**2. Addressing the late effects of cancer treatment**

#### **2.1 Definition of late effects**

There is currently no agreed definition for the late effects of treatment with some differentiating between long term effects (those occurring during treatment and persisting after completion) and late effects (toxicities not apparent during primary treatment but manifesting some time later). However, the internationally accepted classification of adverse effects of treatment, the Common Toxicities Common Adverse Effects criteria (CTCAE) does not distinguish "acute" and "late" effects.

In response to this, the National Cancer Survivorship Initiative Late Effects workstream has proposed the following definition that "late effects are the long-term consequences of cancer and its treatment, including those which appear during, or soon after treatment, as well as those which appear months or years later".

These effects include:


#### **2.2 Treatment related late effects**

4 Topics in Cancer Survivorship

A quarter of cancer patients will experience long-term effects that compromise their quality of life. These effects may manifest up to 10 years later and range from minor ailments in the majority to complex and debilitating problems for an unlucky few. Treatments now used to cure patients may no longer be considered ideal when treatment related adverse effects are taken into account and although most will be able to cope with minor conditions, a substantial minority will not. As a result, we must recognise and address the needs of these individuals. Early detection of symptoms, appropriate management and patient education are all key aspects to this. As curative approaches to different cancers become increasingly widespread, the focus needs to be more on quality of survival and reducing the disability

At present it is estimated that almost half a million cancer survivors in the UK suffer from a chronic treatment related condition which impacts their quality of life. In the United States, a National Health Interview study (Hewitt et al., 2003) compared 5,000 cancer survivors with 90,000 people without any history of cancer. It found that cancer survivors were more likely to report being in poor health both psychologically and physically. As we move forward, this will translate into a huge burden on our health resources, especially in the primary care setting. These findings are mirrored by results of similar studies in the UK which have also highlighted the financial impact on cancer patients as a result of no longer being able to work or who are subject to extra costs incurred due to their treatment and/or long-term disability (Fobair, 2007; Macmillan Cancer Support, 2006; Yabroff et al., 2007). It is

There is currently no agreed definition for the late effects of treatment with some differentiating between long term effects (those occurring during treatment and persisting after completion) and late effects (toxicities not apparent during primary treatment but manifesting some time later). However, the internationally accepted classification of adverse effects of treatment, the Common Toxicities Common Adverse Effects criteria (CTCAE) does

In response to this, the National Cancer Survivorship Initiative Late Effects workstream has proposed the following definition that "late effects are the long-term consequences of cancer and its treatment, including those which appear during, or soon after treatment, as well as

associated with them. This is our challenge for the future.

important therefore, that measures are put in place now to minimise this.

Heart (e.g. heart failure following anthracyclines and herceptin)

 Brain (eg impact on cognition following chemotherapy or radiotherapy) Peripheral nerves (eg neuropathy related to platinum based drugs)

Endocrine system (eg growth, fertility, thyroid deficiency, early menopause)

**2. Addressing the late effects of cancer treatment** 

**2.1 Definition of late effects** 

These effects include:

Kidneys (e.g. cisplatin)

Sexual interest and function

not distinguish "acute" and "late" effects.

those which appear months or years later".

Lungs (e.g. radiotherapy, bleomycin)

 Gastrointestinal tract (eg pelvic radiotherapy) Musculoskeletal system (eg amputations) Lymphatic system (eg lymphoedema)

Surgery, chemotherapy and radiotherapy all have consequences, which may become apparent immediately or after several years. These include urinary, bowel and sexual dysfunction, neuropathy, cardiovascular and endocrine abnormalities. Those treated as children are at greater risk of complex and inter-related issues arising after a substantial period of time with the risk of a second malignancy becoming an increasingly real threat.

Surgery and radiotherapy can result in significant ongoing co-morbidities. For those patients, for example, who underwent bowel resections, gastrointestinal sequelae of treatment can be severe and most often manifest as loose stool and incontinence. Pelvic radiotherapy has led to increasing cure rates of many cancers but the incidence of long term gastrointestinal problems is even higher (Flentje & Guckenberger, 2006) than with surgery including problems such as urgency, flatulence, abdominal pain and intermittent or regular soiling. Studies report that only a third of patients report normal or good bowel function (Lundby et al., 2005; Marijnen et al., 2005). Despite this, only few gastroenterologists feel adequately trained to deal with such side effects of treatment.

Management of long-term gastrointestinal effects is poorly represented in the literature with little research in the field. Such problems are often very embarrassing to patients and therefore under-reported. Patients may feel that nothing can be done and physicians may not encourage patients to discuss these issues due to their minimal experience in dealing with them (Andreyev et al., 2003a, Andreyev et al., 2003b; Putta & Andreyev, 2005). Such patients inevitably withdraw from social interaction from fear of uncontrollable symptoms (Faithfull, 1995). It is not just bowel related difficulties that these patients face but also urological and sexual dysfunction. Furthermore, fractures, neurological issues and thromboembolic phenomena are also seen, although less frequently. 17,000 patients a year are treated with radiotherapy to the pelvis with almost 80,000 survivors of this treatment in the UK. Almost half of these individuals feel that sequelae of treatment has had an impact on their quality of life with 27,000 describing this impact as moderate to severe. These figures are probably an underestimation, particularly as follow-up times for most studies preclude the true magnitude of late effects. Furthermore, few patients freely admit to diarrhoea or incontinence unless directly asked and therefore questionnaires may be too insensitive and not reproducible. The British Society of Gastroenterology is due to publish guidelines on the management of treatment-related late effects this year.

The formation of RAGE (Radiotherapy Action Group Exposure) campaign was to address and improve conditions for patients with breast cancer who experienced late radiation injury as a consequence of radiotherapy at a time when there were no national standards in the United Kingdom. Although radiation damage is relatively rare, serious injuries such as those to the brachial plexus nerves causing weakness of the ipsilateral shoulder, arm and hand and vascular compromise have been reported. Less serious consequences such as rib fractures and skin discoloration may also arise. However, with many women now alive more than a decade after their diagnosis, the consequences of treatment of radiotherapy are becoming an increasing reality and a burden. Macmillan Cancer Support UK have focused on six main areas in response to RAGE (Hanley & Staley, 2006).

Living With and Beyond Cancer: New Challenges 7

Mullan (1985) in his seminal paper "Seasons of Survival" describes the evolving process of surviving cancer as beginning from diagnosis and involving the following 3 phases (Mullan,

The **acute phase** is particularly difficult with a multitude of physical and psychosocial issues that patients may face. The organic side effects of treatment are the first hurdle but with the completion of treatment, a whole host of unexpected emotions such as uncertainty, fear of recurrence and abandonment may surface (Pelusi, 1997). There are huge psychological hurdles that patients may need to deal with; a sustained mortal threat, unrelenting personal and domestic turmoil, long difficult medical treatments and a prolonged uncertainty about the future. At this point, patients may find that they need to face up to the realities from being an ill person to being a survivor, from feeling time is unlimited to a having finite lifespan and from being fully able to living with a disfigurement or disability. Returning to work can be a huge physical and mental challenge. Patients' view of themselves may have changed and side effects of treatment such as mood changes and hot flushes may make social interaction difficult (Charmaz, 1983; Wyatt 1996). Hospitals form a protective bubble, having become a familiar and comfortable place in which patients often feel a sense of togetherness and reassurance. The sudden foray into the world outside can therefore be lonely and unpredictable. As time passes, most begin to feel a sense of security return and find that their health becomes more predictable. However a significant proportion, approximately 20-30%, will still suffer from continuing distress (Absolom, 2009; Foster, 2009) and will require increasing support in the community. Predictors of persistent, moderate and severe problems with daily living may include a high level of unmet physical needs, fear of recurrence, stress of looking after a family and increasing imposition on their

**Extended survival** is the period where active hospital based surveillance is the mainstay of follow-up. However, these first five years after treatment has ended also represent the period of highest recurrence risk. Reduced levels of activity and less acute symptomatology may persist which over time could erode into the ability to enjoy life and maintain relationships. For example, menopausal symptoms are experienced by 70% of patients treated for breast cancer and can persist for several years impacting severely on quality of life (Carpenter & Andrykowski, 1999; Fenlon et al., 2009; Hunter et al., 2004; Walker et al., 2007). An online survey found that over 30% of breast cancer survivors stopped adjuvant aromatase inhibitor therapy due to their side effects (Zivian & Salgado, 2007). Long term sexual difficulties are also a challenge, with loss of libido, decreased orgasm and physical difficulties (retrograde ejaculation and impotence in men on GHRH antagonists, dyspareunia in women on endocrine therapy). Such issues are often considered taboo or difficult to discuss with medical professionals. Many more women are being diagnosed at a younger age due to screening programmes and therefore wish to maintain fertility. Access to fertility preserving facilities is variable and simply potentiates an already sensitive issue

**Permanent survival** refers to treatment related problems that emerge years or decades after the initial diagnosis. This is most apparent in children, a group in whom, as cancer treatment has become more successful, has an increasing number of survivors developing treatment

Acute Survival: the first year, recovery from the diagnosis and treatment.

Extended Survival: five years after treatment.

health by unrelated co-morbidities or iatrogenic interventions.

(Amir & Ramati, 2002; Bloom et al., 2004; Broeckel et al., 2002).

Permanent Survival: the long term.

**3. Surviving cancer** 

1985):


It is not just surgery and radiotherapy that have consequences. Chemotherapy is toxic and mutagenic, causing short-term multi-organ toxicity and increasing the risk of secondary malignancy. Two of the biggest hurdles women with breast cancer face after treatment is the fatigue associated with the cumulative effect of months of treatment and the after-effects of chemotherapy, together with mild cognitive impairment such as memory deficits, often termed "chemobrain" (Tannock et al., 2004). Furthermore, ongoing treatments in patients with breast cancer such as endocrine therapies which are often continued for at least five years, can affect recovery, leaving patients with physical problems such as fatigue, hot flushes, weight gain, joint pains and muscle aches. Tamoxifen can cause endometrial hyperplasia and increase the risk of endometrial malignancy. Osteoporosis and arthalgia are potential adverse effects that can arise from the use of aromatase inhibitors. Although hospital based follow-up systems have been developed to help monitor and detect any late toxicities, it may actually be more effective to educate patients to recognize problems. It is also important that adaptive strategies are discussed with patients in order to help them cope with these side-effects.

#### **2.3 Complex treatment related late effects**

A small proportion will suffer from severe or complex problems associated with treatment requiring specialist input. Some of these could be avoided through the prompt recognition and correct management of symptoms thereby avoiding the potential distressing complications resulting from inappropriate procedures. Occasionally, there may be people with unexpected effects associated with treatments which may require a national process of recall, reassessment and commissioning of new services. An example of this is in the group of young patients who received "Mantle" field radiotherapy for Hodgkin's lymphoma which was subsequently associated with a high incidence of breast cancer. There are challenges both in identifying which patients should be recalled as well as how to link them to appropriate specialist multidisciplinary management.

#### **2.4 Secondary malignancies**

Secondary malignancies can develop as a consequence of primary treatment, in particular, for patients who received treatment for a childhood cancer. Treatment for Hodgkin's lymphoma is associated with secondary leukaemia and breast cancer. Secondary malignancies are the sixth most common cancer in the USA (after skin, breast, prostate, bowel and lung cancers) and a cancer survivor has twice the risk of a comparable individual without cancer of developing another primary. This makes it all the more important to educate patients and GPs about potential warning signs of another malignancy.
