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Quality-of-Life Considerations in Patients with Advanced Lung Cancer: Effect of Topotecan on Symptom Palliation and Quality of Life

Richard J. Gralla

New York Lung Cancer Alliance, New York, New York, USA

Correspondence: Richard J. Gralla, M.D., New York Lung Cancer Alliance, 459 Columbus Avenue (PMB-187), New York, New York 10024-5129, USA. Telephone: 212-579-6084; Fax: 801-365-6442; e-mail: rgralla{at}att.net


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Role of QOL in...
 Role of Chemotherapy in...
 Role of Topotecan in...
 Oral Chemotherapy
 Oral Topotecan
 Summary
 References
 
After completing this course, the reader will be able to:

  1. Explain the rationale for evaluating quality of life as a treatment end point.
  2. Describe the multidisciplinary dimensions incorporated into validated quality-of-life questionnaires.
  3. Discuss the impacts on quality of life and symptoms (patient reported outcomes [PROs]) resulting from the use of topotecan given either i.v. or orally.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Role of QOL in...
 Role of Chemotherapy in...
 Role of Topotecan in...
 Oral Chemotherapy
 Oral Topotecan
 Summary
 References
 
Key goals in the treatment of lung cancer are to improve both survival and quality of life (QOL). While formal techniques are frequently used to evaluate survival and response, such rigor is used less often in assessing the impact of treatment on quality of life. Many patients with lung cancer are elderly and have complex medical histories and a myriad of comorbidities. In these patients, with limited survival expectations, symptom palliation, quality of life, and convenience of therapy are especially important end points. Indeed, clinical trials are now incorporating symptom scores and QOL outcomes in their designs (now combined as "patient reported outcomes" or PROs). Moreover, symptom palliation correlates well with QOL and survival duration, providing further rationale for therapy selection based on these parameters. The potential palliative and QOL benefits of chemotherapy have been investigated for several agents in lung cancer trials. Of these, topotecan (Hycamtin®; GlaxoSmithKline; Philadelphia, PA) is the best characterized in relapsed small cell lung cancer (SCLC). In a phase III trial of topotecan versus cyclophosphamide, doxorubicin (Adriamycin®; Bedford Laboratories; Bedford, OH), and vincristine (Oncovin®; Eli Lilly and Company; Indianapolis, IN) (CAV) in patients with recurrent SCLC, topotecan was associated with statistically significant (p < 0.05) improvements in general symptoms (e.g., fatigue and interference with daily activity) and disease-specific symptoms (e.g., dyspnea and hoarseness). Moreover, the introduction of oral therapies, such as oral topotecan, may increase the convenience of therapy by reducing the time needed for therapy and the need for frequent venipuncture. This review summarizes the role of chemotherapy in symptom palliation, with an emphasis on the impact of topotecan therapy on symptom parameters in patients with relapsed SCLC and the emerging role of oral therapy in this setting.

Key Words. Non-small cell lung carcinoma • Oral administration • Quality of life • Small cell lung carcinoma • Palliative therapy • Topotecan


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Role of QOL in...
 Role of Chemotherapy in...
 Role of Topotecan in...
 Oral Chemotherapy
 Oral Topotecan
 Summary
 References
 
Lung cancer is an aggressive malignancy with 2-year survival rates for patients with metastatic small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) of approximately 15% and 11%, respectively [1, 2]. Unfortunately, for patients whose disease recurs after standard first-line platinum-based therapy, expected survival is measured in months, even with the most aggressive therapies [1–4]. Therefore, although for both clinicians and regulatory purposes, overall survival is generally the most important measurement of efficacy, patients and caregivers alike are placing an increasingly greater emphasis on quality of life (QOL) and patient preferences during therapy. This is especially true in cases in which therapy is unlikely to be curative. Indeed, even in the absence of survival benefits, chemotherapy can provide important palliative benefits to patients with advanced lung cancer. Therefore, understanding the relative effects of chemotherapy on QOL and patient preferences is important for effective decision making in this setting.

Patients with lung cancer often suffer an ongoing erosion in QOL. The vast majority of lung cancer patients die of their disease, and most experience debilitating symptoms (e.g., pain, dyspnea, fatigue) during disease progression [5, 6]. Undertreatment of these cancer symptoms—pain symptoms in particular—has been widely chronicled in the medical literature [7–9]. Undertreatment of cancer-related symptoms occurs despite the availability of general practice guidelines [10] and guidelines specific to the treatment of lung cancer patients [11]. In addition to the available consensus guidelines, there are a number of useful QOL assessment instruments for patients with lung cancer, and results from such assessments suggest that treatment can provide important benefits [12–14].

One reason for the undertreatment of patients with advanced lung cancer is the high prevalence of risk factors for adverse events during salvage chemotherapy. Approximately 66% of lung cancer patients in the U.S. are over the age of 65 years [15], consistent with the higher rates of cancer, in general, in the elderly population. In addition, lung cancer patients may have poor performance status (PS) scores because of worsening clinical symptoms, disease progression, comorbidities, and toxicities associated with prior therapy. Elderly patients or patients with poor PS scores often cannot tolerate many of the chemotherapy regimens used in the relapsed disease setting. However, because these patients typically have limited survival, QOL, including both physical and psychosocial well-being, is an especially important concern. An appropriate therapy regimen for these patients would be well tolerated, free from potential cumulative toxicities, and effective at palliating disease symptoms. Moreover, oral therapy regimens, which reduce the need for frequent venipuncture and trips to infusion centers for treatment, would provide further QOL benefits for patients and caregivers alike.

Herein, the role of chemotherapy in the palliation of lung cancer symptoms is discussed, with an emphasis on the impact of topotecan (Hycamtin®; GlaxoSmithKline, Philadelphia, PA) therapy on symptom and QOL parameters in patients with relapsed SCLC. The emerging role of oral therapy in patients with advanced cancer is also discussed.


   ROLE OF QOL IN THE TREATMENT OF PATIENTS WITH ADVANCED LUNG CANCER
Top
 Learning Objectives
 Abstract
 Introduction
 Role of QOL in...
Role of Chemotherapy in...
 Role of Topotecan in...
 Oral Chemotherapy
 Oral Topotecan
 Summary
 References
 
QOL, survival, and tumor response are all interrelated parameters that are dependent on both the malignancy itself and the treatment strategies used to combat it (Fig. 1Go). Indeed, Hollen et al. [16] reported that QOL at baseline may be of greater prognostic value than disease stage or performance status. Therapy can both positively and negatively affect QOL; tumor response can have a positive impact on survival and QOL, whereas side effects from various treatments can have a negative impact on these parameters. However, many of the serious toxicities associated with chemotherapy are manageable through either pretreatment (e.g., antiemetics, antidiarrheals, and corticosteroids) or posttreatment (e.g., growth factor support) measures, through adjustments in the dose level or frequency, or through the use of alternative schedules, routes of drug delivery, or combination regimens. Therefore, the appropriate management of treatment-associated toxicities will limit their negative effects on a patient’s QOL.



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  		Figure 1. Relationship of treatment end points in cancer patients.

 
Recognition of QOL as a Clinical End Point
Although the importance of the QOL end point is universally recognized, its importance relative to other end points is viewed differently by oncologists treating patients in clinical trials than by those in clinical practice (Table 1Go). In phase III clinical trials, survival is generally the preferred end point, and end points based on objective responses do not capture possible benefits from disease stabilization [17–21]. However, survival results from large trials can only be used for treatment selection recommendations, not for ongoing decisions as to whether to continue chemotherapy or not. In that setting, physicians generally use objective response rates when making decisions regarding the continuation of chemotherapy, perhaps also using that end point as a surrogate for symptom palliation. When there is no apparent survival advantage among treatments, possible effects on QOL become the deciding factor. Indeed, in clinical practice, preserving QOL can sometimes take precedence over survival when treating patients with diseases associated with poor prognoses.


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  		Table 1. End points in treatment decisions
 
Hollen et al. [16] have recommended that assessment of QOL should be incorporated into the evaluation of all new agents or regimens undergoing regulatory consideration. The U.S. Food and Drug Administration (FDA) and many European agencies recognize that end points other than survival may be important in evaluating the efficacies of new oncology products. Relief of tumor-specific symptoms provided support for the FDA approval of 13 (23%) of the 57 oncology drug approvals between January 1, 1990, and November 1, 2002 [22]. The FDA now strongly encourages sponsors and investigators to include end points that address symptom-based clinical benefits in cancer patients in pivotal phase III clinical studies [22]. The European Agency for the Evaluation of Medicinal Products (EMEA) standards still need to be developed for the measurement and reporting of QOL [23].

Assessing QOL in Clinical Trials
The use of QOL as an end point is challenging because of the necessity to statistically quantify subjective measurements. Several QOL instruments for patients with lung cancer have been developed. The three most common QOL questionnaires are: the European Organization for Research and Treatment of Cancer Quality-of-Life Lung Cancer Questionnaire (EORTC QLQ-C30, QOL-LC13 module), which includes the EORTC core QOL questionnaire plus lung-cancer-related symptoms and treatment side effects [24]; the Lung Cancer Symptom Scale (LCSS), which includes a questionnaire based on lung-cancer-related symptoms reported by both the patient and the observer [25]; and the Functional Assessment of Cancer Therapy-Lung (FACT-L), which includes a questionnaire based on physical, social, emotional, and functional well-being, lung cancer symptoms, and the relationship with the physician [26]. However, because of limited survival and other confounding factors, it is often difficult to obtain serial measurements of QOL in patients with lung cancer [16]. In addition, the relative importance of certain dimensions may differ among the patient, the caregivers, and the health care workers [27]. Further, physicians may consistently underestimate the severity of physical symptoms [28]. As limitations are identified, QOL instruments will continue to evolve, an unfortunate ramification of which is that it is difficult to compare QOL outcomes among studies. Nonetheless, evaluating patient-reported outcomes, such as QOL, helps to identify treatment regimens that may be beneficial to patients and families.

QOL in Clinical Practice
While QOL evaluation is important in clinical trials, it may be even more vital in daily patient management. An ongoing challenge will be to make QOL assessment easy to incorporate into individual patient care. Several QOL dimensions must be addressed while caring for cancer patients [29]. It is anticipated that cancer care will optimize the QOL of patients throughout the course of their illness. However, treatment-related toxicities, social and psychological concerns, and disease progression often undermine this goal. Improvements in the physical and functional dimensions of QOL can be achieved with increased efficacy and decreased toxicity of treatment options. Increased efficacy results in improvements in and control of cancer-related symptoms. Decreased toxicity helps to minimize any adverse effects of treatment on the physical and functional dimensions. Psychological, social, and spiritual dimensions are often considered beyond the scope of the treating physician; however, improvements in the physical and functional dimensions can have a positive impact on these other major patient concerns. Symptom palliation correlates well with QOL [12, 13], providing rationale for using therapies that provide symptom benefits. Based on these findings, maintaining QOL in the individual patient involves the selection of treatment based on maximal symptom palliation and minimal nonhematologic side effects and the use of established supportive care strategies to minimize the risk of adverse events that could have a negative impact on QOL.


   ROLE OF CHEMOTHERAPY IN PALLIATION OF LUNG CANCER SYMPTOMS
Top
 Learning Objectives
 Abstract
 Introduction
 Role of QOL in...
 Role of Chemotherapy in...
Role of Topotecan in...
 Oral Chemotherapy
 Oral Topotecan
 Summary
 References
 
Lung cancer-related symptoms that may require palliation include symptoms associated with the primary tumor itself (e.g., dyspnea, hemoptysis, fatigue, pain), symptoms associated with regional metastases (e.g., pleural effusions, superior vena cava syndrome), and symptoms from potential distant metastatic sites (e.g., brain, bone). These symptoms can have profound negative impacts on patient QOL. For example, dyspnea is often associated with the frightening sensation of air hunger, which induces a high anxiety level and which has an impact on the patient’s physical, social, and psychological well-being [30, 31]. Patients with higher dyspnea symptom scores generally have lower QOL [30]. Therefore, palliation of dyspnea and other symptoms will likely improve the overall QOL of lung cancer patients.

Although most palliation studies in lung cancer have been performed in patients receiving palliative radiotherapy [32], chemotherapy also appears to provide QOL benefits. Several studies have reported symptom palliation in patients with NSCLC who were treated with platinum-based chemotherapy (Table 2Go) [33–39]. In those phase II studies, a considerable proportion of patients experienced symptom palliation. Patients treated with platinum-based regimens with bleomycin (Blenoxane®; Bristol-Myers Squibb), etoposide (Etopophos®; Bristol-Myers Squibb), vinblastine (Velban®; Eli Lilly and Company; Indianapolis, IN), mitomycin (Mutamycin®; Bristol-Myers Squibb), vincristine (Oncovin®; Eli Lilly and Company), and/or ifosfamide (Ifex®; Bristol-Myers Squibb; Princeton, NJ) experienced symptom improvements in cough, hemoptysis, pain, and malaise. Interestingly, the symptom improvements in those studies appeared to have a greater impact than the overall response rate, supporting the notion that symptom palliation with stable disease may have an equivalent impact to tumor response and further demonstrating the benefits of treatment outside more conventional or traditional end point measures [11, 40].


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  		Table 2. Symptom palliation in patients with NSCLC treated with platinum-based chemotherapy
 
QOL in First-Line Treatment of Lung Cancer
Despite the recognized importance of symptom palliation and QOL, few clinical trials in the past have prospectively evaluated QOL during first-line chemotherapy for SCLC, and none have identified significant differences among regimens. Etoposide plus cisplatin (Platinol®; Bristol-Myers Squibb)—the regimen considered the standard of care for the first-line treatment of SCLC—and the four-drug combination regimen of etoposide plus cisplatin, cyclophosphamide, and epirubicin (Ellence®; Pharmacia and Upjohn; Portage, MI) have demonstrated similar improvements in global health status as evaluated by the EORTC QOL-LC13 questionnaire in patients with extensive SCLC [41]. Although the combination regimen of etoposide plus cisplatin was superior to the cyclophosphamide, epirubicin, and vincristine regimen in a phase III trial in patients with SCLC, QOL assessment revealed no major differences between the two regimens [42]. Interestingly, although the added convenience of oral therapy over i.v. therapy was expected to provide QOL benefits, oral etoposide in combination with cisplatin did not provide any significant QOL advantages over i.v. etoposide plus cisplatin in previously untreated patients with SCLC [43]. In a phase III Eastern Cooperative Oncology Group (ECOG) trial, Schiller et al. [44] investigated topotecan versus observation after etoposide plus cisplatin in previously untreated patients with extensive SCLC. QOL was assessed using the FACT-L instrument. There appeared to be no differences in QOL between topotecan and observation. However, the QOL assessment of the observation arm may have been biased by the discontinuation of patients with progressive disease, preventing presumably more ailing patients from completing the FACT-L questionnaire.

Although many studies have used FACT-L assessment during chemotherapy for advanced NSCLC, data on differences between treatment groups are limited [45, 46]. Nonetheless, clinical trials have shown that chemotherapy provides QOL benefits over supportive care in patients whose lung cancer responds or stabilizes in response to chemotherapy, perhaps through symptom palliation and improvement in physical function [14]. Therefore, it is likely that standard first-line NSCLC therapies have similar QOL benefits.


   ROLE OF TOPOTECAN IN PROVIDING SYMPTOM PALLIATION IN RELAPSED SCLC
Top
 Learning Objectives
 Abstract
 Introduction
 Role of QOL in...
 Role of Chemotherapy in...
 Role of Topotecan in...
Oral Chemotherapy
 Oral Topotecan
 Summary
 References
 
Topotecan is a water-soluble semisynthetic analogue of camptothecin that is currently approved in many countries as an i.v. formulation for the treatment of relapsed SCLC [4, 47–49] and is investigational in the first-line SCLC setting and in NSCLC. The standard dosing regimen for topotecan (1.5 mg/m2/day on days 1–5 of a 21-day cycle) has a well-established clinical profile, including response rates ranging from 19%–38% in chemosensitive SCLC patients and dose-limiting toxicity consisting of myelosuppression [4, 47–50]. Nonhematologic toxicities are seldom dose limiting or the cause of treatment discontinuation. Other dosing regimens that may be better suited to particular patient subgroups are under investigation in advanced lung cancer patients [51].

Topotecan has demonstrated significant palliation of disease-related symptoms in patients with recurrent SCLC [4]. In a phase III trial of topotecan versus cyclophosphamide, doxorubicin (Adriamycin®; Bedford Laboratories; Bedford, OH), and vincristine (CAV) in patients with recurrent SCLC, topotecan was associated with significant improvements in general symptoms (p < 0.05), including anorexia, fatigue, and interference with daily activity, and pulmonary symptoms, including dyspnea and hoarseness (Table 3Go) [4]. Additionally, topotecan treatment significantly slowed the progression of dyspnea (p = 0.046) and anorexia (p = 0.003) [4]. Topotecan improved symptoms of insomnia, hoarseness, anorexia, and dyspnea in 33%, 33%, 32%, and 28% of patients who reported these symptoms at baseline, respectively. In that study, the objective tumor response rate was 24%, all of which were partial responses (PRs). The proportion of patients who reported symptom relief in many instances was higher than the objective response rate, suggesting that patients who did not attain the threshold for objective tumor response achieved clinical benefit. However, the investigators did not report symptom palliation scores by tumor response.


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  		Table 3. Symptom improvement compared with baseline in patients with SCLC treated with i.v. topotecan or CAV
 
Similar palliative benefits were reported in a phase II trial comparing oral topotecan with i.v. topotecan (Table 4Go) [50]. At baseline, the most common symptoms among patients with relapsed SCLC included cough, fatigue, interference with daily activities, and dyspnea. The greatest improvements from baseline in symptoms among patients receiving i.v. topotecan occurred for hemoptysis (40%), hoarseness (38%), chest pain (32%), and anorexia (31%) [50]. Although the duration of symptom improvement was not reported in that trial, symptom score improvements were noted for two or more consecutive assessments after baseline, which corresponded to two or more 21-day cycles of therapy. These results demonstrate that patients achieved palliative benefits from both oral and i.v. topotecan for a minimum of 6 weeks, and potentially longer. Similar to the topotecan trial in SCLC conducted by von Pawel et al. [4], symptom improvements were observed in a greater proportion of patients than the objective tumor response rate of 19% [50].


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  		Table 4. Symptom improvement compared with baseline in patients with SCLC treated with either oral or i.v. topotecan
 
Topotecan in Patients with Poor PS Scores
Although PS score is not a direct measure of QOL, it has been viewed by some investigators as an important predictor of survival and QOL [52]. Indeed, in several studies, there has been a significant correlation between PS and QOL, including the psychological, physical, and symptomatic distress aspects of QOL [24, 53, 54]. Additionally, in a systematic assessment of QOL in patients with NSCLC, change in QOL correlated with change in PS [55].

Recently, the safety and efficacy of topotecan in patients with poor PS scores were reported in a retrospective review of five clinical trials in relapsed SCLC patients (n = 479) [56]. A total of 98 patients with PS scores of 2 at baseline was included in the analysis. All patients received topotecan (1.5 mg/m2/day) on days 1–5 of a 21-day course. Treatment was similarly tolerated, and benefits (including symptom palliation) were similar between patients with PS scores <2 and those with PS scores = 2 [56]. Indeed, patients with PS scores of 2 who received topotecan achieved greater improvements in fatigue, insomnia, and chest pain than patients with PS scores <2 [56]. In a further analysis on PS conversion from a PS score of 2 to a PS score of 0/1, those authors reported that, of the 98 patients with PS scores of 2, 32 (33%) experienced a PS score improvement to 0/1 during topotecan treatment [57]. Approximately two-thirds of those patients had improvements in their PS scores after the first course of topotecan, and 24 of the 32 patients maintained those improvements for at least two courses. The overall antitumor response rate for topotecan was 46% in patients who experienced PS score improvements, compared with 8% in other patients. Similarly, the median overall survival time in patients with PS score improvements was 37 weeks (95% confidence interval [CI] = 30–45 weeks), compared with 12 weeks (95% CI = 9–16 weeks) for patients with no improvement. The investigators concluded that patients with relapsed SCLC and a PS score of 2 could experience an improvement in PS and should not be denied treatment with topotecan. Further studies are needed to determine whether similar improvements in PS can be achieved with topotecan in patients with NSCLC.


   ORAL CHEMOTHERAPY
Top
 Learning Objectives
 Abstract
 Introduction
 Role of QOL in...
 Role of Chemotherapy in...
 Role of Topotecan in...
 Oral Chemotherapy
Oral Topotecan
 Summary
 References
 
In an early patient survey on side-effect concerns with chemotherapy, the primary physical concerns included vomiting, nausea, and alopecia [58]. However, 54% of the concerns were nonphysical, with inconvenience of having to go to a hospital for treatment, time required for each treatment session, and venipuncture being ranked highest among the nonphysical concerns. With the introduction of new antiemetic regimens and improvements in chemotherapy, more recent patient surveys have reported a decrease in the severity of some of the physical side effects associated with chemotherapy and a trend toward an increase in psychosocial concerns [59, 60]. The effects on friends and family, work or home duties, and social activities have become primary concerns of patients receiving chemotherapy.

As reflected by the shifting pattern of patient concerns, there is an increased demand for oral chemotherapy agents, particularly for established agents currently available as i.v. formulations [61]. Previous studies have shown that oral therapies are preferred by patients over i.v. therapies, provided the two formulations offer equivalent efficacies [61]. Oral formulations provide several advantages over i.v. therapies. First, oral formulations allow self-administration of the drug, which minimizes disruption of daily life and increases patient convenience by eliminating the need for transportation to infusion centers. In addition, oral agents are less invasive than i.v. lines, which are a major source of stress and discomfort for patients [58] and are associated with infections [62]. Further, oral formulations are often associated with fewer adverse events than their i.v. counterparts, which has a positive impact on patient QOL [63, 64]. Finally, the convenience of oral formulations reduces the cost of chemotherapy administration and overall health care expenditures.

In a recent survey of patients with incurable cancer who were likely to receive palliative chemotherapy, 89% stated that they would prefer to receive an oral rather than an i.v. chemotherapy regimen [61]. Convenience and elimination of venipuncture were reasons for this preference. However, 70% and 74% of the patients surveyed were not willing to accept a lower response rate or a shorter duration of response, respectively, to retain their preference for an oral formulation. Therefore, although QOL, family burden, and convenience are all concerns of the patient, efficacy remains the primary objective of chemotherapy. Patient preference for an oral formulation supports the continued focus on the development of oral chemotherapy agents with reliable bioavailabilities, equal or greater efficacies, similar or superior toxicity profiles compared with their i.v. counterparts, greater convenience and acceptance, and favorable economic profiles.


   ORAL TOPOTECAN
Top
 Learning Objectives
 Abstract
 Introduction
 Role of QOL in...
 Role of Chemotherapy in...
 Role of Topotecan in...
 Oral Chemotherapy
 Oral Topotecan
Summary
 References
 
On the basis of the antitumor activity and reported symptom palliation with i.v. topotecan, an oral formulation of topotecan, provided it has equivalent efficacy and safety, may be an appropriate treatment option that addresses some of the convenience and accessibility issues.

Pharmacokinetics of Topotecan
In aqueous solutions, topotecan undergoes reversible, pH-dependent hydrolysis, achieving equilibrium between its closed-ring lactone and open-ring carboxylate forms [65]. The lactone form is the active form of the drug and is required for passive diffusion of topotecan into cells. Hydrolysis from the lactone to the carboxylate form occurs quickly; 15 minutes after a 30-minute i.v. infusion, only 30% of topotecan in the plasma is in the lactone form. The pharmacokinetic profile of i.v. topotecan is linear, with proportional increases in the area under the plasma concentration-time curve (AUC), plasma peak, and steady-state plasma concentration with increasing doses [66].

The pharmacokinetic profile of oral topotecan has some distinctive characteristics compared with the profile of i.v. topotecan that may lead to superior safety and efficacy profiles. Peak plasma concentrations for oral topotecan occur within 1 hour after ingestion, and maximal plasma concentrations (Cmax) and exposure (AUC) are lower than with i.v. topotecan [67, 68]. However, the apparent terminal half-life (t1/2) of oral topotecan is significantly higher than that of i.v. topotecan (3.9 versus 2.7 hours; p < 0.001) [69, 70]. In addition, the mean residence time for oral topotecan (6–8 hours) is twice that of i.v. topotecan (3–4 hours) [70]. Therefore, the higher t1/2 and longer mean residence time may result in a longer duration of drug concentration above 5–10 nmol, the estimated clinical threshold, while the lower Cmax and AUC for oral topotecan may reduce toxicity. Finally, the bioavailability of oral topotecan is approximately 40% (range 30%–45%), with little intrapatient variability [67–70].

Oral Topotecan in Previously Untreated Lung Cancer
Oral topotecan is feasible and has demonstrated activity in patients with previously untreated advanced NSCLC [71, 72]. In the first of these studies [71], 30 patients were treated with oral topotecan at a starting dose of 2.3 mg/m2/day for 5 days every 21 days. Grade 3/4 neutropenia was reported in 14 (47%) patients, and grade 3 thrombocytopenia was reported in one (3%) patient. Grade 3 nausea (13%) and vomiting (13%) were the most severe nonhematologic toxicities. Oral topotecan treatment was associated with disease-related symptom palliation, including improvements in dyspnea, cough, and fatigue. The feasibility of oral topotecan plus i.v. paclitaxel (Taxol®; Bristol-Myers Squibb) has also been investigated in advanced NSCLC [72]. In combination with paclitaxel (175 mg/m2 on day 1), the maximum tolerated dose of oral topotecan was 1.25 mg/m2/day when administered for 5 days every 21 days.

Oral topotecan is also feasible and active in the untreated SCLC setting. In a phase II study, Eckardt et al. [73, 74] tested oral topotecan in 41 previously untreated patients with extensive SCLC who were considered ineligible for i.v. topotecan therapy. Because this was a high-risk population, the starting dose of oral topotecan was 2.0 mg/m2/day for 5 days every 21 days (26 patients) and was later amended to 1.7 mg/m2/day (15 patients) after two patients at the higher dose developed fatal sepsis. Grade 3/4 neutropenia was reported in 63% of patients and 21% of courses, and grade 3/4 thrombocytopenia was reported in 44% of patients and 9% of courses. The vast majority of nonhematologic toxicities were mild (grade 1 or 2); there were no cases of grade 3 nausea and only two cases of grade 3 vomiting. Twelve (29%) patients had responses to oral topotecan, including one complete response (CR) and 11 PRs. Oral topotecan (1.75 mg/m2/day for 5 days) in combination with i.v. paclitaxel (175 mg/m2 on day 5 of a 28-day cycle) with G-CSF support has also been investigated in previously untreated patients with extensive SCLC who were not at high risk [75]. Treatment resulted in grade 3/4 neutropenia and thrombocytopenia in 40% and 16% of patients, respectively, and an overall response rate of 45% with three CRs and 14 PRs.

Oral Topotecan in Relapsed SCLC
The results of the phase II comparator study by von Pawel et al. [50] suggested that oral topotecan may have a favorable toxicity profile and a similar efficacy profile compared with i.v. topotecan in patients with chemosensitive relapsed SCLC (n = 106). Overall response rates for oral and i.v. topotecan were 23% and 15%, and median survival times were 32 weeks and 25 weeks, respectively. Both therapies were generally well tolerated, and fewer patients in the oral topotecan group than in the i.v. topotecan group had nausea or severe myelosuppression.

Preliminary results of a follow-up, multinational, phase III study comparing oral with i.v. topotecan in patients with limited or extensive SCLC who had responded to first-line therapy were recently presented by Eckardt et al. [76]. A total of 153 patients were randomized to receive oral topotecan (2.3 mg/m2/day), and 151 patients were randomized to receive i.v. topotecan (1.5 mg/m2/day) on days 1–5 of a 21-day cycle. Consistent with the phase II study, oral and i.v. topotecan were generally well tolerated, with higher incidences of grade 4 neutropenia and grade 3 or 4 anemia, but a lower incidence of grade 4 thrombocytopenia in patients treated with i.v. topotecan than in patients who received oral topotecan. A final report on this important phase III study is eagerly awaited.

Recently, we reported that, although there were no differences in FACT-L, Trial Outcome Index (TOI), or individual well-being subscale scores (physical, social/family, functional, emotional, including the lung cancer scale) between treatment groups, both oral and i.v. topotecan provided benefits over baseline [77, 78]. Likewise, there were no differences between oral and i.v. topotecan in symptoms of clinical concern, including nausea, pain, dyspnea, cough, chest tightness, and fatigue [77]. These findings support the similar efficacies of oral and i.v. topotecan and suggest that oral topotecan may be an alternative to traditional i.v. therapy in patients with recurrent SCLC.


   SUMMARY
Top
 Learning Objectives
 Abstract
 Introduction
 Role of QOL in...
 Role of Chemotherapy in...
 Role of Topotecan in...
 Oral Chemotherapy
 Oral Topotecan
 Summary
References
 
Symptom palliation and attentiveness to patient QOL are clinical imperatives in the management of patients with lung cancer—important future goals of new treatments. Interventions should focus on improving survival without compromising QOL, which is particularly important in patients with relapsed disease, the elderly, or patients with poor PS scores. In this respect, therapies that are active, well tolerated, exhibit no progressively worsening toxicities, and offer flexible dosing and scheduling are attractive options for this palliative setting. Oral regimens are an emerging treatment option because of patient preference, convenience, and possible economic benefits. Recent clinical trial evidence suggests that chemotherapy is feasible in patients with advanced lung cancer and may provide palliative benefits even when objective tumor responses are unlikely. The application of QOL assessment techniques and the role of i.v. and oral chemotherapy in the relapsed setting in patients with advanced lung cancer will continue to evolve.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Role of QOL in...
 Role of Chemotherapy in...
 Role of Topotecan in...
 Oral Chemotherapy
 Oral Topotecan
 Summary
 References
 
Supported by GlaxoSmithKline, Philadelphia, PA.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Role of QOL in...
 Role of Chemotherapy in...
 Role of Topotecan in...
 Oral Chemotherapy
 Oral Topotecan
 Summary
 References
 

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Received October 4, 2004; accepted for publication October 9, 2004.




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