ancer TreatmentReviews"( 1991) 18, 85 93

~ o w should n a u s e a be a s s e s s e d in patients receiving :hemotherapy? ;tanley B. K a y e

%atson Oncology Centre, Western Infirmary, Glasgow G I 1 6NT, U.K.

3 l. MAR 92 GY ~:'n CT?:j? ............

Introduction

\lthough myelosuppression is considered to be the major dose-limiting toxic effect of :ytostatic chemotherapy, when patients are asked which adverse event affects them most lausea and vomiting is generally the most common reply (6). Chemotherapy most often nduces nausea and vomiting within 1 2 h of treatment and the acute emesis usually lasts or 24 h (15). Most studies of anti-emetic treatments have examined emesis control in this )eriod. The best treatment available betbre the advent of the 5-HT3 receptor antagonists, ligh-dose metoclopramide, is only partially effective in patients receiving highly emeto,~enic chemotherapy such as high-dose cisplatin even when used in combination with )ther agents. Complete anti-emetic control in the acute period is important. The main :onsequence of poor initial control is that 1-57°,,o of patients will suffer from anticipatory lausea, depending on the emetogenicity of their chemotherapy regimen, which may lead o refusal of further potentially curative courses of chemotherapy (3, 26, 27). The medical complications of persistent vomiting include: dehydration, electrolyte mbalance, metabolic alkalosis, decreased renal elimination of drugs, malnutrition, vitamin teficiencies, oesophageal tears, aspiration pneumonia and pathological fractures (21). In tddition, patients receiving monthly cycles of chemotherapy may experience delayed ~ausea and vomiting tbr up to 3 weeks out of every 4, and the effects of this on their tuality oflit~ include anxiety, depression, restriction of social life, job loss and even suicide 21, 34). Thus, there is clearly a need for anti-emetics which a~e not only effective tgainst vomiting, but also proved to be effective against nausea because the mechanisms mderlying the development of nausea may be substantially different from those involved n vomiting. The identification of such treatments will require a standardized, simple, ~ccurate and reproducible method tbr assessing the patient's experience of nausea and the mpact of anti-emetic treatment on it.

C u r r e n t m e t h o d s o f a s s e s s m e n t and the i m p o r t a n c e o f the a s s e s s m e n t o f n a u s e a

Mthough there have been many anti-emetic studies during the last decade, it is difficult o draw conclusions t?om them because of methodological differences (26). Foremost )305 7372/91/020085 + 09 $03.00/0

© 1991 Academic Press Limited 85

86

S.B. KAYE 1.

Table

K e y i s s u e s in t h e ment

• • • • •

assess-

of nausea

Types of assessment scales Time of assessment Indirect measures Who does the assessment Anticipatory nausea

[Adapted from Morrow (28), with permission from the author and Cancer.]

among these deficiencies are differences in the criteria used to assess emesis. A detailed review of this problem was published by Morrow (28) who examined the assessment of nausea and vomiting in 120 studies involving 1512 cancer patients. The key issues in the assessment of nausea are outlined in Table 1. According to Morrow, global assessments of efficacy have been made in anti-emetic studies without taking into account that nausea and vomiting are separate phenomena and that different drug regimens do not have uniform effects on all the characteristics of chemotherapy-induced emetic side-effects. Nausea is a subjective sensation for which patient self-assessment must be the primary measurement tool (30). Although Morrow's survey showed that self-report measures of frequency and severity of nausea were more commonly used than observer ratings, the duration of nausea was rated considerably less often than the above parameters, by both patients and observers, despite the tinct that duration of nausea will cause patients just as much concern (Figure 1). The use of observer-rated measures is an appropriate means of assessment for the frequency of vomiting but its accuracy in nausea is doubtful. Methods of assessment should be both simple and reproducible. A large number of evaluation points, or multiplying several variables together, to score a subjective experience does not necessarily increase the quantitative accuracy of the assessment (20, 30). Simple

60

Self-report

~

Observer- rated

5O 40 "6 E

30 1 I i Nausea

Vomiting

Nclusea

Vomiting

Figure 1. The percentage of studies using self-report or observer rated methodology for dimensions of nausea and vomiting [after Morrow (28), with permission from the author and Cancer].

HOW SHOULD NAUSEA BE ASSESSED IN PATIENTS RECEIVING CHEMOTHERAPY? T a b l e 2.

87

Scheme for anti-emetic assessment

Nausea Pretreatmcnt Post-treatment Severity [4-pnint scale (none, mild, moderate and severe)] Duration (h) Vomiting No. of episodes Pretreatment (0 2, 2 4, 24 h) Other parameters and toxicity Anxiety (4-point scale) Sedation [none, mild, moderate and severe (duration of sleep)] Specific toxic efl'eets Benzodiazepines (amnesia) Cannabinoids (dysphoric reactions) 4-point scale (none, mild, moderate and severe) Response Complete rcsponse (no nausea or vomiting) Lesser response State sexerity of nausea on 4-point scalc No. of vomhing episodes during study Patient's overall assessment 4-point scale (very well to very poorly) Commellts Patients report why anti-emetic not tolerated [Adapted ti'om Otver el al. (30), with permission from the author and Cancer Treatment Reports.] o r d i n a l scales with 3 - 4 points seem to be a p p r o p r i a t e , as exemplified in a study of l o r a z e p a m in which patients experienced difficulty with linear a n a l o g u e scales (28, 30). F u r t h e r s u p p o r t i n g evidence for the use of simple rating scales comes from a comparison of 7-point a n d visual a n a l o g u e scales in a r a n d o m i z e d d o u b l e - b l i n d placebo-controlled study o f d i g o x i n in patients with h e a r t failure (20). J a e s c h k e et al. (20) found that the two methods of presenting response options showed c o m p a r a b l e responsiveness and validity. However, the 7-point ordinal scale was r e c o m m e n d e d because of its ease of use and i n t e r p r e t a t i o n . In addition, it is i m p o r t a n t to select a consistent time frame for measuring change, that makes sense clinically, or which has been d e m o n s t r a t e d to be a peak period for nausea a n d v o m i t i n g in o r d e r to i m p r o v e the accuracy of the assessment. It should also be borne in m i n d that anti-emetic t r e a t m e n t m a y affect the time course (duration) as well as the severity of emesis (28). T h e use of indirect measures of nausea and v o m i t i n g is v a l u a b l e because they allow assessment of the i m p a c t of reduction of nausea and vomiting on other aspects of the patients thnctional abilities. T h e y include m e a s u r e m e n t of appetite, the elapsed time before r e s u m p t i o n of eating and drinking, general well-being and preferred anti-emetic t r e a t m e n t (28). O l v e r el al. (30) described the greatest difficulty with the m e t h o d o l o g y of anti-emetic studies as the lack of b r o a d l y accepted definitions of response. T h e y r e c o m m e n d e d that fbr nausea a 4-point psychometric scale g r a d e d as " n o n e " , " m i l d " , " m o d e r a t e " or "severe" could be used. This scale was i n c o r p o r a t e d into a global scheme for anti-emetic assessment (Table 2) which defined complete response as the absence of both v o m i t i n g and nausea, as opposed to the simple absence of vomiting. Despite this considerable b o d y of evidence, which points to the i m p o r t a n c e of assessing nausea t h r o u g h the use of simple ordinal scales, some recent studies of anti-emetics have only used the t?equency of v o m i t i n g to define the anti-emetic response. In the studies

26 MET resistant pts

18 children

11 pts

44 pts

40 pts

42 pts

Bruera et al. (5)

Dalzel[ et al. (8)

DeJong el al. (10)

Goldstein et al. (14)

Ibrahim et al. (19)

Markman et al. (25)

Niiranen and Mattson (29) 40 pts

60 pts

Patient Nos.

NAB/DEX

N A B vs

DEX vs PC

High doses DEX vs MET

D E X vx PC

M E T vs SUL

NAB > D O M

MET/PLBO vs MET/DEX

DEX vs DEX/ MET/DIPH

Comparator anti-emetic regimens = DEX

Nausea NAB = NAB/DEX Vomiting NAB/DEX > NAB Appetite/food intake NAB - NAB/DEX

Nausea D E X > PC (p < 0.02) Vomiting D E X > PC (p < 0.03) Complete absence of N + V D E X > PC (p < 0.001) (for both)

Nausea SUL > M E T Vomiting SUL > M E T Equal efficacy in terms of duration of nausea and duration of vomiting Vomiting DEX > M E T (p < 0.025) Appetite D E X > M E T 00 < 0.025) Activity D E X > MET (p < 0.01)

NAB > D O M Vomiting (p < 0.01) Nausea (p = 0.01)

M E T / D E X > MET/PLBO (p < 0.001)

DEX/MET/DIPH

Anti-emetic efficacy

Patient preference and comments

=

PC

NAB = NAB/DEX

Somnolence PC > DEXp < 0.001

M E T > DEX

DEX

Patient preference DEX = 70% MET = 5% No difference = 20% No order effect found Patient preference DEX = 50% PC = 12% Both equally effective = 21% Neither effective - 14% With DEX the majority ofpts had a normal appetite Patient preference NAB/DEX = 66% NAB = 34% p < 0.05

Patient preference was also split equally between treatments and no preference

Patient preference DEX = 62% DEX/MET/DIPH = 23% No difference = 15% No order effect found M E T / D E X = MET/PLBO M E T / D E X had significantly greater anti-nausea and antivomiting efficacy NAB > D O M Patient/Parent preference (mainly due to drowsiness andNAB = 67% mood DOM = 5% changes) No preference = 28% SUL = M E T No data?

D E X / M E T / D I P H > DEX

Adverse events

S u m m a r y of r a n d o m i z e d c r o s s o v e r s t u d i e s o f a n t i - e m e t i c s in c a n c e r c h e m o t h e r a p y that e x a m i n e d p a t i e n t p r e f e r e n c e

Al-Idrissi et al. (2)

Study

Table 3.

,
M E T (fl < 0.01)

N a u s e a L O R / D E X > M E T (p < 0.01) V o m i t i n g L O R / D E X > M E T (p < 0.01)

MP/DRO > MET/DRO

Nausea (severity) L O R / P C > P L B O / P C (p - 0.002) (duration) L O R / P C > P L B O / P C (p = 0.0016) V o m i t i n g (severity) L O R / P C > P L B O / P C (p = 0.006) No. of episodes) L O R / P C > / P L B O / P C (p = NS) Anxiety LOR/PC = PLBO/PC N a u s e a D E X ~> M E T (p = NS) V o m i t i n g D E X >~ M E T (p = NS)

Nausea MP > PLBO Vomiting MP > PLBO O v e r a l l effectiveness MP > PLBO LN = PC

S o m n o l e n c e due to PB was re~arded as a desirable sideeffect

Drowsiness with L O R / D E X was r e g a r d e d as a desirable side-effect

MET > DEX ( m a i n l y due to e x t r a p y r a m i d a l effects)

Sedation was r e g a r d e d as a desirable side-effect

L N > PC

Patient preference DEX MET O t h e r anti-emetics Patient preference MP/DRO MET/DRO Patient preference LOR/DEX MET No preference P a t i e n t preference PC/DEX/PB MET

Patient preference PC LN Neither d r u g Patient preference LOR/PC PLBO/PC

Patient prelkrence MP > PLBO

KEY: D E X = d e x a m e t h a s o n e : D I P H = D i p h e n h y d r a m i n e : D O M = d o m p e r i d o n e ; D R O = droperidol; L N = l e v o n a n t r a d o l ; L O R = l o r a z e p a m ; metoclopramide; NIP = methylprednisolone; NAB = nabilone; PB = p e n t o b a r b i t a l ; PC = prochlorpcrazinc; P L B O = placebo; S U L = sulpiride.

127 pts

O s o b a et al. (31)

MET =

= 100% = 0%

= 70°Jo = 12~!o = 18%

= 82% = 18%

= 70% = 22% - 8%

= 56% = 44%

= 44% - 31% = 25°"0

>

m

©

m

©




>

>

~Z

m ©

90

S.B. KAYE

conducted by Hesketh et al. (18) and Kris et al. (23), the complete anti-emetic response was defined simply as the absence of vomiting or retching. Nausea was assessed (extent of nausea) by using a 100 m m visual analogue scale, and the treatment effects on nausea were reported separately from vomiting. Comparisons between different studies are very difficult to make because of the methodological problems of anti-emetic studies, in patients receiving chemotherapy. These have recently been highlighted by Grunberg (16), who called for the development of a consensus on the establishment of common criteria for evaluating response. In addition, in a recently retrospective analysis of 275 cancer patients, who suffered from nausea, Del Favero et al. (9) supported the recommendations made by Morrow (28) and Olver et al. (30). They found that analogue scales did not offer any specific advantage over a simple 4-point psychometric rating scale, irrespective of the dimension of nausea that was measured, and that there may also be a potential disadvantage with analogue scales because patients must be carefully instructed by trained personnel to produce reliable answers. Their analysis showed that the correlation between nausea and vomiting was weaker in those treated to control emesis than in untreated patients. This was due to the variable response of nausea to anti-emetic therapy which meant that while patients may be released from vomiting some 10% may continue to suffer from nausea. Therefore, nausea should be regarded as a separate component of emesis, included in any assessment of the response to anti-emetic therapy, and complete protection from nausea (and vomiting) must continue to be the main efficacy parameter with which to assess the validity of any new anti-emetic therapy. In view of the fact that nausea has such a great impact on patients' quality of life, and because it can persist even when anti-emetic therapy has eliminated vomiting, patients are likely to prefer anti-emetic therapies that have been proved to be effective against nausea. However, the validity of patient preference is not universally accepted as a measure of anti-emetic performance. Methodological differences, particularly relating to the assessment of nausea, make it very difficult to make comparisons between different new antiemetic treatments, e.g., the 5-HT3 receptor antagonists.

The importance of patient preference The usefulness of patient preference as an index of anti-emetic performance can be most reliably assessed by examination of the results of randomized crossover studies. In an area such as nausea, where assessment is subjective it seems attractive to have the patient serve as his/her own control. In addition, through avoidance ofinterpatient variability, and by evaluating each patient receiving both treatments, it may be possible to reduce the number of patients required for a trial (30). The main potential confounding factor with this method of study is the possibility of the relative efficacy of the two treatments being different in the second period than in the first because patients may have developed anticipatory nausea after their first session of chemotherapy. However, Willan and Pater (35) have concluded that cross-over studies are a practical method for assessing patient preference for anti-emetics because the amount of carry-over nausea from the first period would have to be very substantial in order to confound the results and, therefore, this would be unlikely to occur. Furthermore, because of the reduction in variance gained by using the patient as his own control, crossover studies have much greater power for a given sample size than parallel designs (32). Consequently, a small overall difference between regimens can be statistically significant

HOW SHOULD NAUSEA BE ASSESSED IN PATIENTS RECEIVING CHEMOTHERAPY?

91

if it is consistently present in each patient and, more i m p o r t a n t l y , this design allows patients to state a global preference for one anti-emetic t h e r a p y or another. This c a p a b i l i t y seems to be the key to the assessment of anti-emetic regimens, which are b e c o m i n g more intense a n d which m a y not be well tolerated. P a t e r a n d W i l l a n (32) illustrate this point by discussing the case of a study in which a regimen with similar activity against v o m i t i n g was strongly preferred by patients because of its lower toxicity. T a b l e 3 summarizes the results of r a n d o m i z e d cross-over studies of anti-emetics, illustrates patient preferences where this i n f o r m a t i o n was available, and supports the use of p a t i e n t preference in the assessment of anti-emetics. F o r example, the table indicates t h a t where anti-emetic t r e a t m e n t s are e q u i v a l e n t in efficacy, patients prefer the best tolerated regimen, a n d where anti-emetic t r e a t m e n t s are different in efficacy patients prefer the most effective, Thus, it would seem that p a t i e n t preference provides a reliable measure of an anti-emetic's performance and it follows from the a r g u m e n t s presented above that where treatments are equally effective against v o m i t i n g patients are likely to prefer that which is most effective against nausea.

Conclusions I n s u m m a r y , clinical trials of anti-emetic agents in cancer c h e m o t h e r a p y must i n c o r p o r a t e assessments o f the patients' subjective experience of nausea into their definitions of antiemetic response. This is because nausea is a separate p h e n o m e n o n from v o m i t i n g which m a y persist, a n d have negative effects on patients q u a l i t y of life, even after v o m i t i n g has been suppressed. F o r this reason, patients are likely to prefer anti-emetic therapies t h a t have p r o v e n efficacy against nausea. E x p e r i m e n t a l d a t a from r a n d o m i z e d , cross-over studies have been presented to support the view that patient preference is a reliable measure of anti-emetic performance. I n the final analysis, there is evidence to suggest that dose is a critical factor in c h e m o t h e r a p y schedules (12, 17) a n d in some types of cancer relative dose intensity of c h e m o t h e r a p y has been correlated significantly with m e d i a n survival time (24). I n view of this, it is i m p e r a t i v e that the anti-emetic regimens which p r o d u c e the most effective control of nausea, as well as v o m i t i n g a n d which are the most a c c e p t a b l e to patients, are identified in o r d e r to m a x i m i z e p a t i e n t c o m p l i a n c e with c h e m o t h e r a p y regimens.

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30. Olver, I. N., Simon, R. M., Aisner, J. !1986) Anticmetic studies: a methodological discussion. Cancer Treatment Re];. 70: 555~ 563. 31. Osoba, D., Erlichman, C., Willan, A. R., Brigden, M. L., Geggie, P., Pater, J. L., Rusthoven, J . J . , Wilson, K. S. (1988 i Failure of methylprednisolone acetate tu prolong the aminauseant effect of intravenous methyleprednisolone sodium succinate in patients receiving chemotherapy. Clin. Invest. Med. 11:377 379. 32. Pater, J. L., Willan, A. R. (1984) Methodologic issues in trials ofantiemctics. J. Clin, Oncol. 2:484 487. 33. Sheidler, V. R., Ettinger, D. S., Diasio, R. P., Enterline, J. P., Brown, M. D. !1984) Double-blind multipledose crossover study of the antielnetic eft'ect nfintramuscular lewmantradol (:ompared to prochlorperazine. ,]. Clin. Pharmacol. 24. 155 159. 34. Whitehead, V. M. (1975) Cancer treatment needs better antiemetk:s. N. l~Slgl. J. Med. 293:199 200. 35. Willan, A. R., Pater, J. L. (1986) Carryover and the two-period crossover clinical trial. Biometrics 42:593 599.