Aprepitant versus metoclopramide, both combined with dexamethasone, for the prevention of cisplatin-induced delayed emesis: a randomized, double-blind study.

BACKGROUND: A combination of aprepitant, a 5-HT3 receptor antagonist (r.a.), and dexamethasone is recommended for the prophylaxis of cisplatin-induced nausea and vomiting in the acute phase, and aprepitant + dexamethasone (A + D) in the delayed phase. The aim of this study was to verify if A + D is superior to metoclopramide plus dexamethasone (M + D) in preventing delayed emesis in cancer patients receiving the same prophylaxis for acute emesis. PATIENTS AND METHODS: A randomized double-blind study comparing A + D versus M + D was completed in previously untreated cancer patients. Before chemotherapy, all patients were treated with intravenous palonosetron 0.25 mg and dexamethasone 12 mg, and oral aprepitant 125 mg. On day 2-4, patients randomly received oral dexamethasone 8 mg plus aprepitant 80 mg once daily (days 2-3) or metoclopramide 20 mg four times daily plus dexamethasone 8 mg bid. Primary endpoint was rate of complete response (no vomiting, no rescue treatment) in day 2-5 after chemotherapy. RESULTS: Due to difficulty in the accrual of patients, 303 of the 480 planned patients were enrolled, 284 were fully evaluable, 147 receiving A + D, 137 M + D. Day 1 results were similar in both arms. On day 2-5, complete response rate was not significantly different (80.3% with A + D versus 82.5% with M + D, P < 0.38, respectively), and all secondary endpoints were also similar (complete protection, total control, no vomiting, no nausea, and score of Functional Living Index-Emesis; P < 0.24). Adverse events incidence was not significantly different between the two treatments. CONCLUSIONS: In cancer patients submitted to cisplatin-based chemotherapy, receiving the same antiemetic prophylaxis for acute emesis, A + D is not superior to M + D in preventing delayed emesis, and both treatments present similar toxicity. CLINICALTRIALSGOV NUMBER: NCT00869310.

Dental caries and bone mineral density: a cross sectional study.

AIM: The relationship between bone mineral density (BMD), age and dental caries has been studied. Quantitative ultrasonography (QUS) is an economic, non invasive, and reproducible method for measuring both bone mineral density and bone elasticity in growing subjects in large populations. METHODS: This study evaluated the relationship between BMD and prevalence of dental caries (Decayed Missing Filled Tooth - DMFT) in 540 healthy adolescent with mean age 12.3 years, age range 10 to 15 years, resident in two provinces in south Italy. BMD was measured using QUS by calculating the speed of sound (m/s) on the last four fingers of the non dominant hand, with the estimate thus obtained being defined as the AD-SoS (Amplitude-Dependent Speed of Sound and categorised as AD-SoS < or = 1900 m/s and AD-SoS > 1900 m/s). Occurrence of dental caries was defined using the DMFT index (DMFT=0 and DMFT > 0). RESULTS: The results of the multifactorial analysis, carried out with logistic model, confirms the expected statistically significant association between response (DMFT) and explicative variables -- AD-SoS (P < 0.006) and Age (P < 0.004). CONCLUSION: Greater bone mineralisation (AD-SoS1900 m/s) and younger age (Age < or =12 years) are dental caries prevention factors: the probability to have caries for the subjects in such conditions is 0.34, about the half of that recorded in the subjects with lower bone mineralisation and older age (0.62).

Antiemetic activity of high doses of metoclopramide combined with methylprednisolone versus metoclopramide alone in cisplatin-treated cancer patients: a randomized double-blind trial of the Italian Oncology Group for Clinical Research.

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.

5-HT3 receptor antagonists: differences and similarities.

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.

Ondansetron.

Ondansetron is the first selective antagonist of the 5-hydroxytryptamine receptors (type 3) marketed for the prevention of emesis induced by antineoplastic agents. Ondansetron has been shown to be more active and less toxic than high-dose metoclopramide in patients submitted to cisplatin chemotherapy. Furthermore, when dexamethasone was added to ondansetron, its antiemetic efficacy increased significantly. In the prevention of emesis induced by a high single dose of cisplatin or by repeated low doses, ondansetron combined with dexamethasone has been shown to be the more efficacious and less toxic antiemetic treatment. However, in the prevention of delayed emesis from cisplatin, its role is still to be defined. In patients submitted to moderately emetogenic chemotherapeutic agents, ondansetron has shown an efficacy superior or equal to standard doses of metoclopramide, but is less toxic. Moreover, when compared with dexamethasone, its antiemetic efficacy and tolerability is similar; in this group of patients ondansetron should be used only when steroids fail. Ondansetron toxicity is generally mild; in particular, it does not induce extrapyramidal reactions. The most frequent side-effects are headache and constipation.

Reliability and validity of a quality of life questionnaire in cancer patients.

Two studies were sequentially conducted to validate a new questionnaire which takes into consideration the most important variables which could influence quality of life evaluation. Particular attention was given to the methodology employed to collect data and to the patients' characteristics. In the first study 80 consecutive cancer patients were randomised to twice fill in one of four different types of questionnaire, each one characterised by a different polarisation of semantic and syntactic extreme values of the visual linear analogue (for instance, "very much" always on the right, regardless of the semantic value of the answer; positive semantic value always on the right, regardless of whether it was "very much" or "not at all"; and so on). The second study, conducted on 60 lung cancer patients, consisted in testing the reliability (by measuring the reproducibility in different ways) and the validity (by performing a factor analysis) of the type of questionnaire indicated by the first study as the most reliable. The internal coherence was also evaluated by measuring the effects of physical and psychological conditions on the responses.

Treatment of advanced non-small cell lung cancer (NSCLC): the "Umbria" cooperative study.

One hundred fifty-six patients with metastatic or locally advanced non-small cell lung cancer (NSCLC) were randomized to 3-week cycles of treatment with either: (A) cisplatin (120 mg/m2 on day 1); (B) cisplatin (120 mg/m2 on day 1) plus etoposide (VP-16) (100 mg/m2 on days 1-3; and (C) the cisplatin plus etoposide (VP-16) regimen plus mitomycin C (10 mg/m2 on days 1, 21, and 42; then every 6 weeks for a maximum dose of 100 mg). The overall objective response rates for the combination regimens (30% with two drugs and 26% with three drugs) were superior to that obtained with one drug (4%). Likewise, the median duration of survival with the combination therapy arms (8 to 9 months) was superior to that obtained with the single agent (5 months). Both performance status and limited disease were correlated with response in all groups, and with survival in the combined chemotherapy arms. The dose-limiting toxicity was myelosuppression, especially for the group receiving the three-drug regimen. In summary, combination chemotherapy using cisplatin and etoposide (VP-16) appears to be the most active and safest regimen in NSCLC.

Inhibition of spontaneous platelet aggregation by sulfinpyrazone.

In a randomized double-blind crossover study in 16 patients with enhanced in vitro spontaneous platelet aggregation, sulfinpyrazone proved to be effective in normalizing platelet aggregability within 4 days after initiation of therapy.

A phase II antiemetic combination (COMD) for cisplatin-induced nausea and vomiting.

Thirteen patients resistant to high-dose metoclopramide (greater than or equal to 5 emetic episodes in 24 h following chemotherapy) were treated in the subsequent course of CDDP chemotherapy with COMD (chlorpromazine, orphenadrine, metoclopramide, dexamethasone). A statistically significant reduction in the number of vomiting episodes was obtained, and 69% of patients showed a better acceptance of CDDP treatment. Subsequently, the same antiemetic combination was administered to 31 untreated patients receiving CDDP alone for the first time: 67.7% obtained complete protection from vomiting with minimal toxicity. According to our experience, COMD is an efficacious and well-tolerated antiemetic combination in cisplatin-treated patients; however, further studies with larger numbers of patients are required to confirm these preliminary results.

A randomized trial fo three cisplatin-containing regimens in advanced non-small-cell lung cancer (NSCLC): a study of the Umbrian Lung Cancer Group.

Survival in patients with locally advanced (stage III Mo) and metastatic (Ml) non-small-cell lung cancer (NSCLC) is short. Phase II studies have reported objective responses ranging from 20% to 60% using cisplatin-based chemotherapeutic regimens, yet few have shown improvement in median survival. In our phase II pilot studies with cisplatin (CDDP) and etoposide (VP-16), we observed a 26% response rate; with CDDP, VP-16, and mitomycin-C, a 38% response rate was obtained in advanced NSCLC patients. A total of 156 consecutive patients with locally advanced and metastatic NSCLC were randomized to one of three treatment arms to determine whether the chemotherapy protocols had any effect on response rate and median survival in a large, randomized study. Arm 1 consisted of CDDP (120 mg/m2 x 3 weeks); arm 2, of CDDP (120 mg/m2) and VP-16 (100 mg/m2 given i.v. on days 1-3), repeated every 3 weeks; and arm 3, of CDDP (120 mg/m2) and VP-16 (100 mg/m2 on days 1-3) given every 3 weeks, plus mitomycin C (10 mg/m2 on days 1, 21, and 42, then every 6 weeks, for a maximal dose of 100 mg). After 71 patients had been enrolled in the study, we stopped accrual in the CDDP arm due to a lack of response [1 complete response (CR) in 24 patients; 4%] and continued enrollment in the two combination-chemotherapy arms. In the CDDP/VP-16 arm a 30% response rate [1 CR, 18 partial responses (PRs)] was obtained, and in the CDDP/VP-16 mitomycin C arm a 26% response rate (4 CRs, 11 PRs) was seen among a total of 150 evaluable patients. Responses were observed in 31% of patients with favorable performance status (PS) (ECOG 0-1) vs 14% in patients with a poor PS (ECOG 2-3). Of patients with locally advanced disease (III Mo), 17 (33%) obtained an objective response, compared with 20 patients (20%) with metastatic disease. Median survival was 18 weeks in the CDDP arm, 35 weeks in the CDDP/VP-16 arm, and 37 weeks in the CDDP/VP-16/mitomycin C arm. The median survival in the multimodal chemotherapy arms was significantly greater than that obtained with CDDP alone. Toxicity was predominantly myelosuppression in the mitomycin C-containing arm (27%, wtto grade 3-4). Our study shows that combination chemotherapy using CDDP/VP-16 is active and safe in the treatment of advanced NSCLC patients with a good performance status. The addition of mitomycin C did not improve the therapeutic response.

A pilot study of metoclopramide, dexamethasone, diphenhydramine and acupuncture in women treated with cisplatin.

A total of 26 women who submitted to cisplatin chemotherapy received as antiemetic treatment a combination of metoclopramide, dexamethasone and diphenhydramine. Acupuncture according to traditional Chinese medicine was also carried out. The results were compared with those obtained in a similar group of women with cancer, who were treated in the same setting with the same antiemetic combination but without additional acupuncture. Acupuncture was shown to increase complete protection from nausea and to decrease the intensity and duration of nausea and vomiting. However, the difficulties of performing acupuncture routinely in daily practice are a hindrance to its wider use.

Cost and cost-effectiveness analysis of ondansetron versus metoclopramide regimens: a hospital perspective from Italy.

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.

A double-blind trial comparing antiemetic efficacy and toxicity of metoclopramide versus methylprednisolone versus domperidone in patients receiving doxorubicin chemotherapy alone or in combination with other antiblastic agents.

Nausea and vomiting are reported in approximately 60% of neoplastic patients treated with doxorubicin used alone at doses greater than or equal to 50 mg/m2 or in combination with other noncisplatin antiblastic agents. In a double-blind study we compared the efficacy and tolerability of metoclopramide (MTC) versus Domperidone (DMP) versus methylprednisolone (MP) administered intravenously (i.v.) to inpatients. Forty-four patients entered the trial. The three antiemetic regimens were found equally effective. A complete protection from vomiting/nausea was obtained in 14/11 (93.3%/73.3%) of patients treated with MTC, in 15/14 (100%/93%) of those treated with MP and in 11/11 (78.6%/78.6%) of those treated with DMP. Side effects were slight and not significantly different among the three regimens. In conclusion, i.v. MTC and MP (DMP is no longer available in i.v. formulation) as single agents are an adequate treatment for prevention of nausea and vomiting induced by doxorubicin alone or in combination with other noncisplatin antiblastic agents.

Antiemetic activity of high-dose metoclopramide combined with methylprednisolone versus metoclopramide alone in dacarbazine-treated cancer patients. A randomized double-blind study of the Italian Oncology Group for Clinical Research.

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.

Predictive factors of delayed emesis in cisplatin-treated patients and antiemetic activity and tolerability of metoclopramide or dexamethasone. A randomized single-blind study.

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.

Evaluation of the antiemetic activity of bromopride in cancer patients treated with i.v. CMF.

In more than 70% of patients undergoing surgery for breast cancer with histologically positive lymph nodes, precautional therapy with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) causes nausea and vomiting. At the present time, the optimal antiemetic therapy has not been found. From May 1983 to March 1984, 35 patients, of whom 34 were evaluable, were entered in a randomized double blind antiemetic treatment with either bromopride (16 patients), a procainamide derivative structurally similar to metoclopramide, or placebo (18 patients). Bromopride (20 mg) and the placebo were administered in a 3-min i.v. injection half an hour before chemotherapy and at 3 1/2 and 7 1/2 following chemotherapy. A complete antiemetic protection was obtained in 9 patients (56.3%) treated with bromopride compared to 5 patients (27.8%) treated with the placebo. A major antiemetic (less than or equal to 2 vomiting episodes) was obtained in 3 patients (18.7%) treated with bromopride compared to 5 patients (27.8%) treated with the placebo. Statistical analysis showed a trend in favor of bromopride (P = 0.058). The most frequent side effect was sedation reported in 6 patients (37.5%) treated with bromopride and 2 patients (11.1%) treated with the placebo (P = 0.06). The study was interrupted when several patients presented vomiting episodes more than 12 h after CMF administration, and thus beyond the foreseeable protective effect of the antiemetic treatment. It is our opinion that the search for an optimal antiemetic regimen in the course of i.v. CMF therapy should consider the administration of antiemetic drugs at least until 12 h after chemotherapy.

Preliminary observation on the clinical tolerance of interferon-beta in cancer patients.

Nine patients with metastatic solid tumors were given IFN-beta by i.v. bolus injections. Six escalating doses (from 1 to 9 X 10(6) IU) followed by 6 additional injections at the dose of 9 X 10(6) IU were administered every other day (schedule A) in 3 of the 9 patients. IFN dose was also increased to a maximum of 46 X 10(6) IU, and 12 individual injections of 1, 2, 3.3, 5, 7, 9, 12, 16, 21, 27, 34 and 46 X 10(6) IU of IFN were given over a minimum of a 24-day period (schedule B) in 6 of the 9 patients. The single maximal tolerated dose ranged from 9 to 46 X 10(6) IU. The toxicity of IFN-beta given as scheduled in this study was significant but acceptable.

5-Fluorouracil, vincristine and hydroxyurea combination chemotherapy in metastatic colorectal cancer.

Twenty consecutive patients who had biopsy proven metastatic colorectal cancer were treated with combination chemotherapy. The drug regimen (FVH), in a 4 week cycle, consisted of 5-fluorouracil (600 mg/m2 i.v. on days 1, 8, 15 and 22), vincristine (1.4 mg/m2 i.v. on day 4), and hydroxyurea (2400 mg/m2 p.o. on days 3, 10, 17 and 24). Three of the 18 evaluable patients achieved an objective tumor remission (2 CR and 1 PR) and 15 patients had stable disease. The overall response rate to FVH was therefore not superior to that achieved in patients who received 5-fluorouracil alone, and the overall survival in this study was comparable to that of other studies involving patients with metastatic colorectal cancer.

[Evaluation of quality of life in oncology. Rationale and objectives of the first phase of the Quality of Life in Oncology project]. / La valutazione della qualità di vita in oncologia. Razionale ed obiettivi della prima fase del progetto QvOnc.

Although the subjective nature of quality of life perception is generally accepted, less attention has been paid to the procedure of selecting domains to be explored with questionnaires. In most cases domains are selected by panel of experts. It is not known whether these domains are relevant for the patients. Moreover, questionnaires developed in 'foreign' countries may not be culturally sound or relevant for patients living in different cultural background. In order to explore what really contributes to quality of life of Italian patients, a survey was conducted with the aim of identifying any dimension of quality of life, positively or negatively impacted on from the illness and therapies. A sample of two hundred and eighty eight cancer patients with previously specified characteristics (primary tumor, stage of disease and place of residence) were identified. After consenting to partecipate to the study, a staff member (a physician, a nurse or a psychologist) asked the patient to complete an open-ended questionnaire in the out-patient clinic or at home. This questionnaire, partially derived from a study by Padilla et al. made up of 5 questions: 'What does the term quality of life mean to you?', 'What contributes to a good quality of life?', 'What contributes to a poor or bad quality of life?', 'Which either physical or psychological symptom interferes with your quality of life?', 'State any positive or negative change in your quality of life, due to illness or treatments'. The first question was asked to explore the meaning of quality of life for the patient; the second and third question were asked to determine the contents of quality of life not health related; the fourth question and the diary provided information about quality of life contents related to his own experience of disease. Two hundred and forty eight questionnaires (86.1%) were obtained from 7 Cancer Centres participating to the study (Genova, Milano, Roma, Perugia, Napoli, Cagliari, Palermo). All the questionnaires were transcribed and subsequently broken down in phrases on a form that allowed coding. Three raters (a research nurse, an oncologist and a clinical psychologist) made the content analysis using as conceptual framework the list of domains identified by the Italian Society of Psycho-Oncology. The present study shows the possibility to define the content domain of quality of life attributes for cancer patients, using patients as experts.