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Patients’ Estimation of Overall Treatment Burden: Why Not Ask the Obvious?

From the Swiss Institute for Applied Cancer Research, Coordinating Center, Bern; Department of Medicine C, Kantonsspital, St Gallen; Cantonal Institute of Oncology, Ospedale San Giovanni, Bellinzona; and Centre Anticancereux, Clinique de Genolier, Genolier, Switzerland.

Address reprint requests to Jürg Bernhard, PhD, SIAK Coordinating Center, Effingerstr 40, 3008 Bern, Switzerland; email: jbernhard@ sakk.ch.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: We investigated the clinical validity of patients’ estimation of overall treatment burden. This measure was expected to be responsive to the wide spectrum of reactions on treatment and thus less precise for specific effects.

PATIENTS AND METHODS: After the first chemotherapy within a randomized, double-blind trial of the prophylaxis for delayed emesis (SAKK 90/95), 249 patients documented nausea and vomiting daily for 6 days. Over the whole period, they estimated nausea/vomiting (N/V) burden and overall treatment burden by linear analog-self assessment (LASA) indicators and documented other side effects.

RESULTS: At day 6, the two burden indicators were moderately correlated (r = 0.58) in accordance with their different concepts. No, partial, or total control of delayed emesis (days 2 to 6) was reflected in a consistent pattern by both indicators, with a stronger and more significant effect (P < .001) on changes in N/V burden than overall treatment burden. In contrast, toxicity other than N/V, assessed independently by patients and physicians, was mainly associated with overall treatment burden. Patients who indicated at least one other side effect rated their overall burden substantially higher than those with no indication of other toxicity (P < .0001). Physician-rated toxicity had a similar effect (P < .0001).

CONCLUSION: A direct patient estimation of overall treatment burden by a LASA indicator may serve as an end point in clinical trials, particularly when treatments with different toxicity profiles are being compared. It is complementary to physicians’ ratings of specific toxicities and a major component of patient-rated symptom checklists and quality-of-life measures.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IN COMPARING toxicity in randomized controlled clinical trials, investigators are faced with the facts that different regimens may have different toxicity profiles, and that the profiles may vary among subgroups of patients. Separate comparisons of single side effects are helpful but do not give an overall estimate of treatment burden, taking into account the different nature of side effects. Single comparisons cause problems of multiple testing. As an alternative, summative indices, such as for hematologic toxicity,¹ are often used.

This approach is based on predefined weights of the different side effects that are often assumed to be similar. However, patients perceive the impact of different side effects differently.^2,3 Because of anticipation, even the same treatment may be perceived differently, depending on the treatment to be followed.⁴ In addition, the relative importance attached to side effects is known to be influenced by patient and clinical factors such as age, sex,^2,5 type of chemotherapy,² trait anxiety,⁶ and negative affect.⁷ Physician ratings of toxicity cannot reflect patient perception in its entirety.^8,9 The latter requisite was one of the major driving forces in developing symptom checklists and quality-of-life questionnaires for patient self-report. Patients’ estimates of different side effects can similarly be aggregated into summative indices (ie, multi-item scales) but at the cost of requiring predefined weights. This bottom-up approach (whole as sum of its parts) is used in many symptom checklists to construct an overall score.^10-15

We investigated whether we may ask the patient to estimate directly his or her overall treatment burden (ie, not based on external weights). This top-down approach (whole as not merely the sum of its parts) would provide a complementary measure to physicians’ or patients’ ratings of specific side effects. We expected this indicator to be responsive to the whole spectrum of toxicity, and thus function as a comparative measure for overall burden, but to be less precise for specific side effects. This hypothesis is founded on patients’ ability to internally weigh complex issues and to formulate a gestalt opinion.¹⁶ We investigated this hypothesis within a randomized, double-blind trial in the prophylaxis of chemotherapy-induced delayed emesis (Swiss Group for Clinical Cancer Research [SAKK] Trial 90/95).

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The Trial
The trial SAKK 90/95 was designed to compare the clinical efficacy and safety of granisetron, a 5-HT₃ receptor antagonist, to that of metoclopramide, both combined with dexamethasone, in the prophylaxis of chemotherapy-induced delayed emesis.¹⁷ The trial was performed after approval by the ethical committees for all participating institutions. In the first course of single-day emetogenic chemotherapy, patients received granisetron 2 mg orally (PO) and dexamethasone 8 mg PO on day 1 followed for 5 days by dexamethasone 4 mg PO twice daily, combined in double-blinded and double-dummy fashion with either metoclopramide 20 mg PO three times daily or granisetron 1 mg twice daily, starting in the morning after the first 24 hours of exposure to the chemotherapy.

After informed consent, patients were randomized by the minimization method¹⁸ after stratification for center, sex, experience with emetogenic chemotherapy (naive v nonnaive), regular alcohol consumption (yes v no, defined as daily intake, averaged over 1 week, of > 2 dL of wine and/or > 5 dL of beer and/or > 1 measure of spirits) and for type of chemotherapy received (cisplatin/carboplatin v others).

The main end point was partial control of delayed emesis, defined as minimal nausea not interfering with daily life and no emesis during days 2 to 6. Total control of delayed emesis was defined as no nausea and no emesis in this period. Failure to control delayed emesis was defined as one or more episodes of emesis and/or at least severe nausea on one or more days.

Assessment of Toxicity and Burden
In the hospital, at randomization and before starting chemotherapy, patients were instructed by the treating oncologist or a nurse in completing a diary card available in French, German, and Italian. Then they were asked to estimate their baseline scores. Thereafter, the diary card was given to the patients to fill in at home, with a stamped addressed envelope.

The baseline assessment (day 0) consisted of three linear analog self-assessment (LASA) indicators: intensity of nausea/vomiting ("Have you felt nauseated or have you vomited for the past 7 days?"), burden of nausea/vomiting ("To what extent have you felt bothered by nausea/vomiting or related thoughts for the past 7 days?"), and overall treatment burden ("Overall, how much are you bothered by any treatment related difficulties?"). The latter indicator was expected to reflect patients’ subjective experience of treatment on a single dimension, including side effects of the antiemetic regimes (eg, headaches) and any adverse event. All LASA indicators ranged from 0 ("not at all") to 100 ("severely"). In addition, patients indicated their nausea and vomiting of the day before by a categorical, ordinal scale,¹⁹ with 1 indicating no nausea or vomiting, 2 indicating mild nausea with no interference with daily life and no vomiting, 3 indicating severe nausea with interference with daily life but no vomiting, and 4 indicating vomiting with or without nausea.

At home, on days 1 to 6, patients documented their nausea and vomiting for the past 24 hours each morning by the categorical scale. They also checked off daily their intake of the trial medication. On day 6, they summarized their experience over days 0 to 6 in regard to the occurrence of headache, abdominal pain, diarrhea, and constipation. In addition they were asked an open question about other side effects; all but the last item were in a yes/no response format. Finally, patients completed again the three LASA indicators regarding their experience over this period. The indicator for nausea/vomiting intensity was used as an internal reference measure. The wording of the indicator for nausea/vomiting burden was adjusted ("How much have you been bothered by nausea/vomiting for the past 7 days?").

At the first visit after giving the trial treatment, the physicians also documented toxicity other than nausea or vomiting that occurred during antiemetic treatment. This assessment included epigastralgia, restlessness, abnormal body part movements, sleeplessness, constipation, headaches (the latter three only if unusual for patient), unexpected asthenia, and two open categories for other side effects; all but the last items were in a yes/no response format.

Statistical Analysis
Responsiveness to toxicity was used as the main criterion for clinical validity. The indicator for overall treatment burden was expected to be responsive to the whole spectrum of toxicity and thus less precise for specific side effects. Regarding cytotoxic side effects, as in the clinical protocol, the primary comparison for hypothesis testing included the control of delayed emesis as indicated by the patients on the diary card. Regarding toxicity other than nausea or vomiting, the primary comparison included the occurrence of any other side effect documented on the diary card.

The analysis was based on nonparametric methods. The Wilcoxon rank-sum test was used to compare two groups of patients in terms of the absolute values of LASA indicators or the changes between days 0 to 6. For correlation analyses, the Spearman rank correlation coefficient was used.

Sensitivity and specificity of the experimental measure was explored regarding the combined criteria of "no control of delayed emesis" and/or "occurrence of any other toxicity documented on the diary card" versus "total/partial control of delayed emesis" and "no other toxicity." A receiver operating characteristics analysis was based on absolute burden scores at day 6.

The statistical analysis was restricted to the patients who returned a completed diary card, including cases with missing information. No discernible pattern of missing information could be identified. All available information was used for analysis. The secondary comparisons were not adjusted for multiple testing. We relied on their patterns of statistical significance according to our hypothesis. All tests were two-sided.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Sample and Baseline Description
A total of 267 patients from six centers (five from Switzerland and one from Italy) were randomized. Three patients were ineligible. From the remaining 264 patients, 250 (95%) completed a diary card. One patient was confused and had to be excluded, leaving a study sample of 249 patients. Fifty-eight (23%) of the 249 cards had one or more missing answers.

The patient characteristics and chemotherapy at baseline are summarized in Table 1. The majority of patients were female (65%), were older than 50 years (70%), were rated with no impairment in performance status (79%), and indicated no regular alcohol consumption (84%). Breast (32%) and lung (22%) were the most frequent tumor sites. The majority of patients were chemotherapy-naive (94%). Most (56%) were treated with a platinum-based regimen.

Toxicity and Burden During Days 1 to 6
Seventy-six percent of the 249 patients marked on their diary card that they had always taken the trial medication, 18% took it sometimes, and 1% never took it. In 5% of the cases, this information was missing. Three cases received additional antiemetic treatment between days 1 and 5. There was no imbalance between the arms.

At day 6, the reference measure, nausea/vomiting intensity, was highly correlated with nausea/vomiting burden (r = 0.9) and less but substantially with overall treatment burden (r = 0.55), in accordance with the different concepts of these indicators. Similarly, the two burden indicators showed a substantial but not high correlation (r = 0.58). In the following analyses, we report only data of the two burden indicators.

Changes in scores of the burden indicators between baseline and day 6 are displayed in Fig 1 according to type of chemotherapy on day 0. There was no difference by randomized antiemetic treatments. Overall, there was a tendency toward a worsening. Patients who had received cisplatin showed a considerable variation, with more burden by nausea/vomiting than those with carboplatin or other regimens and a tendency toward more overall treatment burden.

View larger version (14K): [in this window] [in a new window]   Fig 1. Changes in burden according to type of chemotherapy. The symbols on the horizontal lines refer to the median (large squares) and the quartiles (small squares). Positive changes indicate an increase in burden.

View larger version (15K): [in this window] [in a new window]   Fig 2. Changes in burden according to control of delayed emesis. The symbols on the horizontal lines refer to the median (large squares) and the quartiles (small squares). Positive changes indicate an increase in burden.

Toxicity other than nausea or vomiting was expected to be more strongly associated with the global indicator for treatment burden than with the specific indicator for nausea/vomiting burden. The association between these side effects and patient burden assessed on day 6 is summarized in Table 2 for toxicity documented by the patients and in Table 3 for toxicity documented by the physicians.

The secondary comparisons of patient-rated toxicity other than nausea or vomiting yielded similar findings. The strongest impact on treatment burden resulted from headache (P < .0001) and abdominal pain (P = .0003). With the exception of diarrhea, these side effects were more strongly associated with the global burden indicator than with the indicator related to nausea/vomiting. These findings were consistent when investigating changes instead of absolute scores, thus controlling for patient and pretreatment clinical factors, as shown for the impact of any toxicity versus no toxicity in Fig 3. It has to be noted that the difference in treatment burden between the groups with versus without any other toxicity was much bigger when based on absolute scores at day 6 (medians, 3 v 25) than on changes from baseline (median changes, 0 v 2).

View larger version (12K): [in this window] [in a new window]   Fig 3. Changes in burden according to patient-rated toxicity other than nausea or vomiting. The symbols on the horizontal lines refer to the median (large squares) and the quartiles (small squares). Positive changes indicate an increase in burden.

Further Exploratory Analyses
We explored whether there was an association between an increased treatment burden at baseline (n = 238; median, 12) and the effect of delayed emesis and of other toxicity on burden at day 6. As shown in Fig 4, no control of delayed emesis was associated with a major increase in burden in patients with a baseline score below 20. The magnitude of change decreased with increasing baseline scores. In patients with control of emesis (ie, total or partial control), there was a small decrease in burden in those with an intermediate to high baseline score. There was also a correlation between the burden at baseline and the burden at day 6 attributable to no versus any other toxicity (data not shown).

View larger version (20K): [in this window] [in a new window]   Fig 4. Changes in burden according to control of delayed emesis and baseline score. Baseline and change scores are displayed in medians. Positive changes indicate an increase in burden. , Control; , no control.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

At baseline, patients reported almost no burden of nausea/vomiting but did report burden of the treatment overall. The pretreatment period is characterized by suffering from psychologic distress and anticipation of treatment burden.²¹ Women expressed greater burden than men, as has been reported elsewhere despite an unclear reason for this discrepancy. As would be expected, cisplatin was associated with more burden than carboplatin. To control for any patient or pretreatment clinical factors, we investigated burden not only in absolute term but also relative to baseline.

Acute, delayed and maximum emesis were reflected in both burden indicators. The specific indicator for nausea/vomiting was more responsive to these outcomes than was the global indicator for treatment burden.

In contrast, toxicity other than nausea or vomiting was expected to be more strongly associated with overall treatment burden than with burden of nausea/vomiting. This assumption was confirmed for various side effects documented both by patient and physician. Side effects considered to be minor, such as constipation, accordingly had a marginal impact. Those patients who reported at least one side effect other than nausea or vomiting clearly contrasted in their treatment burden with the others. However, the median change score in these patients was small. An increase in burden was present in those cases with a low baseline score, whereas those with higher initial burden showed an improvement. In the latter group, the real experience may have been less severe than anticipated by the patient. A ceiling effect, however, cannot be excluded.

In summary, this indicator of treatment burden was responsive to different patterns of nausea and vomiting and to other toxicity. We chose responsiveness as the main criterion for clinical validity, being aware that this may differ among different populations, interventions, and research settings. Our findings are based on a heterogeneous sample with different tumor sites and types of chemotherapy, thus giving sufficient grounds to use this indicator in clinical trials of antiemetics and cytotoxics.

Our trial has some limitations. The categorical reference scale for nausea and vomiting combined activities of daily living with symptoms.¹⁹ Besides, a separate assessment for nausea and vomiting would have given more accurate and precise estimates. The submission rates of completed diaries was high and compares well with other trials.²² However, 23% of all returned diaries had one or more missing items, a known problem with patient-rated diaries.²³ Our findings are mostly consistent and argue against a substantial bias. There was no difference in the control of delayed emesis or any other end point between the randomized treatments. Therefore, we could not further evaluate the discriminative capacity of this indicator.

Why not ask the obvious? The advantages of this simple indicator for data collection are clear-cut but need to be judged for a given purpose and trial design. As previously demonstrated in clinical trials for several global indicators,^4,24-27 although less precise for specific treatment effects, this type of measure is responsive to the wide spectrum of reactions seen in patients on and off treatment and will detect these changes on single dimensions, allowing for comparison across treatments. The investigation of toxicity profiles and the clinical management of toxicity, however, require an assessment of symptom characteristics.

Single-item measures are generally expected to have lower reliability than sound multi-item measures.²⁸ For example, we expect an overall rating to be more affected by patient factors, such as anticipation. Regarding global indicators as end points in cancer clinical trials, this property affects more their discriminant validity than responsiveness to treatment and other clinical factors²⁹; discriminant validity refers to a higher correlation between this measure and the concepts intended to be measured than those not intended to be measured. This is less decisive in large sample sizes. Responsiveness to a broad range of clinical factors is important because disease and treatment factors may change over the course of disease. Our findings suggest an acceptable sensitivity and specificity.

This indicator is designed to reflect the patients’ subjective view, as an alternative to externally defined weights and distinct from measures of health status.³⁰ We built on the existing experience with patient-rated symptom assessment scales.^10-15,20 All these measures are based on the assumption of the subjective nature of symptoms. In some, the impact of symptoms on well-being or functioning is also directly derived from the patient.^13,15 In particular, the question of interference of pain with daily activities has been addressed by this top-down approach,³¹ also in quality-of-life questionnaires.^32,33

We followed the same strategy for the overall burden score. The toxicity profiles may vary among subgroups of patients and be perceived differently.^2,3,5 The perception of a particular aspect and its relative importance may vary also within individuals over time. For example, the subjective experience of endocrine treatment in advanced breast cancer differs in patients with long-term disease stabilization from those with tumor response.²⁷ The influence of personal expectations on quality of life is well known in clinical practice.³⁴ It has been suggested that importance-satisfaction discrepancies regarding quality-of-life domains are central to patients’ perception and indicators of their distress.³⁵ A direct patient estimation of overall treatment burden may take account of these factors. It is a clinically appealing concept to compare treatments but not to determine specific reactions associated with a certain regimen.

Three questions need to be answered. First, the optimal time window between the occurrence of acute, intermediate, or long-term toxicity and the assessment of treatment burden needs to be specified. A clinical model differentiating various types of symptoms and time frames has recently been presented.³⁶ Second, the magnitude of clinically relevant effects needs further investigation regarding different clinical situations. Patients may reframe the internal standards on which they base their estimations in the process of adapting to disease and treatment.^37,38 For quality-of-life–oriented measures, in contrast to health status measures, this observation challenges the concept of disease- or treatment-related norms, referring to an individual perspective.³⁹ Finally, we currently investigate whether this indicator is similarly responsive to the impact of other treatment modalities, especially surgery, radiotherapy, and endocrine therapy. If confirmed, this indicator would be a suitable end point for trials comparing treatments with multiple modalities or different sequence of modalities (eg, neoadjuvant trials).

In conclusion, a direct patient estimation of overall treatment burden by a LASA indicator may serve as an end point in clinical trials, particularly when treatments with different toxicity profiles are being compared. It is complementary to physicians’ ratings of specific toxicities and a major component of patient-rated symptom checklists and quality-of-life measures.

	ACKNOWLEDGMENTS

 
Granisetron was provided by SmithKline Beecham, Thörishaus, Switzerland. The packing of the trial medication was funded also by SmithKline Beecham and performed at the pharmacy of the University Hospital of Geneva, Geneva, Switzerland.

We thank patients, physicians, nurses, and data managers who participated in this trial. We are especially grateful to Franco Nolè for implementation of the trial at the European Institute of Oncology in Milano, Italy; to Corinne Friedli for central trial coordination; and to Harriet Peterson, Alan Coates, Richard Gelber, and Christoph Hürny from the International Breast Cancer Study Group for their input on the development of global indicators for cancer clinical trials.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted September 29, 2000; accepted August 13, 2001.

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