- © 1999 by American Society of Clinical Oncology
Subjective and Objective Prospective, Long-Term Analysis of Quality of Life During Inhaled Interleukin-2 Immunotherapy
- From the Department of Urology, University of Hamburg, and University Clinic Eppendorf, Hamburg, Germany.
- Address reprint requests to Hans Heinzer, MD, Department of Urology, University Clinic Eppendorf, Martinistr 52, 20246 Hamburg, Germany; email heinzer{at}uhr.uni-hamburg.de
Abstract
PURPOSE: We conducted both a subjective and objective, prospective quality-of-life analysis during high-dose (36 × 106 immunizing units/d) inhalational interleukin (IL)-2 treatment (mean treatment time, 13.4 months) of 15 patients with metastatic renal cell carcinoma (mRCC). Additionally, quality of life for 10 patients with mRCC receiving low-dose (9 × 106 IU/m2/d for 5 days) intravenous IL-2 treatment also was evaluated.
PATIENTS AND METHODS: Patients responded to the European Organization for Research and Treatment of Cancer quality-of-life questionnaire QLQ-C30 before and during inhalational IL-2 treatment at 1, 3, 6, 9, and 12 months and before and once during intravenous IL-2 treatment. A clinician assessed patient well-being using the Quality of Well-Being scale to calculate once weekly quality-adjusted life-years (QALYs) during inhalational IL-2 treatment.
RESULTS: Patients completed 103 questionnaires and clinicians performed 892 QALY calculations. For patients treated with inhalational IL-2, the mean quality-of-life score deteriorated modestly but significantly 1 month after treatment initiation (15.1%, P = .01) but did not differ significantly from pretreatment scores after 3, 6, 9, and 12 months of treatment. Inhalational IL-2 therapy stabilized patient quality of life for a mean of 13.4 months. The resulting QALY calculation for patients on inhalation IL-2 was 70.1% of 13.4 months, representing 9.4 months of QALY. In comparison, patients who received intravenous IL-2 showed a more marked, statistically significant deterioration in mean quality-of-life score during treatment (27%, P = .006); moreover, three of these 10 patients experienced treatment-related toxicity that prevented questionnaire completion.
CONCLUSION: Quality-of-life analysis during immunotherapy provides valuable information regarding cancer treatment outcomes.
TREATMENT OF METASTATIC renal cell cancer (mRCC) with interleukin (IL)-2 has been shown to be effective for some patients.1,2 Treatment administered by constant or bolus intravenous infusion3-5 or by subcutaneous injection6-9 results in objective response rates of 10% to 30%. However, such immunotherapy is limited by severe, dose-dependant side effects10-12 and is tolerated by only select patients having no comorbidities. The median duration of objective response in these patients is approximately 12 months, and long-lasting complete remission in metastatic renal cell carcinoma after immunotherapy is rare.8,13
Experimental14 and clinical treatment models15 show that continuous topical IL-2 application (avoiding delivery through the vascular system), even in high doses, has minimal toxicity when compared with systemic treatment. Similarly, clinical studies have demonstrated that local IL-2 application by inhalation for patients with pulmonary mRCC is effective and associated with low toxicity,16-18 the latter presumably reflecting minimal absorption of the cytokine into the bloodstream after inhalation.
It is becoming increasingly accepted that, in addition to traditional measurements of therapeutic outcome, such as tumor response, time to progression, and disease-free and overall survival, quality-of-life assessments are essential in the clinical evaluation of advanced cancer treatments.19 However, limited information is available about the quality of life experienced by advanced cancer patients receiving IL-2 immunotherapy. Joffe et al20 described significant worsening of symptoms for patients receiving systemic combination immunotherapy consisting of IL-2, interferon-α, and fluorouracil, as assessed by the Rotterdam Symptom Check List.21 However, only a few questionnaires were completed, complicating the interpretation of the data. There was no reason given by the authors for the poor compliance in completing these questionnaires. Litwin et al22 retrospectively assessed health-related quality of life in a highly selected group of patients with advanced renal cell carcinoma who were treated with nephrectomy and tumor infiltrating lymphocyte therapy in combination with IL-2. General health-related quality of life was measured with a RAND 36-item Health Survey 1.0, and cancer-specific quality of life was evaluated using the Cancer Rehabilitation Evaluation System-Short Form. Renal cell cancer patients reported better health-related quality of life than patients with other malignancies and better physical function than patients with congestive heart failure. However, quality of life for these cancer patients was worse than that reported by the general population and similar to or worse than that determined for patients with hypertension or type 2 diabetes. The authors suggested several important limitations of this pilot study, including its retrospective, single-point nature, small sample size (n = 20), and a sampling strategy potentially biased toward the selection of the most fit and optimistic or the most ill and desperate survivors. They concluded that future prospective studies are necessary.
The most internationally recognized instrument for the evaluation of patient outcome in cancer research is the Quality-of-Life Questionnaire-C30 (QLQ-C30) developed by the European Organization for Research and Treatment of Cancer.23-25 Kaplan et al26,27 proposed a model based on the Quality of Well-Being scale (QWB) as a means of expressing a treatment effect as quality-adjusted life-years (QALYs). These units mathematically represent side effects and benefits of treatment by integrating into a single number mortality, morbidity, and duration of each health state. Using this method, it is possible to estimate the QALYs lost to cancer and those restored by cancer treatment.
The aim of this study was to evaluate the quality of life experienced by patients receiving high-dose inhalational IL-2 immunotherapy. To this end, we used the well-established QLQ-C30 questionnaire and QWB scale and calculated the patient QALYs. Additionally, using a nonrandomized approach, we evaluated changes in QLQ-C30 scores for patients who received systemic immunotherapy to examine score changes associated with low-dose systemic IL-2 treatment, which has acceptable toxicity and can be administered without intensive care. The quality-of-life measurements for patients receiving high-dose inhalational IL-2 immunotherapy were compared with those determined for patients receiving low-dose intravenous IL-2 immunotherapy.
PATIENTS AND METHODS
Inclusion Criteria
This study was approved by the University of Hamburg Review Board. Informed written consent was given by each patient before enrollment. Adult patients of either sex were eligible for the study. Patients who received inhalational IL-2 therapy had histologically confirmed renal cell carcinoma and documented progressive pulmonary or mediastinal metastases. Patients who received intravenous IL-2 therapy had histologically confirmed renal cell carcinoma and documented progressive disease. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 and organ function sufficient to meet protocol requirements.
Exclusion Criteria
With respect to intravenous IL-2 treatment, patients were not enrolled onto this study if they had an ECOG performance status greater than 2, a history or current evidence of severe cardiac disease, any pre-existing severe major organ dysfunction, CNS metastases, seizure disorders, or evidence of active infection. Patients with the simultaneous presence of an ECOG performance status greater than 1, more than one organ with metastatic disease sites, and a period of less than 24 months between initial diagnosis of primary tumor and study entry were excluded. Patients also were excluded if they had a known history of hypersensitivity to human recombinant IL-2, a partial pressure of oxygen less than 60 mmHg during rest, a WBC count less than 4,000/μL, a platelet count less than 100,000/μL, a hematocrit less than 30%, or serum bilirubin and creatinine levels outside the normal range.
With respect to inhalational IL-2 treatment, patients were disallowed from study participation if they had clinically significant cardiac diseases, serious active infections (including human immunodeficiency virus infection and infectious hepatitis), or inoperable CNS metastases. Regardless of IL-2 treatment route, patients with organ allografts, likely to require corticosteroids, or with pre-existing autoimmune disease were excluded from this study.
High-Dose Inhalational IL-2 Therapy
Fifteen patients were treated consecutively with high-dose inhalational IL-2 and very low-dose systemic immunotherapy and observed prospectively. Treatment was performed as published previously.18 In brief, 36 × 106 immunizing units (IU) of IL-2 were given as a daily dose. Ninety percent of the dose was given by inhalation as five separate applications daily, and 10% was given by subcutaneous injection. Treatment was performed exclusively on an outpatient basis. Inhalation of IL-2 was performed with a Salvia Lifetec Jetair δ20 nebulizer (Hoyer, Bremen, Germany). Subcutaneous injections were administrated by the patients themselves. An additional dose of 15 × 106 IU/wk of interferon-α also was administered in most patients.
Low-Dose Intravenous IL-2 Therapy
Ten patients received a total of 13 cycles of low-dose intravenous IL-2 therapy. Treatment was performed exclusively on an inpatient basis. Intravenous recombinant IL-2 was given at a dose of 9 × 106/m2/d continuously for 5 days. Seven patients received a single cycle of treatment. Three patients received a second cycle of treatment 2 weeks after completing the first cycle.
Assessment of Toxicity
Patients were seen in our outpatient clinic or contacted by phone every week for a detailed evaluation of side effects. A self-assessment score for toxicity was provided by patients once every week. Evaluation of toxicity was based on World Health Organization (WHO) criteria.28 WHO grade 3 toxicity led to 50% dose reduction until symptoms improved.
Treatment Duration, Toxicity, and Evaluation of Response
Response evaluations were performed as published previously,16-18 but, given the focus of this manuscript on patient quality of life, a description is beyond the scope of this manuscript. Measurement of response was based on WHO criteria28 and included a computerized tomography scan every 3 months. Treatment was continued unless the patient showed disease progression. Survival was measured from start of therapy to date of death or to the last known date to be living.
QLQ-C30 Questionnaire: Subjective Evaluation of Quality of Life
The QLQ-C30 questionnaire consists of 47 items that are answered by the patient without help or influence.29 Each item is scored from 1 to 2, 1 to 4, or 1 to 10 points, giving a possible range of total scores from 47 to 148. These scores provide information about quality of life independent of underlying factors (eg, tumor disease and side effects of treatment). A lower score represents a better quality of life. Thus, scores close to 47 reflect a largely unimpaired quality of life, whereas scores close to 148 reflect severe impairment. Consequently, a negative change from pretreatment score represents an improvement in quality of life with treatment.
The questionnaire permits the grouping of individual items into six functional domains: global symptoms (eg, pain, fatigue, and sleepiness), special symptoms (eg, lack of appetite, vomiting, and compromised sexual function [lack of interest or enjoyment]), psychologic distress, activities of daily living, intrusive thoughts regarding cancer, and interference with family/social life. Each patient of the inhalational treatment group completed a questionnaire before and during treatment at 1, 3, 6, 9, and 12 months. Patients of the intravenous treatment group completed the questionnaire before and once during treatment, at day 3 or 4 of the cycle. This interval was selected to evaluate patients receiving low-dose intravenous IL-2 treatment during the time of their predicted maximum immunostimulation and possible peak toxicity. This approach permitted comparison between the two treatment groups with respect to changes in quality-of-life scores.
Assessment of QALYs: Objective Evaluation of Quality of Life
Assessments of QALYs were conducted by the same doctor (T.S.M.) each time the patient was evaluated using the QWB scale.26 Symptoms and activities (symptom/problem component, mobility scale, physical scale, and social activity scale) for each patient were documented every week throughout the treatment. Because of relatively short treatment times, QALY assessments were not completed for patients receiving intravenous therapy. A two-tailed Mann-Whitney U test was used for statistical analysis of the data.
RESULTS
Patient demographic characteristics are summarized in Table 1. The group of patients receiving inhalational IL-2 therapy had a greater proportion of elderly and male patients when compared with the group receiving intravenous IL-2 therapy. Moreover, all patients receiving inhalational IL-2 had undergone a prior nephrectomy, whereas only 43% of the patients receiving intravenous IL-2 had undergone this procedure. However, both groups included similar proportions of patients characterized by specific risk factors and had a median ECOG performance status of 1.
Patient Demographic Characteristics
Treatment Duration and Toxicity
The 15 patients receiving inhalational IL-2 therapy were treated for a mean duration of 16.1 months (range, 4.5 to 30.2 months). One patient died 7 months after treatment initiation. Eight patients are still alive and five patients remain on treatment after completing the study. The majority of patients experienced cough as a local side effect of inhalation. Some patients experienced nausea (n = 4, 27%) and minor skin reactions (n = 6, 40%). Overall toxicity was mild to moderate in severity. No toxic death or severe toxicity was observed. No patient experienced any significant clinical manifestations of capillary leakage, such as pulmonary edema.
Toxicity with intravenous IL-2 treatment included anemia, fatigue, nausea, vomiting, diarrhea, flushing, sweating, rash, dry skin, desquamation, oliguria, edema, weight gain headaches, hypotension, elevated creatinine, and disorientation up to WHO grade 4 toxicity. No toxicity-associated death occurred. All side effects subsided within a few days of treatment discontinuation.
Evaluation of Questionnaires
Acceptance of the QLQ-C30 questionnaire was 100% for the patients receiving inhalational IL-2 treatment and 70% for patients treated with intravenous IL-2. A total of 83 QLQ-C30 questionnaires were completed by patients receiving inhalational IL-2. All 15 patients completed at least four questionnaires; most patients completed six questionnaires. All 15 patients completed questionnaires before IL-2 treatment and at 1, 3, and 6 months after the start of treatment. Fewer patients completed the questionnaire after 9 and 12 months of treatment; after 9 months, 12 patients completed the questionnaire, and, after 12 months, 11 patients continued treatment and were evaluated using the QLQ-C30.
Of the 10 patients receiving low-dose intravenous IL-2 treatment, seven patients who received a total of 10 treatment cycles completed the questionnaire. All seven patients completed the QLQ-C30 questionnaire both before and during 10 treatment cycles, resulting in 20 answered questionnaires. The remaining three patients, who received a total of three treatment cycles, refused to complete the questionnaire and to participate in the quality-of-life assessments during therapy because they did not feel well enough to do so given the side effects experienced with low-dose intravenous IL-2 treatment. The pretreatment (ie, baseline) quality-of-life scores for these three patients were not included in the analyses because no posttreatment scores were available for comparison.
Table 2 lists the overall results obtained with the QLQ-C30. The range of scores before IL-2 treatment varied widely for both the inhalation and intravenous groups (ranges, 52 to 79 and 49 to 93, respectively). Given the variability in QLQ-C30 scores, pretreatment scores were defined as 100%, and percentage changes from the pretreatment score were calculated accordingly, allowing for a comparison of change scores across patients and between treatment groups. Figure 1 illustrates the percentage change from pretreatment QLQ-C30 score as a function of IL-2 treatment type and duration. Patients treated with inhalational IL-2 showed a statistically significant 15% increase (ie, deterioration) in QLQ-C30 score after 1 month of treatment (P = .01), followed by a gradual decline (ie, improvement) in this score from the pretreatment score after 3, 6, and 9 months of treatment (Table 2, Fig 1). The differences between quality-of-life scores at each of these time points and the pretreatment score were not statistically significant. After 12 months of treatment, patients receiving inhalational IL-2 once again tended toward a larger increase (9%) in the QLQ-C30 score, but this deterioration in quality-of-life score was also not statistically significant. Patients treated with intravenous IL-2 exhibited a statistically significant increase (27%) in the QLQ-C30 score after treatment when compared with the pretreatment score (P = .0006), reflecting a marked deterioration in their quality of life with treatment (Table 2, Fig 1).
QLQ-C30 Quality-of-Life Questionnaire Evaluation of Patients Receiving IL-2 Immunotherapy
Percentage change (mean ± SD) from pretreatment QLQ-C30 questionnaire scores for patients with mRCC treated with IL-2. Positive changes represent a deterioration in quality-of-life score (*P < .05 v pretreatment score; Tx, treatment).
To determine which functional domains were most impacted by treatment-mediated changes in patient quality of life, the six specific QLQ-C30 domain scores were evaluated individually. The results are summarized diagrammatically in Fig 2. The decrease in quality of life experienced during the first months by patients treated with inhalational IL-2 mainly was attributable to a worsening of their global and special symptoms (Fig 2A and 2B). These patients also experienced a statistically significant deterioration (35%, P = .046 when compared with pretreatment score) in their ability to conduct a “normal” family/social life (Fig 2F). In contrast, the decrease in quality of life reported by patients during the first months of inhalational IL-2 treatment was less attributable to a change in ability to perform activities of daily living (Fig 2D) or the presence of intrusive thoughts regarding cancer (Fig 2E). Interestingly, the level of psychologic distress had a tendency to improve with inhalational IL-2 treatment, as reflected by improved scores when compared with pretreatment values (P = not significant; Fig 2C).
(A-F) Percentage change (mean ± SD) from pretreatment QLQ-C30 questionnaire specific functional domain scores for patients with mRCC treated with IL-2. Positive changes represent a deterioration in quality-of-life score (*P < .05 v pretreatment score; Tx, treatment).
Patients who received intravenous IL-2 treatment demonstrated a deterioration in quality-of-life scores for all six of the functional domains (Fig 2). A statistically significant (P < .05) deterioration in quality-of-life scores was observed for four of these six domains, including global and special symptoms (Fig 2A and 2B), psychologic distress (Fig 2C), and activities of daily living (Fig 2D).
QALYs
During a mean follow-up of 13.4 months (range, 5.6 to 22.4 months), QALY was assessed weekly in all patients receiving inhalational IL-2 therapy. A total of 892 calculations based on QWB scale scores were completed. For the symptom/problem component of the calculations, only 4.7% of the evaluations indicated the absence of symptoms. The most frequently observed symptoms in inhalation IL-2 patients were nausea (23%), fatigue (29%), cough (16%), and the need for co-medication (21%). Based on the mobility scale score, 96% of patients were unimpaired. The physical activity and the social activity scale scores revealed that 96% and 90% of patients, respectively, were unimpaired with regard to these functions. The mean QALY, based on the 892 calculations, was determined to be 9.4 months, corresponding to 70% of the follow-up time.
DISCUSSION
The 15 inhalation IL-2 patients evaluated by the current subjective and objective quality-of-life analyses are characterized by survival times comparable to those described previously for patients treated with inhalational IL-2.18 The current analyses provide information that is highly relevant to the quality of life experienced by patients during long-term inhalational IL-2 therapy.
The long-term treatment of patients with inhalational IL-2 requires the active and motivated cooperation of the patient, as well as a change in home life. This contrasts sharply with patient participation in systemic immunotherapies that are cyclic and relatively short in duration; systemic immunotherapies may impair the patient on the days of treatment but do not substantially impact the patient's life at home.
Intravenous IL-2 treatment is not an appropriate long-term therapy and, consequently, is not conducive to long-term quality-of-life evaluations. Nonetheless, to assess the effects of systemic immunotherapy on patient QLQ-C30 scores, we elected to include in a nonrandomized fashion 10 nonselected patients administered treatment with low-dose intravenous IL-2 (the given dose represents 50% of the dose approved in Europe for the treatment of mRCC). To date, no data have been published that describe the impact of inhalational or systemic IL-2 treatment on patient QLQ-C30 scores.
Because of the different treatment regimens used during systemic versus inhalational immunotherapy in the current study, patients treated with systemic IL-2 were assessed with respect to quality of life at day 3 or 4 of treatment, the time at which maximal immunostimulation may be predicted and peak toxicity expected. In contrast, patients treated with inhalational IL-2 were evaluated with respect to quality of life at 1, 3, 6, 9, and 12 months of therapy to generate data regarding long-term impairment. An evaluation of inhalational IL-2 treatment effect on quality of life after only a few days of treatment would not provide realistic information about the impairments caused by such treatment.
Because systemic and inhalational IL-2 treatment regimens are associated with different toxicity profiles, patients enrolled onto the study were subject to different inclusion and exclusion criteria. Consequently, patients receiving intravenous IL-2 treatment tended to be younger with a maximum age of 60 years, whereas nine of 15 patients receiving inhalational IL-2 treatment were more than 60 years of age. Furthermore, the two patient groups differed with respect to functional status, with more patients who received inhalational therapy versus systemic therapy tending to have a poorer status (ie, ECOG score = 0). Although we have no evidence that the differences in inclusion and exclusion criteria influenced the outcome of the analysis, we cannot dismiss this possibility. Thus, it is possible that differences among patients in age and/or performance status may influence patient acceptance of treatment-related toxicity, treatment modalities, and perception of quality of life. This could not be addressed in detail in the current study.
The aim of the current study was not to directly compare systemic versus inhalational IL-2 therapy as regards quality-of-life measures. It should be emphasized that these two treatment approaches are neither competitive nor mutually exclusive. Indeed, the two treatment approaches may be complementary. Treatment with inhalational IL-2 may intensify treatment with systemic IL-2, without augmenting adverse effects. Depending on the underlying disease and the patient's potential to withstand the toxicity associated with systemic therapies, inhalational IL-2 treatment may be combined with systemic immunotherapy, chemotherapy, or immunochemotherapy. Such therapeutic options have been reported to be viable for the treatment of different tumors metastasizing to the lung, including renal cell carcinoma, melanoma, breast cancer, and other primary malignancies.30
Clinical response rates with IL-2–based immunotherapies for mRCC are approximately 15%, and fewer than 5% of patients experience a long-lasting, complete remission. Therefore, for most patients, the more realistic clinical aim is to achieve tumor palliation with improved survival. As a result, quality-of-life issues become a critical clinical consideration. In 1993, it was suggested by the Outcomes Working Group of the American Society of Clinical Oncology that “patient outcomes (eg, survival and quality of life) should receive higher priority than cancer outcomes (eg, response rate) [when evaluating anticancer therapeutic strategies], but both types of outcomes are important in technology assessment and guideline development.”31 Such suggestions should help define a new standard when cancer treatments are being developed and assessed.
Long-term follow-up evaluations of cancer treatment with quality-of-life measures, such as the QLQ-C30 questionnaire and QALY calculations, have a high acceptance among patients. Quantified quality-of-life information is valuable for assessing the impact of immunotherapy on this important additional parameter of cancer treatment outcome. In the current study, the patients seemed to perceive the QLQ-C30 questionnaire positively, a finding that may encourage other medical professionals to use quality-of-life evaluations during cancer treatment.
Before the start of IL-2 treatment in this study, patients reported a wide range of quality-of-life scores, most likely reflecting heterogeneity with respect to differences in age, performance status, tumor burden, and tumor-related symptoms. For this reason, we chose not to use the total and mean quality-of-life scores to compare treatment effects across time points and treatment groups; instead, we elected to evaluate percentage changes calculated based on pretreatment score.
In the current analysis of patients who received inhalational IL-2 therapy, the QLQ-C30 score at 4 weeks of treatment represented the only statistically significant deterioration of patient quality of life. This may reflect the fact that inhalational IL-2 therapy requires organizational changes in the patient's everyday life, resulting from multiple daily dosing schedules and side effects (predominantly cough and minor general impairment) with which the patient must contend. After 4 weeks of treatment, patients receiving inhalational IL-2 treatment seemed to adapt to the immunotherapy, as evidenced by improved quality-of-life scores at 3, 6, 9, and 12 months of treatment when compared with the 4-week score. Thus, the IL-2 immunotherapy seems to become more compatible with the patient over time. Such quality-of-life information, when imparted to the patient, may be associated with enhanced patient motivation to continue therapy despite adverse effects experienced during early treatment courses. Similarly, a patient with the knowledge that, after the initial courses of therapy and the adjustment to the treatment, he/she will experience an improved quality of life when compared with initial treatment experiences may lead to increased patient compliance.
The results of our analysis suggest that the impact of IL-2 immunotherapy on quality-of-life scores varies with the functional domain. The QLQ-C30 questionnaire permits the evaluation of six different functional domains in the assessment of quality of life. For example, the functional domain analysis revealed that for the 15 patients who received 9 months of inhalational IL-2 treatment, there existed a trend toward a reduced level of psychologic distress and decreased intrusive thoughts regarding cancer. This finding may reflect the psychologic relief experienced by patients with the knowledge that a life-threatening tumor has been controlled for several months. Thus, the QLQ-C30 questionnaire is a valuable tool that may be used to help counsel patients by indicating to them what may be expected from their treatment regarding different quality-of-life modalities.
The current evaluation of patient quality-of-life using the QLQ-C30 questionnaire has impacted the information that we now provide to our patients. Based on the global and special symptoms scores determined in our analysis, we explain to our patients that they may experience an improvement in quality of life during treatment with inhalational IL-2, particularly after the initial few months. However, we also emphasize the need for patients to be aware that their family and social lives may be more severely impaired than with intravenous IL-2 treatment, which is provided on an inpatient basis and has less effect on daily home life. Additionally, we attempt to involve a patient's domestic partner and family members when sharing treatment-related quality-of-life information. Although the patient's activities of daily living may be impaired only during the initial months of treatment and the degree of psychologic distress and intrusive thoughts may be stable and even have a tendency to improve during long-term treatment with inhalational IL-2, as suggested by the results of the current analysis, support from loved ones may help the patient cope with the disease and its treatment. Thus, quality-of-life information may help patients to select a treatment option that is appropriate for them because it may be of considerable importance to the patient whether treatment approaches impact quality of life because of the nature of their administration regimens (eg, inpatient v outpatient) or their associated toxicities (see below).
Inhalational IL-2 therapy is associated with very low toxicity, allowing for complete outpatient treatment, but is still effective.15,16 In a previous study, the overall objective response rate for 116 patients was 15%, and the median survival time was 11.8+ months.18 In 70% of these IL-2–treated patients, pulmonary progression was stopped for a median duration of 8.1+ months. These results are comparable to those achieved with high-dose bolus IL-2 treatment, which resulted in a 15% objective response rate and a median survival time of 16.3 months.32 However, high-dose bolus IL-2 treatment (6 × 105 to 7.2 × 105 IU/kg intravenous every 8 hours) requires strict patient selection because of the potential for serious treatment-associated adverse effects. Unfortunately, this restricts treatment (and response) opportunities to only a minority of patients with the disease. Such patient selection is not required for inhalational IL-2 treatment. Furthermore, impaired quality of life is not a clinical issue with local IL-2–based treatment modalities because treatment-associated toxicity is relatively low. In contrast, however, our patients treated intravenously with IL-2, even when administered low doses (9 × 106 IU/m2), experienced a compromised quality of life.
Patients in this study who received intravenous IL-2 had after treatment, as compared with before, a greater impairment in their quality of life than that observed for the patients receiving inhalational IL-2. Thus, despite the fact that the daily intravenous IL-2 dose (9 × 106 IU/m2) was very low and was administered for only 5 consecutive days, patients who received intravenous IL-2 treatment experienced a more profound decline in quality of life than did their counterparts who received inhalational IL-2 treatment. In addition, three of the 10 patients receiving intravenous IL-2 treatment refused to complete the QLQ-C30 questionnaire because of their impairment during treatment. All three of these patients reported that toxicity of therapy impeded their ability to complete the questionnaire. The exclusion of these nonresponders from the analysis most likely biased the results. The results for the systemic treatment modality may be falsely positive because significant toxicities experienced by the three patients were not included in the analyses. It is possible that therapies even more toxic than the low-dose intravenous IL-2 treatment used here may not be assessable using questionnaires that require the patients' cooperation.
This quality-of-life analysis demonstrates the potential for and relevance of measuring patient subjective and objective improvements with IL-2–based cancer immunotherapy. Such analyses should be included in the documentation for potentially toxic and burdening therapies to better judge their value in regard to clinical benefits. This is particularly true for cancers such as mRCC, for which, even with treatment, the prognosis for long-term survival is poor.33 In the context of a poor prognosis for survival, quality of life becomes an even more important issue for both the patient and the clinician.
In summary, we used both a subjective and objective analysis to evaluate quality of life experienced by advanced cancer patients treated with high doses of inhalational IL-2. Compliance of patients with this analysis of quality of life was excellent. Inhalational IL-2 therapy was associated with a maintained patient quality of life when compared with pretreatment assessments. Our data emphasize the importance of systematic quality-of-life analyses for demonstrating beneficial effects of immunotherapy on quality-of-life parameters. Finally, prospective long-term evaluation of quality of life for cancer patients receiving immunotherapy has a high acceptance among patients and provides valuable information to both patients and clinicians.
Acknowledgments
Supported by Chiron Therapeutics, Ratingen, Germany.
We thank Barbara Kherad and Susanne Wittneben for their help in caring for the patients and for maintaining medical documentation.
Footnotes
-
Financial disclosure: H.H., T.S.M., E.H., and H.H. do not own stock or options in Chiron Therapeutics but have received research support from Chiron Therapeutics.
- Received March 23, 1999.
- Accepted June 28, 1999.
