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Drug development in patients with advanced non-small cell lung cancer and poor performance status
Drug Development in Patients With Advanced Non–Small Cell Lung Cancer and Poor Performance Status Thomas E. Stinchcombe and Mark A. Socinski Drug development represents a significant challenge in patients with advanced non–small cell lung cancer and poor performance status (PS) because of the short survival time of these patients and heterogeneity in the cause of poor PS. Historically, these patients have been excluded from clinical trials. However, there is now evidence that certain treatments can produce responses and increase survival in patients with poor PS. Several clinical trials have been conducted recently to investigate treatment options in these patients. This article reviews the need for such trials, the potentially greater risks with evaluating new drugs in such patients, recommendations for designing trials in the population, and the results in recently completed and ongoing clinical trials designed specifically for the PS2 population. Semin Oncol 31(suppl 11):21-26 © 2004 Elsevier Inc. All rights reserved.
T
he development of drugs in patients with poor performance status (PS) is complicated by the lack of data in this population, their short survival time, and heterogeneity in the etiology of their poor PS. It has been shown that patients with a good PS will benefit in quality of life (QOL), palliation of symptoms, and survival from platinum-based therapy.1-3 However, there is debate about the benefits of platinum-based chemotherapy in patients with a poor PS (ie, an Eastern Cooperative Oncology Group [ECOG] PS of ⱖ2), which is discussed further by Kelly4 elsewhere in this supplement. The clinical benefit of palliative chemotherapy has been difficult to quantitate in this patient population because of its short survival. The most recent guidelines of the American Society of Clinical Oncology for the treatment of metastatic non–small cell lung cancer (NSCLC) recommend that single-agent chemotherapy be considered in patients with poor PS but do not recommend platinum-based or doubleagent chemotherapy regimens.5 However, new data and novel agents may affect treatment decisions in PS2 patients.
Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC. Address reprint requests to Tom Stinchcombe, MD, Multidisciplinary Thoracic Oncology Program, 3009 Old Clinic Building CB 7305, Chapel Hill, NC 27599.E-mail: [email protected]
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.10.005
Previous Experience of Patients With Performance Status 2 in Clinical Trials The benefits of palliative chemotherapy in patients with PS2 are less clear because these patients either have accounted for only a small proportion of patients in clinical trials or have been excluded from them. An ECOG trial of four different platinum-based treatments that included 92 patients with PS2 (19% of the patients enrolled) was conducted from 1981 to 1983. Median survival was significantly shorter in the PS2 patients (PS2 v PS1, 10 v 26 weeks; PS2 v PS0, 10 v 36 weeks; both P ⫽ .001), and treatment-related mortality was significantly greater in the PS2 population.6 The investigators concluded that PS2 patients should be excluded from future clinical trials. ECOG trial E1594 also compared four platinum-based treatments and included PS2 patients. However, their inclusion was halted by the data monitoring committee after a substantial rate of adverse events was observed in the PS2 patients. This led to patient PS value being used as an exclusion or inclusion criterion in many clinical trials. The decision to exclude patients with poor PS has been reevaluated, however, by using data from the study. Sixty-eight PS2 patients had been enrolled when further enrollment was halted, 64 of whom were assessable for efficacy and safety.7 There were five deaths in these 68 patients (7%), but analysis found that only two of those deaths were attributable to the therapy, 21
T.E. Stinchcombe and M.A. Socinski
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Table 1 Major Grade 3 or 4 Toxicities With Platinum-Based Doublets in Patients With Advanced NSCLC With PS2: Final Subanalysis of ECOG E1594
Neutropenia Thrombocytopenia Anemia Febrile neutropenia Renal Emesis Diarrhea Liver Cardiac Neuropathy
PC (n ⴝ 18)
GC (n ⴝ 13)
DC (n ⴝ 18)
PCb (n ⴝ 15)
60 0 25 5 6 40 5 5 0 15
58 50 33 0 24 42 8 16 16 13
59 0 6 12 0 41 18 0 0 18
47 7 20 0 0 0 0 7 0 20
Abbreviations: NSCLC, non–small cell lung cancer; PS, performance status; ECOG, Eastern Cooperative Oncology Group; P, paclitaxel; C, cisplatin; G, gemcitabine; D, docetaxel; Cb, carboplatin. From: Sweeney et al: Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: A phase II trial in patients with metastatic nonsmall cell lung carcinoma. Cancer 92:2639-2647, 2001. Adapted and reprinted with permission from Wiley-Liss, Inc.7
and the others were because of disease progression. There were no differences in the rates of grade 3 or 4 adverse events in the PS2 patients and the PS0 and PS1 patients (Table 1). Overall survival in PS2 patients was 4.1 months. A recent trial by Cancer and Leukemia Group B (CALGB), CALGB 9730, which compared the combination of carboplatin and paclitaxel with paclitaxel alone in advanced NSCLC, included PS2 patients. The 99 PS2 patients (18% of the 561 patients) were the largest group of PS2 patients accrued to a cooperative group trial.8 This study found that the response rate was higher in PS2 patients treated with the combination (24% v 10%), median survival was longer (4.7 months v 2.4 months), and 1-year survival was higher (18% v 10%) (Fig 1). Additionally, analysis of QOL measures showed no detriments in QOL in the PS2 patients treated with the combina-
tion therapy.8 The results of this trial are provocative and have renewed debate about the benefits of double-agent or platinum-based chemotherapy in this patient population.
Challenges in Conducting Trials in Patients With Performance Status 2 The limited life expectancy of PS2 patients, along with reports of excessive toxicity, have led many trials to exclude PS2 patients. Even when they have been included in clinical trials, PS2 patients have accounted for approximately 20% of the patients enrolled, creating a situation in which there is a small sample size and a limited data set from which to draw
Figure 1 Overall survival in performance status 2 patients with advanced non–small cell lung cancer treated with paclitaxel (n ⫽ 50) or paclitaxel and carboplatin (n ⫽ 49) in Cancer and Leukemia Group B (CALGB) 9730. (Adapted and reprinted from Lilenbaum R: Management of advanced non–small-cell lung cancer in patients with a performance status of 2. Clin Lung Cancer 5:209-213, 2004, with permission from Cancer Information Group, L.P.8)
Drug development in PS2 patients Table 2 Difficulties in Conducting Trials in PS2 Patients Patients not referred to an oncologist; perceived as being too ill to tolerate or benefit from chemotherapy. Significant heterogeneity in the PS2 patient population; poor PS may be due to malignancy, comorbidities, age, or a combination of these factors. Modest survival benefit with chemotherapy despite a possible clinically significant improvement in QOL. Short survival times limit the feasibility of crossover trials. Clinical investigators may be hesitant about testing new drugs or combinations in PS2 patients because reduced median survival may obscure the activity of the new therapy, indicating a low therapeutic index. Abbreviations: PS, performance status; QOL, quality of life.
conclusions. Another problem in drawing conclusions about the PS2 patient population is that a significant percentage of these patients may never be referred to an oncologist because they are perceived as being too ill to tolerate or benefit from chemotherapy. Earle et al9 recently reported that 36% of Medicare patients in whom metastatic NSCLC had been diagnosed were not referred to a physician for an evaluation of the potential benefits of palliative chemotherapy.9 It is therefore difficult to accurately determine the true numbers of the PS2 population. An additional problem is that there can be significant heterogeneity in the PS2 patient population, and the causes of their poor PS have not been evaluated. For instance, a patient’s poor PS may be because of symptoms related to his or her malignancy (such as bone pain, anorexia, and fatigue), severe comorbidities (such as chronic obstructive pulmonary disease, congestive heart failure, and anemia), or age. Thus, PS in patients whose initial poor PS is due to malignancyrelated symptoms may improve with chemotherapy treatment or supportive care measures, such as adequate analgesics or erythropoietin therapy. On the other hand, PS in patients with several severe comorbidities may not improve with chemotherapy treatment, and they may be at a higher risk for adverse effects (Table 2). Another aspect of the debate is that PS2 patients may have only a small survival benefit with chemotherapy, but they may have a clinically significant improvement in QOL. An analysis by Billingham and Cullen10 of data from phase III trials of mitomycin, ifosfamide, and cisplatin found that there was no survival benefit with chemotherapy in PS2 patients, but improvement in QOL in the first 6 weeks of therapy was greater than in PS0 and PS1 patients. The results of CALGB 9730 provide evidence for the benefit of chemotherapy, but they also illustrate the difficulties in conducting studies in this patient population; median survival is modest and there is a rapid decline in survival during the first several months of treatment in both treatment arms. The median survival of 2.4 months in the single-agent treatment arm has caused many investigators and clinicians to question whether single-agent chemotherapy is better than best supportive care or has a QOL benefit. Trials that compare active treatment with best supportive
23 care have been difficult to conduct in the United States because of physician and patient preferences. This cultural preference is particularly problematic in the PS2 population, in whom short survival times limit the feasibility of crossover trials, in which patients who were randomized initially to best supportive care could be switched to the treatment arm on disease progression or clinical decline. An additional obstacle to conducting studies in this patient population is that clinical investigators may be hesitant to test new drugs or combinations in PS2 patients. This concern is due, in part, to the fact that the short median survival may obscure the activity of the new therapy. Another concern is that it has been believed that the toxicity of chemotherapy is excessive in this population. Thus, there is hesitancy about testing new drugs in this population because of the possibility that the drug will be perceived as having a low therapeutic index. Consequently, whereas PS2 patients are a significant population routinely assessed and treated by clinicians, there remains a paucity of data on the best treatment approaches.
Clinical Trial Strategies Because of the importance of the PS2 patient population, several strategies are being developed and implemented to better study the effects of therapy, one of which is to have separate trials in PS2 patients. The trial ECOG 1599, which evaluated the tolerability of attenuated doses of cisplatin and gemcitabine and standard doses of carboplatin and paclitaxel in PS2 patients is such an example.11,12 Another strategy is to preferentially use agents that have minimal toxicity and have shown efficacy in NSCLC, such as the epidermal growth factor receptor inhibitors gefitinib and erlotinib. In a randomized phase II trial of two different doses of gefitinib, only 1.9% of patients treated with 250 mg/d were withdrawn from the study because of drug-related adverse events.13 Additionally, erlotinib has been shown to extend survival and provide symptomatic relief to a greater extent than best supportive care in NSCLC patients who had progressed after first-line therapy.14 Lastly, an advantage of these agents is that they are given orally, which is more convenient for patients with poor PS, because treatment does not necessitate a trip to the hospital or clinic. A crucial aspect of future clinical trials in PS2 patients will be to better define the comorbidities in this population and the causes of their poor PS. This can be difficult because many of these patients may have problems with several systems. The cumulative effects of these comorbidities may be quite debilitating, but the effects of a single problem may be minimal. To determine the effects of numerous comorbidities, a scale, such as the Cumulative Illness Rating scale for Geriatrics (CIRS-G),15 which assesses 13 different organ systems and grades illness severity, may be useful (Table 3).16 Another useful scale is the Charlson scale, a weighted index of 19 different clinical conditions that have been associated with a greater risk of 1-year mortality.17 A study by Firat et al18 found that the Karnofsky PS and the CIRS-G score were both important independent prognostic factors in patients with stage III NSCLC treated with radiotherapy alone. In
T.E. Stinchcombe and M.A. Socinski
24 Table 3 Construction of Common Comorbidity Scales Scale
Type
Charlson
Weighted
Cumulative Illness Rating Scale-Geriatric (CIRS-G)
Weighted
Items and Rating 19 diseases weighted 1 to 6 Total: 0-30 13 or 14 organ system categories, rated 0-4 Total: 0-52
How Constructed Internal medicine patients: 1-year mortality Comprehensive listing of diseases weighted by clinician estimate or manual detailing several geriatric problems
Interrater Reliability
Test-Retest Reliability
0.16-0.95
0.86-0.92
0.59-0.88
0.57-0.95
From: Extermann M: Measuring comorbidity in older cancer patients. Eur J Cancer 36:453-471, 2000. Adapted and reprinted with permission from Elsevier.16
particular, a CIRS-G severity score of 4 and a severity index of 3 or higher were independently associated with significantly lower overall survival. Frasci et al19 compared the combination of gemcitabine and vinorelbine with vinorelbine alone in patients with stage IIIB or stage IV NSCLC who were older than 70 years and found that the Charlson score was strongly correlated with the tolerance of treatment and overall survival.19 Median survival was 28 weeks in patients with no comorbidities, 21 weeks in those with a Charlson score of 1 or 2, and 16 weeks in those with a Charlson score of 3 or higher. The correlation between Charlson score and survival was stronger than that between ECOG PS and survival in this study. A Charlson score of 3 or higher was also associated with a greater likelihood of early treatment discontinuation (82% v 30%). The CIRS-G scale is thought to be more reliable than the Charlson scale because it assesses more organ systems. A study of the 2 scales in patients with cancer found a prevalence of comorbidities of 94% with the CIRS-G scale and of 36% with the Charlson scale.16 Future studies in PS2 patients will likely have to include some assessment of comorbidities so that their effects on dose intensity, adverse events, and survival can be evaluated. Another important issue in designing trials in this patient population is QOL and symptom relief. Studies may show only modest increases in survival but clinically significant improvements in QOL and symptoms. It is likely that symptoms will be more severe in PS2 patients and treatment will, therefore, produce greater improvements in symptoms and in QOL. With recent improvements in supportive care, there may be improvements in patient QOL as well as reduced toxicity. One of the most common complications with chemotherapy is anemia. It has been estimated that grade 1 or 2 anemia develops in 10% to 60% of patients with NSCLC treated with chemotherapy, and grade 3 or 4 develops in 5% to 25%.20 The high incidence of treatment-related anemia can be particularly troublesome in patients with lung cancer because many of them have underlying pulmonary or cardiovascular disease and may be severely affected by even mild anemia. Langer et al21 found a direct relation between anemia and a decline in QOL that was independent of the response to treatment. Thus, any clinical trials in which QOL is an endpoint should require close monitoring and adherence to
guidelines for the use of erythropoietic-stimulating agents. It is also possible that with greater use of supportive care measures, more patients will be able to tolerate longer durations of treatment with chemotherapy. Improvements in antiemetics and appetite stimulants may also have a significant role in diminishing patients’ symptoms and improving their QOL.
Emerging Data and Ongoing Trials in Patients With Performance Status 2 Results of several trials in PS2 patients were presented at the 2004 American Society of Clinical Oncology meeting, the majority of which were phase II trials with approximately 25 to 100 patients. These trials provide preliminary evidence of efficacy and safety, and a basis for further clinical trials. The results of these trials are reviewed in the article by Langer and Lilenbaum22 in this supplement. Several ongoing phase III trials include PS2 patients (Table 4). Several of them use paclitaxel poliglumex, a macromolecular taxane (paclitaxel linked to a water-soluble polyglutamate backbone) that targets tumors with a unique intracellular mechanism of action. Because this agent is water soluble, it does not require routine premedication with antihistamines and steroids to prevent hypersensitivity reactions. In addition, paclitaxel poliglumex has a potentially better safety profile than the current taxanes. Median survival in a phase II trial in 28 patients with advanced NSCLC who were PS2 or 70 years old or older and received paclitaxel poliglumex was 5.4 months,23 which compares favorably with the 4.7-month median survival with carboplatin and paclitaxel in CALGB 9730. Grade 4 neutropenia developed in 3 patients, grade 3 fatigue in 3, grade 3 neuropathy in 3, and febrile neutropenia in 1 patient. Neuropathy and fatigue were seen in patients with disease progression and significant disease-related comorbidities. These encouraging results led to the development of the Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reactions (STELLAR) trials. One of these trials, STELLAR 2, has completed enrollment with 840 PS0 to PS2 patients with advanced NSCLC. This second-line trial compares single-agent docetaxel 75 mg/m2 every 3 weeks with paclitaxel poliglumex 210 mg/m2 every 3 weeks in PS0/1 patients and 175 mg/m2 every 3 weeks in PS2 patients. STEL-
Drug development in PS2 patients
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Table 4 Ongoing Phase II and III Trials of PS2 Patients With Advanced Non-Small Cell Lung Cancer Dose
Target No. of Patients
Results Due
Trial
Study Regimen
Comparator
STELLAR 2 2nd-line NSCLC PS0-PS2 Phase III STELLAR 3 1st-line NSCLC PS2 Phase III STELLAR 4 1st-line NSCLC PS2 Phase III
Paclitaxel poliglumex 210 mg/m2 in PS0 and PS1; 175 in PS2 every 3 weeks Paclitaxel poliglumex 210 mg/m2 ⴙ carboplatin AUC 6 mg/mL· min every 3 weeks Paclitaxel poliglumex 175 mg/m2 every 3 weeks
Docetaxel 75 mg/m2 every 3 weeks
840 (closed)
Q3 2005
Paclitaxel 225 mg/m2 ⴙ carboplatin AUC 6 mg/ mL· min every 3 weeks
400 (closed)
Q1 2005
477 (closed)
Q1 2005
Celecoxib* 1st-line NSCLC PS2 Phase II Erlotinib 1st-line NSCLC PS2 Phase II
Celocoxib/docetaxel
Gemcitabine 1000 mg/m2 days 1, 8, 15 every 4 weeks or vinorelbine 30 mg/m2 days 1, 8, 15 every 4 weeks Docetaxel
Erlotinib monotherapy
Paclitaxel/carboplatin
Active
Active
Abbreviations: NSCLC, non-small cell lung cancer; PS, performance status. *Population includes elderly in addition to PS2.
LAR 3 is a first-line trial in PS2 patients randomized to the combination of paclitaxel poliglumex 210 mg/m2 and carboplatin dosed to an area under the time-concentration curve of 6 mg/mL ⫻ min every 3 weeks or the reference treatment of paclitaxel 225 mg/m2 and carboplatin at the same dose every 3 weeks. This carboplatin and paclitaxel regimen is also used in CALGB 9730, with which there was a survival advantage over single-agent paclitaxel in PS2 patients. Another trial, STELLAR 4, compares paclitaxel poliglumex 175 mg/m2 every 3 weeks with either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks or vinorelbine 30 mg/m2 on days 1, 8, and 15 every 4 weeks in first-line PS2 patients. Enrollment in STELLAR 3 and STELLAR 4 has been completed with 400 and 477 patients, respectively. The results are expected in early 2005. Because STELLAR 3 and STELLAR 4 are the largest trials to date conducted solely in PS2 patients, their findings should be particularly significant. The CALGB is designing a trial in PS2 patients with advanced NSCLC who will be randomized to docetaxel with cetuximab or docetaxel with bortezomib. Cetuximab, a monoclonal antibody that targets the epidermal growth factor receptor, has shown activity in patients with advanced NSCLC.24 Kim et al25 conducted a phase II study of cetuximab and docetaxel in 47 patients with refractory or resistant advanced NSCLC and a median Karnofsky PS of 80% who were treated with a median of ten cycles.25 There was a partial response in 13 patients (28%) and stable disease in 8 patients (17%). The most common grade 3 toxicities were infection (21%), fatigue (21%), and acneiform (19%). There were allergic reactions that necessitated discontinuing the cetux-
imab in 4 patents (9%). Bortezomib, a reversible inhibitor of the 26S proteasome of the ubiquitin protein degradation pathway, has shown activity in NSCLC. A randomized phase II trial that is currently enrolling patients is evaluating bortezomib with or without docetaxel in patients with a Karnofsky PS of at least 70% in whom NSCLC has progressed after treatment with at least one chemotherapy regimen.26 Preliminary data indicate that nausea (34%), fatigue (28%), and neutropenia (23%) are the most common drug-related adverse events.
Conclusion Patients with PS2 have comprised a small percentage of the patients in clinical trials in advanced NSCLC. Consequently, there are few data on PS2 patients on which to base treatment decisions. Even with data, they are often treated according to their physician’s experience or preferences. There have been difficulties in defining the PS2 patient population and difficulties in conducting clinical trials in PS2 patients because they often have significant comorbidities, they are symptomatic because of their malignancy, and their condition is often deteriorating rapidly. Fortunately, several large planned or ongoing trials are now evaluating new agents and regimens in PS2 patients, and they are expected to provide much-needed data on which treatment decisions can be based.
References 1. Stephens R: The Big Lung Trial: Determining the value of cisplatinbased chemotherapy for all patients with non–small cell lung cancer
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(NSCLC): Preliminary results in the supportive care setting. Proc Am Soc Clin Oncol 21:291a, 2002 (abstr 1161) Cullen MH, Billingham LJ, Woodroffe CM, et al: Mitomycin, ifosfamide, and cisplatin in unresectable non–small-cell lung cancer: Effects on survival and quality of life. J Clin Oncol 17:3188-3194, 1999 Anderson H, Hopwood R, Stephens R: Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non–small cell lung cancer—A randomized trial with quality of life as the primary outcome. Br J Cancer 83:447-453, 2000 Kelly K: Challenges in defining and identifying patients with non–small cell lung cancer and poor performance status. Semin Oncol 31:3-7, 2004 (suppl 11) Pfister DG, Johnson DH, Azzoli CG, et al: American Society of Clinical Oncology treatment of unresectable non–small-cell lung cancer guidelines: Update 2003. J Clin Oncol 22:330-353, 2004 Ruckdeschel JC, Finkelstein DM, Ettinger DS: A randomized trial of the four most active regimens for metastatic non–small-cell lung cancer. J Clin Oncol 4:14-22, 1986 Sweeney CJ, Zhu J, Sandler AB: Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: A phase II trial in patients with metastatic nonsmall cell lung carcinoma. Cancer 92:2639-2647, 2001 Lilenbaum R: Management of advanced non–small-cell lung cancer in patients with a performance status of 2. Clin Lung Cancer 5:209-213, 2004 Earle CC, Neumann PJ, Gelber RD, et al: Impact of referral patterns on the use of chemotherapy for lung cancer. J Clin Oncol 20:1786-1792, 2002 Billingham LJ, Cullen MH: The benefits of chemotherapy in patient subgroups with unresectable non–small-cell lung cancer. Ann Oncol 12:1671-1675, 2001 Langer C, Stephenson P, Schiller J, et al: ECOG 1599: Randomized phase II study of paclitaxel/carboplatin vs cisplatin/gemcitabine in performance status (PS) 2 patients with treatment-naive advanced NSCLC. Lung Cancer, 41:S18, 2003 (suppl 2) Tester WJ, Stephenson P, Langer CJ, et al: ECOG 1599: Randomized phase II study of paclitaxel/carboplatin or gemcitabine/cisplatin in performance status (PS) 2 patients with advanced non–small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 23:627, 2004 (abstr 7055) Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non–small-cell lung cancer. J Clin Oncol 21:2237-2246, 2003 Shepherd FA, Pereira J, Ciuleanu TE, et al: A randomized placebocontrolled trial of erlotinib in patients with advanced non–small cell
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lung cancer (NSCLC) following failure of 1st or 2nd line chemotherapy: A National Institute of Canada Clinical Trials Group (NCIC CTG) trial. Proc Am Soc Clin Oncol Late-Breaking Abstracts Booklet 23:18, 2004 (abstr 7022) Miller MD, Paradis CF, Houck PR, et al: Rating chronic medical illness burden in geropsychiatric practice and research: Application of the Cumulative Illness Rating Scale. Psychiatry Res 41:237-248, 1992 Extermann M: Measuring comorbidity in older cancer patients. Eur J Cancer 36:453-471, 2000 Charlson ME, Pompei P, Ales KL, et al: A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 40:373-383, 1987 Firat S, Byhardt RW, Gore E: Comorbidity and Karnofksy performance score are independent prognostic factors in stage III non–small-cell lung cancer: An institutional analysis of patients treated on four RTOG studies. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 54:357-364, 2002 Frasci G, Lorusso V, Panza N, et al: Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non–small cell lung cancer. J Clin Oncol 18:2529-2536, 2000 Groopman JE, Itri LM: Chemotherapy-induced anemia in adults: Incidence and treatment. J Natl Cancer Inst 91:1616-1634, 1999 Langer C, Barsevick A, Bruner D, et al: Correlation of quality of life (QOL) with survival, treatment response, and anemia in patients with advanced non–small cell lung cancer (NSCLC) treated with carboplatin and paclitaxel. Lung Cancer 18:23, 1997 (abstr) Langer C, Lilenbaum R: Role of chemotherapy in patients with poor performance status and advanced non–small cell lung cancer. Semin Oncol 31:8-15, 2004 (suppl 11) Norton MS, Neubauer M, Harper H, et al: Phase 2 study of first line chemotherapy using CT-2103 in patients with non–small-cell lung cancer who are ⱖ70 years of age or performance status (PS) ⫽ 2. Proc Am Soc Clin Oncol 22:653, 2003 (abstr 2626) Aghajanian C, Soignet S, Dizon D, et al: A phase I trial of the novel Proteasome Inhibitor PS341 in advanced solid tumor malignancies. Proc Am Soc Clin Oncol 20:85a, 2001 (abstr) Kim ES, Mauer AM, Tran HT, et al: A phase II study of cetuximab, an epidermal growth factor receptor (EGFR) blocking antibody, in combination with docetaxel in chemotherapy refractory/resistant patients with advanced non–small cell lung cancer: Final report. Pro Am Soc Clin Oncol 22:642, 2003 (abstr 2581) Fanucchi MP, Belt RJ, Fossella FV, et al: Phase (ph) II study of bortezomib ⫾ docetaxel in previously treated patients with advanced non– small cell lung cancer (NSCLC): Preliminary results. Proc Am Soc Clin Oncol 23:640, 2004 (abstr 7107)
T
he development of drugs in patients with poor performance status (PS) is complicated by the lack of data in this population, their short survival time, and heterogeneity in the etiology of their poor PS. It has been shown that patients with a good PS will benefit in quality of life (QOL), palliation of symptoms, and survival from platinum-based therapy.1-3 However, there is debate about the benefits of platinum-based chemotherapy in patients with a poor PS (ie, an Eastern Cooperative Oncology Group [ECOG] PS of ⱖ2), which is discussed further by Kelly4 elsewhere in this supplement. The clinical benefit of palliative chemotherapy has been difficult to quantitate in this patient population because of its short survival. The most recent guidelines of the American Society of Clinical Oncology for the treatment of metastatic non–small cell lung cancer (NSCLC) recommend that single-agent chemotherapy be considered in patients with poor PS but do not recommend platinum-based or doubleagent chemotherapy regimens.5 However, new data and novel agents may affect treatment decisions in PS2 patients.
Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC. Address reprint requests to Tom Stinchcombe, MD, Multidisciplinary Thoracic Oncology Program, 3009 Old Clinic Building CB 7305, Chapel Hill, NC 27599.E-mail: [email protected]
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.10.005
Previous Experience of Patients With Performance Status 2 in Clinical Trials The benefits of palliative chemotherapy in patients with PS2 are less clear because these patients either have accounted for only a small proportion of patients in clinical trials or have been excluded from them. An ECOG trial of four different platinum-based treatments that included 92 patients with PS2 (19% of the patients enrolled) was conducted from 1981 to 1983. Median survival was significantly shorter in the PS2 patients (PS2 v PS1, 10 v 26 weeks; PS2 v PS0, 10 v 36 weeks; both P ⫽ .001), and treatment-related mortality was significantly greater in the PS2 population.6 The investigators concluded that PS2 patients should be excluded from future clinical trials. ECOG trial E1594 also compared four platinum-based treatments and included PS2 patients. However, their inclusion was halted by the data monitoring committee after a substantial rate of adverse events was observed in the PS2 patients. This led to patient PS value being used as an exclusion or inclusion criterion in many clinical trials. The decision to exclude patients with poor PS has been reevaluated, however, by using data from the study. Sixty-eight PS2 patients had been enrolled when further enrollment was halted, 64 of whom were assessable for efficacy and safety.7 There were five deaths in these 68 patients (7%), but analysis found that only two of those deaths were attributable to the therapy, 21
T.E. Stinchcombe and M.A. Socinski
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Table 1 Major Grade 3 or 4 Toxicities With Platinum-Based Doublets in Patients With Advanced NSCLC With PS2: Final Subanalysis of ECOG E1594
Neutropenia Thrombocytopenia Anemia Febrile neutropenia Renal Emesis Diarrhea Liver Cardiac Neuropathy
PC (n ⴝ 18)
GC (n ⴝ 13)
DC (n ⴝ 18)
PCb (n ⴝ 15)
60 0 25 5 6 40 5 5 0 15
58 50 33 0 24 42 8 16 16 13
59 0 6 12 0 41 18 0 0 18
47 7 20 0 0 0 0 7 0 20
Abbreviations: NSCLC, non–small cell lung cancer; PS, performance status; ECOG, Eastern Cooperative Oncology Group; P, paclitaxel; C, cisplatin; G, gemcitabine; D, docetaxel; Cb, carboplatin. From: Sweeney et al: Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: A phase II trial in patients with metastatic nonsmall cell lung carcinoma. Cancer 92:2639-2647, 2001. Adapted and reprinted with permission from Wiley-Liss, Inc.7
and the others were because of disease progression. There were no differences in the rates of grade 3 or 4 adverse events in the PS2 patients and the PS0 and PS1 patients (Table 1). Overall survival in PS2 patients was 4.1 months. A recent trial by Cancer and Leukemia Group B (CALGB), CALGB 9730, which compared the combination of carboplatin and paclitaxel with paclitaxel alone in advanced NSCLC, included PS2 patients. The 99 PS2 patients (18% of the 561 patients) were the largest group of PS2 patients accrued to a cooperative group trial.8 This study found that the response rate was higher in PS2 patients treated with the combination (24% v 10%), median survival was longer (4.7 months v 2.4 months), and 1-year survival was higher (18% v 10%) (Fig 1). Additionally, analysis of QOL measures showed no detriments in QOL in the PS2 patients treated with the combina-
tion therapy.8 The results of this trial are provocative and have renewed debate about the benefits of double-agent or platinum-based chemotherapy in this patient population.
Challenges in Conducting Trials in Patients With Performance Status 2 The limited life expectancy of PS2 patients, along with reports of excessive toxicity, have led many trials to exclude PS2 patients. Even when they have been included in clinical trials, PS2 patients have accounted for approximately 20% of the patients enrolled, creating a situation in which there is a small sample size and a limited data set from which to draw
Figure 1 Overall survival in performance status 2 patients with advanced non–small cell lung cancer treated with paclitaxel (n ⫽ 50) or paclitaxel and carboplatin (n ⫽ 49) in Cancer and Leukemia Group B (CALGB) 9730. (Adapted and reprinted from Lilenbaum R: Management of advanced non–small-cell lung cancer in patients with a performance status of 2. Clin Lung Cancer 5:209-213, 2004, with permission from Cancer Information Group, L.P.8)
Drug development in PS2 patients Table 2 Difficulties in Conducting Trials in PS2 Patients Patients not referred to an oncologist; perceived as being too ill to tolerate or benefit from chemotherapy. Significant heterogeneity in the PS2 patient population; poor PS may be due to malignancy, comorbidities, age, or a combination of these factors. Modest survival benefit with chemotherapy despite a possible clinically significant improvement in QOL. Short survival times limit the feasibility of crossover trials. Clinical investigators may be hesitant about testing new drugs or combinations in PS2 patients because reduced median survival may obscure the activity of the new therapy, indicating a low therapeutic index. Abbreviations: PS, performance status; QOL, quality of life.
conclusions. Another problem in drawing conclusions about the PS2 patient population is that a significant percentage of these patients may never be referred to an oncologist because they are perceived as being too ill to tolerate or benefit from chemotherapy. Earle et al9 recently reported that 36% of Medicare patients in whom metastatic NSCLC had been diagnosed were not referred to a physician for an evaluation of the potential benefits of palliative chemotherapy.9 It is therefore difficult to accurately determine the true numbers of the PS2 population. An additional problem is that there can be significant heterogeneity in the PS2 patient population, and the causes of their poor PS have not been evaluated. For instance, a patient’s poor PS may be because of symptoms related to his or her malignancy (such as bone pain, anorexia, and fatigue), severe comorbidities (such as chronic obstructive pulmonary disease, congestive heart failure, and anemia), or age. Thus, PS in patients whose initial poor PS is due to malignancyrelated symptoms may improve with chemotherapy treatment or supportive care measures, such as adequate analgesics or erythropoietin therapy. On the other hand, PS in patients with several severe comorbidities may not improve with chemotherapy treatment, and they may be at a higher risk for adverse effects (Table 2). Another aspect of the debate is that PS2 patients may have only a small survival benefit with chemotherapy, but they may have a clinically significant improvement in QOL. An analysis by Billingham and Cullen10 of data from phase III trials of mitomycin, ifosfamide, and cisplatin found that there was no survival benefit with chemotherapy in PS2 patients, but improvement in QOL in the first 6 weeks of therapy was greater than in PS0 and PS1 patients. The results of CALGB 9730 provide evidence for the benefit of chemotherapy, but they also illustrate the difficulties in conducting studies in this patient population; median survival is modest and there is a rapid decline in survival during the first several months of treatment in both treatment arms. The median survival of 2.4 months in the single-agent treatment arm has caused many investigators and clinicians to question whether single-agent chemotherapy is better than best supportive care or has a QOL benefit. Trials that compare active treatment with best supportive
23 care have been difficult to conduct in the United States because of physician and patient preferences. This cultural preference is particularly problematic in the PS2 population, in whom short survival times limit the feasibility of crossover trials, in which patients who were randomized initially to best supportive care could be switched to the treatment arm on disease progression or clinical decline. An additional obstacle to conducting studies in this patient population is that clinical investigators may be hesitant to test new drugs or combinations in PS2 patients. This concern is due, in part, to the fact that the short median survival may obscure the activity of the new therapy. Another concern is that it has been believed that the toxicity of chemotherapy is excessive in this population. Thus, there is hesitancy about testing new drugs in this population because of the possibility that the drug will be perceived as having a low therapeutic index. Consequently, whereas PS2 patients are a significant population routinely assessed and treated by clinicians, there remains a paucity of data on the best treatment approaches.
Clinical Trial Strategies Because of the importance of the PS2 patient population, several strategies are being developed and implemented to better study the effects of therapy, one of which is to have separate trials in PS2 patients. The trial ECOG 1599, which evaluated the tolerability of attenuated doses of cisplatin and gemcitabine and standard doses of carboplatin and paclitaxel in PS2 patients is such an example.11,12 Another strategy is to preferentially use agents that have minimal toxicity and have shown efficacy in NSCLC, such as the epidermal growth factor receptor inhibitors gefitinib and erlotinib. In a randomized phase II trial of two different doses of gefitinib, only 1.9% of patients treated with 250 mg/d were withdrawn from the study because of drug-related adverse events.13 Additionally, erlotinib has been shown to extend survival and provide symptomatic relief to a greater extent than best supportive care in NSCLC patients who had progressed after first-line therapy.14 Lastly, an advantage of these agents is that they are given orally, which is more convenient for patients with poor PS, because treatment does not necessitate a trip to the hospital or clinic. A crucial aspect of future clinical trials in PS2 patients will be to better define the comorbidities in this population and the causes of their poor PS. This can be difficult because many of these patients may have problems with several systems. The cumulative effects of these comorbidities may be quite debilitating, but the effects of a single problem may be minimal. To determine the effects of numerous comorbidities, a scale, such as the Cumulative Illness Rating scale for Geriatrics (CIRS-G),15 which assesses 13 different organ systems and grades illness severity, may be useful (Table 3).16 Another useful scale is the Charlson scale, a weighted index of 19 different clinical conditions that have been associated with a greater risk of 1-year mortality.17 A study by Firat et al18 found that the Karnofsky PS and the CIRS-G score were both important independent prognostic factors in patients with stage III NSCLC treated with radiotherapy alone. In
T.E. Stinchcombe and M.A. Socinski
24 Table 3 Construction of Common Comorbidity Scales Scale
Type
Charlson
Weighted
Cumulative Illness Rating Scale-Geriatric (CIRS-G)
Weighted
Items and Rating 19 diseases weighted 1 to 6 Total: 0-30 13 or 14 organ system categories, rated 0-4 Total: 0-52
How Constructed Internal medicine patients: 1-year mortality Comprehensive listing of diseases weighted by clinician estimate or manual detailing several geriatric problems
Interrater Reliability
Test-Retest Reliability
0.16-0.95
0.86-0.92
0.59-0.88
0.57-0.95
From: Extermann M: Measuring comorbidity in older cancer patients. Eur J Cancer 36:453-471, 2000. Adapted and reprinted with permission from Elsevier.16
particular, a CIRS-G severity score of 4 and a severity index of 3 or higher were independently associated with significantly lower overall survival. Frasci et al19 compared the combination of gemcitabine and vinorelbine with vinorelbine alone in patients with stage IIIB or stage IV NSCLC who were older than 70 years and found that the Charlson score was strongly correlated with the tolerance of treatment and overall survival.19 Median survival was 28 weeks in patients with no comorbidities, 21 weeks in those with a Charlson score of 1 or 2, and 16 weeks in those with a Charlson score of 3 or higher. The correlation between Charlson score and survival was stronger than that between ECOG PS and survival in this study. A Charlson score of 3 or higher was also associated with a greater likelihood of early treatment discontinuation (82% v 30%). The CIRS-G scale is thought to be more reliable than the Charlson scale because it assesses more organ systems. A study of the 2 scales in patients with cancer found a prevalence of comorbidities of 94% with the CIRS-G scale and of 36% with the Charlson scale.16 Future studies in PS2 patients will likely have to include some assessment of comorbidities so that their effects on dose intensity, adverse events, and survival can be evaluated. Another important issue in designing trials in this patient population is QOL and symptom relief. Studies may show only modest increases in survival but clinically significant improvements in QOL and symptoms. It is likely that symptoms will be more severe in PS2 patients and treatment will, therefore, produce greater improvements in symptoms and in QOL. With recent improvements in supportive care, there may be improvements in patient QOL as well as reduced toxicity. One of the most common complications with chemotherapy is anemia. It has been estimated that grade 1 or 2 anemia develops in 10% to 60% of patients with NSCLC treated with chemotherapy, and grade 3 or 4 develops in 5% to 25%.20 The high incidence of treatment-related anemia can be particularly troublesome in patients with lung cancer because many of them have underlying pulmonary or cardiovascular disease and may be severely affected by even mild anemia. Langer et al21 found a direct relation between anemia and a decline in QOL that was independent of the response to treatment. Thus, any clinical trials in which QOL is an endpoint should require close monitoring and adherence to
guidelines for the use of erythropoietic-stimulating agents. It is also possible that with greater use of supportive care measures, more patients will be able to tolerate longer durations of treatment with chemotherapy. Improvements in antiemetics and appetite stimulants may also have a significant role in diminishing patients’ symptoms and improving their QOL.
Emerging Data and Ongoing Trials in Patients With Performance Status 2 Results of several trials in PS2 patients were presented at the 2004 American Society of Clinical Oncology meeting, the majority of which were phase II trials with approximately 25 to 100 patients. These trials provide preliminary evidence of efficacy and safety, and a basis for further clinical trials. The results of these trials are reviewed in the article by Langer and Lilenbaum22 in this supplement. Several ongoing phase III trials include PS2 patients (Table 4). Several of them use paclitaxel poliglumex, a macromolecular taxane (paclitaxel linked to a water-soluble polyglutamate backbone) that targets tumors with a unique intracellular mechanism of action. Because this agent is water soluble, it does not require routine premedication with antihistamines and steroids to prevent hypersensitivity reactions. In addition, paclitaxel poliglumex has a potentially better safety profile than the current taxanes. Median survival in a phase II trial in 28 patients with advanced NSCLC who were PS2 or 70 years old or older and received paclitaxel poliglumex was 5.4 months,23 which compares favorably with the 4.7-month median survival with carboplatin and paclitaxel in CALGB 9730. Grade 4 neutropenia developed in 3 patients, grade 3 fatigue in 3, grade 3 neuropathy in 3, and febrile neutropenia in 1 patient. Neuropathy and fatigue were seen in patients with disease progression and significant disease-related comorbidities. These encouraging results led to the development of the Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reactions (STELLAR) trials. One of these trials, STELLAR 2, has completed enrollment with 840 PS0 to PS2 patients with advanced NSCLC. This second-line trial compares single-agent docetaxel 75 mg/m2 every 3 weeks with paclitaxel poliglumex 210 mg/m2 every 3 weeks in PS0/1 patients and 175 mg/m2 every 3 weeks in PS2 patients. STEL-
Drug development in PS2 patients
25
Table 4 Ongoing Phase II and III Trials of PS2 Patients With Advanced Non-Small Cell Lung Cancer Dose
Target No. of Patients
Results Due
Trial
Study Regimen
Comparator
STELLAR 2 2nd-line NSCLC PS0-PS2 Phase III STELLAR 3 1st-line NSCLC PS2 Phase III STELLAR 4 1st-line NSCLC PS2 Phase III
Paclitaxel poliglumex 210 mg/m2 in PS0 and PS1; 175 in PS2 every 3 weeks Paclitaxel poliglumex 210 mg/m2 ⴙ carboplatin AUC 6 mg/mL· min every 3 weeks Paclitaxel poliglumex 175 mg/m2 every 3 weeks
Docetaxel 75 mg/m2 every 3 weeks
840 (closed)
Q3 2005
Paclitaxel 225 mg/m2 ⴙ carboplatin AUC 6 mg/ mL· min every 3 weeks
400 (closed)
Q1 2005
477 (closed)
Q1 2005
Celecoxib* 1st-line NSCLC PS2 Phase II Erlotinib 1st-line NSCLC PS2 Phase II
Celocoxib/docetaxel
Gemcitabine 1000 mg/m2 days 1, 8, 15 every 4 weeks or vinorelbine 30 mg/m2 days 1, 8, 15 every 4 weeks Docetaxel
Erlotinib monotherapy
Paclitaxel/carboplatin
Active
Active
Abbreviations: NSCLC, non-small cell lung cancer; PS, performance status. *Population includes elderly in addition to PS2.
LAR 3 is a first-line trial in PS2 patients randomized to the combination of paclitaxel poliglumex 210 mg/m2 and carboplatin dosed to an area under the time-concentration curve of 6 mg/mL ⫻ min every 3 weeks or the reference treatment of paclitaxel 225 mg/m2 and carboplatin at the same dose every 3 weeks. This carboplatin and paclitaxel regimen is also used in CALGB 9730, with which there was a survival advantage over single-agent paclitaxel in PS2 patients. Another trial, STELLAR 4, compares paclitaxel poliglumex 175 mg/m2 every 3 weeks with either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks or vinorelbine 30 mg/m2 on days 1, 8, and 15 every 4 weeks in first-line PS2 patients. Enrollment in STELLAR 3 and STELLAR 4 has been completed with 400 and 477 patients, respectively. The results are expected in early 2005. Because STELLAR 3 and STELLAR 4 are the largest trials to date conducted solely in PS2 patients, their findings should be particularly significant. The CALGB is designing a trial in PS2 patients with advanced NSCLC who will be randomized to docetaxel with cetuximab or docetaxel with bortezomib. Cetuximab, a monoclonal antibody that targets the epidermal growth factor receptor, has shown activity in patients with advanced NSCLC.24 Kim et al25 conducted a phase II study of cetuximab and docetaxel in 47 patients with refractory or resistant advanced NSCLC and a median Karnofsky PS of 80% who were treated with a median of ten cycles.25 There was a partial response in 13 patients (28%) and stable disease in 8 patients (17%). The most common grade 3 toxicities were infection (21%), fatigue (21%), and acneiform (19%). There were allergic reactions that necessitated discontinuing the cetux-
imab in 4 patents (9%). Bortezomib, a reversible inhibitor of the 26S proteasome of the ubiquitin protein degradation pathway, has shown activity in NSCLC. A randomized phase II trial that is currently enrolling patients is evaluating bortezomib with or without docetaxel in patients with a Karnofsky PS of at least 70% in whom NSCLC has progressed after treatment with at least one chemotherapy regimen.26 Preliminary data indicate that nausea (34%), fatigue (28%), and neutropenia (23%) are the most common drug-related adverse events.
Conclusion Patients with PS2 have comprised a small percentage of the patients in clinical trials in advanced NSCLC. Consequently, there are few data on PS2 patients on which to base treatment decisions. Even with data, they are often treated according to their physician’s experience or preferences. There have been difficulties in defining the PS2 patient population and difficulties in conducting clinical trials in PS2 patients because they often have significant comorbidities, they are symptomatic because of their malignancy, and their condition is often deteriorating rapidly. Fortunately, several large planned or ongoing trials are now evaluating new agents and regimens in PS2 patients, and they are expected to provide much-needed data on which treatment decisions can be based.
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