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Phase II Study of Docetaxel and Celecoxib, a Cyclooxygenase-2 Inhibitor, in Elderly or Poor Performance Status (PS2) Patients with Advanced Non-small Cell Lung Cancer
ORIGINAL ARTICLE
Phase II Study of Docetaxel and Celecoxib, a Cyclooxygenase-2 Inhibitor, in Elderly or Poor Performance Status (PS2) Patients with Advanced Non-small Cell Lung Cancer Shirish M. Gadgeel, MD,* Antoinette Wozniak, MD,* John C. Ruckdeschel, MD,* Lance K. Heilbrun, PhD,* Raghu Venkatramanamoorthy, MS,* Ruth A. Chaplen, MSN, RN,* Michael J. Kraut, MD,*† and Gregory P. Kalemkerian, MD‡
Introduction: The utility of two-drug chemotherapy regimens in elderly or performance status (PS 2) patients with advanced nonsmall cell lung cancer (NSCLC) remains to be established. Preclinical studies suggested that celecoxib, a Cyclooxygenase-2 inhibitor, has antitumor activity in NSCLC and can enhance the activity of chemotherapy drugs. We conducted a phase II study to evaluate the efficacy of the combination of weekly docetaxel and celecoxib in advanced NSCLC patients, who were either elderly (ⱖ70 years) or PS2. Methods: Patients with stage IIIB (with pleural effusion) or IV NSCLC who were ⱖ70 years and had a PS of 0 –2 or patients of any age with a PS of 2 were included. Patients should have been off any nonsteroidal anti-inflammatory drug for 30 continuous days before study enrollment. Patients were treated with weekly docetaxel 36 mg/m2 i.v. on days 1, 8, 15 of a 28 day cycle and Celecoxib 400 mg po twice daily. Disease assessment was performed after every two cycles. The study design required 39 patients. Results: Study was terminated after 34 patients were enrolled due to safety concerns regarding celecoxib. Thirty patients were evaluable. The response rate was 15%. The median progression free survival and median survival were 2.3 months and 5.0 months, respectively. The median survival of patients ⱖ70 years old with a PS of 0 –1 was 8.3 months and the median survival of PS2 patients was 2.8 months. The combination was well tolerated with fatigue as the most common adverse effect. Two patients developed arterial thrombotic events. *Thoracic Oncology Program, Karmanos Cancer Institute/Wayne State University, Detroit, Michigan; †Providence Hospital, Southfield, Michigan; and ‡Division of Hematology & Oncology, Department of Medicine, University of Michigan, Ann Arbor, Michigan. Disclosure: Dr. Gadgeel: Speaker’s Bureau, Sanofi-Aventis, Research funding from Pfizer. Dr. Wozniak: Speaker’s Bureau, Sanofi-Aventis, served on Advisory boards for Sanofi-Aventis. Aventis (Currently Sanofi-Aventis) provided funding. Celecoxib was provided by Pharmacia (Currently Pfizer). Supported in part by Cancer Center Support Grant CA-22453, from the National Cancer Insitute. Address for correspondence: Shirish M. Gadgeel, MD, 4100 John R, 4 HWCRC, Detroit, MI 48201. E-mail: [email protected] Michael J. Kraut is currently at Providence Hospital, Southfield, Michigan. Copyright © 2008 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/08/0311-1293
Conclusion: In these ‘special populations’ of patients with advanced NSCLC, the addition of celecoxib to docetaxel did not seem to improve the outcome compared with single agent docetaxel. Key Words: Elderly, PS2, COX-2, Docetaxel, Celecoxib, Nonsmall cell lung cancer. (J Thorac Oncol. 2008;3: 1293–1300)
L
ung cancer is the most common cause of cancer related mortality in the United States.1 The high rate of mortality is primarily due to the advanced stage of lung cancer in most patients at presentation. Two-drug chemotherapy regimens are the current standard of care for patients with advanced non-small cell lung cancer (NSCLC), because they can improve overall survival and quality of life. However, the benefits of such therapy are modest, with a median progression free survival of 4 months and median survival of 8 to 10 months.2 The median age at presentation of lung cancer patients in United States is currently 71 years, and is likely to increase further with the continued aging of the population.3,4 Elderly patients often have age-related changes in organ function and multiple comorbidities requiring medications that increase the risk of adverse drug interactions.5,6 These factors can make decisions regarding therapy for advanced lung cancer in this patient population very challenging. Retrospective analyses of clinical trials assessing two-drug chemotherapy regimens have shown that the therapeutic benefits in elderly patients are similar to those in younger patients.7,8 In addition, studies have suggested that age alone is not a negative prognostic factor.9,10 However, elderly patients are significantly underrepresented in therapeutic trials, so these results may be influenced by a selection bias.11,12 The largest prospective study conducted specifically in elderly patients with NSCLC failed to show an advantage for a two-drug chemotherapy regimen over single-agent therapy.13 It is also clear that certain toxicities, particularly myelosuppression and fatigue, are greater with two-drug regimens in the elderly. Based on these data the current American Society of Clinical
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Oncology guidelines consider single-agent therapy or a twodrug regimen as acceptable alternatives for the treatment of elderly patients with advanced NSCLC.14 Performance status (PS) has consistently emerged as an independent prognostic factor for patients with NSCLC.15,16 PS represents the impact of tumor-related symptoms, comorbidities, and complications of medical interventions on the patient. Like elderly patients, patients with poor PS are underrepresented in clinical trials since many studies have restricted eligibility to patients with a PS of 0 –1. The utility and toxicity of two-drug chemotherapy regimens in PS2 patients remains unresolved.17–19 Cyclooxygenase (COX) is a rate-limiting enzyme involved in the conversion of arachidonic acid to prostaglandins (PG).20 COX-2, an isoform of COX, is overexpressed in neoplastic tissues in response to various stimuli21–23 and, through the production of PG, COX-2 is involved in both carcinogenesis and tumor progression.24 –27 Many NSCLCs express COX-2, and preclinical evidence suggests that the selective COX-2 inhibitor, celecoxib, can inhibit NSCLC growth, both alone and in conjunction with cytotoxic chemotherapy.28 –30 In addition, taxanes and vinca alkaloids can induce the expression of COX-2 in tumors, potentially limiting the antitumor activity of these agents and inducing adverse side-effects.31,32 Therefore, the addition of a COX-2 inhibitor may enhance the activity of cytotoxic drugs by blocking COX-2 induction. We hypothesized that addition of a ‘biologic agent’ to a cytotoxic drug in elderly and poor PS patients may be more effective than single chemotherapy drug but better tolerated than two-drug chemotherapy regimens. Based on the promising preclinical activity of COX-2 inhibitors in combination with chemotherapy agents, particularly taxanes, we conducted a phase II study evaluating the addition of celecoxib to docetaxel in previously untreated elderly (ⱖ70 years) or PS 2 patients with advanced NSCLC. Celecoxib was administered at a dose of 400 mg twice daily based on the results of studies in patients with familial adenomatous polyposis coli33 and docetaxel, administered weekly, was selected as the cytotoxic agent based on prior phase II studies that suggested lower toxicity and comparable efficacy.34
Treatment Patients were instructed to take celecoxib 400 mg po twice daily with meals. One week after starting celecoxib patients were started on docetaxel at 36 mg/m2 IV on days 1, 8, and 15 of a 28 day cycle. Thus, the first cycle was 5 weeks long, while subsequent cycles were of 4 weeks duration. Patients were premedicated for docetaxel with dexamethasone 4 mg the evening before the day of treatment and twice on the day of treatment. Antiemetic prophylaxis and management and use of hematopoietic growth factors was left to the discretion of each treating physician. While on therapy each patient was assessed every 2 weeks with history and physical examination and laboratory evaluation. After 4 cycles, patients could be evaluated every 4 weeks if they did not have any toxicity ⬎ grade 2. Response was assessed every two cycles according to the Response Evaluation Criteria in Solid Tumors criteria.35 Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. Appropriate dose-modification and dose-delay of docetaxel were planned for hematologic and hepatic toxicities, peripheral neuropathy, and stomatitis. The dose of celecoxib was reduced by 25% for an increase in serum creatinine of 50 to 100% over baseline, and celecoxib was held for an increase ⬎100%. Both drugs were held for a maximum of 14 days for any other grade 3– 4 toxicity and could be restarted at the same dose upon recovery to grade 1. Patients could continue on one of the drugs if the other drug was held due to specific toxicity.
Statistical Methods
PATIENTS AND METHODS Patient Selection Eligible patients included those with histologically or cytologically confirmed, previously untreated stage IIIB (with pleural effusion) or IV NSCLC who were ⱖ70 years of age with PS 0 –2 or ⱖ18 years of age with PS 2. Patients could have undergone prior surgery or radiation therapy but were not eligible if they had received any prior chemotherapy. Other inclusion criteria were: measurable or evaluable disease; bilirubin ⱕ upper limit of normal (ULN); aspartate transaminase and alanine aminotransferase ⱕ2.5 ⫻ ULN; alkaline phosphatase ⱕ5 ⫻ ULN; creatinine ⱕ1.5 ⫻ ULN; hemoglobin ⱖ8 g/dL; neutrophil count ⱖ1.5 ⫻ 109/liter; platelets ⱖ100,000 ⫻ 109/liter. Patients were excluded if they were taking nonsteroidal anti-inflammatory drugs for more than 30 continuous days
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before enrollment. Patients were instructed not to take nonsteroidal anti-inflammatory drugs while on study, except for aspirin ⱕ325 mg/d. Patients were excluded if they had an allergy to sulfa drugs or a history of gastrointestinal hemorrhage, MI, or cerebrovascular event within 6 months. Patients with history of venous thromboembolic phenomena within 4 weeks of study entry were excluded. Patients with brain metastases were eligible as long as they had been treated and had no symptoms from the brain metastases. All patients were required to provide signed informed consent before enrollment. The Human Investigation Committees of participating institutions approved the protocol.
The primary objective of this study was to assess the 6-month survival rate in patients treated with the combination of docetaxel and celecoxib. PS was assessed according to the Southwest Oncology Group criteria that define PS 2 as ‘Ambulatory and capable of all self-care but unable to carry out any work activities; Up and about more than 50% of waking hours.’ Secondary endpoints were response, toxicity, progression free survival (PFS), and overall survival (OS). PFS was defined as the time from the first day of treatment until the date when progressive disease was documented or death from any cause, whichever came first. Surviving patients who did not progress were censored for PFS as of the date of their last tumor assessment. OS was defined as the time from the first day of treatment until the date of death from any cause. Patients were deemed evaluable for response if they received at least one dose of each drug.
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This phase II trial was planned with a Simon two-stage minimax design.36 The primary end point was survival for at least 6 months (yes/no). We wished to distinguish these regions of the true, unknown 6 month survival proportion: at most 0.35 versus at least 0.55. The two-stage design called for a maximum of 39 evaluable patients, 21 in stage 1 and 18 in stage 2. The design had power of 0.80 and overall Type I error of 0.05. At least nine 6-month survivors among the first 21 patients were needed to justify beginning stage 2 of the study design. We observed nine 6-month survivors during stage 1. Enrollment to the trial slowed considerably due to increasing number of reports regarding the safety of COX-2 inhibitors. Therefore accrual was stopped after 34 patients had been registered on the trial which reduced the power of the study design slightly, to 0.761. With only 14 six-month survivors among the 34 patients (sample estimate of 41%), it was concluded that the true, unknown 6 month survival proportion was at most 0.35. Exact, minimum-width 90% confidence intervals (CI) for response and toxicity rates were calculated using the
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Casella method37 as implemented in StatXact software.38 Standard Kaplan-Meier estimates of the censored PFS and OS distributions were computed. Due to the small sample sizes, survival statistics (e.g., median) were estimated more conservatively using linear interpolation among successive event times on the Kaplan-Meier curves.39
RESULTS Patient Characteristics Thirty-four patients were enrolled from November 2001 to October 2004 (Table 1) at the two participating institutions. The median age was 73 years for all patients (range, 51– 82 years) and 71% were male. Of the 34 patients enrolled, 27 (79%) were ⱖ70 years old and of the elderly patients, 15 (44%) had a PS of 0 –1. Overall, 19 (56%) patients had PS2, including 12 who were ⱖ70 years of age and 7 who were ⬍70 years of age. Ten patients were older than 75 years and 5 of them had a PS of 2. Only 2 patients had stage IIIB disease.
Response and Survival TABLE 1. Patient Demographics Number Age Range (yr) Median (yr) Gender Males Females Stratification group Age ⱖ70 yr Age ⱖ70 yr, PS 0–1 PS 2, any age Stage IV IIIB
34 51–82 73 24 (71%) 10 (29%) 27 (79%) 15 (44%) 19 (56%) 32 (94%) 2 (6%)
PS, performance status.
Four patients did not receive at least one dose of both drugs and therefore were not evaluable for response (Table 2 and Figures 1–3). One patient, who previously had episodic hyperkalemia due to renal tubular acidosis, developed hyperkalemia after being on celecoxib for 4 days and was taken off study. Three patients started on celecoxib, but did not receive their first dose of docetaxel due to a decline in PS (2 patients) or a fall resulting in hip fracture (1 patient). Response rate and survival were analyzed according to both intention to treat analysis and according to protocol-defined analysis (evaluable patients only), and all the end-points were similar by both analyses. Results are presented according to the intention to treat analysis. Among the 34 enrolled patients, 1 patient had a complete response (CR) and 4 patients had a partial response (PR), for an overall response rate of 15% (Table 2). Ten other patients had stable disease, for an overall clinical benefit rate of 44% (90% CI, 0.15– 0.46). The response rate for the 15 patients with PS 0 –1 was 20% and for the 19 patients with PS 2 was 11%.
TABLE 2. Response Rate (RR), Progression Free Survival (PFS), and Overall Survival (OS) with Docetaxel Plus Celecoxib (90% Confidence Interval) PFS
OS
Patients
N
RR
Median (mo)
6-mo Rate
Median (mo)
6-mo Rate
All patients
34
15% (0.06–0.30)
2.3 (1.4–3.4)
14% (0.05–0.24)
5.0 (2.4–7.9)
38% (0.25–0.52)
ⱖ70 yr All
27
19% (0.09–0.35) 20% (0.08–0.42)
3.4 (2.0–3.8) 3.9 (3.4–5.7)
18% (0.06–0.30) 20% (0.03–0.37)
5.7 (2.6–9.1) 8.3 (4.7–10.2)
44% (0.29–0.60) 60% (0.39–0.80)
11% (0.03–0.27)
2.0 (1.8–2.2)
8% (0.00–0.17)
2.8 (2.1–4.8)
21% (0.06–0.36)
PS0–1
15
Any age PS 2
19
RR, response rate; PS, performance status; PFS, progression free survival; OS, overall survival.
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FIGURE 1. The Kaplan-Meier estimate of progression free survival (PFS) in the 34 patients. The dashed lines represent the 90% confidence interval (CI) about each successive estimate of the progression free rate.
The median PFS for all 34 patients (Figure 1) was 2.3 months, and the 6-month progression-free survival rate was 14%. For the 15 patients ⱖ70 years old with PS 0 –1, the median PFS was 3.9 months, and the 6-month progressionfree survival rate was 20%. For the 19 patients with PS 2, the median PFS was 2.0 months, and the 6-month progressionfree survival rate was 8%. The median OS for all 34 patients (Figure 2) was 5.0 months, and the 6-month OS rate was 38%. For the 15 elderly patients with PS 0 –1, the median survival (Figure 3) was 8.3 months and the 6-month OS rate was 60%. For the 19 patients with PS 2, the median survival was 2.8 months, and the 6-month survival rate was 21%. The median OS of the 10 patients ⱖ75 years old was 2.7 months, and the 6-month survival rate was 28%. Detailed information on treatment after discontinuation of study treatment was not collected. Nevertheless none of the patients with PS 2 were able to receive subsequent therapy.
Toxicity Eighty-two cycles of combination therapy were administered and the median number of cycles was 2 (range, 1– 6). Only 3 patients continued celecoxib after docetaxel was discontinued (Table 3). The combination was generally well tolerated. The main nonhematologic toxicity was fatigue. None of the patients required dose modifications and all but two patients discontinued therapy for progression of disease. One patient discontinued treatment because of emesis and
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one patient for fatigue. Two patients developed arterial thrombotic events, 65-year-old male with a myocardial infarction (MI) and 71-year-old with a cerebrovascular event. In addition, two patients developed venous thrombotic events. One patient with a history of prior intestinal surgery and adhesions developed a fatal intestinal obstruction. No death was deemed to be directly related to the treatment though the patient with MI died of cardiac complications.
DISCUSSION In this phase II study we attempted to develop a regimen that would be less toxic than standard two-drug chemotherapy regimens and more effective than single-agent therapy in select patients with advanced NSCLC. Nevertheless, it seems that the results obtained with celecoxib plus weekly docetaxel in elderly and/or PS 2 patients with advanced NSCLC are similar to those expected with docetaxel alone. Two-drug chemotherapy regimens are the current standard for the management of patients with advanced NSCLC, but are not accepted as the sole standard for elderly and PS 2 patients. The primary concern with two-drug chemotherapy regimens in these patients is the occurrence of undue toxicity that could diminish the magnitude of any potential benefit. Therefore, elderly and PS 2 patients were frequently lumped together in trials evaluating treatment strategies that are presumed to have lower toxicity.40,41 It is now increasingly clear that these two groups of patients should be evaluated
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Phase II Study of Docetaxel and Celecoxib
FIGURE 2. The Kaplan-Meier estimate of overall survival (OS) in the 34 patients. The dashed lines represent the 90% confidence interval (CI) about each successive estimate of the survival rate. The 12-month OS rate is 17%, with 90% CI of 0.06 – 0.27.
separately since each group has distinct clinical issues and prognoses that require independent evaluation. Docetaxel is considered one of the most active agents in the management of NSCLC.42 In a phase III study reported by Kudoh et al.43 every 3 week docetaxel demonstrated superior PFS and response rate as compared with vinorelbine in elderly patients. A higher rate of neutropenia and emesis was observed in patients who received docetaxel and this is consistent with other docetaxel trials.44,45 In a recently reported randomized phase II study by Lilenbaum et al. evaluating weekly docetaxel versus every 3 week docetaxel in the same population as our study, the weekly schedule resulted in fewer hematologic toxicities and slightly better survival, with median PFS of 2.3 months and median survival of 6.7 months.46 Nevertheless there were no differences in infection/ febrile neutropenia rate, the rate of nonhematologic toxicities and there was no difference in the quality of life between the two schedules. These outcomes are very similar to the outcomes observed in our current study, suggesting that the addition of celecoxib did not augment the activity of docetaxel. It has become increasingly evident that age alone should not determine therapeutic decisions. Nonetheless, deciding upon therapy in the elderly, particularly in patients over 75 years of age can be very challenging. It is important to note that the number of patients over 75 years old is small even in elderly-specific studies, and therefore the data available to guide therapy in this population is very limited. In the Multicenter Italian Lung Cancer in the Elderly Study, only
33% of patients were ⱖ75 years old and only 3% were ⱖ80 years old.13 In our study 30% of patients were ⱖ75 years old and 9% were ⱖ80 years old. The median survival of these 10 patients ⱖ75 years old was only 2.7 months. Therefore, even though two-drug therapy is often considered in elderly patients with good PS, appropriate clinical assessment of the patient’s disease status, comorbid illnesses, and functional status are critical in deciding upon the appropriate therapy for any particular elderly patient, particularly those who are ‘very’ old. The investigators of the Multicenter Italian Lung Cancer in the Elderly Study recently reported that pretreatment quality of life and functional status predicted prognosis in elderly patients.47 Utilizing these assessments prospectively in future trials may help define elderly patients who could tolerate and benefit from two-drug therapy. The results in PS 2 patients in our study are disappointing in that they are again similar to those of prior studies evaluating single-agent therapy. Many large randomized trials have excluded PS 2 patients and prospective trials specifically targeting PS 2 patients are limited, making therapeutic decisions challenging. Eastern Cooperative Oncology Group 1599 was the first prospective PS 2 specific clinical trial conducted in the United States. This randomized phase II trial evaluating paclitaxel or gemcitabine in combination with carboplatin found median survival greater than 6 months in both arms.48 Cancer and Leukemia Group B (CALGB) 9730 is the only US-based clinical trial that compared a thirdgeneration single agent, paclitaxel versus the combination of
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FIGURE 3. The Kaplan-Meier estimate of overall survival (OS) in the 15 elderly patients with PS 0 –1. The dashed lines represent the 90% confidence interval (CI) about each successive estimate of the survival rate. The 12-month OS rate is 18%, with 90 CI of 0.02– 0.34. TABLE 3. Toxicity Grade of Toxicity Toxicity
n (%)a
1
2
3
4
Fatigue Anorexia Nausea/emesis Renal Edema Arterial/venous thrombosis Anemia Neutropenia Thrombocytopenia
9 (30%) 7 (23%) 7 (23%) 3 (10%) 5 (17%) 4 (13%) 7 (33%) 6 (20%) 5 (17%)
2 6 5 2 4
1 1 2 1 1
2
4
1 4 5
2 2
4
4
One patient each was admitted to the hospital with myocardial infarction, cerebrovascular event, pulmonary embolism, deep venous thrombosis, pneumonia, bowel obstruction, syndrome of inappropriate antidiuretic hormone. a Number of patients who developed all grades of the particular toxicity. Thirty patients were evaluable for toxicity.
paclitaxel and carboplatin in advanced NSCLC. The study prespecified analysis of patient outcomes based on PS status. The median survival of 4.7 months with the combination among the PS 2 subset was significantly better than the median survival of 2.4 months with single-agent paclitaxel (p ⫽ 0.0213).19 The results of both these trials support the use of two drug cytotoxic therapy in PS 2 patients. Nevertheless in a randomized phase II study from Greece the outcomes in
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PS 2 patients with gemcitabine alone or carboplatin plus gemcitabine were similar.18 Results in PS 2 patients need to be viewed with caution due to the recognized variability in PS assessment and in the causes for poor PS. An emerging strategy that has not been validated in clinical trials is to differentiate patients with PS 2 due to comorbid illnesses from those with PS 2 as a result of NSCLC-related symptoms, and to use two-drug regimens in patients with impaired PS due to NSCLC and single-agent therapy in those with PS 2 due to comorbid illnesses. Based on preclinical data regarding the role of COX-2 in carcinogenesis and tumor progression, COX-2 inhibitors have been evaluated in both cancer prevention and therapy. In prospective randomized trials, celecoxib has reduced the incidence of precancerous colonic lesions,33,49,50 suggesting a potential role in cancer prevention. Nevertheless, the results achieved with COX-2 inhibitors in therapeutic trials have been less convincing.51–54 In a recent randomized CALGB trial, the addition of celecoxib to a platinum-based two-drug chemotherapy regimen did not provide any additional benefit in patients with advanced NSCLC.55 Nevertheless, a retrospective analysis from the CALGB study suggests that patients with tumors that expressed COX-2 at moderate or high levels did have an improvement in survival with the addition of celecoxib. In addition patients with tumors that had low expression of COX-2 had inferior survival, if they received celecoxib as compared with if they just received chemotherapy. Thus these results suggest that celecoxib may be bene-
Copyright © 2008 by the International Association for the Study of Lung Cancer
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ficial in patients with tumors that express COX-2 but it maybe detrimental in patients with low expression of COX-2 in their tumors. Based on the results of this study there is an interest in conducting a trial evaluating a COX-2 inhibitor in patients with NSCLCs that express COX-2. It is possible that the disappointing results noted in our trial could be due to lack of preselection of patients with COX-2 expressing tumors. Csiki et al.51 evaluated docetaxel plus celecoxib in patients with previously treated NSCLC. Though the overall results did not suggest an improvement in survival with the addition of celecoxib, the investigators did observe that patients who had the greatest proportional drop in urinary prostaglandin E (PGE-M), a metabolite of PGE-2 and a marker of systemic PGE-2 levels, had a substantially reduced risk of death compared with patients in whom no change in PGE-M levels were observed. There are also data to suggest that appropriate characterization of the enzymes involved in PGE2 synthesis and metabolism in a patient’s tumor may be important in selecting patients for treatment with COX-2 inhibitors.56 For example, 15- PG dehydrogenase, an enzyme responsible for PGE2 elimination, may be down-regulated in some NSCLCs, and in patients with such tumors celecoxib may actually promote tumor proliferation. Recent results have shown that the risk of cardiovascular events is increased with the use of COX-2 inhibitors. In two large randomized studies evaluating celecoxib for chemoprevention, the incidence of cardiovascular events was 1.3 to 3.4 times higher than in patients receiving placebo.49,50 It may be reasonable to assume that elderly patients might be at particular higher risk for such an effect. In our study two patients developed arterial thrombotic events while on therapy. The increased incidence of cardiovascular events with COX-2 inhibitors may limit their use in elderly patients. In conclusion, the results of this study show that the addition of celecoxib to weekly docetaxel does not seem to be beneficial in elderly and/or PS 2 patients with advanced NSCLC. It is possible that this strategy may be beneficial if patients are selected based on COX-2 expression. The concept of combining single-agent chemotherapy with a biologic agent to minimize toxicity and improve efficacy over twodrug cytotoxic chemotherapy regimens should also be further explored in these ‘special populations.’
5. 6. 7. 8.
9. 10. 11. 12. 13.
14. 15. 16.
17.
18.
19. 20.
ACKNOWLEDGMENTS Supported by Aventis (currently Sanofi-Aventis) provided funding. Celecoxib was provided by Pharmacia (currently Pfizer). Supported, in part, by Cancer Center Support Grant CA-22453 from the National Cancer Institute.
21.
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genase 2 occurs frequently in human cancers, specifically in adenocarcinomas. Cancer Res 1998;58:3761–3764. Wolff H, Saukkonen K, Antilla S, et al. Expression of cyclooxygenase in human lung carcinoma. Cancer Res 1998;58:4997–5001. Hida T, Kozaki K, Muramatsu H, et al. Cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines. Clin Cancer Res 2000;6:2006 – 2011. Subbaramaiah K, Marmo TP, Dixon DA, et al. Regulation of cyclooxgenase-2 mRNA stability by taxanes: evidence for involvement of p38, MAPKAPK-2, and HuR. J Biol Chem 2003;278:37637–37647. Altorki NK, Port JL, Zhang F, et al. Chemotherapy induces the expression of cyclooxygenase-2 in non-small cell lung cancer. Clin Cancer Res 2005;11:4191– 4197. Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000;342:1946 –1952. Hainsworth JD, Burris HA, Litchy S, et al. Weekly docetaxel in the treatment of elderly patients with advanced non-small cell lung carcinoma. A Minnie Pearl Cancer Research Network Phase II Trial. Cancer 2000;89:328 –333. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205–216. Simon R. Optimal Two-Stage designs for phase II clinical trials. Controlled Clinical Trials 1989;10:1–10. Casella G. Refining binomial confidence intervals. Can J Stat 1986;14: 113–129. Mehta C, Patel N. StatXact 6: statistical software for exact nonparametric inference, user manual. Cambridge, MA: Cytel Software Corporation, 2003. Pp. 1–29. Lee E. Statistical Methods for Survival Data Analysis, 3rd Ed. New York, NY: Wiley & Sons Inc., 2003. Pp. 76 –91. Hesketh PJ, Chansky K, Lau DH, et al. Sequential vinorelbine and docetaxel in advanced non-small cell lung cancer patients age 70 and older and/or with a performance status of 2: a phase II trial of the Southwest Oncology Group (S0027). J Thorac Oncol 2006;1:537–544. Hainsworth JD, Spigel DR, Farley C, et al. Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced non-small cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network. Cancer 2007;110:2027–2034. Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21:3016 –3024. Kudoh S, Takeda K, Nakagawa K, et al. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-
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45.
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47.
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49. 50. 51. 52.
53. 54.
55.
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cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol 2006;24:3657–3663. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095–20103. Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354 –2362. Lilenbaum R, Rubin M, Samuel J, et al. A randomized phase II trial of two schedules of docetaxel in elderly or poor performance status patients with advanced non-small cell lung cancer. J Thorac Oncol 2007;2:306 – 311. Maione P, Perone F, Gallo C, et al. Pretreatment quality of life and functional status assessment significantly predict survival of elderly patients with advanced non-small-cell lung cancer receiving chemotherapy: a prognostic analysis of the multicenter Italian lung cancer in the elderly study. J Clin Oncol 2005;23:6865– 6872. Langer C, Li S, Schiller J, et al. Randomized phase II trial of paclitaxel plus carboplatin or gemcitabine plus cisplatin in Eastern Cooperative Oncology Group performance status 2 non-small-cell lung cancer patients: ECOG 1599. J Clin Oncol 2007;25:418 – 423. Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006;355:873– 884. Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006;355:885– 895. Csiki I, Morrow JD, Sandler A, et al. Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer: a phase II trial of celecoxib and docetaxel. Clin Cancer Res 2005;11:6634 – 6640. Gadgeel SM, Thatai L, Kraut M, et al. Phase II study of celecoxib and docetaxel in non-small cell lung cancer (NSCLC) patients with progression after platinum-based therapy. Proc Am Soc Clin Oncol 2003;22: abstract 2749. El-Rayes BF, Zalupski MM, Shields AF, et al. A phase II study of celecoxib, gemcitabine, and cisplatin in advanced pancreatic cancer. Invest New Drugs 2005;23:583–590. Lilenbaum R, Socinski MA, Altorki NK, et al. Randomized phase II trial of docetaxel/irinotecan and gemcitabine/irinotecan with or without celecoxib in the second-line treatment of non-small-cell lung cancer. J Clin Oncol 2006;24:4825– 4832. Edelman MJ, Watson DM, Wang X, et al. Eicosanoid modulation in advanced lung cancer: cyclooxygenase-2 expression is a positive predictive factor for celecoxib ⫹ chemotherapy–Cancer and Leukemia Group B Trial 30203. J Clin Oncol 2008;26:848 – 855. Csiki I, Johnson DH. Did targeted therapy fail cyclooxygenase too? J Clin Oncol 2006;24:4798 – 4800.
Copyright © 2008 by the International Association for the Study of Lung Cancer
Phase II Study of Docetaxel and Celecoxib, a Cyclooxygenase-2 Inhibitor, in Elderly or Poor Performance Status (PS2) Patients with Advanced Non-small Cell Lung Cancer Shirish M. Gadgeel, MD,* Antoinette Wozniak, MD,* John C. Ruckdeschel, MD,* Lance K. Heilbrun, PhD,* Raghu Venkatramanamoorthy, MS,* Ruth A. Chaplen, MSN, RN,* Michael J. Kraut, MD,*† and Gregory P. Kalemkerian, MD‡
Introduction: The utility of two-drug chemotherapy regimens in elderly or performance status (PS 2) patients with advanced nonsmall cell lung cancer (NSCLC) remains to be established. Preclinical studies suggested that celecoxib, a Cyclooxygenase-2 inhibitor, has antitumor activity in NSCLC and can enhance the activity of chemotherapy drugs. We conducted a phase II study to evaluate the efficacy of the combination of weekly docetaxel and celecoxib in advanced NSCLC patients, who were either elderly (ⱖ70 years) or PS2. Methods: Patients with stage IIIB (with pleural effusion) or IV NSCLC who were ⱖ70 years and had a PS of 0 –2 or patients of any age with a PS of 2 were included. Patients should have been off any nonsteroidal anti-inflammatory drug for 30 continuous days before study enrollment. Patients were treated with weekly docetaxel 36 mg/m2 i.v. on days 1, 8, 15 of a 28 day cycle and Celecoxib 400 mg po twice daily. Disease assessment was performed after every two cycles. The study design required 39 patients. Results: Study was terminated after 34 patients were enrolled due to safety concerns regarding celecoxib. Thirty patients were evaluable. The response rate was 15%. The median progression free survival and median survival were 2.3 months and 5.0 months, respectively. The median survival of patients ⱖ70 years old with a PS of 0 –1 was 8.3 months and the median survival of PS2 patients was 2.8 months. The combination was well tolerated with fatigue as the most common adverse effect. Two patients developed arterial thrombotic events. *Thoracic Oncology Program, Karmanos Cancer Institute/Wayne State University, Detroit, Michigan; †Providence Hospital, Southfield, Michigan; and ‡Division of Hematology & Oncology, Department of Medicine, University of Michigan, Ann Arbor, Michigan. Disclosure: Dr. Gadgeel: Speaker’s Bureau, Sanofi-Aventis, Research funding from Pfizer. Dr. Wozniak: Speaker’s Bureau, Sanofi-Aventis, served on Advisory boards for Sanofi-Aventis. Aventis (Currently Sanofi-Aventis) provided funding. Celecoxib was provided by Pharmacia (Currently Pfizer). Supported in part by Cancer Center Support Grant CA-22453, from the National Cancer Insitute. Address for correspondence: Shirish M. Gadgeel, MD, 4100 John R, 4 HWCRC, Detroit, MI 48201. E-mail: [email protected] Michael J. Kraut is currently at Providence Hospital, Southfield, Michigan. Copyright © 2008 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/08/0311-1293
Conclusion: In these ‘special populations’ of patients with advanced NSCLC, the addition of celecoxib to docetaxel did not seem to improve the outcome compared with single agent docetaxel. Key Words: Elderly, PS2, COX-2, Docetaxel, Celecoxib, Nonsmall cell lung cancer. (J Thorac Oncol. 2008;3: 1293–1300)
L
ung cancer is the most common cause of cancer related mortality in the United States.1 The high rate of mortality is primarily due to the advanced stage of lung cancer in most patients at presentation. Two-drug chemotherapy regimens are the current standard of care for patients with advanced non-small cell lung cancer (NSCLC), because they can improve overall survival and quality of life. However, the benefits of such therapy are modest, with a median progression free survival of 4 months and median survival of 8 to 10 months.2 The median age at presentation of lung cancer patients in United States is currently 71 years, and is likely to increase further with the continued aging of the population.3,4 Elderly patients often have age-related changes in organ function and multiple comorbidities requiring medications that increase the risk of adverse drug interactions.5,6 These factors can make decisions regarding therapy for advanced lung cancer in this patient population very challenging. Retrospective analyses of clinical trials assessing two-drug chemotherapy regimens have shown that the therapeutic benefits in elderly patients are similar to those in younger patients.7,8 In addition, studies have suggested that age alone is not a negative prognostic factor.9,10 However, elderly patients are significantly underrepresented in therapeutic trials, so these results may be influenced by a selection bias.11,12 The largest prospective study conducted specifically in elderly patients with NSCLC failed to show an advantage for a two-drug chemotherapy regimen over single-agent therapy.13 It is also clear that certain toxicities, particularly myelosuppression and fatigue, are greater with two-drug regimens in the elderly. Based on these data the current American Society of Clinical
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Oncology guidelines consider single-agent therapy or a twodrug regimen as acceptable alternatives for the treatment of elderly patients with advanced NSCLC.14 Performance status (PS) has consistently emerged as an independent prognostic factor for patients with NSCLC.15,16 PS represents the impact of tumor-related symptoms, comorbidities, and complications of medical interventions on the patient. Like elderly patients, patients with poor PS are underrepresented in clinical trials since many studies have restricted eligibility to patients with a PS of 0 –1. The utility and toxicity of two-drug chemotherapy regimens in PS2 patients remains unresolved.17–19 Cyclooxygenase (COX) is a rate-limiting enzyme involved in the conversion of arachidonic acid to prostaglandins (PG).20 COX-2, an isoform of COX, is overexpressed in neoplastic tissues in response to various stimuli21–23 and, through the production of PG, COX-2 is involved in both carcinogenesis and tumor progression.24 –27 Many NSCLCs express COX-2, and preclinical evidence suggests that the selective COX-2 inhibitor, celecoxib, can inhibit NSCLC growth, both alone and in conjunction with cytotoxic chemotherapy.28 –30 In addition, taxanes and vinca alkaloids can induce the expression of COX-2 in tumors, potentially limiting the antitumor activity of these agents and inducing adverse side-effects.31,32 Therefore, the addition of a COX-2 inhibitor may enhance the activity of cytotoxic drugs by blocking COX-2 induction. We hypothesized that addition of a ‘biologic agent’ to a cytotoxic drug in elderly and poor PS patients may be more effective than single chemotherapy drug but better tolerated than two-drug chemotherapy regimens. Based on the promising preclinical activity of COX-2 inhibitors in combination with chemotherapy agents, particularly taxanes, we conducted a phase II study evaluating the addition of celecoxib to docetaxel in previously untreated elderly (ⱖ70 years) or PS 2 patients with advanced NSCLC. Celecoxib was administered at a dose of 400 mg twice daily based on the results of studies in patients with familial adenomatous polyposis coli33 and docetaxel, administered weekly, was selected as the cytotoxic agent based on prior phase II studies that suggested lower toxicity and comparable efficacy.34
Treatment Patients were instructed to take celecoxib 400 mg po twice daily with meals. One week after starting celecoxib patients were started on docetaxel at 36 mg/m2 IV on days 1, 8, and 15 of a 28 day cycle. Thus, the first cycle was 5 weeks long, while subsequent cycles were of 4 weeks duration. Patients were premedicated for docetaxel with dexamethasone 4 mg the evening before the day of treatment and twice on the day of treatment. Antiemetic prophylaxis and management and use of hematopoietic growth factors was left to the discretion of each treating physician. While on therapy each patient was assessed every 2 weeks with history and physical examination and laboratory evaluation. After 4 cycles, patients could be evaluated every 4 weeks if they did not have any toxicity ⬎ grade 2. Response was assessed every two cycles according to the Response Evaluation Criteria in Solid Tumors criteria.35 Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. Appropriate dose-modification and dose-delay of docetaxel were planned for hematologic and hepatic toxicities, peripheral neuropathy, and stomatitis. The dose of celecoxib was reduced by 25% for an increase in serum creatinine of 50 to 100% over baseline, and celecoxib was held for an increase ⬎100%. Both drugs were held for a maximum of 14 days for any other grade 3– 4 toxicity and could be restarted at the same dose upon recovery to grade 1. Patients could continue on one of the drugs if the other drug was held due to specific toxicity.
Statistical Methods
PATIENTS AND METHODS Patient Selection Eligible patients included those with histologically or cytologically confirmed, previously untreated stage IIIB (with pleural effusion) or IV NSCLC who were ⱖ70 years of age with PS 0 –2 or ⱖ18 years of age with PS 2. Patients could have undergone prior surgery or radiation therapy but were not eligible if they had received any prior chemotherapy. Other inclusion criteria were: measurable or evaluable disease; bilirubin ⱕ upper limit of normal (ULN); aspartate transaminase and alanine aminotransferase ⱕ2.5 ⫻ ULN; alkaline phosphatase ⱕ5 ⫻ ULN; creatinine ⱕ1.5 ⫻ ULN; hemoglobin ⱖ8 g/dL; neutrophil count ⱖ1.5 ⫻ 109/liter; platelets ⱖ100,000 ⫻ 109/liter. Patients were excluded if they were taking nonsteroidal anti-inflammatory drugs for more than 30 continuous days
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before enrollment. Patients were instructed not to take nonsteroidal anti-inflammatory drugs while on study, except for aspirin ⱕ325 mg/d. Patients were excluded if they had an allergy to sulfa drugs or a history of gastrointestinal hemorrhage, MI, or cerebrovascular event within 6 months. Patients with history of venous thromboembolic phenomena within 4 weeks of study entry were excluded. Patients with brain metastases were eligible as long as they had been treated and had no symptoms from the brain metastases. All patients were required to provide signed informed consent before enrollment. The Human Investigation Committees of participating institutions approved the protocol.
The primary objective of this study was to assess the 6-month survival rate in patients treated with the combination of docetaxel and celecoxib. PS was assessed according to the Southwest Oncology Group criteria that define PS 2 as ‘Ambulatory and capable of all self-care but unable to carry out any work activities; Up and about more than 50% of waking hours.’ Secondary endpoints were response, toxicity, progression free survival (PFS), and overall survival (OS). PFS was defined as the time from the first day of treatment until the date when progressive disease was documented or death from any cause, whichever came first. Surviving patients who did not progress were censored for PFS as of the date of their last tumor assessment. OS was defined as the time from the first day of treatment until the date of death from any cause. Patients were deemed evaluable for response if they received at least one dose of each drug.
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This phase II trial was planned with a Simon two-stage minimax design.36 The primary end point was survival for at least 6 months (yes/no). We wished to distinguish these regions of the true, unknown 6 month survival proportion: at most 0.35 versus at least 0.55. The two-stage design called for a maximum of 39 evaluable patients, 21 in stage 1 and 18 in stage 2. The design had power of 0.80 and overall Type I error of 0.05. At least nine 6-month survivors among the first 21 patients were needed to justify beginning stage 2 of the study design. We observed nine 6-month survivors during stage 1. Enrollment to the trial slowed considerably due to increasing number of reports regarding the safety of COX-2 inhibitors. Therefore accrual was stopped after 34 patients had been registered on the trial which reduced the power of the study design slightly, to 0.761. With only 14 six-month survivors among the 34 patients (sample estimate of 41%), it was concluded that the true, unknown 6 month survival proportion was at most 0.35. Exact, minimum-width 90% confidence intervals (CI) for response and toxicity rates were calculated using the
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Casella method37 as implemented in StatXact software.38 Standard Kaplan-Meier estimates of the censored PFS and OS distributions were computed. Due to the small sample sizes, survival statistics (e.g., median) were estimated more conservatively using linear interpolation among successive event times on the Kaplan-Meier curves.39
RESULTS Patient Characteristics Thirty-four patients were enrolled from November 2001 to October 2004 (Table 1) at the two participating institutions. The median age was 73 years for all patients (range, 51– 82 years) and 71% were male. Of the 34 patients enrolled, 27 (79%) were ⱖ70 years old and of the elderly patients, 15 (44%) had a PS of 0 –1. Overall, 19 (56%) patients had PS2, including 12 who were ⱖ70 years of age and 7 who were ⬍70 years of age. Ten patients were older than 75 years and 5 of them had a PS of 2. Only 2 patients had stage IIIB disease.
Response and Survival TABLE 1. Patient Demographics Number Age Range (yr) Median (yr) Gender Males Females Stratification group Age ⱖ70 yr Age ⱖ70 yr, PS 0–1 PS 2, any age Stage IV IIIB
34 51–82 73 24 (71%) 10 (29%) 27 (79%) 15 (44%) 19 (56%) 32 (94%) 2 (6%)
PS, performance status.
Four patients did not receive at least one dose of both drugs and therefore were not evaluable for response (Table 2 and Figures 1–3). One patient, who previously had episodic hyperkalemia due to renal tubular acidosis, developed hyperkalemia after being on celecoxib for 4 days and was taken off study. Three patients started on celecoxib, but did not receive their first dose of docetaxel due to a decline in PS (2 patients) or a fall resulting in hip fracture (1 patient). Response rate and survival were analyzed according to both intention to treat analysis and according to protocol-defined analysis (evaluable patients only), and all the end-points were similar by both analyses. Results are presented according to the intention to treat analysis. Among the 34 enrolled patients, 1 patient had a complete response (CR) and 4 patients had a partial response (PR), for an overall response rate of 15% (Table 2). Ten other patients had stable disease, for an overall clinical benefit rate of 44% (90% CI, 0.15– 0.46). The response rate for the 15 patients with PS 0 –1 was 20% and for the 19 patients with PS 2 was 11%.
TABLE 2. Response Rate (RR), Progression Free Survival (PFS), and Overall Survival (OS) with Docetaxel Plus Celecoxib (90% Confidence Interval) PFS
OS
Patients
N
RR
Median (mo)
6-mo Rate
Median (mo)
6-mo Rate
All patients
34
15% (0.06–0.30)
2.3 (1.4–3.4)
14% (0.05–0.24)
5.0 (2.4–7.9)
38% (0.25–0.52)
ⱖ70 yr All
27
19% (0.09–0.35) 20% (0.08–0.42)
3.4 (2.0–3.8) 3.9 (3.4–5.7)
18% (0.06–0.30) 20% (0.03–0.37)
5.7 (2.6–9.1) 8.3 (4.7–10.2)
44% (0.29–0.60) 60% (0.39–0.80)
11% (0.03–0.27)
2.0 (1.8–2.2)
8% (0.00–0.17)
2.8 (2.1–4.8)
21% (0.06–0.36)
PS0–1
15
Any age PS 2
19
RR, response rate; PS, performance status; PFS, progression free survival; OS, overall survival.
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FIGURE 1. The Kaplan-Meier estimate of progression free survival (PFS) in the 34 patients. The dashed lines represent the 90% confidence interval (CI) about each successive estimate of the progression free rate.
The median PFS for all 34 patients (Figure 1) was 2.3 months, and the 6-month progression-free survival rate was 14%. For the 15 patients ⱖ70 years old with PS 0 –1, the median PFS was 3.9 months, and the 6-month progressionfree survival rate was 20%. For the 19 patients with PS 2, the median PFS was 2.0 months, and the 6-month progressionfree survival rate was 8%. The median OS for all 34 patients (Figure 2) was 5.0 months, and the 6-month OS rate was 38%. For the 15 elderly patients with PS 0 –1, the median survival (Figure 3) was 8.3 months and the 6-month OS rate was 60%. For the 19 patients with PS 2, the median survival was 2.8 months, and the 6-month survival rate was 21%. The median OS of the 10 patients ⱖ75 years old was 2.7 months, and the 6-month survival rate was 28%. Detailed information on treatment after discontinuation of study treatment was not collected. Nevertheless none of the patients with PS 2 were able to receive subsequent therapy.
Toxicity Eighty-two cycles of combination therapy were administered and the median number of cycles was 2 (range, 1– 6). Only 3 patients continued celecoxib after docetaxel was discontinued (Table 3). The combination was generally well tolerated. The main nonhematologic toxicity was fatigue. None of the patients required dose modifications and all but two patients discontinued therapy for progression of disease. One patient discontinued treatment because of emesis and
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one patient for fatigue. Two patients developed arterial thrombotic events, 65-year-old male with a myocardial infarction (MI) and 71-year-old with a cerebrovascular event. In addition, two patients developed venous thrombotic events. One patient with a history of prior intestinal surgery and adhesions developed a fatal intestinal obstruction. No death was deemed to be directly related to the treatment though the patient with MI died of cardiac complications.
DISCUSSION In this phase II study we attempted to develop a regimen that would be less toxic than standard two-drug chemotherapy regimens and more effective than single-agent therapy in select patients with advanced NSCLC. Nevertheless, it seems that the results obtained with celecoxib plus weekly docetaxel in elderly and/or PS 2 patients with advanced NSCLC are similar to those expected with docetaxel alone. Two-drug chemotherapy regimens are the current standard for the management of patients with advanced NSCLC, but are not accepted as the sole standard for elderly and PS 2 patients. The primary concern with two-drug chemotherapy regimens in these patients is the occurrence of undue toxicity that could diminish the magnitude of any potential benefit. Therefore, elderly and PS 2 patients were frequently lumped together in trials evaluating treatment strategies that are presumed to have lower toxicity.40,41 It is now increasingly clear that these two groups of patients should be evaluated
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Phase II Study of Docetaxel and Celecoxib
FIGURE 2. The Kaplan-Meier estimate of overall survival (OS) in the 34 patients. The dashed lines represent the 90% confidence interval (CI) about each successive estimate of the survival rate. The 12-month OS rate is 17%, with 90% CI of 0.06 – 0.27.
separately since each group has distinct clinical issues and prognoses that require independent evaluation. Docetaxel is considered one of the most active agents in the management of NSCLC.42 In a phase III study reported by Kudoh et al.43 every 3 week docetaxel demonstrated superior PFS and response rate as compared with vinorelbine in elderly patients. A higher rate of neutropenia and emesis was observed in patients who received docetaxel and this is consistent with other docetaxel trials.44,45 In a recently reported randomized phase II study by Lilenbaum et al. evaluating weekly docetaxel versus every 3 week docetaxel in the same population as our study, the weekly schedule resulted in fewer hematologic toxicities and slightly better survival, with median PFS of 2.3 months and median survival of 6.7 months.46 Nevertheless there were no differences in infection/ febrile neutropenia rate, the rate of nonhematologic toxicities and there was no difference in the quality of life between the two schedules. These outcomes are very similar to the outcomes observed in our current study, suggesting that the addition of celecoxib did not augment the activity of docetaxel. It has become increasingly evident that age alone should not determine therapeutic decisions. Nonetheless, deciding upon therapy in the elderly, particularly in patients over 75 years of age can be very challenging. It is important to note that the number of patients over 75 years old is small even in elderly-specific studies, and therefore the data available to guide therapy in this population is very limited. In the Multicenter Italian Lung Cancer in the Elderly Study, only
33% of patients were ⱖ75 years old and only 3% were ⱖ80 years old.13 In our study 30% of patients were ⱖ75 years old and 9% were ⱖ80 years old. The median survival of these 10 patients ⱖ75 years old was only 2.7 months. Therefore, even though two-drug therapy is often considered in elderly patients with good PS, appropriate clinical assessment of the patient’s disease status, comorbid illnesses, and functional status are critical in deciding upon the appropriate therapy for any particular elderly patient, particularly those who are ‘very’ old. The investigators of the Multicenter Italian Lung Cancer in the Elderly Study recently reported that pretreatment quality of life and functional status predicted prognosis in elderly patients.47 Utilizing these assessments prospectively in future trials may help define elderly patients who could tolerate and benefit from two-drug therapy. The results in PS 2 patients in our study are disappointing in that they are again similar to those of prior studies evaluating single-agent therapy. Many large randomized trials have excluded PS 2 patients and prospective trials specifically targeting PS 2 patients are limited, making therapeutic decisions challenging. Eastern Cooperative Oncology Group 1599 was the first prospective PS 2 specific clinical trial conducted in the United States. This randomized phase II trial evaluating paclitaxel or gemcitabine in combination with carboplatin found median survival greater than 6 months in both arms.48 Cancer and Leukemia Group B (CALGB) 9730 is the only US-based clinical trial that compared a thirdgeneration single agent, paclitaxel versus the combination of
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FIGURE 3. The Kaplan-Meier estimate of overall survival (OS) in the 15 elderly patients with PS 0 –1. The dashed lines represent the 90% confidence interval (CI) about each successive estimate of the survival rate. The 12-month OS rate is 18%, with 90 CI of 0.02– 0.34. TABLE 3. Toxicity Grade of Toxicity Toxicity
n (%)a
1
2
3
4
Fatigue Anorexia Nausea/emesis Renal Edema Arterial/venous thrombosis Anemia Neutropenia Thrombocytopenia
9 (30%) 7 (23%) 7 (23%) 3 (10%) 5 (17%) 4 (13%) 7 (33%) 6 (20%) 5 (17%)
2 6 5 2 4
1 1 2 1 1
2
4
1 4 5
2 2
4
4
One patient each was admitted to the hospital with myocardial infarction, cerebrovascular event, pulmonary embolism, deep venous thrombosis, pneumonia, bowel obstruction, syndrome of inappropriate antidiuretic hormone. a Number of patients who developed all grades of the particular toxicity. Thirty patients were evaluable for toxicity.
paclitaxel and carboplatin in advanced NSCLC. The study prespecified analysis of patient outcomes based on PS status. The median survival of 4.7 months with the combination among the PS 2 subset was significantly better than the median survival of 2.4 months with single-agent paclitaxel (p ⫽ 0.0213).19 The results of both these trials support the use of two drug cytotoxic therapy in PS 2 patients. Nevertheless in a randomized phase II study from Greece the outcomes in
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PS 2 patients with gemcitabine alone or carboplatin plus gemcitabine were similar.18 Results in PS 2 patients need to be viewed with caution due to the recognized variability in PS assessment and in the causes for poor PS. An emerging strategy that has not been validated in clinical trials is to differentiate patients with PS 2 due to comorbid illnesses from those with PS 2 as a result of NSCLC-related symptoms, and to use two-drug regimens in patients with impaired PS due to NSCLC and single-agent therapy in those with PS 2 due to comorbid illnesses. Based on preclinical data regarding the role of COX-2 in carcinogenesis and tumor progression, COX-2 inhibitors have been evaluated in both cancer prevention and therapy. In prospective randomized trials, celecoxib has reduced the incidence of precancerous colonic lesions,33,49,50 suggesting a potential role in cancer prevention. Nevertheless, the results achieved with COX-2 inhibitors in therapeutic trials have been less convincing.51–54 In a recent randomized CALGB trial, the addition of celecoxib to a platinum-based two-drug chemotherapy regimen did not provide any additional benefit in patients with advanced NSCLC.55 Nevertheless, a retrospective analysis from the CALGB study suggests that patients with tumors that expressed COX-2 at moderate or high levels did have an improvement in survival with the addition of celecoxib. In addition patients with tumors that had low expression of COX-2 had inferior survival, if they received celecoxib as compared with if they just received chemotherapy. Thus these results suggest that celecoxib may be bene-
Copyright © 2008 by the International Association for the Study of Lung Cancer
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ficial in patients with tumors that express COX-2 but it maybe detrimental in patients with low expression of COX-2 in their tumors. Based on the results of this study there is an interest in conducting a trial evaluating a COX-2 inhibitor in patients with NSCLCs that express COX-2. It is possible that the disappointing results noted in our trial could be due to lack of preselection of patients with COX-2 expressing tumors. Csiki et al.51 evaluated docetaxel plus celecoxib in patients with previously treated NSCLC. Though the overall results did not suggest an improvement in survival with the addition of celecoxib, the investigators did observe that patients who had the greatest proportional drop in urinary prostaglandin E (PGE-M), a metabolite of PGE-2 and a marker of systemic PGE-2 levels, had a substantially reduced risk of death compared with patients in whom no change in PGE-M levels were observed. There are also data to suggest that appropriate characterization of the enzymes involved in PGE2 synthesis and metabolism in a patient’s tumor may be important in selecting patients for treatment with COX-2 inhibitors.56 For example, 15- PG dehydrogenase, an enzyme responsible for PGE2 elimination, may be down-regulated in some NSCLCs, and in patients with such tumors celecoxib may actually promote tumor proliferation. Recent results have shown that the risk of cardiovascular events is increased with the use of COX-2 inhibitors. In two large randomized studies evaluating celecoxib for chemoprevention, the incidence of cardiovascular events was 1.3 to 3.4 times higher than in patients receiving placebo.49,50 It may be reasonable to assume that elderly patients might be at particular higher risk for such an effect. In our study two patients developed arterial thrombotic events while on therapy. The increased incidence of cardiovascular events with COX-2 inhibitors may limit their use in elderly patients. In conclusion, the results of this study show that the addition of celecoxib to weekly docetaxel does not seem to be beneficial in elderly and/or PS 2 patients with advanced NSCLC. It is possible that this strategy may be beneficial if patients are selected based on COX-2 expression. The concept of combining single-agent chemotherapy with a biologic agent to minimize toxicity and improve efficacy over twodrug cytotoxic chemotherapy regimens should also be further explored in these ‘special populations.’
5. 6. 7. 8.
9. 10. 11. 12. 13.
14. 15. 16.
17.
18.
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ACKNOWLEDGMENTS Supported by Aventis (currently Sanofi-Aventis) provided funding. Celecoxib was provided by Pharmacia (currently Pfizer). Supported, in part, by Cancer Center Support Grant CA-22453 from the National Cancer Institute.
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