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Purpose: A combination of aprepitant, a 5-HT3 receptor antagonist, and dexamethasone is recommended for the prophylaxis of acute or delayed emesis induced by chemotherapy containing anthracyclines plus cyclophosphamide in patients with breast cancer. The aim of this study was to verify whether dexamethasone is superior to aprepitant in preventing delayed emesis in patients receiving the same prophylaxis for acute emesis., Patients and Methods: A randomized double-blind study comparing aprepitant versus dexamethasone was completed in chemotherapy-naive patients with breast cancer treated with anthracyclines plus cyclophosphamide. Before chemotherapy, all patients were treated with intravenous palonosetron 0.25 mg, dexamethasone 8 mg, and oral aprepitant 125 mg. On days 2 and 3, patients randomly received oral dexamethasone 4 mg twice per day or aprepitant 80 mg once per day. Primary end point was rate of complete response (ie, no vomiting or rescue treatment) from days 2 to 5 after chemotherapy., Results: Of 580 enrolled patients, 551 were evaluable: 273 received dexamethasone, and 278 received aprepitant. Day 1 complete response rates were similar: 87.6% for dexamethasone and 84.9% for aprepitant (P < .39). From days 2 to 5, complete response rates were the same with both antiemetic prophylaxes (79.5%; P < 1.00), as were results of secondary end points (ie, complete protection, total control, no vomiting, no nausea, score of Functional Living Index-Emesis; P < .24). Incidences of insomnia (2.9% v 0.4%; P < .02) and heartburn (8.1% v 3.6%; P < .03) were significantly greater with dexamethasone on days 2 to 5., Conclusion: In patients with breast cancer treated with anthracycline plus cyclophosphamide chemotherapy and receiving the same antiemetic prophylaxis for acute emesis, dexamethasone was not superior to aprepitant but instead had similar efficacy and toxicity in preventing delayed emesis.

Purpose: An update of the recommendations for the prophylaxis of delayed emesis induced by moderately emetogenic chemotherapy discussed during the third Perugia Consensus Conference (June 2009) sponsored by MASCC-ESMO was presented. The review considered new studies published since the second consensus conference (April 2004)., Methods: An online search was used conducting PubMed and the search terms moderately, chemotherapy, and emesis with a restriction to papers in English., Results: Overall, nine randomized controlled studies were included: four evaluating NK1 receptor antagonists, one palonosetron, and four dopamine receptor antagonists., Conclusions: In patients receiving a combination of anthracycline plus cyclophosphamide treated with a combination of aprepitant, a 5-HT(3) receptor antagonist and dexamethasone to prevent acute nausea and vomiting, aprepitant is suggested to prevent delayed emesis. In patients who do not receive aprepitant for the prophylaxis for acute emesis and in which palonosetron is recommended, a multiday oral dexamethasone is the preferred treatment for the prevention of delayed emesis. Levels of evidence and of consensus for both recommendations are moderate.

In this update of our 2005 document, we used an evidence-based approach whenever possible to formulate recommendations, emphasizing the results of controlled trials concerning the best use of antiemetic agents for the prevention of emesis and nausea following anticancer chemotherapies of high emetic risk. A three-drug combination of a 5-hydroxytryptamine type 3 receptor (5-HT(3)) receptor antagonist, dexamethasone, and aprepitant beginning before chemotherapy and continuing for up to 4 days remains the standard of care. We address issues of dose, schedule, and route of administration of five selective 5-HT(3) receptor antagonists. We conclude that, for each of these five drugs, there is a plateau in therapeutic efficacy above which further dose escalation does not improve outcome. In trials designed to prove the equivalence of palonosetron to ondansetron and granisetron, palonosetron proved superior in emesis prevention, while adverse effects were comparable. Furthermore, for all classes of antiemetic agents, a single dose is as effective as multiple doses or a continuous infusion. The oral route is as efficacious as the intravenous route of administration.

For patients treated with low or minimally emetogenic chemotherapy there is little evidence from clinical trials supporting the choice of a given antiemetic therapy or of any treatment at all. The panel recognized the necessity of considering the introduction into clinical practice of new agents in these categories, particularly oral cytotoxic agents and targeted biological agents and also the possibility of over-treatment with antiemetics. There was consensus among panel members regarding the recommended treatment for patients receiving chemotherapy agents with low and minimal emetic risk. Patients without a history of nausea and vomiting for whom minimally emetic risk chemotherapy is prescribed should not routinely receive antiemetic prophylaxis. A single agent such as a low-dose corticosteroid is suggested for patients receiving agents of low emetic risk. If nausea and vomiting occurs during subsequent cycles of chemotherapy, prophylaxis with a single agent such as a substituted benzamide, a corticosteroid, or a phenothiazine should be administered. Only patients with persistent nausea and vomiting despite treatment with these recommended agents should receive a 5-HT3 receptor antagonist in the following cycles.

Data on the incidence and efficacy of antiemetic prophylaxis against delayed emesis induced by moderately emetogenic chemotherapy are scanty. An overview of the literature has been done that showed the efficacy of dexamethasone in two of three randomized trials. Its optimal dose and duration of administration has not been defined. Only one of four randomized studies showed a statistically significant efficacy of 5-HT(3) antagonists. Finally, only weak evidence has been published on the efficacy of dopamine receptor antagonists.

Development of effective antiemetic therapy depends upon an understanding of both the antiemetic agents and the emetogenic challenges these agents are designed to address. New potential antiemetic agents should be studied in an orderly manner, proceeding from phase I to phase II open-label trials and then to randomized double-blind phase III trials comparing new agents and regimens to best standard therapy. Use of placebos in place of antiemetic therapy against highly or moderately emetogenic chemotherapy is unacceptable. Nausea and vomiting should be evaluated separately and for both the acute and delayed periods. Defining the emetogenicity of new antineoplastic agents is a challenge, since such data are often not reliably recorded during early drug development. A four-level classification system is proposed for emetogenicity of intravenous antineoplastic agents. A separate four-level classification system for emetogenicity of oral antineoplastic agents, which are often given over an extended period of time, is also proposed.

Establishing appropriate and practical methodology is a key to progress in the investigation of chemotherapy-induced nausea and vomiting. Critical issues include patient response assessment, proper trial design for evaluating new agents, and the definition of chemotherapy emetogenicity. In assessing antiemetic response, the primary end-point should be complete control of emesis and nausea. Emesis and nausea should be independently assessed with the period of observation defined (acute, delayed, anticipatory). Emesis can be evaluated by measuring the number of emetic episodes either by direct observation or by patient self-report using patient-completed diaries. Nausea should be measured by patient self-report with the standard parameters, including frequency and intensity. New antiemetic drug development should proceed in an orderly progression from open-label phase I-II trials defining tolerance and minimally fully effective dose to phase III comparative trials. A randomized, parallel, double-blind study is the preferred design for the latter, and the comparator arm should always include the current best available treatment. Antiemetic placebos are no longer acceptable with chemotherapy regimens known to produce emesis in a majority of patients. None of the emetogenic classifications proposed to date adequately accounts for all known important patient- and treatment-related prognostic variables. A modification of a recently reported schema is proposed for use in making antiemetic treatment recommendations and defining the emetogenic challenge in clinical trials.

Differences among 5-HT3 receptor antagonists have been reported in pharmacological studies with regard to selectivity of receptor binding, potency, duration of action and dose-response curves. However, whether these pharmacological differences can affect clinical efficacy and safety remains to be determined. A careful analysis of the literature revealed 22 comparative studies among the 5-HT3 receptor antagonists available for review. Unfortunately, several of these trials have some important shortcomings especially in the study design, the size of population studied and the type of anti-emetic treatment selected, making their conclusions often difficult to interpret. However, among these studies, seven large, double-blind clinical trials have clearly shown that the antiemetic activity and tolerability of ondansetron, granisetron, tropisetron and dolasetron is almost identical at least in the prevention of cisplatin-induced emesis. Therefore, from the efficacy and safety point of view, there is no reason to prefer one with respect to the other compound. From the economic perspective, instead, differences may exist and they are strictly related to the dose and schedule of administration chosen for each compound. The information available on the use of 5-HT3 receptor antagonists in the prevention of emesis induced by moderately emetogenic chemotherapy is at best scant. Contrasting results have been reported and only one well-conducted study has been published in full. Therefore, the possible differences among the various compounds are difficult to evaluate. More studies should be carried out in this group of patients.

During the 1995 Multinational Association of Supportive Care in Cancer (MASCC) Congress, a consensus conference was planned by the Subcommittee for Antiemetics. To define the topics to be discussed, a questionnaire containing both clinical and methodological issues was sent to 118 experts in 31 countries. The questionnaire contained 33 items on clinical and 19 items on methodological issues, and each response was rated on a 4-level categorical scale. The clinical issues were evaluated for interest, that is clinical importance, and feasibility, that is availability of sufficient data to make them suitable topics for the consensus conference. About 60% of questionnaires were returned, with a small number of missing responses. The responses to the items of clinical interest showed that about two-thirds of the issues identified by the Subcommittee were found by the experts to be of at least high interest, but often the availability of data was found to be insufficient for their discussion. Prevention of acute emesis induced by cisplatin and by moderately emetogenic chemotherapy and the optimal intravenous dose and schedule of the 5-HT3 receptor antagonists were the items with the highest interest and feasibility. The issues in the methodological section were also mostly found to be of at least high interest. The distinction between acute and delayed emesis, the evaluation of the persistence of antiemetic efficacy in subsequent cycles of chemotherapy and the statistical analysis of delayed emesis were the methodological issues in which the highest interest was recorded. Data collected will be used to define the main topics to be discussed during the planned consensus conference.

Since 1981, when high-dose intravenous metoclopramide was demonstrated to be efficacious, slow but constant improvement in the prevention of chemotherapy-induced emesis has been achieved. Today, a combination of a serotonin receptor 3 (5-HT3) antagonist plus dexamethasone can be considered the most efficacious treatment for the prevention of emesis induced by cisplatin and by moderately emetogenic chemotherapy. Which 5-HT3receptor antagonist should be used? Preclinical differences among 5-HT3receptor antagonists have been reported with regard to selectivity of receptor binding, potency, dose response, and duration of action. Twelve comparative studies among 5-HT3receptor antagonists have been carried out. Unfortunately, all these trials have some important shortcomings (patient population not large enough to show small but clinically important differences; not blinded studies; no association with steroids to maximize treatment efficacy) and, therefore, no definitive conclusions can be drawn. Very recently three large, well-conducted double-blind comparative studies have been published. All three showed that 5-HT3receptor antagonists have almost identical antiemetic efficacy and tolerability. Therefore, the choice among the 5-HT3receptor antagonists should be based only on the acquisition cost of the prescribed dose in each country for each compound.

Chemotherapy-related nausea and vomiting can today be controlled with available antiemetics in a high percentage of patients but emesis remains a problem for some patients, with certain drugs and with repeated cycles of chemotherapy. The fundamental steps of clinical research in antiemetics towards the improvement of the control of nausea and vomiting with new drugs or combinations are presented. Special emphasis is given to cisplatin-induced nausea and vomiting because of the frequency and relevance of this phenomenon. The use of high-dose metoclopramide, its combination with steroids, and later the addition of lorazepam or diphenhydramine represented the evolving standard of the 1980s, with the level of complete protection from vomiting improving from 30%-40% to 60%-70% with the three-drug combination. The introduction of new agents such as the 5-hydroxytryptamine 3 (5-HT3) receptor antagonists has recently offered new possibilities because of their activity and lack of toxicity. In particular, the combination of ondansetron plus dexamethasone is today the most efficacious and least toxic antiemetic treatment for prevention of emesis in patients treated with a single high dose or low repeated doses of cisplatin. A comparison of different 5-HT3 antagonists, always in combination with steroids, is now considered necessary. For patients treated with moderately emetogenic chemotherapy the use of steroids can still be considered the standard treatment. In this setting, the role of 5-HT3 receptor antagonists, alone or in combination with steroids, has to be better defined through large, well-planned clinical trials, which should have a cost-effectiveness analysis as one of their goals.

In a large double-blind study of antiemetic therapy conducted in Italy, 289 patients underwent 3 consecutive cycles of cisplatin chemotherapy. Antiemetic treatment with ondansetron plus dexamethasone was more efficacious and better tolerated, but also more expensive, than treatment with metoclopramide plus both dexamethasone and diphenhydramine. To evaluate the different costs of the 2 antiemetic regimens, we conducted a retrospective cost-effectiveness analysis from a hospital perspective. Direct costs of antiemetic therapy (acquisition cost of drugs, materials and time spent by nurses to prepare and administer therapies), cleanup after emesis, rescue medication and adverse events were evaluated. Antiemetic drug acquisition costs per patient were 5.23-fold higher for the ondansetron regimen than for the metoclopramide regimen. However, when the costs of materials and nursing time required to prepare and administer the antiemetic regimens were included, this ratio was 3.77. Furthermore, including the cost of emesis, rescue antiemetic treatments and medication used to treat adverse events, hospital costs per patient were 3.21-fold higher with the ondansetron regimen during the first cycle, 3.08-fold higher during second cycle and 2.89-fold higher during third cycle of chemotherapy. Complete protection from vomiting and from both vomiting and nausea with ondansetron occurred, respectively, in 78.7 and 69.1% of patients in the first cycle, 73.8 and 57.3% in the second cycle, and 74.2 and 58.1% in third cycle of chemotherapy. Corresponding figures for the metoclopramide regimen were 59.5 and 50.4%, 53.6 and 37.1%, and 46.8 and 27.3%, respectively. Thus, the cost per successfully treated (completely protected) patient was 2.43- and 2.34-fold higher, respectively, for ondansetron at the first cycle, 2.23- and 1.99-fold higher, respectively, at second cycle, and 1.82- and 1.36-fold higher, respectively, at third cycle. In conclusion, the study demonstrates that, while ondansetron has a greater acquisition cost than metoclopramide, the ondansetron regimen costs per successfully-treated patient substantially decrease when all direct hospital costs are taken into account.

Nausea and vomiting are among the most distressing adverse effects of cancer chemotherapy. In the last 10 years considerable advances in the prevention of chemotherapy-induced emesis have been made. From an analysis of the results obtained in patients receiving moderately- to severely-emetogenic drugs the following guidelines in choosing the best antiemetic treatment can be given: 1. For the prevention of acute emesis induced by a high single dose of cisplatin (> or = 50 mg/m2) or by low doses (20 to 40 mg/m2) repeated for 4 to 5 days, the combination of ondansetron plus dexamethasone is the most efficacious and least toxic antiemetic therapy. 2. For the prevention of delayed emesis the combination of oral dexamethasone plus metoclopramide seems to offer the best protection, although over 40% of patients still experience delayed nausea and vomiting. 3. For the prevention of acute emesis induced by moderately emetogenic drugs, corticosteroids (dexamethasone or methylprednisolone) are efficacious and safe antiemetic agents. Although equally efficacious, the serotonin (5-HT)3 receptor antagonists, due to their higher acquisition costs, are indicated only in patients refractory to corticosteroids or in those who cannot use them. Unresolved problems in antiemetic research include: (i) identification of the best antiemetic treatment for those areas of cancer chemotherapy where adequate data are lacking, such as high dose regimens for bone marrow transplantation; (ii) optimisation of treatment for the most widely used chemotherapy regimens; and (iii) identification of the best rescue treatment for patients who fail to respond to antiemetic prophylaxis. Although many new 5-HT3 antagonists are currently being studied, the possible improvement in efficacy and tolerability brought about by these agents will probably only be marginal.

In the last decade research on antiemetic therapy has determined relevant advances in the prevention of chemotherapy-induced emesis. In fact, 70-80% of patients submitted to highly or moderately emetogenic drugs achieve complete protection against vomiting during the first cycle of chemotherapy. In the prevention of acute emesis induced by a high single dose (> or 50 mg/m2) or a low dose (20-40 mg/m2) of cisplatin repeated for 4-5 days, a combination of ondansetron plus dexamethasone was shown to be more efficacious and less toxic than the combination of high dose metoclopramide plus dexamethasone plus diphenhydramine. Few studies have been performed for the prevention of delayed emesis induced by cisplatin. At present, the combination of oral dexamethasone plus metoclopramide seems to offer the best protection and should be considered the treatment of choice. For the prevention of acute emesis induced by moderately emetogenic drugs, corticosteroids (dexamethasone and methylprednisolone) and the new 5-HT3 receptor antagonists have a similar efficacy and a low toxicity. On a cost basis, corticosteroids must be considered the drug of choice while 5-HT3 receptor antagonists should be used only in patients refractory to corticosteroids or in those who cannot tolerate them.

Measurement of nausea is essential for the evaluation of efficacy of antiemetic treatment. Frequency, duration and intensity of nausea should be assessed in all trials. Three different methods: a discrete scale (DS), a visual analogue scale (VAS) and a continuous chromatic analogue scale (ACCS) of measuring nausea and four different dimensions maximal intensity, (MI); entity, (E); duration, (D) and quantity, (Q) were evaluated in 849 cancer patients undergoing chemotherapy. A substantial agreement between the different scales was found and no advantage was shown for using an analogue (VAS) rather than a discrete (DS) scale. There was a trend towards increasing sensitivity in detecting differences as the dimension of nausea used encompassed wider aspects of this symptom (Q more sensitive than E more sensitive than MI).

The antiemetic activity of two different high doses and schedules of metoclopramide in dacarbazine-treated cancer patients was compared in a double-blind crossover study. Regimen A consisted of metoclopramide [2 mg/kg x 4 intravenously (i.v.)] plus methylprednisolone (250 mg x 2 i.v.) plus diphenhydramine (50 mg x 2 i.v.). Regimen B consisted of metoclopramide (3 mg/kg x 2 i.v.) plus dexamethasone (20 mg i.v.) and diphenhydramine (50 mg i.v.). Both treatments were administered for the first 2 days of 5-day dacarbazine chemotherapy. Thirty-two patients (13 men and 19 women) affected by melanoma and sarcoma were entered in the study. Complete protection against nausea and vomiting for the first 2 days of chemotherapy in both antiemetic regimens was not significantly different. Patient preference and tolerance of the two antiemetic treatments were similar. Regimen B, employing a lower dosage of metoclopramide and steroids and using a more simple schedule of administration should be the preferred treatment.

To prevent delayed emesis induced by cisplatin (mean dose 90 mg/m2), 120 consecutive patients were randomized to receive, in a 7-day crossover design, oral metoclopramide (20 mg q.i.d.), dexamethasone (1 mg q.i.d.) or placebo (two tablets q.i.d.) starting 24 hours after the end of chemotherapy. Complete protection from nausea, but not from vomiting. was significantly increased by both dexamethasone and metoclopramide with respect to placebo. Important prognostic factors favoring the appearance of delayed emesis were incomplete protection from vomiting during the first 24 hours after cisplatin, female gender, and highest cisplatin doses. Tolerability of both drugs was good. Larger and randomized controlled trials are necessary to identify better preventive treatment of delayed emesis induced by cisplatin.

Ondansetron (OND) is a new 5-HT3 receptor antagonist that give complete protection from emesis/nausea in approximately 50% of cisplatin (CDDP)-treated patients. To evaluate if dexamethasone (DEX) added to OND increases antiemetic efficacy, we carried out a double-blind randomized crossover study to compare the antiemetic activity of OND with OND plus DEX. One hundred two chemotherapy-naive patients (44 women and 58 men) scheduled to receive CDDP chemotherapy at doses greater than or equal to 50 mg/m2 entered the study. Eighty-nine patients completed both cycles with the following results: complete protection from emesis/nausea was obtained in 57/59 patients (64.0%/66.3%) with OND and in 81/79 (91.0%/88.8%) with OND plus DEX (P = .0005/P = .0021). At the end of the study, 53% of the patients expressed a treatment preference, and of these, 74% chose OND plus DEX compared with 26% who preferred OND alone, a statistically significant difference (P less than .003). Side effects were very mild and not significantly different between the two treatments. We conclude that OND plus DEX is more efficacious than OND in protecting patients from CDDP-induced emesis and nausea.

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.

In a double-blind crossover antiemetic study in cisplatin-treated cancer patients, metoclopramide 4 mg/kg as a single intravenous dose (regimen A) was compared with 3 mg/kg in two doses (regimen B). In both regimens, metoclopramide was combined with dexamethasone and diphenhydramine. 65 consecutive, chemotherapy-naïve inpatients (45 males and 20 females) treated with high doses (at least 50 mg/m2) of cisplatin entered the study and 54 completed both treatments. Complete protection from vomiting and nausea, mean number of emetic episodes, mean maximum intensity of nausea and mean duration of emesis or nausea were similar with the two antiemetic regimens. 23 patients (43%) did not express a treatment preference, while 16 (30%) preferred regimen B and 15 (28%) preferred regimen A. Side-effects were similar with the two metoclopramide schedules. A combined antiemetic regimen of a single high dose of metoclopramide (4 mg/kg) can preserve efficacy and tolerability and thus should be preferred.

Ondansetron as a single agent has been shown to be superior to metoclopramide in the control of acute nausea and vomiting induced by high-dose cisplatin, complete or major control (0-2 emetic episodes) being achieved in 65-75% of patients. In an attempt to further improve efficacy in this group of patients, a randomised, double-blind, crossover study was carried out comparing ondansetron with ondansetron plus dexamethasone. Ondansetron was given as three intravenous doses (0.15 mg/kg) 2-hourly and dexamethasone as a single intravenous dose of 20 mg prior to cisplatin (median 70 mg/m2, range 50-120 mg/m2). Complete control of emesis was achieved in 91% of patients receiving the combination of ondansetron plus dexamethasone and in 64% of patients receiving ondansetron alone (P less than 0.001). Nausea was absent in 89% of patients receiving the combination and in 66% of patients receiving ondansetron alone (P less than 0.0025). Both treatments were well tolerated. The addition of a single dose of dexamethasone to ondansetron significantly improves the control of emesis and nausea compared to ondansetron monotherapy in patients receiving high-dose cisplatin.

Sixty five chemotherapy naive patients receiving cisplatin (50-120 mg/m2) containing chemotherapy participated in an evaluation of ondansetron, a 5-HT3 receptor antagonist, in the prophylaxis of acute and delayed nausea and emesis. Ondansetron was given as three 0.15 mg/kg doses intravenously (0.5 h before, 3.5 h and 7.5 h after cisplatin) for acute emesis followed by 8 mg orally 8-hourly for five days at 24 h post-cisplatin for delayed emesis. For acute emesis (first 24 h, n = 63), complete control was achieved in 34 patients (54%) and major control (1-2 episodes) in 16 patients (25%). Complete protection from acute nausea was achieved in 48 patients (76%). For delayed emesis (days 2-6, n = 55), 33 patients (60%) were completely protected or reported one to two episodes during the entire 5-day observation period; 63% reported only mild or no nausea. Ondansetron was well tolerated with no significant drug-related adverse events. These results are consistent with serotonin being a significant transmitter of cisplatin-induced emesis.

In a pilot study we evaluated the efficacy and tolerability of a four-drug antiemetic combination (metoclopramide, dexamethasone, diphenhydramine and lorazepam) in cancer patients submitted to cisplatin chemotherapy at doses greater than or equal to 50 mg/m2. Fifty male patients entered the study. Complete protection from vomiting and nausea was obtained in 41 patients (82%) (95% confidence limits 71 and 93%). Toxicity was slight except for moderate sedation in 10% of patients necessitating their hospitalization. Only one extrapyramidal reaction (akathisia) was observed. When these results were compared to our previous experience in male patients treated with a combination of metoclopramide, dexamethasone and diphenhydramine without lorazepam, used at the same doses and schedule, no clear benefit and higher toxicity was observed.

High-dose metoclopramide has been proposed as an effective antiemetic agent in patients treated with cisplatin. Its optimal dosage schedule, however, has not yet been completely defined. We report the results of a multicenter, double-blind, randomized clinical trial where the efficacy and safety of two fixed high-dose regimens of metoclopramide (60 and 120 mg, respectively) have been tested in 112 patients receiving cisplatin treatment. No statistically significant difference has been found between the two groups. In patients treated with cisplatin at doses greater than 100 mg/m2, the higher dose regimen seems more efficacious, but this result should be confirmed in a larger group of patients. Treatment was generally well-tolerated. However, a consistent percentage of patients (about 60%) still present with vomiting, and this makes further investigation necessary.

Despite treatment, emesis remains a major problem with cisplatin (CDDP) chemotherapy. Reasons for variability in antiemetic response among patients and in subsequent cycles are largely unknown and toxicity is sometimes severe. We have, therefore, carried out a multicenter, double-blind randomized trial comparing a combination of high-dose metoclopramide (MTC) (1 mg/kg x 4) and methylprednisolone (P) (treatment A) with a shorter but higher single-dose schedule of metoclopramide (3 mg/kg x 2) combined with dexamethasone (DEX) and diphenhydramine (DIP) to prevent extrapyramidal reactions (treatment B). Three hundred sixty-seven consecutive patients treated with various chemotherapy combinations containing CDDP were studied. Complete protection from vomiting/nausea was, at first cycle, 72.5%/79.5% with treatment B and 55.8%/65.1% with treatment A, a statistically significant difference (P less than .002/P less than .005). In subsequent cycles, protection from emesis significantly decreased with no difference between the two treatments. Multifactorial analysis shows that women, younger patients, outpatients, and patients who experienced emesis in previous cycles were at higher risk of suffering nausea and/or vomiting. Both regimens were well tolerated, but patients treated with treatment B had significantly less extrapyramidal reactions (1.7%/6.1%, P = .053). Treatment B is preferred due to its greater efficacy and lower incidence of extrapyramidal reactions. Trials on antiemetic therapy should take into account the important variables able to influence the efficacy of treatment. There is still a need for improving prevention of emesis in CDDP-treated patients.

A dose-finding multicenter study was undertaken to evaluate the antiemetic efficacy of domperidone, an antidopaminergic drug, which has been proposed as a suitable alternative to high-dose metoclopramide in the control of cisplatin-induced nausea and vomiting. Forty-five patients were treated with different increasing high doses of domperidone (30, 60, 120 or 150 mg) administered by i.v. infusion over 20 min every 2 hr for a total of four doses for each patient, starting 30 min before chemotherapy. The number of episodes of emesis, the duration of nausea and vomiting and side-effects were recorded. Results do not suggest any specific difference in protective effect between the regimens tested. Moreover, occurrence of serious side-effects indicated that the safety of high-dose domperidone is doubtful.

The antiemetic efficacy and toxicity of methylprednisolone (MP) and metoclopramide (MTC) in prevention of nausea and vomiting in breast cancer patients receiving intravenous cyclophosphamide methotrexate 5-fluorouracil (CMF) chemotherapy has been evaluated in a double-blind trial. The two antiemetic drugs (MP vs. MTC) offered the majority of patients a similar complete protection from vomiting (76.5 vs. 66.7%) and nausea (82.4 vs. 81.8%), but in older patients MTC seems more efficacious than MP. Sedation was found more frequently (p = 0.02) in patients treated with MTC. In conclusion, in patients treated with CMF the use of MP as preventive therapy of nausea and vomiting is to be preferred to MTC due to its better tolerability, but in older patients MTC should be considered if MP fails.

In a double-blind randomized trial, we compared the efficacy and tolerability of high-dose (2 mg/kg X 4) intravenous metoclopramide (MTC) versus metoclopramide plus high-dose (250 mg X 2) intravenous methylprednisolone (MP) administered for the first 2 days in untreated patients submitted to dacarbazine chemotherapy for 5 days. Thirty-four patients entered the study. Complete protection from nausea and vomiting was achieved in the majority of patients all through the study period with both antiemetic treatments, with slightly greater efficacy at day 2 for the combination. However, after suspension of the antiemetic therapy, there was a relapse of vomiting in patients. Side effects were not different between the two treatments, but extrapyramidal reactions were significantly increased on the second day of antiemetic therapy. In conclusion, high-dose MTC with or without MP can give good antiemetic protection and the combination seems to be slightly more efficacious. However, the relapse of vomiting after discontinuing antiemetic treatment and the high incidence of extrapyramidal reactions justify further studies to find a better antiemetic treatment.

We designed a multicenter, double-blind randomized study to determine the safety and antiemetic effectiveness of intravenous (IV) methylprednisolone (P) combined with high-dose IV metoclopramide (MTC) v MTC alone in 200 untreated cancer patients receiving cisplatin chemotherapy. One hundred eighty-five patients were evaluable for treatment efficacy. MTC plus P was significantly superior to MTC alone in reducing the number and length of vomiting episodes (P = .001 and P = .0008, respectively) and the maximal intensity of nausea (P = .0124 with a score system; P = .0155 with a linear analogue scale) and length of nausea (P = .0056). The subgroup with a major incidence of nausea and vomiting was women, especially young women, outpatients, and those treated with higher doses of cisplatin. Side effects were low and equally distributed between the two treatment groups. We conclude that MTC plus P has greater antiemetic activity than MTC alone in patients receiving cisplatin chemotherapy.

Sixty-two patients treated for the first time with i.v. CMF were included in a double-blind comparative study aimed at evaluating the efficacy of 3 different drugs (methylprednisolone (MP), metoclopramide (MTC), and domperidone (DMP) in preventing chemotherapy-induced nausea and vomiting. Complete protection from vomiting/nausea was obtained in 85%/80% in the group treated with MP; in 60%/65% in the group treated with MTC and in 38%/42% in the group treated with DMP. Average number of vomiting episodes was 2.4 with MP, and 1.7 with MTC and 6.2 with DMP. Older patients seem to be a prognostically unfavorable subgroup. Side-effects were mild and infrequent. We conclude that MP and MTC are probably equally efficacious antiemetic treatments in patients undergoing i.v. CMF chemotherapy, but due to the risk of extrapyramidal reactions with MTC, MP probably should be the treatment of choice in these patients.