Targeted anti-cancer therapy in the elderly

Critical Reviews in Oncology/Hematology 78 (2011) 227–242

Targeted anti-cancer therapy in the elderly Wilson Gonsalves a , Apar Kishor Ganti b,c,∗ a Department of Internal Medicine, Creighton University Medical Center, Omaha, NE, United States Section of Oncology-Hematology, Department of Internal Medicine, VA Medical Center, Omaha, NE, United States Section of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States b

c

Accepted 8 June 2010

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tyrosine kinase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Erlotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Non-small cell lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Pancreatic cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Sorafenib. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Renal cell carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Hepatocellular carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Sunitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Renal cell carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Gastrointestinal stromal tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Lapatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1. Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Imatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.1. Chronic myeloid leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.2. Gastrointestinal stromal tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Dasatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.1. Chronic myeloid leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.2. Acute lymphoid leukemia with Philadelphia chromosome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Monoclonal antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Non-small cell lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Colon cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4. Renal cell carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.5. Glioblastoma multiforme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Cetuximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Colon cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Head and neck cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Panitumumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Colon cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Trastuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: Department of Internal Medicine, 987680 Nebraska Medical Center, Omaha, NE 68198-7680, United States. Tel.: +1 402 559 6210; fax: +1 402 559 6520. E-mail address: [email protected] (A.K. Ganti).

1040-8428/$ – see front matter. Published by Elsevier Ireland Ltd. doi:10.1016/j.critrevonc.2010.06.001

228 228 228 230 231 231 231 231 232 232 232 232 232 232 232 233 233 233 233 233 233 233 234 234 234 234 234 235 235 235 235 236 236

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3.5.

4.

5.

Rituximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1. Non-Hodgkin’s lymphoma (diffuse large B-cell) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Ibritumomab tiuxetan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.1. Non-Hodgkin’s lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Tositumomab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.1. Non-Hodgkin’s lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Bortezomib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Multiple myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Mantle cell lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Thalidomide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1. Multiple myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Lenalidomide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1. Multiple myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2. Myelodysplastic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

236 236 236 237 237 237 237 237 237 237 238 238 238 238 239 239 239 239 239 242

Abstract Cancer is a disease of the elderly with the majority of new diagnoses and deaths from cancer occurring in persons greater than 65 years of age. A major goal of cancer therapy, in the elderly is the preservation of functional independence and quality of life. The advent of targeted therapies has raised the hope that older patients with cancer could be treated as effectively as younger patients and without added toxicities. However, caution must be exercised while addressing the use of these therapies in the elderly population and only after taking into consideration the risks, benefits and prognosis of patients on an individual basis. This article reviews the current literature on the efficacy, cost-effectiveness and toxicity of the currently approved targeted agents in the elderly population. Published by Elsevier Ireland Ltd. Keywords: Elderly; Targeted therapy; Small molecule inhibitors; Monoclonal antibodies

1. Introduction Approximately 60% of all new cases of cancer and 70% of all cancer-related deaths occur in the elderly population (≥65 years) [1]. Old age is associated with a progressive decline in the functional status and reserve of organ systems [2]. This process tends to compromise the tolerance of stress on one’s body and makes it hard for elderly patients to tolerate traditional cytotoxic chemotherapy [2–4]. In addition to treating the cancer and prolonging survival, a major goal of cancer therapy, especially in the elderly is the preservation of functional independence and quality of life. Such functional independence has been shown to be compromised by fatigue which has been a major complaint after administration of most traditional cytotoxic chemotherapy treatments [5,6]. Advances in the knowledge of the molecular pathogenesis of cancer have led to the development of targeted therapies that interfere with specific pathways required for tumor development and growth [7–9]. It is widely believed that targeted agents provide effective and less toxic therapy while at the same time allowing patients maintain their functional independence. Their use in the elderly patients has been embraced with great hope and growing interest. This manuscript pro-

vides a review of the existing literature on the effects of targeted therapies in the elderly population with emphasis on outcomes and side effect profiles compared to their younger counterparts and also on the cost-effectiveness of these therapies (Table 1).

2. Tyrosine kinase inhibitors 2.1. Erlotinib Erlotinib is a small molecule tyrosine kinase inhibitor (TKI) targeting the human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) pathway. It prevents the intracellular phosphorylation of tyrosine kinase associated with the EGFR. It undergoes hepatic metabolism primarily by P450 CYP3A4 as well as CYP1A2 and CYP1A1. It is mainly secreted via the gut (83%) and partly by the kidneys (8%) [10]. It is currently approved for the second-line treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen and for the first-line treatment in locally advanced, metastatic or unresectable pancreatic cancer in combination with gemcitabine.

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229

Table 1 Comparison of efficacy and toxicity of various targeted therapies between younger and older patients. Study

Primary tumor site

No. of elderly patients

Efficacy compared to young

Toxicity compared to young

Erlotinib Wheatley-Price et al. [12]

Lung

163 (≥70 years)

Same OS

Greater grade ≥3 toxicities, especially rash, fatigue, stomatitis and dehydration, but quality of life effects were the same

Sorafenib Eisen et al. [21]

Kidney

115 (≥70 years)

Age did not affect PFS

Bukowski et al. [22]

Kidney

1135 (≥65 years)

Same ORR

Cheng et al. [25]

Liver

32 (≥65 years)

Similar hazard ratio (but not significant in the elderly)

Greater grade 3 toxicities; increased discontinuation of therapy in elderly Similar rates of clinically manageable grade 2 and grade ≥3 adverse events Not assessed

Sunitinib Gore et al. [30]

Kidney

N/A

Same PFS and ORR

Similar incidence of grade 3–4 non-hematological toxicity; fatigue was more common in the elderly

Lapatinib Geyer et al. [34]

Breast

28 (≥65 years)

N/A

Same

Imatinib Bassi et al. [38]

CML

58 (≥65 years)

Lower RR, but same OS

More hematologic and non-hematologic toxicity

Bevacizumab Ramalingam et al. [46]

Lung

224 (≥70 years)

Greater

Kabbinavar et al. [49]

Colon

439 (≥65 years)

Elderly patients had no improvement in OS compared to chemotherapy alone NR

Kozloff et al. [50]

Colon

896 (≥65 years)

Same 1 year survival and PFS

Bajetta et al. [55]

Kidney

240 (≥65 years)

Similar improvement in PFS

Nghiemphu et al. [56]

Glioblastoma

N/A (age cut-off of ≥55 years)

Scappaticci et al. [57]

All

618 (≥65 years)

Significantly better PFS and OS N/A

Cetuximab Bouchahda et al. [60]

Colon

67 (≥70 years)

Sastre et al. [61]

Colon

41 (≥70 years)

Vermorken et al. [65]

Head/neck

77 (≥65 years)

Trastuzumab Brunello et al. [77]

Breast – metastatic

50 (≥70 years)

Greater side effects compared to chemotherapy alone Increased arterial thromboembolic events in patients ≥75 Increased grade 3 or higher toxicities; mainly asthenia/fatigue N/A Greater arterial thromboembolic events when given with chemotherapy

Comparable to historical data on younger patients Comparable to historical data on younger patients Worse OS and PFS

Comparable to historical data on younger patients Comparable to historical data on younger patients N/A

Response rate and time to progression for elderly patients comparable to historical data

Toxicity was not associated with age

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Table 1 (Continued) Study

Primary tumor site

No. of elderly patients

Efficacy compared to young

Toxicity compared to young

Fyfe et al. [78]

Breast

109 (≥60 years)

Addition of trastuzumab improved response rate and survival

Cardiac toxicity greater in older patients

Ibritumomab tiuxetan Emmanouilides et al. [84]

NHL

98 (≥60 years)

Similar response rates and duration

Similar incidence of hematologic and non-hematologic toxicities

Tositumomab Gregory et al. [86]

Low grade NHL

409 (≥60 years)

Response rates and durations better in younger patients

Similar overall and acute hematologic toxicity

Panitumumab Van Cutsem et al. [67]

Colon

158 (≥65 years)

Douillard et al. [69]

Colon

262 (≥65 years

Effects were not associated with age No clear efficacy benefit

Tolerability was not associated with age Comparable toxicities between the two groups

Bortezomib Richardson et al. [89]

Multiple myeloma

243 (≥65 years)

NR

Patients ≥ 65 years increased diarrhea, nausea, constipation, fatigue, peripheral neuropathy, thrombocytopenia

Thalidomide Rajkumar et al. [93]

Multiple myeloma

NR

DVT greater in the elderly, but not statistically significant

Lenalidomide Reece et al. [97]

Multiple myeloma

Comparable response rates, PFS and OS

More elderly patients discontinued treatment due to toxicity

24 (≥65 years)

2.1.1. Non-small cell lung cancer Erlotinib was approved by the FDA in 2004 after the NCIC BR.21 trial demonstrated that it improved survival in patients with advanced NSCLC who had failed prior chemotherapy by approximately 2 months as compared to placebo [11]. A subgroup analysis of the elderly patients enrolled in the BR.21 trial [12], found no significant difference in survival between elderly and young patients randomly assigned to placebo (HR = 0.81; 95% CI: 0.57–1.14; P = 0.22) or to erlotinib (HR = 1.02; 95% CI: 0.81–1.30; P = 0.85). Also, progression-free survival was significantly better in both the elderly and young populations who received erlotinib (elderly: 3.0 months vs. 2.1 months, P = 0.009; young: 2.1 months vs. 1.8 months, P < 0.001). However, elderly patients on erlotinib suffered more grade ≥3 toxicities (35% vs. 18%), especially rash (16% vs. 6%, P = 0.003), fatigue (7% vs. 2%, P = 0.005), stomatitis (3% vs. <1%, P = 0.04) and dehydration (4% vs. <1%, P = 0.03). The mean relative dose intensity (DI) in the elderly group was significantly lower than in younger patients (88% vs. 93%, P = 0.0012). Elderly patients were significantly less likely to have a DI of more than 90% (64% vs. 82%, P < 0.001) and more likely to receive <80% of the total planned dose (29% vs. 14%, P < 0.001). Pro-

longed dose interruptions were more common in the elderly group (35% vs. 18%, P < 0.001) and the elderly patients were more likely to discontinue the drug as a result of treatment-related adverse events (12% vs. 3%, P = 0.003). However, quality of life (QOL) benefits were similar in elderly and young patients in terms of cough, dyspnea and pain. Another study looking at the effects of erlotinib in the elderly was conducted by Jackman et al. [13] that looked at 82 patients >70 years with advanced NSCLC (phase II study). The median time to progression (TTP) was 3.5 months (95% CI: 2.0–5.5 months). The median survival time was 10.9 months (95% CI: 7.8–14.6 months). The 1- and 2-year survival rates were 46% and 19%, respectively. The most common toxicities were acneiform rash (79%) and diarrhea (69%). Four patients developed interstitial lung disease of grade 3 or higher, with one treatment-related death. Molecular analysis in NSCLC has become important before initiating erlotinib therapy because in the phase III TRIBUTE trial, mutations in exons 18 through 21 of the tyrosine kinase domain of EGFR have shown to predict a greater likelihood of response to erlotinib [14]. Whereas the mutations in codons 12 and 13 in exon 2 of the K-RAS gene in

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NSCLC have showed poorer clinical outcomes when treated with erlotinib and chemotherapy [15]. A cost–utility analysis found that the quality-adjusted life years (QALYs) were slightly greater for erlotinib versus docetaxel and pemetrexed by only 2% and 1% respectively [16]. Hence, in molecularly favorable NSCLC, erlotinib is a cost effective treatment that provides similar survival benefit in the elderly as that in younger patients with a mild increase in toxicities. 2.1.2. Pancreatic cancer In 2005, the FDA approved erlotinib to be used along with gemcitabine for the treatment of locally advanced, unresectable or metastatic pancreatic cancer. This approval was based on a phase III NCIC trial that demonstrated an improved overall survival with a combination of erlotinib and gemcitabine versus gemcitabine alone (6.24 months vs. 5.91 months, HR = 0.82; 95% CI: 0.69–0.99; P = 0.038) [17]. Progression-free survival was also significantly longer with an estimated erlotinib/gemcitabine arm (3.75 months vs. 3.55 months, HR = 0.77; 95% CI: 0.64–0.92; P = 0.004). However, patients receiving erlotinib and gemcitabine experienced higher frequencies of rash, diarrhea, infection and stomatitis but these were generally grade 1 or 2. Subset analysis of the elderly assessing the efficacy and treatment toxicities are lacking to date. The incremental cost-effectiveness ratio of adding erlotinib to gemcitabine was $410,000 per year of life saved which is far above the commonly accepted cost-effectiveness threshold of $50,000 to $100,000 per QALY [18]. Thus although erlotinib in pancreatic cancer is not well studied in the elderly, it provides only minimal survival benefit even in the general population and moreover is not cost effective. 2.2. Sorafenib Sorafenib is an oral, novel multi-kinase inhibitor that is currently approved for advanced renal cell carcinoma and advanced hepatocellular carcinoma. It targets the MAPK pathway at the level of raf kinase and induces tumor cell apoptosis. It also potently inhibits vascular endothelial growth factor receptor VEGFR-1, VEGFR-2, VEGFR-3 and platelet derived growth factor (PDGFR) beta tyrosine kinase autophosphorylation [19]. It undergoes hepatic metabolism primarily via CYP3A4 and UGT1A9. It is mainly secreted via the gut (75%) and partly by the kidneys (20%). It is currently approved for the first-line treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma. 2.2.1. Renal cell carcinoma Sorafenib was approved in 2005 after the phase III randomized, double-blinded TARGET study demonstrated that sorafenib prolonged progression-free survival in patients with advanced, relapsed clear cell renal cell carcinoma com-

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pared to placebo (24 weeks vs. 12 weeks) [20]. A subset analysis of this study comparing outcomes between younger (<70) and older (>70) patients [21] showed that the difference in response rate between sorafenib and placebo was lower for younger patients than for older patients (8.7% vs. 15.7%). This would suggest a larger benefit with sorafenib for the elderly. However, since the elderly patients comprised of a substantially smaller proportion of patients, this difference was not statistically significant. Progression-free survival among sorafenib treated patients was approximately double that observed in placebo treated patients, regardless of age (26.3 weeks in older patients; HR = 0.43; 95% CI: 0.26–0.69 and 23.9 weeks in younger patients; HR = 0.55; 95% CI: 0.47–0.66). The overall incidence of all adverse events in the sorafenib group was 94.2% in younger and 98.6% in older patients. Slightly more grade 3 (40% vs. 29.4%) toxic effects were reported in older patients. Older patients had more gastrointestinal symptoms and fatigue. A larger proportion of elderly patients (21.4% vs. 8.1%) discontinued therapy, mainly due to gastrointestinal and dermatologic toxicity. Dose reductions occurred in 43 (11.3%) younger and 15 (21.4%) older patients; in the older patients most frequently because of hand–foot skin reactions and gastrointestinal events. Results from the advanced renal cell carcinoma expanded access program in North America (ARCCS) found similar rates (≥5%) of clinically manageable grade 2 and grade ≥3 adverse events (AEs) such as rash, fatigue, hypertension, diarrhea, anorexia and nausea in elderly patients with advanced renal cell carcinoma as compared to younger patients. Moreover, partial response was reported in 3% and stable disease in 81% of patients, similar to the younger patients in the study [22]. Finally, a cost-effectiveness analysis comparing sorafenib to best supportive care treatment only yielded an incremental cost–effectiveness ratio (ICER) of $75,354 per life-year gained [23]. Therefore, sorafenib’s significant survival benefit with mildly increased toxicities in elderly patients with advanced RCC appears to be appropriate and cost-effective. 2.2.2. Hepatocellular carcinoma A couple of years after being approved for use in advanced kidney cancer, sorafenib was shown to be efficacious and well-tolerated in patients with advanced hepatocellular carcinoma as per the phase III (SHARP) study [24]. The median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. A parallel study of the SHARP trial in China showed that sorafenib provided clinical benefit in older patients (>65 years) as well as in the younger population (0.74 (0.32–1.70) vs. 0.66 (0.47–0.92) respectively) [25]. The hazard ratio was inferior for patients ≥65 years of age, which might be attributed to small numbers (n = 32). A cost–benefit analysis of sorafenib versus best supportive care (BSC) in hepatocellular carcinoma found that the incremental cost–effectiveness ratio was $75,821 per life-year gained

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[26]. Hence, sorafenib is believed to be cost effective and efficacious in the elderly with unresectable hepatocellular carcinoma but not without an increased incidence of toxicity. 2.3. Sunitinib Sunitinib is a multi-kinase inhibitor with effects on VEGFR2, PDGFRB, with less potent activity against fibroblast growth receptor factor 1 (FGFR1) tyrosine kinase [27]. It undergoes hepatic metabolism primarily via CYP3A4. It is mainly secreted via the gut (60%) and partly by the kidneys (15%). Sunitinib is currently approved for the treatment of metastatic renal cell carcinoma and imatinib resistant gastrointestinal stromal tumors (GIST). 2.3.1. Renal cell carcinoma Results of a randomized phase III trial comparing sunitinib with interferon-␣ showed a longer progression-free survival and higher response rates with sunitinib, but there was no survival benefit [28]. A subgroup analysis of this study showed progression-free survival with sunitinib in patients aged ≥65 was almost identical to that of the younger patients [29]. In another subpopulation analysis of patients treated with sunitinib [30], patients aged over 65 had a similar incidence of grade 3–4 non-hematological adverse events such as diarrhea and mucositis as compared to the overall population; however fatigue was more common in the elderly. Disease control rate in this analysis was comparable between the younger and older patients (52.3% vs. 52.1%). The median PFS for the entire sunitinib treated population was similar to that seen in the elderly (8.9 months vs. 10.1 months). Thus, the efficacy of sunitinib seems to be the same in the elderly as in younger patients without a significant increase in toxicity. The cost-effectiveness analysis found that sunitinib was a cost-effective alternative to IFN-␣ as first-line treatment in mRCC with the incremental cost–effectiveness ratios of sunitinib versus interferon-␣ over 10 years being $67,215 per life year and $52,593 per QALY gained [31]. Due to its efficacy, mild toxicity and cost-effectiveness, sunitinib is an appropriate treatment for the metastatic renal cancer in the elderly. 2.3.2. Gastrointestinal stromal tumor Sunitinib has also been shown to be efficacious in patients with GIST that have progressed after being on imatinib therapy. However, there have not been any studies assessing the efficacy and toxicities of sunitinib in the treatment of GIST among the elderly. However, a European costeffective analysis of sunitinib versus best supportive care in GIST as a second-line treatment showed that the incremental cost–effectiveness ratios were D 30,242 per life year and D 49,090 per QALY gained making it a cost-effective option [32].

2.4. Lapatinib Lapatinib is a dual HER-1 and HER-2 tyrosine kinase inhibitor. Lapatinib reversibly binds to the intracellular cytoplasmic site of tyrosine kinase at the ATP-binding site, inhibits receptor phosphorylation and activation of HER1 and HER2 homodimers and heterodimers, thereby blocking the downstream signaling pathway involved in cell proliferation, survival and invasion. It undergoes hepatic metabolism primarily via CYP3A4 and CYP3A5 and is mainly secreted via the gut [33]. It has been approved for use in combination with capecitabine for the treatment of patients with refractory metastatic HER-2-positive breast cancer following trastuzumab failure. 2.4.1. Breast cancer In a study by Geyer et al. [34], out of 198 patients with metastatic breast cancer, 17% were 65 years or older. No overall differences in safety or effectiveness of the combination of lapatinib and capecitabine were observed between these patients or their younger counterparts. Cost-effective analysis assessing the addition of lapatinib to capecitabine in the treatment of HER-2-positive advanced breast cancer found an incremental cost–effectiveness ratio of $166,113 per QALY gained [35]. Hence, lapatinib is found to be both efficacious and not overly toxic in elderly women with metastatic HER-2 breast cancer after failure on traztuzumab; but it is not a very cost effective second-line treatment for now. 2.5. Imatinib Imatinib is a selective competitive inhibitor of the BCR–ABL tyrosine kinase approved for the treatment of Philadelphia chromosome positive chronic myelogenous leukemia (CML), hypereosinophilic syndrome, relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), gastrointestinal stromal tumor (GIST), dermatofibrosarcoma protuberans, myelodysplastic/myeloproliferative disorders and systemic mastocytosis. It undergoes hepatic metabolism primarily via P450 CYP3A4, CYP1A2, CYP2D6, CYP2C9 and CYP2C19. It is mainly secreted via the gut (68%) and the kidneys (13%). 2.5.1. Chronic myeloid leukemia Rousselot et al. [36] reported results of a prospective study of imatinib in elderly patients aged 70 years and older with chronic phase CML. The most commonly reported non-hematological toxicities were edema (71%) and gastrointestinal symptoms (38%). The toxicity of imatinib appeared more pronounced on the red cell lineage in elderly patients. Transient or permanent dosage reduction was noted in 52.3%. Cumulative incidence of complete cytogenetic response was 71.4% and 77% at 12 and 24 months respectively and major molecular response was seen in 25% and 56% at 12 and 24 months. Moreover, a high level of sus-

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tained cytogenetic and molecular responses was observed in the elderly. Ata et al. [37] studied the effects of imatinib mesylate in 28 patients 75 years of age or older. They too found high intolerability rates with 15 patients (53.5%) needing a dose reduction and 6 (21.4%) discontinuing imatinib due to toxicity. Grade 3/4 hematological and non-hematological toxicities were observed in 7 (25%) and 12 (42.8%) patients, respectively. Nevertheless, 22 (78.6%) patients did achieve a complete hematological response with 16 of them (57%) achieving a complete cytogenetic response. In a study by Bassi et al. [38], when compared to younger patients, older patients experienced more hematologic (86% vs. 60%, P = 0.0001) and non-hematologic (29% vs. 10%, P = 0.0001) adverse events with lower hematologic (91% vs. 99%, P = 0.001) and cytogenetic (36% vs. 57%, P = 0.001) response rates. Nevertheless, the overall survival was not different between the two age groups and rate of progression to accelerated/blast phase was the same (10%). In a cost-effectiveness analysis, the incremental cost–effectiveness ratio ranged from $46,082 to $57,103 per QALY [39]. Overall, even though these studies show excellent efficacy and cost-effectiveness of imatinib in the elderly, it is probably not as well-tolerated by the elderly and hence one needs to be vigilant for toxicity and intolerance needing dose reductions. 2.5.2. Gastrointestinal stromal tumors There have not been any studies assessing the efficacy and toxicities of imatinib in the treatment of GIST among the elderly. However, in a cost-effectiveness analysis, the annual incremental cost–effectiveness ratio was $15,882 per median life-year gained making imatinib for advanced GIST a costeffective treatment [40]. 2.6. Dasatinib Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinase inhibitor that is approved for use in patients with CML resistant to or intolerant of prior therapy. It is also approved for use in the treatment of adults with Ph+ ALL. It undergoes hepatic metabolism primarily via P450 CYP3A4. It is mainly secreted via the gut (85%) and partly by the kidneys (4%) [41]. 2.6.1. Chronic myeloid leukemia Iuliano et al. [42] assessed the toxicity profile in 4 elderly patients with CML. At a median follow-up of 12 months, they found hematologic toxicity (grade 3 thrombocytopenia and leukopenia) in two patients, grade 2 muscular-skeletal toxicity and fatigue in two patients and non-hematologic toxicity consisting mainly of grade 1 diarrhea and headache. One patient was intolerant to dasatinib. Nevertheless, all the patients had a complete hematologic response, and two patients had a partial cytogenetic response. In an Austrian study, over a lifetime, dasatinib was associated with a gain of 0.57 QALY and cost savings of an estimated D 15,200 mak-

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ing it a cost effective option. However, data on efficacy and tolerability is still sparse to date [43]. 2.6.2. Acute lymphoid leukemia with Philadelphia chromosome There are no studies looking specifically at the outcomes of dasatinib used to treat ALL positive for the Philadelphia chromosome in the elderly. This is probably due to scarcity of this condition in the elderly. However, on a cost-effectiveness analysis, the weighted comparative analysis of dasatinib versus salvage chemotherapy and imatinib in Ph+ ALL patients who have failed prior therapy estimated the incremental cost-effectiveness ratio between $75,000 and $105,000 per additional year of survival. Thus it may be a cost effective regimen for Ph+ ALL (Source: Bristol Myers Squibb PBAC Meeting 2007).

3. Monoclonal antibodies 3.1. Bevacizumab Bevacizumab is an anti-VEGF recombinant humanized monoclonal IgG1 antibody. It binds to vascular endothelial growth factor (VEGF) and inhibits the interaction of VEGF to Flt1 and KDR receptors on the surface of endothelial cells thus preventing the proliferation of endothelial cells and formation of new blood vessels. It is currently approved for the first-line treatment of metastatic HER-2 negative breast cancer, first-line treatment of unresectable or metastatic nonsmall cell (non-squamous) lung cancer as well as recurrent non-squamous NSCLC. It is also approved for the first and second-line treatment of metastatic colon cancer, firstline treatment of metastatic renal cell carcinoma along with interferon-␣ and as a single agent second-line treatment for glioblastoma [44]. 3.1.1. Non-small cell lung cancer Bevacizumab demonstrated a survival advantage for patients with advanced non-squamous NSCLC when used in combination with carboplatin and paclitaxel [45]. However, a recent subgroup analysis of this study looking at the outcomes in the elderly in this study demonstrated a higher degree of toxicity (at least one episode of ≥ grade 3) in the elderly patients who received bevacizumab (87–61%, P < 0.001) [46]. Elderly patients receiving bevacizumab had significantly more episodes of neutropenic fever, hemorrhage, nausea, anorexia and hypertension compared to chemotherapy alone. Moreover, when compared to younger patients, the elderly experienced more toxicity with the bevacizumabregimen. At least one episode of grade 3 or worse toxicity was noted in 87% of the elderly patients, compared with 70% of the younger patients on the bevacizumab arm (P = 0.001). Despite this, there was no improvement in survival compared with chemotherapy alone (11.3 months vs. 12.1 months, P = 0.4). Moreover, in terms of cost-effectiveness, the addi-

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tion of bevacizumab to chemotherapy costs $345,762 per year of life gained. When compared to other treatments found to be beneficial in survival in NSCLC such as chemotherapy vs. supportive care, two-agents vs. one and the choice of which platinum agent to use, the addition of bevacizumab is the least cost-effective of any intervention [47]. Hence, bevacizumab does not have significant survival benefit in elderly, is more toxic and not a cost effective regimen when used for non-small cell lung cancer. 3.1.2. Colon cancer In metastatic colon cancer, bevacizumab was shown to extend overall survival by about 5 months when given in combination with irinotecan, 5-FU and leucovorin (IFL) [48]. In a pooled analysis of patients older than 65 years, Kabbinavar et al. [49] found that elderly patients had improved overall survival and progression-free survival when given a bevacizumab-regimen compared to chemotherapy alone. Median overall survival with bevacizumab plus chemotherapy was 19.3 months compared to 14.3 months with chemotherapy (HR = 0.70; 95% CI: 0.55–0.90; P = 0.006), while the median progression-free survival was 9.2 months compared to 6.2 months for chemotherapy patients (HR = 0.52; 95% CI: 0.40–0.67; P = 0.0001). However, elderly patients who received bevacizumab had increased incidence of arterial thromboembolic events, GI perforation, rates of wound healing abnormalities and hypertension compared to chemotherapy alone (7.6% vs. 2.8%, 2.9% vs. 0%, 2.4% vs. 0% and 13.8% vs. 1.8% respectively). Results from the BRiTE registry analysis concluded that the safety and effectiveness of bevacizumab plus chemotherapy (FOLFOX or FOLFIRI) were comparable in patients greater than and younger than 65 years of age [50]. However, in another analysis, Raman et al. did find a trend of increasing incidence of arterial thrombosis and hypertension in the elderly population especially >75 years of age; the study however was severely underpowered due to a small sample size [51]. The cost-effectiveness of bevacizumab plus fluorouracil/leucovorin (IFL) was found unlikely to be better than £62,857 per QALY gained and in bevacizumab plus 5-fluorouracil/folinic acid (5-FU/FA) versus 5-FU/FA it is unlikely to be better than £88,658 per QALY gained; both of which are higher than the proposed willingness-to-pay threshold of £60,000 [52]. Hence, bevacizumab provides survival benefit in the elderly with metastatic colon cancer. However, its borderline cost-effectiveness and its increased risk for arterial thromboembolic events should be noted and considered when used in the elderly. 3.1.3. Breast cancer In breast cancer, bevacizumab was approved in combination with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic HER-2 negative breast cancer due to demonstration of an improvement in progression-free survival seen in the E2100 trial [53]. How-

ever there is no data from trials that assess the risks and benefits of bevacizumab in older patients with breast cancer. A cost-effectiveness analysis based on the E2100 trial was performed and it is found that the addition of bevacizumab to weekly paclitaxel is estimated to yield a gain of 0.22 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio of D 189,427/QALY gained [54]. Hence, the addition of bevacizumab to paclitaxel in metastatic breast cancer patients is expensive given the clinical benefit in terms of QALYs gained. 3.1.4. Renal cell carcinoma In a European placebo controlled study, adding bevacizumab to interferon benefited older patients (≥65 years) to the same extent as their younger counterparts [55]. In both arms of the study, 37% of patients were in the older age group. For PFS, the HR among patients receiving combination therapy was 0.77 (95% CI: 0.58–1.03) in older patients, and 0.54 (92% CI: 0.43–0.68) in those under 65 years. In both age groups, the combination of bevacizumab and IFN was welltolerated. However, there was a slight increase overall in the proportion of elderly patients who experienced an adverse event of grade 3 or greater severity (66% vs. 58%), predominantly fatigue and asthenia. In a cost-effectiveness appraisal, the comparison of bevacizumab plus IFN-␣ with IFN-␣ alone produced a base case ICER of £74,999 per QALY gained (http://www.nice.org.uk/guidance/index.jsp?action= article&o=41473). Thus, bevacizumab may not be costeffective (estimated £30,000 cut off for willingness to pay). 3.1.5. Glioblastoma multiforme In a single institution study of 113 patients with recurrent glioblastoma, 44 patients received bevacizumab and 79 patients were not treated with bevacizumab [56]. There was a significant improvement in PFS and OS in the bevacizumab-treated group. Patients of older age (≥55 years) had significantly better PFS and an increased OS when treated with bevacizumab compared to younger patients (<55 years). Moreover, VEGF expression was significantly higher in older glioblastoma patients (aged ≥55 years) suggesting biologic differences in the tumor in different age groups [56]. Unfortunately there are no cost-effectiveness analysis studies done looking at the treatment of glioblastoma with bevacizumab. Finally, in a pooled analysis of patients with all types of cancer from five randomized trials showed that patients over the age of 65 years are at increased risk of arterial thromboembolic events, particularly when bevacizumab is given in combination with chemotherapy (P = 0.01) [57]. 3.2. Cetuximab Cetuximab is a monoclonal antibody against the extracellular domain of the epidermal growth factor receptor (EGFR) [58], approved for the treatment of EGFR-expressing, metastatic colorectal carcinoma in patients refractory to

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irinotecan-based chemotherapy [59]. It is also approved for use in combination with radiation therapy for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN) or as a single agent for the treatment of patients with recurrent or metastatic SCCHN on progression following platinum-based therapy. It binds to EGFR blocking phosphorylation and activation of receptorassociated kinases, resulting in inhibition of growth and survival of tumor cells that over-express the EGFR. 3.2.1. Colon cancer A European retrospective study explored the tolerability and activity of cetuximab combined with irinotecan in an unselected population of elderly patients with irinotecanrefractory metastatic colorectal cancer [60]. The disease control rate (partial and complete responses and stable disease) was 53%. Most frequent toxicities included grade 2 and grade 3 acneiform skin rash, diarrhea and neutropenia. These results were comparable to the outcomes in younger patients. In a trial of cetuximab as a first-line single agent for metastatic colorectal cancer in 41 elderly patients ≥ 70 years old [61], toxicities were also similar to those expected, i.e. acneiform rash (10%), grade 1-2 nail toxicity (7%) and grade 1-2 infusion related toxicity grades (5%). Only two patients required dose reduction of cetuximab due to toxicity, and there was a dose delay of one week in 12 patients (29%), achieving a median relative dose intensity of 80%. Of the 39 patients evaluable for efficacy, 1 had a complete response, 5 showed a partial response, 15 had stable disease and 18 progressed. Overall response rate was 15.4% and tumor growth control was seen in 54%. These results were also comparable to previous studies including younger populations. KRAS mutations in the tumor seem to predict for response to cetuximab. Overall survival of patients without KRAS mutation was significantly higher compared with those patients with a mutated tumor (median, 16.3 months vs. 6.9 months, P = 0.016) [62]. This holds true for elderly patients as seen in a recent European trial that assessed the combination of cetuximab and capecitabine in 66 elderly patients [63]. The relative response rate for the entire population was 33.3% (95% CI: 22.2–46.0%). Relative response according to the KRAS status were 48.3% (95% CI: 29.4–67.5%) in KRAS wild-type patients and 24.1% (95% CI: 10.3–43.5%) in KRAS mutated. Progression-free survival (PFS) and overall survival (OS) for the entire population were 7.2 and 16.5 months, respectively. Median PFS was 6.0 months for K-RAS mutated and 8.6 months for KRAS wild-type, respectively (P = 0.02); while median OS was 13.4 and 19.0 months respectively (P = 0.04). Cetuximab showed an incremental cost–effectiveness ratio of $199,742 per life-year gained and an incremental cost–utility ratio of $299,613 per QALY gained in metastatic colon cancer [64]. These amounts decreased to $120,061 per life-year gained and $186,761 per QALY gained when the analysis was limited to patients with wild-type KRAS tumors. Thus, the elderly treated with cetuximab for metastatic colon cancer, have a similar sur-

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vival/response rate benefit and toxicity profile as younger patients. However, it may not be a cost-effective regimen even after selecting for the K-RAS wild-type tumors only. 3.2.2. Head and neck cancer In squamous cell cancer of the head and neck, a trial by Vermorken et al. showed that adding cetuximab to platinum-based chemotherapy with fluorouracil (platinum–fluorouracil) significantly prolonged the median OS from 7.4 to 10.1 months (HR = 0.80; 95% CI: 0.64–0.99; P = 0.04) [65]. The median PFS increased from 3.3 to 5.6 months (HR = 0.54; P < 0.001) while the response rate increased from 20% to 36% (P < 0.001). Elderly population (>65 years) represented 17% of patients in this study and the subgroup analysis according to age suggested an inferior advantage in terms of overall survival (HR: 0.745 (0.59–0.94) for <65 vs. 1.07 (0.65–1.77) for >65) and progression-free survival (HR 0.54 (0.43–0.69) for <65 vs. 0.65 (0.38–1.12) for >65). A Canadian cost effective analysis study estimated the incremental cost–utility of cetuximab plus radiotherapy (CxRT) versus cisplatin plus radiotherapy (CsRT) among platinum eligible patients and versus RT alone in platinum ineligible patients. The ICERs comparing CxRT to RT were $19,740/QALY among platinum ineligible patients and for CxRT versus CsRT, was $99,147/QALY among platinum eligible patients [66]. Thus cetuximab use in the elderly with squamous head and neck cancer is possibly associated with inferior outcomes compared to younger patients. Moreover, cost-effectiveness of this drug in head and neck cancer barely meets the cutoff for appropriate willingness to pay. 3.3. Panitumumab Panitumumab is a fully human IgG2 monoclonal antibody that blocks the binding of EGF and TGF-␣ to the EGF receptor. Like cetuximab, it has been approved for the treatment of patients with EGFR-expressing, metastatic colorectal cancer. 3.3.1. Colon cancer In a subset analysis of the original registration trial that looked at patients with metastatic colorectal cancer (mCRC) who received panitumumab plus best supportive care (BSC) versus BSC alone, the influence of patient’s age was assessed in terms of its efficacy and tolerability [67]. The treatment effect on progression-free survival favored panitumumab regardless of age (<65 years: HR 0.51, 95% CI 0.40–0.67, P < 0.001; >65 years: HR 0.60, 95% CI 0.43–0.83, P = 0.0019). Furthermore, among the panitumumab treated patients, similar progression-free survival, overall survival times and overall response rate were seen in elderly and younger patients. The most common adverse events seen with panitumumab were skin toxicities (91%). No grade 3/4 infusion reactions were reported. Thus, efficacy and tolerability of panitumumab in metastatic colorectal cancer does not seem to be affected by age.

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Similarly to cetuximab, panitumumab response rates are also dependent on the presence of wild-type or mutant KRAS gene. A randomized phase III study looked at panitumumab with FOLFIRI versus FOLFIRI alone as second-line treatment in patients with mCRC [68]. They found that patients with wild-type KRAS treated with FOLFIRI + panitumumab had a median PFS of 5.9 months compared to 3.9 months with FOLFIRI (HR = 0.73; 95% CI: 0.593–0.903; P = 0.004). The median OS was 14.5 months for panitumumab + FOLFIRI and 12.5 months for FOLFIRI (HR = 0.85; 95% CI: 0.702–1.039; P = 0.115) while response rates were 35% and 10% respectively. There was no difference in PFS, OS, or response rate among patients with the mutant KRAS who received panitumumab. The PRIME trial was a randomized, multicenter, phase III study designed to evaluate the efficacy and safety of panitumumab with FOLFOX4 versus FOLFOX4 alone as first-line treatment for mCRC [69]. The subgroup analysis of the elderly patients older than 65 years suggested no clear benefit for panitumumab in patients older than 65 years (HR = 1.02; 95% CI: 0.7–1.38). Cost effective analysis of panitumumab plus BSC versus BSC alone in chemorefractory mCRC patients with WT KRAS tumor status showed a $59,440 per QALY gained [70]. Hence, panitumumab is a cost effective drug that produces fairly similar adverse events as those in younger patients, however its efficacy in the elderly is not entirely known due to mixed results.

all treated populations. A similar retrospective analysis by Fyfe et al. [78] analyzed 109 patients older than 60 years of age and found that trastuzumab added to chemotherapy improved the response rate from 28% to 44% and survival from 14 to 19 months. Cardiac toxicity was greater in the older patients (21% vs. 11%). Thus, although elderly patients with metastatic breast cancer benefit from treatment with trastuzumab, periodical assessment of cardiac safety is recommended in these patients due to frequent concomitant cardiovascular co-morbidity. Adjuvant trastuzumab increased life expectancy by 1.54 quality-adjusted life years (QALYs) and achieves its clinical benefit at a cost of D 14,861 (95% CI: D 3917 to D 44,028) and $18,970 (95% CI: $6014 to $45,621) per QALY saved [79]. However, the incremental cost-effectiveness was higher than D 50,000/QALY (or $60,000/QALY) at time horizons shorter than 7.8 years and for patients older than 76 years or with a 10-year risk of relapse lower than 15%. Thus, in a long-term horizon, adjuvant trastuzumab is a cost-effective therapy that has similar efficacy and toxicities for elderly patients as well as younger patients with HER-2-positive, high-risk, early breast cancer. 3.5. Rituximab Rituximab is a chimeric human/mouse anti-CD20 antibody that binds to the CD20 antigen expressed on B-cells [80].

3.4. Trastuzumab Trastuzumab is a recombinant humanized IgG monoclonal antibody that selectively binds to the extracellular domain of HER2 [71]. It is currently used in patients as adjuvant therapy [72,73] and for the treatment of metastatic [74] HER-2 over-expressing breast cancer. However, few patients aged 70 years or over have been included in the trials evaluating trastuzumab. Most of the concerns with trastuzumab revolve around congestive heart failure and cardiomyopathy [75]. Age is a risk factor for congestive heart failure in patients receiving trastuzumab, but probably depends more on pre-existing co-morbidities than on age alone [76]. 3.4.1. Breast cancer However, no specific trial on activity and safety of trastuzumab has addressed patients older than 70 years, and the only available data are taken from subgroup analyses [77]. In this retrospective analysis, 50 patients ≥ 70 years of age with inoperable locally advanced/metastatic breast cancer treated with chemotherapy and trastuzumab in 9 Italian centers were reviewed. The median age of this cohort was 73.8 years (range, 70–92 years). Toxicity did not correlate with chemotherapy regimen or age. A reduction of LVEF > 10% but <20% was observed in 9% patients who had serial echocardiograms. Response rate and time to progression for elderly patients receiving chemotherapy plus trastuzumab was comparable to published data of the over-

3.5.1. Non-Hodgkin’s lymphoma (diffuse large B-cell) A randomized study looking at the long-term effects (>5 years) of rituximab in addition to CHOP therapy in the elderly improved event-free survival, progressionfree survival, disease-free survival, and overall survival in diffuse large B-cell lymphoma (P = 0.00002, P = 0.00001, P = 0.00031, and P = 0.0073, respectively) [81]. Although rituximab did not add toxicity to the CHOP regimen in the elderly, there was a trend to increased infections in elderly patients who received rituximab. Although deaths without disease progression were more frequent in R-CHOP patients, no specific pattern of causes of death was observed. Habermann et al. confirmed this low toxicity profile other than a possible increase in grade 3–4 neutropenia with maintenance rituximab after induction treatments in 632 patients older than 60 years of age [82]. A cost-effectiveness study assessed the incremental cost–effectiveness ratio of CHOP versus CHOP plus rituximab (R-CHOP) in diffuse large B-cell lymphoma patients. The ICER was D 13,983 for younger and D 17,933 for older patients per QALY gained [83]. Hence, rituximab with CHOP is seen to be cost effective, well-tolerated and efficacious regimen in the elderly. 3.6. Ibritumomab tiuxetan 90 Y

ibritumomab tiuxetan is a radiolabelled antibody against CD20, approved for B-cell non-Hodgkin’s lym-

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phoma (NHL) in patients who have relapsed following rituximab. 3.6.1. Non-Hodgkin’s lymphoma In a meta-analysis assessing the safety and efficacy of 90 Y ibritumomab tiuxetan in older patients with non-Hodgkin’s lymphoma, Emmanouilides et al. [84] found that patients ≥70 years had a similar incidence of grade 3 or 4 neutropenia (68% vs. 66%), thrombocytopenia (68% vs. 70%) and non-hematologic adverse events (23% vs. 19%) as compared to patients <60 years. Response rates (range, 71–80%) and the durations of response (median of 9.9, 11.0, and 9.4 months) were also similar. This favorable safety profile and clinical response of the regimen makes it an effective treatment for older patients. The mean cost per disease-free month of a single dose of 90 Y-Zevalin 0.4 mCi/kg compared with: (1) standard rituximab treatment of 375 mg/m2 weekly for 4 weeks (4-dose rituximab) and (2) standard rituximab followed by 4 weeks of maintenance therapy (8-dose rituximab) in patients with follicular lymphoma was D 1138, D 1544 and D 1674 respectively [85]. Hence, 90 Y ibritumomab tiuxetan in older patients with non-Hodgkin’s lymphoma had similar efficacy and toxicities compared to younger patients and was also more cost effective than standard 4- and 8-week rituximab treatments. 3.7. Tositumomab Tositumomab is an 131 I bound anti-CD20 monoclonal antibody. It is approved by the FDA to treat certain types of non-Hodgkin lymphoma (NHL) in patients who have relapsed following rituximab. 3.7.1. Non-Hodgkin’s lymphoma Gregory et al. [86] examined the efficacy of tositumomab in elderly patients with relapsed/refractory low grade follicular or transformed NHL. Complete response rates post-treatment were higher for patients in every age group compared with those without the therapy. These rates were nearly doubled for patients aged between 60 and 70 years (23% vs. 12%) and tripled for patients >70 years (23% vs. 7%). Moreover, of all the previously treated patients >60 years, ≥50% achieved a response post-131 I tositumomab therapy and nearly 25% of patients >60 years achieved a complete response, with a median duration of 32.3 months. Although response rates and durations of response were better in younger patients, elderly patients in this study presented with poorer prognostic features at baseline. Overall toxicity and acute hematologic toxicity associated with 131 I tositumomab in older patients >60 years was similar to that observed in patients ≤60 years. A cost-effectiveness analysis of tositumomab compared to alternative therapies in first-, second-, and third-line NHL therapy found that the tositumomab had an ICER less than the cost-effectiveness threshold of $50,000 per life-year gained [87]. Hence this was a favorable cost-effectiveness profile to alternative strategies

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including rituximab maintenance (RXM) in first-, second, and third-line NHL therapy. Moreover, it had comparable efficacy and toxicities to those seen in younger patients.

4. Miscellaneous 4.1. Bortezomib Bortezomib is a proteasome inhibitor targeting the ubiquitin-proteasome pathway and is approved for patients with multiple myeloma and patients with mantle cell lymphoma who have received at least one prior therapy. 4.1.1. Multiple myeloma Mateos et al. [88] looked at bortezomib combined with melphalan and prednisone (VMP) for the treatment of newly diagnosed multiple myeloma in patients ≥ 65 years. The most common grade 3/4 adverse events were thrombocytopenia (51%), neutropenia 43%), peripheral neuropathy (17%), and diarrhea (16%). Dose reduction was seen in 14 (23%) patients. After 1 cycle of VMP, a higher response rate (70%) was seen than with 6 cycles of MP in controls (42%). Patients who received bortezomib had a longer event-free survival (83% vs. 51%) and overall survival (90% vs. 62%) at 16 months. The median time to progression with VMP was 27.2 months, compared with 20.0 months with MP. The median overall survival with VMP was not reached versus 26 months with MP. However, it should be noted that all these comparisons done by Mateos et al. were versus historic controls in previous phase II trials conducted by the same authors; no randomized comparisons were performed to attain this data. In a subgroup analysis of the in elderly (age ≥ 65 years) patients in the phase III APEX trial of bortezomib versus dexamethasone [89], the, response rates (34–40% vs. 13–19%), including complete response rate (5–8% vs. 0–1%), were significantly higher with bortezomib. Similarly, median time to progression and 1-year survival probability was significantly higher with bortezomib. Although patients aged ≥ 65 years had an increased incidence of diarrhea, nausea, constipation, fatigue, thrombocytopenia and peripheral neuropathy, the overall incidence of grade 3/4 adverse events was similar in both arms (46% vs. 47%). Finally, as a third-line treatment for patients with relapsed and refractory MM, relative to best supportive care in the UK, the incremental cost–effectiveness ratio for bortezomib was in the range of £17,161–£33,539 per life-year gained and £26,714–£51,666 per quality-adjusted life-year gained [90]. Thus bortezomib appears to be a cost effective drug that has excellent efficacy with similar tolerability to other therapies in the elderly myeloma population. 4.1.2. Mantle cell lymphoma Bortezomib was approved for the treatment of refractory or recurrent mantle cell lymphoma by the FDA in 2006 after an open label, single-arm, multicenter trial of 155 patients

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found an overall response rate of 31% and a median response duration was 9.3 months [91]. However, no specific trials in the elderly and no cost-effective analysis in mantle cell lymphoma are available to date. 4.2. Thalidomide Thalidomide is an immunomodulatory agent, which has been approved in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma. 4.2.1. Multiple myeloma Ludwig et al. [92] looked at thalidomide–dexamethasone (TD) versus melphalan–prednisone (MP) in elderly patients with multiple myeloma. The thalidomide–dexamethasone (TD) group had a higher proportion of complete and near-complete remissions (26% vs. 13%, P = 0.006) and overall responses (68% vs. 50%, P = 0.002). However, time to progression (21.2 months vs. 29.1 months, P = 0.20) and progression-free survival were similar (16.7 months vs. 20.7 months, P = 0.10), but interestingly, overall survival was significantly shorter in the thalidomidedexamethasone TD group (41.5 months vs. 49.4 months, P = 0.024). Toxicities such as thromboembolic events, neuropathy, constipation, and psychological disturbances were significantly more frequent with thalidomide. Mortality was significantly associated with poor performance status and predominantly seen in patients older than 75 years. Similar toxicities were also seen in a phase III trial assessing the combination of thalidomide and dexamethasone versus just dexamethasone alone [93]. Deep vein thrombosis occurred more frequently with thalidomide (17% vs. 3%, P = 0.001); more commonly in patients ≥ 65 years as compared to younger patients (22% vs. 12%). However, this was not found to be statistically significant (P = 0.29). Palumbo et al. [94] compared oral melphalan/prednisone plus thalidomide (MPT) with melphalan/prednisone (MP) in patients aged 60–85 years. They found that the combined complete or partial response rates were 76% for MPT and 47.6% for MP alone, and the near-complete or complete response rates were 27.9% and 7.2%, respectively. The 2year event-free survival rates were 54% for MPT and 27% for MP (hazard ratio: 0.51; 95% CI: 0.35–0.75; P = 0.0006). Grade 3–4 adverse events were reported in 62 (48%) MPT patients and in 32 (25%) MP patients (P = 0.0002). In 12 patients, the dose of thalidomide maintenance therapy was reduced due to the occurrence of grade 2 peripheral neuropathy. The incidence of infections was also higher in patients receiving thalidomide. Hence elderly patients with poor performance status should not be started on highdose dexamethasone in combination with thalidomide and if thalidomide regimens are used, toxicities should be assessed carefully. Finally a randomized trial assessed 447 previously untreated patients with multiple myeloma to see whether

the addition of thalidomide to MP improved survival compared to reduced-intensity stem cell transplantation or just MP [95]. Nearly 41% of the patients were 70 years or older. After a median follow-up of 51.5 months, median overall survival times was 33.2 months for MP, 51.6 months for MPT, and 38.3 months for the reduced-intensity stem cell transplantation. The MPT regimen was associated with a significantly better overall survival than was the MP regimen (hazard ratio 0.59; 95% CI: 0.46–0.81; P = 0.0006) or transplant (0.69; 0.49–0.96; P = 0.027). In the MPT group, the occurrence of neutropenia, thromboembolism, peripheral neuropathy, somnolence, fatigue, dizziness and constipation was significantly higher, but no other severe toxicities were noted. Currently, there are no economic evaluations of thalidomide in the treatment of multiple myeloma. Hence, thalidomide provides significant efficacy in elderly patients with multiple myeloma, however, it also increases the risk of thromboembolism and peripheral neuropathy which have to be considered. 4.3. Lenalidomide Lenalidomide is a member of the class of immunomodulatory drugs that modulate immunologic and inflammatory responses [96]. It is a more potent inhibitor of (TNF)-␣ production than thalidomide. Its immunomodulatory activities range from inhibition of cyclooxygenase-2, interleukin (IL)-1␤, transforming growth factor-␤, and IL-6 induction to potentiation of IL-2 generation. It has direct antitumor effects via its inhibitory effects on supportive stroma and its ability to augment tumor selective T-cell and natural killer cell immune responses. It is currently approved for use in patients with transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS) associated with a deletion 5q with or without additional cytogenetic abnormalities. It is also approved for use in combination with dexamethasone in patients with relapsed multiple myeloma. 4.3.1. Multiple myeloma Reece et al. [97] evaluated the outcome of patients 65 years and older who received lenalidomide-based regimens through Celgene’s Expanded Access Program in Canada and compared the results with younger patients in that study. Although the incidence of higher-grade side effects was not increased in older patients when compared with their younger counterparts, older patients (12.5%) discontinued treatment due to toxicity compared to younger patients (4%). Nevertheless, older patients with multiple myeloma achieved comparable response rates (≈60%). The progression-free survival and overall survival were not affected by age. In another analysis [98], examining the clinical benefit of lenalidomide plus dexamethasone combination in elderly patients enrolled in 2 phase III clinical trials, Chanan-Khan et al. found that lenalidomide combined with dexamethasone improved overall response rate, prolonged

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time to progression and overall survival in elderly patients with relapsed/refractory multiple myeloma. Lenalidomide thus offers an important treatment option for the elderly patient population. Currently, there are no economic evaluations of lenalidomide in the treatment of multiple myeloma. 4.3.2. Myelodysplastic syndrome Lenalidomide was approved for the treatment of transfusion-dependent patients with del(5q) MDS by the FDA in 2005. The pathogenesis of MDS involves several complex series of events such as increased angiogenesis, overproduction of pro-inflammatory cytokines, accelerated apoptosis of hematopoietic progenitors and autocrine stimulation by vascular endothelial growth factor [99]. Immunomodulatory drugs such as lenalidomide potentially interfere with this complex series of events. In addition, lenalidomide is able to potentiate erythropoietin-induced hematopoietic response and restore erythroid differentiation potential [99]. The MDS003 clinical trial evaluated the efficacy of lenalidomide in lower-risk, transfusion-dependent patients with a chromosome 5q31 deletion with or without other cytogenetic abnormalities [100]. Overall, 76% of patients who received lenalidomide had a 50% or greater reduction in transfusion requirements; 67% became transfusion-independent, with a rise in hemoglobin of ≥1 g/dL. The most common adverse events were neutropenia and thrombocytopenia. These results are applicable to the elderly population since the majority of patients with myelodysplastic syndromes (MDS) are >55 years of age.

5. Conclusions Although not universally true with all targeted agents, these findings do raise concerns about the safety of molecular targeted therapies in elderly and confirm the need for more long-term and specific trials in the elderly population. However, there is no doubt that even though the efficacy of these drugs have been commendable, their promise in providing better tolerability has not lived up to its expected potential. If anything, their tolerability has been equivalent to or only marginally better than cytotoxic therapies. It would be worthwhile to design clinical trials having the elderly as the target population in order to better define the clinical use and safety of these drugs in this subset of patients. Until then, use of molecular targeted therapies in the elderly population should be exercised with caution and assessed on an individual basis taking into consideration the risks, benefits and prognosis of patients.

Conflict of interest statement None of the authors has any conflict of interest with this manuscript.

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Reviewers Javier Sastre, Ph.D., HC San Carlos, Medical Oncology, c/Martin Lagos s/n, E-28040 Madrid, Spain. Tracy L. O’Connor, M.D., Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, United States. Stuart M. Lichtman, M.D., Memorial Sloan-Kettering Cancer Center, Department of Medicine, 650 Commack Road, Commack, NY 11725, United States.

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Biography Apar Kishor Ganti, M.D. is an Assistant Professor of Medicine at the University of Nebraska Medical Center and a Staff Oncologist at the Veterans’ Affairs Nebraska-Western Iowa Health Care System in Omaha, NE. He completed his medical training at the B.J. Medical College in Pune, India in 1996 and subsequently completed residencies in Pharmacology and Internal Medicine and a fellowship in Medical Oncology. He specializes in the care of patients with lung and head and neck cancer. His research interests include lung cancer, cancer in the elderly and identifying novel biomarkers for lung cancer.