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Evaluation of Adverse Events Experienced by Older Patients Participating in Studies of Molecularly Targeted Agents Alone or in Combination

Authors' Affiliation: Princess Margaret Hospital Phase II Consortium, Ontario, Canada

Requests for reprints: Lillian L. Siu, Princess Margaret Hospital, University Health Network, 610 University Avenue, Suite 5-210, Toronto, Ontario, M5G 2M9, Canada. Phone: 416-946-2911; Fax: 416-946-6546; E-mail: lillian.siu{at}uhn.on.ca.

	Abstract

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Background: The tolerability of molecularly targeted agents in older patients has not been specifically examined. Adverse event data from clinical trials in the Princess Margaret Hospital Phase II Consortium database were analyzed to address this question.

Methods: The Consortium database collects trial information on all patients treated with either a molecularly targeted agent alone or in combination since 2001. The frequency of adverse events was determined and analyzed by two different age groups, <65 years and 65 years. Toxicity indices (TI) and frequencies of dose-limiting toxicities (DLT), based on adverse events of all causalities (TI_ALL and DLT_ALL), and on adverse events that were at least possibly related to the molecularly targeted agent (TI_MTA and DLT_MTA), were calculated for both age groups.

Results: Four hundred and one patients who received 1,252 treatment cycles were analyzed from 19 different studies. Baseline performance status was similar between both age groups, but fewer older patients have had multiple prior regimens of chemotherapy or prior radiation therapy. A comparison of the proportions of younger and older patients experiencing DLT_ALL and DLT_MTA showed similar results. The TI_MTA values were comparable between the two age groups in both single agent (3.25 versus 3.00, for <65 versus 65 years) and multi-agent (3.65 versus 3.00, for <65 versus 65 years) trials.

Conclusions: Older patients seem to tolerate molecularly targeted therapies either alone or in combination with chemotherapy as well as younger patients. Age alone should not be a barrier in the administration of targeted agents.

Unfortunately, the current literature is not helpful in educating physicians who accept a stereotype that all older patients have poor tolerance to chemotherapy or radiation therapy. Many studies have investigated this phenomenon, but reports are contradictory. Several trials using cytotoxic therapy have shown an increased risk of toxicity including myelotoxicity in the elderly (7–13), although other studies have shown almost equivalent toxicity profiles between older and younger patients (14–18).

Molecularly targeted agents are currently emerging as a new cancer treatment strategy. Theoretically, they are more specific against cancer targets than conventional cytotoxic chemotherapy, and as such, may be better tolerated by all patients, including those of more advanced age. As yet, no age-specific analysis evaluating the tolerability of molecularly targeted agents in this population have been reported.

This study uses the Princess Margaret Hospital Phase II Consortium database to examine the tolerability of molecularly targeted agents alone or in combination with chemotherapy in two different age groups, those <65 years and those 65 years old. If evidence of good tolerability of molecularly targeted agents in older patients can be provided to clinicians, their enrollment on clinical trials may be increased, more treatment options may be offered, and care may be improved in this population.

	Materials and Methods

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The Princess Margaret Hospital Phase II Consortium database collects data on all clinical trials done through the Consortium from the year 2001 to the present. The Consortium is contracted to conduct early phase clinical trials under the auspices of the Cancer Therapy and Evaluation Program of the U.S. National Cancer Institute. The majority of the clinical trials done by the Consortium are phase II disease-specific trials to determine therapeutic efficacy, and a minority are dose- and toxicity-finding phase I or phase I/II trials. All trials done by the Consortium to date have involved molecularly targeted agents, either given alone or in combination with a cytotoxic chemotherapeutic agent. The data collected by the Consortium database include baseline demographic information, baseline comorbidities as reported by the patients, response evaluations based on Response Evaluation Criteria in Solid Tumors criteria for solid tumors or standard response criteria for hematologic malignancies for each patient, toxicity and adverse event reports on all trial patients which are captured at the cycle level. Furthermore, the doses of study drug(s) received by patients are recorded on a per cycle basis into the database.

For this project, the Consortium database was used to compare adverse events experienced by patients participating in Consortium studies as stratified by age. Patients were divided into two age groups: <65 years and 65 years. These cutoffs were chosen in order to be consistent with the current literature examining the recruitment of older patients with cancer into clinical trials which has typically used 65 years to define the elderly population (19). A recent study examining the tolerability of bevacizumab in an elderly population has also used 65 as the cutoff age (20, 21). Results were grouped into studies evaluating molecularly targeted anticancer agents given as monotherapy, and studies comprised of a combination of a molecularly targeted agent and chemotherapy. Baseline demographics such as age, performance status and prior treatments were obtained from the database. Comorbidities were taken from baseline case report forms and were quantified based on the Charlson Comorbidity Index (22). Best responses to treatment on the Consortium studies were recorded for all patients. For each patient, dose intensity was calculated by taking the actual dose received divided by the expected dose x 100%. The expected dose was calculated by taking the total dose a patient should have received as per protocol for the length of time they were on the study and assuming no dose reductions, delays, or omissions occurred. When dosing was based on body surface area or weight, the baseline values of height and weight were used in the calculation of the expected dose. Thus, if a patient had an increase in weight, which led to a greater body surface area while on study treatment, it is possible that >100% dose intensity can be achieved. For patients treated with a combination of chemotherapy and molecularly targeted agent, the dose intensities were calculated for both agents.

A modified toxicity index (TI) was calculated using the methods of Rogatko et al. (23). Depending on the protocol, adverse events were graded on Consortium studies by the National Cancer Institute Common Toxicity Criteria versions 2.0 or 3.0. All adverse events for each patient are ordered from most severe to least severe using National Cancer Institute Common Toxicity Criteria versions 2.0 or 3.0: x₁, x₂, ..., x_n, where x_i is the grade of the ith most severe adverse event for each patient. Then, the TI is calculated as:

The TI is a patient level statistic between 0 and 6 describing the cumulative toxicity experienced by each patient where the integer number indicates the grade of the highest grade adverse event experienced for each patient. All other adverse events are accounted for in the final TI score. However, lower grade adverse events contribute less to the final score as a large number of similarly graded adverse events create a TI score slightly lower than a single adverse event of the next highest grade. For our analysis, hematologic adverse events for the leukemia or lymphoma studies were excluded as these patients often have abnormal pretreatment hematologic values due to their disease, but grade 5 adverse events (e.g., on-study deaths) were included.

The causality of adverse events that occur on Consortium studies are attributed based on the treating physician's opinion regarding their relationship to the study drug(s). The existing categories include adverse events that are definitely related, probably related, possibly related, unlikely related, or unrelated to the study drug(s). For the purpose of this project, the TI was calculated in two ways. First, inclusion of adverse events into the TI_ALL was based on incorporating adverse events of all attributions, regardless of the perceived causal relationship between the study drug(s) and the development of the adverse event. A second calculation of the TI, TI_MTA, was done by including only adverse events which were at least possibly related (i.e., possibly, probably, and/or definitely related) to the molecularly targeted agent. For studies which were comprised of a combination of a molecularly targeted agent and a cytotoxic chemotherapeutic agent, only the molecularly targeted agent was considered in the derivation of the TI_MTA. Adverse events related only to the chemotherapeutic agent, in the combination trials, were not included when calculating the TI_MTA. Adverse events related at least possibly to either the molecularly targeted agent, or the chemotherapeutic agent, in the combination trials, would be included in the calculation of the TI_MTA. If a patient experienced the same adverse event multiple times in the same cycle, only the worst grade adverse event was included in the calculation of the TI.

In addition to the TI, the frequencies of dose-limiting toxicities (DLT) were compared between age groups. A DLT was defined as any grade 3 nonhematologic adverse event, or any grade 4 hematologic adverse event, except for the leukemia or lymphoma studies, in which only the nonhematologic and grade 5 adverse events were included. Analyses were done based on the number of patients who experienced at least one DLT, as well as the number of cycles in which at least one DLT occurred, were calculated. Similar to the abovementioned derivations of TI_ALL and TI_MTA, the frequencies of DLT were reported in two ways. DLT_ALL incorporated DLT of all attributions, regardless of the perceived causal relationship between the study drug(s) and the development of the adverse event. DLT_MTA included only DLT, which were at least possibly related (i.e., possibly, probably, and/or definitely related) to the molecularly targeted agent, in monotherapy or combination studies.

Generalized estimating equations with a compound symmetry correlation matrix for patients within the same trial were used to test whether the TI was different for patients <65 versus patients 65 and older. A similar analysis was used to test whether the dose intensity was different between patients from different age groups. Logistic regression with a compound symmetry correlation matrix was used to test for differences in the frequency of DLT between patients from different age groups. When examining at the frequency of DLT per cycle, an association was assumed to exist between patients from the same trial and between cycles from the same patient. Cycles closer to one another were assumed more likely to be associated, thus, a first-order autoregressive correlation matrix was assumed between cycles for the same patient with patients nested within the same trial. The correlation matrix is included as it is likely that the TI and the probability of having a DLT for patients within the same trial, and the probability of having a DLT for cycles from the same patient, are associated with one another. In other words, it is likely that patients given the same treatment will have similar levels of adverse events. Each analysis was done separately for monotherapy and combination trials. Statistical significance was defined as P 0.05 and all tests were two-sided. As a check of the results, a secondary analysis was done with age defined as a continuous variable, however, the results were similar, thus only the categorical results are shown for simplicity. Approval for this retrospective data analysis was obtained from the Princess Margaret Hospital Research Ethics Board.

	Results

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Molecularly targeted agents evaluated. All patients accrued to a Consortium trial that included a molecularly targeted drug, alone or in combination with a cytotoxic chemotherapeutic agent, were included in this study. A total of 401 patients who received 1,252 treatment cycles on 19 studies were analyzed (Table 1 ). Most studies were phase II, but three phase I and three phase I/II studies were also included. Only 32% of all patients were age 65 years or older, however, all studies had accrued at least one patient in both the older and younger age groups. The molecularly targeted agents evaluated in these studies have diverse mechanisms of anticancer activities by acting on a variety of cellular pathways. Examples include inhibitors of the epidermal growth factor receptor tyrosine kinase, mTOR pathway, and proteasome-ubiquitin pathway. A listing of the class of each molecularly targeted agent, based on its proposed mechanism(s) of anticancer activity, is included in Table 2 . The Consortium studies accrued patients from many different tumor sites, with gastrointestinal, gynecologic, genitourinary, head and neck cancers, and leukemia/lymphoma studies enrolling the greatest numbers of patients (Table 3 ).

Best response. The best objective responses achieved by the 401 patients are listed in Table 5, based on monotherapy versus multi-agent studies, and by age groups. The range of outcomes observed was similar between the two age groups. A comparison of treatment outcome by study type showed higher objective response and stabilization rates for the multi-drug trials than the single agent trials. This is an expected finding because the addition of a cytotoxic agent to a molecularly targeted agent in combination trials is likely to increase their response and stable disease rates.

Toxicity index and dose-limiting toxicities. The median TI_ALL observed by age group including adverse events of all causalities is shown in Table 6 . In all groups, the median TI_ALL was between 3 and 3.9, demonstrating that more than half of patients had at least one grade 3 adverse event while on study. No statistically significant difference was found for any comparison between age groups. When the TI_MTA is calculated based on adverse events that are at least possibly related to the molecularly targeted agent (Table 7 ), the results show a slightly lower TI but still consist of values between 3 and 3.9. This is an expected finding, as the TI should decrease when some adverse events are excluded from the total calculation; however, adverse events of a high grade are not likely to be attributed as unrelated to the molecularly targeted drug under evaluation, and therefore, the overall TI_MTA value still remains in the 3 to 3.9 range.

The detailed listing of TI_ALL and TI_MTA values by individual study for both age groups is provided in Table 8 . In general, the values of TI_ALL between the younger and older age groups were very similar, regardless of study type. The TI_MTA values in the older age group were slightly higher than those in the younger age groups in some studies, but the small number of older patients in these studies preclude any meaningful comparisons.

	Discussion

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With an aging population, there is an urgent need to optimize how we manage older patients with cancer. There are data suggesting that this portion of the population may be undertreated due to misconceptions of both clinicians and the patients themselves, about their ability to tolerate cancer treatment. Novel biologically targeted agents that aim to disrupt specific key properties of a tumor's neoplastic activities, whereas interfering with host functions to a relatively minor degree, promise a better therapeutic index than many conventional drug therapies. This study was undertaken based on the hypothesis that better evidence of the ability of older cancer patients to tolerate anticancer drug therapy, and molecularly targeted agents in particular, might result in greater clinical trial enrollment, and ultimately more and better anticancer treatment in this group.

Although these results are preliminary, our analyses show no clear differences in the frequency, type, or severity of toxicities between patients under or over 65 years of age treated with molecular-based therapies in the setting of clinical trials by our group. The baseline pretreatment characteristics of the two age groups were comparable, although older patients had more comorbidities than the younger group, and a higher proportion of the younger patients had received prior chemotherapy and radiotherapy. Dose intensities were calculated to ensure that older patients were not receiving less intensive therapy. Our results revealed that older patients were receiving dose intensities of molecularly targeted and chemotherapeutic agents comparable to their younger counterparts, and that there were no statistically significant differences between the frequencies and intensities of adverse events experienced by the different age groups. The use of generalized estimating equation modeling is necessary to allow for dependence between patients from the same trial (for patient-level outcomes), and between cycles of treatment received by the same patient. As a result of the modeling, statistical tests are not unduly influenced by one or two agents/trials with excess toxicity and variable age distributions compared with other agents/trials. These hierarchical-type statistical methods, although more complicated, are necessary to reduce the chance of observing an artificial relationship between age and toxicity. One further caveat that warrants cautious interpretation are the comparisons of median TI values and frequencies of DLT occurrences between age groups in Tables 6 and 7. It is possible that small differences in the frequency or intensity of adverse events experienced by the two age groups may exist, and the power to detect these differences was limited in this study. However, it is evident from the tables that these variables are similar between the older and younger patients. We estimated the differences in the median TI values and in the rates of DLT between age groups (data not shown), and no significant pattern was observed. Thus, although we cannot rule out the possibility of a small difference, we believe any difference is not likely to be clinically important.

The results can be considered internally valid, as patients entered into studies in which a molecularly targeted agent was combined with chemotherapy were consistently observed to have experienced more adverse events, regardless of age, than the patients entered into monotherapy studies involving a molecularly targeted agent alone. In particular, hematologic adverse events were more severe in these combination studies as expected.

Our analyses are limited in several ways. First, although a comparison of the patients' comorbidities was done, our database only captures those factors reported by the patients and subsequently recorded in source documents by the clinical trials team. As such, the capture of comorbid conditions depends largely on the completeness of the patients' reporting and some information may be missing. Second, the proportion of older patients accrued into clinical trials has been consistently lower than younger patients in the literature (19), and this is the case with our protocols as well. Therefore, there were greater numbers of younger patients included in the analysis for both monotherapy and combination trials than older patients. In addition, older patients accrued to these studies were required to meet certain baseline physical and metabolic criteria to be eligible. These patients are selected and likely represent the "well" elderly and our results may not be generalizable to all older patients. In clinical practice, comorbid illnesses are more prevalent among elderly patients than younger patients (24). In our study, older patients had more comorbidities than the younger patients but the difference was not statistically significant. This finding could likely be explained by patient selection, although one may conversely conclude that, as long as protocol eligibility criteria such as those specifying organ functions, performance status, and other conditions are met, chronological age alone should not influence enrollment decisions. Finally, our study has evaluated multiple molecularly targeted drugs in various tumor types, thus, our results cannot necessarily be applicable to all such agents in a specific way in view of the variety of these agents, their heterogeneous mechanisms of action, and adverse event profiles in different patient populations. Of note, another group examining the effects of patient characteristics on acute treatment toxicity in early phase clinical trials has used a similar methodology (23).

Molecularly targeted agents present a unique challenge when attempting to identify possible predictors of drug-related toxicity. Because molecularly targeted agents differ greatly in their modes of action, it is difficult to generalize the risk factors for toxicities to such varied groups of compounds. As these agents gain increased clinical use, more can be learned about the predictive factors for toxicities that are encountered by patients. For example, baseline hypertension may predispose to difficulties in tolerating antiangiogenic compounds (20, 21). These caveats, in most instances, have come from practical experiences in early clinical studies rather than from preclinical models.

There are few trials of molecularly targeted therapies in older populations with which to draw comparisons to our study. Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been evaluated retrospectively in an elderly population (25–28). Cappuzzo et al. showed that disease control could be obtained in >50% of 40 elderly patients with a median age of 74 years (range, 70-88 years) treated with gefitinib at a daily oral dose of 250 mg for advanced non–small cell lung cancer. Although no direct comparison was made between older and younger age groups in this study, it was found that the patients in the older age group tolerated the treatment extremely well (25). Grades 1 to 2 diarrhea occurred in only 24% of patients and only one patient experienced a grade 4 diarrhea. Grades 1 to 2 skin toxicity, the most common toxicity observed with gefitinib, occurred in 20 (50%) patients in this retrospective series. Other small subpopulation studies have found similar results both in Europe and in the U.S. where elderly patients with non–small cell lung cancer have tolerated this molecularly targeted agent very well based on the low number of adverse events (26–28).

Another molecularly targeted agent, bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, has been evaluated in a population at high risk (20, 21). In a randomized phase II trial, patients with metastatic colorectal cancer received bolus 5-fluorouracil and leucovorin with either bevacizumab or placebo. Patients accrued to this study had to be considered nonoptimal candidates for first-line irinotecan therapy based on age, performance status, previous treatment, or low baseline albumin levels. The median ages for patients on the bevacizumab and placebo arms were 70.7 and 71.3, respectively. Patients in the bevacizumab arm tolerated the regimen well and had a longer median survival than the control arm. The tolerability and efficacy of other molecularly targeted agents, however, has not been evaluated prospectively and specifically in older patients.

In order to accurately determine whether molecularly targeted treatments are similarly tolerated and effective in older cancer patients, prospective clinical trials need to be done enrolling these subjects in numbers sufficiently large to draw valid conclusions. Our study has provided some preliminary evidence suggesting that chronological age alone should not be a barrier to the consideration of treatment with these novel agents in an older patient population. With the increasing integration of molecularly targeted therapy in standard anticancer regimens, further research in this area is urgently needed.

	Footnotes

 
Grant support: Clinical Trial Contracts from the U.S. National Cancer Institute, No. N01-CM-17107.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/16/05; revised 12/15/05; accepted 12/21/05.

	References

Top Abstract Materials and Methods Results Discussion References

 

1. Yancik R. Cancer burden in the aged: an epidemiologic and demographic overview. Cancer 1997;80:1273–83.[CrossRef][Medline]
2. Ries LAG, Eisner MP, Kosary CL, et al., editors. SEER Cancer Statistics Review, 1975–2001, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2001/; 2004.
3. Hamerman D. Toward an understanding of frailty. Ann Intern Med 1999;130:945–50.[Free Full Text]
4. Balducci L. Geriatric oncology. Crit Rev Oncol Hematol 2003;46:211–20.[Medline]
5. Dale DC. Poor prognosis in elderly patients with cancer: the role of bias and undertreatment. J Support Oncol 2003;4:11–7.
6. Terret C. Management and geriatric assessment of cancer in the elderly. Expert Rev Anticancer Ther 2004;4:469–75.[CrossRef][Medline]
7. Magagnoli M, Castagna L, Timofeeva I, et al. High-dose chemotherapy supported by peripheral blood stem cell transplantation in elderly versus younger lymphoma patients: a matched analysis. Leuk Lymphoma 2003;44:1439–40.[CrossRef][Medline]
8. Jantunen E, Mahlamaki E, Nousiainen T, et al. Feasibility and toxicity of high-dose chemotherapy supported by peripheral blood stem cell transplantation in elderly patients (>/= 60 years) with non-Hodgkin's lymphoma: comparison with patients <60 years treated within the same protocol. Bone Marrow Transplant 2000;26:737–41.[CrossRef][Medline]
9. Tirelli U, Zagnoel V, Serraino D, et al. Non-Hodgkin's lymphomas in 137 patients age 70 and older: a retrospective European Organization for Research and Treatment of Cancer Lymphoma Group Study. J Clin Oncol 1988;6:1708–13.[Abstract/Free Full Text]
10. Silliman RA, Guadagnoli E, Weitberg AB. Age as a predictor of diagnostic and initial treatment intensity in newly diagnosed cancer patients. J Gerontol 1989;44:M46–50.
11. Gomez H, Mas L, Casanova L, et al. Elderly patient's with aggressive non-Hodgkin's lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor: identification of two age groups with differing hematologic toxicity. J Clin Oncol 1998;16:2352–8.[Abstract]
12. Christman K, Muss HB, Case LD, Stanley V. Chemotherapy of metastatic breast cancer in the elderly. The Piedmont Oncology Association experience. JAMA 1992;268:57–62.[Abstract/Free Full Text]
13. Sekine I, Yamamoto N, Kunitoh H, et al. Treatment of small cell lung cancer in the elderly based on a critical literature review of clinical trials. Cancer Treat Rev 2004;30:359–68.[CrossRef][Medline]
14. Ceccaroni M, D'Agostino G, Ferrandina G, et al. Gynecological malignancies in elderly patients: is age 70 a limit to standard dose chemotherapy? An Italian retrospective and multicentric study. Gynecol Oncol 2002;85:445–50.[CrossRef][Medline]
15. Goffin JR, Rajan R, Souhami L. Tolerance of radiotherapy and chemotherapy in elderly patients with bladder cancer. Am J Clin Oncol 2004;27:172–77.[CrossRef][Medline]
16. Giovanazzi-Banon S, Rademaker A, Lai G, Benson AB III. Treatment tolerance of elderly cancer patients entered onto phase II clinical trials: an Illinois Cancer Center study. J Clin Oncol 1994;112:2447–52.
17. Shepherd FA, Abratt RP, Anderson H, et al. Gemcitabine in the treatment of elderly patients with advanced non-small cell lung cancer. Semin Oncol 1997;24:S7-50–5.
18. Fata F, Mirza A, Craig G, et al. Efficacy and toxicity of adjuvant chemotherapy in elderly patients with colon carcinoma: a 10 year experience of the Geisinger Medical Center. Cancer 2002;94:1931–8.[CrossRef][Medline]
19. Townsley CA, Selby R, Siu LL. Systematic review of barriers to the recruitment of older patients with cancer onto clinical trials. J Clin Oncol 2005;23:3112–24.[Abstract/Free Full Text]
20. Kabbinavar FF, Schulz J, McCleod M, et al. Addition of Bevacizumab to bolus Fluorouracil and Leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005;23:3697–705.[Abstract/Free Full Text]
21. Kabbinavar FF, Ellis LM. Can inhibition of angiogenic pathways increase the efficacy of intravenous 5-fluorouracil-based regimens? Clin Colorectal Cancer 2004;4:S69–73.
22. Charlson ME, Pompei P, Ales KL, Mackenzie CR. A new method of classifying prognostic co-morbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83.[CrossRef][Medline]
23. Rogatko A, Babb JS, Wang H, et al. Patient characteristics compete with dose as predictors of acute treatment toxicity in early phase clinical trials. Clin Cancer Res 2004;10:4645–51.[Abstract/Free Full Text]
24. Boyd CM, Darer J, Boult C, et al. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA 2005;294:716–24.[Abstract/Free Full Text]
25. Capuzzo F, Bartolini S, Ceresoli GL, et al. Efficacy and tolerability of gefitinib in pretreated elderly patients with advanced non-small-cell lung cancer (NSCLC). Br J Cancer 2004;90:82–6.[CrossRef][Medline]
26. Stahel R, Rossi A, Petruzelka L, et al. Lessons from the Iressa expanded access programme: gefitinib in special non-small-cell lung cancer patient populations. Br J Cancer 2003;89:S19–23.
27. Copin M, Kommareddy A, Behnken D, et al. Gefitinib in elderly patients with non-small cell lung cancer (NSCLC) [abstr 3048]. Proc Am Soc Clin Oncol 2003;22:758.
28. Soto Parra H, Cavina R, Zucali P, et al. Gefitinib in elderly patients with progressive, pretreated, non-small cell lung cancer: results from the Istituto Clinico Humanitas. Br J Cancer 2003;89:S25–35.[CrossRef]

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