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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

Rogerio Lilenbaum, Mark A. Socinski, Nasser K. Altorki, Lowell L. Hart, Roger S. Keresztes, Subramanian Hariharan, Mark E. Morrison, Rana Fayyad, Phillip Bonomi

From the Mount Sinai Cancer Center, Miami Beach; Florida Cancer Specialists, Fort Myers, FL; Linberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; Weill Medical College of Cornell University; Pfizer Oncology, New York, NY; and Rush-Presbyterian St Lukes Medical Center, Chicago, IL

Address reprint requests to Rogerio Lilenbaum, MD, Mount Sinai Cancer Center, 4306 Alton Rd, Miami Beach, FL 33140; e-mail: rlilenbaum{at}aptiumoncology.com

	ABSTRACT

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PURPOSE: Trials combining irinotecan/docetaxel and irinotecan/gemcitabine in second-line treatment of non–small-cell lung cancer (NSCLC) have yielded promising results. Preliminary data suggested that the selective cyclooxygenase -2 inhibitor celecoxib (CBX) might enhance efficacy of chemotherapeutic regimens. This multicenter, phase II, randomized trial investigated efficacy and safety of irinotecan and docetaxel and irinotecan and gemcitabine, with or without CBX, in second-line treatment of NSCLC.

PATIENTS AND METHODS: Patients 18 years or older were randomly assigned to receive irinotecan 60 mg/m² and docetaxel 35 mg/m², or irinotecan 100 mg/m² and gemcitabine 1,000 mg/m², with or without CBX 400 mg twice daily, for four cycles. Primary efficacy end points were median and 1-year survival probabilities. Patient-reported symptoms were assessed by the Lung Cancer Symptoms Scale (LCSS).

RESULTS: A total of 133 patients were assessable for efficacy and safety. Median survival time was 6.31 months for patients treated with CBX and 8.99 months for those treated with chemotherapy alone. One-year survival rates were 24% and 36% respectively. The overall toxicity rates and LCSS scores were similar between patients treated or not treated with CBX. Four deaths were considered possibly treatment related.

CONCLUSION: Survival results for the second-line regimens in this study were similar to results reported for single-agent therapy in this setting. CBX did not appear to enhance efficacy or improve patient-reported symptoms. The addition of high-dose CBX to second-line chemotherapy in NSCLC cannot be recommended.

	INTRODUCTION

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Second-line therapy for non –small-cell lung cancer (NSCLC) is well established.¹ Docetaxel, pemetrexed, and erlotinib are currently approved for this indication. Further, gemcitabine² and, more recently, oral topotecan³ have also shown activity in this setting. Selected phase II trials of irinotecan, alone or in combination with other agents, have shown efficacy comparable to other regimens in the treatment of advanced NSCLC. In particular, irinotecan in combination with gemcitabine or docetaxel has shown promising results and acceptable toxicity in the first- and second-line settings.^4-6

Experimental evidence suggests that cyclooxygenase-2 (COX-2) may be an appropriate target for anticancer therapy in NSCLC. Increased levels of COX-2 and prostaglandin biosynthesis have been observed in multiple tumor types and have been shown to stimulate angiogenesis and to reduce response of malignant cells to cytotoxic therapy.^7,8 Further, COX-2 inhibitors have been shown to induce apoptosis of NSCLC cell lines and to enhance the activity of standard chemotherapeutic agents, providing the rationale for combining celecoxib (CBX) with cytotoxic therapy in the treatment of NSCLC.⁹ Indeed, preliminary data indicate that CBX appears to improve the activity of paclitaxel and carboplatin when used in the preoperative setting.¹⁰

On the basis of this rationale, we investigated the use of irinotecan/docetaxel and irinotecan/gemcitabine, with or without CBX, in the second-line treatment of NSCLC. We aimed to assess the activity of these two regimens as well as the impact of CBX when added to chemotherapy.

	PATIENTS AND METHODS

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Eligibility
Patients with histologically confirmed advanced NSCLC who experienced treatment failure with one prior platinum-containing regimen were eligible for this trial. All patients had clinical stage IIIB or IV disease, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and measurable or nonmeasurable lesions. Measurable lesions were defined as 20 mm or larger measured with conventional techniques or 10 mm or larger measured with spiral computed tomography (CT) scanning outside a previous radiation port. All other lesions were defined as nonmeasurable disease, including small lesions (< 20 mm with conventional techniques or < 10 mm with spiral CT scanning) and truly nonmeasurable lesions (eg, bone lesions, leptomeningeal disease, pleural/pericardial effusion, lymphangitis cutis/pulmonis, abdominal masses, and/or cystic lesions). Patients with known brain metastases were eligible if they were asymptomatic and off corticosteroids. Discontinuation of COX-2 inhibitors and nonsteroidal anti-inflammatory agents was required, although use of low-dose aspirin ( 325 mg per day) was permitted if medically indicated.

Patients were required to have adequate hematologic (absolute neutrophil count 1,500/mm³ and platelet count 100, 000/mm³), hepatic (total serum bilirubin at the upper limit of normal [ULN] or lower, AST and/or ALT < 2.5x ULN, alkaline phosphatase [ALP] 2.5x ULN), and renal (serum creatinine < 1.6 mg/dL or calculated creatinine clearance 40 mL/min) function. Patients with known hypersensitivity to any of the study medications, with certain previous or concurrent malignancies, prior radiation therapy to more than 50% of the pelvis, known Gilbert's disease, a history of clinically important GI or cardiovascular disease, diabetes, uncontrolled infection, or significant mental impairment were excluded from the study. Patients were stratified according to sensitivity to chemotherapy, with sensitivity defined as disease progression occurring at least 4 months, and resistance defined as disease progression occurring sooner than 4 months from the start of previous anticancer treatment.

The study was approved by the institutional review boards of participating institutions; signed informed consent was obtained from all patients.

Treatment Plan
Patients received chemotherapy for four cycles. Irinotecan (Camptosar, Pfizer Inc, New York, NY) 60 mg/m² plus docetaxel 35 mg/m² (ID; Taxotere, Aventis Pharmaceuticals, Bridgewater, NJ) or irinotecan 100 mg/m² plus gemcitabine 1000 mg/m² (IG; Gemzar, Eli Lilly, Indianapolis, IN) were administered on days 1 and 8 of each 21-day cycle in the order shown in Table 1. CBX (Celebrex, Pfizer Inc) 400 mg twice daily was initiated on day 1 of treatment and continued until withdrawal or study end point. Patients were randomly assigned to treatment groups as follows: ID + CBX (arm A1), ID –CBX (arm A2), IG + CBX (arm B1), IG –CBX (arm B2).

Re-treatment criteria for patients receiving ID (arms A1 and A2) included an absolute neutrophil count of at least 1,500/mm³ and a platelet count of at least 100,000/mm³ within 48 hours of the next cycle; total serum bilirubin at ULN or lower; AST and/or ALT less than 2.5x and ALP and 2.5x ULN or lower; resolution of treatment-related nonhematologic toxicities (excluding alopecia) to grade 1 or better; and resolution of diarrhea to pretreatment levels.

Patients receiving CBX continued treatment until disease progression. Appropriate supportive care, including antibiotic therapy, antiemetics, anticholinergics, and antianemia and antidiarrheal medications, was provided as necessary.

Evaluations
Baseline evaluations conducted before study entry included history and physical examination, assessment of ECOG PS, CBC, biochemical profile, ECG, serum pregnancy test, and Lung Cancer Symptoms Scale (LCSS)¹¹; assessments were conducted on day 1 of each treatment cycle, and complete blood counts were obtained on days 1, 8, and 15 of each treatment cycle.

Measurable lesions (five or fewer lesions per organ or 10 lesions representative of all involved organs) were identified as target lesions. Target lesions were reassessed by appropriate imaging studies at the end of every second cycle.

End-point evaluations were conducted 30 days after treatment discontinuation. Evaluations included assessment of ECOG PS, tumor assessment by imaging studies, LCSS, and adverse event (AE) assessments. Thereafter, patients were followed quarterly for ECOG PS, tumor status, AEs, and survival. To assess symptom effects, patients were asked to complete the LCSS before random assignment, before every treatment cycle, and at the end of treatment.

Response Criteria
Response Evaluation Criteria in Solid Tumors (RECIST) were used to categorize response to treatment.¹² Complete response (CR) was defined as disappearance of all target lesions. Partial response (PR) was defined as a decrease of at least 30% in the sum of the longest diameter of target lesions compared with pretreatment values. Progressive disease (PD) was defined as an increase of at least 20% in the sum of the longest diameter of target lesions compared with the smallest values obtained at the start of treatment, or the appearance of at least one new lesione. Stable disease was defined as insufficient decrease or increase in number of new lesions or summed size of lesions to qualify for PR or PD.

Statistical Analyses
Sample size was based on the assumption that the historic 1-year survival rate is 32% to 37% in patients receiving docetaxel alone.^13,14 Given this assumption and that a relative 35% improvement in 1-year survival was considered sufficient evidence to move a regimen into a phase III study, each treatment arm was planned to have 54 assessable patients. The docetaxel arms were combined for analysis, as were the gemcitabine arms and the CBX arms. Therefore, a planned random assignment of 108 assessable patients to each treatment regimen would provide 80% statistical power to find a 35% improvement in 1-year survival, with a .05 (one-sided) significance level over historic control. A 2 x 2 factorial design that assumed no interaction between chemotherapy treatment and use of CBX was used, with "no interaction" indicating that if CBX was efficacious, it would produce the same level of benefit in the ID arm as in the IG arm.

The primary efficacy end points were median and 1-year survival probabilities associated with each treatment regimen. Survival curves were determined using the Kaplan-Meier method. Time to progression, defined as the number of months from administration of first study medication to first documentation of disease progression, was estimated using the cumulative incidence model, adjusting for competing risks. Progression-free survival, defined as the number of months from administration of first study medication to date of progressive disease or death, was estimated using the Kaplan-Meier method; events were defined as the earliest occurrence of either disease progression or death. Cox regression analysis was performed to determine prognostic factors for progression-free survival. The influence of pretreatment patient characteristics on survival was examined using Cox regression, including stratification by age, sex, PS, disease stage, and response to treatment. In the LCSS scale used to assess patient-reported symptoms, the average score of the nine items was used to classify patients as improved (average score decreased > 10 mm from baseline), declined (average score increased > 10 mm from baseline), or stable (otherwise) at each postbaseline visit. Similar classification also was performed for the six lung cancer symptoms (items 1 to 6 of the LCSS). The percentage of patients with improved, declined, or stable symptoms was computed for each treatment regimen for each cycle.

Safety analyses included all patients who received at least one dose of study medication. AEs were recorded and graded according to the NCI CTC, version 2.0. The percentage of patients who experienced a specific AE was tabulated by CTC medical term, body system, and by treatment group. Hematologic and blood chemistry data were classified according to CTC severity grade.

	RESULTS

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Patient Disposition and Demographics
A total of 133 patients were enrolled in 32 sites in the United States from February 2002 to September 2003. The study was discontinued early because of decreased patient enrollment over time; as a result, the treatment groups were not large enough to detect statistical significance as per study design. Baseline patient demographics are shown in Table 2. Minor differences in baseline sensitivity to prior chemotherapy were seen; approximately one third of the patients overall demonstrated a response to prior chemotherapy.

View larger version (12K): [in this window] [in a new window]   Fig 1. Overall survival by treatment arm. Irinotecan 60 mg/m2 and docetaxel 35 mg/m2 (ID): arms A1 + A2; irinotecan 100 mg/m2 and gemcitabine 1,000 mg/m2 (IG): arms B1 + B2; with celecoxib (+ CBX): arms A1 + B1 (ID + CBX and IG + CBX); without celecoxib (–CBX): arms A2 + B2 (ID alone and IG alone).

View larger version (10K): [in this window] [in a new window]   Fig 2. Progression-free survival. Irinotecan 60 mg/m2 and docetaxel 35 mg/m2 (ID): arms A1 + A2; irinotecan 100 mg/m2 and gemcitabine 1,000 mg/m2 (IG): arms B1 + B2; with celecoxib (+ CBX): arms A1 + B1 (ID + CBX and IG + CBX); without celecoxib (–CBX): arms A2 + B2 (ID alone and IG alone). PD, progressive disease.

Safety
The incidence of toxicities by study group is presented in Table 5. Patients receiving IG without CBX had the fewest discontinuations because of treatment-related AEs, whereas patients treated with ID and CBX had the most. Grade 3/4 toxicities are listed in the table and consisted primarily of neutropenia, diarrhea, dehydration, and asthenia. The rate of grade 3/4 neutropenia was higher in the ID + CBX arm. However, febrile neutropenia was limited to one episode. Thrombocytopenia, as expected, was higher with gemcitabine-containing regimens, particularly in combination with CBX. Dose reductions in docetaxel and gemcitabine were generally more common in patients treated with than without CBX: 5.9% versus 2.9% for docetaxel and 15.2% versus 3.2% for gemcitabine. For irinotecan, dose reductions were similar at 5.9% versus 5.7%.

Patient-Reported Symptoms
In general, patients who received regimens without CBX had a slightly higher (worse) baseline mean LCSS score (36.2%) than did patients who received CBX (31.5%). In all treatment regimens, more than 80% of patients completed the LCSS survey throughout all treatment cycles, with a 63.9% completion rate at end of treatment. Patients treated without CBX appeared to have the best completion rate throughout all cycles (more than 92%) and at end of treatment (69.7%) when compared with the other treatment regimens. For the LCSS total score, improvement was observed in 16.7%, and 17.9% of patients in the + CBX and –CBX groups, respectively (Table 6). Of the six item scores (appetite loss, fatigue, cough, shortness of breath, blood in sputum, and pain), more patients treated with –CBX regimens compared with + CBX regimens showed improvement for the item scores of fatigue, cough, and shortness of breath; as expected, more patients receiving CBX experienced improvement in pain (20 v 14 patients).

	DISCUSSION

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The median survival times of 6.41 months and 8.85 months and estimated 1-year survival rates of 20% and 41% with ID and IG, respectively, suggest that these combination regimens provide efficacy outcomes comparable to previously evaluated second-line therapies. Although the survival results are numerically superior in the IG arm, the study was not sufficiently powered to detect statistical differences between the two regimens, and neither regimen achieved the statistical end point of superiority over historic controls. More importantly, median survival (6.31 months) and 1-year survival rates (24%) for patients treated with CBX were numerically inferior to those for patients treated with chemotherapy alone (8.99 months and 36%, respectively). Although, again, the number of patients lacked statistical power to detect significance, this is a noteworthy observation and provides a cautionary message against the routine addition of CBX to palliative chemotherapy in clinical practice.

Other studies testing chemotherapy and CBX have demonstrated an acceptable toxicity profile. In a recent phase II study of 58 patients,¹⁸ the combination of weekly paclitaxel and CBX was safe and resulted in 1-year survival of 42.5%. Similar data were reported with CBX in combination with docetaxel.¹⁹ A synergistic or additive interaction among the toxicities of irinotecan, docetaxel, and CBX may exist, accounting for the higher rates of toxicity, particularly diarrhea in patients treated with ID + CBX. The rate of thrombocytopenia with IG + CBX was also substantially higher than that seen with IG alone. However, despite the toxicity profile, the LCSS data, with a 63.9% completion rate by the end of treatment, showed similar symptom profiles for patients receiving and not receiving CBX. Although it is reassuring that a decrement in quality of life was not observed, we could not demonstrate an improvement with CBX in any of the major symptoms recorded by the LCSS with the exception of pain.

The lack of benefit with the addition of CBX to the chemotherapy regimens in our study did not corroborate in vitro evidence that COX-2 inhibition enhances the efficacy of cytotoxic regimens.^20-23 There are several theoretical explanations for this observation, but most likely the potential impact of COX-2 inhibition will be better appreciated in the early development of carcinogenesis rather than in fully developed and advanced malignancies.²⁴ More recent research has focused on the combination of CBX and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, based on cross talk between the EGFR and COX-2 signaling pathways.²⁵ In a phase I study investigating the combination of CBX and erlotinib in 21 patients with advanced NSCLC, patients received escalating doses of CBX from 200 to 800 mg twice daily, along with a fixed dose of erlotinib. Seven partial responses and five instances of stable disease were noted, along with an acceptable toxicity profile. The authors suggested the optimal dose of CBX in this setting to be 600 mg twice daily.²⁶ Another phase I study in patients with recurrent head and neck carcinoma tested the combination of CBX (200 to 400 mg twice daily) and gefitinib and reported partial responses in four of 18 assessable patients, with no dose-limiting toxicities.²⁷ Further study is needed to elucidate the optimal biologic dose of CBX.

In summary, our data suggest that although the combination of irinotecan and gemcitabine may be a reasonable option in the second-line setting, neither IG nor ID is likely to provide efficacy results superior to those of currently available regimens. Further, the addition of CBX to these regimens in patients who experience treatment failure with first-line therapy did not enhance efficacy or minimize toxicity. Thus, at this time, the use of CBX in combination with standard chemotherapy in the palliative treatment of advanced NSCLC cannot be recommended. Further research should focus on the possibility of synergy between COX-2 and EGFR inhibitors and on the development of biomarkers to better select patients who may benefit from COX-2 inhibition.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Rogerio Lilenbaum Genentech (A); AstraZeneca (A) Sanofi-Aventis (A) Mark A. Socinski Lilly (B); Genentech (B); Sanofi-Aventis (B) Lilly (B); Genentech (C); Pfizer (B); Amgen (B); Sanofi-Aventis (B); Astra-Zeneca (B); EMD Pharmaceuticals (B) Nasser K. Altorki Pfizer (B) Lowell L. Hart Pfizer (B) Subramanian Hariharan Pfizer (N/R) Pfizer (B) Mark E. Morrison Pfizer (N/R) Pfizer (B) Rana Fayyad Pfizer (N/R) Pfizer (B) Philip Bonomi Imclone (A); Pfizer (A); OSI Pharm (A); Eli Lilly (A); Cell Therapeutics Inc (A); AstraZeneca (A); EMP Pharm (A) EMP Pharm (A); AstraZeneca (A); Genentech (B); Pfizer (A); OSI Pharma (A); Eli Lilly (A); Cell Therapeutics Inc (A); ImClone (A) Genentech (B); Pfizer (B); OSI Pharma (B); Eli Lilly (B); AstraZeneca (B); Cell Therapeutics Inc (B)

Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Rogerio Lilenbaum, Mark A. Socinski, Subramanian Hariharan, Mark E. Morrison, Rana Fayyad, Philip Bonomi Administrative support: Subramanian Hariharan, Mark E. Morrison, Rana Fayyad, Philip Bonomi Provision of study materials or patients: Rogerio Lilenbaum, Mark A. Socinski, Nasser K. Altorki, Lowell L. Hart, Roger S. Keresztes Data analysis and interpretation: Rogerio Lilenbaum, Mark A. Socinski, Subramanian Hariharan, Mark E. Morrison, Rana Fayyad, Philip Bonomi Manuscript writing: Rogerio Lilenbaum, Mark A. Socinski Final approval of manuscript: Rogerio Lilenbaum, Mark A. Socinski, Nasser K. Altorki, Lowell L. Hart, Roger S. Keresztes, Subramanian Hariharan, Mark E. Morrison, Rana Fayyad, Philip Bonomi

 

	NOTES

 
Presented in abstract form at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA; and at the 10th and 11th World Conferences on Lung Cancer, August 10-14, 2003, Vancouver, British Columbia, Canada, and July 3-6, 2005, Barcelona, Spain, respectively.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

R.L. and M.A.S. contributed equally to this manuscript.

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Submitted May 17, 2006; accepted July 11, 2006.

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