Targeted therapy and elderly people: A review

European Journal of Cancer 69 (2016) 199e215

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Review

Targeted therapy and elderly people: A review Amaury Daste a,b,*, Camille Chakiba b,c, Charlotte Domblides a, Marine Gross-goupil a, Amandine Quivy a, Alain Ravaud a,b, Pierre Soubeyran b,c a

Department of Medical Oncology, Hoˆpital Saint-Andre´, Bordeaux University Hospital-CHU Bordeaux, France University of Bordeaux, Bordeaux, France c Department of Medical Oncology, Institut Bergonie´, Bordeaux, France b

Received 21 September 2016; accepted 5 October 2016

KEYWORDS Targeted therapy; Elderly people; Adverse events

Abstract The use of targeted therapy (TT) has radically changed the outcome of various cancers and introduces the era of personalised medicine. Elderly patients (
65 years) represent the majority of cancer diagnoses and deaths by age group with an increase expected over the next decade. This group of patients is heterogeneous with three categories of patients: fit, vulnerable and frail, with specific treatment for each subgroup. In this review, we assess safety and efficacy of TT in elderly patients, principally from data of pivotal clinical trials with subgroup analysis, but elderly people represented a small percentage of the total number of patients. Few specific trials have been carried out for TT in elderly people with most patients considered to be fit. However, tolerance and efficacy of TT in elderly patients seems similar to that for younger patients, with an increase in incidence of specific adverse events in elderly patients for selected TTs. An adapted geriatric selection and strict monitoring could help to decrease toxicity, and specific clinical trials for elderly cancer patients would be useful. ª 2016 Elsevier Ltd. All rights reserved.

1. Introduction

* Corresponding author: Department of Medical Oncology, Hoˆpital Saint-Andre´, Bordeaux University Hospital-CHU Bordeaux, 1 Rue Jean Burguet, 33000 Bordeaux, France. Fax: þ33 5 56 79 58 96. E-mail address: [email protected] (A. Daste). http://dx.doi.org/10.1016/j.ejca.2016.10.005 0959-8049/ª 2016 Elsevier Ltd. All rights reserved.

Elderly patients, defined as
65 years, represent the majority of cancer diagnoses and deaths by age group. In the United States of America, approximately 53% and 27.9% of new cases and 69% and 44% of cancer related deaths occur in people
65 years and
75 years respectively [1]. These results are relatively similar to

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those in other western countries. In the next decade the proportion of new cases in elderly people will continue to increase due to the increase in life expectancy, and will represent 70% of the total of new cancers diagnosed [2]. Despite these statistics, and the increasing incidence of cancers in elderly, older or very old people (
75 years) are often under represented in clinical trials [3,4], and particularly in clinical trials assessing targeted therapy (TT) with only 32% of all patients aged 65 years or older in specific clinical trials [5]. The decline in functional reserve, increased comorbidities and polymedication have been the principal reasons for the low inclusion of the geriatric population in clinical trials. Consequently, probably because of an active selection of patients, toxicity seems to be similar between young and old patients. Balducci and Extermann [6], were the first to suggest individualisation of three groups among the elderly according to the results of comprehensive geriatric assessment (CGA): fit, vulnerable and frail. This classification may allow to tailor cancer treatment with cytotoxic chemotherapy according to their specific characteristics in terms of toxicity risks with standard treatment, adaptation of chemotherapy and palliative treatment in fit, vulnerable and frail patients, respectively. For the vulnerable geriatric population, intervention can help patients before and during treatment and permit the use of standard treatment. Most elderly people included in these trials were considered to be fit, however they do not represent the entire elderly population, only a part of it to which treatment will be applied in clinical practice. In the last decade, TT has radically changed the outcome of various cancers with a new management approach: personalised cancer medicine with treatment directed at specific molecular anomalies of the cancer. For elderly people, little data concerning efficacy and safety is described in the literature although each of these drugs is associated with specific adverse events (AEs) and many potential interactions with other treatments, often linked to CYP 450. Indeed, since polypharmacy is a common fact in the elderly, major detrimental interactions may be anticipated and thus should be studied in clinical studies. Particularly, events with no life-threatening consequences in young patients such as hand-foot syndrome or diarrhoea have a greater impact on general status in older patients with major effect and even life-threatening. There have been few clinical trials testing TT in this specific population and data has been principally extracted from phase III clinical trials which also include younger people.

2. Materials and methods To point out these difficulties, we decided to gather the available data about cancer TT in the elderly. This

review reports specific data on TT in elderly people with solid-tumour cancers. We searched for publications in the English language in PubMed, Google Scholar and Medscape. Mesh terms used were ‘aged, elderly, targeted therapy, renal-cell carcinoma (RCC), melanoma, lung cancer, colorectal cancer, breast cancer, ovarian cancer, gastrointestinal stroma tumour (GIST)’. We selected pivotal phase III studies or clinical trials with special interest for each solid tumour and analysed data on the elderly population in each article.

3. Results 3.1. Renal-cell carcinoma 3.1.1. Anti-angiogenic therapies Sunitinib was the first drug to demonstrate efficacy in first-line for metastatic renal-cell carcinoma (mRCC with an increase of median progression-free survival (PFS; 11 months versus 5 months [interferon a], hazard ratio (HR): 0.42, 95% CI, 0.32e0.54; p < 0.001). Efficacy was similar between patients <65 years (63%) and
65 years (37%) [7]. In first-line, median PFS and median overall survival (OS) were similar in both groups: 9.9 versus 11 months and 23.6 versus 25.6 months in younger and elderly groups for median PFS and OS, respectively. Hutson et al. [8] confirmed these results by analysing 1059 patients included in six clinical trials treated with sunitinib for mRCC comparing safety and efficacy between patients
70 (n Z 202; 19%)and <70 (n Z 857, 81%) years old. Regarding tolerance, in this selected elderly population, some toxicities were significantly more frequent in the elderly, such as fatigue (69% versus 60%), cough (29% versus 20%), peripheral oedema (27% versus 17%), anaemia (25% versus 18%), decreased appetite (29% versus 13%), and thrombocytopaenia (25% versus 16%), p < 0.05. Although AEs were more frequent in the elderly, this group presented less grade I or II AEs than the younger population, but more grade III AEs and similar grade
IV AEs. Only hand-foot syndrome was less frequent in older people (24 versus 32%). These results concerned patients included in clinical trials and probably with less comorbidity and better organ function than the average elderly patient due to strict inclusion criteria. However, in real life this data seems to be similar. Brunello et al. [9], analysed 68 patients with a median age of 74 years (range 70e88), treated with sunitinib in six Italians centres. The majority of patients presented one or more cardiovascular risks factors (80.9%) with mostly hypertension (58.8%), and a mean number of 1.9 comorbidities (range 1e5). Few people presented severe comorbidities with 9 cases (13%) of grade III or IV according to the cumulative illness rating scale for geriatrics (CIRS-G) scale and mainly cardiovascular 3.1.1.1. Sunitinib.

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effects. Half the population received a CGA and 13 patients were fit, 14 patients vulnerable and 7 frail. No correlation was found between frailty at CGA and serious AEs, but this result was limited by the small number of patients. Efficacy was similar to other clinical trials, with median PFS of 13.6 months. The majority of patients had dose reduction (69.2%). Dose reduction, or adapted schedule with full dose with 2 weeks on and 1 week off, seemed interesting in elderly people with less toxicity and the same efficacy, but only in retrospective data [10,11]. Sunitinib may therefore be proposed in some selected patients with relative efficacy. Sunitinib may be started either full dose or with a dose reduction and intra-patient escalation according to tolerability may be useful. Decision should be based on the aim of treatment notably if any rapid impact of detrimental symptoms of RCC is anticipated. No data is available to help physicians select patients that can be treated with sunitinib, but particular vigilance, notably on cardiovascular comorbidities, and strict monitoring is necessary regarding the most frequent AEs, in particular fatigue [8,9]. Jang et al. [12] noted the highest risk of stroke for patients who were 66 e 74 years old and treated with sunitinib. In addition no specific recommendation of pharmacokinetic (PK) survey has been developed in order to optimally adapt the dosage to the efficacy/side effects balance, even the recommended plasma concentration should be around 50 ng/ml [13,14]. Sorafenib. Sorafenib, another vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitor (TKI), demonstrated efficacy on mRCC in a randomised phase III versus placebo study with an increased median PFS (8.2 versus 5.5 months, p < 0.001) [15]. A retrospective subgroup analysis of patients
70 and <70-years old [16] showed that elderly people presented more arterial hypertension (66% versus 36%), diabetes mellitus (20% versus 11%) and breathing abnormalities (16% versus 9%) than younger people in the sorafenib group at baseline. The increase of comorbidities could explain the higher grade III or more AEs in the elderly patients arms (45.7% versus 36.7%), even if the frequency of any AE was similar between the two groups. Anorexia was the principal AE increased in the elderly arm. Despite the higher dose reduction in the elderly group (21.4% versus 11.3%) efficacy was similar with a median PFS of 26.3 versus 23.9 weeks in older and younger groups, respectively. Even if sorafenib lead to toxicity, the benefit seems to be real with an increase in the median number of days to health status deterioration, compared to placebo. Procopio et al. [17], confirmed these results with an analysis of six clinical trials and two expanded-access studies assessing sorafenib in monotherapy. Elderly people presented more comorbidities at baseline, and more grade III or 3.1.1.2.

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higher AEs (33% versus 41%) during follow-up. Fatigue and anorexia (including grade IIIeIV) were the two AEs more frequent in the elderly population. Interestingly, arterial hypertension was not more frequent in elderly people. As with sunitinib, sorafenib seems to have the same efficacy in younger and older selected populations with more toxicity. However, although this toxicity may be acceptable, an adapted strategy seems necessary to optimise the management of complications, as for all oral anti-angiogenic therapies. Pazopanib was tested in naive or cytokine pre-treated mRCC versus placebo [18] Median PFS was increased in pazopanib arms (9.2 versus 4.2 months, HR, 0.46; 95% CI, 0.34e0.62; p < 0.0001) but the prolonged PFS was less significant in elderly arms (HR 0.40 versus 0.50 for <65 and
65 years, respectively). Pazopanib was not inferior to sunitinib in first-line with similar PFS [19]. However, the analysis of 434 patients
65 years old, showed better but not statistically significant efficacy in the sunitinib arm. Pazopanib seems to be preferred by the patients compared to sunitinib in first-line due to less fatigue and better quality of life with identical efficacy, but was only assessed in a short duration exposure, while adaptation of sunitinib tolerance may be assumed after the first cycles of treatment [20]. Pazopanib could be an alternative in first-line in elderly people, but more specific studies are necessary especially with surveillance of hepatic toxicity notably with drug interaction. No PK recommendation has been proposed to optimally adapt the dose of pazopanib [21]. 3.1.1.3. Pazopanib.

Axitinib was compared to sorafenib in first or second line for mRCC and proved significantly more effective in second-line treatment independently of age [22] while the difference did not reach significance in first-line [23]. Axitinib appears to be efficient and with an acceptable safety profile in older people and could be proposed in second-line treatment, but little data is available concerning the characteristics of this geriatric population. However, specific impacting side effects such as mucositis, diarrhoea and hand-foot syndrome are considered less frequent than with other options.

3.1.1.4. Axitinib.

In a phase III study, bevacizumab plus interferon a demonstrated efficacy with increased median PFS versus interferon a in a general population [24]. Analysis of subpopulations showed that bevacizumab þ interferon a was always efficient in elderly people (
65 years) but the benefit was less substantial in older groups than in younger groups with an HR of 0.77 (0.58e1.03) and 0.54 (0.43e0.68), respectively. Contrary to TKI, little data is available concerning the safety and efficacy of bevacizumab þ interferon a for mRCC in the elderly. 3.1.1.5. Bevacizumab.

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In addition, there is a major concern about the immunocompetence that might be sollicited by interferon a in this combination due to immunosenescence [25]. In addition, interferon a induces frequent mood disturbances and/or depressive symptoms requiring specific attention in this setting [26]. Khambati et al. [27] reported the safety and efficacy analysis of anti VEGF TT in first-line for mRCC in elderly people (
75 years), collected through the International mRCC Database Consortium from 12 centres. Among the 144 patients included, only seven were treated with bevacizumab. There was no difference between older and younger patients concerning overall response rate (ORR), treatment duration and OS.

most frequent AE under everolimus in the elderly group with the same frequency as in the younger population. Pneumonitis was not increased in elderly people but cough was more frequent in the everolimus group of elderly people than in the younger group, but some AEs, including cough, occurred more frequently in the elderly population independent of treatment group. Peripheral oedema, fatigue and diarrhoea were the main AEs increased in the elderly population. Everolimus was well tolerated with less fatigue than TKI and could be proposed for older patients in secondline after failure of VEGF-R TKI. Data from 1st line do not support the use of everolimus in first-line setting [33].

Recently cabozantinib, a TKI targeting VEGF-R, MET and AXL, demonstrated better efficacy for mRCC after failure with VEGF-R targeted therapy versus everolimus [28]. More than 60% of the patients had to decrease the dose. No data concerning the elderly people was described. But due to the toxicity with, notably, diarrhoea (74% at any grade and 11% of grade IIIeIV), fatigue (56%, grade IIIeIV: 9%), nausea (50%, grade IIIeIV: 4%), decreased appetite (46%, grade IIIeIV: 2%), palmarplantar erythrodysesthesia syndrome (42%, grade IIIeIV: 8%), hypertension (37%, grade IIIeIV: 15%), vomiting (32%, grade IIIeIV: 2%), weight decrease (31%, grade IIIeIV: 2%), this drug must be used with caution in the elderly population with strict monitoring, which was already a major concern in trial with cabozantinib in prostate cancer [29].

3.2. Melanoma

3.1.1.6. Cabozantinib.

3.1.2. M-TOR inhibitors The mammalian target of rapamycin (M-TOR) pathway has a role in RCC growth in subset patients. Two drugs targeting this pathway demonstrated efficacy in mRCC. Temsirolimus, demonstrated efficacy in patients with a poor prognosis, with increased median OS, compared to interferon a. In a population
65 years (n Z 129, 31%), this efficacy was not confirmed (a better outcome was obtained in the interferon a arm) [30].

3.1.2.1. Temsirolimus.

Everolimus, an oral M-TOR inhibitor, increases median PFS in second-line and more after failure of at least one VEGF-R TKI against placebo [31]. In a subgroup analysis of elderly people, Porta et al. [32], reported an increased median PFS in all subgroups (5.1 versus 1.9 months, HR: 0.19; 95% CI, 0.09e0.37; p < 0.001 for
70 years) with a comparable decrease in tumour burden and a mean dose intensity lower in everolimus-treated patients
70 years old compared to the entire group. Toxicities were similar in terms of frequency and intensity in elderly and general populations, notably for dyslipidemia and increased glucose. Stomatitis was the

3.1.2.2. Everolimus.

3.2.1. B-RAF inhibitors 3.2.1.1. Vemurafenib. Vemurafenib, a B-RAF inhibitor, was approved in first-line for locally advanced or metastatic melanoma presenting BRAF V600E mutation with increase of median PFS compared to dacarbazine (6.9 versus 1.6 months; HR 0.38; 95% CI, 0.32e0.46; p < 0.0001) and median OS (13.6 versus 9.7 months; HR 0.70; 95% CI, 0.57e0.87; p Z 0.0008) [34]. The survival benefit was observed in all age groups with a slight decrease in efficacy for patients
75-years old with an HR for OS of 0.12 (0.03e0.47) and 0.60 (0.23e1.55) for patients 65e74 and
75 years old, respectively [35]. However, these results must be used with prudence due to the small number of patients in the elderly group. Larkin et al. [36], reported the results of an open label study including 3226 patients with 257 (8%)
75 years treated with vemurafenib. Elderly patients had an increased incidence of serious AEs (grade III or more) with 59% versus 43% in younger people. Cutaneous squamous cell carcinoma (18% versus 6%), kerathoacanthoma (10% versus 6%) and QT prolongation (3% versus <1%) were the main AEs increased in the geriatric population. However, toxicity of vemurafenib was acceptable with few serious AEs. 3.2.1.2. Dabrafenib. Dabrafenib, another B-RAF inhibitor, demonstrated efficacy for the same indication with increased median PFS compared to dacarbazine. Dabrafenib seems to be well tolerated with a similar profile to vemurafenib [37]. No specific data concerning the elderly population for this drug was available but its safety means it can be proposed for elderly people.

3.2.2. Combination of B-RAF and MEK inhibitors 3.2.2.1. Dabrafenib and trametinib. The simultaneous inhibition of the two targets of the mitogen-activated protein kinase (MAPK) pathway (BRAF and MEK) increased the efficacy of each drug used separately for melanoma with B-RAF mutant. The combination of

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dabrafenib and trametinib [38] versus vemurafenib improved OS for patients with unresectable stage IIIc or IV melanoma with BRAF V600 mutations previously untreated. At the interim analysis, median OS was increased in the combination arms and the study was stopped due to efficacy. About one quarter were
65 years (n Z 166, 23.6%) and presented similar efficacy for median OS (HR: 0.61 versus 0.74) and median PFS than younger groups. Pyrexia (53%), nausea (35%), diarrhoea (32%), chills (31%), fatigue (29%), headache (31%) and vomiting (29%) were the most frequent AEs described in the combination arms. The serious AE was pyrexia (4%). No data concerning age and toxicity was noted but a decrease in ejection fraction occurred in 8% of patients and in 4% for serious AEs. Abnormal ejection fraction was frequent in general elderly population making use this combination with caution in this patient group. This result was confirmed in another phase III study comparing dabrafenib and trametinib versus dabrafenib and included a subgroup analysis for patient
65 years (n Z 118, 27.9%) [39]. In the same population presenting mutant V-600, vemurafenib and another MEK inhibitor (cobimetinib) demonstrated efficacy with increased median PFS versus vemurafenib alone. In elderly subgroups (
65 years) efficacy remained similar where HR for median PFS was 0.45 (95% CI, 0.25e0.79) and 0.54 (95% CI, 0.39e0.75) for younger subgroups [40]. The profile of tolerance was similar to the other combinations. No data concerning the safety with elderly people was described but we noted 8% decrease in ejection fraction [40]. Interestingly, Long et al. [39] noted better efficacy for patients <65 years versus elderly patients with better OS at 2 and 3 years (55% and 41% versus 36% and 27%, respectively) but only 11 patients were present in the elderly group. 3.2.2.2. Vemurafenib and cobimetinib.

3.3. Lung carcinoma More than 30% of non small cell lung cancer (NSCLC) are currently diagnosed in patients >70 years. In this subpopulation, an association of carboplatin AUC 6 and weekly paclitaxel is commonly administered in patients with PS 0e1, according to a prospective trial [41]. Unlike chemotherapies, there is little data on the safety and efficacy of targeted treatments in the elderly population, except from small prospective or retrospective studies or subgroup analysis. 3.3.1. EGFR inhibitors TKIs have dramatically changed the outcome for patients with Epidermal Growth Factor Receptor (EGFR) mutation-positive non-small-cell lung adenocarcinoma in first-line with improved survival [42,43]. Numerous

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retrospective or phase II studies on elderly patients treated with erlotinib or gefitinib have been published. The usual patients with EGF-R mutation were described as young Asian women who never smoked, but in an American retrospective study, the median age was 64 years [44]. BR 21 was a randomised phase III study which compared erlotinib versus chemotherapy after failure of first or second-line chemotherapy. A subgroup analysis of 163 elderly (
70 years) and 568 younger (<70 years) patients was carried out [45]. The efficacy was similar between the two groups concerning median PFS, OS and best objective response, with a slightly better but not statistically significant response in favour of the geriatric arm. In this selected population, serious toxicity (grade
III) was more substantial in the elderly than in the younger group with 35 and 18% (p < 0.001), respectively. The elderly group presented more grade
III toxicities of rash, fatigue, stomatitis or dehydration as well as any grade of anorexia and fatigue than younger patients. In addition, they were more likely to discontinue treatment because of drugrelated toxicities (12% versus 3% in younger patients). Despite this increase in toxicity, the benefit with regard to quality of life was similar between older and younger subgroups. In a phase IV study of unselected patients, an analysis of elderly patients (
70 years, 7% n Z 485) treated with erlotinib in first-line was carried out [46]. The disease control rate was increased in the elderly population versus the entire cohort (79% versus 69%). The median PFS and OS were similar between the two groups. Although the rate of AEs was relatively low, toxicity was more frequent (18 in elderly versus 12% in younger patients) and more serious (7% and 4%) in elderly patients. Discontinuation of treatment due to AEs was increased in the elderly group (10% versus 5%). Kurushima et al. [47], reported in an observational study including 307 Japanese patients (
75 years, n Z 74 patients), a similar efficacy and toxicity of erlotinib treatment in elderly and younger groups. The interest of this study was the description of a very old population subgroup (
80 years). This population presented the same disease control rate and toxicity as the rest of the population. The expression of EGFR mutation is important. In the majority of the preceding studies, the search for an EGFR mutation was not systematic. In a large specific geriatric phase II study, Heigener et al. [48], compared the efficacy of first-line erlotinib versus carboplatin/ vinorelbine in elderly patients (
70 years). Few patients presented a mutation of EGFR and median PFS was inferior in erlotinib groups (2.4 versus 4.6 months HR: 1.6; 95% CI, 1.22e2.09; p: 0.0005). But this study was carried out in an unselected cohort of patients, and there 3.3.1.1. Erlotinib.

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was no subgroup analysis according to EGFR status. A phase II study is currently ongoing (NCT00678964) assessing the efficacy and safety profile of erlotinib versus the combination of carboplatin and vinorelbine in an elderly population. 3.3.1.2. Gefitinib. The INVITE trial was the largest cohort of unselected elderly patients (n Z 196). This study compared gefitinib with monochemotherapy to vinorelbine alone, and showed similar ORR, PFS and OS with a better tolerability for gefitinib. Gefitinib was also assessed in four phase II studies including a specific geriatric population harbouring the EGFR mutation [49e52]. The population in each study was small (17e31 patients). The ORR was significant (59e74%). The median PFS in all studies was over 10 months except for Inoue et al. [49], with a median PFS of 6.5 months [45]. The toxicity was relatively similar in the four studies. Rash, diarrhoea, anorexia and elevated enzymatic liver were the most significant toxicities. However, the serious toxicities (
grade III) were low (15e29%) and principally with elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT). In these studies, patients enrolled were selected (adequate liver, renal and haematological function and a performance status [PS] 0, 1 or 2) except for the study of Inoue et al. [49] In this study patients enrolled presented elevated PS and adequate liver function. Despite this low selection, the treatment demonstrated a benefit with a better PS during the treatment. In an observational study including 55 patients
75 years treated with gefitinib in first-line and presenting the EGFR mutation, Tateishi et al. [53], confirmed these results. The rate of response was 72.7% and median PFS and OS were 13.8 and 29.1 months, respectively. In this unselected population, with geriatric comorbidities, toxicity appears to be similar to the other studies [53]. In conclusion, in a geriatric population presenting the EGFR mutation, gefitinib or erlotinib appears to be as efficient as in the overall population with a slightly increased toxicity, but the tolerance was more acceptable than chemotherapy and must be privileged in the case of EGFR mutation. In addition, the use of an EGFR-TKI is associated with an improvement in quality of life, meaning that patients probably retain their autonomy. Overall, the choice of elderly patients is the most important element in decisions regarding cancer treatment. An early study published in 1994 showed that when patients were asked to choose between quality of life and survival in the choice of treatment for lung cancer, for most of them, quality of life was more important than survival [54].

Afatinib, a more recent anti EGF-R drug, demonstrated efficacy in patients with NSCLC harbouring EGF-R mutation versus chemotherapy notably del 19 mutation [55]. No data

3.3.1.3. Others anti EGF-R.

concerning elderly populations with EGF-R mutation was described but the median OS was better for patients
65 years (31%, n Z 196) versus <65 years (HR 0.67 versus 0.85). The profile of tolerance was similar to other anti EGF-R drugs but more grade III AEs were described for older patients in the afatinib arms. In addition, afatinib seems to be slightly more toxic than erlotinib and gefitinib, in particular for digestive toxicities. Currently, a new anti EGF-R treatment targeting the T790M mutation, a mutation frequently harboured in case of anti EGF-R resistance, demonstrated efficacy in phase I [56]. Two of these molecules, rociletinib (CO1686) and osimertinib (AZD-9291), are currently approved for use by the Food and Drug Administration, and are being investigated in a phase III trial before their approval by the European medicines agency (EMA). The tolerance of these drugs seems acceptable, although better for osimertinib, and could be proposed for elderly patients. But just as with the first and second generations of EGFR-TKIs, these molecules have not been specifically assessed in the elderly population. This highlights the question of the diagnosis of the molecular mechanism in relapses in elderly populations. For patients with a driver mutation, identification of the molecular pathway leading to acquired resistance is fundamental in order to adapt treatment. But elderly patients are often vulnerable, and biopsies cannot be performed. Liquid biopsies can overcome this problem. Indeed, in the case of radiologically proved relapse, a blood sample can provide molecular information, thanks to circulating DNA (cDNA). Indeed, cDNA analysis has been proved to be as effective as tissue biopsies to assess the molecular profile of tumours in the overall population.

3.3.2. ALK inhibitors 3.3.2.1. Crizotinib. ALK fusion genes occur in about 5% of non-small-cell lung carcinomas. Crizotinib, an oral TKI, targeting ALK, and also MET and ROS1, demonstrated efficacy after failure of chemotherapy for patients harbouring ALK fusion genes with a response rate of 64% (95% CI, 58e72) versus 20% (95% CI, 14e26; p < 0.001) in chemotherapy arms. Only 14% (n Z 50) of patients included were over 65 years old because the ALK fusion gene was more frequently present in the younger population [57]. Common AEs were visual disorders, gastrointestinal disorders or elevated liver enzymes and mostly grade I or II. grade III or IV AEs were elevated liver enzymes (16%). Data concerning the specific geriatric population was limited, but in first-line, crizotinib had a similar efficacy in both elderly (
65 years) and younger (<65 years) patients, with a response rate of 65% (95% CI, 40.8e84.6) and 60.2% (95% CI, 50.9e68.9), respectively, but only 13 patients were included in the elderly subgroup [58]. With a low toxicity, crizotinib may be a suitable

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treatment for elderly patients with non-small-cell lung carcinoma ALK fusion genes. In case of resistance to crizotinib, ceritinib demonstrated efficacy for patients with ALK-rearranged NSCLC [59]. In this phase I study, no specific data concerning elderly patients was reported, but some older patients were included [22e80] and the tolerance appeared acceptable with notably elevated liver enzymes and diarrhoea. Similar results were described for alectinib in a phase II study (n Z 87) with some older people [29e79] [60]. 3.3.3. Anti VEGF The benefit of adjunction of bevacizumab in combination with chemotherapy in NSCLC adenocarcinoma is debated for elderly populations. The subset analysis of elderly populations in 2 phase III trials showed a benefit for one [61] and no efficacy for the second [62]. These studies included fit elderly patients with an Eastern Cooperative Oncology Group (ECOG) of 0 or 1, adequate bone marrow, hepatic and renal function. The toxicity was more substantial in the elderly group in ECOG-4599 with at least one episode of grade III or worse AEs in 87% of the elderly patients versus 70% in younger patients (<70 years old) treated with bevacizumab (p < 0.001) [62]. This difference was not shown in the standard chemotherapy arms. There was no difference in the AVAIL study [61]. An observational study including 4168 patients
65 years of age treated with chemotherapy and with or without bevacizumab reported no benefit for median OS for elderly patients receiving bevacizumab [63]. In addition, the place of maintenance on bevacizumab needs to be assessed in specific trials in elderly populations. The SAIL study assessed the effect of maintenance in a subset of 623 patients, showing the same efficacy and toxicity profile as younger patients [64]. It is not clear whether bevacizumab offers a survival benefit in the elderly when combined with standard chemotherapy. The benefit-risk ratio should be taken into account before deciding to administer bevacizumab to elderly patients, notably due to the increased toxicity for this population. 3.3.3.1. Bevacizumab.

3.4. Colorectal cancer 3.4.1. Anti-EGFRs Anti-EGFR TT (cetuximab or panitimumab) has demonstrated efficacy in metastatic colorectal cancer (mCRC) for patients harbouring no KRAS or NRAS mutations [65e67]. In these studies, patients
65 years of age represented about 40% of the entire cohort with the same rate in cases of wild type Ras tumours. However, little data concerning very old patients are available with only 8.5% of patients age
75 years and no

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KRAS mutation in the prime study with no benefit of adjunction of panitimumab in this subgroup (HR: 1.34; 95% CI, 0.72e2.50) [65]. Cetuximab was used in two specific geriatric phase II studies in mCRC. Sastre et al. [68] included 41 patients age
70 years. Two patients achieved a complete response and 4 patients had a partial response. None of them presented KRAS mutations. The most common AEs were cutaneous with grade III skin toxicity reported in 12.2% of patients. Asthenia, diarrhoea, nausea and anorexia were serious (grade III or IV) in less than 5%. Sastre et al. [69] reported another geriatric-specific phase II study where 66 patients age
70 were included. These patients received cetuximab and capecitabine. Patients with wild type KRAS tumours presented good efficacy with median PFS and OS of 8.4 and 18.8 months, respectively. The side-effects were acceptable with a majority of cutaneous AEs. Dose reduction of capecitabine allowed a significant decrease in paronychia from 29.6% to 7.7% grade III or more. The serious AEs other than cutaneous were diarrhoea (12.8%), pulmonary embolism (7.7%) and mucositis (2.6%). In these two studies the patients included presented adequate bone marrow, renal and hepatic functions and the presence of one or more criteria of frailty were exclusion criteria. Cetuximab seems to be safe and effective in selected populations. In an observational study of unselected patients, Jehn et al. [70], included 614 patients, 95% of whom received at least one chemotherapy for mCRC. Cetuximab had the same efficacy in younger patients (65 years) as in the elderly (>65 years) with a median PFS of 6.5 and 7 months, respectively [70]. Interestingly, the elderly population presented more comorbidities, in particular cardiovascular diseases. According to the Charlson comorbidity study [71], the two groups presented a statistical difference in terms of comorbidities with 40% and 48% of moderate and severe comorbidity in elderly arms versus 28% and 23% in younger arms, respectively. Although elderly groups harboured more medical disorders, there was no difference for toxicity with the same rate of grade III or IV AEs except for a slight increase in cutaneous AEs in elderly arms (8.8% versus 10.9%). The proportion of non-cutaneous toxicity was similar in each group with 51.6% and 48.4% in the younger and elderly groups, respectively. In a multivariate analysis, only ECOG status had a negative impact on PFS (HR: 0.675, 95% CI, 0.53e0.87; p Z 0.0019). In summary, antiEGFR therapy presents low toxicity in both younger and elderly patients with the same efficacy, and must be proposed for elderly patients without the RAS mutation, even in cases of severe comorbidities. 3.4.2. Anti VEGF Bevacizumab has demonstrated efficacy in mCRC. Cassidy et al. [72], reported the 3.4.2.1. Bevacizumab.

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analysis of four phase II/III clinical trials testing bevacizumab; three in first-line and one in second-line and included over 1,100 patients aged
65 years and 712 aged
75 years. For each age group, the efficacy was in favour of bevacizumab. The median PFS for bevacizumab was similar independently of age with 9.5, 9.3 and 9.2 months for patients <65 years,
65 years and
75 years, respectively. The median OS was similar for the three age groups with a slight increase for younger patients (19.9 and 17.4 months for patients <65 years and
75 years, respectively). Concerning the specific bevacizumab AEs (bleeding, hypertension, proteinuria, arterial thromboembolic events (ATEs), venous thromboembolic events (VTEs), wound-healing complications, fistulae, gastrointestinal perforation and congestive heart failure), only ATEs were increased in the elderly population with 2%, 5.7% and 6.7% for patients <65 years,
65 years and
75 years of age, respectively. However, ATEs and VTEs were greater in elderly than in younger patients in the control and bevacizumab groups. In a phase III study including only patients aged
70 years and considered unable to receive a doublet of chemotherapy, bevacizumab was tested in combination with Capecitabine [73]. Even though patients were not eligible to a doublet of chemotherapy, they were selected on cardiovascular history with no clinically significant cardiovascular disease or history of ATEs or VTEs within the previous 6 months. In this study, including 64% (n Z 179) of patients aged
75 years, bevacizumab demonstrated efficacy in combination with capecitabine versus capecitabine alone, with increased median PFS (median 9.1 versus 5.1 months, HR 0.53, 95% CI, 0.41e0.69; p < 0.0001). These results were confirmed for median OS (20.7 versus; 16.8 months, HR 0.79, 95% CI, 0.57e1.09; p Z 0.18). An additional analysis suggested that the efficacy of bevacizumab was comparable in both age groups. The safety was similar to the other bevacizumab phase III trial with increased specific bevacizumab AEs notably with increased ATE’s even in this selected older patient group. Hypertension arterial (HTA) was observed in 19% but serious (grade
III) in only 2% versus 1% in the capecitabine arm. This result was confirmed by a large observational study, with no exclusion criteria, including patients treated with bevacizumab in first-line for mCRC. In the subgroup analysis of 896 patients aged
65 years, Kozloff et al. [74], reported a less aggressive chemotherapy regime in combination with bevacizumab and more patients with poor, altered ECOG (
2) in the older population (4.9%, 13.4% and 11.8% for patients 65 years, 75e80 years and
80 years of age, respectively). Median PFS was similar in all age subgroups and median OS decreased with age, but elderly patients received less second-line treatment after first-line progression

compared to the younger population. ATEs were the only AEs increased in elderly patients although elderly patients presented more HTA and history of arterial disease. These results encourage the use of bevacizumab for elderly patients presenting mCRC with few cardiac disorders. Regorafenib. Regorafenib, a TKI targeting VEGF-R, demonstrated efficacy after failure of standard treatment versus best supportive care [75]. In this study, 37.5% of patients were aged
65 years, and all patients were ECOG 0 or 1. The efficacy of regorafenib was less substantial in elderly than in younger people. Due to the little data available regarding regorafenib in the elderly population and the low proportion of elderly patients with ECOG 0 or 1 after multiple treatments for mCRC, this drug should be used with caution in an elderly population. 3.4.2.2.

3.5. Gastrointestinal stroma tumour 3.5.1. KIT inhibitor Imatinib mesylate, a tyrosine kinase inhibiting KIT, PDGFR, ABL and BCR-ABL, demonstrated efficacy for GIST in adjuvant [76,77] and metastatic settings with increased survival. In an adjuvant setting, the efficacy of three years of imatinib treatment seemed similar between patients under 65 years and those older, with similar HR for recurrence-free survival at 0.47 and 0.49, respectively [76]. Regarding the metastatic setting, all patients over 70 years of age were included [78] but D’Ambrosio et al. [79], analysed the experience of 23 consecutive patients
75 years affected by GIST and treated with imatinib with good efficacy. In an elderly population, tolerance seems similar to that in a younger population with oedema, rash, anaemia and ocular disorders as serious AEs (grade III or more). These results were similar in cases of use of imatinib for chronic myeloid leukaemia, with increased toxicity in elderly people (
65 years) only for anaemia, oedema and dermatological toxicities [80]. Even though little data regarding elderly patients treated for GIST with imatinib is available, due to its low toxicity, imatinib can probably be used in this setting. 3.6. Breast cancer 3.6.1. HER2-positive breast cancer Twelve percent of elderly patients with breast cancer present an over-expression of HER2 [81]. Little data is available regarding the efficacy or specific toxicity of anti-HER2 drugs in an elderly population. The main concern with anti-HER2 treatment is cardiac toxicity. This cardiac toxicity is in most cases reversible when treatment is stopped.

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3.6.1.1. Monoclonal antibodies 3.6.1.1.1. Trastuzumab. Trastuzumab is a monoclonal

antibody that has shown efficacy in advanced [82] and early HER2-positive breast cancer [83e87]. In an adjuvant setting, various studies have shown that elderly patients were less likely to receive trastuzumab [88] or to receive a standard chemotherapy in combination with trastuzumab [89], or to continue treatment for the recommended duration of one year [90]. Age and comorbidities were among factors that were associated with treatment completion, and rates of significant cardiac events were higher in those who did not complete therapy. Regarding cardiac toxicity, a retrospective study was conducted on 9,535 patients over 66 years of age treated with adjuvant chemotherapy, of whom 23.1% received trastuzumab. Trastuzumab users were more likely to develop cardiac heart failure than nontrastuzumab users (29.4% versus 18.9%). Among trastuzumab-treated patients, greater age, coronary heart disease and weekly trastuzumab administration increased the risk of cardiac heart failure [91]. The rates of cardiac heart failure are higher in this study than in randomised clinical trials either in the metastatic or adjuvant/neoadjuvant setting: in the pivotal trials, rates of cardiac toxicity vary from 0.5% [83] in the adjuvant setting to 27% in the metastatic setting (in the arm containing anthracyclines and trastuzumab) [82]. 3.6.1.1.2. Pertuzumab. Pertuzumab is also a monoclonal anti-HER2 antibody targeting another subdomain of the receptor involved in the dimerisation of HER2 with HER3. It has been approved for advanced and early HER2-positive breast cancer after positive randomised phase III studies [92,93]. In the metastatic setting, a recent subgroup analysis from the CLEOPATRA study was carried out: 127 patients (out of the 808 patients included in the study) were 65 years of age or older (placebo arm: 67, pertuzumab arm: 60). Patients in both age groups experienced PFS benefit with treatment in the pertuzumab arm. Diarrhoea, fatigue, asthenia, decreased appetite, vomiting, and dysgeusia were reported more frequently in patients
65 years of age compared with younger patients. Neutropenia and febrile neutropenia were reported less frequently in the elderly group. No additional cardiac toxicity was reported in the elderly subgroup [94]. There is no specific data about elderly patients in the neoadjuvant setting. 3.6.1.2. Tyrosine kinase inhibitors 3.6.1.2.1. Lapatinib. Lapatinib is a TKI directed

against HER2 and EGFR. This drug has shown efficacy in the metastatic setting in trastuzumab-resistant HER2positive breast cancer [95] and in early settings in combination with trastuzumab [96e100]. Little data is available on the specific efficacy or toxicity of lapatinib in elderly patients. Most common toxicities are diarrhoeas and skin rash. Grade III diarrhoeas were more

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frequent in elderly patients than in younger patients [101]. The consequences of severe diarrhoea can also be expected to be more disabling in elderly patients. 3.6.1.3. Antibody drug conjugate 3.6.1.3.1 TDM-1. TDM-1

(ado trastuzumabemtansine) is an antibodyedrug conjugate consisting of the monoclonal antibody trastuzumab linked to the cytotoxic agent mertansine. After having targeted HER2overexpressing cells, the drug enters cells and destroys them by binding to tubulin. The pivotal study in the metastatic setting (EMILIA) showed, for patients resistant to trastuzumab and taxanes, that TDM-1 significantly prolonged PFS and OS with limited toxicity (thrombocytopaenia, increased serum aminotransferase levels) [102]. There is no specific study on elderly patients with TDM-1, but the EMILIA study included patients up to 84 years old. The benefit of TDM-1 existed in both >65 and <65-years old, even if it was higher in the younger subgroup. According to the targeted delivery of the cytotoxic drug, TDM-1 is expected to be well tolerated in elderly patients. In another phase III trial, TH3RESA, assessing TDM-1 in HER2-positive breast cancer treated with two or more HER2-directed regimens in the advanced setting, the benefit of TDM-1 was consistent across subgroups defined by age [103]. 3.6.2. M-TOR inhibitor For postmenopausal women with advanced oestrogen receptorepositive HER2-negative breast cancer recurring or progressing during or after treatment with nonsteroidal aromatase inhibitors, everolimus in addition to exemestane has been shown to improve PFS as compared to exemestane alone [104]. The addition of everolimus improved PFS regardless of age. Specific toxicity of everolimus included stomatitis, infections, rash, pneumonitis and hyperglycaemia. Elderly patients had similar incidence of these AEs as did younger patients but had more on-treatment deaths [105].

3.7. Ovarian cancer 3.7.1. Anti VEGF Bevacizumab plus chemotherapy improved median PFS in ovarian cancer in several settings versus chemotherapy alone. In the adjuvant setting [106], the HR for median PFS seems similarly in favour of bevacizumab for patients
70 years of age versus <60 years with 0.82 and 0.84 respectively, but the elderly population was small (n Z 150, 9.8%). For patients previously untreated, and with incompletely resectable stage III or any stage IV, the HR of median PFS was in favour of the arms treated with chemotherapy and bevacizumab independently of age (<60 years HR: 0.680, n Z 630, 33.6%;
70 years HR: 0.678, n Z 210, 11.2%) [107]. In the recurrent setting, adjunction of bevacizumab to chemotherapy increased median PFS. This benefit was

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Table 1 Main adverse events with targeted therapy and the adverse events more frequent in older population. Family of targeted therapy

Type of tumours

Principal AEs

Principal serious AEs

AEs increased in older people

Anti-angiogenic Sunitinib [7e11]

Renal

Diarrhoea, nausea, stomatitis, vomiting, hypertension, hand and foot syndrome, rash, leucopoenia, anaemia, thrombocytopaenia, hypothyroidism Hypertension, diarrhoea, fatigue, nausea, anorexia, constipation, vomiting, cough, rash, hand and foot syndrome, anaemia, Diarrhoea, hypertension, nausea, vomiting, anorexia, fatigue, asthenia, elevated enzymatic liver, leucopenia, anaemia, thrombocytopaenia, hyperglycaemia, hand and foot syndrome, dysgueusia, hand and foot syndrome, rash, constipation Diarrhoea, hypertension, weight decrease, fatigue, anorexia, hand and foot syndrome, dysphonia, hypothyroidism, nausea, rash, anaemia, thrombocytopaenia, constipation Diarrhoea, fatigue, nausea, decreased appetite, palmar-plantar erythrodyesesthesia syndrome, hypertension, vomiting, weight decreased, constipation, dysgeusia, stomatitis, hypothyroidism, dysphonia, mucosal inflammation, asthenia, dyspnoea Fatigue, asthenia, hypertension, proteinuria, bleeding, anorexia, diarrhoea, headache,

Hypertension, fatigue, diarrhoea, vomiting, hand and foot syndrome, nausea, neutropenia, hypothyroidism, cough

Fatigue, cough, peripheral oedema, anaemia, decreased appetite, thrombocytopaenia

Hypertension, anaemia, fatigue, constipation,

Anorexia, fatigue

Sorafenib [15e17]

Renal

Pazopanib [18e20]

Renal

Axitinib [22,23]

Renal

Cabozantinib [28]

Renal

Bevacizumab [24e26, 61e64,73,74, 106e109]

Renal, colon, Lung, ovarian

Regorafenib [75]

Colon

Fatigue, hand and foot syndrome, diarrhoea, anorexia, dysphonia, hypertension, rash, oral mucositis, thrombocytopaenia

Fatigue, hand and foot syndrome, diarrhoea, hypertension, rash

Renal, Breast

Stomatitis, Rash, Fatigue, diarrhoea, Anorexia, nausea, vomiting, cough, Hypercholesterolaemia, anaemia, hyperglycaemia, peripheral oedema, creatinine increased, dysgeusia, infection Asthenia, rash, anaemia, nausea, anorexia, dyspnoea, hyperlipidaemia, infection, diarrhoea, cough, peripheral oedema, hyperglycaemia, cough, stomatitis, infection

Anaemia, hyperglycaemia, Stomatitis, fatigue, pneumonitis

M-TOR inhibitor Everolimus [31,32,104,105]

Temsirolimus [30]

Renal

Diarrhoea, hypertension, anorexia, vomiting, asthenia, elevated enzymatic liver, hand and foot syndrome

Diarrhoea, hypertension, weight decrease, fatigue, anorexia, hand and foot syndrome

Diarrhoea, fatigue, hypertension, nausea, palmar-plantar erythrodyesesthesia syndrome

Fatigue, hypertension, bleeding, anorexia, arterial thromboembolic event, gastrointestinal perforation

Venous thrombus events, Thrombocytopaenia, Bleeding, ATE’s, gastrointestinal perforation

Cough, fatigue, peripheral oedema, diarrhoea, creatinine increased, dysgeusia

Asthenia, anaemia, dyspnoea, hyperglycaemia,

B-RAF inhibitor Vemurafenib [34e36]

Melanoma

Fatigue, rash, arthralgia, cutaneous squamous cell carcinoma, nausea, keratoacanthoma

Rash, cutaneous squamous cell carcinoma, keratoacanthoma, elevated enzymatic liver

MEK inhibitor Dabrafenib [37]

Melanoma

Hyperkeratosis, squamous cell carcinoma, keratoacanthoma, arthralgia, pyrexia, fatigue

Hyperkeratosis, squamous cell carcinoma, keratoacanthoma

Cutaneous squamous cell carcinoma, kerathoacanthoma, QT prologation

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Table 1 (continued ) Family of targeted therapy

Type of tumours

Principal AEs

Combination MEK and B-RAF inhibitor Vemurafenib and Melanoma Diarrhoea, nausea, vomiting, rash, cobimetinib [40] photosensitivity reaction, fatigue, pyrexia, arthralgia, hyperkeratosis, elevated enzymatic liver Trametinib and Melanoma Pyrexia, chills, fatigue, rash, dabrafenib [38,39] nausea, headache, diarrhoea, arthralgia, elevated enzymatic liver, peripheral oedema Anti-EGFR Gefitinib [43,49e53] Lung Rash, diarrhoea, anorexia, elevated enzymatic liver, pruritus, stomatitis, nausea, anorexia, paronyhia, vomiting, constipation Erlotinib [42,45e48] Lung Fatigue, rash, diarrhoea, anaemia, arthralgia, alopecia Afatinib [55]

Lung

AZD9291a [56]

Lung

Cetuximab [66e69]

Colon

Panitimumab [65]

Colon

Diarrhoea, rash and acne, stomatisis or mucositis, paronychia, decreased appetite, pruritis, nausea, fatigue Diarrhoea, rash and acne, nausea, decreased appetite, dry skin, pruritus Diarrhoea, rash, dermatisis acne form, hypomagnesaemia Skin toxicity, diarrhoea, mucositis, panonychia,

Principal serious AEs

Diarrhoea, rash, fatigue, elevated enzymatic liver, cutaneous squamous cell carcinoma, decreased ejection fraction Pyrexia, elevated enzymatic liver, cutaneaous squamous cell carcinoma, ejection fraction decreased Diarrhoea, rash, anorexia

Anaemia, increased enzymatic liver

Rash, diarrhoea, fatigue, anorexia

Rash, fatigue, stomatitis, dehydratation, anorexia, elevated enzymatic liver

Rash and acne, diarrhoea, stomatisis or mucositis

Diarrhoea, rash and acne

Skin toxicity, diarrhoea

Lung

Ceritiniba [59]

Lung

Alectiniba [60]

Lung

Kit inhibitor Imatinib [76e80]

GIST

Fatigue, diarrhoea, nausea, oedema, anaemia, rash

Anaemia, diarrhoea

Anti-HER2 Trastuzumab [82e88]

Breast, gastric

Cardiac, fatigue, asthenia, decreased appetite, vomiting, nausea, diarrhoea, dysgeusia, pain, fever, skin rash, neutropenia, infection Cardiac, diarrhoea, fatigue, asthenia, decreased appetite, vomiting, dysgeusia

Diarrhoea, fatigue, asthenia, decreased appetite, vomiting, nausea

Pertuzumab [92e94]

Breast

Lapatinib [95e100]

Breast

TDM-1 [102,103]

Breast

Diarrhoea, skin toxicity, nausea, vomiting, anorexia, epistaxis, cough, dyspnoea, pain, asthenia Diarrhoea, vomiting, nausea, fatigue, anaemia, thrombocytopaenia, elevated liver enzymes

AE Z adverse events, ATE Z arterial thromboembolic events. a Not phase III study.

No difference

Skin toxicity, diarrhoea

ALK inhibitor Crizotinib [57,58]

Visual disorders, diarrhoea, nausea, constipation, elevated liver enzymes, oedema, fatigue, dysgeusia Elevated liver enzymes, diarrhoea, vomiting Constipation, fatigue, myalgia, peripheral oedema

AEs increased in older people

Elevated liver enzymes

Elevated liver enzymes, increased lipase levels Elevated creatine phosphokinase, elevated liver enzymes

Febrile neutropenia, diarrhoea

Diarrhoea, nausea, vomiting, skin toxicity, fatigue Thrombocytopaenia, elevated liver enzymes

Anaemia, oedema, rash, occular disorders

Diarrhoea, fatigue, asthenia, decreased appetite, vomiting, dysgeusia

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Table 2 Major drugs suspected of potential drug interaction with targeted agents. Cytochromes P450

Substrates

Inhibitors

Inducers

CYP 1A2

Anti migraine: amitriptyline; Anti emetics: ondansetron Anti arrhythmic: propranolol

Antibiotics: ciprofloxacin, Enixacine Antidepressant: fluvoxamine

Alcohol, tobacco, broccoli, brussel sprouts PPI’s: omeprazole St John’s Wort

CYP 2C8 CYP 2C9

CYP 2C19 CYP 2D6

CYP 3A4

Anticoagulant warfarin Oral Hypoglycemic Agents: tolbutamide1, glipizide Angiotensin II blockers: iosartan, irbesartan NSAIDs: diclofenac1, ibuprofen, lornoxicam,meloxicam PPIs: esomeprazole, lansoprazole, omeprazole, pantoprazole Hormonotherapy: tamoxifen Antidepressants: amitriptyline, clomipramine, desipramine, fluoxetine, imipramine, paroxetine Antipsychotics: haloperidol Antalgic: oxycodone, tramadol Immune modulators: cyclosporine, tacrolimus anti-arrhythmics: quinidine Calcium channel blockers: felodipine, lercanidipine, verapamil HMG CoA reductase inhibitors: atorvastatin, cerivastatin, lovastatin Benzodiazepines: alprazolam, diazepam, midazolam

Hypolipidemia: gemfibrozil Angiotensin II Blockers Losartan, Irbesartan Fluconazole

Antidepressants: fluoxetine, paroxetine, Anti-arrhythmics: quinidine Antipsychotic: thioridazine

(Hypericum perforatum)

Grapefruit juice, Anti arrhythmic: amiodarone, dysopyramide calcium channel blockers diltiazem, verapamil, amlodipine, antifungal: ketoconazole, itraconazole, voriconazole, posaconzole, fluconazole, miconazole, Anti infectionritonavir, nelfinavir, amprenavir, indinavir, atazanavir, Macrolide erythromycin, clarithromicine, josamycine, telithromycine

Carbamazepine, phenobarbital, phenytoine, rifampycine, rifabutine, efavirenz, nevirapine, griseofulvine

Abbreviations: CYP cytochrome P450, PPI’s: Proton pump inhibitors, NSAIDs: non-steroidal anti-inflammatory drug.

similar in analysis of subgroups according to age (<65 and
65 years) [108,109]. In the various studies, the use of bevacizumab showed a common related toxicity (bleeding, hypertension, gastrointestinal perforation, proteinuria, arterial thromboembolic event). To our knowledge, no data regarding age and toxicity with bevacizumab has been described for ovarian cancer, but in the elderly population, bevacizumab must be used with caution, mainly due to the frequency of cardiovascular events in this population.

4. Conclusion The elderly population is heterogeneous and, according to the study by Balducci and Extermann [6] , can be divided into three groups: fit, vulnerable and frail. This classification was designed for the areas of cytotoxic chemotherapy and local treatment [110] but could be applied in the area of TT because it relates to the ability of older people to adapt to stress. For vulnerable elderly people, geriatric intervention can help a patient to receive standard treatment. Some studies looked for predictive factors of toxicity for standard chemotherapy in the elderly population [111,112]. Recently, Corre et al. [113], described the use

of CGA to help physicians having elderly patients with NSCLC, and demonstrated that in CGA arms, patients presented the same outcome as standard arms but received less chemotherapy and more best supportive care. Also that in CGA arms, patients presented less toxicity than standard arms 85.6% versus 93.4%, respectively (p Z 0.015). However, these studies do not include TT. It is unclear whether the same tool was used for TT due to the specific AEs with the off target effect. TT seems attractive with less general toxicity than chemotherapy, but each TT has specific AEs and their predictive factors need to be recognised (Table 1). For example, Kozloff et al. [74], reported baseline ECOG PS, HTA requiring medication, anticoagulation therapy and arterial disease as significant risk factors for ATE’s in elderly patients treated with bevacizumab. Consequently, elderly people with these ATE risk factors were not the best candidates to receive bevazicumab. In real life, increased ageing and comorbidity was associated with cardiotoxicity (stroke, congestive heart failure and cardiomyopathy) for people treated with sunitinib or sorafenib for mRCC [12]. This observational study assessed the risk of cardiovascular events in an elderly population treated with anti VEGF-R TKI and demonstrated the increased of risk of stroke for patients >65 years (nearly 3-fold). However, specific AEs have

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been relatively common for TT and cause decompensation in other diseases because in elderly people, each disease can affect another one. This includes AEs which have no consequences for young people, but this is not the case for an elderly patient with decompensation of another illness. For example, an elderly person with hand and foot syndrome or cutaneous toxicity, quickly presents decreased mobility or grip trouble, general, eating or hydration disorders, notably if problems regarding mobility were present before instauration of TT. As defined by the common terminology criteria for AEs, the same AEs do not have the same consequences in younger and older patients. For example, grade II diarrhoea with 4e6 stools per day does not have the same results in a younger person without comorbidity, but could decrease mobility and therefore the general status of an elderly person. A novel approach regarding grading of toxicity could be proposed for elderly patients in clinical trials. The aim of TT management in an older population is to decrease serious AEs, but also all grades of AE. Because of their numerous comorbidities, elderly people are often exposed to a combination of a large number of drugs [114]. This exposes them to drug interactions, especially with the TKI family, eliminated via the CYP 450. This cytochrome was found to be involved in the elimination of numbers of other drugs. The other drugs can be induced or inhibited by CYP 450. They can have the same cytochrome as the TT and thus decrease the metabolism of each treatment (Table 2). These drug interactions expose patients to a risk of increased toxicity or decreased efficacy of TT, but also to loss of efficacy of their usual medications. The management of some AEs was more complicated with concomitant therapy. For example, a patient presenting a bleeding episode due to TT, will likely have increased episodes if they are taking anticoagulants, frequently used in the elderly population. The similar efficacy but slightly increased toxicity between elderly and younger populations could lead to an elevated concentration of drugs for elderly people. The decline of renal and hepatic function for elderly patients may explain this increase in drug concentration. The interactions of TT with several other drugs could modify the concentrations too. Therapeutic drug monitoring in patients receiving TKI is uncommon for the majority of TT. Application of therapeutic drug monitoring may be reserved for some TTs and particular situations including severe toxicity, drugedrug interaction. Biological monitoring of the pharmacokinetics of TT in elderly groups could help to find the appropriate drug dose and therefore decrease toxicity with similar efficacy, and finally, optimise adherence to the treatment. However, this therapeutic drug monitoring needs to be corroborated in a larger study [115].

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Strict surveillance with a nurse telephoning the patient to detect early drug toxicities could be proposed for elderly patients treated with TT. The aim being to propose an adaptation of concomitant treatments, or a decrease, or temporary interruption of TT as soon as toxicity occurs, but this also needs to be assessed in terms of cost-benefit. To our knowledge, data concerning safety and toxicity of TT in older people is limited and most of it is from subgroup analysis of pivotal trials. Older people included in clinical trials are not representative of the entire cohort of older people with cancer and thus the results cannot be generalised for all geriatric cancer patients. Specific clinical trials for the elderly population, both fit and frail, need to be developed. Because of drug interaction and hepatic or renal dysfunction, pharmacokinetic data is necessary for better management of this new therapy for elderly people. Although the majority of TTs can be proposed for elderly patients, strict monitoring is necessary, especially in the case of numerous comorbidities. No data concerning a tool for predictive toxicity for elderly people treated with TT exists, unlike that for cytotoxic chemotherapy. A better understanding of the predictive factors for response or toxicity is required in order to better select patients eligible for TT. Conflict of interest statement Gross-goupil have consulting fees or honorarium from Pfizer, Novartis and MSD, Ravaud is member of Hlobal, European and/or French advisory board in RCC for Pfizer, Novartis, BMS, received institutional grant support by Pfizer and Novartis and housing and travelling support for meeting by Pfizer, Novartis and BMS. Pierre Soubeyran have honoraria from Spectrum Pharmaceuticals, Pierre Fabre, Consulting or Advisory Role from Teva Pharmaceutical Industries, CELGENE, Research Funding from Roche and Travel, Accommodations, Expenses: Teva Pharmaceutical Industries, Celgene, Hospira The other authors declare that they have no conflicts of interest.

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