Management of elderly patients with locoregionally confined head and neck cancer

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Head and neck cancer 3 Management of elderly patients with locoregionally confined head and neck cancer Sandro V Porceddu, Robert I Haddad

Head and neck cancer in elderly patients represents a major health burden because its management provides unique and complex challenges for multidisciplinary teams, such as reduced treatment tolerance, multiple comorbidities, and altered pharmacokinetics and pharmacodynamics. Despite the prominent challenges involved, high-level evidence for the management of this group of patients is scarce. Substantial advances in treatment, such as robotic surgery, dynamic intensity-modulated radiation therapy, immunotherapy, and de-escalation trials, might allow for improved treatment tolerance in this patient population. Advanced age alone does not appear to be a contraindication to curative treatment. Evaluation of age-specific factors such as life expectancy, impaired functional status, and cognitive decline warrant consideration as part of the management decision process. In this Review, we provide an update of the available evidence on the management of locoregionally confined head and neck cancer in elderly patients and propose a practical treatment algorithm for clinicians to help manage this patient population.

Introduction Head and neck cancer comprises a heterogeneous group of cancers that arise from several sites with diverse histopathological changes and which present at different stages. Treatment of head and neck cancer is often based on clinicopathological findings, treatment intent (curative vs palliative), and organ preservation and function. It typically involves—either as a single modality or in combination—surgery, radiotherapy, or systemic therapy. According to the 2012 International Agency for Research on Cancer GLOBOCAN report,1 the estimated global incidence of head and neck cancer is just over 510 000 cases per year. Most cases (about 90%) are of squamous-cell carcinoma arising from the mucosal lining of the oral cavity, oropharynx, larynx, and hypopharynx; its incidence typically peaks in the sixth decade of life, and is usually related to a history of tobacco and alcohol misuse.2 In response to poor 5-year survival rates for stage III–IV head and neck cancer (in the range of 30–60% from the late 1980s to the early 2000s2), studies3–5 investigated treatment escalation strategies, such as surgery with postoperative chemoradiotherapy, altered fractionated radiotherapy, and concurrent chemoradiotherapy, with or without induction chemotherapy. The standard of care for organ preservation in patients with locally advanced head and neck cancer consists of 7 weeks of radiotherapy (70 Gy), with high-dose (100 mg/m²) cisplatin delivered in weeks 1, 4, and 7.6 In those patients who undergo curative surgery, the addition of concurrent chemotherapy to adjuvant radiotherapy is favoured in high-risk patients—namely those with positive surgical margins or who have extracapsular nodal extension.7,8 In selected cases, induction chemotherapy is used to determine the biological responsiveness of the tumour, or to downstage the disease before proceeding to radiotherapy or surgery.9 Although evidence from randomised controlled trials

and meta-analyses9,10 has confirmed the benefit of treat­ ment intensification (mostly with platinum-based chemo­ therapy) on loco­ regional control and overall survival, this benefit has been offset by worsened acute toxicity and increased rates of severe long-term morbidity, such as the need for permanent enteral feeding. Investigators have sought to reduce the burden of treatment through the use of less aggressive surgery, highly conformal radiotherapy techniques such as intensity-modulated radiotherapy, or alternative systemic drugs, such as the anti-EGFR antibody, cetuximab.11–13 After the emergence of human papillomavirus (HPV)associated oro­pharyngeal cancer, which is generally more favourable than traditional head and neck cancers in terms of its demographic profile, carcinogenesis, responsiveness to therapy, and prognosis, de-escalation trials are being done to investigate less intensive treatments schedules.14 Although HPV-associated oropharyngeal cancer tends to occur in younger patients (typically patients in their 50s), this disease is not exclusive to this patient population. By contrast, head and neck cancer remains predominantly a disease of elderly people. Because of the ageing population, treatment of locoregionally confined head and neck cancer in the elderly population has become a major health burden and its management provides unique and complex challenges for multidisciplinary management teams. This Review will focus on the management of elderly patients with locoregionally confined squamous-cell carcinoma of the head and neck, focusing on old and new treatment modalities that include surgery, radiotherapy, and targeted agents.

Lancet Oncol 2017 Published Online April 26, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30229-2 See Online/Comment http://dx.doi.org/10.1016/ S1470-2045(17)30269-3 This is the third in a Series of four papers about head and neck cancer Department of Radiation Oncology, Cancer Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia (Prof S V Porceddu MD); University of Queensland, Brisbane, Queensland, Australia (Prof S V Porceddu); Disease Center Leader, Head and Neck Oncology, DanaFarber Cancer Institute, Boston, MA, USA (R I Haddad MD); and Harvard Medical School, Boston, MA, USA (R I Haddad) Correspondence to: Prof Sandro V Porceddu, Department of Radiation Oncology, Cancer Services, Princess Alexandra Hospital, Brisbane 4102, Queensland, Australia [email protected]. gov.au

Burden of disease The global population is ageing because of worldwide improvements in health care. In the UK, the median age of the population has increased from 33·9 years in 1974

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to 40 years in 2014.15 In the USA, the number of people aged 65 years and older is projected to be 83·7 million by 2050, which is almost double the 43·1 million estimate from 2012.16 Consistent with cancer being a disease of elderly people, in 2014, the incidence of cancer in the USA was 11 times higher in people older than 65 years than in those younger than 65 years. Furthermore, there were an estimated 42 400 new cases of oral and pharynx cancer, of which nearly 50% of cases were in those aged 65 years and older.17 A report18 commissioned by the Institute of Medicine concluded that cancer care delivery in the USA was in crisis, partly because of the increasing demand for cancer care as a result of an ageing population.

Definition of elderly Elderly is referred to in various terms, including older adult, senior adult, advanced age, high age, and geriatric. There is no universal cutoff age that exists for defining elderly patients. However, the Oxford English Dictionary defines geriatric as relating to old people, especially with regard to their health care. 65 years is the accepted age to define elderly individuals in high-income countries and is used to define elderly in this Review, unless otherwise specified. The United Nations defines elderly as 60 years or older to account for shorter life expectancies in lowincome countries. The National Institute on Aging at the National Institutes of Health classify elderly patients into three categories: young old (65–74 years), older old (75–85 years), and oldest old (>85 years).19

Chronological age versus biological age The issue of chronological versus biological age is a common dilemma faced by clinicians in the daily care of patients. Whereas the term elderly refers to chronological age, the term frail (or infirm) relates to a biological syndrome of decreased reserve and resistance to stressors, leading to the risk of falls, disability, hospital admission, and death. Because the risk of frailty increases with age, particularly at the extreme end of age, the terms should be considered as distinct entities.20 Although chronological age is an important con­ sideration, biological age is the dominant factor in the selection of the best treatment approach for patients with locoregionally confined head and neck cancer. A clinician is concerned with whether a patient is fit old (ie, likely to withstand curative radical treatment) or frail old (unlikely to withstand such therapy). Although these categories are somewhat arbitrary, they help guide the clinician in determining the aggressiveness of treatment and likely tolerance. Elderly patients who fall into an intermediate category between fit old and frail old are the greatest dilemma for clinicians. These patients might not be able to withstand a full radical course of treatment, but could possibly benefit from a modification to the standard of care. Such a compromise could offer a balance between the 2

probability of cure and the reduction of unwanted side-effects. Elderly patients might be considered for deescalatation treatment because of patient preference or clinician concerns about likely tolerance and compliance. High-level evidence about the optimal de-escalated treatment for elderly patients remains scarce. This modification to standard of care is therefore often based on the preferences of the clinician or institution.21

Management of the elderly population Elderly patients often have a higher number of comorbidities and a lower performance status than do younger patients, which reduces their suitability for the optimal standard of care and probability of cure. Elderly patients are often under-represented in clinical trials and trials are often biased toward the fit-old group, restricting the applicability of their results somewhat, particularly for the intermediate group who were unlikely to have been treated on these clinical trials and who might also not be suitable for the standard of care.22,23 Major improvements in cancer therapies, particularly modalities that de-escalate toxicity, suggest that compliance could be improved in elderly patients and allow the possibility of pushing the boundaries of treatment. For the purpose of this Review, frail elderly patients are those considered not suitable to any form of radical or modified radical treatment. These patients are generally treated with symptom control and palliative care. Management of this group of patients is individualised and tailored to patient preference, symptoms, and institution or clinician preferences, rather than by the use of high-level evidence.

Surgery Despite the move toward organ preservation treatment with chemoradiotherapy over the past three decades, surgery remains the mainstay of treatment for many patients with head and neck cancer. Differences in outcomes (ie, locoregional control and survival) for elderly patients compared with younger patients are mainly based on retrospective series and case-control studies at single institutions.24–26 Additionally, in most studies, patient cohorts have been too small to provide any meaningful statistical comparisons.24,25 Perioperative and postoperative complications, surgical mortality, and control rates for elderly patients are conflicting and appear to be highly dependent on patient selection.25 In a large retrospective study from nearly 35 years ago, Morgan and colleagues26 reported a significant difference in perioperative mortality and non-lethal complications between 810 patients who were 65 years or older and 963 patients who were younger than 65 years (29 [3·5%] patients aged ≥65 years vs eight [0·8%] patients aged <65 years died within 30 days after surgery; p<0·001). Patients aged ≥65 years had a complication rate of 32% compared to 21% for patients aged <65 years.

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Despite significant outcomes, the numerical difference in complication rates between elderly and younger patients was small, leading the authors to conclude that advancing age should not be a deterrent for aggressive surgery.26 Notably, patients were not matched for confounding factors, such as the type of head and neck cancer, stage, or surgical procedure. Kowalski and colleagues27 reported on the survival and complication rates of 115 patients who were 70 years or older compared with 115 controls matched by site and clinical stage who were undergoing surgery. Although more deaths were seen in the elderly group than in the control group, the difference did not reach statistical significance, with a 5-year survival rate of 43% for the elderly group compared to 56% for the control group (p=0·10). The study27 also reported no difference in local or systemic complications.

Radiotherapy Evidence from randomised controlled trials and metaanalyses3,23 have demonstrated better locoregional control and overall survival with hyperfractionated accelerated radiotherapy compared with conventionally fractionated radiotherapy, although patient enrolment was biased towards patients younger than 65 years. In a large retrospective study28 of patients with head and neck cancer who were selected for definitive radiotherapy, 238 elderly patients (75 years or older) showed no difference in treatment interruption, completion rates, or treatment-related deaths compared with 1249 patients younger than 75 years. The only statistically significant difference was in the 2-year cause-specific survival, which was lower for elderly patients than for younger patients (72% vs 86%; p<0·01).28 Pignon and colleagues23 analysed the outcomes of 1589 patients from five EORTC prospective radiotherapy trials examining the impact of age on survival and toxicity. Outcomes according to age were analysed after dividing the cohort into eight groups: younger than 50 years (281 [17·7%] patients), 50–54 years (237 [14·9%] patients), 55–59 years (279 [17·6%] patients), 60–64 years (297 [18·7%] patients), 65–69 years (223 [14·0%] patients), 70–75 years (155 [9·8%] patients), older than 75 years (30 [1·9%] patients), and age not specified (87 [5·5%] patients). Increasing age did not affect overall survival, locoregional control, distribution of acute objective mucosal reactions, weight loss, or late toxicity.23 However, the occurrence of severe functional (symptomatic) mucosal reactions significantly increased with increasing age (p<0·001).23 The authors concluded that chronological age is irrelevant for therapeutic decisions. However, it can be argued that subjective acute toxicity and lower tolerance to treatment are more commonly seen in elderly patients. A meta-analysis3 by the MARCH Collaborative Group on the use of hyperfractionated and accelerated radio­ therapy in patients with head and neck cancer, that

involved 6515 patients from 15 trials, found that altered fractionated radiotherapy was associated with a significant survival benefit, with an absolute benefit of 3·4% at 5 years (hazard ratio 0·92, 95% CI 0·86–0·97; p=0·003). The absolute difference at 5 years between altered fractionated radiotherapy and conventional radiotherapy was 6·4%; p<0·0001).3 MARCH also did a trend test by age (≤50 years, 51–60 years, 61–70 years, or ≥71 years), which revealed a significant interaction between age and treatment effect for overall survival (p=0·007), with the greatest benefit seen in the youngest group and a decreasing benefit seen with increasing age. The trend test between age and treatment effect was also significantly associated with cancer-related death (p=0·008), local control (p=0·002), and locoregional control (p=0·002). Altered fractionated radiotherapy also had a greater effect on tumour control in patients with good performance statuses than in those with a poor performance status. The authors suggested that the relation between altered fractionated radiotherapy, age, and performance status, might be partly explained by an excess of non-cancer-related deaths in patients aged 71 years or older and a lower compliance and tolerance threshold for these patients, particularly in those with a poor general health status.

Chemotherapy Although randomised controlled trials have demonstrated superiority for concurrent chemoradiotherapy com­pared with radiotherapy alone, data about the benefit of chemoradiotherapy in elderly patients is conflicting.4,5 In RTOG 91-11,6 concurrent bolus cisplatin and radiotherapy achieved the highest proportion of patients with larynx preservation, albeit with more toxicity than with induction chemotherapy followed by radiotherapy or radiotherapy alone. Although this study did not assess treatment outcome by age, it did demonstrate a balanced distribution across the three groups with respect to the number of patients who were younger than 60 years and those who were 60 years or older; the median age was 59–60 years and the upper age range was 78–79 years. This finding supported the notion that concurrent chemotherapy benefits all ages, including elderly patients, as long as they have a good performance status and few comorbidities.6 Notably, assessment of the longterm toxicity outcomes of RTOG 91-11 showed that an increased number of deaths could not be attributed to larynx cancer or treatment with concomitant chemo­ radiotherapy.29 In a subset analysis, Machtay and colleagues10 found that older age was an independent prognostic factor for the development of severe late toxicity after the addition of chemotherapy to radiotherapy in three RTOG trials. In an updated meta-analysis5 of chemotherapy in head and neck cancer, which involved 93 randomised trials comprising 17  346 patients, the use of concomittant chemoradio­ therapy resulted in an absolute survival benefit of 6·5% at 5 years compared with locoregional

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treatment without chemotherapy (p<0·0001). Pignon and colleagues5 found a decreasing benefit of concomitant chemotherapy on survival with increasing age (p=0·003, test for trend). Of the 9280 patients assessed, only 692 (7·5%) were aged 71 years or older, restricting the applicability of these findings to a broader elderly population. The Department of Veterans Affairs Laryngeal Cancer Study Group9 found that patients of any age who respond to induction chemotherapy can safely undergo radio­ therapy for laryngeal preservation without survival detriment compared to non-responders who undergo surgery and postoperative radiotherapy. The TAX 323 and TAX 324 trials,30,31 which both administered induction chemotherapy before radiotherapy treatment, confirmed a survival benefit with a combination of docetaxel, cisplatin, and fluorouracil compared with cisplatin and fluorouracil without docetaxel. However, the additive benefit of induction chemotherapy to standard concurrent chemoradiotherapy remains controversial.30–33 In the TAX323 trial,30 patients older than 70 years were excluded, with only 10% of patients being older than 65 years in both groups. Although patients older than 80 years were included in the TAX324 trial,31 the exact percentage is unknown. Neither study did a subset analysis of tolerance or treatment benefit based on age, although most patients had an Eastern Cooperative Oncology Group (ECOG) performance status of less than one. In the initial MACH-NC meta-analysis,4 the addition of induction chemotherapy to radiotherapy was associated with a non-significant survival benefit of 3% at 2 years (43% vs 40%) and at 5 years (27% vs 24%) compared to concomitant or alternating chemoradiotherapy. The updated meta-analysis5 demonstrated a 5-year absolute survival benefit of only 2·4%. Further, two retrospective studies34,35 that interrogated large national databases both reported conflicting conclusions with regard to the benefit of the addition of chemotherapy to radiotherapy on survival in elderly people. However, both studies suggested comorbidities as an important prognostic factor.34,35 Bonner and colleagues13 reported that the addition of cetuximab to radiotherapy was superior to radiotherapy alone for the treatment of locally advanced head and neck cancer. Improvement of overall survival outcomes appeared to be, however, restricted to patients younger Men

Women

Australia

19·2

France

19·3

22·1 23·6

Japan

19·1

24·1

UK

18·6

20·9

USA

17·9

20·5

Table 1: Life expectancies (years) of men and women aged 65 years in 2013 who were living in selected Organisation for Economic Co-operation and Development countries38

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than 65 years on the basis of a subset analysis.13 Furthermore, no additional toxicity within the radio­ therapy field was seen with the combined treatment,13 although Pryor and colleagues36 described increased skin and mucosal toxicity with the addition of cetuximab to radiotherapy. In summary, there is no convincing evidence of a marked differential response to treatment for head and neck cancer when comparing elderly patients with younger patients across treatment modalities. Although complication rates are often higher in elderly patients than in younger patients, the available data suggest that, with appropriate patient selection and support, old age should not be the sole determinant in excluding patients for optimal surgical management. Treatment inten­sifi­ cation with either altered fractionation radio­therapy or chemotherapy results in increased toxicity and reduced tolerance in elderly patients; however, this should not be in itself a contraindication to the consideration of elderly patients for radical treatment. Reduced tolerance to treatment might account for decreased locoregional control in elderly patients in some studies. Elderly patients are also more likely to die from non-cancerrelated causes. Increased toxicity from the treatment of locally advanced head and neck cancer supports the need for meticulous assessment of elderly patients.

Assessment of the elderly population Assessment of elderly patients includes the evaluation of clinicopathological and age-specific factors. A clinico­ pathological assessment involves routine multidisciplinary assessment, as is done for newly diagnosed head and neck cancer, wherein tumour extent (TNM staging) and organ function are determined and the optimal evidence-based treatment for locoregional control is selected. Age-specific assessment involves life expectancy estimation and evaluation of comorbidities, performance and functional statuses, and psychosocial supports. Whether a compre­ hensive geriatric assessment (CGA) should be done for all patients who are 65 years or older is debatable, particularly for those that fall under the so-called fit-old category. Deciding whether a CGA should be done is where frailty prescreening of elderly people is of relevance.

Life expectancy Life expectancy is of particular relevance when determining the likely long-term gain of curative treatment for elderly patients. Life tables help to provide an estimate of the life expectancy of an otherwise healthy individual. Life tables are based on the average number of years a person born in a particular country is expected to live, if mortality rates at each age are to remain steady in the future. Life expectancy is affected by factors such as sex, ethnic background, and available health care. For high-income countries, the average life expectancy of a man and a woman aged 65 years ranges between 17–19 years and 18–20 years, respectively.37 Table 1 shows

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Panel 1: Charlson Comorbidity Index43

Panel 2: Lawton instrumental activities of daily living scale

Score 1: Myocardial infart, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue disease, ulcer disease, mild liver disease, and diabetes

• The Lawton instrumental activities of daily living scale is made up of eight domains: ability to use the telephone, shop, prepare food, do housekeeping, do laundry, use transportation, handle medications, and manage finances • Each domain is given a score by use of one of two scoring options: • Dichotomous • Less able=0 • More able=1 • Maximum score=8 • Trichotomous • Unable=1 • Needs assistance=2 • Independent=3 • Maximum score=24 • The higher the score, the greater the function

Score 2: Hemiplegia, moderate or severe renal disease, diabetes with end-organ damage, any tumour, leukaemia, and lymphoma Score 3: Moderate or severe liver disease Score 6: Metastatic solid tumour and acquired immune deficiency syndrome Scores are added to provide a cumulative score. For an age-adjusted score, one point is added for each decade of life over 50 years.

the life expectancies of men and women at 65 years in selected Organisation for Economic Co-operation and Development countries from 2013.38

Comorbidity and survival Evidence supports the importance of comorbidity as an independent predictor of survival in elderly patients with head and neck cancer.39–41 Several validated prognostic tools based on comorbidities have been developed for research and clinical purposes,40 such as the Adult Comorbidity Evaluation,27,42,43 the Charlson Comorbidity Index (CCI),44 and the Cumulative Illness Rating Scale.45 Additionally, web-based prognostic calculators are also readily available to provide quick and simple prognostic estimation. The CCI (panel 1) is a useful prognostic tool that assigns a score based on various conditions, such as vascular disease, stroke, and diabetes, which vary in weight from one to six and provides 1-year and 10-year survival probabilities.43,44 Because age is an independent prognostic variable, an age-adjusted CCI score is calculated by the addition of one point for each decade of life over 50 years. Using files from the Surveillance, Epidemiology and End Results Program, Reid and colleagues39 assessed the CCI in more than 9300 elderly patients with head and neck cancer and, after adjusting for variables such as age, date of diagnosis, tumour site and stage, marital status, ethnicity, sex, and socioeconomic status, found that relative hazards increased with increasing CCI scores (p<0·0001). The adjusted relative hazard for CCI (categorised as 0 vs ≥1) of 1·50 (95% CI 1·43–1·68), and the strong dose-response association when categorised as 0, 1, or 2 or more (p<0·0001), provides evidence that comorbidity is an independent determinant of survival and should form part of the initial assessment when deciding treatment intensity.39

Performance and functional status The prognostic significance of performance status (ECOG and Karnofsky) in cancer outcomes at any age has been well documented.46 Further, performance status measures, such as the Timed Up and Go test, provide additional information in the assessment of elderly patients. The Timed Up and Go test requires a person to stand up from a sitting position, walk 3 m, and return to the chair; the normal cutoff time for this is less than 12 s. Longer intervals to complete the test might indicate the need for mobility assistance in the community or identify those individuals who are a high risk of falls.47,48 Assessment of functional status includes the inves­ tigation of both activities of daily living and instrumental activities of daily living. Extermann and colleagues49 found poor to no correlation between comorbidity and functional status across all measures when they compared the Cumulative Illness Rating Scale-Geriatric and CCI with the ECOG performance status, activities of daily living, and instrumental activities of daily living. The inability to do activities, such as driving a car, has been shown to be a significant adverse prognostic factor for survival in elderly people.50 The Lawton instrumental activities of daily living is a simple and validated tool that takes 10–15 min to complete and is made up of eight domains. It consists of two scoring options but, essentially, the higher the score, the greater the function (panel 2).

Psychosocial factors and quality of life The positive benefits of social support from family members and friends on the ability of patients with head and neck cancer to adapt to the psychological and physical effects of their cancer and treatment and on health-related quality of life have been reported elsewhere.51–53 However, data about the effect of head and neck cancer diagnosis and treatment on the quality of life of elderly patients are scarce. Although elderly patients might start with a lower

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Comorbidities

Geriatric syndromes • Dementia • Osteoporosis • Osteoarthritis

Performance status • ECOG • Karnofsky

Geriatric patient

Socioeconomic and psychosocial status • Family support • Living conditions • Financial status • Depression

Functional status • ADL • IADL

Polypharmacy

Figure 1: Comprehensive geriatric assessment ECOG=Eastern Cooperative Oncology Group. ADL=activities of daily living. IADL=instrumental activities of daily living.

social, and functional wellbeing and can be used to guide interventions to optimise their health and improve tolerance to treatment.54 Although both the US National Comprehensive Cancer Network and the International Society of Geriatric Oncology recommend that a CGA should be done for all elderly patients, its original intent was not to identify the preferred treatment.55,56 In a systematic review of CGA in oncology, Puts and colleagues54 found that only four of 83 published articles examined the effect of a CGA on cancer treatment, of which only two showed that a CGA affected treatment in 50% of decisions. As a CGA can be time-consuming and not all elderly patients necessarily need it, prescreening tools have been developed to identify at-risk patients. In a systematic review by Hamaker and colleagues,57 the Geriatric-8 screening tool (table 2) was found to provide the highest sensitivity (>80%) for frailty screening. A study58 that examined the use of the Geriatric-8 tool for the assessment of elderly patients with head and neck cancer found that it identified twice the number of patients as vulnerable compared with assessment and treatment based solely on recommendations by the multidisciplinary team. Furthermore, a trend towards longer postoperative stay and lower completion rates for radiation therapy in patients deemed vulnerable by the Geriatric-8 tool was observed.58

Chemotherapy screening Score* Age (years)

0=>85; 1=80–85; 2=<80

BMI (kg/m²)

0=<19; 1=19 to <21; 2=21 to <23; 3=≥23

Weight loss over past 3 months (kg)

0=>3; 1=unknown; 2=1–3; 3=no weight loss

Food intake over past 3 months

0=severe decrease; 1=moderate decrease; 2=no decrease

Number of daily medications more than three

0=yes; 1=no

Mobility

0=bed or chair bound; 1=able to get out of bed or chair but does not go out; 2=goes out

Patient’s view on health status relative to peers

0=not as good; 0·5=does not know; 1=as good; 2=better

Neuropsychological problems

0=severe; 1=mild; 2=none

*Score ranges from 0–17; a score of ≤14 indicates a need for comprehensive geriatric assessment.

Table 2: Geriatric-8 screening tool

quality of life, they might experience fewer changes in quality of life than do younger patients, who might have more difficulty in accepting their diagnosis and experience more changes in their daily life, such as the requirement to take time off work and loss of earnings.52

Comprehensive geriatric assessment Elderly patients are likely to have age-specific issues related to social isolation, diminished cognition, depression, progressive multiorgan impairment, decreased nutritional status, and reduced mobility, all of which are potentially exacerbated by polypharmacy. The CGA (figure 1) is a multidisciplinary process for determining an elderly patient’s physical, psychological, 6

Given the age-specific issues and polypharmacy seen in elderly people, it is intuitive to seek a chemotherapyspecific screening tool to predict likely tolerance to chemotherapy.59 No tools have been universally adopted for the prediction of chemotherapy toxicity and tolerance. By use of a set of pretreatment parameters, Extermann and colleagues60 have developed a tool known as the Chemotherapy Risk Assessment Scale for High-Age Patients, which classifies patients into four risk categories related to toxicity risk with chemotherapy: low, mediumlow, medium-high, and high. Using an independent cohort of 250 patients, Hurria and colleagues61 validated a previously reported predictive model for chemotherapy toxicity based on 11 domains. The authors concluded that the model appears to have applicability when discussing the risks and benefits of chemotherapy in older patients.

Preoperative screening There is a need to develop a practical and universally adopted tool to assess the fitness of elderly patients before surgery to reduce the rate of perioperative and postoperative complications and mortality. In the mid-2000s, a composite tool was developed known as the Preoperative Assessment of Cancer in the Elderly,62 which incorporates several validated tools, including Satariano’s modified index of comorbidities, mini-mental state inventory, activities of daily living, instrumental activities of daily living, geriatric depression scale, brief

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fatigue inventory, ECOG performance status, and the American Society for Anaesthesiologists scale. This assessment tool was found to correlate with the degree of patient comorbidity and probably has an association with an increased risk of surgery.62 The comprehensiveness and time-consuming nature of this tool makes its universal application to all elderly patients difficult. The preferred method for preoperative assessment of elderly patients is clinician-based and institution-based rather than a specific globally adopted method.

Advances in treatment Advances in treatment aim to improve the therapeutic ratio by improving the separation between tumour control probability and normal tissue complication probability curves.

Surgery Use of transoral endoscopic surgery for patients with head and neck cancer has gained popularity because of its minimally invasive technique and improved visualisation. Transoral robotic surgery and transoral laser microsurgery reduce the need for disfiguring and invasive surgery and reduce recovery time and long-term sequelae, such as speech and swallowing complications.11 These novel approaches are of impor­ tance to elderly patients who might be less tolerant than younger patients in undergoing major operations, prolonged anaesthetic exposure, and reconstructive surgery. Numerous institution studies and some multicentre studies have demonstrated high rates of local control for transoral robotic surgery and transoral laser microsurgery in patients with head and neck cancer.63 Dziegielewski and colleagues64 found that patient-reported quality-of-life scores returned to normal 1 year following transoral robotic surgery. Several prospective studies, such as the ECOG 3311 (NCT0189894) and ADEPT (NCT01687413) trials, are investigating the role of endoscopic surgery in the management of patients with head and neck cancer.

Radiotherapy Advances in tumour delineation through the fusion of high-quality diagnostic and functional imaging with planning scans, alongside highly conformal radiotherapy techniques such as intensity-modulated radiation therapy, has led to an increase in the expected tumour control probability. Overgaard65 reported an improvement in locoregional control from about 27% to 80% with the use of radiotherapy over a 30-year period. The normal tissue complication probability has received substantial attention over the past 20 years because improved cure rates have meant that people are living longer with the effects of treatment. Improvements in the understanding of tolerance doses for at-risk organs that impact on quality of life, such as the parotid glands, alongside the sparing of these organs, have allowed a

reduction in the normal tissue complication probability without com­ promising the probability of tumour control.66 Further separation of the normal tissue compli­ cation probability and tumour control probability curves can be achieved through attempts to spare the normal aerodigestive mucosa, pharyngeal constrictors, and mandible, thereby reducing rates of mucositis, dysphagia, the need for enteral feeding, and osteoradionecrosis.67 Highly conformal techniques are aided by image guidance, which allows tighter margins around target volumes because of improved accuracy. Additionally, changes in tumour volume and patient contours due to factors such as weight loss during a course of radiotherapy can be addressed with adaptive radiotherapy.68 In the future, adaptation might be facilitated through the dose painting paradigm, whereby subvolumes within a tumour receive different doses because of particular biological, molecular, or imaging characteristics.12 Numerous trials69,70 have investigated reducing the normal tissue complication probability through the use of radioprotectants, particularly in the mucosa and parotid glands. However, the widespread use of radioprotectants is restricted because of concerns about side-effects, the risk of tumour protection, their cost, and difficulty in accessing these agents.71 In a randomised study,72 the Trans Tasman Radiation Oncology Group demonstrated that humidified air delivered during radiotherapy resulted in significantly fewer mean days in hospital compared with the control arm (4·1 [95% CI 2·7–6·0] vs 2·3 [1·5–3·5]; p=0·017). In addition, investigators found that the proportion of patients who needed a feeding tube was reduced compared with the control arm of just radiotherapy (p=0·04). Proton therapy differs in physical characteristics to photon beams in terms of the maximal dose deposited to a small area, the Bragg peak, with no further dose deposited downstream (ie, beyond the tumour and through the normal tissues). Coupled with a series of other modulated proton beams, it is possible to increase the therapeutic ratio by increasing the dose to a tumour without increasing the dose to the surrounding tissues. Although proton therapy has advantages compared with intensity-modu­ lated radiotherapy, particularly for paediatric patients with cancer and for reirradiation, it is costly and the dose distribution benefit in adult patients with head and neck cancer has narrowed with improvements in technologies such as dynamic intensity-modulated radiotherapy.73 Radiotherapy de-escalation is an appealing and simple method of reducing toxicity if it can be achieved without a compromise in cure. Preclinical evidence74 has demonstrated that HPV cell lines have enhanced radiosensitivity because of factors such as upregulation of wild-type TP53 after cellular injury and an impaired capacity for double-stranded DNA repair. This biological property of HPV cells is being exploited in prospective trials (NCT01855451, NCT01302834, NCT01874171, NCT01084083, NCT01706939, and NCT02254278) that are testing the safety of radiotherapy de-escalation in the

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Search strategy and selection criteria

Elderly patient with locoregionally confined head and neck cancer

Clinical impression of biological age

Intermediate

Frail

Fit

We searched PubMed using the terms “older adult”, “senior adult”, “advanced age”, “high-age”, “geriatric”, “head and neck cancer”, “surgery”, “chemotherapy”, “systemic therapy”, and “radiotherapy”. We included studies published in English from Jan 1, 1980 to Dec 31, 2016 and involved patients with head and neck cancer. We also did a search on ClinicalTrials.gov to identify any relevant clinical trials. The relevant clinical trials were selected at our own discretion.

G8 screening tool ≤14

Systemic therapy

>14

Comprehensive geriatric assessment

No

Patient preference is to be considered for curative treatment Yes Assessment of age-specific factors

Poor

Life expectancy Good

High

Comorbidity (CCI) Low

Poor

Assessment of PS and FS • ECOG PS • Timed up and go • ADL, Lawton IADL Good

Palliative care and symptom control • Radiotherapy surgery, systemic therapy

Consider MDT consensus of optimal curative management or clinical trial • Non-evidence based de-escalation of treatment intensity might be required for perceived tolerance or compliance issues or patient preference

Figure 2: Recommended treatment algorithm for elderly patients with head and neck cancer G8=Geriatric-8. CCI=Charlson Comorbidity Index. PS=performance status. FS=functional status. ECOG=Eastern Cooperative Oncology Group. ADL=activities of daily living. IADL=instrumental activities of daily living. MDT=multidisciplinary team.

curative disease setting. In one such prospective study, ECOG 1308 (NCT01084083),75 HPV-positive patients with stage III–IVb resectable oropharyngeal squamous-cell carcinoma were treated with three cycles of induction chemotherapy that included paclitaxel, cisplatin, and cetuximab. The proportion of patients who achieved a complete response received a radiotherapy dose reduction to 54 Gy with cetuximab, whereas those who did not achieve a complete response received the conventional radiotherapy dose of 66–70 Gy with cetuximab. For all patients who experienced dose reduction, progression-free survival at 23 months was 84%, and overall survival at 2 years was 95%.75 8

Altered pharmacodynamics and kinetics due to progressive decline in organ function contributes to an increased frequency of chemotherapy-related toxicity.56 A gradual decline in immune functions occurs as part of the ageing process, but also because of ongoing chronic inflammatory responses. These factors might play a role in the increased incidence of cancer in elderly patients.76 Recent advances in systemic therapy for head and neck cancer have focused on the role of checkpoint inhibitors in the treatment of recurrent and metastatic disease. Early indications point to promising activity in patients who have progressed on platinum-based therapy, with a response rate of 10–20%.77,78 Nivolumab and pembrolizumab are two drugs that have been studied the most in the platinum refractory setting, and there is support for a move to these drugs as the standard of care for this setting.77,78 These drugs appear to be well tolerated by elderly patients and, as of yet, there has been no early indications of increased toxicity in this patient population.77,78 Although no data currently support the incorporation of these drugs into the curative setting, numerous trials (NCT01860430, NCT02764593, and NCT02819752) are investigating this possibility.79

Conclusion Although treatment tolerance might differ in elderly patients compared with younger patients, there is insufficient high-level evidence supporting the notion that tumours respond differently between young and old patient populations and that cancer-related survival outcomes are necessarily inferior in elderly patients. Advanced age alone should not be a contraindication to effective treatment. Selection for curative treatment should be based on an assessment of life expectancy, comorbidities, performance and functional statuses, social support, and patient preference. Prospective trials of elderly patients with locoregionally confined head and neck cancer are warranted, particularly for the so-called intermediate group who represent the greatest challenge for clinicians to effectively manage. Studies that have examined less intensive treatment programmes for elderly patients to guide management and improve tolerance are scarce. Trials to confirm screening tools that allow appropriate selection of these

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patients for standard curative intent treatment or a modified less intensive treatment are required. In the absence of high-level evidence, however, we recommend a treatment algorithm for elderly patients with head and neck cancer that helps guide the management process (figure 2). Contributors SVP conceptualised and designed the study. SVP and RIH wrote and edited the manuscript. Both authors have approved the manuscript. Declaration of interests SVP declares no competing interests. RIH reports grants to his institution from Bristol-Myers Squibb, Merck, AstraZeneca, and VentiRx, and personal fees from BMS, Merck, AstraZeneca, and Pfizer outside of the submitted work. References 1 IARC. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/Pages/fact_ sheets_population.aspx (accessed Nov 26, 2016). 2 Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med 2008; 359: 1143–54. 3 Bourhis J, Overgaard J, Audry H, et al, for the Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck (MARCH) Collaborative Group. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006; 368: 843–54. 4 Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000; 355: 949–55. 5 Pignon JP, le Maitre A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17 346 patients. Radiother Oncol 2009; 92: 4–14. 6 Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003; 349: 2091–98. 7 Bernier J, Domenge C, Ozsahin M, et al, for the European Organization for Research and Treatment of Cancer Trial 22931. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004; 350: 1945–52. 8 Cooper JS, Pajak TF, Forastiere AA, et al, for the Radiation Therapy Oncology Group 9501/Intergroup. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004; 350: 1937–44. 9 Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991; 324: 1685–90. 10 Machtay M, Moughan J, Trotti A, et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol 2008; 26: 3582–89. 11 Holsinger C, Ferris R. Transoral endoscopic head and neck surgery and its role within the multidisciplinary treatment paradigm of oropharynx cancer: robotics, lasers, and clinical trials. J Clin Oncol 2015; 33: 3285–92. 12 Grégoire V, Langendijk J, Nuyts S. Advances in radiotherapy for head and neck cancer. J Clin Oncol 2015; 33: 3277–84. 13 Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567–78. 14 Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010; 363: 24–35. 15 Office for National Statistics. Life expectancies. https://www.ons. gov.uk/peoplepopulationandcommunity/ birthsdeathsandmarriages/lifeexpectancies (accessed Nov 23, 2016). 16 Ortman JM, Velkoff VA, Hogan H. An aging nation: the older population in the United States. US Census Bureau. https://www.census.gov/prod/2014pubs/p25-1140.pdf (accessed Aug 23, 2016).

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