gastrointestinal

Following radiotherapy to the pelvis, or abdomen, acute toxicity to the bowel is well known due to inflammation of the intestinal organs. Late toxicity is often underestimated but accounts for significant morbidity (Box 6.8). Intermittent subacute bowel obstruction also occurs. All these symptoms can have a range of causes so referral to a gastroenterologist is recommended for appropriate investigation. Rectal bleeding in particular must not be ignored as this may represent a second malignancy, especially in those who have had pelvic radiotherapy.

Cardiological

Cardiac toxicity can take several forms following treatment including cardiac failure, arrhythmias and increased risk of myocardial infarction (Table 6.2). The major risk factors are mediastinal or left chest wall radiotherapy, anthracyclines and vincristine. Asymptomatic arrhythmias are common. Children treated with anthracyclines have reduced left ventricular wall thickness and reduced left ventricular function which can continue to deteriorate many years after treatment. Treatment with angiotensin converting enzyme inhibitors has been shown to improve left ventricular function in the short term but did not prove effective in symptomatic patients in the longer term.

Table 6.2 Major cardiac problems associated with cancer treatments

Nature of cardiac problem	Causative agent(s)
Arrhythmias (many asymptomatic with impact unknown)	Radiotherapy, multiple chemotherapy agents e.g. anthracyclines, taxanes
Cardiac failure	Radiotherapy Anthracyclines Trastuzumab

Coronary artery disease and myocardial infarction Note: hypercholesteralaemia is common after chemotherapy  

From the available literature it is difficult to make recommendations on the management and follow up of cardiac and pulmonary complications. It would seem prudent however to reduce other known cardiac risk factors (smoking cessation, and blood pressure and cholesterol control) as part of the suggested lifestyle modifications after treatment.

Pulmonary

Long-term pulmonary toxicities are wide ranging and account for a significant amount of morbidity and later mortality. The types of damage that can occur include fibrosis (from radiotherapy or bleomycin), pneumonitis (radiotherapy, gemcitabine), asymptomatic abnormalities of lung function tests (radiotherapy and combination chemotherapy) or lung cancer (especially after radiotherapy and chemotherapy in patients who continue to smoke). Patients given hemi-thorax radiotherapy for metastatic Wilms’ tumours in childhood are at particular risk.

Endocrine

Endocrine abnormalities can occur in any endocrine organ. The most frequently affected are those who have received radiotherapy close to the pituitary or thyroid (Table 6.3). Hormonal replacement may be necessary for these patients as the hormones involved have significant systemic functions. Abnormalities do not occur immediately after treatment, particularly those from the pituitary or thyroid, so they should be screened for starting at least 1 year post treatment or earlier with symptoms. Adrenal insufficiency should always be considered in patients who have received high-dose steroids, particularly during a period of infection.

Table 6.3 Overview of most common endocrine abnormalities and their cause

Endocrine organ affected	Hormones affected	Causative agent
Pituitary	Growth hormone TSH FSH/LH

Radiotherapy to brain (pituitary region) Thyroid Thyroxine Radiotherapy to neck or upper chest >15 Gy (scatter effect) Gonads Adrenals Cortisol High-dose steroids (mostly haematological malignancies)

Endocrine input is essential in the assessment of late effects in the follow-up clinic.

Obesity

Obesity is a significant problem for survivors of cancer, especially those treated in childhood. The risks are greatest for those treated with cranial radiotherapy, females and those aged 0–4 years at diagnosis. Survivors of ALL have the greatest risk, thought to be due to a combination of cranial prophylaxis with radiotherapy and the high doses of corticosteroids used.

Chronic health conditions

In addition to specific toxicities the overall health of an individual is likely to be affected after treatment for cancer. Chronic health conditions can include overall health, or any of the above medical conditions which have a chronic effect on an individual’s health. It also includes symptoms of chronic fatigue which can cause limitations of everyday life and persist for many years after treatment is complete. In a study of childhood survivors, chronic health conditions occurred in almost all patients with 27.5% experiencing severe or life-threatening health effects. Multiple chronic conditions were also more frequent with 37.6% experiencing at least 2 and 23.8% experiencing at least three significant co-morbidities.

Causes of death after cancer treatment

The main cause of death following a diagnosis of cancer is the cancer itself even after surviving over 5 years from diagnosis. After recurrence the greatest risk of death is from a second malignancy followed by pulmonary then cardiac problems. In one study the standardized mortality ratio was 19.4 for second malignancy, 8.2 for cardiac death and 9.2 for pulmonary death with other causes at 3.3. The risk of death was greatest for women, those diagnosed before age 5 and those with an initial diagnosis of leukaemia or CNS tumour. Given the recent change in treatment to reduce mediastinal radiotherapy (a major cause of these sequelae in Hodgkin’s disease) it is hoped that these will reduce in the future.

Psychological impact of cancer diagnosis and treatment

Following a diagnosis with cancer patients and their families make psychological adjustments to cope with the treatment and potential outcome. Stress is, not surprisingly, very common and occurs in over 95% of patients. The majority of these will have anxiety and mild depression which may not require treatment. However some will have more significant psychological symptoms and needs including depression, post-traumatic stress disorder, suicidal ideation and various psychoses.

In survivors of childhood cancer there is a greater degree of some aspects of psychological distress in the parents than in the patient themselves. Parents were more concerned about their child’s health and thought more often of the cancer and its diagnosis than the patient.

Suicidal ideation and previous attempts at suicide have been shown to be present in up to 12.83% of childhood cancer survivors. Standardized mortality ratios for deaths as a result of suicide in cancer patients are in the order of 1.35–2.9 compared with the general population. Risk factors include male sex, older age, higher disease stage, poor prognosis, poor performance status, alcoholism, other psychiatric illness, fatigue, pain, loss of function and previous or family history of suicide attempts. Lack of family or social support also correlates with increased suicide risk.

Mental health issues must not be underestimated and addressing them throughout treatment will aid with patients seeking help if necessary, even many years later. Recognizing that this is a potential problem and consequence of losses associated with cancer and its treatment allows it to be seen as a normal process which, like the rest of oncology supportive care, should be appropriately managed.

Relationships

On average cancer survivors are less likely to be married and have a higher incidence of divorce than their peers.

Social consequences

When compared with age matched controls cancer survivors have a lower income. They are more likely to have difficulties obtaining life and health insurance or a mortgage after surviving cancer.