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Keywords:

  • targeted therapy;
  • chemotherapy;
  • elderly;
  • advanced nonsmall cell lung carcinoma

Abstract

  1. Top of page
  2. Abstract
  3. CURRENT TREATMENT OF ADVANCED NSCLC IN THE ELDERLY
  4. NOVEL TARGETED THERAPY STRATEGIES FOR ELDERLY PATIENTS WITH ADVANCED NSCLC
  5. ONGOING TRIALS OF TARGETED THERAPY IN ELDERLY PATIENTS WITH ADVANCED NSCLC AND FUTURE DIRECTIONS
  6. REFERENCES

BACKGROUND

More than 50% of all lung carcinoma cases are diagnosed in patients age > 65 years, and approximately 30% are diagnosed in patients age > 70 years. Elderly patients do not tolerate chemotherapy as well as their younger counterparts do, primarily because of the increased prevalence of comorbid conditions and organ failure. Thus, at present, the majority of elderly patients with malignant disease do not receive aggressive chemotherapy. For such elderly patients, alternatives to conventional chemotherapy, such as novel molecularly targeted therapy regimens, are of interest.

METHODS

The current review summarizes contemporary approaches to and recent advances in the treatment of elderly patients with nonsmall cell lung carcinoma (NSCLC) and offers perspectives on the future of molecularly targeted therapy in this population. Inhibitors of epidermal growth factor receptor, vascular endothelial growth factor, and cyclooxygenase-2 are discussed in the current report, with such inhibitors being, in our opinion, among the best candidates for clinical development in the setting of interest.

RESULTS

Novel biologic agents with putative activity against advanced NSCLC are at various stages of clinical development. Some of these agents have yielded benefits in terms of disease-related symptom reduction, quality of life, and survival. For elderly patients, the potential advantages of such agents include improved tolerability compared with conventional chemotherapy. This feature also makes these novel agents attractive alternatives for younger patients who cannot tolerate or are reluctant to receive conventional chemotherapy.

CONCLUSIONS

Current studies are investigating the safety and efficacy of these novel biologic agents administered alone, in combination with other noncytotoxic agents, and in combination with conventional chemotherapy. These studies will help elucidate the role of targeted therapy in the management of elderly patients with advanced NSCLC. Cancer 2004. © 2004 American Cancer Society.

The majority of lung carcinoma cases are diagnosed in elderly patients. More than 50% of all cases are diagnosed in patients age > 65 years, and approximately 30% of all cases are diagnosed in patients age > 70 years.1, 2 Furthermore, more than two-thirds of all patients who die of lung carcinoma in the United States are older than age 65 years.3 In 2000, more than 80% of all lung carcinoma–related deaths occurred in patients age ≥ 60 years, with patients age ≥ 80 years accounting for 20% of all lung carcinoma–specific mortality.3 The most common lung carcinoma subtype is nonsmall cell lung carcinoma (NSCLC), which accounts for approximately 80% of all lung malignancies.4 Age 70 years appears to be the optimal cutoff point for distinguishing elderly patients with NSCLC from younger patients. This age can be considered the lower boundary of senescence because the majority of age-related changes have been found to occur after age 70 years.5

Because most patients with NSCLC have advanced disease at diagnosis, chemotherapy is the mainstay of this malignancy's management. In clinical practice, cisplatin-containing combinations have become the most widely used regimens in the treatment of advanced NSCLC ever since a metaanalysis6 revealed a slight improvement in survival (increase in median survival, 6 weeks) for patients receiving cisplatin-based chemotherapy compared with patients receiving best supportive care. Elderly patients tend to tolerate chemotherapy poorly because of their increased likelihood of developing comorbid conditions or experiencing organ failure. The prevalence of comorbid conditions in elderly patients is approximately twice the prevalence documented in the general population of patients with lung carcinoma.7 Progressive deterioration of organ functioning and the risk of developing significant toxicity should be taken into account in deciding whether to administer platinum-based chemotherapy to elderly patients, including those with good performance status.

Although chemotherapy is appropriate for selected patients with favorable performance status, recent studies have demonstrated that the majority of elderly patients with advanced NSCLC do not receive aggressive chemotherapy.8 Earle et al.8 examined 6308 Medicare recipients who were older than age 65 years and who had been diagnosed with AJCC Stage IV NSCLC and found that only 21.5% of patients had received any chemotherapy for their metastatic disease. Skepticism on the part of the physician regarding the benefits of chemotherapy for NSCLC has been reported by Raby et al.,9 who found that only 20% of all Canadian physicians surveyed believed that chemotherapeutic treatment of advanced NSCLC was worthwhile, and by Crook et al.,10 who reported that 11% of all British clinicians surveyed would recommend chemotherapy for qualified patients, with that proportion increasing to 26% when clinicians were asked to consider only patients younger than age 50 years.

New modalities may increase physicians' interest in using chemotherapy to treat advanced NSCLC and thus also increase the proportion of patients who actually receive chemotherapy. Novel biologic agents with putative activity against NSCLC are at various stages of clinical development, and some have already been shown to yield benefits in terms of disease-related symptom reduction and quality of life for patients with advanced NSCLC.11, 12 Improved tolerability (as evidenced by a more favorable toxicity profile compared with conventional chemotherapy), better target selectivity, availability for chronic use, and (in some cases) oral availability have made these targeted compounds the most promising investigational agents for the treatment (including first-line treatment) of elderly patients with advanced NSCLC.

The current review focuses on contemporary approaches, recent advances, and other considerations in the treatment of elderly patients with NSCLC, and it also offers perspectives on the future of molecularly targeted therapy in this setting.

CURRENT TREATMENT OF ADVANCED NSCLC IN THE ELDERLY

  1. Top of page
  2. Abstract
  3. CURRENT TREATMENT OF ADVANCED NSCLC IN THE ELDERLY
  4. NOVEL TARGETED THERAPY STRATEGIES FOR ELDERLY PATIENTS WITH ADVANCED NSCLC
  5. ONGOING TRIALS OF TARGETED THERAPY IN ELDERLY PATIENTS WITH ADVANCED NSCLC AND FUTURE DIRECTIONS
  6. REFERENCES

A metaanalysis of randomized trials comparing chemotherapy with best supportive care in patients with advanced NSCLC revealed a slight survival advantage (increase in median survival, 6 weeks) for patients who received cisplatin-based chemotherapy.6 No age-related differences were observed in that study. Recently, a retrospective investigation of 6232 elderly patients who were included in the National Cancer Institute Surveillance, Epidemiology, and End Results tumor database found that in the treatment of metastatic NSCLC, chemotherapy was as effective for elderly patients as it was for younger and more highly selected patients.13 Therefore, all patients with advanced NSCLC who are qualified to receive palliative chemotherapy should be given the option to do so.

Overall, the few prospective clinical investigations of cisplatin-based chemotherapy in elderly patients with NSCLC that have been reported on have indicated that cisplatin is particularly difficult for elderly patients to tolerate, due to renal and neurologic side effects and potential hydration-related problems.14, 15 Nonetheless, neither concerns regarding the toxicity of cisplatin-based chemotherapy in elderly patients nor the widespread practice of withholding such chemotherapy from elderly patients is well supported by the findings of large prospective clinical trials.

The issue of cisplatin-based therapy's suitability for elderly patients with advanced NSCLC has recently been addressed in a number of retrospective analyses.16–19 The first of these analyses examined outcomes in elderly participants (age > 70 years) and younger participants in an Eastern Cooperative Oncology Group (ECOG) Phase III randomized trial (ECOG 5592) of cisplatin-based regimens for the treatment of NSCLC. The response rates, side effects, and survival rates observed in elderly patients appeared to be similar to those documented in younger patients, except that leukopenia and neuropsychiatric side effects were more common among the elderly. The investigators who conducted that analysis concluded that advanced age alone should not preclude the use of cisplatin-based chemotherapy to treat NSCLC.16 More recently, Langer et al.17 conducted an age-specific retrospective analysis of all patients enrolled in a Phase III trial (ECOG 1594) comparing four different platinum-based combination regimens. In that study, older patients (age ≥ 70 years) accounted for 20% of the cohort being investigated. Although older patients were found to have significantly more cardiovascular (P < 0.00001) and other noncardiorespiratory comorbid conditions (P = 0.008), treatment completion rates, rates of incidence of Grade ≥ 4 toxicity, response rates, progression-free survival results, and overall survival results were equivalent for older patients and patients age < 70 years. Similar results, along with evidence of the feasibility and efficacy of cisplatin-based doublet regimens in elderly patients, have been reported in retrospective analyses of two Southwest Oncology Group (SWOG) trials (SWOG 9508 and SWOG 9308)18 and in the TAX 326 trial.19

Data on chemotherapy outcomes for patients with NSCLC who are older than age 80 years are very limited. The aforementioned age-specific subanalysis of the ECOG 1594 trial revealed that chemotherapy had poor activity and efficacy in the 9 patients age > 80 years who were examined (1% of all enrollees; response rate, 0%; median progression-free survival, 2.2 months; median survival, 4.2 months), with these results being comparable to those observed in patients with an ECOG performance status of 2.17

The idea of substituting cisplatin with its analogue carboplatin in both younger patients and elderly patients is appealing. In fact, carboplatin causes less nausea, emesis, nephrotoxicity, and neurotoxicity compared with its parent compound, and it does not necessitate additional hydration. Nonetheless, carboplatin is more myelotoxic than cisplatin is, and myelotoxic effects are sometimes difficult to manage in elderly patients. Recently, no difference in survival was noted between patients younger than age 70 years and patients older than age 70 years who were enrolled in the randomized Cancer and Leukemia Group B 9730 trial,20 which compared carboplatin plus paclitaxel with paclitaxel alone; furthermore, in that study, elderly patients who received combination chemotherapy had a survival advantage over elderly patients who received single-agent chemotherapy. Hensing et al.21 also found no difference in terms of toxicity or survival between patients age ≥ 70 years and patients age < 70 years who were treated with carboplatin and paclitaxel.

It must be noted that the aforementioned analyses could have been affected by selection biases. Older patients enrolled in such trials may be representative not of the elderly population as a whole but rather of a small subgroup of patients thought by investigators to be eligible for aggressive treatment.22 The percentage of elderly patients out of all patients diagnosed with lung carcinoma in clinical practice is much greater than the percentage of elderly patients out of all patients enrolled in clinical trials of lung carcinoma treatment regimens. Thus, prospective clinical trials of cisplatin-based chemotherapy that are limited to elderly patients with NSCLC are necessary.

Another topic of interest is the use of novel treatment schedules and attenuated cisplatin doses, which may be more suitable for elderly patients. Berardi et al.23 reported good tolerability and good response rates in association with the use of weekly cisplatin and gemcitabine, and Madronal et al.24 reported similar findings in association with the use of a low-dose (50 mg/m2) cisplatin regimen. Nonetheless, at present, cisplatin-based chemotherapy continues to be the standard treatment option for patients with advanced NSCLC.25, 26 Consequently, we believe that it is appropriate to investigate the use of cisplatin-based chemotherapy at suitable doses and in suitable schedules for elderly patients with good performance status.27

In recent years, new active and well tolerated agents (e.g., vinorelbine, gemcitabine, and taxanes) have been investigated in clinical trials involving elderly patients with NSCLC.28–31 In addition, a multicenter Phase III trial involving 191 patients (the Elderly Lung Cancer Vinorelbine Italian Study) demonstrated that single-agent vinorelbine led to improved quality of life and survival results compared with supportive care alone (median survival, 27 weeks vs. 21 weeks; P = 0.04).32

The development of non-cisplatin-based combinations represents an intriguing approach to improving upon results obtained using single-agent chemotherapy for elderly patients with advanced NSCLC. The possibility of developing active and well tolerated chemotherapeutic options that preserve quality of life is an attractive one. The best-studied non-cisplatin-based regimen for the treatment of NSCLC is the combination of gemcitabine and vinorelbine. Phase II trials of this combination have reported promising activity and good tolerability.30 Nonetheless, a large randomized Phase III trial involving approximately 700 elderly patients (the Multicenter Italian Lung Cancer in the Elderly Study) found that the combination of vinorelbine and gemcitabine was no more effective than single-agent vinorelbine or single-agent gemcitabine in the treatment of elderly patients with advanced NSCLC. In that study, quality of life results were similar across the three treatment arms, although the combination regimen was more toxic than either of the two agents administered individually.33 Given these findings, and until the results of prospective randomized trials of cisplatin-based chemotherapy become available, single-agent chemotherapy should be considered a reasonable treatment option for unselected elderly patients with advanced NSCLC. Results of the major Phase II and Phase III chemotherapy trials involving this patient population are summarized in Table 1.

Table 1. Results of Major Phase II and III Chemotherapy Trials Involving Elderly Patients with Advanced NSCLC
AuthorAgents usedPatient age (yrs)No. of patientsOR rate (%)MST (weeks)Major toxicities
  • NSCLC: nonsmall cell lung carcinoma; OR: objective response; MST: median survival time; VNR: vinorelbine; GEM: gemcitabine; NR: not reported; TXT: docetaxel; PCL: paclitaxel; CDDP: cisplatin; ELVIS: Elderly Lung Cancer Vinorelbine Italian Study; BSC: best supportive care; G: Grade.

  • a

    Phase II trial.

  • b

    Randomized Phase III trial.

  • c

    Statistically significant difference.

Gridelli et al., 199731,aVNR> 70432336G3–4 leukopenia (33%), G2–3 anemia (19%)
Gridelli et al., 200130,aGEM≥ 704918NRG4 thrombocytopenia (1/49), G2 hepatic toxicity (1/49), G2 pulmonary toxicity (2/49)
Hainsworth et al., 200029,aTXT≥ 65391821.4G3 leukopenia (8%), G3–4 fatigue (10%)
Fidias et al., 200128,aPCL> 70352346.3G3–4 neutropenia (6%), G3–4 infection (9%), G3–4 hyperglycemia (18%)
Gridelli et al., 200130,aGEM + VNR≥ 704918NRG4 neutropenia (2%), G4 thrombocytopenia (2%), G3 anemia (4%), G4 fever (4%)
Berardi et al., 200223,aWeekly CDDP + weekly GEM≥ 70462640.5G3–4 leukopenia (9%), G3–4 thrombocytopenia (41%)
Madronal et al., 200224,aLow-dose CDDP + GEM≥ 70463749.5G3–4 neutropenia (9%), G3–4 anemia (2%)
ELVIS Group, 199932,bBSC vs. BSC + VNR> 7019120 (BSC + VNR)21 (BSC), 27 (BSC + VNR)cBSC + VNR: G3–4 constipation (5%)
Gridelli et al., 200133,bVNR or GEM vs. GEM + VNR≥ 7070718.5 (VNR), 17.3 (GEM), 20.0 (GEM + VNR)37 (VNR), 28 (GEM), 32 (GEM + VNR)VNR: G3–4 neutropenia (25%); GEM: G3–4 neutropenia (8%), G3–4 thrombocyto penia (3%); GEM + VNR: G3–4 neutropenia (18%), G3–4 thrombocytopenia (3%)

NOVEL TARGETED THERAPY STRATEGIES FOR ELDERLY PATIENTS WITH ADVANCED NSCLC

  1. Top of page
  2. Abstract
  3. CURRENT TREATMENT OF ADVANCED NSCLC IN THE ELDERLY
  4. NOVEL TARGETED THERAPY STRATEGIES FOR ELDERLY PATIENTS WITH ADVANCED NSCLC
  5. ONGOING TRIALS OF TARGETED THERAPY IN ELDERLY PATIENTS WITH ADVANCED NSCLC AND FUTURE DIRECTIONS
  6. REFERENCES

Novel biologic agents that selectively target molecular mechanisms involved in malignant cell progression currently are undergoing extensive clinical evaluation as potential anticancer compounds (Fig. 1). Of these novel agents, small-molecule tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) family; molecules directed against vascular endothelial growth factor (VEGF); and inhibitors of cyclooxygenase (COX)-2 are the most promising for elderly patients with NSCLC, due to their favorable toxicity profiles and their possible oral availability. In the following sections of the current review, emphasis will be given to biologic agents that are considered to be the best candidates for clinical development as treatment options for elderly patients with advanced NSCLC.

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Figure 1. Treatment of metastatic solid tumors: moving from chemotherapy to molecularly targeted therapy.

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Anti-EGFR Therapy

There are numerous approaches to blocking EGFR. Monoclonal antibodies, small-molecule tyrosine kinase inhibitors, toxin conjugates, and antisense oligonucleotides all have been investigated as potential anti-EGFR agents.34–37

Gefitinib

Gefitinib is an orally available compound that selectively and reversibly blocks EGFR's activity by competitively inhibiting the binding of adenosine triphosphate, which is required for receptor autophosphorylation and kinase activation.

Two large Phase II trials of gefitinib monotherapy for patients with advanced NSCLC that could not be controlled by one or more previous chemotherapy regimens have been conducted. In a multicenter randomized Phase II trial of gefitinib as second- or third-line single-agent therapy (the Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL] 1 trial), 210 patients from Europe or Japan who had advanced NSCLC and who were unselected with respect to EGFR expression received either 250 or 500 mg oral gefitinib daily.11 In that trial, overall response rates of 18.4% and 19%, disease stabilization rates of 36% and 32%, symptom improvement rates of 40.3% and 37%, median progression-free survival durations of 2.7 months and 2.8 months, and median overall survival durations of 7.6 months and 8.0 months were observed in the 250 mg arm and the 500 mg arm, respectively. Thus, it was concluded that the 250 mg dose was as active as the 500 mg dose, and the tolerability of the 250 mg dose was found to be significantly superior. A parallel randomized Phase II study conducted in the United States (IDEAL 2) involved 216 unselected symptomatic patients with advanced NSCLC that was resistant to at least 2 previous chemotherapy regimens, one of which contained a platinum derivative and the other of which contained docetaxel.12 In that trial, improvement in NSCLC symptoms (as measured by an increase of ≥ 2 points on the Lung Cancer subscale of the Functional Assessment of Cancer Therapy) was observed in 43% of all patients receiving 250 mg gefitinib and in 35% of all patients receiving 500 mg gefitinib, with this improvement occurring within 3 weeks in 75% of all patients who experienced responses. Furthermore, partial responses were documented in 12% and 9% of patients who were treated with 250 mg and 500 mg gefitinib, respectively, and symptom improvement was observed in 96% of all patients who had partial responses. The 1-year overall survival rate for patients in the IDEAL 2 trial was 25%, and the higher gefitinib dose (500 mg) was found to be associated with more severe side effects, such as an acnelike skin rash and diarrhea.

On the basis of these clinical trials, the use of gefitinib in the third-line treatment of platinum/docetaxel-refractory advanced NSCLC has been approved in several countries, including Japan, Australia, and the United States.38 Thus, gefitinib is the first approved targeted anti-EGFR agent. The antitumor activity of single-agent gefitinib was confirmed in a large, international expanded-access program in which this compound was administered at a dose of 250 mg to patients with advanced NSCLC that had progressed after standard chemotherapy and/or radiotherapy.39, 40 In this program, objective responses were observed in 10–15% of all patients.

Although, to our knowledge, no prospective clinical trial has examined the safety and efficacy of gefitinib in untreated or pretreated elderly patients with NSCLC, clinical activity and very low levels of toxicity have been reported in association with gefitinib use in such patients and also in patients with poor performance status.41–45 In fact, subset analyses of patients included in the abovementioned expanded-access protocol supported the use of gefitinib in further clinical trials involving elderly patients with NSCLC. Among the 61 patients age ≥ 70 years at the time of enrollment in that protocol (39% of whom were untreated and deemed ineligible to receive any chemotherapy), no Grade 3 or 4 side effects were reported. Furthermore, 2 partial responses (3%) and 16 cases of disease stabilization (26%) were observed, and 21% of all patients in this subanalysis had progression-free survival lasting ≥ 4 months.41 Similarly, Gridelli et al.,42 examining a series of 59 pretreated patients with NSCLC who were elderly or ineligible for treatment and who were participating in a compassionate-use program, documented a response rate of 3.4%, an overall disease control rate of 15.2%, and the presence of an excellent safety profile. In a series of 31 elderly patients with NSCLC, 15 of whom had previously received treatment and 11 of whom were chemonaive and were deemed ineligible to receive any chemotherapy, Soto Parra et al.43 observed a favorable toxicity profile and a disease stabilization rate of 58% in association with gefitinib use. Furthermore, Cappuzzo et al.,45 in a series of 40 previously treated elderly patients with NSCLC, observed 1 complete response (2.5%), 1 partial response (2.5%), and 18 cases of disease stabilization, for an overall disease control rate of 50%; in addition, the side effects documented in that study (primarily diarrhea and skin-related toxicity) were generally mild. Nonetheless, the response rates observed among elderly patients in the international expanded-access trial of gefitinib were globally lower than those reported in either of the IDEAL trials, and thus, the activity of gefitinib in this population requires confirmation in prospective clinical trials.

It is not known whether elderly patients' rates of response to gefitinib therapy and to other molecularly targeted treatment approaches will be higher than, lower than, or equivalent to the response rates observed in younger patients. It recently was demonstrated that a subgroup of patients with NSCLC had specific mutations in the EGFR kinase domain that were correlated with clinical responsiveness to gefitinib.46, 47 Thus, screening for such mutations in lung malignancies may lead to the identification of patients who are more likely to experience responses to treatment. Assessment of whether these mutations are more common, less common, or equally common in elderly patients with NSCLC compared with their younger counterparts is of interest, as the findings of such an analysis will allow the role of gefitinib therapy in the elderly population to be evaluated more completely.

With regard to the possibility of using gefitinib therapy in combination with chemotherapy, two large Phase III trials involving younger patients with NSCLC48, 49 have reported that platinum-based polychemotherapy plus gefitinib does not yield any survival benefit compared with chemotherapy alone. These findings have been confirmed in the elderly in a recent randomized Phase II study of gefitinib used in conjunction with single-agent chemotherapy (vinorelbine or gemcitabine).50 In that study, the combination of vinorelbine and gefitinib was deemed unacceptable because of its unfavorable toxicity profile (Grade 3–4 neutropenia in 72% of patients), whereas the combination of gemcitabine and gefitinib, although safe, was not found to be particularly active.

Erlotinib

Erlotinib is an orally available small molecule designed to target the EGFR pathway in a reversible manner. A Phase II trial of erlotinib in the treatment of patients with NSCLC progression following treatment with a platinum-based chemotherapy regimen recently was conducted.51 In that study, which included patients with positive EGFR status, measurable disease, ECOG performance status 0–2, and adequate organ function, 1 complete response (2%), 6 partial responses (10%), and 20 cases of disease stabilization (35%) were reported; with regard to toxicity, severe (Grade 3) rash and diarrhea each occurred in only 2% of patients. Single-agent erlotinib also has been tested in a Phase II trial involving patients with bronchioloalveolar cell carcinoma, and the preliminary results of that trial are encouraging, with 13 of 50 patients (26%) having experienced partial responses.52 Furthermore, in a randomized, placebo-controlled Phase III trial, erlotinib was found to prolong survival (6.7 months [erlotinib arm] vs. 4.7 months [placebo arm]; P = 0.001) in patients with NSCLC that persisted after first-line or second-line chemotherapy.53 Analyses of quality of life and time to deterioration of patient-reported symptoms revealed statistically and clinically meaningful benefits for patients randomized to receive erlotinib in that trial; furthermore, erlotinib proved to be both active (response rate, 8.9%) and safe (toxicity-related treatment discontinuation rate, 5%).

Erlotinib use recently was investigated in a prospective Phase II study involving patients age > 70 years who had previously untreated advanced NSCLC. Preliminary data on 30 patients suggest that erlotinib is well tolerated and possesses encouraging activity (response rate, 13.3%) as a first-line treatment agent for elderly patients with advanced NSCLC.54 Nonetheless, as is the case with gefitinib, two large randomized Phase III trials involving younger patients have demonstrated that the use of erlotinib in combination with platinum-based polychemotherapy confers no survival benefit beyond the benefits associated with chemotherapy alone.55, 56

Cetuximab

Cetuximab is a human-mouse chimeric anti-EGFR monoclonal antibody. Preliminary clinical data indicate that antitumor activity is significantly enhanced when cetuximab is used in conjunction with cytotoxic chemotherapy.57 Recently, the combination of cetuximab, carboplatin, and paclitaxel or gemcitabine was found to be well tolerated in patients with advanced NSCLC.58, 59 Furthermore, a Phase II study has revealed that the combination of cetuximab and docetaxel possesses promising activity and a favorable safety profile in the second-line treatment of this malignancy.60 To our knowledge, no data on cetuximab therapy in elderly patients with NSCLC have been reported, but this agent's safety profile appears to indicate that it is suitable for use in such patients. Table 2 provides information on anti-EGFR agents that are undergoing clinical development at present.

Table 2. Anti-EGFR Agents in Clinical Development
AgentTargetStage of development
  1. EGFR: epidermal growth factor receptor; TKI: tyrosine kinase inhibitor; NSCLC: nonsmall cell lung carcinoma; moAb: monoclonal antibody.

GefitinibReversible TKIPhase III; approved to treat advanced chemorefractory NSCLC in several countries
CetuximabChimeric moAbPhase III; approved for use in combination with irinotecan to treat advanced chemorefractory colorectal malignancies in Switzerland and the United States
ErlotinibReversible TKIPhase III concluded with positive results in advanced chemorefractory NSCLC; submitted for approval
PKI-166Reversible dual EGFR/HER-2 TKIPhase I
ABX-EGFHuman moAbPhase I
EMD 72000Humanized moAbPhase I
h-R3Humanized moAbPhase I
CI-1033Irreversible pan-HER TKIPhase I
EKI-569Irreversible dual EGFR/HER-2 TKIPhase I
GW-2016Reversible dual EGFR/HER-2 TKIPhase I

Angiogenesis Inhibitors

VEGF is a key endothelial cell–specific mitogen that is involved in the process of tumor neovascularization.61, 62 Several endogenous angiogenesis inhibitors targeting the VEGF pathway are under development as potential agents for the treatment of NSCLC.

Antibodies against VEGF

A humanized version of the murine antibody against VEGF has been found to inhibit endothelial cell proliferation in vitro and in vivo and to reduce tumor growth in vivo.63 Furthermore, in a randomized Phase II study involving 99 patients with Stage IIIB or IV NSCLC, the combination of carboplatin and paclitaxel was tested with and without the addition of the recombinant humanized monoclonal anti-VEGF antibody bevacizumab (7.5 or 15 mg/kg)64; in that study, response rates were approximately 10% higher when the antibody was included in the regimen, and the time to tumor progression was approximately 3 months longer in the high-dose antibody arm compared with the control arm (7.5 months vs. 4.5 months). One issue that warranted concern, however, was the finding that six patients in that study developed severe hemoptysis, which was fatal in four cases. In an evaluation of potential risk factors, it was found that only squamous histologic subtype and bevacizumab use were associated with this side effect. Recent findings from a randomized Phase II study suggest that the addition of bevacizumab to carboplatin and paclitaxel may prolong survival in patients with nonsquamous NSCLC without leading to additional mortality.65 In that study, objective response rates (32% vs. 12%) and time to progression (30 weeks vs. 17 weeks) were superior for patients receiving bevacizumab plus chemotherapy compared with patients receiving chemotherapy alone. Nonetheless, due to the limited number of patients enrolled and the Phase II design of that study, a meaningful comparison of efficacy endpoints was not possible. The ECOG currently is evaluating the effects of administering 15 mg/kg bevacizumab in combination with carboplatin and paclitaxel to patients with advanced nonsquamous NSCLC.66 To our knowledge, no data on bevacizumab use in elderly patients have been reported to date.

VEGF receptor tyrosine kinase inhibitors

VEGF activity also can be blocked via inhibition of the VEGF receptor tyrosine kinase by targeted small molecules.

ZD6474 is an orally available anilinoquinazoline derivative that possesses potent inhibitory activity against VEGF receptor 2 (kinase domain region) on endothelial cells.67, 68 It also has recently been shown that ZD6474 inhibits the EGFR and Ret tyrosine kinases.69 In an ongoing Phase I dose-escalation study, 41 patients with various solid tumors have been treated with ZD6474.70 Reported treatment-related side effects in that study have been minimal, with only two National Cancer Institute (NCI) Grade 1 events (facial flushing and facial rash) and one NCI Grade 2 event (fatigue) observed; no Grade 3 or 4 side effects have been documented to date. Disease stabilization has been reported in 2 patients (one with a gastrointestinal stromal tumor and the other with melanoma) after 56 days of treatment, and accrual of patients to the study is ongoing. At present ZD6474 is in Phase II.

ZD2171 is an orally available and highly potent inhibitor of VEGF receptors 1, 2, and 3 but does not possess activity against the EGFR tyrosine kinase. At present, ZD2171 is in Phase I of clinical development. Both ZD6474 and ZD2171 are candidates for evaluation in elderly patients with NSCLC.

Eicosanoid Pathway Inhibitors

It has been suggested that arachidonic acid may serve as a mitogenic signal, and this compound also is a precursor of several eicosanoids that possess potent biologic effects, including the stimulation of cellular inflammation and growth. Arachidonic acid can be metabolized by three major pathways: the COX pathway, which leads to the formation of prostaglandins and thromboxane; the lipoxygenase (LOX) pathway, which leads to the formation of hydroxyeicosatetraenoic acids and leukotrienes; and the cytochrome p450 monooxygenase pathway, which leads to the formation of epoxides. The COX and LOX pathways appear to play important roles in tumorigenesis as well as in the development and metastatic spread of malignant disease.

COX-2 inhibitors

There are two isoforms of COX. COX-1 is constitutively expressed, whereas COX-2 expression can be induced by growth factors, oncogenes, carcinogens, and tumor-promoting phorbol esters. A substantial body of preclinical evidence supports the idea of an interrelation among COX-2, prostaglandins, and the development of malignant disease. COX-2 is overexpressed in a number of human malignancies,71 and this overexpression is an important early event in the development of selected human tumors, including lung carcinoma.72–74

The most thoroughly investigated COX-2 inhibitors are celecoxib, rofecoxib, valdecoxib, and etoricoxib. Synergistic cytotoxicity has been observed in NSCLC cell lines treated with coxibs plus various chemotherapeutic agents or radiation75, 76; however, to date, few clinical studies dealing with this issue have been reported on. Preliminary results from a Phase II trial of docetaxel plus celecoxib in pretreated patients with NSCLC indicate that celecoxib inhibits intratumoral COX-2, resulting in a marked decrease in tumor prostaglandin E2 levels.77 Another Phase II study of docetaxel plus celecoxib in the second-line treatment of NSCLC documented a response rate that was similar to the one yielded by single-agent docetaxel, although the combination regimen produced an unexpectedly high rate of neutropenic fever.78 Altorki et al.79 recently reported on a Phase II trial in which the antitumor activity of neoadjuvant chemotherapy (carboplatin plus paclitaxel) in 29 patients with Stage IB–IIIA NSCLC was enhanced by the addition of 400 mg celecoxib twice daily. In fact, the response rate observed in that study (65%) compared favorably with results in historical control patients, and furthermore, the addition of celecoxib was found to reverse the marked increase in prostaglandin E2 levels that was observed in primary tumors after treatment with paclitaxel and carboplatin only. We currently are conducting a Phase III trial aimed at evaluating the survival benefit derived from using rofecoxib in conjunction with cisplatin and gemcitabine in the treatment of advanced NSCLC.

Given their mild toxicity profiles, COX-2 inhibitors may prove to be useful in the treatment of elderly patients with cancer. The combination of celecoxib and docetaxel currently is under evaluation in elderly patients with advanced NSCLC as well as in patients with advanced NSCLC who have ECOG performance status 2. Preliminary data on the first 21 patients in that trial were recently reported: the study regimen appeared to be well tolerated by those patients (no Grade 3–4 hematologic toxicity), and it exhibited encouraging activity (response rate, 21%).80

LOX inhibitors

The LOX family is a collection of enzymes that carry out the stereospecific and regiospecific conversion of 1,4-cis,cis double bonds in unsaturated fatty acids to 1,3-cis,trans-5-hydroperoxides. Numerous studies have shown that inhibitors of various functions of LOX molecules can prevent or attenuate malignant disease. 5-LOX is expressed in lung malignancies, and 5-hydroxyeicosatetraenoic acid has been found to stimulate lung carcinoma cell growth, whereas 5-LOX inhibitors are known to impede tumor cell growth in vitro and tumorigenesis in vivo.81, 82 LY293111, a modulator of multiple eicosanoid pathways, is a novel, orally available agent that inhibits the synthesis of 5-LOX. A randomized Phase II trial of LY293111 used in combination with cisplatin and gemcitabine to treat patients with advanced NSCLC is currently being conducted; however, data on the use of this agent in the treatment of elderly patients with cancer are not available at present.

Combinations of Biologic Therapy Options

Because it is conceivable that multiple growth-controlling pathways are altered in malignant cells, biologic therapy combinations targeting two or more such pathways should be tested in the clinical setting, and this testing should be conducted with the aim of developing a polytargeted treatment strategy based on a rational approach addressing the alterations that are present in patients with cancer. In preclinical experimental models, it has been demonstrated that significant and sustained antitumor activity can be achieved in vitro and in vivo using anti-EGFR compounds in combination with other antisignaling agents, such as cyclic adenosine monophosphate–dependent protein kinase (type I protein kinase alpha) inhibitors,83VEGF antisense oligonucleotides,84 and the anti-ErbB-2 monoclonal antibody trastuzumab.85 An alternative strategy involves the use of agents with inhibitory activity against both EGFR signaling and VEGF receptor signaling; one such agent is ZD6474, an orally available small-molecule inhibitor of kinase domain region/VEGF receptor 2 tyrosine kinase activity that also exhibits selectivity against a variety of other tyrosine and serine-threonine kinases, including those activated by EGFR.67 Another possible combination therapy strategy involves the use of VEGF receptor or COX-2 inhibitors in conjunction with EGFR inhibitors. The combination of the EGFR inhibitor erlotinib and the VEGF inhibitor bevacizumab is considered particularly promising in the treatment of patients with recurrent NSCLC, as has been demonstrated in a recent Phase I/II trial86; in that trial, which involved 40 patients, a response rate of 17.5% and a favorable safety profile were documented.

ONGOING TRIALS OF TARGETED THERAPY IN ELDERLY PATIENTS WITH ADVANCED NSCLC AND FUTURE DIRECTIONS

  1. Top of page
  2. Abstract
  3. CURRENT TREATMENT OF ADVANCED NSCLC IN THE ELDERLY
  4. NOVEL TARGETED THERAPY STRATEGIES FOR ELDERLY PATIENTS WITH ADVANCED NSCLC
  5. ONGOING TRIALS OF TARGETED THERAPY IN ELDERLY PATIENTS WITH ADVANCED NSCLC AND FUTURE DIRECTIONS
  6. REFERENCES

Although the number of elderly patients is growing, and although these patients have unique needs and concerns that must be considered, few controlled clinical trials of potential treatments for elderly patients with NSCLC have been performed. In recent years, however, elderly patients with cancer have come to be a focus of clinical research. Consequently, in the near future, we expect to see clinical trials designed specifically to test therapeutic options in elderly patients with NSCLC. Current NSCLC treatments have reached a plateau in terms of their effectiveness in extending patient survival. Thus, a search for new treatment strategies is necessary.

As laboratory investigations continue to elucidate the mechanisms underlying malignant phenotypes, new molecular targets for anticancer therapy are constantly emerging, and consequently, novel targeted agents are continually being proposed and developed. Several biologic agents aimed at treating NSCLC have been introduced, and the majority of these agents remain in Phase I or II of clinical evaluation at present. To our knowledge, only one report of a prospective Phase II trial of targeted therapy in elderly patients with NSCLC has been published to date,54 but a number of clinical trials are underway or are planned to begin in the near future. Ongoing clinical trials of biologic agents for the treatment of elderly patients with NSCLC are summarized in Table 3. At a minimum, Phase I–III trials of targeted compounds in younger patients indicate that most of these novel agents have safety profiles that make them more suitable than cytotoxic agents for use in the treatment of elderly patients. Gefitinib and erlotinib, two EGFR tyrosine kinase inhibitors, were the first targeted agents found to be effective in patients with chemotherapy-refractory NSCLC. Due to their excellent safety profiles, which have been confirmed in elderly patients with advanced disease, these two agents are among the best candidates for prospective testing as first-line monotherapeutic agents (i.e., as potential alternatives to cytotoxic chemotherapy) in such patients. In addition to gefitinib and erlotinib, the VEGF receptor tyrosine kinase inhibitors ZD6474 and ZD2171, two orally administered biologic agents, also are excellent candidates for evaluation in elderly patients. Nonetheless, although the hypothesis that molecularly targeted treatments, with their mild toxicity profiles, are appropriate for elderly patients has intuitive appeal, this hypothesis must be tested in clinical trials rather than being immediately adopted as a part of therapeutic practice.

Table 3. Ongoing Clinical Trials of Targeted Therapy in Elderly Patients with Advanced NSCLC
Study regimenInvestigatorProtocol ID no.PhaseStudy population
  1. NSCLC: nonsmall cell lung carcinoma; ID: identification; PS: performance status; WSU: Wayne State University (Detroit, MI); NCCTG: North Central Cancer Treatment Group.

Celecoxib + docetaxelDr. Shirish M. GadgeelWSU-C-2305IIElderly patients and patients with PS 2
Carboplatin/paclitaxel ± gefitinibDr. Aminah JatoiNCCTG-N0222IIElderly patients
Docetaxel ± ifliximabNCCTGIIElderly patients and patients with poor PS 

The ongoing first generation of clinical trials of targeted therapy for elderly patients has explored single-agent strategies as well as combination regimens involving cytotoxic agents. Clinical trials of combined targeted therapy options may constitute the second generation of studies in this field.

REFERENCES

  1. Top of page
  2. Abstract
  3. CURRENT TREATMENT OF ADVANCED NSCLC IN THE ELDERLY
  4. NOVEL TARGETED THERAPY STRATEGIES FOR ELDERLY PATIENTS WITH ADVANCED NSCLC
  5. ONGOING TRIALS OF TARGETED THERAPY IN ELDERLY PATIENTS WITH ADVANCED NSCLC AND FUTURE DIRECTIONS
  6. REFERENCES
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