- Email: [email protected]
Treatment approaches in patients with advanced non-small cell lung cancer and poor performance status
Treatment Approaches in Patients With Advanced Non–Small Cell Lung Cancer and Poor Performance Status Ramaswamy Govindana and David H. Garfieldb It is estimated that 30% to 40% of patients with advanced non–small cell lung cancer (NSCLC) have a poor performance status (PS)— defined as a score of 2 or higher on the Eastern Cooperative Oncology Group scale— because of their disease burden, comorbidities, or both. Survival is shorter in these patients than in those with a better PS, and they do not tolerate chemotherapy as well. There is now evidence that PS2 patients with advanced NSCLC can benefit from single-agent chemotherapy with drugs such as vinorelbine, gemcitabine, paclitaxel, pemetrexed, and docetaxel and that combination chemotherapy may have additional advantages. The optimal treatment for PS2 patients with NSCLC, however, has yet to be determined. The case histories in this article demonstrate that PS2 patients are a heterogeneous group and that selecting the chemotherapy for each patient must take into consideration comorbidities and disease-related symptoms, as well as the potential toxicity of treatment. Large prospective clinical trials are needed to determine whether, and in which patients, combination chemotherapy or novel agents, such as the epidermal growth factor receptor inhibitors or paclitaxel poliglumex, have advantages. Three large phase III trials—Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reactions trials (STELLAR)—are now being conducted in PS2 patients with NSCLC. It is hoped that their findings will aid in determining the best treatment options for these patients. Semin Oncol 31(suppl 11):27-31 © 2004 Elsevier Inc. All rights reserved.
L
ung cancer is a major cause of mortality throughout the world, with estimates of more than 170,000 new cases being diagnosed in 2004 in the United States alone.1 Non–small cell lung cancer (NSCLC) accounts for the vast majority of the cases of lung cancer.2 Because locally advanced or metastatic disease is likely at the time of diagnosis, chemotherapy is required to reduce tumor size and alleviate cancer-related symptoms.3,4 Patients with poor performance status (PS)—a score of 2 or higher on the Eastern Cooperative Oncology Group (ECOG) scale5— because of either significant disease burden, comorbidities, or both, present a therapeutic dilemma for oncologists. Survival is shorter in patients with poor PS, and they often do not tolerate chemotherapy as well as PS0/1 patients.3,6,7 aWashington
University School of Medicine, St Louis, MO. of Medicine, University of Colorado, Denver, CO. Dr Govindan has received research support and speaking honoraria from Aventis, Bristol Myers Squibb, Pfizer, Eli Lilly, and AstraZeneca. Dr Garfield has received speaking honoraria from AstraZeneca. Address reprint requests to David H. Garfield, MD, Division of Oncology, University of Colorado, 57 Hyde Park Circle, Denver, CO 80209. E-mail: [email protected]
bDepartment
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.10.006
Thus, PS2 patients are underrepresented in clinical trials, and the influence of comorbidities (such as cardiovascular, renal, and hepatic diseases, and chronic obstructive pulmonary disease [COPD]) on patient responsiveness to or tolerance of treatment is not well defined.
Selecting Chemotherapy for PS2 Patients With Advanced Non–Small Cell Lung Cancer A number of newer chemotherapy drugs, such as gemcitabine, vinorelbine, paclitaxel, docetaxel, irinotecan, and topotecan, have been shown to be effective in patients with metastatic (“wet” IIIB and stage IV) NSCLC when they are used in combination with platinum and nonplatinum compounds.4 No regimen appears to be superior to another, however, in producing objective tumor responses and increasing survival. The choice of therapy is generally based on factors, such as familiarity with the regimen, convenience of administration, tolerability, and cost.4 The current treatment guide27
R. Govindan and D.H. Garfield
28 lines of the American Society of Clinical Oncology recommend a two-drug regimen for metastatic (stage IIIB/IV) NSCLC— either a platinum-based or a nonplatinum combination, administered for no more than six cycles in patients with good PS (ie, PS0 or PS1).8 Combination regimens may not be appropriate for PS2 patients, however, because their toxicity is greater than that of single-agent regimens, which has frequently led to such patients not being offered combination chemotherapy.9 Consequently, it remains uncertain whether the benefits of combination chemotherapy extend to PS2 patients. Thus, the American Society of Clinical Oncology guidelines currently recommend single-agent chemotherapy in these patients (eg, vinorelbine, gemcitabine, paclitaxel, or docetaxel).8 Subgroup analysis of data from a randomized clinical trial has shown, however, that median survival was significantly longer in PS2 patients treated with the combination of paclitaxel and carboplatin than in those treated with paclitaxel monotherapy.8,10 Combination chemotherapy may, therefore, be appropriate in some PS2 patients, such as those with a bulky disease, a rapidly progressing tumor, or tumor-related symptoms.9 The role of novel targeted therapies, such as epidermal growth factor receptor (EGFR) inhibitors (eg, the tyrosine kinase inhibitors gefitinib and erlotinib and the monoclonal antibody cetuximab), in PS2 patients with advanced NSCLC is also not well defined. Gefitinib has been reported to have some efficacy and to be well tolerated in elderly patients and those with PS2 or greater, and it appears to have a role in salvage therapy. A number of questions remain unanswered in determining which patients are likely to benefit from treatment with EGFR inhibitors, even though major responses are more likely in those with mutations in the EGFR tyrosine kinase domain, women, nonsmokers, and those with features of adenocarcinoma or bronchioloalveolar carcinoma.11-13 Additionally, a recent report from Japan raises concern about a possible increased risk for the development or worsening of interstitial lung disease, especially in patients with a history of scleroderma using gefitinib.14 Novel therapies with greater tolerability, such as paclitaxel poliglumex, have shown promising efficacy in phase I and II trials that included PS2 patients. With more than 400 patients treated, paclitaxel poliglumex is generally well tolerated and has a safety profile similar to that of paclitaxel, except that the severity and frequency of its adverse events are less than with paclitaxel in similar settings. Three large randomized phase III trials, known as the Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reactions (STELLAR) trials, have recently completed enrollment and are evaluating paclitaxel poliglumex in first- and second-line settings in PS2 patients. Several recent case histories of patients treated at our institutions illustrate the problems that oncologists face in determining the appropriate chemotherapy for PS2 patients with advanced NSCLC.
Case Histories Cases One and Two Cough and shortness of breath developed in 2 patients: a 65-year-old woman who was a nonsmoker and a 66-year-old
man who was a smoker. In both cases chest radiographs and computerized tomography scans showed numerous 2- to 3-mm nodules throughout both lungs. Bronchoscopies and sputum cytology tests were nondiagnostic and positron emission tomography scans were negative, but open-lung biopsies showed mucinous bronchioloalveolar carcinomas. Both patients required continuous oxygen and were classified as PS2. There was significant progression of lesions within a few months, and the duration of the illness in both patients was 3 months. The treatment options considered in both patients were (1) paclitaxel every 1 to 3 weeks for four to six cycles, (2) a combination of paclitaxel and carboplatin every 3 weeks for four to six cycles, and (3) gefitinib. Because of its rapid onset of action, its activity as single-agent therapy for bronchioloalveolar carcinoma, and its greater efficacy in women and nonsmokers,15,16 gefitinib was considered appropriate for the non-smoker. A combination of paclitaxel and carboplatin was considered appropriate for the male patient with a history of smoking.
Case Three Large-cell NSCLC in one lung with metastases to the liver was diagnosed in an 82-year-old man with a long-standing history of tobacco smoking and previous therapy with pelvic radiation for prostate cancer. He was fatigued, had lost more than 10% of his weight, and was classified as PS2. The patient was treated with two cycles of carboplatin (area under the curve of 4.0) plus paclitaxel (175 mg/m2) administered every 3 weeks. Two weeks after the second cycle of chemotherapy, his absolute neutrophil count was 0.6 ⫻ 109/L and his platelet count was 75 ⫻ 109/L. Follow-up examination showed a decrease in the number of liver lesions. His PS improved to ECOG 1 with improvement in his appetite and daily activities. The options for continuing treatment in this patient were (1) two to four further cycles of carboplatin and paclitaxel at the same doses, (2) two to four further cycles of carboplatin and paclitaxel at lower doses (in view of the myelosuppression after the first two cycles), and (3) two to four further cycles of paclitaxel alone. Because the toxicity of carboplatin and paclitaxel is generally cumulative, and the patient had been treated with radiotherapy to the pelvic region, there was concern about further myelosuppression. Single-agent paclitaxel was therefore chosen for this patient in view of its activity as single-agent therapy in advanced NSCLC.17
Case Four A 60-year-old woman who was a smoker presented with stage IV squamous cell carcinoma with metastases to both lungs. At presentation she was classified as PS1. Treatment with four cycles of cisplatin plus docetaxel produced a partial tumor response, but her PS remained at PS1. Six weeks after her fourth cycle of treatment she developed cough, severe anorexia, and fatigue, and was considered to have a PS of 2. A chest radiograph showed tumor progression to a size slightly
Treatment approaches in PS2 patients larger than that at the initial presentation. The patient was reclassified as PS2. The salvage treatment options considered in this patient were (1) gefitinib, (2) gemcitabine, and (3) best supportive care. Women appear to respond better to second-line gefitinib therapy than men,18 but survival is shorter in smokers than nonsmokers.19 In addition, because the patient presented with squamous cell carcinoma, gefitinib was considered less appropriate because the response rates are likely to be higher in those with adenocarcinoma. Although larger studies are needed to confirm these observations (the lack of impressive benefit seen in men in general and those with squamous cell cancer in particular), single-agent gemcitabine was selected. An alternative therapy that is now available is the novel antifolate agent pemetrexed, which has been reported to have response rates and survival similar to those with docetaxel in second-line patients with advanced NSCLC.20-22
Case Five A 65-year-old man who was a smoker presented with metastatic NSCLC (adenocarcinoma histology) with lung and liver involvement. He had normal renal and liver function, but there were numerous comorbidities, including COPD (requiring oxygen), hypertension, peripheral vascular disease, abdominal aortic aneurysm, and transient ischemic attacks, and he had undergone coronary artery bypass surgery. He spent less than half of his waking hours in bed, occasionally required assistance with his activities of daily living, and was classified as PS2. The treatment options considered were (1) vinorelbine, (2) gemcitabine, (3) paclitaxel, and (4) gefitinib. Because of the patient’s comorbidities, combination regimens were avoided to minimize toxicity, and he was treated with gemcitabine.
Case Six A 70-year-old Japanese woman who was a lifelong nonsmoker and had a history of scleroderma presented with malignant pleural effusion and a 2-cm lesion in the upper lobe of the left lung. Pleural fluid cytology was consistent with adenocarcinoma. She also had a long history of hypertension and had mildly impaired baseline renal function (serum creatinine level, 1.9 mg/dL). She was symptomatic, required periodic bed rest during the day, and was classified as PS2. The treatment options considered were (1) vinorelbine, (2) gemcitabine, (3) docetaxel, (4) paclitaxel plus carboplatin, and (5) gefitinib. She was treated with vinorelbine. Monotherapy with gemcitabine or vinorelbine was considered appropriate because these agents have been found to be as effective as and better tolerated than combination therapy in elderly patients with advanced NSCLC.23 This patient had active interstitial lung disease. Because gefitinib has been associated with interstitial lung disease and gemcitabine has been associated with hypersensitivity pneumonitis more of-
29 ten than vinorelbine, vinorelbine was considered appropriate in this setting.
Case Seven A 40-year-old man with a history of infection with human immunodeficiency virus (HIV) who was being treated with protease inhibitors presented with cough and fatigue. A subsequent workup showed a right upper lobe mass and a large adrenal lesion. Biopsy findings were consistent with NSCLC. At presentation, he had grade 2 neuropathy secondary to the antiretroviral therapy. However, his renal and liver functions were normal, as was his complete blood count. His PS at the time of presentation was 2. The treatment options considered were (1) best supportive care, (2) gemcitabine, (3) vinorelbine and (4) gefitinib. The patient was treated with gemcitabine monotherapy. A small retrospective study reported that HIV status did not influence the outcomes in advanced NSCLC.24 Treatment with taxanes or vinca alkaloids was not considered as the patient had grade 2 neuropathy at baseline. Therefore, he was treated with gemcitabine as a monotherapy.
Case Eight A 65-year-old woman with hypertension and chronic renal failure on hemodialysis presented with cough and dyspnea on exertion. The subsequent workup showed bilateral lung nodules and biopsy findings consistent with adenocarcinoma. She had lost 10% of her body weight in the past 4 months. Five years earlier, end-stage renal disease had been diagnosed, and she was being treated with hemodialysis, leading to a PS2 classification. She was unwilling to consider chemotherapy. The treatment options considered were (1) gefitinib, and (2) best supportive care. Because there are no data on the tolerability and safety of gefitinib in patients with chronic renal failure on hemodialysis, she was referred to hospice services for best supportive care.
Case Nine A 54-year-old woman with a diagnosis of stage IIIB NSCLC was found to have a 3-cm right upper lobe lesion with bulky mediastinal lymph node involvement. She had recent loss of appetite, but there was no weight loss. She had a history of COPD, coronary artery disease, and peripheral vascular disease, and a PS (ECOG 2) at the time of initial presentation. The treatment options considered were (1) single-agent chemotherapy, (2) sequential chemotherapy followed by radiotherapy, and (3) concurrent chemotherapy and radiotherapy. The addition of chemotherapy to thoracic radiation has been shown to improve survival in patients with locally advanced unresectable NSCLC. Concurrent administration of chemotherapy with radiation therapy has been shown to be superior to sequential chemotherapy followed by radiation in patients with locally advanced NSCLC who have a good PS and no significant weight loss. However, the optimal management of patients with locally advanced NSCLC and PS2 is
R. Govindan and D.H. Garfield
30 Table 1 Treatment Options in PS2 Patients with NSCLC Treatment Single-agent chemotherapy Paclitaxel (P) Docetaxel (D) Gemcitabine Vinorelbine Combination chemotherapy Platinum-based Non–platinum-based
Treatments in development EGFR inhibitors Gefitinib (approved for relapse) Erlotinib (phase III) Cetuximab, monoclonal antibody (phase II)
Novel taxanes Paclitaxel poliglumex (phase III) Nab paclitaxel (phase II)
Advantages
Disadvantages
Improved survival and QOL versus best supportive care
Premedications necessary for P and D Longer infusion time in P and D Solubilizing agents required for P No tumor specificity
Longer median survival with platinum combination than with single-agent therapy in a subset analysis10
Potential for greater toxicity than single-agent therapy Non–platinum-based combinations may offer little survival benefit with no apparent reduction in toxicity
Oral administration except cetuximab (IV) Reduced toxicity
Partial response with significant clinical improvement likely only in specific populations (ie, mutations in EGFR tyrosine kinase domain) Some increased risk of interstitial lung disease14 Lacking data from large randomized clinical trials in NSCLC Lacking data from large randomized clinical trials in NSCLC
Role in salvage therapy and possibly first-line
Tumor versus normal tissue specificity Reduced toxicity Shorter infusion time No premedications No solvents needed
Abbreviations: PS, performance status; NSCLC, non–small cell lung cancer; P, paclitaxel; D, docetaxel; QOL, quality of life; EGFR, epidermal growth factor receptor; IV, intravenous.
unknown as these patients have been excluded from the studies of combined modality therapy in locally advanced NSCLC. Concurrent chemoradiation has been associated with higher incidence of esophagitis and pneumonitis than sequential chemotherapy followed by radiation treatment. Radiation alone has been associated with a dismal outcome in stage III NSCLC.25,26 The Southwest Oncology Group conducted a phase II study of carboplatin, etoposide, and concurrent radiation therapy in patients with significant comorbidities or poor PS. Of 60 eligible patients, only 18% had poor PS. The median survival was 13 months, with a 2-year survival rate of 21% in all patients.27 Given the tolerability of sequential chemotherapy followed by radiation treatment and the survival advantage seen with the addition of chemotherapy to radiation, this patient was treated with sequential chemoradiation.
Conclusion These case histories illustrate the heterogeneity of PS2 patients with locally advanced or metastatic NSCLC. Their poor PS may be a result of the disease burden (eg, pain, fatigue, malaise, anorexia, weight loss, fever, infection), the presence of various comorbidities (eg, cardiovascular, renal, or liver disease, COPD, diabetes), or both. There is now evidence that PS2 patients benefit from chemotherapy, at least in terms of symptom improvement and possibly survival.8,10 It is not
clear whether combination chemotherapy is better than monotherapy with drugs such as vinorelbine, gemcitabine, paclitaxel, and docetaxel in these patients. It is important to avoid cytotoxic drugs that can worsen a preexisting comorbid condition. For example, it is important to avoid taxanes and vinorelbine in patients with preexisting neuropathy. Some PS2 patients, such as those with bulky disease, may benefit from combination regimens (eg, paclitaxel and carboplatin), but definitive proof awaits the results of prospective randomized clinical trials. Therefore, no optimal chemotherapy regimen is available for PS2 patients, and the choice of treatment in each patient must take into consideration the patient’s comorbidities and the potential for toxicity (Table 1). In addition to clarifying whether combination chemotherapy has advantages over single-agent chemotherapy in PS2 patients, the role of targeted therapies, such as the EGFR inhibitors gefitinib and erlotinib and the monoclonal antibody cetuximab, in this population needs to be defined in future studies. Furthermore, it is important to define the role of cytotoxic agents that have a lower toxicity profile, such as paclitaxel poliglumex, and pemetrexed, in this patient population. Large prospective randomized clinical trials to investigate these questions and help improve the outcomes in PS2 patients with advanced NSCLC are needed, and the findings from the recently enrolled STELLAR trials are awaited (see article by Stinchcombe and Socinski28 elsewhere in this supplement).
Treatment approaches in PS2 patients
31
References 1. Jemal A, Tiwari RC, Murray T, et al: Cancer statistics, 2004. CA Cancer J Clin 54:8-29, 2004 2. Page NC, Read WL, Tierney RM, et al: The epidemiology of small cell lung carcinoma. Proc Am Soc Clin Oncol 221:305a, 2002 (abstr) 3. Govindan R: Management of patients with non–small cell lung cancer and poor performance status. Curr Treat Options Oncol 4:55-59, 2003 4. Ettinger DS: Is there a preferred combination chemotherapy regimen for metastastic non–small cell lung cancer? Oncologist 7:226-233, 2002 5. Radzikowska E, Glaz P, Roszkowski K: Lung cancer in women: Age, smoking, histology, performance status, stage, initial treatment and survival. Population-based study of 20,561 cases. Ann Oncol 13:10871093, 2002 6. Sweeney CJ, 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 nonsmall cell lung carcinoma. Cancer 92:2639-2647, 2001 7. Gridelli C: Does chemotherapy have a role as palliative therapy for unfit or elderly patients with non–small-cell lung cancer? Lung Cancer 38: S45-S50, 2002 (suppl 2) 8. Pfister DG, Johnson DH, Azzoli CG, et al: American Society of Clinical Oncology treatment of unresectable non–small-cell lung cancer guideline: Update 2003. J Clin Oncol 22:330-353, 2004 9. Eckardt J: Single-agent chemotherapy for non–small cell lung cancer. Lung Cancer 41:S17-S22, 2003 (suppl 4) 10. Lilenbaum RC, Herndon J, List M, et al: Single-agent (SA) versus combination chemotherapy (CC) in advanced non–small cell lung cancer (NSCLC): A CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness. Proc Am Soc Clin Oncol 21:1a, 2002 (abstr) 11. Gridelli C, Maione P, Castaldo V, et al: Gefitinib in elderly and unfit patients affected by advanced non–small-cell lung cancer. Br J Cancer 89:1827-1829, 2003 12. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non– small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 13. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304: 1497-1500, 2004 14. Takano T, Ohe Y, Kusumoto M, et al: Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non–small cell lung cancer treated with gefitinib. Lung Cancer 45:93-104, 2004 15. West H, Franklin WA, Gumerlock PH, et al: Gefitinib (ZD1839) ther-
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apy for advanced bronchioloalveolar lung cancer (BAC): Southwest Oncology Group (SWOG) study S0126. Proc Am Soc Clin Oncol 23:618, 2004 (abstr) Yano S, Kanematsu T, Miki T, et al: A report of two bronchioloalveolar carcinoma cases which were rapidly improved by treatment with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa). Cancer Sci 94:453-458, 2003 Socinski MA: Single-agent paclitaxel in the treatment of advanced non– small cell lung cancer. Oncologist 4:408-416, 1999 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 Villaflor VM, Polowy CR, Coon JS, et al: Potential clinical prognostic factors in non–small cell lung cancer (NSCLC) patients treated with gefitinib. Proc Am Soc Clin Oncol 23:635, 2004 (abstr 7089) Ettinger DS: Pemetrexed (Alimta): A new antifolate for non–small-cell lung cancer. Clin Lung Cancer 3:S22-S25, 2002 (suppl 1) Fossella FV: Pemetrexed for treatment of advanced non–small cell lung cancer. Semin Oncol 31:100-105, 2004 (suppl 1) Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589-1597, 2004 Gridelli C, Perrone F, Gallo C, et al: Chemotherapy for elderly patients with advanced non–small-cell lung cancer: The Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 95:362-372, 2003 Powles T, Thirwell C, Newsom-Davis T, et al: Does HIV adversely influence the outcome in advanced non–small-cell lung cancer in the era of HAART. Br J Cancer 89:457-459, 2003 Dillman RO, Herndon J, Seagren SL, et al: Improved survival in stage III non–small-cell lung cancer: Seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst 88:1210-1215, 1996 Curran WJ Jr, Werner-Wasik M: Issues in nonoperative management of locally advanced non–small-cell lung cancer. Oncology 12:60-66, 1998 (suppl 2) Lau DH, Crowley JJ, Gandara DR, et al: Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non–small-cell lung cancer. J Clin Oncol 16:30783081, 1998 Stinchcombe TE, Socinski MA: Drug development in patients with advanced non–small cell lung cancer and poor performance status. Semin Oncol 31:21-26, 2004 (suppl 11)
L
ung cancer is a major cause of mortality throughout the world, with estimates of more than 170,000 new cases being diagnosed in 2004 in the United States alone.1 Non–small cell lung cancer (NSCLC) accounts for the vast majority of the cases of lung cancer.2 Because locally advanced or metastatic disease is likely at the time of diagnosis, chemotherapy is required to reduce tumor size and alleviate cancer-related symptoms.3,4 Patients with poor performance status (PS)—a score of 2 or higher on the Eastern Cooperative Oncology Group (ECOG) scale5— because of either significant disease burden, comorbidities, or both, present a therapeutic dilemma for oncologists. Survival is shorter in patients with poor PS, and they often do not tolerate chemotherapy as well as PS0/1 patients.3,6,7 aWashington
University School of Medicine, St Louis, MO. of Medicine, University of Colorado, Denver, CO. Dr Govindan has received research support and speaking honoraria from Aventis, Bristol Myers Squibb, Pfizer, Eli Lilly, and AstraZeneca. Dr Garfield has received speaking honoraria from AstraZeneca. Address reprint requests to David H. Garfield, MD, Division of Oncology, University of Colorado, 57 Hyde Park Circle, Denver, CO 80209. E-mail: [email protected]
bDepartment
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.10.006
Thus, PS2 patients are underrepresented in clinical trials, and the influence of comorbidities (such as cardiovascular, renal, and hepatic diseases, and chronic obstructive pulmonary disease [COPD]) on patient responsiveness to or tolerance of treatment is not well defined.
Selecting Chemotherapy for PS2 Patients With Advanced Non–Small Cell Lung Cancer A number of newer chemotherapy drugs, such as gemcitabine, vinorelbine, paclitaxel, docetaxel, irinotecan, and topotecan, have been shown to be effective in patients with metastatic (“wet” IIIB and stage IV) NSCLC when they are used in combination with platinum and nonplatinum compounds.4 No regimen appears to be superior to another, however, in producing objective tumor responses and increasing survival. The choice of therapy is generally based on factors, such as familiarity with the regimen, convenience of administration, tolerability, and cost.4 The current treatment guide27
R. Govindan and D.H. Garfield
28 lines of the American Society of Clinical Oncology recommend a two-drug regimen for metastatic (stage IIIB/IV) NSCLC— either a platinum-based or a nonplatinum combination, administered for no more than six cycles in patients with good PS (ie, PS0 or PS1).8 Combination regimens may not be appropriate for PS2 patients, however, because their toxicity is greater than that of single-agent regimens, which has frequently led to such patients not being offered combination chemotherapy.9 Consequently, it remains uncertain whether the benefits of combination chemotherapy extend to PS2 patients. Thus, the American Society of Clinical Oncology guidelines currently recommend single-agent chemotherapy in these patients (eg, vinorelbine, gemcitabine, paclitaxel, or docetaxel).8 Subgroup analysis of data from a randomized clinical trial has shown, however, that median survival was significantly longer in PS2 patients treated with the combination of paclitaxel and carboplatin than in those treated with paclitaxel monotherapy.8,10 Combination chemotherapy may, therefore, be appropriate in some PS2 patients, such as those with a bulky disease, a rapidly progressing tumor, or tumor-related symptoms.9 The role of novel targeted therapies, such as epidermal growth factor receptor (EGFR) inhibitors (eg, the tyrosine kinase inhibitors gefitinib and erlotinib and the monoclonal antibody cetuximab), in PS2 patients with advanced NSCLC is also not well defined. Gefitinib has been reported to have some efficacy and to be well tolerated in elderly patients and those with PS2 or greater, and it appears to have a role in salvage therapy. A number of questions remain unanswered in determining which patients are likely to benefit from treatment with EGFR inhibitors, even though major responses are more likely in those with mutations in the EGFR tyrosine kinase domain, women, nonsmokers, and those with features of adenocarcinoma or bronchioloalveolar carcinoma.11-13 Additionally, a recent report from Japan raises concern about a possible increased risk for the development or worsening of interstitial lung disease, especially in patients with a history of scleroderma using gefitinib.14 Novel therapies with greater tolerability, such as paclitaxel poliglumex, have shown promising efficacy in phase I and II trials that included PS2 patients. With more than 400 patients treated, paclitaxel poliglumex is generally well tolerated and has a safety profile similar to that of paclitaxel, except that the severity and frequency of its adverse events are less than with paclitaxel in similar settings. Three large randomized phase III trials, known as the Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reactions (STELLAR) trials, have recently completed enrollment and are evaluating paclitaxel poliglumex in first- and second-line settings in PS2 patients. Several recent case histories of patients treated at our institutions illustrate the problems that oncologists face in determining the appropriate chemotherapy for PS2 patients with advanced NSCLC.
Case Histories Cases One and Two Cough and shortness of breath developed in 2 patients: a 65-year-old woman who was a nonsmoker and a 66-year-old
man who was a smoker. In both cases chest radiographs and computerized tomography scans showed numerous 2- to 3-mm nodules throughout both lungs. Bronchoscopies and sputum cytology tests were nondiagnostic and positron emission tomography scans were negative, but open-lung biopsies showed mucinous bronchioloalveolar carcinomas. Both patients required continuous oxygen and were classified as PS2. There was significant progression of lesions within a few months, and the duration of the illness in both patients was 3 months. The treatment options considered in both patients were (1) paclitaxel every 1 to 3 weeks for four to six cycles, (2) a combination of paclitaxel and carboplatin every 3 weeks for four to six cycles, and (3) gefitinib. Because of its rapid onset of action, its activity as single-agent therapy for bronchioloalveolar carcinoma, and its greater efficacy in women and nonsmokers,15,16 gefitinib was considered appropriate for the non-smoker. A combination of paclitaxel and carboplatin was considered appropriate for the male patient with a history of smoking.
Case Three Large-cell NSCLC in one lung with metastases to the liver was diagnosed in an 82-year-old man with a long-standing history of tobacco smoking and previous therapy with pelvic radiation for prostate cancer. He was fatigued, had lost more than 10% of his weight, and was classified as PS2. The patient was treated with two cycles of carboplatin (area under the curve of 4.0) plus paclitaxel (175 mg/m2) administered every 3 weeks. Two weeks after the second cycle of chemotherapy, his absolute neutrophil count was 0.6 ⫻ 109/L and his platelet count was 75 ⫻ 109/L. Follow-up examination showed a decrease in the number of liver lesions. His PS improved to ECOG 1 with improvement in his appetite and daily activities. The options for continuing treatment in this patient were (1) two to four further cycles of carboplatin and paclitaxel at the same doses, (2) two to four further cycles of carboplatin and paclitaxel at lower doses (in view of the myelosuppression after the first two cycles), and (3) two to four further cycles of paclitaxel alone. Because the toxicity of carboplatin and paclitaxel is generally cumulative, and the patient had been treated with radiotherapy to the pelvic region, there was concern about further myelosuppression. Single-agent paclitaxel was therefore chosen for this patient in view of its activity as single-agent therapy in advanced NSCLC.17
Case Four A 60-year-old woman who was a smoker presented with stage IV squamous cell carcinoma with metastases to both lungs. At presentation she was classified as PS1. Treatment with four cycles of cisplatin plus docetaxel produced a partial tumor response, but her PS remained at PS1. Six weeks after her fourth cycle of treatment she developed cough, severe anorexia, and fatigue, and was considered to have a PS of 2. A chest radiograph showed tumor progression to a size slightly
Treatment approaches in PS2 patients larger than that at the initial presentation. The patient was reclassified as PS2. The salvage treatment options considered in this patient were (1) gefitinib, (2) gemcitabine, and (3) best supportive care. Women appear to respond better to second-line gefitinib therapy than men,18 but survival is shorter in smokers than nonsmokers.19 In addition, because the patient presented with squamous cell carcinoma, gefitinib was considered less appropriate because the response rates are likely to be higher in those with adenocarcinoma. Although larger studies are needed to confirm these observations (the lack of impressive benefit seen in men in general and those with squamous cell cancer in particular), single-agent gemcitabine was selected. An alternative therapy that is now available is the novel antifolate agent pemetrexed, which has been reported to have response rates and survival similar to those with docetaxel in second-line patients with advanced NSCLC.20-22
Case Five A 65-year-old man who was a smoker presented with metastatic NSCLC (adenocarcinoma histology) with lung and liver involvement. He had normal renal and liver function, but there were numerous comorbidities, including COPD (requiring oxygen), hypertension, peripheral vascular disease, abdominal aortic aneurysm, and transient ischemic attacks, and he had undergone coronary artery bypass surgery. He spent less than half of his waking hours in bed, occasionally required assistance with his activities of daily living, and was classified as PS2. The treatment options considered were (1) vinorelbine, (2) gemcitabine, (3) paclitaxel, and (4) gefitinib. Because of the patient’s comorbidities, combination regimens were avoided to minimize toxicity, and he was treated with gemcitabine.
Case Six A 70-year-old Japanese woman who was a lifelong nonsmoker and had a history of scleroderma presented with malignant pleural effusion and a 2-cm lesion in the upper lobe of the left lung. Pleural fluid cytology was consistent with adenocarcinoma. She also had a long history of hypertension and had mildly impaired baseline renal function (serum creatinine level, 1.9 mg/dL). She was symptomatic, required periodic bed rest during the day, and was classified as PS2. The treatment options considered were (1) vinorelbine, (2) gemcitabine, (3) docetaxel, (4) paclitaxel plus carboplatin, and (5) gefitinib. She was treated with vinorelbine. Monotherapy with gemcitabine or vinorelbine was considered appropriate because these agents have been found to be as effective as and better tolerated than combination therapy in elderly patients with advanced NSCLC.23 This patient had active interstitial lung disease. Because gefitinib has been associated with interstitial lung disease and gemcitabine has been associated with hypersensitivity pneumonitis more of-
29 ten than vinorelbine, vinorelbine was considered appropriate in this setting.
Case Seven A 40-year-old man with a history of infection with human immunodeficiency virus (HIV) who was being treated with protease inhibitors presented with cough and fatigue. A subsequent workup showed a right upper lobe mass and a large adrenal lesion. Biopsy findings were consistent with NSCLC. At presentation, he had grade 2 neuropathy secondary to the antiretroviral therapy. However, his renal and liver functions were normal, as was his complete blood count. His PS at the time of presentation was 2. The treatment options considered were (1) best supportive care, (2) gemcitabine, (3) vinorelbine and (4) gefitinib. The patient was treated with gemcitabine monotherapy. A small retrospective study reported that HIV status did not influence the outcomes in advanced NSCLC.24 Treatment with taxanes or vinca alkaloids was not considered as the patient had grade 2 neuropathy at baseline. Therefore, he was treated with gemcitabine as a monotherapy.
Case Eight A 65-year-old woman with hypertension and chronic renal failure on hemodialysis presented with cough and dyspnea on exertion. The subsequent workup showed bilateral lung nodules and biopsy findings consistent with adenocarcinoma. She had lost 10% of her body weight in the past 4 months. Five years earlier, end-stage renal disease had been diagnosed, and she was being treated with hemodialysis, leading to a PS2 classification. She was unwilling to consider chemotherapy. The treatment options considered were (1) gefitinib, and (2) best supportive care. Because there are no data on the tolerability and safety of gefitinib in patients with chronic renal failure on hemodialysis, she was referred to hospice services for best supportive care.
Case Nine A 54-year-old woman with a diagnosis of stage IIIB NSCLC was found to have a 3-cm right upper lobe lesion with bulky mediastinal lymph node involvement. She had recent loss of appetite, but there was no weight loss. She had a history of COPD, coronary artery disease, and peripheral vascular disease, and a PS (ECOG 2) at the time of initial presentation. The treatment options considered were (1) single-agent chemotherapy, (2) sequential chemotherapy followed by radiotherapy, and (3) concurrent chemotherapy and radiotherapy. The addition of chemotherapy to thoracic radiation has been shown to improve survival in patients with locally advanced unresectable NSCLC. Concurrent administration of chemotherapy with radiation therapy has been shown to be superior to sequential chemotherapy followed by radiation in patients with locally advanced NSCLC who have a good PS and no significant weight loss. However, the optimal management of patients with locally advanced NSCLC and PS2 is
R. Govindan and D.H. Garfield
30 Table 1 Treatment Options in PS2 Patients with NSCLC Treatment Single-agent chemotherapy Paclitaxel (P) Docetaxel (D) Gemcitabine Vinorelbine Combination chemotherapy Platinum-based Non–platinum-based
Treatments in development EGFR inhibitors Gefitinib (approved for relapse) Erlotinib (phase III) Cetuximab, monoclonal antibody (phase II)
Novel taxanes Paclitaxel poliglumex (phase III) Nab paclitaxel (phase II)
Advantages
Disadvantages
Improved survival and QOL versus best supportive care
Premedications necessary for P and D Longer infusion time in P and D Solubilizing agents required for P No tumor specificity
Longer median survival with platinum combination than with single-agent therapy in a subset analysis10
Potential for greater toxicity than single-agent therapy Non–platinum-based combinations may offer little survival benefit with no apparent reduction in toxicity
Oral administration except cetuximab (IV) Reduced toxicity
Partial response with significant clinical improvement likely only in specific populations (ie, mutations in EGFR tyrosine kinase domain) Some increased risk of interstitial lung disease14 Lacking data from large randomized clinical trials in NSCLC Lacking data from large randomized clinical trials in NSCLC
Role in salvage therapy and possibly first-line
Tumor versus normal tissue specificity Reduced toxicity Shorter infusion time No premedications No solvents needed
Abbreviations: PS, performance status; NSCLC, non–small cell lung cancer; P, paclitaxel; D, docetaxel; QOL, quality of life; EGFR, epidermal growth factor receptor; IV, intravenous.
unknown as these patients have been excluded from the studies of combined modality therapy in locally advanced NSCLC. Concurrent chemoradiation has been associated with higher incidence of esophagitis and pneumonitis than sequential chemotherapy followed by radiation treatment. Radiation alone has been associated with a dismal outcome in stage III NSCLC.25,26 The Southwest Oncology Group conducted a phase II study of carboplatin, etoposide, and concurrent radiation therapy in patients with significant comorbidities or poor PS. Of 60 eligible patients, only 18% had poor PS. The median survival was 13 months, with a 2-year survival rate of 21% in all patients.27 Given the tolerability of sequential chemotherapy followed by radiation treatment and the survival advantage seen with the addition of chemotherapy to radiation, this patient was treated with sequential chemoradiation.
Conclusion These case histories illustrate the heterogeneity of PS2 patients with locally advanced or metastatic NSCLC. Their poor PS may be a result of the disease burden (eg, pain, fatigue, malaise, anorexia, weight loss, fever, infection), the presence of various comorbidities (eg, cardiovascular, renal, or liver disease, COPD, diabetes), or both. There is now evidence that PS2 patients benefit from chemotherapy, at least in terms of symptom improvement and possibly survival.8,10 It is not
clear whether combination chemotherapy is better than monotherapy with drugs such as vinorelbine, gemcitabine, paclitaxel, and docetaxel in these patients. It is important to avoid cytotoxic drugs that can worsen a preexisting comorbid condition. For example, it is important to avoid taxanes and vinorelbine in patients with preexisting neuropathy. Some PS2 patients, such as those with bulky disease, may benefit from combination regimens (eg, paclitaxel and carboplatin), but definitive proof awaits the results of prospective randomized clinical trials. Therefore, no optimal chemotherapy regimen is available for PS2 patients, and the choice of treatment in each patient must take into consideration the patient’s comorbidities and the potential for toxicity (Table 1). In addition to clarifying whether combination chemotherapy has advantages over single-agent chemotherapy in PS2 patients, the role of targeted therapies, such as the EGFR inhibitors gefitinib and erlotinib and the monoclonal antibody cetuximab, in this population needs to be defined in future studies. Furthermore, it is important to define the role of cytotoxic agents that have a lower toxicity profile, such as paclitaxel poliglumex, and pemetrexed, in this patient population. Large prospective randomized clinical trials to investigate these questions and help improve the outcomes in PS2 patients with advanced NSCLC are needed, and the findings from the recently enrolled STELLAR trials are awaited (see article by Stinchcombe and Socinski28 elsewhere in this supplement).
Treatment approaches in PS2 patients
31
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