Chemotherapy for elderly patients with advanced cancer: is it worth it?

Introduction
Managing advanced cancer in the elderly is an increasing problem. The percentage of our population over 65 years old is climbing and the incidence and mortality of cancer increases with ageing. The problem is compounded by older patients being a heterogeneous population. They often have comorbid illnesses and are taking multiple drugs. Moreover the decision as to whether or not to use cytotoxic anticancer chemotherapy is made more difficult because the elderly are under-represented in clinical trials.

For each patient the decision whether or not to have cytotoxic chemotherapy for advanced cancer is a balance between the potential benefits and adverse effects. Both of these involve value judgements by individual patients. The perspective of older patients may differ from that of younger patients. Short-term quality of life and the ability to continue managing their activities of daily living may be more important than a modest survival advantage when deciding whether to accept chemotherapy. Conversely, some fit older patients may seek aggressive chemotherapy if they can expect a similar outcome to younger patients.

Ethics
Ethically, clinicians making decisions about chemotherapy for elderly patients are likely to be guided by a principle of non-maleficence: do no harm. This is usually interpreted as ensuring that the risk: benefit ratio is favourable. The patient will expect to be allowed to make an autonomous decision about chemotherapy, but will be reliant on accurate information about the potential risks and benefits.

There is a view that a doctor's inclination is to offer active treatment rather than offer 'no treatment' or symptomatic care. The opposite may apply in an environment of economic rationalism with limited resources, and is arguable in today's society with the increasing influence of palliative care.¹

From society's viewpoint a major issue is resource allocation. To deny expensive drugs to the elderly purely because of age, is 'ageism' and is as difficult to justify as discrimination against any sub-group of society. There are complex issues here.² A resource allocation formula based on years of expected benefit certainly appears to disadvantage the elderly who place the same value on 'the rest of their lives' as younger patients, irrespective of that life's duration. Alternatively, it could be argued that preferentially allocating resources to younger patients and successfully treating them would allow more to reach older ages. However, if the risks of chemotherapy do increase substantially with age, then a medical decision based on the risk: benefit ratio may differ in older patients purely on that basis and not because of age.

Factors complicating chemotherapy in the elderly
To assist decision making about the treatment of advanced cancer in the elderly we need to examine the likelihood of response to chemotherapy and survival benefit. We also need to review the factors that may complicate chemotherapy in the elderly.³ These factors include the physiological changes accompanying ageing and the impact of comorbid diseases.⁴ Loss of organ function will affect cytotoxic drug metabolism. Changes in kidney or liver function or bone marrow reserve are particularly problematic when giving chemotherapy. It can be difficult to evaluate the physiological status of an elderly patient with the exception of renal function and the use of simple scales to assess their ability to perform the activities of daily living.

Renal function
The glomerular filtration rate decreases with age. Calculating the creatinine clearance using a formula, such as the Cockcroft-Gault formula (see box), that accounts for age and weight will reasonably accurately assess renal function. Just using the serum creatinine can overestimate renal function, given that less creatinine is produced as lean body mass decreases with age. Formulae have been developed to adjust the dose of renally excreted cytotoxic drugs, such as methotrexate and carboplatin, for changes in creatinine clearance. This ensures that the drugs can be given at an intensity which does not compromise efficacy, but avoids the excess adverse effects that occur if the drug accumulates because of delayed renal excretion.

Patients over 70 years old are similar to younger patients in developing nephrotoxicity when exposed to drugs such as cisplatin. They can be protected by hydration and diuresis, as long as they can tolerate the fluid load. Drugs such as doxorubicin or the taxanes that are predominantly metabolised by the liver can often be given in full doses to patients with renal impairment.

Liver function
Assessing the degree of liver impairment in the elderly that will impact on cytotoxic drug metabolism is difficult. Certainly, liver blood flow, serum albumin and cytochrome P450 function are all decreased with ageing. The cytochrome P450 mechanism may also be a problem if elderly patients are given cytotoxics in addition to other drugs metabolised by this system. Commonly used drugs, such as cimetidine, will inhibit the P450 system.

Several anticancer drugs need to have their doses adjusted if the patient's bilirubin is high. Anthracyclines and taxanes are the best examples, but there is a paucity of data on the precise adjustments required for various liver function abnormalities. Low albumin will lead to increased liver extraction of some drugs but the increase in body fat with age may decrease the peak dose of a drug, yet increase the half-life of fat-soluble drugs. The initial absorption of oral cytotoxics, such as etoposide, may be altered in patients with the atrophic gastritis of age.

Bone marrow
The elderly can have unpredictable myelosuppression, particularly if malnourished. The lack of bone marrow reserve may manifest itself as more prolonged myelosuppression with successive cytotoxic drug doses. The colony stimulating factors such as G-CSF which reverse myelosuppression may be required more often in elderly patients. They can allow adequate doses of chemotherapy to be given without as great a risk of life-threatening febrile neutropenia.

Non-haematological toxicity
Cytotoxic drugs such as the vinca alkaloids, taxanes and cisplatin can be neurotoxic or ototoxic. These toxicities can be considerably more debilitating in the elderly who may already have compromised mobility, sensation or hearing. Of the other non-haematological adverse effects only the cardiac toxicity of doxorubicin and lung toxicity of bleomycin are known to be accelerated in the elderly.

Adverse effects
In fit elderly patients with normal organ function the adverse effects will be comparable to those seen in younger patients and are managed in a similar way.⁵ Within hours many cytotoxic drugs will cause nausea and vomiting. This acute emesis is best managed by premedicating patients with 5HT₃ receptor antagonists and dexamethasone. Less severe emesis can be treated with metoclopramide or prochlorperazine although prolonged emesis lasting for several days is best managed with dexamethasone in combination with these antiemetic drugs.⁶ Patients may become neutropenic approximately 10 days after treatment. An infection at this time is potentially life threatening and should be urgently treated with intravenous broad spectrum antibiotics.⁷ Subsequent courses of chemotherapy may require dose reductions or support with haematopoietic growth factors. Thrombocytopenia with bleeding can be managed with platelet transfusions. Mucositis occurs in the same time frame and requires symptomatic treatment with local anaesthetic mouth washes plus treatment of any secondary infections due to candida or herpes.

A further group of toxicities which require monitoring involve cumulative damage to organs over several months. This can be a particular problem in the elderly whose organ function may have deteriorated before chemotherapy. Liver and renal function should be measured with each course, and for specific drugs cardiac and pulmonary function should be monitored. Deterioration in organ function may require cessation of chemotherapy.

With worsening organ function the adverse effects of chemotherapy increase and the balance between efficacy and toxicity is no longer in the patients' favour. Adverse effects can impact on quality of life and the patients' ability to cope with daily activities. This also increases the burden on their carers.

The efficacy of chemotherapy in the elderly
There is no evidence that there is any general decrease in efficacy of chemotherapy in the elderly, although some studies suggest that this is the case in Hodgkin's disease and acute leukaemia. In non-Hodgkin's lymphoma, for example, the complete response rates with aggressive chemotherapy are equal in patients over and under 60 years old. The survival of the older patients is less, however, because of deaths unrelated to the lymphoma or its treatment.⁸ Overall response rates to chemotherapy in small cell lung cancer are also similar in younger and older patients, and age has not been found to be an adverse prognostic factor.⁹ Survival rates are similar in older patients despite the dose intensity often being less and despite them having a greater number of comorbid conditions.

Some cancers may behave differently in the elderly and warrant different treatment approaches from those in younger patients. In breast cancer for example, the risk of local recurrence after lumpectomy declines with age. This may decrease the need for postoperative radiotherapy in older women. In the Oxford meta-analysis adjuvant chemotherapy was associated with decreasing survival benefit with increasing age particularly in the over 70 age group.¹⁰ Individual older women at high risk of recurrence, however, may obtain some benefit from adjuvant systemic therapy.

Conclusion
In most cancers the elderly will respond as well as their younger counterparts provided the chemotherapy can be given safely. This may depend on physiological changes in organ function, particularly renal and hepatic function. Deteriorating organ function will make adverse effects and therefore an adverse impact on quality of life more likely.

Elderly patients should be given the option of chemotherapy for responsive advanced cancers. As with younger patients they make their decision balancing any predicted positive outcome against the treatment's adverse effects that, even if temporary, will impact upon their quality of life.