This article will review the methods available for assessing older patients being considered for chemotherapy and the chemotherapeutic options for common cancers encountered in the older population. These will include chemotherapy used in adjuvant (given following surgery or radiotherapy to reduce recurrence), neo-adjuvant (given to decrease tumour burden prior to definitive treatment by other modalities) and palliative (given to improve symptoms) settings.
Dr Joanna Davies Specialist Registrar, Geriatric Medicine, Barnet Hospital, Wellhouse Lane, Barnet Hertfordshire
Dr Ajay Aggarwal Specialist Registrar, Clinical Oncology, University College Hospital, London
Dr Heather Payne Consultant Clinical Oncologist, University College Hospital, London
Cancer is primarily a disease of older people, with incidence rates increasing with age for most cancers.1 More than three out of five (63%) cancers are diagnosed in people aged 65 and over, with around a third (36%) diagnosed in those aged 75 and over.1 Approximately 60% of cancer deaths occur in patients older than 70 years,2 and clearly as the proportion of elderly patients in the UK increases these percentages are likely to rise. Despite the high prevalence of cancer in the elderly there has historically been a lack of trial data to inform clinical guidelines for the optimum treatment in this population.3,4 This can create uncertainty in the treating physician with regards to determining the most appropriate course of management. This may in part explain why older patients are less likely to receive standard chemotherapy regimens than younger patients.5,6 Fortunately with the increasing interest in the field of geriatric oncology the knowledge base in this area is improving. It is now believed that for the most part healthy older patients, in keeping with their younger counterparts, will benefit from standard chemotherapy regimens and that biological age is of greater importance than chronological age when making treatment decisions.
Efficacy versus tolerability of chemotherapy
Across Europe, oncologists rarely have the opportunity to collaborate on a regular basis with a geriatrician.7 There is therefore a growing requirement for them to confidently assess this patient group themselves in order to plan appropriate treatment. One factor that may influence decisions regarding chemotherapy is the individual’s life expectancy as this is clearly useful in determining who will derive survival benefit from a proposed chemotherapy regimen. This can be estimated based solely on age. However there will be a wide range of life spans for a given age so a more individualised assessment based on a range of factors is much more relevant.8 The inclusion of comorbidities gives a more accurate assessment of life expectancy, with the number of individual comorbidities known to negatively impact on survival in breast and colorectal cancers.8,9 In addition to judging life expectancy, more emphasis is now being placed on risk stratifying elderly cancer patients based on their functional status and comorbidities.10 It is now believed that a more comprehensive assessment is required than the Eastern Cooperative Oncology Group Performance Status (box 1) and the Karnofsky Scale (box 2), which are widely used in the general oncology population and in the trial setting.11 Unsurprisingly older patients have a greater incidence of comorbidities,12 polypharmacy, cognitive issues and social considerations than their younger counterparts. Although there is no consensus as to the most appropriate assessment, there is increasing evidence that the Comprehensive Geriatric Assessment (CGA) is a useful tool, which can be used to predict survival and tolerance to chemotherapy and detect unsuspected health problems.13,14 The CGA involves a multidisciplinary assessment of an older individual’s functional status, comorbidites, cognition, social situation, nutrition and medications. This information can be used to provide a well rounded view of a patient’s overall suitability for a given intervention. In addition, studies have also shown a role for multidisciplinary interventions in older cancer patients based on the individual’s CGA with resultant improvements in function,15 pain, mental health scores,16 and survival.17 It is however a relatively time consuming tool and work is ongoing in attempting to validate low burden instruments that assist in risk stratifying older patients and guiding interventions.
Chemotherapy regimens for common cancers
Te following sections will discuss chemotherapeutic management for cancers which occur commonly in older people. The discussion will focus on the evidence base for efficacy and tolerability of different regimens in older people and any specific considerations that need to be given to individual agents. Chemotherapy toxicities referred to are graded according to National Cancer Institute Common Toxicity Criteria version 3.018 with grade 4 toxicity, being the most severe.
Prostate cancer is the commonest cancer in men in the UK with over 35,000 new cases diagnosed each year with peak incidence between the ages of 70 and 75 years.19 There has been a significant (50%) increase in incidence over the past 10 years, which relates to increased detection through prostate specific antigen (PSA) testing and histological diagnoses following surgical treatment of benign prostatic hypertrophy.20 Five year survival rates remain favourable at approximately 70% and an estimated 215,000 males are living with the disease in the UK.19 Androgen deprivation therapy is first line in the management of metastatic disease and options on progression involve further hormone manipulation. Discussion of this, however, is beyond the scope of this paper. Chemotherapy may be considered in hormone resistant prostate cancer where there is evidence of rapid disease progression (either biochemical or radiological) or in patients with symptoms from disseminated disease. In metastatic disease, the NICE licensed chemotherapy agent is docetaxel in combination with prednisolone.21 As well as an improvement in overall survival and reduction in measurable disease there is an improvement in quality of life outcomes.22 Te TAX 327 trial on which this evidence is based, found that 35% of patients experienced a significant reduction in pain following treatment.22 In the study 20% of those receiving docetaxel were 75 years or over with a median age of 68 years.22 Rates of severe toxicity were low and the commonest side effects were largely well tolerated. These included fatigue, diarrhoea, nausea, alopecia, nail changes and sensory neuropathy. Te extended analysis of the TAX 327 study included subgroup analyses and demonstrated survival benefits for men both younger than 65 years and older than 75 years of age.23 In summary, hormonal manipulation is the cornerstone of managing advanced disease. However chemotherapy with docetaxel is used successfully in a large proportion of elderly patients and has shown excellent efficacy and tolerability in this group. Continued research is focusing on new chemotherapy strategies in the event of docetaxel resistance.
Colorectal cancer (CRC) is the third commonest malignancy in the UK.24 Te incidence of colorectal cancer is strongly related to age and 83% of cases arise in patients over the age of 60 years.25 Chemotherapy, both in the adjuvant and metastatic setting, plays an important role in improving rates of disease free and overall survival as well as palliating symptoms. Commonly used chemotherapy drugs include the fluoropyrimidines such as 5-fluorouracil (5FU) or capecitabine (oral prodrug preparation of 5FU), as well as a combination of these drugs with oxaliplatin and irinotecan such as FOLFOX (5FU/oxaliplatin) and FOLFIRI (5FU/irinotecan). Te frequency of recruitment of elderly patients to CRC chemotherapy trials is relatively low.26 However, valuable information has been gained from pooled retrospective analyses of trials as well as prospective data from phase II trials. Of note most of the trials defined “elderly” as patients over the age of 70 years. Both 5FU and capecitabine have demonstrated equivalent efficacy and tolerability in the ft elderly population both in the adjuvant and metastatic setting.26 Apart from an increased rate of leucopenia, there appears to be no significant increase in severe (grade 3 or 4) toxicity observed.27,28 There was also no apparent difference in outcomes in terms of response rate, disease free survival and overall survival when compared with younger populations.27,28 Pooled analyses of adjuvant29 and metastatic30 trials using FOLFOX in the elderly population have demonstrated similar results irrespective of age but small yet significant increases in grade 3 or 4 neutropenia and thrombocytopenia were observed. Tere was no signifcant increase in non-haematological toxicity apart from fatigue. Phase II results support these findings but highlight the toxicity associated with standard dose oxaliplatin31 with a recommendation for fractionating the dose or dose reduction in the elderly population.32 Capecitabine in combination with oxaliplatin (Xelox) appears to be well tolerated in the elderly with no compromise in efcacy.33 The FOLFIRI regimen which is used in advanced CRC has been shown in prospective trials to have similar efficacy in elderly patients with an acceptable degree of toxicity.34 This has been supported in retrospective analyses.35 Capecitabine and irinotecan were noted to be a highly effective regimen but associated with higher rates of adverse events particularly diarrhoea in elderly patients.36 Chemotherapy drugs for CRC appear effective in the elderly population with no clear difference in overall outcomes. However, there is a variation in toxicity profiles in the elderly between the chemotherapeutic agents. It is also known that 30%–60% of patients older than 65 years who initiate adjuvant therapy discontinue before finishing, which increases the risk of cancer related death.37 It is therefore important to ensure careful patient selection for regimens, which may cause higher rates of haematological toxicity and other complications. Consideration should be given to treatment modifications such as possible dose escalation, reduced treatment duration and assessing tolerability of single agent regimens prior to the addition of other chemotherapy agents with future cycles.
Breast cancer is the commonest cancer in women in the UK accounting for 31% of all cancer cases.38 Te incidence increases with age, and in the UK 48% of new cases are diagnosed in women aged 50–69 years.38 It is also a major cause of mortality in women, and lags behind only lung cancer as the commonest cause of cancer death.38 Over half of these deaths are in women over the age of 70 years.38 Treatment options for patients are dependent on a number of factors including tumour size, node positivity, oestrogen receptor (ER) and progesterone receptor (PR) status, age, Human Epidermal Growth Factor Receptor 2 (HER 2) status and histological grade. Treatment options are influenced by these factors and include surgery, radiotherapy and hormonal therapies as well as more orthodox chemotherapies and newer targeted agents. Evidence exists however that older women are less likely to receive standard care for their disease39 and have worse outcomes in terms of disease recurrence and mortality compared to their younger counterparts.40 The reasons for this are multifactorial but are likely to relate to the paucity of randomised phase III data for efficacy and tolerability of chemotherapy regimens in elderly patients, a variation in tumour biology in the elderly population as well as a natural bias against offering treatment in this cohort for fear of causing undue toxicity.41 Given the high rates of ER positive tumours in the elderly population, hormone treatment with oestrogen receptor antagonists, such as tamoxifen, or aromatase inhibitors, such as anastrozole, form the basis for adjuvant therapy. They are effective in improving disease free and overall survival.42 Evidence relating to adjuvant chemotherapy in patients over 70 years is restricted due to poor recruitment into trials. For example in the EBCTGG43 and CALGB44 overviews only 4.3% and 2% of women accrued in the chemotherapy trials analysed were over 70 years. This lack of data has limited development of guidelines for elderly patients. However, retrospective analyses have shown a beneft for adjuvant chemotherapy (decreased mortality and improved disease free survival) in elderly women, particularly those with node positive, ER negative disease (which are poor prognostic factors).44,45 Older patients were found to have worse overall survival compared with younger patients mainly due to comorbidities and higher rates of treatment related mortality, although this was small (1.5%).44 The optimum adjuvant chemotherapy regimen and scheduling has not yet been identified. In younger patients anthracycline based chemotherapy such as FEC (5-FU, epirubicin and cyclophosphamide) forms the mainstay of therapy with or without docetaxel. These regimens have also shown efficacy in elderly patients in this setting.46 However, there is concern regarding the increased risk of cardiotoxicity associated with anthracyclines such as doxorubicin and epirubicin. Te higher rate of impaired cardiac function in the elderly compared to younger patients has negatively influenced their inclusion in these trials.47 In the metastatic setting chemotherapy treatment aims to palliate symptoms and improve quality of life. Options include combination treatments or sequential single agent drugs. Prospective trial data in elderly populations have shown reduced dose capecitabine to be safe and effective especially compared to the standard dose regimen which is associated with a higher incidence of adverse events.48 Alternative options include weekly paclitaxel49 and single agent epirubicin. The latter however, was associated with higher rates of cardiac events when compared with gemcitabine in a phase III study.50 Likewise vinorelbine provides another tolerable and effective option in elderly patients.51 Future trials plan to assess pegylated liposomal doxorubicin in patients with metastatic disease as this is known to have lower rates of cardiotoxicity compared to standard doxorubicin.41 Elderly patients with breast cancer who are fit with good performance status (0–1) are likely to derive benefit from chemotherapy in the adjuvant and metastatic setting. Consideration needs to be given to the choice of agent and scheduling to minimise toxicity. It is hoped that future phase III trials will add direction in this area especially given the high burden of disease in this age group and the increasingly refined treatment options.
Non-Small-Cell Lung Cancer (NSCLC)
Lung cancer is the second most common cancer in the UK,24 with NSCLC representing approximately 80% of all cases. It accounts for 6% of all deaths and 22% of cancer deaths in the UK per annum.25 Five year overall survival rates remain poor (7.3% in men and 8.3% in females).1 Those affected are predominantly smokers, elderly (86% are over 60 years) and from lower socioeconomic backgrounds.24 Cytotoxic chemotherapy has been the mainstay of treatment in advanced NSCLC with response rates for first line platinum doublet therapy in the region of 20–35%,52,53,54 and median survival between 8–12 months.55,56,57 No significant difference has been demonstrated in terms of overall survival between different platinum containing regimens (cisplatin/ paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel, carboplatin/ paclitaxel).57 Single agent docetaxel chemotherapy is reserved for second line treatment, however, response rates are approximately 6%, with median survival of 7.5 months.58 No phase III studies have been conducted to see whether these results are reproducible in the elderly. Retrospective analyses of randomised trials using cisplatin/ carboplatin based therapy in elderly populations have shown no significant difference in survival compared with younger individuals but small but significant increases in toxicity.59,60 There is, however, a concern regarding bias in retrospective analyses of phase III trials as the younger population are likely to be very fit with excellent performance status and few comorbidities making them more amenable to aggressive intervention.61 Caution therefore needs to be applied when using platinum based agents in the elderly. Cisplatin can cause signifcant toxicity in elderly patients with little gain in survival or quality of life and increased chemotherapy related deaths.61 Side effects include myelosuppression, nephrotoxicity, ototoxicity and neurotoxocity and patients require a thorough assessment of their renal function and relevant comorbidities prior to embarking on treatment. Carboplatin has been used as an alternative to cisplatin and is often preferred in elderly patients due to the lower rates of neuro and nephrotoxicity. However it does cause more haematological toxicity especially when used with additional myelotoxic agents.62 For elderly patients of borderline fitness, single agent non-platinum based chemotherapy provides a valuable alternative and there is prospective phase III data supporting their use. The ELVIS study63 demonstrated that single agent vinorelbine improved quality of life and overall survival (27 versus 21 weeks) compared to best supportive care in patients over the age of 70 years. Single agent taxanes have also shown efficacy in the elderly. Te WJTOG 9904 study64 randomised patients to either dose reduced docetaxel (60mg/m2) or vinorelbine. Tere was no significant difference in median survival but response rates and progression free survival were superior in the docetaxel arm, although with higher rates of grade 3 or 4 neutropenia. Te number of patients recruited to these studies was small, however they do confirm that single agent chemotherapy is largely well tolerated in the elderly population and provide a valuable alternative to platinum doublet therapy. Although not cytotoxic agents, the molecular targeted agents gefitinib and erlotinib provide another treatment option. These small molecule tyrosine kinase inhibitors (TKIs) have shown efficacy in NSCLC and are used in advanced stage disease. They target the ATP cleft within the tyrosine kinase epidermal growth receptors which are known to be expressed in 40–80% of NSCLCs.65 Erlotinib65 is licensed as second line treatment for those patients who have failed platinum doublet chemotherapy first line. NICE recently approved first line gefitinib66 in advanced stage disease for patients harbouring epidermal growth factor tyrosine kinase mutations. Oral TKIs have a more tolerable side effect profile than chemotherapy with the main side effects being rash, fatigue and diarrhoea.67 Their use allows eligible patients to avoid the toxicity of chemotherapy and treatment for those with poor performance status who would previously have been not deemed fit enough for chemotherapy. These are clearly positive implications for the frail older adult with NSCLC. Although cisplatin based chemotherapy has an established role in adjuvant treatment of stage II to IIIA NSCLC, there have been no prospective trials of adjuvant chemotherapy in the elderly population. This makes it difficult to address concerns that elderly patients may be unable to tolerate treatment post extensive surgery. Te most informative data in the adjuvant setting comes from a Canadian retrospective analysis of the BR10 trial, which looked at the impact of age on treatment efficacy and tolerability.54 Patients were randomised to receive cisplatin and vinorelbine versus observation. Their findings were positive, in that despite fewer patients over 65 completing treatment, there was an overall survival benefit with no significant increase in toxicity. Chemotherapy is also administered concurrently or sequentially with radiotherapy to improve locoregional control and overall survival in locally advanced NSCLC (stage IIIA, IIIB). The majority of trials used either cisplatin or carboplatin, ofen with the addition of another agent such as vinorelbine. Despite improving survival compared to sequential treatment, concurrent chemoradiation causes signifcantly more grade 3 or 4 oesophagitis.68 Again there is limited phase III data regarding the use of chemoradiation in elderly patients. A meta-analysis by Auperin et al68 comparing outcomes between sequential and concurrent treatment, highlighted the under representation of older and frailer individuals. Only 35% and 40% of patients in the two arms were over 65 years and nearly 100% had a performance status of 0–1.68 Retrospective analysis of the Phase III Radiation Therapy Oncology Group Protocol 94- 10 study69 (where patients were randomised between concurrent and sequential therapy with the addition of cisplatin/vinorelbine chemotherapy) demonstrated similar survival rates in patients >70 years (18% of total cohort) to younger individuals. However, episodes of acute toxicity (grade 3 or 4 neutropenia and oesophagitis) were higher in elderly patients. These findings were consistent with other retrospective analyses of phase III trials, which in addition also noted a significant increase in rates of nephrotoxicity.70 Chemoradiation is therefore used with caution and some centres advocate a sequential approach where tolerability to platinum chemotherapy can be assessed to ensure no unnecessary delays occur in delivery of radiotherapy. The application of chemotherapy in NSCLC is extensive with platinum based agents forming the cornerstone of treatment. As with other disease sites, phase III prospective trial data of the efficacy and tolerability of these agents in the elderly is limited. However, all chemotherapy options should be considered with or without radiotherapy in elderly patients. Fitness may preclude stage IV patients from frst line platinum doublet chemotherapy. However, it is important to ensure that treatment choices palliate symptoms and improve quality of life in what is an aggressive disease with poor overall survival. As such, tolerability of treatment is vitally important and alternative chemotherapy options should be considered.
Although there is still a relative paucity of trial data in older patients the data that exists suggests that efficacious and tolerable chemotherapeutic options are available. Rather than basing decisions on age it appears that the older adult needs a more thorough individual assessment of fitness in order to guide management and tools are available to that effect. In order to better inform decisions regarding chemotherapy in older patients further trials need to be directed specifically at this group as well as further work aimed at developing tools to assess older individual’s fitness for intervention. Progress in this area is likely to involve closer collaboration between the fields of geriatric medicine and oncology with exciting prospects for improving cancer care in the older patient.
Conflict of interest: Dr Payne has attended and received honorarium for advisory boards and has served as a consultant for a number of pharmaceutical companies.
References available on online version at www.gmjournal. co.uk