- Email: [email protected]
Maintenance Therapy for Advanced Non–Small-Cell Lung Cancer: A Pilot Study on Patients’ Perceptions
ORIGINAL ARTICLE
Maintenance Therapy for Advanced Non–Small-Cell Lung Cancer A Pilot Study on Patients’ Perceptions Lies Peeters, RN, Anne Sibille, MD, Bea Anrys, RN, Christel Oyen, RN, Christophe Dooms, MD, PhD, Kristiaan Nackaerts, MD, PhD, Isabelle Wauters, MD, and Johan Vansteenkiste, MD, PhD
Introduction: Several randomized trials on maintenance therapy (MT) for metastatic non–small-cell lung cancer (NSCLC) have demonstrated benefit in progression-free survival. More recently, a study with pemetrexed and one with erlotinib also showed significant gains in overall survival (OS). Yet, in this palliative treatment setting, the benefit has to be weighed against the potential burden of treatment, and thus patients’ preferences should be taken into account. Methods: In the absence of data on this topic, we undertook a pilot survey with 10 questions covering the overall patient attitude toward MT, the benefit expected by patients, and the acceptance of side effects or modes of administration. Included patients had stage IV NSCLC and were planned to start first-line platinum-based doublet chemotherapy. The questionnaire was submitted at the start of and after two and four cycles of chemotherapy. Results: Thirty patients were included. Overall, patients had a positive attitude toward MT. At baseline, it was considered worthwhile by 83%, 67%, and 43% of patients for an OS benefit of 6, 3, or 1 month, respectively, with some decrease over time. Effects on symptom control were crucial for about 90% of the patients. There was a slight preference for oral versus intravenous administration. Side effects were accepted by most patients as long as they were mild to moderate. Conclusion: Our pilot survey showed that metastatic NSCLC patients in general are in favor of MT. They expect either an OS benefit of at least several months, or better symptom control, in balance with mild-to-moderate side effects. Key Words: Non–small-cell lung cancer, Maintenance treatment, Patients’ attitudes, Chemotherapy, Targeted therapy, Questionnaires. (J Thorac Oncol. 2012;7: 1291–1295)
Respiratory Oncology Unit (Pulmonology) and Leuven Lung Cancer Group, University Hospital Gasthuisberg, Leuven, Belgium. Disclosure: Johan Vansteenkiste, MD, PhD, is holder of the Eli-Lilly Chair in Respiratory Oncology at the Leuven University (research funding). The other authors declare no conflict of interest. Address for correspondence: Johan Vansteenkiste, MD, PhD, Respiratory Oncology Unit (Pulmonology), University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected] Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0708-1291
N
on–small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. The majority of patients present with advanced disease, for which four to six cycles of platinum-doublet chemotherapy is the standard first-line treatment for those with a good performance status (PS).1 This approach is beneficial in terms of survival, symptom control, and quality of life (QoL), but long-term survival rates remain poor. Recent strategies to improve on the classical platinumdoublet chemotherapy are customizing chemotherapy by histological subtype (pemetrexed for nonsquamous tumors),2 adding a monoclonal antibody to the chemotherapy (bevacizumab and3,4 cetuximab),5 or personalizing treatment by the use of targeted agents in molecularly selected subgroups of oncogene-driven tumors, such as NSCLC harboring, for example, an activating endothelial growth factor receptor mutation6 or an echinoderm microtubule-associated proteinlike 4-anaplastic lymphoma kinase translocation.7 Given the observation that most of the patients who obtain disease control experience disease progression only 2 to 3 months after the end of first-line chemotherapy, maintenance treatment (MT) is another strategy that gained much interest over the last years. The principle of MT is to try to prolong disease control obtained with first-line chemotherapy by additional therapy, in an attempt to improve overall survival (OS), with preserved QoL. MT can be either prolongation of a drug already used in the first-line treatment (so-called “continuation” MT), or early introduction of another non–cross-resistant agent (“switch” or consolidation MT). Until a few years ago, no MT studies could show an OS benefit. One of the reasons was that the toxicity profile of the drugs used impeded long-term administration (e.g., neurotoxicity with prolonged paclitaxel).8 Two recent switch MT studies, using better-tolerated agents— pemetrexed9 or erlotinib10—have shown significant OS benefit and have changed our treatment paradigm (Table 1). They were the basis for this investigation. Indeed, in the noncurative context of metastatic NSCLC, the benefits of MT also need to be weighed against factors such as cumulative toxicity, cost, and patients’ compliance. Therefore, the patients’ opinion must be critically considered. In the lack of structured data
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TABLE 1. Core Data of Two Recent Large Phase III Studies on Maintenance Therapy That Reported Significant Overall Survival Benefits First author/ Study Acronym
Comparison Maintenance
Number Randomized
Median OS HR (95% CI)
Ciuleanu JMEN9
Pemetrexed Placebo
441 222
Erlotinib Placebo
438 451
13.4 mo 10.6 mo 0.79 (0.65–0.95) 12.0 mo 11.0 mo 0.81 (0.70–0.95)
Capuzzo SATURN10
OS, overall survival; HR, hazard ratio; 95% CI, 95% confidence interval; mo: months.
on this aspect, we developed this pilot protocol to explore patients’ attitudes.
PATIENTS AND METHODS Our objective was to evaluate patients’ attitudes toward MT at the start of first-line chemotherapy and at different times during treatment. Included patients had stage IV NSCLC (7th tumor, node, metastasis classification)11 of all histological subtypes and were scheduled to start first-line platinum-based doublet chemotherapy. Exclusion criteria were participation in a therapeutic clinical trial, non-Dutch–speaking patients, and patients unsuitable for repeated questionnaires, in the opinion of the treating respiratory oncologist. A questionnaire was set up by respiratory oncologists, a psychologist, and data managers working at the Respiratory Oncology Unit of the Leuven tertiary academic center. The questionnaire was a two-page document with 10 questions on MT. First, a brief and simple summary of the JMEN9 and Sequential Tarceva in Unresectable NSCLC (SATURN)10 study findings was listed. Question 1 then addressed the patient’s overall opinion on MT as receiving further treatment immediately after first-line treatment versus preference of a treatment-free period with careful follow-up. In the latter case, the reason was asked and the questionnaire ended there. When patients considered MT, another eight questions with a “yes,” “no,” or “don’t know” choice followed. Four questions examined acceptance of MT in case of an expected median OS benefit of 1 year, 6 months, 3 months, or 1 month, respectively; one question examined prolonged symptom relief in the absence of expected OS benefit, and one prolonged radiological tumor stabilization in the absence of both expected OS benefit or effect on symptoms. The next two questions were related to the maintenance drug itself: acceptance of MT with a once-in-3-weeks intravenous (i.v.) administration (referring to the JMEN trial); or with a daily oral drug and monthly outpatient control visit (referring to the SATURN trial). Question 10 dealt with possible side effects, and here the answers were acceptance of MT in case of no, mild, moderate, or severe side effects (4-point Likert scale). Nausea and fatigue were chosen as two important possible side effects of pemetrexed, whereas diarrhea and skin rash were taken as side effects for erlotinib. A full version of the questionnaire is presented as
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Supplemental Appendix (Supplemental Digital Content 1, http://links.lww.com/JTO/A290). The questionnaire was given to patients by a colleague (L.P.) not involved in any treatment decision. She explained that the questionnaire was hypothetical, i.e., would not affect any treatment decision, because MT was not reimbursed in Belgium during the time interval of the study. She provided explanation of questions when asked, but did not interfere in completion of the form by the patients. Patients were asked to fill in the questionnaire at three time points: at the start of first-line chemotherapy (time point T0), after two cycles of chemotherapy (T1), and after four (T2) cycles of chemotherapy. At T1 and T2, the questionnaire was completed before the results of computed tomography tumor evaluation were communicated to the patient. The protocol was approved by our institutional review board and patients gave informed consent.
RESULTS In the pilot phase, 30 eligible patients started with the questionnaire between May 2010 and July 2011. They were a typical cross-section of our nontrial patients starting chemotherapy for stage IV NSCLC: sex was well balanced (13 women and 17 men), and median age was 66 years (range, 32–79). Twenty-five patients had nonsquamous histology and five squamous histology. PS was 0–1 in 28 patients; two patients had a PS of 2. Disease control was obtained after four cycles of chemotherapy in 60% of patients. The flow of patients is illustrated in Figure 1. At T0, 60% of the patients were in favor of MT, 40% were unsure (Fig. 2). At T1, about two-thirds were in favor, with six of 27 undecided, and three no longer considering MT. The reason given by these three patients were: toxicities during the first two cycles and the wish for a period of rest after first-line treatment; they ended the questionnaire after question 1 at that time point. At T2, we saw a similar attitude, with two-thirds of the patients still in favor and one-third undecided.
FIGURE 1. Flow chart of the patients. Time points are start of first-line chemotherapy (T0), after two cycles (T1), and after four cycles (T2). *At T1, three patients answered “no” to the first question, and did not complete the next nine questions.
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 7, Number 8, August 2012
FIGURE 2. Answers to the general question “Do you think maintenance therapy is worthwhile?” T0, time at start of first-line chemotherapy; T1, after two cycles of chemotherapy; T2, after four cycles of chemotherapy.
FIGURE 3. Answers to questions regarding whether maintenance therapy would be worthwhile in relation to different predefined expected overall survival benefits. T0, time at start of first-line chemotherapy; T1, after two cycles of chemotherapy; T2, after four cycles of chemotherapy; OS, overall survival; mo, months.
Questions on expected benefits from MT are depicted in Figure 3. The majority of patients considered MT for an expected OS benefit of 6 months to 1 year, and this at all three time points. An OS benefit of 3 months was acceptable for two-thirds at T0, but decreased slightly to 56% at T2, whereas one-third of respondents no longer considered MT at T2. The median OS benefit of 1 month was appealing for only 13 of 30 at T0, and this decreased further at T1 and T2. No increase in OS but longer symptom relief by MT was important for a large majority of patients consistently throughout the study period (26 of 30, 19 of 24, and 16 of 18 at T0, T1, and T2, respectively) (Fig. 4). Radiological tumor control—even in the absence of OS benefit or symptom benefit—was of high importance for 80% of the patients at T0 and T1, decreasing to 67% after four cycles of chemotherapy. Questions concerning the administration schedule indicate that both i.v. and oral MT were well accepted, with a slight preference for oral medication (Fig. 5). This attitude was constant over time for oral treatment (about 90% at all
Maintenance Therapy: Patients’ Perceptions
FIGURE 4. Answers to questions regarding whether maintenance therapy would be worthwhile if there would be no survival difference, but benefit in symptom control or imaging findings. T0, time at start of first-line chemotherapy; T1, after two cycles of chemotherapy; T2, after four cycles of chemotherapy.
FIGURE 5. Answers to questions regarding whether maintenance therapy would be worthwhile in relation to the mode of administration. T0, time at start of first-line chemotherapy; T1, after two cycles of chemotherapy; T2, after four cycles of chemotherapy. i.v., intravenous; Q3wk, every 3 weeks; OD, once daily.
time points), whereas for the i.v. administration, there was an increase in acceptance once the patients had experienced some cycles of first-line chemotherapy. The last question asked which grade of typical side effects of MT (nausea, fatigue, diarrhea, and skin rash, respectively) patients would accept during MT. About 10% to 15% would accept MT only in case of no side effects. About 75% to 80% of the patients would accept it in case of mild-to-moderate grade side effects, whereas 5% to 10% would accept it even in case of severe side effects. These findings were constant over time.
DISCUSSION Several strategies have recently been developed to improve OS, symptom control, and QoL in patients with advanced NSCLC. One of these, MT, is the prolonged
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administration of a cytotoxic or targeted agent beyond the standard four to six cycles of first-line chemotherapy. Given the noncurative nature of treatment in advanced NSCLC, benefits need to be weighed against burden. Potential patients’ benefits are rewarding median OS differences (e.g., 5.2 months in patients with nonsquamous tumors in the JMEN trial),9 together with manageable side effects, and preservation, i.e., no worsening, of QoL. Possible burden for patients constitutes of toxicity of continued administration, absence of QoL improvement in each of the trials, and higher intensity of hospital or outpatient contacts. Even when recent randomized MT studies point at possible factors to select patients for MT—e.g., PS or tumor response after first-line treatment12—the choice for the patient remains between MT or close follow-up and timely/appropriate use of second-line therapy. Consequently, the patients’ preferences should be taken into account in the treatment strategy, but there are very little data on this question. This study wanted to offer pilot data on this issue. We had a short timeframe during which we could perform the survey in a “neutral” hypothetical context—i.e., without possible treatment consequences—as MT was not approved in Belgium during the study interval. This was made very clear to the patients when they agreed to participate in the questionnaire. Overall, patients had a positive attitude toward MT, with a little increase of the proportion of questioned patients over time (60% at baseline and 67% after four cycles). Patients favorable to MT were questioned regarding a “nonrealistic” median OS benefit of 1 year, a “high” OS benefit of 6 months, a “realistic” benefit of 3 months, and a “small” benefit of 1 month only. Not surprisingly, the benefits at 1 year and 6 months were convincing enough for the vast majority of patients to undergo MT. Three months was acceptable for two-thirds, decreasing to about half, and 1 month was appealing for less than half the patients, decreasing to onethird during first-line therapy. Change over time is probably because of side effects of first-line treatment. This is of particular interest in relation to the currently available results of randomized controlled trials with documented OS benefits. Indeed, the SATURN trial proved a median OS benefit of 1 month with the use of erlotinib (12 versus 11 months for erlotinib versus placebo, respectively), whereas the JMEN trial showed a median OS benefit of 2.8 months in all patients (5.2 months in nonsquamous tumors). Our survey thus suggests that the majority of patients are in favor of MT only if the extra time is at least some months. Patients attached high value to symptom relief, even in the absence of survival benefit, at each time point. This is in line with the work of Silvestri et al.,13 who questioned patients scheduled for first-line chemotherapy regarding their attitude of acceptance of toxicity (mild versus severe) in relation to a certain OS benefit, and on their opinion on best supportive care compared with active chemotherapy treatment. Overall, patients valued symptom control much more than gain in survival. Only about one-fifth of the patients would choose chemotherapy for a likely benefit in survival of 3 months, but most of them (68%) would do so if QoL was improved, even without prolongation of life.
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The ability of first-line chemotherapy to improve symptoms in most patients with disease response, and quite some with disease stabilization, is well defined.14 Patients randomized into MT trials demonstrated disease control after firstline treatment and therefore little additional symptom control is expected, but the aim of MT is to defer symptom deterioration by prolonging a therapy with mild toxicity. According to our results, this prolonged symptom control or delay of time to worsening of symptoms is very important for patients with metastatic NSCLC. We added the question of whether patients valued radiological stabilization in the absence of OS benefit as a patient-oriented surrogate for the clinical trial endpoint of progression-free survival. Interestingly, patients were clearly in favor of this aim of MT. This probably reflects the assumption of patients that—if imaging remains stable—so will their clinical condition. Although one could hypothesize that, in a life-threatening disease, survival gain is probably what matters the most to patients, it seems that avoiding further clinical deterioration is valued as well. At baseline, the oral mode of administration of the MT agent was preferred to the i.v. route (90% versus 67%). Intravenous administration became more acceptable during ongoing cycles of chemotherapy, which may reflect that some patients experienced the (symptom) benefits and good tolerability of chemotherapy after a few cycles. Overall, acceptance of side effects was high, as long as these were of mild or moderate grades (75% of patients). This survey is a pilot investigation on the patients’ attitude toward MT in a clinical setting where MT was not reimbursed. We realize there are many limitations to this work, but it may—in the current absence of further data on this important question—inspire future patient-oriented research on MT. First, our patient numbers are small, not allowing definitive conclusions. Second, this survey does not reflect the situation of MT patients per se, as only patients with disease control after first-line chemotherapy will be considered for MT. Third, each question was analyzed as a single entity, whereas the effects surveyed by the questions could be interrelated, but the small numbers did not allow further analysis. Last, as there is an inevitable drop-out in all studies of stage IV NSCLC populations, the answers to the questions during the course of firstline therapy reflect the opinion of the nonprogressive patients with a reasonable tolerance of treatment, and thus may be too positive. We nonetheless believe that our study holds precious information for colleagues who have to discuss this issue in daily practice with their patients. It reminds us that patients suffering from a lethal disease such as advanced NSCLC can view the purpose of MT in a different way than doctors do, and place personal, subjective factors above “expected gains” from clinical trials. In conclusion, our survey indicates that a majority of patients have a rather positive attitude toward MT, especially if the expected survival benefit is at least several months. Even in the absence of OS benefit, patients attach high value to delay of symptom worsening or even mere radiological disease stabilization. The overall attitude did not change much over the course of first-line chemotherapy.
Copyright © 2012 by the International Association for the Study of Lung Cancer
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REFERENCES 1. Felip E, Gridelli C, Baas P, Rosell R, Stahel R; Panel Members. Metastatic non-small-cell lung cancer: consensus on pathology and molecular tests, first-line, second-line, and third-line therapy: 1st ESMO Consensus Conference in Lung Cancer; Lugano 2010. Ann Oncol 2011;22:1507–1519. 2. Scagliotti G, Brodowicz T, Shepherd FA, et al. Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J Thorac Oncol 2011;6:64–70. 3. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–2550. 4. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009;27:1227–1234. 5. Pirker R, Pereira JR, Szczesna A, et al. FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009;373:1525–1531. 6. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–957. 7. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363: 1693–1703.
Maintenance Therapy: Patients’ Perceptions
8. Socinski MA, Schell MJ, Peterman A, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 2002;20:1335–1343. 9. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for nonsmall-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009;374:1432–1440. 10. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. SATURN investigators. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010;11:521–529. 11. Goldstraw P, Crowley J, Chansky K, et al. International Association for the Study of Lung Cancer International Staging Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007;2:706–714. 12. Sibille A, Wauters I, Vansteenkiste J. Maintenance therapy for advanced non-small-cell lung cancer: ready for clinical practice? Expert Rev Anticancer Ther 2012;12:529–539. 13. Silvestri G, Pritchard R, Welch HG. Preferences for chemotherapy in patients with advanced non-small cell lung cancer: descriptive study based on scripted interviews. BMJ 1998;317:771–775. 14. Dooms CA, Pat KE, Vansteenkiste JF. The effect of chemotherapy on symptom control and quality of life in patients with advanced non-small cell lung cancer. Expert Rev Anticancer Ther 2006;6:531–544.
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Maintenance Therapy for Advanced Non–Small-Cell Lung Cancer A Pilot Study on Patients’ Perceptions Lies Peeters, RN, Anne Sibille, MD, Bea Anrys, RN, Christel Oyen, RN, Christophe Dooms, MD, PhD, Kristiaan Nackaerts, MD, PhD, Isabelle Wauters, MD, and Johan Vansteenkiste, MD, PhD
Introduction: Several randomized trials on maintenance therapy (MT) for metastatic non–small-cell lung cancer (NSCLC) have demonstrated benefit in progression-free survival. More recently, a study with pemetrexed and one with erlotinib also showed significant gains in overall survival (OS). Yet, in this palliative treatment setting, the benefit has to be weighed against the potential burden of treatment, and thus patients’ preferences should be taken into account. Methods: In the absence of data on this topic, we undertook a pilot survey with 10 questions covering the overall patient attitude toward MT, the benefit expected by patients, and the acceptance of side effects or modes of administration. Included patients had stage IV NSCLC and were planned to start first-line platinum-based doublet chemotherapy. The questionnaire was submitted at the start of and after two and four cycles of chemotherapy. Results: Thirty patients were included. Overall, patients had a positive attitude toward MT. At baseline, it was considered worthwhile by 83%, 67%, and 43% of patients for an OS benefit of 6, 3, or 1 month, respectively, with some decrease over time. Effects on symptom control were crucial for about 90% of the patients. There was a slight preference for oral versus intravenous administration. Side effects were accepted by most patients as long as they were mild to moderate. Conclusion: Our pilot survey showed that metastatic NSCLC patients in general are in favor of MT. They expect either an OS benefit of at least several months, or better symptom control, in balance with mild-to-moderate side effects. Key Words: Non–small-cell lung cancer, Maintenance treatment, Patients’ attitudes, Chemotherapy, Targeted therapy, Questionnaires. (J Thorac Oncol. 2012;7: 1291–1295)
Respiratory Oncology Unit (Pulmonology) and Leuven Lung Cancer Group, University Hospital Gasthuisberg, Leuven, Belgium. Disclosure: Johan Vansteenkiste, MD, PhD, is holder of the Eli-Lilly Chair in Respiratory Oncology at the Leuven University (research funding). The other authors declare no conflict of interest. Address for correspondence: Johan Vansteenkiste, MD, PhD, Respiratory Oncology Unit (Pulmonology), University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected] Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0708-1291
N
on–small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. The majority of patients present with advanced disease, for which four to six cycles of platinum-doublet chemotherapy is the standard first-line treatment for those with a good performance status (PS).1 This approach is beneficial in terms of survival, symptom control, and quality of life (QoL), but long-term survival rates remain poor. Recent strategies to improve on the classical platinumdoublet chemotherapy are customizing chemotherapy by histological subtype (pemetrexed for nonsquamous tumors),2 adding a monoclonal antibody to the chemotherapy (bevacizumab and3,4 cetuximab),5 or personalizing treatment by the use of targeted agents in molecularly selected subgroups of oncogene-driven tumors, such as NSCLC harboring, for example, an activating endothelial growth factor receptor mutation6 or an echinoderm microtubule-associated proteinlike 4-anaplastic lymphoma kinase translocation.7 Given the observation that most of the patients who obtain disease control experience disease progression only 2 to 3 months after the end of first-line chemotherapy, maintenance treatment (MT) is another strategy that gained much interest over the last years. The principle of MT is to try to prolong disease control obtained with first-line chemotherapy by additional therapy, in an attempt to improve overall survival (OS), with preserved QoL. MT can be either prolongation of a drug already used in the first-line treatment (so-called “continuation” MT), or early introduction of another non–cross-resistant agent (“switch” or consolidation MT). Until a few years ago, no MT studies could show an OS benefit. One of the reasons was that the toxicity profile of the drugs used impeded long-term administration (e.g., neurotoxicity with prolonged paclitaxel).8 Two recent switch MT studies, using better-tolerated agents— pemetrexed9 or erlotinib10—have shown significant OS benefit and have changed our treatment paradigm (Table 1). They were the basis for this investigation. Indeed, in the noncurative context of metastatic NSCLC, the benefits of MT also need to be weighed against factors such as cumulative toxicity, cost, and patients’ compliance. Therefore, the patients’ opinion must be critically considered. In the lack of structured data
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TABLE 1. Core Data of Two Recent Large Phase III Studies on Maintenance Therapy That Reported Significant Overall Survival Benefits First author/ Study Acronym
Comparison Maintenance
Number Randomized
Median OS HR (95% CI)
Ciuleanu JMEN9
Pemetrexed Placebo
441 222
Erlotinib Placebo
438 451
13.4 mo 10.6 mo 0.79 (0.65–0.95) 12.0 mo 11.0 mo 0.81 (0.70–0.95)
Capuzzo SATURN10
OS, overall survival; HR, hazard ratio; 95% CI, 95% confidence interval; mo: months.
on this aspect, we developed this pilot protocol to explore patients’ attitudes.
PATIENTS AND METHODS Our objective was to evaluate patients’ attitudes toward MT at the start of first-line chemotherapy and at different times during treatment. Included patients had stage IV NSCLC (7th tumor, node, metastasis classification)11 of all histological subtypes and were scheduled to start first-line platinum-based doublet chemotherapy. Exclusion criteria were participation in a therapeutic clinical trial, non-Dutch–speaking patients, and patients unsuitable for repeated questionnaires, in the opinion of the treating respiratory oncologist. A questionnaire was set up by respiratory oncologists, a psychologist, and data managers working at the Respiratory Oncology Unit of the Leuven tertiary academic center. The questionnaire was a two-page document with 10 questions on MT. First, a brief and simple summary of the JMEN9 and Sequential Tarceva in Unresectable NSCLC (SATURN)10 study findings was listed. Question 1 then addressed the patient’s overall opinion on MT as receiving further treatment immediately after first-line treatment versus preference of a treatment-free period with careful follow-up. In the latter case, the reason was asked and the questionnaire ended there. When patients considered MT, another eight questions with a “yes,” “no,” or “don’t know” choice followed. Four questions examined acceptance of MT in case of an expected median OS benefit of 1 year, 6 months, 3 months, or 1 month, respectively; one question examined prolonged symptom relief in the absence of expected OS benefit, and one prolonged radiological tumor stabilization in the absence of both expected OS benefit or effect on symptoms. The next two questions were related to the maintenance drug itself: acceptance of MT with a once-in-3-weeks intravenous (i.v.) administration (referring to the JMEN trial); or with a daily oral drug and monthly outpatient control visit (referring to the SATURN trial). Question 10 dealt with possible side effects, and here the answers were acceptance of MT in case of no, mild, moderate, or severe side effects (4-point Likert scale). Nausea and fatigue were chosen as two important possible side effects of pemetrexed, whereas diarrhea and skin rash were taken as side effects for erlotinib. A full version of the questionnaire is presented as
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Supplemental Appendix (Supplemental Digital Content 1, http://links.lww.com/JTO/A290). The questionnaire was given to patients by a colleague (L.P.) not involved in any treatment decision. She explained that the questionnaire was hypothetical, i.e., would not affect any treatment decision, because MT was not reimbursed in Belgium during the time interval of the study. She provided explanation of questions when asked, but did not interfere in completion of the form by the patients. Patients were asked to fill in the questionnaire at three time points: at the start of first-line chemotherapy (time point T0), after two cycles of chemotherapy (T1), and after four (T2) cycles of chemotherapy. At T1 and T2, the questionnaire was completed before the results of computed tomography tumor evaluation were communicated to the patient. The protocol was approved by our institutional review board and patients gave informed consent.
RESULTS In the pilot phase, 30 eligible patients started with the questionnaire between May 2010 and July 2011. They were a typical cross-section of our nontrial patients starting chemotherapy for stage IV NSCLC: sex was well balanced (13 women and 17 men), and median age was 66 years (range, 32–79). Twenty-five patients had nonsquamous histology and five squamous histology. PS was 0–1 in 28 patients; two patients had a PS of 2. Disease control was obtained after four cycles of chemotherapy in 60% of patients. The flow of patients is illustrated in Figure 1. At T0, 60% of the patients were in favor of MT, 40% were unsure (Fig. 2). At T1, about two-thirds were in favor, with six of 27 undecided, and three no longer considering MT. The reason given by these three patients were: toxicities during the first two cycles and the wish for a period of rest after first-line treatment; they ended the questionnaire after question 1 at that time point. At T2, we saw a similar attitude, with two-thirds of the patients still in favor and one-third undecided.
FIGURE 1. Flow chart of the patients. Time points are start of first-line chemotherapy (T0), after two cycles (T1), and after four cycles (T2). *At T1, three patients answered “no” to the first question, and did not complete the next nine questions.
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 7, Number 8, August 2012
FIGURE 2. Answers to the general question “Do you think maintenance therapy is worthwhile?” T0, time at start of first-line chemotherapy; T1, after two cycles of chemotherapy; T2, after four cycles of chemotherapy.
FIGURE 3. Answers to questions regarding whether maintenance therapy would be worthwhile in relation to different predefined expected overall survival benefits. T0, time at start of first-line chemotherapy; T1, after two cycles of chemotherapy; T2, after four cycles of chemotherapy; OS, overall survival; mo, months.
Questions on expected benefits from MT are depicted in Figure 3. The majority of patients considered MT for an expected OS benefit of 6 months to 1 year, and this at all three time points. An OS benefit of 3 months was acceptable for two-thirds at T0, but decreased slightly to 56% at T2, whereas one-third of respondents no longer considered MT at T2. The median OS benefit of 1 month was appealing for only 13 of 30 at T0, and this decreased further at T1 and T2. No increase in OS but longer symptom relief by MT was important for a large majority of patients consistently throughout the study period (26 of 30, 19 of 24, and 16 of 18 at T0, T1, and T2, respectively) (Fig. 4). Radiological tumor control—even in the absence of OS benefit or symptom benefit—was of high importance for 80% of the patients at T0 and T1, decreasing to 67% after four cycles of chemotherapy. Questions concerning the administration schedule indicate that both i.v. and oral MT were well accepted, with a slight preference for oral medication (Fig. 5). This attitude was constant over time for oral treatment (about 90% at all
Maintenance Therapy: Patients’ Perceptions
FIGURE 4. Answers to questions regarding whether maintenance therapy would be worthwhile if there would be no survival difference, but benefit in symptom control or imaging findings. T0, time at start of first-line chemotherapy; T1, after two cycles of chemotherapy; T2, after four cycles of chemotherapy.
FIGURE 5. Answers to questions regarding whether maintenance therapy would be worthwhile in relation to the mode of administration. T0, time at start of first-line chemotherapy; T1, after two cycles of chemotherapy; T2, after four cycles of chemotherapy. i.v., intravenous; Q3wk, every 3 weeks; OD, once daily.
time points), whereas for the i.v. administration, there was an increase in acceptance once the patients had experienced some cycles of first-line chemotherapy. The last question asked which grade of typical side effects of MT (nausea, fatigue, diarrhea, and skin rash, respectively) patients would accept during MT. About 10% to 15% would accept MT only in case of no side effects. About 75% to 80% of the patients would accept it in case of mild-to-moderate grade side effects, whereas 5% to 10% would accept it even in case of severe side effects. These findings were constant over time.
DISCUSSION Several strategies have recently been developed to improve OS, symptom control, and QoL in patients with advanced NSCLC. One of these, MT, is the prolonged
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administration of a cytotoxic or targeted agent beyond the standard four to six cycles of first-line chemotherapy. Given the noncurative nature of treatment in advanced NSCLC, benefits need to be weighed against burden. Potential patients’ benefits are rewarding median OS differences (e.g., 5.2 months in patients with nonsquamous tumors in the JMEN trial),9 together with manageable side effects, and preservation, i.e., no worsening, of QoL. Possible burden for patients constitutes of toxicity of continued administration, absence of QoL improvement in each of the trials, and higher intensity of hospital or outpatient contacts. Even when recent randomized MT studies point at possible factors to select patients for MT—e.g., PS or tumor response after first-line treatment12—the choice for the patient remains between MT or close follow-up and timely/appropriate use of second-line therapy. Consequently, the patients’ preferences should be taken into account in the treatment strategy, but there are very little data on this question. This study wanted to offer pilot data on this issue. We had a short timeframe during which we could perform the survey in a “neutral” hypothetical context—i.e., without possible treatment consequences—as MT was not approved in Belgium during the study interval. This was made very clear to the patients when they agreed to participate in the questionnaire. Overall, patients had a positive attitude toward MT, with a little increase of the proportion of questioned patients over time (60% at baseline and 67% after four cycles). Patients favorable to MT were questioned regarding a “nonrealistic” median OS benefit of 1 year, a “high” OS benefit of 6 months, a “realistic” benefit of 3 months, and a “small” benefit of 1 month only. Not surprisingly, the benefits at 1 year and 6 months were convincing enough for the vast majority of patients to undergo MT. Three months was acceptable for two-thirds, decreasing to about half, and 1 month was appealing for less than half the patients, decreasing to onethird during first-line therapy. Change over time is probably because of side effects of first-line treatment. This is of particular interest in relation to the currently available results of randomized controlled trials with documented OS benefits. Indeed, the SATURN trial proved a median OS benefit of 1 month with the use of erlotinib (12 versus 11 months for erlotinib versus placebo, respectively), whereas the JMEN trial showed a median OS benefit of 2.8 months in all patients (5.2 months in nonsquamous tumors). Our survey thus suggests that the majority of patients are in favor of MT only if the extra time is at least some months. Patients attached high value to symptom relief, even in the absence of survival benefit, at each time point. This is in line with the work of Silvestri et al.,13 who questioned patients scheduled for first-line chemotherapy regarding their attitude of acceptance of toxicity (mild versus severe) in relation to a certain OS benefit, and on their opinion on best supportive care compared with active chemotherapy treatment. Overall, patients valued symptom control much more than gain in survival. Only about one-fifth of the patients would choose chemotherapy for a likely benefit in survival of 3 months, but most of them (68%) would do so if QoL was improved, even without prolongation of life.
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The ability of first-line chemotherapy to improve symptoms in most patients with disease response, and quite some with disease stabilization, is well defined.14 Patients randomized into MT trials demonstrated disease control after firstline treatment and therefore little additional symptom control is expected, but the aim of MT is to defer symptom deterioration by prolonging a therapy with mild toxicity. According to our results, this prolonged symptom control or delay of time to worsening of symptoms is very important for patients with metastatic NSCLC. We added the question of whether patients valued radiological stabilization in the absence of OS benefit as a patient-oriented surrogate for the clinical trial endpoint of progression-free survival. Interestingly, patients were clearly in favor of this aim of MT. This probably reflects the assumption of patients that—if imaging remains stable—so will their clinical condition. Although one could hypothesize that, in a life-threatening disease, survival gain is probably what matters the most to patients, it seems that avoiding further clinical deterioration is valued as well. At baseline, the oral mode of administration of the MT agent was preferred to the i.v. route (90% versus 67%). Intravenous administration became more acceptable during ongoing cycles of chemotherapy, which may reflect that some patients experienced the (symptom) benefits and good tolerability of chemotherapy after a few cycles. Overall, acceptance of side effects was high, as long as these were of mild or moderate grades (75% of patients). This survey is a pilot investigation on the patients’ attitude toward MT in a clinical setting where MT was not reimbursed. We realize there are many limitations to this work, but it may—in the current absence of further data on this important question—inspire future patient-oriented research on MT. First, our patient numbers are small, not allowing definitive conclusions. Second, this survey does not reflect the situation of MT patients per se, as only patients with disease control after first-line chemotherapy will be considered for MT. Third, each question was analyzed as a single entity, whereas the effects surveyed by the questions could be interrelated, but the small numbers did not allow further analysis. Last, as there is an inevitable drop-out in all studies of stage IV NSCLC populations, the answers to the questions during the course of firstline therapy reflect the opinion of the nonprogressive patients with a reasonable tolerance of treatment, and thus may be too positive. We nonetheless believe that our study holds precious information for colleagues who have to discuss this issue in daily practice with their patients. It reminds us that patients suffering from a lethal disease such as advanced NSCLC can view the purpose of MT in a different way than doctors do, and place personal, subjective factors above “expected gains” from clinical trials. In conclusion, our survey indicates that a majority of patients have a rather positive attitude toward MT, especially if the expected survival benefit is at least several months. Even in the absence of OS benefit, patients attach high value to delay of symptom worsening or even mere radiological disease stabilization. The overall attitude did not change much over the course of first-line chemotherapy.
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