Aims and background: Rarely are conclusions from clinical trials summarized in international consensus conferences and promptly transferred to patient care. The adjuvant therapy for colorectal cancer used in daily clinical practice in Italy is described and compared with the recommendations of the 1990 NIH Consensus Conference.Patients and methods: We audited prescriptions of adjuvant systemic therapies for Italian colorectal cancer patients in 82 centers during a fixed one-week period.Results: Among 434 patients receiving adjuvant chemotherapy there were 139 (42.5%) colon cancer patients with N- and 169 (51.7%) with N+ regional nodal involvement. Treatment at academic centers, a young age, T4 and a low total number of lymph nodes removed at surgery were the factors potentially justifying the decision for adjuvant chemotherapy in stage II colon cancer patients. The most common chemotherapy used was a bolus of 5-fluorouraci/fiolinic acid for 6 months (75.8%). Adjuvant radiotherapy was not administered to 37 (38.5%) of 96 patients with stage II and III rectal cancer.Conclusions: The study shows that a substantial proportion of patients on adjuvant treatment at a certain time point in a large enough sample of Italian centers are stage II (potential over-treatment) and that an under-treatment of stage II and III rectal cancer patients (lack of radiotherapy) occurs too often in daily clinical practice in this country.

Controversies exist regarding the classification of the emetogenic potential of chemotherapeutic agents such as taxanes, gemcitabine and irinotecan and the antiemetic prophylaxis for acute emesis to be administered. Instead, no prophylaxis for delayed emesis has been suggested. A prospective, observational study was carried out in 103 Italian oncological centers to evaluate the prescriptions of antiemetics and the incidence of nausea and vomiting in patients submitted to these chemotherapy agents. Two hundred and nine patients treated with taxanes, 300 with gemcitabine and 93 with irinotecan were evaluated. For the prophylaxis of acute emesis a 5-HT3 antagonist alone or in combination with a corticosteroid was administered to 86.6% of patients receiving taxanes, to 59.3% of those receiving gemcitabine and to 96.8% of those submitted to irinotecan. 20% to 40% of patients received antiemetic prophylaxis for delayed emesis. In taxane-treated patients the incidence of acute vomiting and nausea was 6.2% and 27.3%, respectively, while in gemcitabine- and irinotecan-treated patients it was 6.0/33.4% and 17.9/58.9%, respectively. In conclusion, the study showed that almost all patients received prophylaxis for acute emesis and that there is overprescription of 5-HT3 antagonists. The incidence of acute emesis is low; therefore, randomized clinical trials are necessary to verify the utility of prophylaxis and to find the best antiemetic treatment.

Aims and Background The necessity of an antiemetic prophylaxis in patients treated with chemotherapy of low emetogenic potential, such as 5-fluorouracil ± folinic acid fractionated over several consecutive days, is controversial. The aim of the study was to evaluate the therapeutic behavior of oncologists on this issue. Methods All consecutive in and out patients who started chemotherapy in 33 Italian oncological departments from June 24 to July 6, 1996, were studied. The antiemetic prescription pattern and its effectiveness, in patients submitted to 5-fluorouracil ± folinic acid were evaluated. Results Of the 1956 patients submitted to cancer chemotherapy, 259 patients received 5-fluorouracil ± folinic acid. Of these, 186 patients were treated for 5 consecutive days, 47 for 4 days, 20 for 3 days and 6 for 2 days. A total of 219 (84.5%) received an antiemetic prophylaxis: 43.4% a 5-HT3 antagonist ± steroids, 37.5% an antidopaminergic drug, 10.9% a steroid ± antidopaminergic drug, and 8.2% other drugs. Only 40 patients (15.5%) did not receive an antiemetic prophylaxis. Overall complete protection from vomiting/nausea was 225/259 (86.9%)/163/259 (62.9%). The complete protection from vomiting/nausea during the 5 days in the 186 patients was not significantly different among patients receiving or not an antiemetic prophylaxis (88.1%/64.9% vs 88.9%/55.6%). At unifactorial analysis, the previous experience of vomiting/nausea caused by chemotherapy was found to be a significant prognostic factor. In fact, overall complete protection from vomiting/nausea was significantly inferior in patients who had previous experience of vomiting/nausea (65.1%/35.0%) with respect to those who did not (91.2%/75.4%, P < 0.001/> 0.001, respectively). Conclusions. The study showed that in clinical practice patients submitted to 5-fluorouracil ± folinic acid obtained a similar high protection from vomiting and nausea regardless of whether or not antiemetic prophylaxis was given. It would be therefore reasonable not to treat patients undergoing such chemotherapy, whereas patients with previous experience of vomiting/nausea caused by chemotherapy should be given an antiemetic prophylaxis.

BACKGROUND The prevention of delayed nausea and vomiting caused by moderately emetogenic chemotherapy for cancer has not been studied systematically. METHODS We enrolled patients who were scheduled to receive chemotherapy for the first time in a double-blind, randomized, multicenter study. All the patients received ondansetron combined with dexamethasone for prophylaxis against emesis that might occur within 24 hours after the start of chemotherapy (acute emesis). They were then divided into two groups: patients who did not have either vomiting or moderate-to-severe nausea (the low-risk group) and patients who had one or both (the high-risk group). Patients in the low-risk group were then randomly assigned to one of the following regimens, given on days 2 through 5 after the start of chemotherapy: oral placebo, 4 mg of dexamethasone given orally twice daily, or 8 mg of ondansetron in combination with 4 mg of dexamethasone, given orally twice daily. Patients in the high-risk group were randomly assigned to receive oral dexamethasone alone or in combination with ondansetron at the same doses as those used in the low-risk group. RESULTS Among the 618 patients in the low-risk group, there was a complete absence of both delayed vomiting and moderate-to-severe nausea in 91.8 percent of those who received ondansetron combined with dexamethasone, 87.4 percent of those who received dexamethasone alone, and 76.8 percent of those who received placebo. The proportions of patients who were protected by dexamethasone combined with ondansetron or by dexamethasone alone were significantly greater than the proportion protected by placebo (P<0.001 and P<0.02, respectively). Of the 87 patients in the high-risk group, complete protection was achieved in 40.9 percent of those treated with ondansetron and dexamethasone and in 23.3 percent treated with dexamethasone alone (P not significant). CONCLUSIONS The best way to prevent delayed nausea and vomiting in patients receiving moderately emetogenic chemotherapy is to control these complications within the first 24 hours after the start of chemotherapy. Dexamethasone alone provides adequate protection against delayed emesis in patients at low risk (those who have not had acute emesis).

Nausea and vomiting induced by chemotherapy are a major cause of distress to patients and reduce compliance with potentially beneficial treatment. Itasetron hydrochloride is a new 5-hydroxytryptamine3 (5-HT3) antagonist with potent antiemetic properties. It is more potent than ondansetron in animal models and in early clinical studies it demonstrates a long half-life and does not undergo hepatic biotransformation before elimination. The aim of this open, uncontrolled study was to establish the effective dose range of itasetron hydrochloride given intravenously (i.v.) to patients due to receive high-dose cisplatin chemotherapy (50-120 mg/m2) for the first time. Thirty-nine patients were enrolled in the trial and received a single i.v. infusion of itasetron hydrochloride at a dose of 17-280 microg/kg body weight before commencing the cisplatin infusion (median dose 90-110 mg/m2). Antiemetic protection was demonstrated by doses in the range of 35-280 microg/kg. The 17 microg/kg dose was not effective. Treatment failure (>5 emetic episodes/24 hours) was reported in only six (16%) of the 38 evaluable patients over all treatment groups. Adverse events were generally mild or moderate and of a similar type and incidence to those of current 5-HT3 antagonists. Physicians' and patients' assessments of efficacy and tolerability of itasetron hydrochloride were similar, the majority rating the treatment as 'good' or 'very good'. In conclusion, itasetron hydrochloride is effective in the dose range 35-280 microg/kg in preventing cisplatin-induced emesis. Taken together with results from a larger dose-finding study, a dose corresponding to 35 microg/kg (equivalent to 2.5 mg itasetron, calculated as free base) has been pursued in Phase III studies with the i.v. formulation.

Aims and background: To evaluate the rate of cancer patients who do not fill out a quality of life (QL) questionnaire, their characteristics and the reasons for not filling out the QL questionnaire.Methods: Consecutive cancer patients who were seen in 79 Italian medical oncology and radiotherapy centers over a period of one week were asked to fill out a questionnaire concerning the importance of 46 domains of quality of life, each one scored on 4 levels (not at all, a little, much, and very much).Results: Of 6,918 cancer patients, 820 (11.9%) did not fill out the questionnaire. The most important reasons for not complying were: illiteracy (17.9%), lack of glasses or poor eye-sight (17.4%), poor physical condition (11.9%), poor psychological condition (5.9%), refusal (28.7%). The questionnaires significantly less filled out were those of older patients with low performance status and educational level or with locally advanced or disseminated disease and inpatients.Conclusions: The results of the study reveal the risk of selection bias in QL assessment in randomized controlled trials and suggest the need for more complete information regarding the aim of QL evaluation and the necessity of a proxy's help to overcome the problem, with the awareness that the proxy's influence could modify the response. The impact of the lack of patient compliance on the QL results still remains to be evaluated.

Background: Studies are available showing that cancer patients in southern Europe may be less well informed about their disease than patients in northern Europe and North America.Patients and methods: In the framework of a survey aimed at exploring the meaning of quality of life for the Italian cancer patient, carried out all over Italy in a one-week time span on 6098 consecutive patients, two visual analogue scales evaluating severity and curability of disease were also submitted to the patients. Four patterns of patients' answers were defined: very easy/difficult-to-cure disease, and not-severe/severe disease. Multifactorial analyses were performed using logistic models for each of the four responses, assuming patient characteristics, time since diagnosis and disease extent as explanatory variables.Results: Only 26% of 2088 patients with disseminated disease believed it to be 'difficult to cure', while 39% felt it to be 'easy to cure'. In the same subgroup of patients, only 47% found their disease `severe'.Conclusions: Authors were impressed by these unexpected results, which are therefore reported separately from the overall analysis of data, aimed at exploring the quality of life domains for the Italian cancer patient. In fact, they would suggest a great lack of awareness of the severity and curability of their disease in a large group of unselected Italian cancer patients. This may depend on various factors, including cross-cultural ones, but could also be partly related to inadequacies in the process by which the Italian patient is informed, and this should be further investigated.

Background: There is convincing evidence from randomized clinical trials that the use of 5-HT3 antagonists has brought about a substantial improvement in the control of chemotherapy-induced nausea and vomiting. However, no data exist to indicate how this new research evidence can be applied to the individual patient. Patients and methods. We carried out a prospective, observational study on the use and effectiveness of antiemetic drugs in patients undergoing cancer chemotherapy in 33 Italian oncology departments. Results: A total of 1,956 consecutive patients entered the study; 1,238 of them underwent a one-day chemotherapy and 718 a chemotherapy fractionated over several consecutive days. The 5-HT3 antagonists, used either alone or in combination with a corticosteroid, have almost completely supplanted all other types of antiemetic regimens for preventing cancer chemotherapy-induced emesis. In fact, 80% of patients, irrespective of whether their emesis was acute or delayed, or of the emetogenic potential of the cancer chemotherapy they received, have been treated with these compounds. However, the practice of participating oncologists with respect to prescriptions has been far from consistent with the evidence provided by randomized controlled trials. Both overtreatment and undertreatment have occurred in many patients, creating unjustified costs and placing the patients at greater risk for emesis. However, when antiemetics are properly used their effectiveness is similar to that seen in randomized controlled trials. Conclusions: Powerful barriers exist between the evidence provided by sound research and clinical practice, and this issue hampers progress toward the optimal use of antiemetic drugs.

Background. The pattern and prognostic factors of delayed nausea an d vomiting induced by moderately emetogenic chemotherapy have not yet been adequately studied.Patients and methods. Data are derived from a large and well defined population of patients studied to evaluate the efficacy and tolerability of granisetron: dexamethasone and their combination in the control of acute emesis over repeated cycles of moderately emetogenic chemotherapy. Patients were monitored on days 2-5 without receiving any prophylactic treatment for delayed emesis.Results. There were 395 evaluable patients at the first, 352 at the second and 319 at the third cycle of chemotherapy. Overall, 32.7% patients suffered symptoms of delayed vomiting and/or moderate-severe nausea at the first, 32.1% at the second and 35.1% at the third cycle of chemotherapy. More precisely, the incidence of delayed vomiting was 21.3% at the first, 18.5% at the second and 21.0% at the third cycle of chemotherapy, while the incidence of delayed moderate-severe nausea was 25.1%, 25.0% and 26.0%, respectively. The incidence of delayed vomiting and moderate-severe nausea was very low in patients who obtained good control of acute vomiting and moderate-severe nausea, but it remained substantial in patients who experienced them during the first 24 hours after chemotherapy. In fact, at first/second/third cycle of chemotherapy delayed vomiting occurred in 12.3%/11.8%/ 13.1% of patients who did not suffer from acute vomiting and in 54.1%148.4%/55.9% of those who had acute vomiting, respectively. Similar data were obtained for delayed moderate-severe nausea.Conclusions. Patients without acute vomiting or moderate-severe acute nausea may not need any antiemetic prophylaxis for delayed vomiting or nausea, while those with a history of acute vomiting or moderate-severe acute nausea should always be treated for delayed emesis. Selection bias and dependence effect of delayed emesis on acute emesis can cause misinterpretation of data derived from clinical trials in patients submitted to multiple cycles of chemotherapy.

Background. Serotonin-receptor antagonists seem to be as effective as corticosteroids in preventing emesis induced by moderately emetogenic antineoplastic agents. We compared the antiemetic effect of a combination of granisetron and dexamethasone with that of granisetron or dexamethasone administered alone.Methods. From December 1992 to January 1994, 428 consecutive patients who were to receive moderately emetogenic chemotherapy for the first time (600 to 1000 mg of cyclophosphamide per square meter of body-surface area, greater than or equal to 50 mg of doxorubicin per square meter, greater than or equal to 75 mg of epirubicin per square meter, or greater than or equal to 300 mg of carboplatin per square meter, alone or in some combination) were enrolled in a double-blind, randomized, multicenter study evaluating the efficacy and toxicity of three antiemetic regimens. The following antiemetic regimens were used: 8 mg of dexamethasone given intravenously before chemotherapy plus 4 mg given orally immediately before chemotherapy and then every six hours for a total of four doses, 3 mg of granisetron given intravenously be fore chemotherapy, or a combination of granisetron and dexamethasone given in the doses used for the single-drug regimens.Results. We evaluated 408 patients (136 receiving dexamethasone, 137 receiving granisetron, and 135 receiving both drugs), In the first 24 hours after chemotherapy, complete protection from vomiting and complete protection from nausea were achieved in 70.6 and 55.1 percent, respectively, of the patients receiving dexamethasone, in 72.3 and 48.2 percent of those receiving granisetron, and in 92.6 and 71.9 percent of those receiving granisetron combined with dexamethasone (P<0.001 for all comparisons). Patients who received granisetron alone had less protection from delayed vomiting and nausea than those who received dexamethasone alone or the two drugs combined. All the regimens were equally well tolerated.Conclusion. Granisetron combined with dexamethasone was the most effective regimen for the prevention of emesis induced by moderately emetogenic chemotherapy.

Background: Differences in pharmacodynamic and pharma- cokinetic characteristics among serotonin-receptor antagonists have been reported in preclinical studies. This prompted us to carry out a study to determine whether such differences are important in terms of clinical efficacy or tolerability.Patients and methods: 973 consecutive cancer patients scheduled to receive cisplatin for the first time (at doses greater than or equal to 50 mg(2)), entered a double-blind multicenter randomized study comparing intravenous ondansetron 8 mg versus granisetron 3 mg. Dexamethasone 20 mg was added to both serotonin antagonists. On days 2 to 4 after chemotherapy all patients received oral metoclopramide plus intramuscular dexamethasone as antiemetic prophylaxis for delayed emesis. Nausea and vomiting were assessed daily until day 6 after chemotherapy.Results: We evaluated 966 patients (483 receiving ondansetron and 483 granisetron). Complete protection from acute vomiting/nausea was obtained in 79.3%/72.0% of patients receiving ondansetron and in 79.9%/71.8% of those receiving granisetron. Complete protection from delayed vomiting/nausea was obtained in 69.7%/52.9% and 70.0%/49.6% of patients receiving the ondansetron or granisetron regimens, respectively. Adverse effects were mild and not significantly different between the two antiemetic regimens.Conclusions: Ondansetron 8 mg and granisetron 3 mg, both combined with dexamethasone, showed similar efficacy and tolerability in the prevention of cisplatin-induced emesis. The choice between the two regimens can be dictated by their respective purchase prices.

Purpose: To evaluate antiemetic efficacy and tolerability of granisetron, dexamethasone, and their combination over repeated courses of moderately emetogenic chemotherapy, and the influence of the prognostic factors on occurrence of nausea and vomiting.Patients and Methods: Four hundred twenty-eight consecutive cancer patients were entered onto multicenter, randomized, double-blind study to compare granisetron 3 mg intravenously, dexamethasone 8 mg intravenously, and 4 mg orally every 6 hours for four doses, or the combination of dexamethasone plus granisetron al the same doses, administered for three consecutive cycles. Occurrence of nausea, retching, and vomiting was monitored for 24 hours after chemotherapy administration by a diary card.Results: Three hundred ninety-eight patients were assessable for clinical efficacy at the first cyle, 354 were assessable at the second cycle, and 322 were assessable at the third cycle of chemotherapy. Dexamethasone plus granisetron induced significantly greater complete protection from vomiting, nausea, and both nausea and vomiting than granisetron alone in all three cycles. With respect to dexamethasone alone, complete protection from vomiting was significantly greater at the first and second cycle, and complete protection from nausea and from both nausea and vomiting only at the first cycle. Complete protection did not differ significantly among the three cycles in patients receiving dexamethasone plus granisetron or dexamethasone alone, whereas it decreased significantly, at least for vomiting, in patients receiving granisetron alone. Protection obtained in the previous cycle of chemotherapy wets the most important prognostic factor in the occurrence of nausea and vomiting.Conclusion: The combination of dexamethasone plus granisetron offers the best antiemetic protection because of its greater efficacy with respect to the other two regimens at first cycle, and because its activity is maintained in the subsequent cycles of chemotherapy. (C) 1995 by American Society of Clinical Oncology.

504 evaluable node positive oestrogen receptor (ER) positive breast cancer patients were randomly allocated to receive either 5 years tamoxifen treatment or chemotherapy [six courses of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) followed by 4 courses of epirubicin] or a combination of both treatments. At a median follow-up of 5 years tamoxifen appeared to be more effective than chemotherapy, the difference being highly significant in postmenopausal women. The addition of chemotherapy to tamoxifen was not able to significantly improve the results achieved by tamoxifen alone, irrespective of menopausal status. Trends were similar even after stratification for the number of involved nodes. The protective effect of tamoxifen in terms of reduction of the odds of death increased with time and no rebound phenomena on recurrence or death has occurred so far after the completion of tamoxifen treatment. Overall, the prognostic value of number of involved nodes and of progesterone receptor (PgR) status was confirmed by multivariate analysis. However, the predictive value of PgR was lost in patients receiving tamoxifen alone. Similarly, the degree of ER positivity was not predictive of the response to tamoxifen. Tamoxifen treatment should still be regarded as the gold standard for postmenopausal ER positive patients. In younger women the antioestrogen proved to be safe and at least as effective as chemotherapy. However, the analysis of the annual risks suggests that the concurrent or the sequential use of chemotherapy and tamoxifen might represent a more appropriate treatment for this patient subset, particularly for those with four or more involved nodes. Different cut-offs of ER and PgR assays from those we have arbitrarily employed in the present analysis should probably be used to select more properly the patients who can benefit from endocrine therapy.

Patients with histologically confirmed advanced colorectal cancer were randomized to receive folinic acid (FA; 500 mg/mq in 2-hour intravenous infusion) and 5-fluorouracil (5FU; 600 mg/mq given as an intravenous bolus 1 hour after FA), beginning every week for 6 weeks, followed by a 2-week rest period, either without hydroxyurea (HU, arm A) or with HU (35 mg/kg per day) given orally in three administrations (every 8 hours) starting 6 hours after 5FU administration (arm B). Six weekly doses were considered one course. One hundred eighty-two patients were randomized in this trial and 162 (89%) were evaluable for response: 81 patients in arm A and 81 patients in arm B. Objective response was observed in 18 (one complete response and 17 partial responses) of 81 evaluable patients (22%; 95% confidence interval, 13-31%) in arm A, and 24 (nine complete responses and 15 partial responses) of 81 patients (30%; 95% confidence interval, 20-40%) in arm B. There was no difference in terms of median time to progression and median survival. Gastrointestinal toxicity was the most frequently observed toxicity in both arms. The double modulation of 5FU, FA plus HU does not appear to be better than the classic 5FU plus FA schedule. This trial confirms that 5FU and FA reached a plateau of 20% to 30%.

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.