European Journal of Pharmacology 722 (2014) 192–196
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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Review
Prognostic factors for chemotherapy induced nausea and vomiting David Warr n Department of Hematology and Medical Oncology, Princess Margaret Cancer Centre, Rm 5-204, 610 University Avenue, Toronto, Ontario, Canada
art ic l e i nf o
a b s t r a c t
Article history: Accepted 8 October 2013 Available online 21 October 2013
Purpose: to review the topic of prognostic factors for chemotherapy-induced nausea and vomiting. Multiple patient factors such as age, gender and alcohol intake have been found that affect the likelihood of emesis with a given chemotherapy. Pharmacogenomics has also been explored as a cause for variation in emetic response. In theory these risk factors could be used to optimize antiemetic therapy for individual patients but guidelines for prophylactic antiemetics are based solely upon the type of chemotherapy administered. Attempts to identify subgroups of patients for whom guidelines recommendations are suboptimal have thus far been unsuccessful except for those with a poor experience in a previous cycle of the same chemotherapy. At present, there is no basis for deviating from evidence-based guidelines when prescribing antiemetics prior to the first cycle of chemotherapy. & 2013 Elsevier B.V. All rights reserved.
Keywords: Emesis Prognostic Chemotherapy Cancer
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Prognostic factors vary in strength of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Nausea and vomiting with previous chemotherapy cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Commonly cited factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Anxiety. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Co-administration of serotonin specific reuptake inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Pharmacogenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. How large is the effect of a prognostic factor? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Predictive models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Control of chemotherapy induced emesis has improved substantially over the last 20 years through the use of prophylactic antiemetics. Antiemetics can, however, be costly and may induce annoying side effects. Chemotherapy agents vary greatly in the likelihood of inducing nausea and vomiting; thus the antiemetics administered should be tailored to the emetic challenge. The antiemetics recommended by guidelines groups such as the Multinational Association of Supportive Care in Cancer (Roila et al., 2010)
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are determined by the probability of a given drug causing emesis when administered without antiemetics. At one end of the spectrum are agents like vinorelbine which have virtually no risk of causing emesis and for which no antiemetics are recommended. At the other end are drugs like high dose cisplatin which cause emesis in virtually 100% of patients and for which a combination of a corticosteroid, 5-hydroxytryptamine3 (5-HT3) receptor antagonist and neurokinin1 (NK1) receptor antagonist is recommended. Each chemotherapy regimen is assigned an antiemetic regimen based upon the most emetogenic drug administered. The evaluation of emetogenicity is complicated by the fact that most chemotherapy protocols consist of combinations of agents and the net result may be a more emetogenic stimulus than a single agent. Only one instance of this enhanced emetic effect
D. Warr / European Journal of Pharmacology 722 (2014) 192–196
due to combination therapy is recognized in the guidelines (an anthracycline plus cyclophosphamide) in that a combination of two “moderately emetogenic” drugs qualifies as a regimen for which the NK1 RA aprepitant is part of recommended therapy (Basch et al., 2011; Roila et al., 2010). The rationale is that two large randomized clinical trials have documented a clinically important improvement in the control of emesis when aprepitant is added (Rapoport et al., 2010; Warr et al., 2005). Although even high dose cisplatin is more emetogenic when combined with cyclophosphamide or doxorubicin (Gralla et al., 2005) and a formula for estimating the emetogenicity of the enormous number of possible combinations was proposed (Hesketh et al., 1997), with that one exception, recommended treatment is based upon single agents. Clinical studies have established that, even with the same chemotherapy, there are patient related factors that alter the risk of emesis such as age, alcohol intake and gender (Hesketh et al., 2010) (Warr et al., 2011). Chemotherapy dose is undoubtedly important but it has been largely unexamined except for high dose cisplatin (Beck et al., 1992; Hesketh et al., 2010). It has been suggested that risk factors might be used to alter the antiemetics administered (Osoba et al., 1997). For example a patient who is about to receive “moderately emetogenic” chemotherapy but who is predicted to be at much higher than average risk for vomiting could in theory be prescribed the same antiemetic combination (a corticosteroid, 5-HT3 receptor antagonist and NK1 receptor antagonist) that would be recommended for patients receiving highly emetogenic chemotherapy. Conversely a patient who is about to receive high dose cisplatin but has a low risk profile might in theory be spared the expense of an NK1 receptor antagonist.
2. Risk Factors 2.1. Prognostic factors vary in strength of evidence The table (Table 1) lists risk factors that have been found in at least two clinical trials of substantial size as well as others for which there is less convincing evidence. The number of patient characteristics found in at least univariate analysis to influence the chance of emesis is sufficiently large that it is not possible to list all of them. Indeed, this area is even more complex because nausea
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and vomiting can be considered separately for risk factors with slightly different predictors in one analysis (Osoba et al., 1997) and emesis during the first 24 h and beyond 24 h may differ in their predictors (Dranitsaris et al., 2012). It has been noted that even in analyses of large databases from antiemetic trials, prognostic factors may be inconsistent across subgroups (Pater et al., 1994). Whether this is true variation or a chance variation due to multiple subgroup analyses is unknown. 2.2. Nausea and vomiting with previous chemotherapy cycle A course of chemotherapy generally consists of repeated administration of the same agents. Although emesis becomes somewhat more likely with successive cycles (de Wit et al., 2003; Herrstedt et al., 2005), it is not surprising that the strongest predictor of nausea or vomiting after the first cycle of chemotherapy is their presence or absence with the previous cycle with the same chemotherapy (Roila, 1996). Thus, for those patients who are already receiving chemotherapy, patient characteristics do not have a major role in determining the subsequent risk of emesis above and beyond knowledge of what happened with the previous cycle of treatment. 2.3. Commonly cited factors For patients with no prior chemotherapy, the most commonly cited high risk factors are young age, female gender, limited or no regular alcohol intake and previous emesis e.g. pregnancy associated vomiting or motion sickness. There is no physiological rational for the most commonly cited risk factors. Some factors may simply represent a different threshold for emesis irrespective of the stimulus. For example emesis is more common in females than males in the settings of palliative care (Kirkova et al., 2012), postoperative care (Leslie et al., 2008) and chemotherapy but the reason is unknown. Although female gender has been associated with poorer results in a large number of antiemetic trials, the combined results from two phase III randomized trials of aprepitant suggested that this gender difference disappeared when aprepitant was added to a 5-HT3 receptor antagonist and dexamethasone i.e. males and females fared equally well in the aprepitant containing arms gender (Hesketh et al., 2006). This surprising finding has not been evaluated in other studies with
Table 1 Risk factors for chemotherapy induced emesis. Risk factor
Established (2 or more studies)
Limited or contradictory evidence
References
Vomiting with previous cycle
✕
Roila (1996), Roila et al. (1989)
Type of chemotherapy administered
✕
Pater et al. (1994) Basch et al. (2011)
Antiemetic administered
✕
Pater et al. (1994) Warr et al. (2011)
Gender
✕
Hesketh et al. (2010), Osoba et al. (1997)
Age
✕
Warr et al. (2011) Hesketh et al. (2010)
Alcohol
✕
Warr et al. (2011) Hesketh et al. (2010)
Pregnancy associated emesis or motion sickness
✕
Warr et al. (2011) Pirri et al. (2011)
Anxiety
✕
Molassiotis et al. (2002)
Expectation
✕
Roscoe et al. (2004)
Concomitant opioid
✕
Shoji et al. (1999)
Concomitant serotonin specific reuptake inhibitors
✕
Koriech (1995) Mir et al. (2012)
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NK1 receptor antagonists and so it is not clear whether this newest of antiemetic classes truly eliminates gender as a risk factor. 2.4. Anxiety Anxiety has been suggested as a risk factor for post chemotherapy nausea and vomiting but the literature is mixed. Molassiotis found that state anxiety was associated with post chemotherapy nausea and vomiting but Pirri using a single item evaluation did not find a statistically significant association (Molassiotis et al., 2002; Pirri et al., 2011). In keeping with those results, Morrow found that anxiety before cycle one was a predictive factor for anticipatory symptoms but only when measured as a constellation of symptoms rather than a single item. Dranitsaris included anxiety as a factor in predicting post chemotherapy results but the patients enrolled often had prior cycles of the same chemotherapy and it is possible that they were anxious because of prior nausea and vomiting rather than it being a true prognostic factor for cycle one (Dranitsaris et al., 2012). A large, double blind study of anxiolytic lorazepam that impaired recall of chemotherapy administration and caused urinary incontinence showed no improvement in control of emesis versus diphenhydramine despite improving anxiety (Kris et al., 1987). Using the right measure for evaluating anxiety may identify patients at higher risk of anxiety but it is premature to conclude that pharmacological approaches will reduce that risk. 2.5. Opioids Opioids are known to cause emesis in some individuals and are commonly used in patients with advanced cancer so opioid use concomitant with chemotherapy is not rare. A cohort study (Shoji et al., 1999) strongly suggested that concomitant opioids enhance the risk of emesis with chemotherapy just as has been shown for postoperative emesis (Leslie et al., 2008). A pro-emetic effect was also found in a series of patients receiving highdose chemotherapy treated with maximal antiemetic therapy (Jordan et al., 2011). Interestingly, in pediatric patients not receiving opioids, the administration of the opioid antagonist naloxone enhanced emesis (Kobrinsky et al., 1988) indicating that endogenous opioids may actually have an antiemetic effect. 2.6. Co-administration of serotonin specific reuptake inhibitors Serotonin specific reuptake inhibitors are commonly prescribed for depression and have nausea as a well recognized side effect. Since depression is common in patients with cancer, they are frequently used. A case series and a cohort study suggested that the administration of serotonin specific re-uptake inhibitors enhanced the risk of emesis even when aprepitant was administered (Koriech, 1995; Mir et al., 2012). The authors hypothesized that the prevention of serotonin re-uptake enhanced post synaptic stimulation of 5-HT3 receptors. 2.7. Pharmacogenomics With the declining cost of detecting the presence of gene mutations, “personalized” therapy for cancer has become a common subject in oncology. Variants in the structure of the 5-HT3 receptors, variation in the rapidity of metabolism of the 5-HT3 antagonists and altered transporter genes for antiemetics have been explored as possible contributors to the risk of emesis. One study suggested that antiemetic therapy could be tailored according to whether their cytochrome P450 2D6 genotype indicated that they were slow or rapid metabolizers (since some 5-HT3 receptor antagonists are metabolized to some extent by that
enzyme) (Kaiser et al., 2002). The potential for clinical application is limited as the authors concluded that approximately 50 patients would have to be genotyped to prevent severe emesis in one patient. A recent review of pharmacogenomics and emesis found a relatively small number of studies with mixed results and concluded that it was premature to incorporate pharmacogenomics into practice (Perwitasari et al., 2011). Despite some initial enthusiasm, pharmacogenomics is unlikely to be of major assistance because of the complexity of the emesis pathway. Although the emphasis thus far has been on issues that might affect 5-HT3 receptor antagonist efficacy, it is well established that NK1 receptor antagonists, corticosteroids and olanzapine also substantially affect the risk of emesis. There is no reason to think that receptor mutation, drug transport and drug metabolism would not also potentially be important for these nonserotonin related pathways.
3. How large is the effect of a prognostic factor? An analysis of the results of several antiemetic studies concluded that the strongest prognostic factors for emesis with the first cycle of chemotherapy were the type of chemotherapy given and the antiemetics administered (Pater et al., 1994). That is not to say, however, that other factors are of trivial impact. Age, gender, alcohol intake may each be associated with an absolute difference of 10–15% in the likelihood of vomiting with chemotherapy such as high dose cisplatin and anthracycline–cyclophosphamide combinations (Hesketh et al., 2010), (Warr et al., 2011). In these studies, it was not possible to identify a subgroup that did not have a clinically important benefit from an NK1 receptor antagonist.
4. Predictive models Simply looking at the number of risk factors may change the average risk substantially but this has rarely been studied (Osoba et al., 1997; Sekine et al., 2013; Warr et al., 2011). Examining a heterogeneous group of chemotherapies given to 832 patients during the course of three randomized trials, a group of prognostic factors for emesis were identified in a multivariate analysis. The risk of emesis ranged from 20% to 75% depending upon the number of risk factors present (Osoba et al., 1997). A much more heterogeneous study of 866 patients receiving an anthracycline plus cyclophosphamide for breast cancer found that the risk of emesis despite receiving ondansetron plus dexamethasone varied from 12% to 61% depending upon whether there were no or three high risk factors (Warr et al., 2011). In theory, one could spare those patients at low risk from the relatively costly aprepitant. That low risk group constituted only 3% of the study population and with only one risk factor, the chance of vomiting was 34%. Thus, in this patient population, a low risk group of meaningful size in whom an NK1 receptor antagonist could be avoided was not identified. What is less clear is whether the identification of a high risk group within “highly emetogenic” chemotherapy is of clinical relevance since, in theory, maximal antiemetic therapy has already been administered. The recent demonstration that olanzapine was dramatically effective in patients who had nausea or vomiting despite maximal prophylactic therapy (Navari et al., 2013) suggests that there may indeed be value in identifying high risk patients who are about to receive highly emetogenic chemotherapy. The value of adding olanzapine to a corticosteroid, 5-HT3 receptor antagonist and an NK1 receptor antagonist for such high risk patients requires study.
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A more complex predictive model that incorporates multiple variables with different weights assigned for each factor has intellectual appeal. A model derived from logistic regression has been proposed for patients receiving a wide variety of cisplatin and non-cisplatin chemotherapy regimens (Dranitsaris et al., 2012). The objective was to predict those patients at risk of at least grade 2 vomiting in the acute phase (first 24 h after chemotherapy) or in the delayed phase (beyond 24 h). This was meant to apply to patients at any point along their course of chemotherapy. For the acute phase there were 10 easily determined factors and for the delayed phase there were eight factors. Although this model was said to be validated there are serious concerns about its utility: a) The current standard is complete protection of emesis (no vomiting or Grade 0) whereas the model was designed to predict Grade 2 severity emesis in the acute phase or the delayed phase separately which represents a substantially poorer goal. b) The strongest predictive factor for how a patient will do on any given cycle is the presence or absence of emesis in a previous cycle yet this parameter was not included in what purports to be a predictor of results over multiple cycles. c) The model makes the assumption that dexamethasone is used in the first 24 h and that aprepitant is not used, neither of which are necessarily true from surveys of antiemetic use. d) Some prognostic factors are not consistent with data or logic. For example, having received at least two prior cycles of chemotherapy or a 5-HT3 receptor antagonist, or taking non prescribed medications for emesis control is associated with a lower risk of vomiting. e) To be useful, the model should predict the probability of emesis at cycle 1 with standard antiemetics and this has not been tested. Given the very large number of chemotherapy regimens and uncertainty of stability of prognostic factors when tested in subsets of even very large datasets (Pater et al., 1994), it will be challenging to develop a robust model. If one assumes that a predictive model could be developed that substantially enhanced the ability to predict the risk of emesis in a patient who is not already receiving maximal therapy, the question is then how to incorporate it into clinical practice. To be user friendly, it would require the development of software that identifies patients who are at higher risk than suggested by guidelines using easily collected data and suggests a more effective antiemetic regimen. Since current antiemetic prescriptions frequently do not conform to guidelines (Aapro et al., 2012), the introduction of software that would suggest an approach that is better than guidelines is premature.
5. Conclusion At present, the strongest predictors of antiemetic success are the antiemetics administered and emesis with the previous cycle of chemotherapy. Factors such as age, gender, alcohol intake, and susceptibility to motion sickness have been shown to be associated with outcome but thus far have not identified patients whose antiemetic treatment should differ from that recommended by guidelines. Although some information has suggested that the risk of emesis may depend upon variation in metabolism of 5-HT3 receptor antagonists or the structure of the 5-HT3 receptor, these variants are not common and not ready for application in the clinic. The best approach is to use recommended antiemetic from the first cycle of chemotherapy and to modify the approach for
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subsequent cycles if the result is not satisfactory. Until guidelinecompliant antiemetic practice is the rule rather than the exception, improvements in outcome are unlikely to emerge from the construction of models that predict the likelihood of emesis.
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vomiting in cisplatin-treated patients: high-dose metoclopramide combined with methylprednisolone versus metoclopramide combined with dexamethasone and diphenhydramine: a study of the Italian Oncology Group for Clinical Research. J Clin Oncol. 7, 1693–1700. Roila, F., Herrstedt, J., Aapro, M., Gralla, R.J., Einhorn, L.H., Ballatori, E., Bria, E., Clark-Snow, R.A., Espersen, B.T., Feyer, P., Grunberg, S.M., Hesketh, P.J., Jordan, K., Kris, M.G., Maranzano, E., Molassiotis, A., Morrow, G., Olver, I., Rapoport, B.L., Rittenberg, C., Saito, M., Tonato, M., Warr, D., Group E.M.G.W., 2010. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann. Oncol. 21 (Suppl. 5), v232–243. Roscoe, J.A., Bushunow, P., Morrow, G.R., Hickok, J.T., Kuebler, P.J., Jacobs, A., Banerjee, T.K., 2004. Patient expectation is a strong predictor of severe nausea after chemotherapy: a University of Rochester Community Clinical Oncology Program study of patients with breast carcinoma. Cancer. 101, 2701–2708. Sekine, I., Segawa, Y., Kubota, K., Saeki, T., 2013. Risk factors of chemotherapyinduced nausea and vomiting: index for personalized antiemetic prophylaxis. Cancer Sci. 104, 711–717. Shoji, A., Toda, M., Suzuki, K., Takahashi, H., Takahashi, K., Yoshiike, Y., Ogura, T., Watanuki, Y., Nishiyama, H., Odagiri, S., 1999. Insufficient effectiveness of 5hydroxytryptamine-3 receptor antagonists due to oral morphine administration in patients with cisplatin-induced emesis. J. Clin. Oncol. 17, 1926–1930. Warr, D.G., Grunberg, S.M., Gralla, R.J., Hesketh, P.J., Roila, F., Wit, R., Carides, A.D., Taylor, A., Evans, J.K., Horgan, K.J., 2005. The oral NK(1) antagonist aprepitant for the prevention of acute and delayed chemotherapy-induced nausea and vomiting: pooled data from 2 randomised, double-blind, placebo controlled trials. Eur. J. Cancer 41, 1278–1285. Warr, D.G., Street, J.C., Carides, A.D., 2011. Evaluation of risk factors predictive of nausea and vomiting with current standard-of-care antiemetic treatment: analysis of phase 3 trial of aprepitant in patients receiving adriamycincyclophosphamide-based chemotherapy. Support. Care Cancer 19, 807–813.
Contents lists available at ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Review
Prognostic factors for chemotherapy induced nausea and vomiting David Warr n Department of Hematology and Medical Oncology, Princess Margaret Cancer Centre, Rm 5-204, 610 University Avenue, Toronto, Ontario, Canada
art ic l e i nf o
a b s t r a c t
Article history: Accepted 8 October 2013 Available online 21 October 2013
Purpose: to review the topic of prognostic factors for chemotherapy-induced nausea and vomiting. Multiple patient factors such as age, gender and alcohol intake have been found that affect the likelihood of emesis with a given chemotherapy. Pharmacogenomics has also been explored as a cause for variation in emetic response. In theory these risk factors could be used to optimize antiemetic therapy for individual patients but guidelines for prophylactic antiemetics are based solely upon the type of chemotherapy administered. Attempts to identify subgroups of patients for whom guidelines recommendations are suboptimal have thus far been unsuccessful except for those with a poor experience in a previous cycle of the same chemotherapy. At present, there is no basis for deviating from evidence-based guidelines when prescribing antiemetics prior to the first cycle of chemotherapy. & 2013 Elsevier B.V. All rights reserved.
Keywords: Emesis Prognostic Chemotherapy Cancer
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Prognostic factors vary in strength of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Nausea and vomiting with previous chemotherapy cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Commonly cited factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Anxiety. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Co-administration of serotonin specific reuptake inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Pharmacogenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. How large is the effect of a prognostic factor? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Predictive models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Control of chemotherapy induced emesis has improved substantially over the last 20 years through the use of prophylactic antiemetics. Antiemetics can, however, be costly and may induce annoying side effects. Chemotherapy agents vary greatly in the likelihood of inducing nausea and vomiting; thus the antiemetics administered should be tailored to the emetic challenge. The antiemetics recommended by guidelines groups such as the Multinational Association of Supportive Care in Cancer (Roila et al., 2010)
n
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192 193 193 193 193 194 194 194 194 194 194 195 195
are determined by the probability of a given drug causing emesis when administered without antiemetics. At one end of the spectrum are agents like vinorelbine which have virtually no risk of causing emesis and for which no antiemetics are recommended. At the other end are drugs like high dose cisplatin which cause emesis in virtually 100% of patients and for which a combination of a corticosteroid, 5-hydroxytryptamine3 (5-HT3) receptor antagonist and neurokinin1 (NK1) receptor antagonist is recommended. Each chemotherapy regimen is assigned an antiemetic regimen based upon the most emetogenic drug administered. The evaluation of emetogenicity is complicated by the fact that most chemotherapy protocols consist of combinations of agents and the net result may be a more emetogenic stimulus than a single agent. Only one instance of this enhanced emetic effect
D. Warr / European Journal of Pharmacology 722 (2014) 192–196
due to combination therapy is recognized in the guidelines (an anthracycline plus cyclophosphamide) in that a combination of two “moderately emetogenic” drugs qualifies as a regimen for which the NK1 RA aprepitant is part of recommended therapy (Basch et al., 2011; Roila et al., 2010). The rationale is that two large randomized clinical trials have documented a clinically important improvement in the control of emesis when aprepitant is added (Rapoport et al., 2010; Warr et al., 2005). Although even high dose cisplatin is more emetogenic when combined with cyclophosphamide or doxorubicin (Gralla et al., 2005) and a formula for estimating the emetogenicity of the enormous number of possible combinations was proposed (Hesketh et al., 1997), with that one exception, recommended treatment is based upon single agents. Clinical studies have established that, even with the same chemotherapy, there are patient related factors that alter the risk of emesis such as age, alcohol intake and gender (Hesketh et al., 2010) (Warr et al., 2011). Chemotherapy dose is undoubtedly important but it has been largely unexamined except for high dose cisplatin (Beck et al., 1992; Hesketh et al., 2010). It has been suggested that risk factors might be used to alter the antiemetics administered (Osoba et al., 1997). For example a patient who is about to receive “moderately emetogenic” chemotherapy but who is predicted to be at much higher than average risk for vomiting could in theory be prescribed the same antiemetic combination (a corticosteroid, 5-HT3 receptor antagonist and NK1 receptor antagonist) that would be recommended for patients receiving highly emetogenic chemotherapy. Conversely a patient who is about to receive high dose cisplatin but has a low risk profile might in theory be spared the expense of an NK1 receptor antagonist.
2. Risk Factors 2.1. Prognostic factors vary in strength of evidence The table (Table 1) lists risk factors that have been found in at least two clinical trials of substantial size as well as others for which there is less convincing evidence. The number of patient characteristics found in at least univariate analysis to influence the chance of emesis is sufficiently large that it is not possible to list all of them. Indeed, this area is even more complex because nausea
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and vomiting can be considered separately for risk factors with slightly different predictors in one analysis (Osoba et al., 1997) and emesis during the first 24 h and beyond 24 h may differ in their predictors (Dranitsaris et al., 2012). It has been noted that even in analyses of large databases from antiemetic trials, prognostic factors may be inconsistent across subgroups (Pater et al., 1994). Whether this is true variation or a chance variation due to multiple subgroup analyses is unknown. 2.2. Nausea and vomiting with previous chemotherapy cycle A course of chemotherapy generally consists of repeated administration of the same agents. Although emesis becomes somewhat more likely with successive cycles (de Wit et al., 2003; Herrstedt et al., 2005), it is not surprising that the strongest predictor of nausea or vomiting after the first cycle of chemotherapy is their presence or absence with the previous cycle with the same chemotherapy (Roila, 1996). Thus, for those patients who are already receiving chemotherapy, patient characteristics do not have a major role in determining the subsequent risk of emesis above and beyond knowledge of what happened with the previous cycle of treatment. 2.3. Commonly cited factors For patients with no prior chemotherapy, the most commonly cited high risk factors are young age, female gender, limited or no regular alcohol intake and previous emesis e.g. pregnancy associated vomiting or motion sickness. There is no physiological rational for the most commonly cited risk factors. Some factors may simply represent a different threshold for emesis irrespective of the stimulus. For example emesis is more common in females than males in the settings of palliative care (Kirkova et al., 2012), postoperative care (Leslie et al., 2008) and chemotherapy but the reason is unknown. Although female gender has been associated with poorer results in a large number of antiemetic trials, the combined results from two phase III randomized trials of aprepitant suggested that this gender difference disappeared when aprepitant was added to a 5-HT3 receptor antagonist and dexamethasone i.e. males and females fared equally well in the aprepitant containing arms gender (Hesketh et al., 2006). This surprising finding has not been evaluated in other studies with
Table 1 Risk factors for chemotherapy induced emesis. Risk factor
Established (2 or more studies)
Limited or contradictory evidence
References
Vomiting with previous cycle
✕
Roila (1996), Roila et al. (1989)
Type of chemotherapy administered
✕
Pater et al. (1994) Basch et al. (2011)
Antiemetic administered
✕
Pater et al. (1994) Warr et al. (2011)
Gender
✕
Hesketh et al. (2010), Osoba et al. (1997)
Age
✕
Warr et al. (2011) Hesketh et al. (2010)
Alcohol
✕
Warr et al. (2011) Hesketh et al. (2010)
Pregnancy associated emesis or motion sickness
✕
Warr et al. (2011) Pirri et al. (2011)
Anxiety
✕
Molassiotis et al. (2002)
Expectation
✕
Roscoe et al. (2004)
Concomitant opioid
✕
Shoji et al. (1999)
Concomitant serotonin specific reuptake inhibitors
✕
Koriech (1995) Mir et al. (2012)
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NK1 receptor antagonists and so it is not clear whether this newest of antiemetic classes truly eliminates gender as a risk factor. 2.4. Anxiety Anxiety has been suggested as a risk factor for post chemotherapy nausea and vomiting but the literature is mixed. Molassiotis found that state anxiety was associated with post chemotherapy nausea and vomiting but Pirri using a single item evaluation did not find a statistically significant association (Molassiotis et al., 2002; Pirri et al., 2011). In keeping with those results, Morrow found that anxiety before cycle one was a predictive factor for anticipatory symptoms but only when measured as a constellation of symptoms rather than a single item. Dranitsaris included anxiety as a factor in predicting post chemotherapy results but the patients enrolled often had prior cycles of the same chemotherapy and it is possible that they were anxious because of prior nausea and vomiting rather than it being a true prognostic factor for cycle one (Dranitsaris et al., 2012). A large, double blind study of anxiolytic lorazepam that impaired recall of chemotherapy administration and caused urinary incontinence showed no improvement in control of emesis versus diphenhydramine despite improving anxiety (Kris et al., 1987). Using the right measure for evaluating anxiety may identify patients at higher risk of anxiety but it is premature to conclude that pharmacological approaches will reduce that risk. 2.5. Opioids Opioids are known to cause emesis in some individuals and are commonly used in patients with advanced cancer so opioid use concomitant with chemotherapy is not rare. A cohort study (Shoji et al., 1999) strongly suggested that concomitant opioids enhance the risk of emesis with chemotherapy just as has been shown for postoperative emesis (Leslie et al., 2008). A pro-emetic effect was also found in a series of patients receiving highdose chemotherapy treated with maximal antiemetic therapy (Jordan et al., 2011). Interestingly, in pediatric patients not receiving opioids, the administration of the opioid antagonist naloxone enhanced emesis (Kobrinsky et al., 1988) indicating that endogenous opioids may actually have an antiemetic effect. 2.6. Co-administration of serotonin specific reuptake inhibitors Serotonin specific reuptake inhibitors are commonly prescribed for depression and have nausea as a well recognized side effect. Since depression is common in patients with cancer, they are frequently used. A case series and a cohort study suggested that the administration of serotonin specific re-uptake inhibitors enhanced the risk of emesis even when aprepitant was administered (Koriech, 1995; Mir et al., 2012). The authors hypothesized that the prevention of serotonin re-uptake enhanced post synaptic stimulation of 5-HT3 receptors. 2.7. Pharmacogenomics With the declining cost of detecting the presence of gene mutations, “personalized” therapy for cancer has become a common subject in oncology. Variants in the structure of the 5-HT3 receptors, variation in the rapidity of metabolism of the 5-HT3 antagonists and altered transporter genes for antiemetics have been explored as possible contributors to the risk of emesis. One study suggested that antiemetic therapy could be tailored according to whether their cytochrome P450 2D6 genotype indicated that they were slow or rapid metabolizers (since some 5-HT3 receptor antagonists are metabolized to some extent by that
enzyme) (Kaiser et al., 2002). The potential for clinical application is limited as the authors concluded that approximately 50 patients would have to be genotyped to prevent severe emesis in one patient. A recent review of pharmacogenomics and emesis found a relatively small number of studies with mixed results and concluded that it was premature to incorporate pharmacogenomics into practice (Perwitasari et al., 2011). Despite some initial enthusiasm, pharmacogenomics is unlikely to be of major assistance because of the complexity of the emesis pathway. Although the emphasis thus far has been on issues that might affect 5-HT3 receptor antagonist efficacy, it is well established that NK1 receptor antagonists, corticosteroids and olanzapine also substantially affect the risk of emesis. There is no reason to think that receptor mutation, drug transport and drug metabolism would not also potentially be important for these nonserotonin related pathways.
3. How large is the effect of a prognostic factor? An analysis of the results of several antiemetic studies concluded that the strongest prognostic factors for emesis with the first cycle of chemotherapy were the type of chemotherapy given and the antiemetics administered (Pater et al., 1994). That is not to say, however, that other factors are of trivial impact. Age, gender, alcohol intake may each be associated with an absolute difference of 10–15% in the likelihood of vomiting with chemotherapy such as high dose cisplatin and anthracycline–cyclophosphamide combinations (Hesketh et al., 2010), (Warr et al., 2011). In these studies, it was not possible to identify a subgroup that did not have a clinically important benefit from an NK1 receptor antagonist.
4. Predictive models Simply looking at the number of risk factors may change the average risk substantially but this has rarely been studied (Osoba et al., 1997; Sekine et al., 2013; Warr et al., 2011). Examining a heterogeneous group of chemotherapies given to 832 patients during the course of three randomized trials, a group of prognostic factors for emesis were identified in a multivariate analysis. The risk of emesis ranged from 20% to 75% depending upon the number of risk factors present (Osoba et al., 1997). A much more heterogeneous study of 866 patients receiving an anthracycline plus cyclophosphamide for breast cancer found that the risk of emesis despite receiving ondansetron plus dexamethasone varied from 12% to 61% depending upon whether there were no or three high risk factors (Warr et al., 2011). In theory, one could spare those patients at low risk from the relatively costly aprepitant. That low risk group constituted only 3% of the study population and with only one risk factor, the chance of vomiting was 34%. Thus, in this patient population, a low risk group of meaningful size in whom an NK1 receptor antagonist could be avoided was not identified. What is less clear is whether the identification of a high risk group within “highly emetogenic” chemotherapy is of clinical relevance since, in theory, maximal antiemetic therapy has already been administered. The recent demonstration that olanzapine was dramatically effective in patients who had nausea or vomiting despite maximal prophylactic therapy (Navari et al., 2013) suggests that there may indeed be value in identifying high risk patients who are about to receive highly emetogenic chemotherapy. The value of adding olanzapine to a corticosteroid, 5-HT3 receptor antagonist and an NK1 receptor antagonist for such high risk patients requires study.
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A more complex predictive model that incorporates multiple variables with different weights assigned for each factor has intellectual appeal. A model derived from logistic regression has been proposed for patients receiving a wide variety of cisplatin and non-cisplatin chemotherapy regimens (Dranitsaris et al., 2012). The objective was to predict those patients at risk of at least grade 2 vomiting in the acute phase (first 24 h after chemotherapy) or in the delayed phase (beyond 24 h). This was meant to apply to patients at any point along their course of chemotherapy. For the acute phase there were 10 easily determined factors and for the delayed phase there were eight factors. Although this model was said to be validated there are serious concerns about its utility: a) The current standard is complete protection of emesis (no vomiting or Grade 0) whereas the model was designed to predict Grade 2 severity emesis in the acute phase or the delayed phase separately which represents a substantially poorer goal. b) The strongest predictive factor for how a patient will do on any given cycle is the presence or absence of emesis in a previous cycle yet this parameter was not included in what purports to be a predictor of results over multiple cycles. c) The model makes the assumption that dexamethasone is used in the first 24 h and that aprepitant is not used, neither of which are necessarily true from surveys of antiemetic use. d) Some prognostic factors are not consistent with data or logic. For example, having received at least two prior cycles of chemotherapy or a 5-HT3 receptor antagonist, or taking non prescribed medications for emesis control is associated with a lower risk of vomiting. e) To be useful, the model should predict the probability of emesis at cycle 1 with standard antiemetics and this has not been tested. Given the very large number of chemotherapy regimens and uncertainty of stability of prognostic factors when tested in subsets of even very large datasets (Pater et al., 1994), it will be challenging to develop a robust model. If one assumes that a predictive model could be developed that substantially enhanced the ability to predict the risk of emesis in a patient who is not already receiving maximal therapy, the question is then how to incorporate it into clinical practice. To be user friendly, it would require the development of software that identifies patients who are at higher risk than suggested by guidelines using easily collected data and suggests a more effective antiemetic regimen. Since current antiemetic prescriptions frequently do not conform to guidelines (Aapro et al., 2012), the introduction of software that would suggest an approach that is better than guidelines is premature.
5. Conclusion At present, the strongest predictors of antiemetic success are the antiemetics administered and emesis with the previous cycle of chemotherapy. Factors such as age, gender, alcohol intake, and susceptibility to motion sickness have been shown to be associated with outcome but thus far have not identified patients whose antiemetic treatment should differ from that recommended by guidelines. Although some information has suggested that the risk of emesis may depend upon variation in metabolism of 5-HT3 receptor antagonists or the structure of the 5-HT3 receptor, these variants are not common and not ready for application in the clinic. The best approach is to use recommended antiemetic from the first cycle of chemotherapy and to modify the approach for
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subsequent cycles if the result is not satisfactory. Until guidelinecompliant antiemetic practice is the rule rather than the exception, improvements in outcome are unlikely to emerge from the construction of models that predict the likelihood of emesis.
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