Chemotherapy can affect the health-related quality of life (HRQoL) of patients in a range of ways - both positively, through alleviating symptoms and slowing, halting or reversing deteriorations in functioning, and negatively, through the impact of side effects. Due to its systemic nature, chemotherapy tends to present with similar side effects regardless of cancer type [1]. Where side effects do vary, this tends to be a function of the drug protocols considered to be most effective in treating each cancer type. Evidence for the benefits and toxicities associated with standard drug protocols used for each cancer type are reported on the website of the Cancer Institute NSW Standard Cancer Treatments. Another useful – if slightly dated - source of information comes in the form of two special issues of Acta Oncologica (2001, Vol. 40, Issues 2-3), which offer systematic reviews of the effects of different chemotherapy regimes in a number of cancer types, including published reports of effects on HRQoL.
The following is a summary of research on the relative importance attributed among profiles of symptoms by patients and healthcare professionals, the relationship between key symptoms and HRQoL, and the psychosocial impacts of undergoing chemotherapy.
It is worth noting that the vast majority of studies do not attempt to separate the side effects of treatment from the impacts of cancer itself. This summary will follow widespread use of the term ‘symptom’ to include subjective reports of the impacts of both cancer and its treatment; ‘side effect’ is used more precisely to mean adverse effects attributable to treatment alone. Fatigue is a good example of a common and pervasive symptom that can arise from either cancer or its treatment; the interaction between factors contributing to fatigue is complex and poorly understood, and fatigue is notoriously difficult to treat as a result [2].
The relative importance of side effects
Both number and severity of side effects contribute to overall symptom burden. As one might expect, a greater number of symptoms tends to be associated with a greater reduction in HRQoL. While many side-effects are short-lived, there is increasing awareness of the HRQoL impact of persistent effects such as peripheral neuropathy and irreversible hair loss, studied under the banner of survivorship research [3]. Relative severity is more difficult to measure because it requires comparison between the impacts that different side effects have on patients’ daily lives and is often distinct from medical risk. Studies have varied in the approaches they have taken to assessing severity, but the following two approaches have proved especially popular.
Ranking the relative severity of symptoms
The most common approach has been to ask patients to rank symptoms taken from a list in order of severity. Because major developments have occurred in chemotherapy over recent years, we include dates for each published study below.
- In 1983, 99 Australian patients with a range of advanced cancers who had recently undergone chemotherapy were asked to select from a list and rank by severity the physical and non-physical symptoms they had experienced. Chemotherapy regimens were arbitrarily separated as to whether they included cisplatin, doxorubicin or neither of these agents (e.g., methotrexate). Across groups, the ten most severe symptoms were, in order of severity: ‘Being sick (vomiting)’, ‘feeling sick (nausea)’, ‘loss of hair’, ‘thought of coming for treatment’, ‘length of time treatment takes at clinic’, ‘having to have a needle’, ‘shortness of breath’, ‘constantly tired’, ‘difficulty sleeping’ and ‘affects family or partner’. Rankings were affected by age, sex, and marital and domestic status [4].
- In 1996, 155 patients with predominantly breast, gynaecologic and lung cancer to rate symptom severity following chemotherapy regimens broadly similar to those above. The majority of these patients reported experiencing nausea, tiredness, hair loss, concern about effects on family, depression, anxiety and dread of treatment, while just under half reported vomiting, difficulty sleeping, loss of taste, loss of appetite, passing more urine, sore mouth, dry skin and effects on their social lives. Nausea was rated as the most severe symptom, followed by tiredness, loss of hair, effect on family, vomiting, depression, dread of treatment, difficulty sleeping, feeling anxious/ tense and having to have a needle. A gender effect was evident, with more women expressing apprehension of treatment and more men voicing concerns over practical issues such as availability of parking [5].
- In 1999, fatigue, nausea, and vomiting were also emphasised in another Australian study; appetite loss, constipation and diarrhoea were also rated highly as symptoms that interfered with normal daily life [6].
- Findings from a 1997 study identified the 5 most severe physical symptoms associated with adjuvant cisplatin treatment in 11 women with ovarian cancer as tiredness, difficulty sleeping, constipation, nausea, change in taste and weight gain [7].
- In 2002, 100 patients with a range of cancers including breast, gastrointestinal, lung and ovarian who had experienced emetogenic (n=41), taxane (n=25) or other (n=34) chemotherapy regimens found ‘affects my family or partner’ to be the most severe symptom, followed by hair loss, fatigue, effects on work or home responsibilities, effects on social activities, and loss of interest in sex. The authors pointed to the fact that vomiting and thought of coming for treatment were relegated to 11th and 33rd places respectively to highlight the progress made in reducing certain toxicities. Nausea and vomiting were only selected in the top 10 by patients undergoing therapy with cisplatin, oxaliplatin or dacarbazine, and fear of needles was not reported by anyone at all [8].
- In a 1997 study restricted to patients who had received antiemetic therapy (5HT3 antagonists) for acute nausea and vomiting while undergoing emetogenic chemotherapy (N =181), patients still ranked nausea, hair loss and vomiting as the three most severe symptoms, with 80% experiencing nausea and 57% experiencing vomiting [9]. Delayed vomiting in particular poses a problem to patients receiving 5HT3 antagonists.
- Research in 2005 and 2006 suggested that nausea and vomiting continued to be problematic to some patients undergoing certain chemotherapy treatments despite the progress made in treatment with antiemetics [10, 11].
- In 2008, nausea and vomiting was found to be associated with loss of physical, cognitive and social functioning, global HRQOL, fatigue, anorexia, insomnia and dyspnea. Patients with uncontrolled symptoms are more likely to suffer from depression and fatigue [12].
Patient preferences for alternative health states
An alternative approach to examining patient perceptions of treatment side effects has involved asking patients to rate the relative desirability of different outcome scenarios. Such studies use a trade-off method in which participants are asked to balance additional life expectancy, improved chances of survival or a specified period of healthy living against scenarios that involve chemotherapy symptoms of specific kinds and/or severity. Studies using this approach may offer insights into the kinds of decision making processes that patients undertake when offered treatments with alternative toxicities.
- Research of this kind carried out in breast cancer has consistently shown that even minimal potential benefits are deemed sufficient by many women to justify symptoms from chemotherapy. Women with dependants, social support, and who have experienced milder symptoms previously judge smaller benefits worthwhile [13].
- Calhoun et al. (1998) asked 15 women with advanced ovarian cancer who had experienced cisplatin therapy to rate health states relating to ototoxicty, nephrotoxicity and neurotoxicity. Ratings were carried out using a time trade-off (TTO) method in which the women identified the number of months of excellent health they would prefer over 1 year with the health state described in each scenario. In this small sample, symptoms associated with neurotoxicity were viewed less favourably than those associated with either ototoxicity or nephrotoxicity [14].
- In a study by Sun et al. (2002), 34 women with ovarian cancer during mobilisation chemotherapy and 6 to 7 weeks after high-dose chemotherapy and stem cell transplantation stated the following preferences from best to worst: no evidence of disease, ideal chemotherapy, alopecia, pancytopenia, ototoxicity, fatigue, neuropathy, mucositis, dysuria, hepatoxicity (including jaundice and rare but potentially fatal liver damage), nausea and vomiting, and worst chemotherapy [15].
- In 2016, chemotherapy-induced nausea and vomiting is still regarded as one of the most debilitating symptoms, although guidelines suggest it may be prevented in as many as 70% of cases with the appropriate administration of antiemetics [16].
Perceptions of health professionals
A small number of studies have investigated health professionals’ perceptions of the relative significance of chemotherapy side-effects. One reason why health professionals’ perceptions might be of interest is that experienced clinicians seem better placed than patients to observe and report relative severity across a range of cancers and drug regimes. However, caution is needed before accepting clinician reports at face value:
- One Australian study found that medical oncologists’ perceptions showed somewhat inconsistent alignment with the physical and psychosocial experiences of their patients, especially with regard to psychological distress [17]. Research carried out in 2008 in the Netherlands suggested that oncologists may tend to underestimate the impact of hair loss in particular [18].
- In another study it was found that oncologists’ ratings of toxicities more closely matched those of naïve patients than of those who had experienced the toxicities in question. Moreover, ratings following experience tended to be more favourable than prior, suggesting that naïve expectations may tend to over-estimate the severity of at least some toxicities [14].
- An Iranian study found significant disagreement between nurses and experienced cancer patients regarding the relative severity of physical and psychosocial stressors, with nurses perceiving key roles for alopecia, fear of recurrence and fear of death while patients emphasised fatigue, dependency and reduced social activity [19].
- A study in 2003 adopted a self-report approach by asking health professionals to identify the symptoms that they believe are most important to monitor when assessing the value of palliative chemotherapy in a number of advanced cancers. In this study, expert doctors and nurses at 17 National Comprehensive Cancer Network (NCCN) member institutions identified fatigue, pain, nausea and weight loss as key to their treatment decisions. Interestingly, these informants also identified two psychological concerns as important - worry about worsening condition and contentment with current HRQoL [20].
- In 2009, Ewing et al. found some consistency between patient-reports and proxy-reports (health professionals or relative) on outcomes that were observable such as physical functioning, whereas there were large discrepancies between patient- and proxy-reports on outcomes that were not observable such as pain and emotional functioning [21].
Correlational evidence
An alternative avenue of enquiry has examined the associations between different symptoms associated with chemotherapy and HRQoL and/or various clinical measures.
- Cella (2003)[22] has offered what he calls the “do something” principle to account for an oft-observed pattern of results in which patients’ emotional wellbeing improves shortly after they begin treatment to a degree that is out of kilter with the rest of their HRQoL profile. The fact that psychological distress has been found to be greater in patients who drop out of chemotherapy [23] may be a further reflection of the psychological benefits associated with undertaking treatment.
- Coates et al. (1983)[24] examined the correlation between the severity of symptoms and general wellbeing in patients with small cell anaplastic bronchogenic carcinoma (SCBC), metastatic melanoma and ovarian cancer. In this study, patients were asked to rate the severity of symptoms relating to mood, pain, nausea/vomiting, appetite (melanoma and SCBC) and pain, breathlessness and physical activity (ovarian). Strong correlations were found between general wellbeing and mood and appetite (melanoma and SCBC groups) and general wellbeing and physical activity (ovarian group).
- Physical functioning, mood and appetite at the beginning of treatment are among the symptoms that have been found to predict survival in women with advanced breast cancer undergoing chemotherapy [25, 26]. However, no such predictive value has been found in women with early breast cancer, leading Coates et al. (2000) to suggest that symptoms from chemotherapy may have masked the prognostic value of HRQoL in this group or else that reports of HRQoL in both groups may have been differentially influenced by patients’ recognition of the severity of their disease.
- Unsurprisingly, chemotherapy patients who experience both nausea and vomiting present with worse HRQoL across a range of domains including physical, cognitive and social functioning, global quality of life, fatigue, anorexia, insomnia and dyspnea[27]. The presence of nausea in the absence of vomiting is associated with less severe impacts on HRQoL. However, while vomiting has been found to have a greater impact on the family, leisure time and performance of household tasks, nausea has been found to have a greater impact on overall functioning [28].
- Chemotherapy patients commonly experience fatigue which often correlates with pain, sleep problems and depression, and less frequently with a host of symptoms that include dyspnoea, nausea and menopausal symptoms. Fatigue shows strong correlations with reduced HRQoL, particularly with regard to the domains of physical and psychological/emotional functioning and daily living [2].
- The psychosocial impacts of alopecia in women with cancer have been well documented and include reduced self-confidence, self-esteem and body image.24 These effects do not always disappear with regrowth of hair and in some cases may negatively impact on sexual functioning and relationships. But despite these impacts, examination of the effects of chemotherapy-induced alopecia on more general HRQoL has so far been limited to descriptive studies rather than controlled designs. Higher level evidence in this area may await the advent of a suitable standardised questionnaire [29].
Psychosocial impacts of chemotherapy
Depression and anxiety
Findings have varied widely regarding the prevalence of depression and anxiety in patients with cancer undergoing chemotherapy. Estimates have included: 4% and 28% respectively [30] and 1% and 12% [31] in women with breast cancer; 19% and 47% in women with ovarian cancer [32]; 24% and 23% in a sample of Australian mixed cancer patients[6]; and recently, as high as 66% and 77% in a sample of Iranian mixed cancer patients receiving chemotherapy as a single treatment [33]. Variation between estimates is likely to be a function of a number of factors that include differences between assessments and the definitions of anxiety and depression used. Importantly, there are reasons to believe that chemotherapy itself has a role to play in causing psychological distress and that this causal role is biological as well as psychosocial. Chemotherapy drugs can cause or contribute to depressed mood in some cancer patients, as some drugs affect hormone function, with potential adverse mood and cognitive side-effects (e.g. medically induced menopause after oophorectomy, or androgen ablation in prostate cancer treatment)[34]. Not only is distress sometimes more common when chemotherapy is added to other treatments [35], but different drug regimens are also associated with different rates of depression [36]. Indeed, it seems likely that depression, anorexia, cachexia, anaemia, pain, sleep disturbance and fatigue may all be caused by pro-inflammatory cytokines produced by cellular enzymes that are activated during chemotherapy [37]. There exist complex relationships between each of these symptoms that are likely to vary between patients and are not well understood. For example, improving the haemoglobin levels of patients suffering from chemotherapy-induced anaemia-related fatigue can also produce significant effects not only on patients' fatigue but also on psychiatric morbidity [38].
See our FAQ on Psychological distress in people with cancer for a more general discussion of depression and anxiety and their measurement in cancer.
Anticipatory symptoms
Chemotherapy reserves a special place among cancer treatments for its potential to elicit anticipatory symptoms in people who have completed part of their treatment and are preparing themselves for a subsequent infusion. Not surprisingly, patients’ previous experience of side effects can affect anxiety when they come to be treated again [39] and sometimes influence decision to undergo further treatment [13]. More uniquely, however, repeated exposure to chemotherapy has the potential to stimulate conditioned responses:
- Sun et al.’s (2002) findings illustrate the powerfully aversive influence that nausea and vomiting exert within the human psyche, presumably for good evolutionary reason. Psychological interactions with nausea are especially pertinent when considering the phenomenon of anticipatory nausea. Anticipatory nausea is predicted by the expectation that one will experience it [40] and by baseline reports of anxiety and depression [41]. While anxiety and anticipatory nausea may be linked in a number of ways, the relationship for which there is most evidence is one in which anxiety exacerbates post-treatment nausea and vomiting and thus increases the risk for anticipatory nausea [42]. In light of this evidence, it is interesting to note that anticipatory nausea appears to be more amenable to behavioural intervention than does nausea that occurs post-chemotherapy [43].
- In addition to anticipatory nausea, there is evidence to suggest that other anticipatory symptoms may emerge through associative learning over time. In 2005, Bovbjerg et al.[44] provided initial evidence that chemotherapy may become paired over time with the clinic environment to produce conditioned fatigue; it may be that needle anxiety can also be conditioned in a similar way [45].
Cancer related cognitive impairment
For some time patients have talked about “chemofog” or the “chemobrain” they experience after cancer treatment. More recently it has become clearer that cognitive changes are present for some people after diagnosis but before any cancer treatment [46], this is commonly referred to as cancer-related cognitive impairment (CRCI) and most commonly features difficulties with planning, memory and concentration [47], and is reported by up to 70% of cancer patients receiving chemotherapy [48]. While studies have identified a variety of contributors such as hormonal imbalance [49], emotional stress/anxiety and fatigue [50], the cause of CRCI remains poorly understood, and there are no proven treatments [51]. One issue is that subjective reports of CRCI are poorly related to objective measures of cognitive function. For example, in a 2017 Australian study by Vardy and colleagues [52], patient self-reports of cognitive impairment were found to correlate with changes in fMRI, worse fatigue, HRQoL, anxiety and depression but not with results of formal cognitive testing. Studies have consistently demonstrated this lack of concordance between CRCI and objective cognitive measures [53], however there have been consistent reports that web-based cognitive rehabilitation programs significantly improved self-reported CRCI [54, 55]. People diagnosed and treated for cancer should be informed that they may notice cognitive changes, but for most people these symptoms resolve within a year of completing treatment. If they are experiencing persistent symptoms, they could consider a cognitive rehabilitation program.
Psychosocial impacts among people beginning chemotherapy for the first time
A different relationship between the side effects of chemotherapy and psychological distress concerns the fearsome reputation that chemotherapy has among the general public - and therefore among people anticipating treatment for the first time - unless intervention is undertaken by the medical team to mediate these fears. Most people judge even small potential benefits as making chemotherapy worthwhile [13]. In a small number of cases, however, fear of the side effects of chemotherapy may be sufficient for people with cancer to refuse treatment. Among women preparing for chemotherapy, hair loss has been cited as the most disturbing anticipated side effect, with 8% being at risk for avoiding treatment [56]. Thus, while many health professionals may not perceive alopecia to be a ‘serious’ medical condition and while more insidious and less anticipated side effects such as fatigue may often turn out to be worse in practice [57], the dissuasive potential and psychosocial impacts of alopecia demand careful attention.
It is interesting to note that, while trait anxiety has been found to predict anxiety before first and subsequent infusions, naïve expectations of side effects do not [39].
Assessing HRQoL in patients undergoing chemotherapy
It is important that assessment of HRQoL in patients who are undergoing chemotherapy should include patients’ reports of the side effects most likely to arise from the regimes involved. A number of chemotherapy-specific questionnaires have been designed for this purpose, of which the Breast Cancer Chemotherapy Questionnaire (BCQ)[58], GLQ-8 [59], FACT and Gynecology Oncologic Group Neurotoxicity Questionnaire (FACT&GOG-Ntx) [60] and FACT-Taxane [61] have the best established validity and reliability. A summary of these and other chemotherapy-specific instruments and their psychometric properties can be found on our measures database: PoD.
Side-effects that are expected to be of particular concern to patients or that may be especially important in distinguishing between treatment arms in a trial may warrant individual or cluster assessment using a dedicated symptom scale. See our FAQ on measuring symptoms for more information and a list of potential measures.
Assessment of side effects in patients undergoing chemotherapy should be timed to capture the cyclical and/or cumulative pattern in which these are likely to occur. The acute toxic effects of chemotherapy may only last a few days, leaving a small window of opportunity for assessing them [62]. Adverse effects such as alopecia may begin 1 to 2 weeks after the first treatment and worsen over the following 1 to 2 months before resolving after treatment is completed [56]; mild cognitive impairment may build over the course of treatment and persist for months or even years afterwards[47]; fatigue presents in a wide variety of patterns but is often at its worst during the first two days following infusion [63]; while the beginning and end of treatment may be times when psychosocial stress is at its most severe [64].
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