New approaches to symptom improvements in lung cancer patients

Lung Cancer Volume 41, Suppl. 4 (2003) S32-S36 www.elsevier.com/locate/lungcan

New approaches to symptom improvements in lung cancer patients Phillip B onomi Department

of Medical

Oncology,

Rush

Cancer

Institute,

Chicago,

USA

Abstract The efficacy of chemotherapy in treating lung cancer continues to be assessed by the impact treatment has on disease progression and survival. Where differences between treatments are marginal and survival times cannot be realistically extended, symptom relief and improving health-related quality of life (QoL) become treatment priorities. Clinical trials in lung cancer often now include an assessment of symptom relief and QoL, and have confirmed the benefit of chemotherapy compared with best supportive care. Collection of symptom relief and QoL data is based on subjective reporting by patients, which can be influenced by extraneous and confounding factors. To ensure reproducibility and interpretability, standardized, validated instruments with known psychometric properties and culturally adapted language are required to capture QoL data from lung cancer patients in clinical trials. A number of available questionnaires, developed and validated for use in oncology studies, are reviewed in this paper. A selection of published lung cancer studies that have used these instruments are described and their outcomes summarized. These studies show that symptom assessment can be integrated in study protocols successfully, but there is a recognized need for improved and consistent measurement in future studies. 0 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Lung cancer; Quality of life; Symptom relief

1. Introduction

The current picture emerging from the treatment of both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) with chemotherapy is that a plateau may have been reached with respect to overall response rates and 2year survival rates. Within the lung cancer population as a whole, the relative proportion of patients with SCLC appears to be decreasing; a recent estimate suggests SCLC now only accounts for 14% of lung cancer patients [ 11. Typically, patients with metastatic SCLC show an overall response rate to treatment of around 60% and a 2-year survival rate of 5% [2]. This compares with corresponding rates of 20% and 1 I%, respectively, for patients with metastatic NSCLC [3]. Current treatment approaches have expanded to include optimal control of disease-related symptoms, in addition to response rate and survival endpoints. This has resulted in an increased emphasis on evaluating progress in the management of disease- and treatment-related symptoms in phase III clinical trials [4]. *Tel: +l 312 942 3312; Fax: +l 312 942 3192 E-mail address: [email protected] (I? Bonomi).

All physicians who treat patients with lung cancer hope that new treatment regimens will improve survival and response rates. Studies evaluating combination regimens, particularly of topoisomerase inhibitors and platinum, are ongoing and the outcomes are eagerly awaited. Although survival advantages for combination chemotherapy over best supportive care have been demonstrated, chemotherapy in NSCLC and SCLC remains primarily palliative [5]. Consequently, while it is important to consider the impact of treatments on disease progression outcomes, it is also important to assesstreatments in terms of their potential to bring much-needed symptomatic relief to patients. This is particularly relevant for patients with advanced lung cancer, poor performance status and limited survival expectations. Relief of distressing symptoms and improvements in health-related quality of life (QoL) represent the primary treatment aims for patients with advanced NSCLC and extensive-stage SCLC. To make valid qualitative and quantitative assessments of any symptomatic or QoL benefits that individual treatments may confer, and to make comparisons between treatments, consistent validated methodology is required in clinical studies. It is quite surprising that only limited clinical attention has been diverted

SO169-5002/03/$ - see front matter 0 2003 Elsevier Science Ireland Ltd. All rights reserved. PII: SSO169-5002(03)00000-0

to studying

the relief

of symptoms

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in lung cancer patients. This paper provides a summary of the methodology and assessment scales available to capture data on symptoms experienced by patients with NSCLC and SCLC. Additionally, selected lung cancer studies that have included symptom assessments to describe treatment outcomes are briefly reviewed.

2. Measuring symptom changes To date, few clinical studies evaluating lung cancer treatments have looked at symptom relief in a systematic way. There are a number of factors to consider relating to the logistics of including symptom assessments in clinical trials, as well as their interpretation. Additional resources are required to oversee the administration of questionnaires and subsequent data management processes, which can have amimpact on trial expenditure. A novel study that included an assessment of symptom relief in patients with lung cancer was conducted at the Royal Marsden Hospital in the UK [5]. Patients (n = 118) with locally advanced or metastatic NSCLC were treated with the combination of mitomycin, vinblastine and cisplatin (MVP). They were assessed for objective responses to treatment and for changes in a range of tumor-related symptoms, including malaise, pain, cough and dyspnea. The investigators reported an objective response in 32% of patients; however, 69% of patients reported complete disappearance or good improvement of at least one tumorrelated symptom. Forty-six of the 76 responding patients (61%) had a symptomatic response after only one course of chemotherapy and 73 (96%) after two courses. The results from the Royal Marsden study indicate that symptom relief is an important treatment outcome in lung cancer therapy and should be assessed using appropriate tools in future studies. Interpretation of symptomatic data needs to be cautious for a number of reasons. Patients’ reports of increased symptom relief may be influenced by concomitant medication(s). Additionally, during clinical trials, increased patient observation and attention from healthcare professionals may trigger significant placebo effects. The multidimensional nature of QoL assessment, the interdependency of patients’ responses and the different methods of measurement argue for interpretation to be based on the overall patterns of results rather than isolated comparisons. A recent editorial [4] has emphasized that the measures used to assess symptom changes in randomized trials must assess the concept of interest, not merely a closely related surrogate. Furthermore, the degree of change in symptoms that is considered to be clinically meaningful must be set and justified on an a priori basis. There are two commonly used instruments for measuring symptoms in lung cancer patients. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) LC13 is a lung cancerspecific subscale of the EORTC QLQ-C30 and was devel-

Table

5’32~S36

1

Symptomsassessed l

. . . . . . . . . . . .

s33

How Did Were Were Were Have Have Have Have Have Have Have Did

with

EORTC

QLQ-LC

13

much did you cough? you cough blood? you short of breath when you rested? you short of breath when you walked? you short of breath when you climbed stairs? you had a sore mouth or tongue? you had trouble swallowing? you had tingling hands or feet? you had hair loss? you had pain in your chest? you had pain in your arm or shoulders? you had pain in other parts of your body? If yes, where? you take any medicine for pain? If yes, how much did it help?

Reproduced

with

permission

from

Bergman

et al., 1994 [7].

oped by the EORTC for use in international clinical trials in oncology [6]. It comprises 13 questions (summarized in Table 1) designed to assesspatients’ respiratory symptoms, any treatment side effects, the location and intensity of their pain, and their requirement for pain relief medication. Each symptom is graded on a four-point scale where ‘not at all’ scores 1 and ‘very much’ scores 4 [7]. The EORTC QLQ-LC13 does not assess fatigue and, as this is reported by many patients with advanced lung cancer, the instrument could be criticized for this omission. The Functional Assessment of Cancer Therapy for patients with Lung cancer (FACT-L) evaluates seven symptoms (Table 2) and each question is graded by the respondent on a 5-point scale where ‘not at all’ scores 0 and ‘very much’ scores 4 [8]. This instrument is a condition-specific subscale of the general (FACT-G) QoL instrument intended for use in a variety of chronic illnesses. The FACT-L does not target fatigue and pain directly, although these assessments, arguably, are embedded indirectly in its subscale questions. Various other assessment scales have been used to assesssymptom changes or QoL in patients with cancer. Some instruments, such as the EORTC SS 14, have a hybrid composition with elements taken from their QLQ-C30 and QLQLC13 instruments [9]. The Rotterdam Symptom Checklist (RSCL) is a self-reporting measure for assessing QoL in cancer patients [lo]. It was originally validated in a Dutch study [ 1l] and has since been used in a number of Dutch and Table 2 Symptoms . . l

. . . l

.

assessed

with

FACT-L

I have been short of breath I am losing weight My thinking is clear I have been coughing I have been bothered by hair loss I have a good appetite I feel tightness in my chest Breathing is easy for me

Reproduced

with

permission

from

Cella et al., 1995 [8].

s34

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British studies. This is a comprehensive instrument with four main domains: physical symptom distress (23 items with a significant focus on pain and fatigue), activity level (eight items), psychological distress (seven items), and a single overall assessment of ‘all things considered’.

3. Clinical trials assessing symptom relief - SCLC The limited number of published studies in SCLC reflects its lower incidence compared with NSCLC. An oral formulation of topotecan is being developed that offers similar efficacy to the intravenous formulation. In a randomized phase II study, 52 patients with relapsed SCLC received oral topotecan (2.3 mg/m2/day for 5 days every 21 days) and 54 patients received intravenous topotecan (1.5 mg/m2/day for 5 days every 21 days) [ 121. The response rates in each arm were 23% and 15%, respectively. Disease-related symptoms were assessed with a scale based on the Lung Cancer Symptom Scale. Patients completed the questionnaire at baseline and immediately before the next cycle of treatment. Improvements in any symptoms had to be sustained until the next cycle to be reported as symptom responses. With both formulations, more than 20% of patients experienced reductions in chest pain, hemoptysis, insomnia, hoarseness and interference with daily living. In a second randomized study, response rates for oral and intravenous topotecan were similar (18.3% versus 21.9%) [ 13,141. The median and one-year survival rates were also similar and both treatment arms were generally well tolerated. No significant differences between treatment groups were observed in the total score from the FACT-L questionnaire, the TOI and the individual well-being subscale scores (physical, social/family, functional emotional), including the lung cancer scale. However, oral topotecan may have additional benefits for patients and their informal carers in terms of convenience and ease of administration, parameters that the current QoL instruments cannot measure. Liu and colleagues [15], for example, found that patients had a clear preference for oral over intravenous chemotherapy, but were not willing to sacrifice efficacy for their preference. The major reasons for preferring oral treatment were convenience, problems with intravenous access or needles, and the comfort of being treated at home. Patients also expressed a preference for oral treatment in a study comparing oral uracil/tegafur and intravenous 5-fluorouracil[16]. Oral chemotherapy also offers convenience to patients in terms of reduced clinic visits and associated travel costs [ 171. In a randomized study [18], 107 patients with SCLC who had relapsed after at least 60 days of first-line therapy were treated with either topotecan or cyclophosphamide, doxorubicin and vincristine (CAV) as a second-line agent. Changes in dyspnea, cough, chest pain, hemoptysis, anorexia, insomnia, hoarseness, fatigue and interference in daily activities were evaluated on a four-point scale where ‘not at all’ scored 1 and ‘very much’ scored 4 in a symptom-specific question-

Table 3 Improvement in symptoms changes with topotecan versusCAv as second-line treatment in SCLC patients Symptom

Topotecan n/N * (%)

CAV n/N * (%)

P

Dyspnea Cough Chest pain Hemoptysis Anorexia Insomnia Hoarseness Fatigue Interference with daily living

19/68 (27.9) 17169 (24.6) 1 l/44 (25.0) 4/ 15 (26.7) 18/56 (32.1) 19/57 (33.3) 13/40 (32.5) 16/70 (22.9) 18/67 (26.9)

4/61 9/61 7/41 4/12 9/57 lo/53 5/38 6/65 7/63

0.002+ 0.160 0.37 I 0.706 0.042+ 0.085 0.043 + 0.032: 0.023’

(6.6) (14.8) (17.1) (33.3) (15.8) (18.9) (13.2) (9.2) (11.1)

*No. of patients showing improvement/no. of patients with baseline or at least one postbaseline assessment (improvement defined as two consecutive improvements over the baseline assessment). + p < 0.05. Adapted from von Pawel et al., 1999 [18]. Reproduced with permission from the American Society of Clinical Oncology.

naire. Although not currently validated, this QoL instrument closely resembles the Lung Cancer Symptom Scale [ 191. Patients who received topotecan compared with CAV treatment reported increased symptomatic improvements. Significant differences, in favor of topotecan, were reported for dyspnea (28% versus 7%; p = 0.002), anorexia (32% versus 16%; p = 0.042), hoarseness (33% versus 13%; p = 0.043), fatigue (23% versus 9%; p = 0.32) and, potentially the most important, interference with daily activity (27% versus 11%; p = 0.023). In contrast, no symptom improvements were statistically superior in the CAV treatment group. Reported changes in symptoms are summarized in Table 3. Some symptoms progressed more slowly in the topotecan group, for example, lengths of time to worsening of dyspnea and anorexia were significantly longer for topotecan-treated patients (p = 0.046 and p = 0.003, respectively). There were no significant differences in efficacy variables between the two treatments. Response rates of 24% and 18% were recorded for topotecan and CAV, respectively. Median times to progression were 13.3 and 12.3 weeks and median survival times were 25 and 24.7 weeks for topotecan and CAV, respectively.

4. Clinical trials assessing symptom relief - NSCLC The Elderly Lung Cancer Vinorelbine Italian Study was a randomized trial that included a comparison of QoL in elderly patients treated with either vinorelbine or best supportive care (BSC) alone [20]. On the EORTC QLQ-C30 symptom scales, vinorelbine scored significantly better than BSC for relief of pain (p = 0.02) and approached significance for nausea and vomiting (p = 0.07), but significantly increased constipation (p = 0.002). On the EORTC QLQLC13 scales, vinorelbine improved dyspnea (p = 0.05) and shoulder pain (p = 0.005). The need for pain medica-

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tion was also significantly reduced (p = 0.01); however, vinorelbine significantly increased neuropathy compared with MC. Hair loss was also significant with vinorelbine (P < 0.001). There was a statistically significant survival advantage with vinorelbine treatment (median increase from 2.1 to 28 weeks; p = 0.03) compared with BSC in this study. The combined results of two large, randomized UK trials were reported by Cullen and colleagues [21]. Patients with localized disease were randomized to mitomycin, ifosfamide and cisplatin (MIC) combination chemotherapy followed by radical radiotherapy (RT) treatment cycles, or RT alone (MICl trial), and patients with extensive disease (MIC2 trial) were randomized to MIC or BSC. The EQRTC QLC-LC13 was used to collect QoL data in a subgroup of patients in each trial. Results in both trials showed that the mean change in QoL score from 0 to 6 weeks improved with chemotherapy and deteriorated significantly with the standard treatments of RT in MICl and BSC in MIC2. The difference between treatment arms was highly significant in each trial (p = 0.0002 for MICl and p = 0.007 for MIC2). After adjusting for patient imbalances between treatment groups, the difference remained highly significant in MICl (p = 0.0003), but was of borderline significance in MIC2 (17 = 0.06). Addition of MIC chemotherapy prolonged median survival times in both trials; this was significant in the MIC2 trial (6.7 versus 4.8 months; p = 0.03). In a UK randomized study, QoL was assessed as the primary outcome in a cohort of 300 patients with locally advanced or metastatic NSCLC, after treatment with either gemcitabine plus BSC or BSC alone [22]. Patients’ assessments of predefined commonly reported symptoms (SS 14) wlere derived from the EORTC QLQ-C30 and QLQ-LC13 scales. Primary endpoints measured were the percentage change in mean SS14 score at 2 months versus baseline and the proportion of patients with a marked (225%) improvement in SS14 score at 2 months that was sustained for a further ~4 weeks. The SS14 score at 2 months had decreased by 10% (indicating improvement) compared with baseline in the gemcitabine plus BSC group, whereas a 1% non-significant increase (indicating deterioration) was evident in the BSC alone treatment group. However, there was a significant difference in the percentage of patients with sustained improvements in QoL; 22% in the gemcitabine group compared with 9% in the BSC group (p = 0.0014). Improvements of > 10% were observed for emotional functioning, pain-symptom scale, chest pain, cough and fatigue in gemcitabine plus BSC patients compared with the BSC group. Improvement was greater in the BSC group for dyspnea only. For deterioration of 11 O%, role function and hair loss were greater for gemcitabine-treated patients, whereas chest pain, shoulder pain and emotional functioning were greater with BSC. At 4 months, between-treatment improvements of 2 10% were evident for six variables (chest pain, shoulder pain, emotional functioning, role domain, social domain and financial impact), but only for patients in the gemcitabine plus

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BSC group. Between-treatment deteriorations of > 10% were reported for four variables: hair loss was greater with gemcitabine plus BSC, whereas deteriorations in social domain, pain symptom scale and constipation were greater in the BSC group. There were no significant differences between treatments for overall survival and survival at 1 year. In an international study conducted in the UK, USA and Canada [23], the Rotterdam Symptom Checklist (RSCL) was used to assess QoL changes in patients with stage IIIB or IV NSCLC treated with either paclitaxel plus BSC or BSC alone. Of the three main domains of the RSCL (physical, functional and activity), only the functional aspects were significantly improved by paclitaxel (p = 0.043). Paclitaxel plus BSC was significantly superior in improving the median survival time compared with BSC alone (6.8 versus 4.8 months; p = 0.037). A European randomized phase III trial assessed QoL using the EORTC QLQ-C30 in patients with metastatic or non-resectable localized NSCLC treated with docetaxel plus BSC or BSC alone [24]. A statistically significant difference between treatments, in favor of docetaxel, was apparent for emotional functioning. Area under the curve (AUC) analyses revealed significant improvements in docetaxeltreated patients for nausea/vomiting (p = 0.04), pain (p < 0.001) and dyspnea (p = 0.02), compared with BSC. There was a statistically significant difference in overall survival in favor of docetaxel (p = 0.026), and in the time to progression (p < 0.001). After 1 year, the survival rate in the docetaxel arm was 25%, versus 16% in the BSC arm. After 2 years, the survival rate was 12% with docetaxel, but no patients survived beyond 20 months in the BSC arm.

5. Conclusions Without doubt, improving survival times remains the most important objective in the treatment of lung cancer patients and the impact on survival will continue to be the gold standard for assessing the efficacy of new treatments. However, when survival outcomes with available chemotherapy options are likely to be very similar, consideration of the symptom relief afforded by individual treatments becomes more significant. When patients’ survival time is limited and realistically cannot be extended, relieving suffering, improving QoL and not adding to the burden of illness for the patient become treatment priorities. Randomized trials that evaluate treatments in lung cancer patients should include symptom relief and control assessments. The data from such assessments would enable clinicians to make informed treatment choices based on the individual patient. However, there remains considerable skepticism, particularly among regulators, on the role of such assessments, as self-reporting of symptoms by patients is a subjective process that can be affected by a variety of confounding factors. It is, therefore, important that symptom evaluations are conducted using robust, well-controlled

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processes. Key to this is the use of standardized, validated instruments with known psychometric properties and questionnaires with culturally adapted language and questions that are meaningful to the patient population in each study. Reproducibility and interpretability are fundamental requirements for studying lung cancer-related symptoms in future studies. Emerging guidelines for designing trials that include cancer-related symptoms and QoL endpoints will help this process [25,26]. In the studies reviewed here, chemotherapy with single agents in addition to BSC provided greater symptomatic relief for patients with NSCLC than BSC alone. In SCLC, data describing symptom relief are limited. However, in a randomized study, topotecan provided significantly greater relief in five of nine symptoms evaluated, compared with the CAV combination. Randomized studies in patients with NSCLC and SCLC are needed to follow up these findings, to characterize potential symptom control and relief benefits of chemotherapy treatments more comprehensively. References [l] Page NC, Read WL, Tiemey RM, Arquette MA, Piccirillo JF, Ramaswamy G. The epidemiology of small cell lung carcinoma. Proc Am Sot Clin Oncol2002;21:A1216. [2] Bonomi P. Review of selected randomized trials in small cell lung cancer. Semin Oncol 1998;25 (Suppl. 9):70-78. [3] Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-98. [4] Varricchio CG, Sloan JA. The need for and characteristics of randomized, phase III trials to evaluate symptom management in patients with cancer. J Nat1 Cancer lnst 2002:94: 1184- 1185. [5] Ellis PA, Smith IE, Hardy JR, Nicolson MC, Talbot DC, Ashley SE, et aI. Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 1995;71:366-370. [6] Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality of life instrument for use in international clinical trials in oncology. J Nat1 Cancer Inst 1993;85:365-376. [7] Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-LC13: a modular supplement to the EORTC core quality of life questionnaire (QLQ-C30) for use in lung cancer clinical trials. Eur J Cancer 1994;3OA:635-642. [S] Cella DF, Bonomi AE, Lloyd SR, Tulsky DS, Kaplan E, Bonomi P. Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Lung Cancer 1995;12:199-220. [9] Hopwood P, Stephens RJ on behalf of the Medical Research Council (MRC) Lung Cancer Working Party. Symptoms at presentation for treatment in patients with lung cancer: implications for the evaluation of palliative treatment. Br J Cancer 1995;71:633-636. [lo] De Haes JCJM, van Knippenberg FCE, Neijt JP. Measuring psychological and physical distress in cancer patients; structure and application of the Rotterdam Symptom Checklist. Br J Cancer 1990;62:1034-1038. 1111 De Haes JCJM, Pruyn JFA, van Knippenberg FCE. Klachtenlijst voor kankerpatienten, eerste ervarigen. Ned Tijdsschr Psycho1 1983;38:403-422.

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