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How Accurate Is Clinician Reporting of Chemotherapy Adverse Effects? A Comparison With Patient-Reported Symptoms From the Quality-of-Life Questionnaire C30

From the Department of Medicine, Divisions of General Medicine and Geriatrics, and Hematology and Medical Oncology, Oregon Health & Science University; the Oregon Health & Science University Center for Ethics in Health Care; and Biostatistics & Bioinformatics Shared Resource, Oregon Health & Science University Cancer Institute, Portland, OR

Address reprint requests to Tomasz M. Beer, MD, Department of Medicine, Oregon Health & Science University, Mail Code CR145, 3181 SW Sam Jackson Park Rd, Portland, OR 97239; e-mail: beert{at}ohsu.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Adverse events in chemotherapy clinical trials are assessed and reported by clinicians, yet clinician accuracy in assessing symptoms has been questioned. We compared patient reporting of eight symptoms using a validated instrument, the European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (QLQ-C30 or QLQ) with physicians' reporting of the same symptoms in the study's adverse events log.

PATIENTS AND METHODS: Thirty-seven men with metastatic, androgen-independent prostate cancer enrolled onto a phase II trial of weekly calcitriol and docetaxel completed the QLQ every 4 weeks for up to 28 weeks. A patient-reported symptom was defined as an increase in a QLQ symptom score by at least 10 points (0 to 100 scale), sustained for at least 4 weeks. A physician-reported symptom was considered present if it was ever documented in the adverse event log.

RESULTS: Forty-nine (new or worsened) symptoms were detected by both physician and QLQ, 48 symptoms were detected by the physician alone, and 55 symptoms were detected by the QLQ alone. They agreed on the absence of a symptom in 102 instances of 254 possible opportunities. Their uncorrected agreement was 59.4%, but Cohen's , a coefficient of agreement that corrects for chance, was 0.15, indicating only slight agreement. Using the QLQ as the standard, overall physician sensitivity and specificity was 47% and 68%, respectively, although it varied considerably among symptoms.

CONCLUSION: Even in a tightly controlled clinical trial, physician reporting was neither sensitive nor specific in detecting common chemotherapy adverse effects. Tools for collecting patient-reported adverse event data in chemotherapy clinical trials should be developed.

	INTRODUCTION

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Adverse events (AEs) are defined by the National Cancer Institute as "any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure..."¹ Physicians and study nurses routinely identify and report AEs in clinical trials of cancer chemotherapy. These AE data are then disseminated to physicians and used to estimate the risks of therapy that patients and their physicians weigh when choosing cancer treatment strategies.

For many AEs, such as abnormal laboratory findings or specific disease states, clinician reporting makes sense. It is less clear if clinician reporting of symptoms is reliable when they are neither directly observable nor objective. In symptom research, the patient's report is the gold standard for assessing symptoms^2-5 and studies consistently show that physicians and nurses underestimate (or, occasionally, overestimate) symptom frequency and severity in comparison with patient ratings.^6-9

Physician reporting of adverse effects has been shown to be insufficiently reliable in studies of prostatectomy for localized adenocarcinoma of the prostate, for which investigators have found that patients report higher frequencies of erectile dysfunction and urinary incontinence after treatment than do physicians.^10-12 Because these findings have been so consistent,¹³ patient report has replaced physician report as the accepted standard for assessing postprostatectomy complications.

Common complications of prostatectomy, such as erectile dysfunction and incontinence, are often uncomfortable topics to discuss, particularly as complications of medical treatment. One might expect physician reporting of less intimate symptoms to be more accurate than reporting of these sensitive symptoms, but this is not necessarily the case. For patients with prostate cancer participating in the Cancer of the Prostate Strategic Urologic Research Endeavor cohort study, although overall concordance was low for all symptoms, urologists somewhat more closely matched patients in identifying erectile dysfunction (52% urologist-reported rate v 97% patient-reported rate) and incontinence (21% urologist-reported rate v 97% patient-reported rate) and less closely matched patients in identifying other symptoms such as bone pain (5% urologist-reported rate v 43% patient-reported rate), fatigue (10% urologist-reported rate v 75% patient-reported rate), and diarrhea or rectal urgency (2% urologist-reported rate v 33% patient-reported rate).⁷

The accuracy of physician reporting of adverse effects has not been scrutinized as carefully for chemotherapy as it has for prostate surgery. We hypothesized that physician reporting of chemotherapy adverse effects would lack sensitivity when compared with patient self-reporting. We then sought to test this hypothesis by comparing patient reporting of eight common cancer symptoms using a validated instrument, the European Organization for the Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire C30, version 3.0¹⁴ (QLQ) with a physician's reporting of the same symptoms in the study's AE log.

	PATIENTS AND METHODS

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Patients
Thirty-seven men with metastatic, androgen-independent prostate cancer enrolled in a phase II trial of weekly calcitriol and docetaxel administered for 6 consecutive weeks repeated every 8 weeks were observed for up to 28 weeks for this analysis. The details of the design of this clinical trial have been published previously.¹⁵ Informed consent was obtained from all patients and the study was approved by the institutional review boards of the Oregon Health & Science University and the Portland VA Medical Center (Portland, OR).

Measures
Permission to use the QLQ instrument was obtained from the European Organization for the Research and Treatment of Cancer, Brussels, Belgium. The QLQ was developed to measure quality of life in cancer patients enrolled onto clinical trials. Although considered a quality-of-life questionnaire, 12 of its 30 questions are devoted to eight symptoms common among cancer patients: three questions are about fatigue, two questions are about nausea or vomiting and pain, and one question each is about dyspnea, sleep disturbance, appetite loss, constipation, and diarrhea. The time referenced is the preceding week, and the response categories for each item are not at all, a little, quite a bit, and very much. Item scores are linearly transformed to range from 0 to 100, with a higher score indicating more severe and/or frequent symptoms.¹⁶

Procedures
Patients reported symptoms by completing the QLQ before therapy and then every 4 weeks. Symptoms were identified in the course of a standard clinic visit that included a patient interview and physical examination by a board-certified medical oncologist who was familiar with chemotherapy AEs and sought to identify them; however, this process was not standardized. The physician also evaluated patients who became acutely symptomatic or otherwise ill at unscheduled visits instigated by the patient, his family, the study coordinator, or the nursing staff in the infusion unit. All new or significantly worsened symptoms were recorded in the study's AE log using the Common Toxicity Criteria (version 2.0 available from the National Cancer Institute) by the physician who was unaware of the QLQ results. The patients' chart notes were reviewed to ensure that all AEs recorded in the medical record were also included in the AE log.

Analysis
A patient-reported symptom was considered present if his QLQ score increased by at least 10 points (0 to 100 scale) on two successive questionnaires at least 4 weeks apart. This degree of change should be easily perceived by patients and therefore is clinically important.^17,18 A physician-reported symptom was considered present if it was ever documented in the AE log. Concordance was assessed using Cohen's , a coefficient of agreement that corrects for chance.¹⁹ Landis and Koch proposed categories for judging values: less than 0.00 was poor, 0.00 to 0.20 was slight, 0.21 to 0.40 was fair, 0.41 to 0.60 was moderate, 0.61 to 0.80 was substantial, and 0.81 to 1.00 was almost perfect.²⁰

Physician sensitivity and specificity for each symptom was calculated using the QLQ as the gold standard. Assuming that false-positives were much less likely than false-negatives, imputed incidence was calculated by counting a symptom as new or worsened if it was detected by either the QLQ or the physician.

Multiple methodologic approaches have been described for analyzing longitudinal symptom and quality-of-life data.^21,22 Although no single method is the best in every circumstance, contrasting the results obtained by different methods can aid data interpretation. If the results are consistent across methods, this supports the robustness of the findings.²³ Accordingly, we also calculated the means of all eight QLQ scores for each symptom for each of four situations: QLQ-positive/physician (MD) -positive, the QLQ was positive and the physician did report that symptom as an AE; QLQ-positive/MD-negative, the QLQ was positive but the physician did not report that symptom as an AE; QLQ-negative/MD-positive, the QLQ was negative but the physician did report that symptom as an AE; or QLQ-negative/MD-negative, the QLQ was negative and the physician did not report that symptom as an AE.

We hypothesized that patients who were both QLQ-positive and MD-positive should have the highest mean symptom scores, given that both methods identified the presence of a new or worsened symptom. Conversely, the patients who were both QLQ-negative and MD-negative should have the lowest mean symptom scores. To test this hypothesis, we performed analysis of variance analyses including contrast coefficients that reflected our hypothesis: QLQ-positive/MD-positive patients were assigned a coefficient of 1 and QLQ-negative/MD-negative patients were assigned a coefficient of –1. We did not have sufficient power to test the hypothesis that symptom scores would be intermediate in patients who were QLQ-positive/MD-negative or QLQ-negative/MD-positive.

	RESULTS

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Patient Characteristics
Thirty-seven men were observed during treatment for up to 28 weeks (median, 28 weeks; mean, 24 weeks) of chemotherapy for this analysis. Their median age was 73 years (range, 46 to 83 years). Their baseline Eastern Cooperative Oncology Group performance scores were 0 or 1 for 75%, 2 for 22%, and 3 for 3%. Metastases were present in bone only (59%), bone and lymph nodes (32%), or lymph nodes only (8%). Eighteen patients had their docetaxel or calcitriol dose decreased by the investigator, and 12 patients discontinued chemotherapy early, after a median of 20 weeks. Compliance with QLQ questionnaires was 94%.

Symptoms Detected
The 37 men reported 152 new or worsened symptoms during the follow-up period: 97 of these were reported to the physician, and 104 were detected by the QLQ. The mean number of symptoms identified for each patient by the QLQ (mean, 2.83; standard deviation [SD], 1.42) and the physician (mean, 2.65; SD, 1.30) were not significantly different (Student's t test, 0.67; P = .51).

Comparison of QLQ and Physician
The QLQ and physician agreed on the presence of a new or worsened symptom in 49 instances (32%), thus the QLQ identified 55 symptoms not identified by the physician, and the physician identified 48 symptoms not identified by the QLQ. Here, agreement meant that both the QLQ and the physician reported the new or worsened symptom at any time during the 28-week study period. In the 49 cases of agreement, the physician identified the symptom within 1 month of the QLQ identification in 16 cases (33%), earlier in 14 cases (29%; mean 93 days; SD, 42 days), and later in 19 cases (38%; mean, 82 days; SD, 46 days). These temporal relationships between physician and QLQ symptom detection should be viewed as exploratory because the QLQ does not ask respondents to specify when a symptom first appears. For this reason we did not include the time at which a symptom was identified as a variable in the analysis of concordance between the QLQ and physician.

When data for all eight symptoms were pooled, was 0.15 (95% CI, 0.02 to 0.28), indicating slight agreement. is a conservative estimate that discounts agreement that would be expected by chance.²⁴ For reference, the physician and QLQ agreed on the presence of a new or worsened symptom in 49 instances, and agreed on the absence of a new or worsened symptom in 102 instances out of 254 possible opportunities—an uncorrected agreement of 59.4%. The overall physician sensitivity and specificity was 47% and 68%, respectively, although it varied considerably among symptom scales. Correlation, sensitivity, specificity, and imputed incidence for each symptom appear in Table 1. The imputed incidence of symptoms that combined MD-positive and QLQ-positive symptoms approximates the incidence of symptoms reported from other metastatic prostate²⁵ and other advanced cancer^25,26 populations. The fraction of symptoms missed by the physician when QLQ is the gold standard is shown in Fig 1.

View this table: [in this window] [in a new window]   Table 1. Correlation Between MD and QLQ, MD Sensitivity and Specificity Using QLQ As a Gold Standard, and Imputed Incidence (a symptom's incidence if either the MD or the QLQ identified it as new or worsened) for Each QLQ Symptom Domain

View larger version (19K): [in this window] [in a new window]   Fig 1. Percentage of European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (QLQ) –identified adverse events that were identified (in black) and missed (in white) by the physician.

	DISCUSSION

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The physician did not report approximately one half of the symptoms identified by the QLQ as AEs, and the QLQ did not detect approximately one half of the symptom AEs reported by the physician. The failure of the physician to identify a substantial number of symptoms identified by the patient-reported instrument is not surprising considering the published experience with prostatectomy and other symptom research. To our knowledge, however, this is the first such analysis aimed specifically at examining the reliability of physician identification of AEs in a chemotherapy clinical trial.

On the basis of the excellent performance of the QLQ in validation studies, we were surprised to find that it failed to identify so many symptoms identified by the physician. We explored the possibility that the physician misclassified a baseline symptom as a new symptom. Our data support this possibility insofar as the baseline scores were significantly higher in the QLQ-negative/MD-positive symptoms than in the QLQ-negative/MD-negative symptoms. However, it is also possible that the QLQ was not sufficiently sensitive to detect a significant number of symptoms. Groenvold et al²⁷ compared 46 female cancer patients' self-reported score for each QLQ question item with an observer's score that was based on the patient's response to the same question in an open-ended interview. They found the agreement for the 12 symptom items to be excellent (median, = 0.825; range, 0.65 to 0.97), although they noted that a few patients did not report symptoms unless they considered them to be significant (eg, if the symptom was new, cancer related, or treatment related). This probably accounts for some of QLQ-negative/MD-positive results.

Other QLQ-negative/MD-positive cases may have been missed because the sustained 10-point increase was insufficiently sensitive. Like any instrument, the sensitivity and specificity of the QLQ depend on how a significant change is defined. We used a 10-point increase sustained over at least two measurements at least 4 weeks apart to increase the likelihood that the increased score represented an AE rather than simply a daily fluctuation in symptom severity. A less stringent criterion would be expected to improve the sensitivity, likely at the expense of specificity. It is reassuring that the mean symptom scores were highest when both the QLQ and MD were positive and lowest when neither the QLQ nor MD were positive, except in the patients with fatigue and dyspnea. Although fatigue is a well-recognized adverse effect of docetaxel,²⁸ it is among the most difficult symptoms to define and measure.² This ambiguity may have limited the sensitivity and specificity of either the physician or QLQ. In contrast, recognition that dyspnea is an adverse effect of docetaxel has been more recent, following reports of its association with pulmonary complications.^29-31 This may explain why physician sensitivity was poorest for this symptom (23%) and why the physician-noted dyspnea was reported in only five patients compared with 13 detected by the QLQ. Finally, missed QLQs could explain some missed data points. Compliance with the QLQ was excellent, however, with 94% of questionnaires returned.

This study has limitations that are important to note. First, although the QLQ has been used in more than 3,000 studies and has been extensively validated,²² it has not been used to identify AEs, per se. Second, the design of the QLQ allowed us to examine only eight adverse experiences rather than a comprehensive set of adverse effects of chemotherapy. Other obvious limitations of these data are that they represent a relatively small sample size and a data set from a single-institution clinical trial. However, this problem is shared by each clinician charged with recording AEs for clinical trials—the sensitivity, specificity, reliability, and validity of their reports may vary among individuals and are in any case unknown.

These findings should be confirmed in a larger, multi-institutional study. If verified, they call into question the reliability of chemotherapy AE reporting that relies solely on the physician and strongly suggest that a mechanism for patient self-reporting of adverse experience should be developed, validated, and incorporated into cancer chemotherapy trials. Because both methods identified potentially important symptoms that the other did not, our findings also suggest that patient self-reporting should complement rather than replace physician assessment of AEs. There are a number of methodologic challenges that need to be overcome before patient self-reporting of AEs in chemotherapy clinical trials can move forward. Lack of truly well-validated instruments, the problems presented by missing data,³² uncertainty about the optimal timing and frequency of administration of questionnaires,³³ and uncertainty about the optimal threshold of positivity³⁴ are among the issues that will need to be addressed.

The need for improvement in AE reporting standards in oncology clinical trials was well articulated in a recent Journal of Clinical Oncology editorial.³⁵ Our study suggests that validated methods for collecting and analyzing patient-reported AE data will be a necessary element of such an effort.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported in part by grant 3M01RR00334-33S2, and a Cancer Center Support grant (P30 CA 69533) from the National Institutes of Health.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted March 3, 2004; accepted June 3, 2004.

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