The Oncologist, Vol. 9, No. 4, 398–405,
July 2004
© 2004 AlphaMed Press
Dilemmas in Management: The Controversial Role of Chemotherapy in PS 2 Advanced NSCLC and the Potential Role of CT-2103 (XyotaxTM)
Corey J. Langer
Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
Corey J. Langer, M.D., Medical Director, Thoracic Oncology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, Pennsylvania 19111. Telephone: 215-728-2985; Fax: 215-728-3639; e-mail: CJ_Langer{at}fccc.edu
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ABSTRACT
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Platinum-based chemotherapy improves long-term survival in patients with advanced non-small cell lung cancer (NSCLC). Meta-analyses have demonstrated an improvement in median and 1-year survival times as well as quality of life. However, these benefits are largely confined to patients with a good performance status (PS), one of the most critical determinants influencing outcome. Several clinical trials that initially included PS 2 patients ultimately discontinued their enrollment due to a high propensity of adverse reactions to treatment. The advent of more active, less toxic agents has revitalized investigator interest in treating PS 2 patients. CT-2103 is a novel paclitaxel conjugate undergoing investigation in the treatment of advanced NSCLC. The median survival for PS 2 patients treated with single-agent CT-2103 in one small trial proved similar to that reported for paclitaxel/carboplatin in NSCLC patients and was associated with an improved safety profile compared with conventional taxanes. Phase III studies comparing CT-2103 as a single agent and in combination with carboplatin to current standards of care are in progress. Unlike a well-defined population with good PS, the therapeutic index in PS 2 patients is narrower and not as clearly defined. These and other efforts will determine the optimal mode of therapy in PS 2 individuals with NSCLC.
Key Words. Carcinoma • Non-small cell lung • Drug therapy • Polyglutamic acid-paclitaxel
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INTRODUCTION
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Systemic platinum-based chemotherapy has improved long-term survival rates in patients with advanced non-small cell lung cancer (NSCLC). Meta-analyses have demonstrated a 2–3 month increase in median survival, a 10% increase in 1-year survival rates, and a substantial improvement in quality of life, using instruments that focus on malignant symptomatology [1, 2].
However, these benefits are largely confined to patients with good performance status (PS), by definition, those with minimal or no symptoms of disease, who are able to maintain their activities of daily living. Benefits for patients with compromised PS, particularly those who spend up to 50% of their waking hours in bed (Eastern Cooperative Oncology Group [ECOG] PS 2), are more uncertain. A retrospective analysis of the ECOG database showed a median survival of only 10 weeks for PS 2 patients, compared with 20 weeks for PS 1 patients (symptomatic but fully functional), and 34 weeks for PS 0 patients (asymptomatic) treated with systemic therapy [3]. A more comprehensive recursive partitioning analysis by Michael Jiroutek, a statistician formerly associated with ECOG, confirms the importance of PS in determining prognosis [4]. Along with gender and appetite/weight loss, PS was the most critical determinant influencing outcome, independent of therapy administered (Tables 1
and 2). The median survival for PS 2 patients treated with a variety of systemic agents in combination was only 3.9 months (at best), and prognosis was worse in patients with compromised PS and declining appetite. In fact, a fourfold difference in median survival existed between such patients and the best prognostic group: women with intact PS and no decline in appetite. Currently, there are no known systemic agents or combinations that can bridge this gap.
Other studies support these observations. Alberola and colleagues, in a randomized phase III trial of gemcitabine/cisplatin (GC) versus gemcitabine/cisplatin/vinorelbine versus sequential therapy with gemcitabine/vinorelbine followed by vinorelbine/ifosfamide for the treatment of advanced NSCLC, demonstrated a median survival of 4.7 months for PS 2 patients versus 9.1 months for PS 0–1 patients. This difference was statistically significant (p = 0.0001) [5]. Similarly, Smit and colleagues, in a phase III trial of paclitaxel/cisplatin (PC) versus GC versus the noncisplatin doublet paclitaxel/gemcitabine noted a median survival of 3.3 months in PS 2 patients versus 8.5 months in PS 0–1 patients (p < 0.0001) [6]. Finally, in the groundbreaking trial establishing the role of vinorelbine in the elderly, Gridelli and associates demonstrated a median survival of only 8 weeks in elderly PS 2 patients receiving best supportive care versus 24 weeks in PS 2 patients receiving cytotoxic therapy, even though objective responses were not observed in the PS 2 patients receiving therapy [7].
The advent of putatively more active, less toxic new agents has revitalized our interest in treating NSCLC in general and in PS 2 patients in particular. ECOG 1594, a randomized phase III trial comparing four different state-of-the-art regimens in the systemic treatment of metastatic and recurrent NSCLC, initially included PS 2 patients (Table 3), but a high incidence of adverse events in this group, particularly in those receiving cisplatin-based treatment, caused the investigators to terminate accrual of PS 2 patients [8]. Overall, 66 PS 2 patients were accrued to ECOG 1594; of these, 64 were evaluable. Demographics are described in Table 4. The median survival time for this group was 4.1 months, with a projected survival of 7.9 months for the 13 PS 2 patients receiving GC and 4.6 months for the 18 PS 2 patients receiving PCb (Table 5). The overall response rate for the evaluable PS 2 enrollees was 14%; for those receiving the GC regimen it was 23%. However, this regimen proved the most toxic among patients with compromised PS. Forty-two percent of patients experienced grade 3/4 nausea and vomiting; 24% experienced grade 3/4 renal toxicity; and 16% experienced significant cardiac and hepatic toxicities (Tables 6 and 7). Paclitaxel/carboplatin proved to be the least toxic regimen. Except for neuropathy, the incidence of side effects was significantly lower for this combination compared with the three cisplatin combinations in all categories including gastrointestinal, genitourinary, hepatic, and cardiopulmonary.
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EVOLUTION OF ECOG 1599
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In the final analysis reported by Sweeney and colleagues, the overall toxicity rate did not ultimately differ significantly from that observed in PS 0–1 patients [8]. Of five deaths among PS 2 patients enrolled on this study, only two were clearly attributable to therapy. The median survival of 4.1 months and 1-year survival rate of 19% were very likely secondary to underlying cancer and associated comorbidities, rather than to toxicity. However, the excess adverse event rate in PS 2 patients enrolled on ECOG 1594 forced investigators to reassess the appropriate role of treatment for this group; ECOG 1599 was the result (Fig. 1). Because paclitaxel and carboplatin (PCb) in combination proved considerably less toxic compared with the cisplatin combinations, this regimen was retained, but the paclitaxel dose was reduced from 225 mg/m2 to 200 mg/m2 in an attempt to ameliorate neurotoxicity.
The GC arm was also retained, but the dose and schedule were modified substantially. In ECOG 1594, GC yielded the highest median survival in PS 2 patients, although, because of underpowered accrual, this was not statistically significant. This observation, however, was undercut by the high incidence of serious or life-threatening toxicities, which were attributed, in large part, to the high dose of cisplatin employed (100 mg/m2 every 4 weeks). Multiple investigators had previously shown that eradication of the day-15 gemcitabine dose could help reduce toxicity. Cardenal and colleagues employed a modified day 1, day 8 schedule of gemcitabine with full-dose cisplatin (100 mg/m2) and demonstrated superior response rate (40.6% versus 21.9%) and time to progression (6.9 months versus 4.3 months) compared with a standard etoposide/cisplatin combination [9]. Crino and colleagues, in a contemporaneous randomized phase II trial, lowered the dose of cisplatin to 70 mg/m2 every 3 weeks in the investigational arm, retained the modified day 1, day 8 gemcitabine schedule (Fig. 1
), and observed a substantially lower incidence of toxicity compared with high-dose cisplatin (100 mg/m2), with no compromise in response rate or survival [10, 11]. On this basis, we opted to retain GC as the second study arm, but to eliminate the day-15 gemcitabine dose and to reduce the cisplatin dose further from 100 mg/m2 to 60 mg/m2 every 3 weeks.
The eligibility for this study (E1599) stipulated treatment-naïve advanced NSCLC with stage IV or recurrent disease, or IIIB disease on the basis of malignant pleural or pericardial effusion. Eligibility further required ECOG PS 2, minimum age of 18 years, adequate physiologic parameters (neutrophil count 
1,500 mm3, platelets 100,000 mm3, bilirubin 
1.5 mg/dl, aspartate aminotransferase 5 x upper limit of normal, and serum creatinine 1.5 mg/dl), no evidence of pre-existing grade 2 sensory neuropathy, no other active malignancies or infections, and no evidence of uncontrolled central nervous system metastases.
A randomized phase II trial design was employed. We projected an accrual of 45 evaluable patients per arm. Assuming a 10% evaluability rate, we anticipated a total accrual of 99 patients, which would prove sufficient to detect a 10% absolute improvement in 1-year survival compared with historic controls (i.e., 1-year overall survival of 30% or better, assuming a control rate of 20%). In addition, an early stopping rule for excess toxicity was instituted to make certain these combinations were safe in PS 2 patients.
The trial was suspended as scheduled in June 2001 (midway through accrual) for an interim toxicity analysis, but only one grade 5 treatment-related adverse event (fatal neutropenic fever in a patient receiving PCb) was observed. As a result, the study reopened. As of December 2002, 103 patients had been accrued, and the study is now closed permanently for analysis. The demographics are delineated in Table 8, and preliminary data are summarized in Table 9 [12]. As expected, the GC arm resulted in a higher incidence of thrombocytopenia, nausea and vomiting, and creatinine elevations, while the PCb arm yielded a higher incidence of peripheral neuropathy and myalgias/arthralgias. Disease control rates (stable disease plus response) at 2 months exceeded 50% in both arms. The median survival for both arms exceeded 6 months. Mature data, including 1-year survival rates, are still pending. If the results prove promising, we may consider a phase III trial comparing single-agent paclitaxel or gemcitabine to the platinum new agent combination. If, however, the outcome measures are disappointing or toxicity is excessive, we will likely mount additional phase II trials evaluating other less risky, yet promising, new agents. In addition we intend to include comorbidity and limited quality-of-life analyses.
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NESTED PHASE III DATA COMPARING COMBINATION CYTOTOXICS WITH MONOTHERAPY
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Cancer and Leukemia Group B (CALGB) 9730 is the only phase III study to date to evaluate combination therapy versus monotherapy in PS 2 patients [13]. Five hundred eighty-four treatment-naïve patients with advanced NSCLC were randomly assigned to either paclitaxel alone or to combination PCb. Each arm was well balanced with respect to stage (III versus IV), gender, and PS (0/1 versus 2). One hundred patients (16%) were PS 2. In the entire cohort of patients (n = 584), the combination arm resulted in a significantly higher response rate (30% versus 16%; p = 0.0001) and median survival (8.8 versus 6.7 months; p < 0.023). The outcome was significantly worse in the PS 2 population, but even in this cohort, the combination arm proved superior with response rate of 24% versus 10% for single-agent paclitaxel and improved 1- and 2-year median survival rates of 4.7 months, 18%, and 9% versus 2.4 months, 10%, and 0% respectively (p = 0.0213). These results support the conclusion that combination therapy has a role in NSCLC patients with impaired PS, and that platinum-based doublets are superior to monotherapy in these patients.
To date, there have been no phase III trials confined exclusively to PS 2 patients, but this deficiency is currently being corrected by the ongoing Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reactions (STELLAR) trials.
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POTENTIAL ROLE OF CT-2103
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Conjugation of paclitaxel to water-soluble polymeric carriers offers an important new approach to improving clinical efficacy and decreasing taxane-associated toxicity in patients. CT-2103 (XyotaxTM; paclitaxel poliglutamex, Cell Therapeutics, Inc.; Seattle, WA) is a novel macromolecular paclitaxel conjugate. In animal models, when compared to conventional paclitaxel, CT-2103 is preferentially localized to tumor tissue [14]. This effect is mediated by increased tumor vascular permeability, allowing selective penetration of CT-2103 into tumor sites versus the relative inability of this large molecule to penetrate normal vasculature. Once inside the tumor, CT-2103 is retained due to the lack of effective lymphatic drainage systems [14, 15]. Because polymeric conjugates like CT-2103 are taken up by tumor cells via pinocytosis, they likely bypass multi-drug resistance (MDR) pumps and are not subject to MDR-mediated resistance [16]. CT-2103 is not readily degraded by plasma esterases and remains stable in plasma. Therefore exposure of normal tissues to active, cleaved paclitaxel is limited [16, 17]. Exposure to free paclitaxel occurs selectively within tumor cells following cleavage of CT-2103 by the lysosomal enzyme cathepsin B, which has been shown to be present in high concentrations in many tumors [15, 17]. The aqueous solubility of CT-2103 eliminates the need for toxic solubilizing agents such as polyoxyethylated castor oil and the requirement for routine premedication with antihistamines and steroids. CT-2103 can be safely infused over 10 minutes through a peripheral vein.
In animal models, the maximum tolerated dose (MTD) of CT-2103 is two to three times that of paclitaxel and antitumor effects are more potent [18, 19]. In the nude mouse xenograft model of the human large cell lung cancer cell line NCI-H460, CT-2103 is more active than equitoxic doses of docetaxel (Cell Therapeutics, data on file).
In single-agent, phase I trials, the predominant toxicity of CT-2103 was reversible neutropenia. Only limited neurotoxicity was observed at higher doses and there was no significant alopecia. Responses were seen in heavily pretreated patients with several tumor types, including NSCLC [20, 21]. No evidence of drug accumulation was noted with every-3-week dosing [20]. A large phase I/II trial in heavily pretreated patients with advanced ovarian cancer supports the safety and activity of this agent [22]. CT-2103 has also been investigated in phase I studies in combination with cisplatin and carboplatin. No evidence of drug interaction has been observed. At doses of CT-2103 up to 250 mg/m2 plus cisplatin 75 mg/m2, side effects were manageable and similar to those expected with cisplatin alone. An increased incidence of neuropathy was observed in patients with prior exposure to neurotoxic agents, patients receiving 5 cycles, or the highest dose of CT-2103 (250 mg/m2). Antitumor activity was observed in a number of tumor types [23]. Similar results were observed at a CT-2103 dose of 210 mg/m2 plus carboplatin at an area under the concentration time curve (AUC) of 6 [24]. In this trial, tumor response and disease stabilization were noted across a range of solid tumors, including NSCLC. The MTD for CT-2103 was 225 mg/m2 in combination with carboplatin AUC 6 [24]. In an ongoing single-agent, phase I trial in chemotherapy-pretreated, relapsed patients with NSCLC (PS 0/1), a formal MTD has not yet been defined. Of six patients reported, one confirmed partial response was observed and two patients had disease stabilization. The principal toxicity observed was grade 3/4 neutropenia, with two grade 3 neuropathies. No other grade 3/4 toxicities were observed. The first-cycle MTD was not determined. Dose escalation was stopped at 270 mg/m2 due to cumulative neuropathy encountered with multiple dosing (>4 cycles) [20].
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PHASE II STUDIES IN NSCLC
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CT-2103 has been investigated as a single-agent for the first-line treatment of advanced NSCLC in a mixed cohort of elderly and PS 2 patients [25]. CT-2103 was administered at a dose of 175 mg/m2 every 3 weeks for up to 8 cycles. Of 28 patients treated, 8 (29%) had PS 2 and 20 (71%) had stage IV disease. Median age was 76 years (range, 49–88 years). Among 28 evaluable patients, there were two (7%) partial responses and 16 (57%) patients with stable disease lasting at least 10 weeks. Overall disease control was achieved in 18 of 28 patients (64%). Median survival was 8.1 months for PS 0–1 patients and 5.4 months for PS 2 patients. The median survival for PS 2 patients treated with single-agent CT-2103 was at least as long as that recently reported for combination treatment with paclitaxel and carboplatin (4.7 months) in the CALGB 9730 trial [13]. Treatment with CT-2103 was associated with an improved safety profile compared with the historical experience with conventional taxanes in high-risk NSCLC patients. Grade 4 neutropenia was seen in one patient, and grade 3 neuropathy was seen in four patients; no grade 4 neuropathy was observed. Neuropathy, as well as generalized weakness and fatigue, were seen mainly in patients with concomitant progressive disease and significant disease-related comorbidities. There were no hypersensitivity reactions and no alopecia was observed.
We recognize that observations generated by subanalyses and historical comparisons between small phase II trials and much larger phase III efforts are potentially confounded by selection bias, but the survival results observed in the PS 2 population in the single-agent CT-2103 trial seem promising. Based on these results, two randomized phase III studies of CT-2103 in PS 2 patients with NSCLC have been initiated. STELLAR 3 is a randomized, open-label trial comparing CT-2103 210 mg/m2 and carboplatin AUC 6 to standard paclitaxel (225 mg/m2) and carboplatin AUC 6 in chemotherapy-naïve PS 2 patients with locally advanced, recurrent, or metastatic disease. The paclitaxel dose was maintained at 225 mg/m2 in the reference arm based on the CALGB 9730 experience in which an identical dose in combination with carboplatin (AUC 6) yielded a survival advantage in PS 2 patients compared with single-agent paclitaxel. The primary end point of the trial is overall survival. Accrual is targeted at 370 evaluable patients in order to allow sufficient power (80%) and type 1 error (p = 0.05) to detect an increase in median survival from 4 to 5.5 months. STELLAR 4 is a randomized, open-label trial comparing single-agent CT-2103 175 mg/m2 to either single-agent gemcitabine or vinorelbine. The original study dose of 235 mg/m2 was amended to 175 mg/m2 based on a small percentage of patients in the study who appeared to develop early (first or second cycle) neutropenic-related toxicities, which may be prevented by administration of a lower dose. The patient population is similar to STELLAR 3; accrual goals are identical, and overall survival likewise is the primary end point. Accrual to the STELLAR trials is currently ongoing.
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CONCLUSIONS
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These and other efforts will further determine the optimal mode of therapy in PS 2 individuals with NSCLC. Off-protocol, monotherapy with a relatively nontoxic agent is reasonable; alternatively, in less frail PS 2 patients, based on the results of CALGB 9730, a combination of carboplatin with a third-generation agent is a justifiable option. Regardless, investigators must pay careful attention to toxicities and to the comorbidities inherent in this population. Unlike a well-defined population with good PS, the therapeutic index in PS 2 patients is much narrower and not as clearly defined. Future trials must also distinguish results based on the underlying reasons for compromised PS: disease burden versus comorbidities versus both. We also need to gauge the influence of age, sites of metastases, and associated cachexia. It is conceivable that those with compromised PS on the basis of concomitant illnesses, but few symptoms directly referable to the underlying malignancy, may fare just as well, if not better, on a single agent compared with a standard combination. In the absence of measurable progression or in patients whose tumors exhibit indolent growth, best supportive care or delaying therapy until symptoms manifest may be a preferred option. On the other hand, patients with rapidly expanding disease burden, secondary symptoms, and swiftly declining PS may profit most from combination therapy since the window of opportunity to treat may close quickly. Hence, diligent surveillance of comorbidities and critical analyses of quality of life may be more crucial in the PS 2 population than in those with intact PS. We must also recognize that trials centering on PS 2 individuals generally include a higher proportion of elderly patients compared with protocols restricted to PS 0–1 patients, and that unique pharmacokinetic and psychosocial concerns are inextricably linked to such efforts [26].
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ACKNOWLEDGMENT
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Dr. Langer receives grant/research support from the following: Bristol Myers Squibb, Pharmacia, Lilly, Schering-Plough Research Institute, Aventis, Amgen, Cell Therapeutics Inc., OrthoBiotech, Celgene, Vertex, Genentech, AstraZeneca, and Pfizer. Dr. Langer is a scientific advisor for the following: ImClone, Bristol Myers Squibb, Aventis, Pharmacia, Intrabiotics, GlaxoSmithKline, Pharmacyclics, Amgen, AstraZeneca, Novartis, Genentech, and Sanofi-Synthelabo. Dr. Langer is on the speakers bureau for the following: Bristol Myers Squibb, Aventis, Pharmacia, Lilly, and OrthoBiotech.
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ADDITIONAL READING
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Alberola V, Camps C, Provencio M et al. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol 2003;21:3207–3213.
Bodkin D, Neubauer M, Bolton MG. Phase 2 study of first line chemotherapy using CT-2103 (XYOTAX) in patients with non-small-cell lung cancer who are >69 years of age or who have performance status (PS) = 2. Eur J Cancer Supplements 2003;1:S242. Abstract 806.
The Elderly Lung Cancer, Vinorelbine Italian Study Group. Effects of Vinorelbine on quality of life and survival of elderly patients with advanced non-small cell lung cancer. J Natl Cancer Inst 1999;91:66–72.
Johnson DH. Chemotherapy for metastatic non-small cell lung cancer. J Natl Cancer Inst 1993;85:766–767.
Sweeney C, Zhu J, Sandler AB et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a phase III trial in patients with metastatic non-small cell lung carcinoma. Cancer 2001;92:2639.
Received January 29, 2004;
accepted for publication May 26, 2004.
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Abstract
Introduction
