Annals of Oncology!: 107-114, 1991. O 1991 Kluwer Academic Publishers. Printed in the Netherlands.
Review Methodology of antiemetic trials: A review M. Tonato,1 F. Roila1 & A. Del Favero2 'Division of Medical Oncology, Policlinico; 2Institute of Internal Medicine I, University, Perugia, Italy
Summary. Chemotherapy-related nausea and vomiting can be controlled with available antiemetics in a high percentage of patients, while emesis remains a critical problem in some subgroups and with certain drugs. In the ceaseless attempt to find newer drugs and better treatment modalities, a sound methodology in antiemetic research is essential. Several factors should always be considered when planning an antiemetic trial: first, the different emetic power of various chemotherapy agents, their dosages and route and schedule of administration and second, the type of antiemetic used, its dosage and timing, and its possible combination with other antiemetics. Important factors which influence outcome but which are often under-evaluated are those related to patient population such as age, gender, and previous experience with chemotherapy. Considering the relevance of subjective phenomena in nausea and vomiting, it is essential that any study be randomized and double blinded. The parallel type of study design is preferable to the cross-over and a large number of patients is usually required to achieve meaningful results. Efficacy and toxicity should be properly evaluated by trained personnel in a standardized way, using a validated, relatively simple methodology. Key words: chemotherapy-induced emesis, antiemetic trials
Introduction During the last ten years considerable progress has been made in the prevention of nausea and vomiting induced by antineoplastic agents, but emesis nevertheless remains a critical problem in cancer chemotherapy, especially in certain subgroups of patients and with certain cytotoxic drugs. Three patterns of emetic problems can be encountered in cancer patients treated with cytotoxic drugs. Acute emesis, which occurs within a short time after the administration of chemotherapy, delayed emesis, which usually appears one or more days after chemotherapy, and anticipatory emesis, which is often found when patients associate a visit to the hospital for chemotherapy with emesis. An additional problem is that of emesis due to other causes (i.e., other medications, tumorrelated complications). Among the various types of emesis there are important differences in the cause of the problem and in the appropriate treatment, but because the most frequently encountered emetic problem is acute chemotherapyinduced emesis and because the majority of antiemetic studies have addressed this problem, acute emesis studies will be the main topic of this review. Improvement in the treatment of this side effect is dependent on optimal use of available treatments and on research to discover new, more effective antiemetic drugs. To accomplish this, well-designed and -con-
ducted clinical trials are essential [1-4]. Unfortunately, many clinical trials in the past generated information that was misleading or limited by faults in patient selection, study design, or evaluation of outcome. Methodological problems in planning and evaluating clinical trials on preventive treatment of chemotherapy-induced nausea and vomiting must therefore receive due attention. This review will discuss the factors which can influence the occurrence and the characteristics of chemotherapy-induced nausea and vomiting (prognostic factors) and identify the main methodological problems encountered in planning and evaluating studies on antiemetic treatment. Prognostic factors in chemotherapy-induced vomiting The most important prognostic factors which should be taken into account in planning or evaluating a clinical trial are summarized in Table 1. Each factor in itself is an important variable but the interrelation among factors should also be considered in the evaluation of chemotherapy-induced nausea and vomiting. Variables related to chemotherapy It is well known that antineoplastic drugs differ quantitatively and qualitatively in their emetogenic potential.
108
Table 2. Emetogenic potential of cancer chemotherapeutic agents'.
onset and duration of nausea and vomiting and tolerance of the emetogenic potential. Some drugs induce nausea and vomiting very early after administration (i.e., mechlorethamine, doxorubicin), others after 2-3 hrs (i.e., most cytotoxic drugs) and in a few cases, even later (9-12 hrs for cyclophosphamide). Reasons for these differences are related to the kinetic characteristics of some drugs (i.e., cyclophosphamide) but for most agents they are generally unknown. Tolerance to emesis can develop with some drugs if they are administered in multiple doses on consecutive days (i.e., cisplatin, cytosine arabinoside, and possibly dacarbazine), but this is not the case if cycles of chemotherapy are given 3-4 weeks apart. The most important practical consequences of these variables are that patients treated with similar chemotherapeutic regimens must be studied and the type and schedule of antiemetic treatment tailored to the anticipated needs of those who will be receiving different chemotherapy regimens.
High
Moderate
Low
Variables related to the patient population
Cisplatin Dacarbazine MechJorethamine Dactinomycin
Cyclophosphamide Cytosine arabinoside Anthracyclines Carboplatin Nitrosoureas Procarbazine
Methotrexate Mitomycin C Bleomycin Busulphan Chlorambucil Melphalan Hydroxyurea Etoposide Teniposide Fluorouracil Vinca Alkaloids
Table 1. Variables affecting chemotherapy-induced vomiting. Variables related to chemotherapy Type of drug or combination Dosage and schedule Route of administration Variables related to patient population Sex Age Setting and environment Previous chemotherapy History of alcohol intake Others (emesis during pregnancy, susceptibility to motion sickness) Variables related to antiemetic treatment Type of drug or combination Dosage and schedule Route of administration Toxicity
Variability in antiemetic response among patients and in the same patient in subsequent cycles of chemotherapy is a common and familiar experience, but only recently have the most important patient-related prognostic factors been defined. Most of these studies have been performed in patients treated with cisplatin, and their conclusions should therefore be applied with caution when treating patients with different cytotoxic drugs. Gender is probably the most important prognostic factor in conditioning response to 1 See text for comment. antiemetic treatment. In support of this hypothesis are consistent data from 3 large double-blind randomized It is usual to classify the different antineoplastic agents clinical trials in cisplatin-treated patients [5,6,7], which according to their emetogenic potential, whether high, show that females vomit more than males (Table 3). moderate or low (Table 2). Although this rating reflects In almost all of these studies, the intensity of nausea, a real difference in the emetogenic capability of differ- the mean number of vomiting episodes, and the duraent drugs, it must be interpreted with caution as it relies tion of nausea and vomiting were also significantly more on empirical clinical observations than on com- greater in females than in males. Gender appears to parative controlled studies and, moreover, it does not affect the incidence of nausea and vomiting irrespective take into consideration the fact that antineoplastic of antiemetic treatment, primary cancer site and other drugs are rarely given alone, and that dose, route and patient-related variables. These results have been conschedule of administration are critical in determining firmed in several studies [8,9] in cisplatin and in doxothe incidence and intensity of nausea and vomiting. rubicin-treated patients [10-111. Usually, as the dose of a cytotoxic drug increases so does its emetogenic potential (i.e., with cisplatin, Table 3. Results of antiemetic therapy by sex. cyclophosphamide, cytosine arabinoside, doxorubicin, methotrexate); as the infusion time of administration of N. pts Antiemetic treatment Complete protec- P Ref. tion (%) the same dose becomes longer, nausea and vomiting decrease (i.e., cisplatin, doxorubicin). Furthermore, a Males Females drug combination is generally thought to be more emetogenic than a single drug, unless each of the agents 112 48.6 18.4 0.001 [6] 60 vs 120mgMTC in the combination is given in less than maximum dose 200 25.0 MTC vs MTC + P 60.8 0.005 42.2 MTC + P vs or the emetogenic potential of an individual drug, as in 367 75.3 0.001 MTC + DEX + DIP [5| cisplatin-containing regimens, clearly overcomes that of the other combined agents [5]. Other important MTC - Metoclopramide; DEX - Dexamethasone; P - Methylpredvariables are differences among antineoplastic drugs in nisolone; DIP - Diphenhydramine.
m
109 The biology underlying this phenomenon is largely unknown. In fact, it is not known whether gender influences sensitivity to the emetogenic potential of antineoplastic agents or the efficacy of antiemetic treatment itself. It is interesting to note, however, that a similar difference between males and females in incidence of emesis caused by opiate analgesics has been reported, and a possible gender difference in neurotransmitter receptor site distribution or emetic drug binding characteristics has been postulated [12]. The age of patients is another important variable in predicting the risk of nausea and vomiting. In one large study [5], complete protection from vomiting/nausea was significantly better in older patients (>65 yrs) (73.9%/78.3%) than in the younger ones (50 mg/m2 with no antiemetic treatment will vomit. This makes the use of placebo in studies with high doses of cisplatin not only useless but also unethical, denying patients the good protection offered by a 'standard' regimen such as that of meto• clopramide + steroids. Unfortunately, the results of such studies continue to be published [31]. Obviously, placebo controlled trials are valid when an effective treatment is lacking and a low prevalence of emesis can be anticipated.
the two groups are then compared. In a cross-over (within subjects) design, each patient receives every drug being studied, 'crossing over' from one drug to the next in a predetermined order. The advantages and disadvantages of the two designs are illustrated in Tables 4 and 5. According to our experience, the parallel design is preferable because the characteristics of the study are more similar to those encountered in daily practice. In particular, this design allows the investigator to evaluate the persistence of antiemetic effectiveness of a drug regimen over multiple anticancer chemotherapy cycles, as is the case when the treatment is administered in normal clinical care. Other types of designs may be considered in particular circumstances. One of the most useful, although rarely used, is the sequential study [32]. This type of design, which favors the utilization of the most efficacious treatment, is of particular help when it is necessary to compare a relatively inefficacious treatment with one considered to be effective. Ethical considerations prompt the use of a design that minimizes the risk of treating patients with the less effective treatment while maintaining a scientifically sound statistical basis. The sequential design may be a good compromise.
The sample size of an antiemetic study is of critical importance. The study must be large enough for there to be sufficient statistical power to detect the smallest difference of clinical importance. Unfortunately, antiemetic trials have generally included fairly small numTwo major trial designs, the parallel and the cross- bers of patients, making the interpretation of their over, are used in antiemetic studies. In a parallel results difficult. Useful information can sometimes be (between subjects) design, the patients are randomized obtained even from small studies if the regimens tested to receive either the study drug or the comparative differ markedly in efficacy or toxicity, but these results treatment during one or several courses of therapy, and almost always necessitate validation by larger, controlled studies. An example of a successful integration of such a research strategy is illustrated in Table 6 where the Table 4. Parallel study design. results of a small open pilot study using the antiemetic Advantages: - Possibility to evaluate the persistence of anticombination of metoclopramide + dexamethasone + emetic efficacy in subsequent cycles. diphenhydramine [30] are compared with those of a Disadvantages: - Larger number of patients are required to show larger randomized double-blind trial which studied the differences between treatments. same combination in comparison with a 'standard' antiemetic regimen [5]. The complete response rates were very close as was the incidence of toxicity, but the Table 5. Crossover study design. large size of the controlled trial, 343 evaluable patients, added substantial evidence to the preliminary results of Advantages: - More powerful (smaller number of patients required). - Possibility to express a preference between treatments. Disadvantages: - Impossibility to evaluate the persistence of antiemetic activity in subsequent cycles. - Inappropriate if number of patients lost after first cycle is >5%. - Necessity to keep the emetic stimulus and the environment unchanged between the two treatments. - Problems of order effects (in relation to order in which the antiemetic treatments are administered) and problems of residual effects (in relation to influence of the previous antiemetic treatment on the subsequent).
Table 6. Evaluation of MDD antiemetic combination. Center Antiemetic treatment Type of study N. of pts Complete protection from vomiting (%) Acute dystonic reaction
MSKCC1 MDD
open 42 81
0
GOIRC MP vs MDD double-blind 343
72.5 1.7
M - Metoclopramide; D - Dexamethasone; D - Diphenhydramine; P - Methylprednisolone. 1 Memorial Sloan-Kettering Cancer Center, [30). b Italian Oncology Group for Clinical Research, [5].
112 the pilot study. Conducting large trials is the only way to pinpoint relatively small differences between treatments, to identify subgroups of patients which differ in response from the general population, and to shorten the time necessary to answer some clinical questions. However, it is implicit that large trials necessitate cooperative studies among institutions that have the interest and expertise in such a research field and this may create further problems. In our experience, the keys to successful collaboration among institutions in carrying out a multicenter trial are a recognized scientific leadership and an efficient organization. Evaluation ofparameters and methodology Studies of antiemetic therapy reveal uncertainties and difficulties in patient assessment mainly because of the problems encountered in defining and quantifying vomiting and nausea. The objective assessment of vomiting would seem to be a relatively simple procedure and could be done by either the patient or, preferably, an observer, who would record the number and duration of emetic episodes and, sometimes, the volume of emesis. In reality, several problems must be considered: the difficulty in separating retching from vomiting, such as in counting the vomiting episodes when vomiting is almost continuous, in measuring the duration of emesis and in monitoring emesis in an out-patient population. In our trials, we adopted the criteria of having an external observer count every single vomiting or retching episode and of measuring the length of vomiting expressed as the time elapsed between the beginning of the emetogenic drug infusion and the last episode of vomiting. Volume of emesis is a less useful parameter and is no longer considered in our trials; moreover, its collection and measurement can be difficult. To make the interpretation of these parameters useful, the time span of emesis assessment should be reported and the duration of the observation should be related to the expected length of vomiting for that particular drug. Monitoring of outpatients, which is necessary when studying delayed emesis, poses additional problems. In fact, follow-up by phone or questioning of the patients on their next hospital visit was found to be an unreliable method. An assessment which relies on the patient filling in a daily diary card (and using a visual analog scale to assess nausea) has been found to be much more satisfactory [33]. Assessment of nausea presents even greater difficulties. Because the experience of nausea is a subjective phenomenon, its assessment has of necessity relied almost entirely on patient reports. The use of objective correlates such as pulse rate, blood pressure and muscle tension has been tried, but without success. Measurement of nausea remains a subject of controversy, with results of individual studies claiming reliability
and advantages for new methods that can scarcely be compared. In order to provide new information on existing methods for evaluation of nausea and the best way to utilize them in clinical trials, we have compared in a standardized assessment three different methods of measuring nausea in 849 patients enrolled in 4 double blind randomized clinical trials and 2 observational studies [34]. Nausea was measured before and at 2, 4, 6, 8 and 24 hrs after chemotherapy by contemporaneously using three types of scales: a discrete descriptive scale (DS) (the four grades being 0 = no nausea, 1 = slight nausea, 2 = moderate and 3 - severe nausea), a linear visual analog scale (VAS), and an analog continuous chromatic scale (ACCS). Four different dimensions of nausea were also identified. 1. Maximal intensity, defined as the highest score value obtained with DS, VAS or ACCS at any evaluation carried out over the 24 hr period. 2. Entity, defined as the sum of all the values of intensity of nausea recorded at each evaluation time. 3. Duration, expressed in minutes. Patients were asked at each point of evaluation how many minutes they had experienced nausea during the previous time period. 4. Quantity, defined as the sum of the products of the intensity multiplied by duration, recorded at each evaluation time. We analyzed the distribution of nausea measurements in the population studied and the agreement among scales and nausea dimensions and their sensitivity. We found substantial equivalence among the different scales used and no advantages in using an analog with respect to a discrete scale. We also found a trend toward increasing sensitivity in detecting differences as the dimensions of nausea studied become more comprehensive of the various aspects of this symptom, quantity being more sensitive than entity, and entity more sensitive than maximal intensity. On the basis of these results we suggest that measurement of quantity of nausea, irrespective of the scale used, is the most valid way to quantify this purely subjective symptom. Since discrete and analogue scales are equivalent in evaluating nausea, the simpler descriptive approach can be adopted to quantify this symptom when analogue instruments are not at hand, provided a standard method of presenting the questionnaire is used and a favorable environment of good nursing care is assured. Antiemetic efficacy alone, however, is not the only evaluation end point Tolerability, compliance with treatment and patient preference are also important parameters. Since many agents have side effects which may limit their use, it is important that these be assessed in detail by general questioning and monitoring of the patient, and be reported according to a widely adopted severity scale. With currently available antiemetic agents, a uniform grading of sedation and diarrhea could be very useful.
113 Finally, an overall statement of preference by the patient himself should balance beneficial with adverse effects. Since it is the patient's quality of life that we are attempting to preserve, this overall assessment should be regarded as an important one. Unfortunately, in comparing different treatments, this global preference stated by the patient is possible only with the crossover design which carries the disadvantages already mentioned. In situations other than the crossover one, this global judgment is difficult to express. Until a better and simpler method is found, the best way to evaluate the antiemetic treatment is by the judgment of the individual patient and of the observer, and it is to be hoped that these will be convergent. Response criteria There is no established manner of expressing overall efficacy. Again, there is a clear need for a consensus for standardized definitions. Since the aim of an antiemetic is to completely abolish nausea and vomiting, it is proper to report complete response rates as complete protection from vomiting, from nausea and from nausea and vomiting, respectively; less than optimal responses are best reported as number of vomiting or retching episodes and quantity of nausea over the study time. We adopted the definitions of major protection when lor 2 episodes of vomiting were recorded, minor protection (3 to 5 episodes) and failure (more than 5). With the adoption of such a quantitative analysis, comparison among studies should become easier.
Conclusions Well designed and better conducted studies are urgently needed to solve many of the pending problems of treatment in chemotherapy-induced nausea and vomiting in cancer patients. Progress in control of emesis relies on a better understanding of the mechanism of vomiting, a thorough knowledge of antiemetic drugs, a controlled experience with their use and a careful consideration of the individual patient's specific emetic problem. Sound methodology in planning and evaluating antiemetic treatments is now at hand and it is to be hoped that it will be more widely adopted, allowing a more correct evaluation of the results of clinical trials and a more efficient utilization of these results in daily clinical practice. The pooling of the skills and experiences of physicians and specialists in oncology nursing are essential in the pursuit and achievement of this goal.
Acknowledgements This paper was presented at the ECCO 5 meeting, London, September, 1989.
The authors thank E. Ballatori of the Department of Statistics, University of Perugia and C. Basurto, S. Bracarda and M. Picciafuoco of the Division of Medical Oncology for their research collaboration. References 1. Carey MP, Burish TG, Brenner DE. Delta-9-tetrahydrocannabinol in cancer chemotherapy: research problems and issues. Ann Intern Med 1983; 99: 106-14. 2. Pater JL, Willan AR. Methodologic issues in trials of antiemetics. J Clin Oncol 1984; 2:484-7. 3. Morrow GR. The assessment of nausea and vomiting. Past problems, current issues, and suggestions for future research. Cancer 1984; 53 (suppl): 2267-80. 4. Olver IN, Simon RM, Aisner J. Antiemetic studies: a methodological discussion. Cancer Treat Rep 1986; 70: 555-63. 5. Roila F, Tonato M, Basurto C et al. Protection from nausea and vomiting in cisplatin-treated patients: high-dose metoclopramide combined with methylprednisolone vs metoclopramide combined with dexamethasone and diphenhydramine: a study of the Italian Oncology Group for Clinical Research. J Clin Oncol 1989; 7: 1693-1700. 6. Roila F, Tonato M, Basurto C et al. Antiemetic activity of two different high doses of metoclopramide in cisplatin-treated cancer patients: a randomized double-blind trial of the Italian Oncology Group for Clinical Research. Cancer Treat Rep 1985; 69: 1353-7. 7. Roila F, Tonato M, Basurto C et al. Antiemetic activity of high doses of metoclopramide combined with methylprednisolone vs metoclopramide alone in cisplatin-treated cancer patients: a randomized double-blind trial of the Italian Oncology Group for Clinical Research. J Clin Oncol 1987; 5: 141-9. 8. Becouarn Y, Bui NB, David M et al. Improved control of cisplatin induced emesis with a combination of high doses of methylprednisolone and metoclopramide: a single blind randomized trial. EurJ Cancer Clin Oncol 1986; 22: 1421-4. 9. Alba E, Bastus R, Castro I et al. Metoclopramida mas difenhidramina frente a clorpromacina en los vomitos inducidos por cisplatino. Estudio aleatorizado cruzado y a doble ciego. Med Clin (Bare) 1987; 89:410-2. 10. Mellink WA, Blijham GH, Van Deyk WA. Amitriptyline plus fluphenazine to prevent chemotherapy-induced emesis in cancer patients: a double-blind randomized cross-over study. Eur J Cancer Clin Oncol 1984; 20: 1147-50. 11. Martin-Jimenez M, Diaz-Rubio E. Clinical evaluation of the simultaneous blockade of the dopamine D-2, histamine H-l, and muscarinic cholinergic receptors in cancer chemotherapyinduced emesis; results of a controlled trial. Cancer Chemother Pharmacol 1986; 18: 168-71. 12. Walsh TD. Antiemetic drug combinations in advanced cancer. Lancet 1982; 1: 1018. 13. Benrubi GI, Norvell M, Nuss RC et al. The use of methylprednisolone in control of emesis in patients receiving cis-platinum. Gynecol Oncol 1985; 21: 306-13. 14. Osterwalder B, Wilder-Smith C, Schimke J et al. Antiemetic combination of metoclopramide, cinnarizine and lorazepam for patients with cisplatin-based combination chemotherapy. ProcASCO1988;7:298. 15. Meyer BR, Lewin M, Drayer DE et al. Optimizing metoclopramide control of cisplatin-induced emesis. Ann Intern Med 1984; 100:393-5. 16. Kessler JF, Alberts DS, Plezia PM et al. An effective five-drug antiemetic combination for prevention of chemotherapyrelated nausea and vomiting. Experience in eighty-four patients. Cancer Chemother Pharmacol 1986; 16:282-6. 17. Roila F, Basurto C, Minotti V et al. Methylprednisolone versus metoclopramide for prevention of nausea and vomiting in
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breast cancer patients treated with intravenous cyclophosphamide methotrexate 5-fluorouracil: a double-blind randomized study. Oncology 1988; 45: 346-9. Kris MG, Tyson LB, Gralla RJ et al. Extrapyramidal reactions with high-dose metoclopramide. N Engl J Med 1983; 309: 433. Roberts WS, Berman M, DiSaia PJ et aL Letter to the Editor. Gynecol Oncol 1984; 17: 249. Aapro MS, Plezia PM, Alberts DS et al. Double-blind crossover study of the antiemetic efficacy of high-dose dexamethasone vs high-dose metoclopramide. J Clin Oncol 1984; 2:46671. Fritak S, Moertel CG, O'Fallon J. Delta-9-tetrahydrocannabinol as an antiemetic in patients treated with cancer chemotherapy: a double comparison with prochlorperazine and a placebo. Ann Intern Med 1979; 91: 825-30. Vincent BJ, McQuistion DJ, Einhorn LH et al. Review of cannabinoids and their antiemetic effectiveness. Drugs 1983; 25:52-62. Gralla RJ, Tyson LB, Kris MG et al. The management of chemotherapy-induced nausea and vomiting. Med Clin North Am 1987; 71: 289-301. Gez E, Catane R, Pfau L et al. High-dose metoclopramide as an antiemetic in patients receiving cis-platinum-based combination chemotherapy. Gynecol Oncol 1985; 21: 18-22. D'Acquisto RW, Tyson LB, Gralla RJ et al. The influence of a chronic high alcohol intake on chemotherapy-induced nausea and vomiting. Proc ASCO 1986; 5: 257. Sullivan JR, Leyden MJ, Bell R. Decreased cisplatin-induced nausea and vomiting with chronic alcohol ingestion. N Engl J Med 1983; 309: 796.
27. Morrow GR. Susceptibility to motion sickness and the development of anticipatory nausea and vomiting in cancer patients undergoing chemotherapy. Cancer Treat Rep 1984; 68:1177-8. 28. Martin M, Diaz-Rubio E. Emesis during past pregnancy: a new factor in chemotherapy-induced emesis. Annals of Oncology 1990; 1:152-3. 29. Pollera CF, Giannarelli D. Prognostic factors influencing cisplatin-induced emesis. Definition and validation of a predictive logistic model. Cancer 1989; 64: 1117-22. 30. Kris MG, Gralla RJ, Tyson LB et al. Improved control of cisplatin induced emesis with high-dose metoclopramide and with combinations of metoclopramide, dexamethasone, and diphenhydramine. Results of consecutive trials in 255 patients. Cancer 1985; 55: 527-34. 31. Cubeddu LX, Hoffmann IS, Fuenmayor NT et al. Efficacy of ondansetron (GR38032F) and the role of serotonin in cisplatin induced nausea and vomiting. N Engl J Med 1990; 322: 810-6. 32. Armitage P. Sequential medical trials. Blackwell - Oxford, 1960. 33. Smyth JF. The problem of emesis induced by cancer chemotherapy. Clinician 1988; 6: 2-12. 34. Del Favero A, Roila F, Basurto C et al. Assessment of nausea. Eur J Clin Pharmacol 1990; 38:115-20. Received 8 February 1990; accepted 21 August 1990. Correspondence to: Prof. Maurizio Tonato Division of Medical Oncology Policlinico 06100 Perugia, Italy
Review Methodology of antiemetic trials: A review M. Tonato,1 F. Roila1 & A. Del Favero2 'Division of Medical Oncology, Policlinico; 2Institute of Internal Medicine I, University, Perugia, Italy
Summary. Chemotherapy-related nausea and vomiting can be controlled with available antiemetics in a high percentage of patients, while emesis remains a critical problem in some subgroups and with certain drugs. In the ceaseless attempt to find newer drugs and better treatment modalities, a sound methodology in antiemetic research is essential. Several factors should always be considered when planning an antiemetic trial: first, the different emetic power of various chemotherapy agents, their dosages and route and schedule of administration and second, the type of antiemetic used, its dosage and timing, and its possible combination with other antiemetics. Important factors which influence outcome but which are often under-evaluated are those related to patient population such as age, gender, and previous experience with chemotherapy. Considering the relevance of subjective phenomena in nausea and vomiting, it is essential that any study be randomized and double blinded. The parallel type of study design is preferable to the cross-over and a large number of patients is usually required to achieve meaningful results. Efficacy and toxicity should be properly evaluated by trained personnel in a standardized way, using a validated, relatively simple methodology. Key words: chemotherapy-induced emesis, antiemetic trials
Introduction During the last ten years considerable progress has been made in the prevention of nausea and vomiting induced by antineoplastic agents, but emesis nevertheless remains a critical problem in cancer chemotherapy, especially in certain subgroups of patients and with certain cytotoxic drugs. Three patterns of emetic problems can be encountered in cancer patients treated with cytotoxic drugs. Acute emesis, which occurs within a short time after the administration of chemotherapy, delayed emesis, which usually appears one or more days after chemotherapy, and anticipatory emesis, which is often found when patients associate a visit to the hospital for chemotherapy with emesis. An additional problem is that of emesis due to other causes (i.e., other medications, tumorrelated complications). Among the various types of emesis there are important differences in the cause of the problem and in the appropriate treatment, but because the most frequently encountered emetic problem is acute chemotherapyinduced emesis and because the majority of antiemetic studies have addressed this problem, acute emesis studies will be the main topic of this review. Improvement in the treatment of this side effect is dependent on optimal use of available treatments and on research to discover new, more effective antiemetic drugs. To accomplish this, well-designed and -con-
ducted clinical trials are essential [1-4]. Unfortunately, many clinical trials in the past generated information that was misleading or limited by faults in patient selection, study design, or evaluation of outcome. Methodological problems in planning and evaluating clinical trials on preventive treatment of chemotherapy-induced nausea and vomiting must therefore receive due attention. This review will discuss the factors which can influence the occurrence and the characteristics of chemotherapy-induced nausea and vomiting (prognostic factors) and identify the main methodological problems encountered in planning and evaluating studies on antiemetic treatment. Prognostic factors in chemotherapy-induced vomiting The most important prognostic factors which should be taken into account in planning or evaluating a clinical trial are summarized in Table 1. Each factor in itself is an important variable but the interrelation among factors should also be considered in the evaluation of chemotherapy-induced nausea and vomiting. Variables related to chemotherapy It is well known that antineoplastic drugs differ quantitatively and qualitatively in their emetogenic potential.
108
Table 2. Emetogenic potential of cancer chemotherapeutic agents'.
onset and duration of nausea and vomiting and tolerance of the emetogenic potential. Some drugs induce nausea and vomiting very early after administration (i.e., mechlorethamine, doxorubicin), others after 2-3 hrs (i.e., most cytotoxic drugs) and in a few cases, even later (9-12 hrs for cyclophosphamide). Reasons for these differences are related to the kinetic characteristics of some drugs (i.e., cyclophosphamide) but for most agents they are generally unknown. Tolerance to emesis can develop with some drugs if they are administered in multiple doses on consecutive days (i.e., cisplatin, cytosine arabinoside, and possibly dacarbazine), but this is not the case if cycles of chemotherapy are given 3-4 weeks apart. The most important practical consequences of these variables are that patients treated with similar chemotherapeutic regimens must be studied and the type and schedule of antiemetic treatment tailored to the anticipated needs of those who will be receiving different chemotherapy regimens.
High
Moderate
Low
Variables related to the patient population
Cisplatin Dacarbazine MechJorethamine Dactinomycin
Cyclophosphamide Cytosine arabinoside Anthracyclines Carboplatin Nitrosoureas Procarbazine
Methotrexate Mitomycin C Bleomycin Busulphan Chlorambucil Melphalan Hydroxyurea Etoposide Teniposide Fluorouracil Vinca Alkaloids
Table 1. Variables affecting chemotherapy-induced vomiting. Variables related to chemotherapy Type of drug or combination Dosage and schedule Route of administration Variables related to patient population Sex Age Setting and environment Previous chemotherapy History of alcohol intake Others (emesis during pregnancy, susceptibility to motion sickness) Variables related to antiemetic treatment Type of drug or combination Dosage and schedule Route of administration Toxicity
Variability in antiemetic response among patients and in the same patient in subsequent cycles of chemotherapy is a common and familiar experience, but only recently have the most important patient-related prognostic factors been defined. Most of these studies have been performed in patients treated with cisplatin, and their conclusions should therefore be applied with caution when treating patients with different cytotoxic drugs. Gender is probably the most important prognostic factor in conditioning response to 1 See text for comment. antiemetic treatment. In support of this hypothesis are consistent data from 3 large double-blind randomized It is usual to classify the different antineoplastic agents clinical trials in cisplatin-treated patients [5,6,7], which according to their emetogenic potential, whether high, show that females vomit more than males (Table 3). moderate or low (Table 2). Although this rating reflects In almost all of these studies, the intensity of nausea, a real difference in the emetogenic capability of differ- the mean number of vomiting episodes, and the duraent drugs, it must be interpreted with caution as it relies tion of nausea and vomiting were also significantly more on empirical clinical observations than on com- greater in females than in males. Gender appears to parative controlled studies and, moreover, it does not affect the incidence of nausea and vomiting irrespective take into consideration the fact that antineoplastic of antiemetic treatment, primary cancer site and other drugs are rarely given alone, and that dose, route and patient-related variables. These results have been conschedule of administration are critical in determining firmed in several studies [8,9] in cisplatin and in doxothe incidence and intensity of nausea and vomiting. rubicin-treated patients [10-111. Usually, as the dose of a cytotoxic drug increases so does its emetogenic potential (i.e., with cisplatin, Table 3. Results of antiemetic therapy by sex. cyclophosphamide, cytosine arabinoside, doxorubicin, methotrexate); as the infusion time of administration of N. pts Antiemetic treatment Complete protec- P Ref. tion (%) the same dose becomes longer, nausea and vomiting decrease (i.e., cisplatin, doxorubicin). Furthermore, a Males Females drug combination is generally thought to be more emetogenic than a single drug, unless each of the agents 112 48.6 18.4 0.001 [6] 60 vs 120mgMTC in the combination is given in less than maximum dose 200 25.0 MTC vs MTC + P 60.8 0.005 42.2 MTC + P vs or the emetogenic potential of an individual drug, as in 367 75.3 0.001 MTC + DEX + DIP [5| cisplatin-containing regimens, clearly overcomes that of the other combined agents [5]. Other important MTC - Metoclopramide; DEX - Dexamethasone; P - Methylpredvariables are differences among antineoplastic drugs in nisolone; DIP - Diphenhydramine.
m
109 The biology underlying this phenomenon is largely unknown. In fact, it is not known whether gender influences sensitivity to the emetogenic potential of antineoplastic agents or the efficacy of antiemetic treatment itself. It is interesting to note, however, that a similar difference between males and females in incidence of emesis caused by opiate analgesics has been reported, and a possible gender difference in neurotransmitter receptor site distribution or emetic drug binding characteristics has been postulated [12]. The age of patients is another important variable in predicting the risk of nausea and vomiting. In one large study [5], complete protection from vomiting/nausea was significantly better in older patients (>65 yrs) (73.9%/78.3%) than in the younger ones (50 mg/m2 with no antiemetic treatment will vomit. This makes the use of placebo in studies with high doses of cisplatin not only useless but also unethical, denying patients the good protection offered by a 'standard' regimen such as that of meto• clopramide + steroids. Unfortunately, the results of such studies continue to be published [31]. Obviously, placebo controlled trials are valid when an effective treatment is lacking and a low prevalence of emesis can be anticipated.
the two groups are then compared. In a cross-over (within subjects) design, each patient receives every drug being studied, 'crossing over' from one drug to the next in a predetermined order. The advantages and disadvantages of the two designs are illustrated in Tables 4 and 5. According to our experience, the parallel design is preferable because the characteristics of the study are more similar to those encountered in daily practice. In particular, this design allows the investigator to evaluate the persistence of antiemetic effectiveness of a drug regimen over multiple anticancer chemotherapy cycles, as is the case when the treatment is administered in normal clinical care. Other types of designs may be considered in particular circumstances. One of the most useful, although rarely used, is the sequential study [32]. This type of design, which favors the utilization of the most efficacious treatment, is of particular help when it is necessary to compare a relatively inefficacious treatment with one considered to be effective. Ethical considerations prompt the use of a design that minimizes the risk of treating patients with the less effective treatment while maintaining a scientifically sound statistical basis. The sequential design may be a good compromise.
The sample size of an antiemetic study is of critical importance. The study must be large enough for there to be sufficient statistical power to detect the smallest difference of clinical importance. Unfortunately, antiemetic trials have generally included fairly small numTwo major trial designs, the parallel and the cross- bers of patients, making the interpretation of their over, are used in antiemetic studies. In a parallel results difficult. Useful information can sometimes be (between subjects) design, the patients are randomized obtained even from small studies if the regimens tested to receive either the study drug or the comparative differ markedly in efficacy or toxicity, but these results treatment during one or several courses of therapy, and almost always necessitate validation by larger, controlled studies. An example of a successful integration of such a research strategy is illustrated in Table 6 where the Table 4. Parallel study design. results of a small open pilot study using the antiemetic Advantages: - Possibility to evaluate the persistence of anticombination of metoclopramide + dexamethasone + emetic efficacy in subsequent cycles. diphenhydramine [30] are compared with those of a Disadvantages: - Larger number of patients are required to show larger randomized double-blind trial which studied the differences between treatments. same combination in comparison with a 'standard' antiemetic regimen [5]. The complete response rates were very close as was the incidence of toxicity, but the Table 5. Crossover study design. large size of the controlled trial, 343 evaluable patients, added substantial evidence to the preliminary results of Advantages: - More powerful (smaller number of patients required). - Possibility to express a preference between treatments. Disadvantages: - Impossibility to evaluate the persistence of antiemetic activity in subsequent cycles. - Inappropriate if number of patients lost after first cycle is >5%. - Necessity to keep the emetic stimulus and the environment unchanged between the two treatments. - Problems of order effects (in relation to order in which the antiemetic treatments are administered) and problems of residual effects (in relation to influence of the previous antiemetic treatment on the subsequent).
Table 6. Evaluation of MDD antiemetic combination. Center Antiemetic treatment Type of study N. of pts Complete protection from vomiting (%) Acute dystonic reaction
MSKCC1 MDD
open 42 81
0
GOIRC MP vs MDD double-blind 343
72.5 1.7
M - Metoclopramide; D - Dexamethasone; D - Diphenhydramine; P - Methylprednisolone. 1 Memorial Sloan-Kettering Cancer Center, [30). b Italian Oncology Group for Clinical Research, [5].
112 the pilot study. Conducting large trials is the only way to pinpoint relatively small differences between treatments, to identify subgroups of patients which differ in response from the general population, and to shorten the time necessary to answer some clinical questions. However, it is implicit that large trials necessitate cooperative studies among institutions that have the interest and expertise in such a research field and this may create further problems. In our experience, the keys to successful collaboration among institutions in carrying out a multicenter trial are a recognized scientific leadership and an efficient organization. Evaluation ofparameters and methodology Studies of antiemetic therapy reveal uncertainties and difficulties in patient assessment mainly because of the problems encountered in defining and quantifying vomiting and nausea. The objective assessment of vomiting would seem to be a relatively simple procedure and could be done by either the patient or, preferably, an observer, who would record the number and duration of emetic episodes and, sometimes, the volume of emesis. In reality, several problems must be considered: the difficulty in separating retching from vomiting, such as in counting the vomiting episodes when vomiting is almost continuous, in measuring the duration of emesis and in monitoring emesis in an out-patient population. In our trials, we adopted the criteria of having an external observer count every single vomiting or retching episode and of measuring the length of vomiting expressed as the time elapsed between the beginning of the emetogenic drug infusion and the last episode of vomiting. Volume of emesis is a less useful parameter and is no longer considered in our trials; moreover, its collection and measurement can be difficult. To make the interpretation of these parameters useful, the time span of emesis assessment should be reported and the duration of the observation should be related to the expected length of vomiting for that particular drug. Monitoring of outpatients, which is necessary when studying delayed emesis, poses additional problems. In fact, follow-up by phone or questioning of the patients on their next hospital visit was found to be an unreliable method. An assessment which relies on the patient filling in a daily diary card (and using a visual analog scale to assess nausea) has been found to be much more satisfactory [33]. Assessment of nausea presents even greater difficulties. Because the experience of nausea is a subjective phenomenon, its assessment has of necessity relied almost entirely on patient reports. The use of objective correlates such as pulse rate, blood pressure and muscle tension has been tried, but without success. Measurement of nausea remains a subject of controversy, with results of individual studies claiming reliability
and advantages for new methods that can scarcely be compared. In order to provide new information on existing methods for evaluation of nausea and the best way to utilize them in clinical trials, we have compared in a standardized assessment three different methods of measuring nausea in 849 patients enrolled in 4 double blind randomized clinical trials and 2 observational studies [34]. Nausea was measured before and at 2, 4, 6, 8 and 24 hrs after chemotherapy by contemporaneously using three types of scales: a discrete descriptive scale (DS) (the four grades being 0 = no nausea, 1 = slight nausea, 2 = moderate and 3 - severe nausea), a linear visual analog scale (VAS), and an analog continuous chromatic scale (ACCS). Four different dimensions of nausea were also identified. 1. Maximal intensity, defined as the highest score value obtained with DS, VAS or ACCS at any evaluation carried out over the 24 hr period. 2. Entity, defined as the sum of all the values of intensity of nausea recorded at each evaluation time. 3. Duration, expressed in minutes. Patients were asked at each point of evaluation how many minutes they had experienced nausea during the previous time period. 4. Quantity, defined as the sum of the products of the intensity multiplied by duration, recorded at each evaluation time. We analyzed the distribution of nausea measurements in the population studied and the agreement among scales and nausea dimensions and their sensitivity. We found substantial equivalence among the different scales used and no advantages in using an analog with respect to a discrete scale. We also found a trend toward increasing sensitivity in detecting differences as the dimensions of nausea studied become more comprehensive of the various aspects of this symptom, quantity being more sensitive than entity, and entity more sensitive than maximal intensity. On the basis of these results we suggest that measurement of quantity of nausea, irrespective of the scale used, is the most valid way to quantify this purely subjective symptom. Since discrete and analogue scales are equivalent in evaluating nausea, the simpler descriptive approach can be adopted to quantify this symptom when analogue instruments are not at hand, provided a standard method of presenting the questionnaire is used and a favorable environment of good nursing care is assured. Antiemetic efficacy alone, however, is not the only evaluation end point Tolerability, compliance with treatment and patient preference are also important parameters. Since many agents have side effects which may limit their use, it is important that these be assessed in detail by general questioning and monitoring of the patient, and be reported according to a widely adopted severity scale. With currently available antiemetic agents, a uniform grading of sedation and diarrhea could be very useful.
113 Finally, an overall statement of preference by the patient himself should balance beneficial with adverse effects. Since it is the patient's quality of life that we are attempting to preserve, this overall assessment should be regarded as an important one. Unfortunately, in comparing different treatments, this global preference stated by the patient is possible only with the crossover design which carries the disadvantages already mentioned. In situations other than the crossover one, this global judgment is difficult to express. Until a better and simpler method is found, the best way to evaluate the antiemetic treatment is by the judgment of the individual patient and of the observer, and it is to be hoped that these will be convergent. Response criteria There is no established manner of expressing overall efficacy. Again, there is a clear need for a consensus for standardized definitions. Since the aim of an antiemetic is to completely abolish nausea and vomiting, it is proper to report complete response rates as complete protection from vomiting, from nausea and from nausea and vomiting, respectively; less than optimal responses are best reported as number of vomiting or retching episodes and quantity of nausea over the study time. We adopted the definitions of major protection when lor 2 episodes of vomiting were recorded, minor protection (3 to 5 episodes) and failure (more than 5). With the adoption of such a quantitative analysis, comparison among studies should become easier.
Conclusions Well designed and better conducted studies are urgently needed to solve many of the pending problems of treatment in chemotherapy-induced nausea and vomiting in cancer patients. Progress in control of emesis relies on a better understanding of the mechanism of vomiting, a thorough knowledge of antiemetic drugs, a controlled experience with their use and a careful consideration of the individual patient's specific emetic problem. Sound methodology in planning and evaluating antiemetic treatments is now at hand and it is to be hoped that it will be more widely adopted, allowing a more correct evaluation of the results of clinical trials and a more efficient utilization of these results in daily clinical practice. The pooling of the skills and experiences of physicians and specialists in oncology nursing are essential in the pursuit and achievement of this goal.
Acknowledgements This paper was presented at the ECCO 5 meeting, London, September, 1989.
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