REVIEW

Placebo Effects in Oncology

Gisèle Chvetzoff, Ian F. Tannock

Affiliations of authors: G. Chvetzoff, Department of Medical Oncology, Centre Léon Bérard, Lyon, France; I. F. Tannock, Princess Margaret Hospital, Toronto, Ontario, Canada.

Correspondence to: I. F. Tannock, M.D., Ph.D., Department of Medical Oncology and Hematology, Princess Margaret Hospital, 610 University Ave., Toronto, Ontario M5G 2M9, Canada (e-mail: ian.tannock{at}uhn.on.ca).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background: Previous studies have suggested that placebo treatment can have positive effects on a variety of disorders and disease-related symptoms. However, the methodology used to collect and interpret the data may not have been ideal, because the studies were not double-blinded or the endpoints were not properly validated. The purpose of the present study was to determine the probability of improvement in symptoms or quality of life and tumor response in cancer patients treated with placebos in randomized controlled trials. We hypothesized that administration of placebos would improve symptom control and quality of life but would not lead to tumor response. Methods: We reviewed reports of randomized controlled trials in which there was a placebo arm (37 trials) or a best supportive care (BSC) arm (10 trials). Results: In trials that assessed average responses for patients in the placebo arm, improvements in average levels of pain were reported in two of six trials and in appetite, in one of seven trials. No improvements in average levels of weight gain (six trials), in quality of life (as assessed by patients; 10 trials), or in performance status (as assessed by physicians; nine trials) were reported. In trials that assessed response to a placebo in individual patients, 0%–21% of patients showed reduced pain or decreased analgesic intake, 8%–27% of patients showed appetite improvement, 7%–17% of patients showed weight gain, and 6%–14% of patients showed improvement in performance status. Quality of life for individual patients was not reported in any trial. Tumor response assessed by World Health Organization criteria was observed in 10 (2.7%) of 375 patients (seven trials total). Response as assessed by a serum marker was observed in 1 (1.7%) of 60 patients (two trials total). The probability of symptom improvement in patients receiving BSC was generally similar to that in patients receiving placebo, although no improvement in pain and only one tumor response among 191 patients (five trials) were reported. Conclusion: In randomized double-blinded, placebo-controlled trials, presumably with minimum sources of bias, placebos are sometimes associated with improved control of symptoms such as pain and appetite but rarely with positive tumor response. Substantial improvements in symptoms and quality of life are unlikely to be due to placebo effects.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The placebo effect was first described by Beecher (1), who suggested that about 35% of patients with a variety of conditions could be improved or cured by placebos. A placebo effect can be defined as "the effect seen in patients who have received an intervention which is believed to lack a specific action" (2). The observed effect of an active drug is a combination of three parameters: the natural course of the disease, the specific effect of the drug, and nonspecific effects including the placebo effect (3). Randomized clinical trials, ideally double-blinded with a placebo control, have become the gold standard for clinical research, because they can separate specific effects of an intervention from those due to variation in the natural course of disease and from placebo effects (4).

Since the publication of Beecher's article, many authors appear to have accepted that up to 35% of patients with a wide variety of disorders respond to placebos (48). Placebo effects have been well documented for relief of postoperative or other types of pain in nonmalignant diseases (4,5), in psychiatric disorders such as anxiety and depression (6,7), and in cardiovascular disease (8). However, Beecher's article has been criticized because of misinterpretation of data and lack of appropriate documentation in his analysis (2,9). It has been suggested that the rate of response to placebo was overestimated. Certainly, responses in patients receiving placebos seem to be more frequent when the effect is a change in subjective sensation or when patients are anxious or depressed (10). Responses in such patients also seem to depend on the doctor–patient relationship, on the expectations of the patients and their doctors, and on the characteristics of the placebo, such as color, name, size, and route of administration (11).

For cancer patients, placebo effects are recognized when treatment is given for relief of symptoms. Placebos are regarded as essential in trials of antiemetics, but effective control of chemotherapy-induced nausea and vomiting does not exceed 15% in placebo groups and cannot be attributed specifically to placebo (12). Moertel et al. (13) performed a review of four double-blinded, placebo-controlled, randomized trials of analgesic medication for cancer pain. They concluded that 113 (39%) of the 288 patients who received placebo experienced 50% or greater relief of pain. However, in these studies, the evaluation of pain was not based on a prospective comparison of validated scales that assessed the level of pain before and after treatment but on patients' estimates of percentage of pain relief. Such estimates depend on the memory of the previous state and might lead to an inflated estimate of benefit. In a more recent study, Boureau et al. (14) used validated scales (the visual analog scale and the French version of the McGill Pain Questionnaire) to assess pain in a double-blinded, placebo-controlled, randomized trial for cancer patients with bone metastases. They reported pain relief (as judged by the patient) in 51% of 38 patients at the end of twice-daily intramuscular injections of placebo, which persisted 7 days later (14). In this study, the authors described the placebo effect but provided no details of the active treatment or of its efficacy.

Many treatments, some with substantial toxicity, are given to patients with cancer. For patients with metastatic disease, it is rare that such treatments lead to improved survival (15), but they may lead to tumor response and/or improve symptoms and quality of life. All or part of these effects might also be due to placebo effects. If this were the case, it would be prudent to select nontoxic alternative treatments. The purpose of this review is to determine, on the basis of a review of the literature, the probability that symptoms and/or quality of life may improve and that tumor response may occur following the administration of placebos to cancer patients. We hypothesized that a substantial improvement in symptom control and quality of life would follow administration of placebos but that tumor response would occur rarely.


    METHODS
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 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We performed a computer-based search of relevant articles in the MEDLINE database using the following terms (combination of keywords): "cancer/placebo effect," "cancer/placebo/randomized [or randomised] trial," "cancer/placebo/tumor [or tumour] response," and "cancer/placebo/quality of life." These searches yielded 27, 790, 413, and 124 articles, respectively, for the period 1966 through April 1, 2000. We then selected trials that satisfied each of the following criteria: 1) they were randomized, with a placebo control arm; 2) they investigated the use of chemotherapy, immunotherapy, hormonal therapy, or ancillary treatments for patients with metastatic tumors; 3) their endpoints included tumor response, quality-of-life, or symptom control; and 4) they were published in English. We excluded articles dealing with the prevention of side effects of specific treatments such as antiemetics or hematopoietic growth factors. We also excluded trials of adjuvant therapy, trials of prevention, and trials in which two or more potentially active agents were compared with a single agent plus placebo. In several trials, patients were randomly assigned to receive an intervention or placebo, and a proportion of them (sometimes not stated explicitly) were already receiving some form of anticancer therapy. We included these trials in our review only if a substantial proportion of patients were not receiving additional treatment and if we judged it unlikely that effects on the outcome parameter under consideration could be due to the cancer therapy. Thus, trials evaluating relatively short-term changes in appetite or weight due to addition of a progestational agent or placebo were included, whereas long-term trials in which a bisphosphonate or placebo was added to changing regimens of chemotherapy or hormonal therapy were excluded. Trials in which some of the patients were receiving anticancer therapy are marked with an asterisk in the summary tables; it is possible that these trials overestimated effects due to treatment with a placebo. The initial selection of clinical trials was augmented by a review of the relevant references cited in the selected articles to give a total of 37 placebo-controlled trials that were reviewed in detail.

Placebo-controlled trials often have the implicit assumption that a comparison is being made between active treatment plus best supportive care (BSC) and placebo plus BSC. To gain insight into possible different effects due to placebo and BSC, we also searched articles with a control arm consisting of BSC alone. Using similar keywords in a MEDLINE search with term "best supportive care" replacing the term "placebo" as stated above, we identified 10 articles in which there was a comparison between active treatment and BSC, with selection criteria similar to those for placebo-controlled trials.

The articles that were reviewed used heterogeneous criteria for the evaluation of symptoms, quality of life, and tumor response; wherever possible, we have described these criteria. Some of the articles described changes in endpoints for individual patients, and we have then indicated the proportion of patients who had a defined improvement, compared with baseline, following initiation of treatment with either the putatively active agent or placebo. Other articles reported only the change in the average (median or mean) score for a given endpoint experienced by the randomized groups compared with baseline. Both of these measures were influenced by loss of patients to follow-up because of death or other cause. Because patients with clinical deterioration were more likely to be lost to follow-up, any apparent improvement in average symptom scores among the remaining group was likely to be due, in part, to selective loss of these patients. When data were available for individual patients, we based the probability of improvement in any endpoint on the number of patients that were evaluated initially (provided that this information is reported in the article). This strategy provides an intent-to-treat analysis, with the implicit assumption that those lost to follow-up did not improve. When average scores were available only for those patients remaining in the study, it was not possible to use an intent-to-treat analysis, and improvement in average scores in such trials should be regarded as weaker evidence for benefit, especially in trials in which a substantial number of patients were lost to follow-up. Estimation of tumor response was based on the number of initially randomly assigned patients with disease that could be assessed for response—either those with bidimensionally measurable lesions or those with an elevated serum marker.

Despite heterogeneity in the criteria used for evaluation of endpoints, we have attempted to provide a rough estimate of the probability of a beneficial effect of placebos from a weighted average of trials that evaluated each outcome measure in individual patients. Here the probability of favorable response in each trial was weighted by the number of patients in the placebo arm.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Thirty-seven randomized, placebo-controlled trials were included in this review. All of the studies were double-blinded. The placebo was given orally in 26 trials, intravenously in six trials, subcutaneously in six trials, and intramuscularly in one trial (two routes of administration were used in two trials). Ten nonblinded, randomized trials that compared an active treatment plus BSC with BSC alone were also reviewed. The results of various trials are reported in Tables 1–6GoGoGoGoGoGo, and when the authors of the trials provided these data, both the total number of randomly assigned patients with the symptom of interest and those that remained on study long enough to be assessed are indicated. The number of patients can differ from one table to another for the same trial because not all of the patients were always assessable for all of the endpoints.


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Table 1. Reduction in pain observed in placebo-controlled trials*
 

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Table 2. Improvement in appetite in randomized controlled trials*
 

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Table 3. Weight gain in randomized controlled trials
 

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Table 4. Improvement in performance status (PS) in randomized controlled trials*
 

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Table 5. Assessment of quality of life in randomized controlled trials*
 

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Table 6. Objective tumor response in randomized controlled trials*
 
Effects of Placebos on Symptoms

Pain. In 12 placebo-controlled trials, pain was an endpoint, and a total of 405 patients with pain were assigned to receive placebo (Table 1Go). Only six relatively small trials (1621), which included 149 patients in the placebo arms, reported individual evaluation of pain scores. An individual reduction of pain and/or of analgesic intake was reported in the placebo arm of five (1721) of these six trials, with the percentage of patients reporting a reduction in pain ranging from 0% to 19% (weighted mean for all six trials was 9%). In one of these trials, 7% of the patients had reduction in pain as measured by a visual analog scale, but 21% reduced their analgesic intake (19). Validated methods were used for evaluation of pain [except for one trial (20)], including visual analog or numeric scales and analgesic consumption. Criteria for pain reduction (usually more than 20%) were defined in only three trials (16,20,21).

The other six trials (2227) involving 256 patients in the placebo arms did not record responses for individual patients. In two of these trials, the investigators reported an improvement in average pain score for the placebo groups (25,26). Even when placebos were unable to improve overall pain control, however, there might have been some individual patients who experienced benefit.

Two randomized trials comparing cancer therapy plus BSC with BSC alone included pain control as a secondary endpoint (28,29). No improvement in pain control was reported in any of 72 patients in the BSC arms, whereas individual improvement was reported in the active treatment arm. The probability of improvement in pain among patients receiving placebos in double-blinded trials (14 of 149 patients) differs statistically significantly from that in patients receiving BSC (0 of 72 patients; P = .003 using a two-sided Fisher's exact test).

Appetite and weight gain. Improvement in appetite was observed in 8%–27% of 365 patients (weighted mean = 20%) included in the placebo arms of five trials (17,3033) in which this was an endpoint (Table 2Go), but there was no improvement in average level of appetite for the placebo arm in these trials. Criteria used for establishing an improvement in appetite were self-evaluation using visual analog scales or specific questionnaires. Criteria for defining a clinically important amount of improvement were not stated. In seven other trials (22,3439) involving 451 patients receiving placebos, the average overall measure of appetite remained stable in five trials (22,34,36,37, 39), decreased in one trial (35), and improved in one trial [(38), Table 2Go]. Information for individual patients was not available in any of these seven trials.

Weight gain was one of the objectives of 11 trials in which 776 patients received a placebo (Table 3Go). Five trials reported weight gain in the placebo arm (using variable criteria to define it) for 7%–17% of patients (weighted mean for the five trials was 11% of 376 patients) (3033,38). In the other six trials (22,3437,39), in which average results were reported for patients randomized to the placebo, there was net weight loss. It is again possible that some individual patients had benefit, but this was not specified. The duration of effect was not documented in any trial.

One trial comparing active treatment with BSC also considered appetite and weight gain, and observed weight gain in nine (18%) of 50 patients receiving BSC for non-small-cell lung cancer (41).

Other symptoms. In the trial comparing methylprednisolone with placebo, Bruera et al. (17) evaluated activity, anxiety, and depression, as well as pain, by using visual analog scales. Forty patients (three without pain) were randomly assigned to active treatment or placebo arms in a crossover design. Improvement in the placebo arm was observed in five, seven, and four patients for activity, anxiety, and depression, respectively, as compared with 19, six, and 22 patients treated with the steroid. Wald et al. (42) conducted a trial comparing alprazolam with placebo for anxiety and depression in cancer patients, using validated scales. They observed a reduction of more than 50% on the Hamilton Anxiety Score in seven (39%) of 18 patients receiving placebo and nine (50%) of 18 of those receiving active treatment. Seven patients in both groups (39%) also improved their Hamilton Depression Score by more than 50%.

In a trial with a crossover design that included nine patients, Mazzocato et al. (43) observed no statistically significant reduction in a mean visual analog score for dyspnea after treatment with a placebo, whereas treatment with morphine improved this score.

Performance Status and Quality of Life

Performance status. In 10 trials in which 436 patients were randomly assigned to receive a placebo, performance status (PS), as assessed by a physician, was used as an endpoint (Table 4Go). An improvement of PS (assessed by Karnofsky index or by Eastern Cooperative Oncology Group score) during placebo administration was reported in 14% and 6% of patients included in two trials (38,44). The amount and duration of improvement was not specified. In one of these trials (38) and in the eight other trials that did not report data for individual patients, average levels of PS for the placebo arm remained stable [six trials (17,22,4547)] or decreased [three trials (32,37,48)].

Evaluation of PS was also performed in five trials with a BSC control arm (41,4952). PS improved in 10 (11%) of 90 patients with advanced colon cancer (49) who received BSC. In the four trials for lung cancer (41,5052), there was a decrease in mean PS for the group receiving BSC in one, while in the other trials, two (4%) of 50 and 19 (19%) of 98 patients randomly assigned to receive BSC were reported to have an improvement in PS. However, in the largest trial (50), 31% of the patients subsequently received chemotherapy, 19% of them within 1 month of randomization. The duration of effect was not reported in any of these trials.

Quality of life. Quality of life was evaluated in 10 trials using a specific questionnaire that was completed by patients (Table 5Go). A total of 538 patients were evaluated in placebo arms. None of these trials recorded changes in quality of life for individual patients. Mean levels of quality of life for patients randomly assigned to placebo arms decreased in five trials involving 313 patients (21,3436,48) and remained stable over the short term in five trials involving 225 patients (3739,46,53).

Quality of life was assessed by a validated scale in three trials designed with a BSC control arm (49,50,56). One trial reported only the mean level of quality of life, which decreased in the BSC arm (49). The two other trials reported individual results of quality-of-life evaluation. Thongprasert et al. (50) evaluated the quality of life of patients with non-small-cell lung cancer receiving either chemotherapy or BSC. They found an improvement of individual scores in 19 (41%) of the 46 patients receiving BSC who completed the questionnaire at 2 months and in nine (50%) of the 18 patients who completed the questionnaire at 6 months. The mean scores of the BSC arm decreased during these two periods. Glimelius et al. (56) also found an improvement in quality of life assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ–C30) in six patients receiving BSC for advanced gastric carcinoma (20% of the BSC arm). One of these six patients had subsequently received chemotherapy. The average global scores of the BSC arm remained stable.

Tumor Response

Objective response of the tumor to treatment was used as an endpoint in 10 trials (Table 6Go). In these trials, 464 patients who could be assessed for tumor response were randomly assigned to a placebo arm. In seven trials, response was defined as a reduction of tumor size according to World Health Organization (WHO) criteria. In six of them (44,48,5961,63), current methods of assessment such as computerized tomographic (CT) scan were available; the other trial was published in 1977 and tumor size was measured by chest x-ray (58). One trial used a more stringent criterion of requiring a 50% reduction in tumor diameter (57), while in the other two trials (53,62), the criterion of response was a 50% or greater reduction in levels of a serum marker (prostate-specific antigen [PSA] or 5-hydroxy indole acetic acid).

Objective response rates in the placebo arms were low but were different from zero in five trials, ranging from 2% to 7% (Table 6Go). In a placebo-controlled trial for renal cancer, Gleave et al. (61) described objective responses in six (6.6%) of 90 patients in the placebo arm with three partial and three complete responses, lasting 2–13 months; by comparison, the response rate was only 4.4% in the interferon {gamma} treatment arm. Rare tumor responses to placebo were also reported in trials for cancers of the lung (58), colon (60), liver (59), and prostate (62).

There are always differences in assessment of response among different trials, and selection of patients influences response rate for all types of cancer. With this caveat, for all the trials included in our review that evaluated objective response of patients with bidimensionally measurable disease (according to WHO criteria), the overall response rate to placebo was 2.7% [10 of 375 patients (44,48,5861,63)]. The response rate was 1.4% (four of 285 patients) if the trial for renal cell cancer (61), in which spontaneous regression is known to occur, was excluded. For the two trials (53,62) that used a 50% decrease in a serum marker as the criterion of response, response rate was 1.7% (one of 60 patients).

Five of the 10 trials with a BSC arm that we included in our study considered objective response rate as a major endpoint (28,29,56,64,65). One of the 191 patients included in the BSC arms achieved an objective response. In two additional trials with a BSC control arm, response was evaluated in the active treatment arm but not in the 138 patients assigned to receive BSC (52,66).

Toxicity

Side effects of treatment in the placebo arms were reported in most of the trials included in our review. They were usually moderate, but in one study they were a reason for withdrawal of eight (12%) of 66 patients receiving placebo (35). In the study of renal cell cancer (61), five (6%) of 90 patients receiving placebo experienced grade III toxicity. Side effects were very similar from one trial to another—nausea and vomiting, abdominal pain, lethargy, dry mouth, diarrhea, and so on—and were present in about 10%–60% of patients. There was an association between the type of and incidence of side effects in the treatment and placebo arms among the randomized trials. These side effects may have been disease-related, or similar to those that are associated with active treatment and were anticipated by patients receiving placebos.


    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
For treatment of nonmalignant diseases, there is evidence that either spontaneous improvement or placebo effects can lead to improvement in a substantial proportion of patients (48). A prior review by Moertel et al. (13) also suggested that placebos could lead to improvement in pain due to cancer, when based on patients' impressions of improvement in comparative trials of analgesic medication. The endpoints used in such trials would not now be regarded as optimal, but if placebo effects are common in oncology, they could explain many of the effects attributed to active agents.

Few clinical trials demonstrate improvement in survival for patients with advanced disease (15), so that palliation depends mainly on improvement in symptoms or in overall quality of life. The probability of improvement in these endpoints following chemotherapy or other treatment is often found to be limited, as is the rate of tumor response for many patients with epithelial cancers. Indeed Oliver (67) questioned whether the effect of cytokines in patients with renal cell carcinoma was a true antitumor effect, a placebo effect, or simply due to spontaneous regression. If one could achieve benefit from placebos similar to that from expensive and toxic anticancer drugs, there would be substantial implications for clinical practice. It would also render difficult or impossible the analysis of trials that were not double-blinded and placebo-controlled.

For the above reasons, we undertook the current review of placebo effects in oncology. We are unaware of previous comprehensive reviews. We recognize that our review has limitations, which are determined by the quality of the data in individual publications and which do not allow the type of rigorous approach that can be used in meta-analyses of clinical trials that have uniform methods of reporting. Variable methods were used for assessment of symptoms, quality of life, and even tumor response, and the criteria used for judging improvement or decline varied and were not always stated explicitly in the papers that we reviewed. Some trials used a binary cutoff for determining response or nonresponse in the outcome measure of interest, whereas others reported change on a continuous scale and usually included an estimate of mean or median change for the active treatment and placebo (or BSC) arms. Dropout of patients from studies causes bias in a comparison of average values for any given endpoint between baseline and a later time; this bias is usually in the direction of overestimation of benefit because patients who are not doing well are those who tend to drop out. For this reason, we have emphasized clinical trials in which symptoms or other scores are provided serially for individual patients, and we have used an intent-to-treat analysis in summarizing data that is based on the number of patients evaluated at baseline. Despite these limitations, our review suggests an upper limit on effects that might be expected from placebos, and we believe that this information is important to cancer clinicians and to those who are designing clinical trials. With the above caveats, and with recognition that weighted means for probability of outcome measures in patients receiving placebos in different trials are subject to error, we summarized our overall results in Table 7Go. Our hypotheses were that placebo effects would be relatively common when the endpoints were symptom control or improved quality of life and uncommon when the endpoint was a measure of tumor response.


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Table 7. Overview of placebo effects
 
Our review suggests acceptance of our second hypothesis—that tumor responses are rare following treatment with a placebo (Tables 6 and 7GoGo). Measurement error (68,69) and nonrigorous criteria of tumor response (70) can lead to a false impression of tumor response, and this may be the cause of apparent response in some trials. In contrast, publication bias might have led to an underestimation of response rate to placebos in our review because studies with statistically significant results are more likely to be published; thus response rates on treatment arms might be overstated and those on placebo arms understated. These effects of measurement error and nonrigorous criteria of response are likely to be more common for trials of slowly growing tumors and when the duration of response is reported to be short, as in the older trial of lung cancer discussed here (58), but some responses were of long duration (up to 13 months). Tumor response to placebo was most common in the trial for renal cell cancer (61), and renal cell carcinomas are known to be capable of spontaneous regression; however, the incidence of such regression is usually reported to be less than 1% (71). Even in unblinded trials, a significant difference in rate of tumor response between active and control arms, determined either by WHO criteria or by reduction of a tumor marker, is unlikely to be due to placebo effects.

Our review could also suggest acceptance of our first hypothesis—that improvement in symptoms may occur following treatment with a placebo. Moderate rates of clinical improvement in patients receiving placebos were observed for assessment of symptoms, such as pain or appetite, and for weight and PS; the probability of improvement in levels of pain appeared to be greater among patients receiving placebos than among those receiving BSC. For symptom control as well as for objective response, the use of rigorous criteria is necessary. Most authors used validated scales to assess symptoms and quality of life (Tables 1–5GoGoGoGoGo), but criteria for the amount of improvement needed for a symptomatic response were rarely available. For this reason, we did not attempt a statistical analysis of heterogeneity in the outcome measures in the mainly small trials reviewed in Tables 1–5GoGoGoGoGo, as would be done in a meta-analysis of large trials with outcome measures such as patient survival.

Because antitumor drugs have limited ability to improve survival for patients with advanced cancer, improvement in quality of life is a major goal in trials of palliation. Several of the trials in our review assessed overall changes in quality of life by validated scales in both the active and the placebo arms, but none of them evaluated the probability of improvement in individual patients. In five of these 10 trials (21,3436,48), average quality of life scores (i.e., mean group scores) declined in the placebo arms, whereas in the other five (3739,46,53) they remained stable for a short period. Interestingly, individual data are available from two BSC-controlled trials (50,56) that show some individual improvement in both arms, even with a deterioration of the mean scores. Individual data are also available from two placebo-controlled trials (38,44) for changes in PS (as measured by the physician), and an improvement was observed in 14% and 6% of the patients receiving placebo; some improvement in PS was also reported for patients receiving BSC in three other trials (41,49,50). Thus, placebo effects to improve quality of life and PS are relatively rare and seem to differ minimally from effects due to supportive management (which may itself include placebo effects from treatment given with the intent of controlling symptoms) or from natural fluctuations in the course of the disease. Although cancers usually progress, transient improvement in symptoms or PS can occur without any cancer-specific intervention.

Negative effects in patients receiving a placebo were reported frequently. There was an association between the probability of toxic effects in the treatment arm and in the placebo arm. These effects may be due either to effects of the cancer itself or to anticipation by patients of side effects that have been described to them as likely to occur in the active treatment arm.

The definition of placebo effect, either explicit or implied, varies considerably in the literature. Here we have distinguished between trials in which a dummy medication (the placebo) was given to patients and those in which the control arm consisted of patients receiving BSC. However, BSC is not equivalent to no treatment, and placebo effects might occur as a result of the therapeutic strategies used to control symptoms as part of BSC. The optimal way to assess placebo effects might be to undertake three-arm randomized trials comparing a putatively active treatment plus BSC, a placebo plus BSC, and BSC alone. This type of trial is unlikely to be acceptable to patients with cancer (or to their physicians) but has been undertaken in patients with nonmalignant disease. The results of 114 trials with placebo and BSC arms were reviewed recently (72). These trials showed no consistent effects of placebos to improve objective or binary outcomes, but there were possible small benefits (as compared with BSC) for subjective outcomes that were evaluated using continuous scales and for the treatment of pain (72). In the present review, we have included an indirect comparison between trials with a placebo arm and those with a BSC arm. There was a small difference in favor of placebo treatment in both tumor response rate ({approx}2.4% versus 0.5%) and the probability of improvement in pain. However, there were few substantial differences in outcome in the control arms of placebo-controlled or BSC-controlled trials. Thus our findings are consistent with those comparing groups receiving placebos and BSC for patients with diseases other than cancer.

The results of our review have implications for the future design of randomized controlled trials, especially those with endpoints such as symptom control or improved quality of life. Validated and quantitative scales, completed by patients before, during, and after therapy should be used to assess these endpoints; they are as reproducible as other measures such as tumor response. The probability of changes of any outcome measure in individual patients should be recorded in both arms using an intent-to-treat analysis rather than average changes in the whole group. Reporting of average changes in the arms of a trial is subject to bias from dropout and may miss important effects in individual patients.

Although our review suggests limited improvement of patients with cancer who are receiving placebos in randomized trials, we strongly support the use of a double-blind, placebo-controlled design for randomized trials whenever this can be done with minimal impact on patients [or on recruitment to the trial (73)]. In an open comparison of BSC plus active treatment with BSC alone, the effects in the active treatment group might be inflated, not only by a true placebo effect but also by biased expectations of the investigator, more encouragement to the patient to report benefit, patient's desire to please, and other influences. A placebo-controlled trial has the advantages of ensuring equal conditions in both arms and of minimizing various types of bias. There are, however, important questions that need to be addressed in a subset of randomized trials in which inclusion of a placebo arm can be either misleading or ethically questionable. Some trials may involve a comparison of intravenous chemotherapy with BSC or with other approaches using oral agents. In this situation, the double-blind, placebo-controlled format requires administration of unnecessary intravenous infusions to patients, which can, of itself, decrease quality of life and occasionally cause toxicity. Moreover, some double-blinded trials compare treatments with quite different side effects, so that most investigators and many patients rapidly become aware of which treatment arm is being administered. In these situations, the benefits of the double-blind design are questionable. The present review suggests that substantial, well-documented, patient-reported improvements in symptom control or quality of life (particularly when supported by objective evidence of tumor response) are unlikely to be due to placebo effects.


    NOTES
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 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Dr. Tannock was supported by an award from the Ministry of Education, Research and Technology of France during his sabbatical year in Lyon.

We thank Drs. Sylvie Negrier (Centre Léon Bérard, Lyon, France) and Kelly-Anne Phillips (Peter MacCallum Cancer Institute, Melbourne, Australia) for their helpful comments.


    REFERENCES
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 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Manuscript received December 28, 2001; revised September 23, 2002; accepted October 25, 2002.


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