Adjuvant systemic therapies in women with breast cancer: an audit of clinical practice in Italy.

BACKGROUND: Evidence-based guidelines, consensus conferences and experts' opinion are rarely promptly transferred to patient care. We audited prescriptions of adjuvant systemic therapies for Italian breast cancer patients and compared them with recommendations of an International Consensus Panel. PATIENTS AND METHODS: Disease characteristics and adjuvant therapies for 768 breast cancer patients referred to 87 Italian centers from 16 to 23 March 2000 were evaluated for adherence to the published recommendations. RESULTS: Endocrine therapy was not prescribed for 102 of 541 patients (19%) with endocrine-responsive disease and for 22 of 45 patients (49%) with unknown hormonal receptor status. Instead, endocrine therapy was prescribed for 22 of 182 patients (12%) with endocrine-unresponsive disease. Adjuvant chemotherapy was prescribed for 98% of the patients. The type of chemotherapy was the cyclophosphamide, methotrexate, 5-fluorouracil regimen for 453 of 754 (60%), while 253 of 754 (34%) received an anthracycline-based regimen. The proportion of patients with anthracyclines increased with the number of involved axillary nodes and grading, and decreased with age. Endocrine therapy was administered to 482 of 768 (63%) and was mainly represented by an antiestrogen. CONCLUSIONS: Lack of adherence to evidence-based guidelines for adjuvant treatment of Italian breast cancer patients was as high as 19%. It might be wise for national health authorities to promote education on life-saving procedures, like adjuvant systemic treatments, in cancer medicine.

Very large amounts of peripheral blood progenitor cells eliminate severe thrombocytopenia after high-dose melphalan in advanced breast cancer patients.

We analyzed the relationship between the reinfusion of large or very large amounts of peripheral blood progenitor cells (PBPC) and hematologic toxicity in twenty-one advanced breast cancer patients subjected to a myeloablative dose of melphalan at the end of a high-dose sequential chemotherapy (HDSC) program. We also evaluated the influence of the white blood cell (WBC) count to predict an optimal PBPC harvest after high-dose chemotherapy and growth factor priming. Twenty-one patients with high-risk or metastatic breast cancer sequentially received: high-dose cyclophosphamide (HD-Cy) and G-CSF followed by PBPC harvest, HD-methotrexate plus vincristine, HD-doxorubicin, cisplatin and finally HD-melphalan 200 mg/m2 (HD-L-PAM) followed by PBPC reinfusion. No growth factor was administered after HD-L-PAM. CD34+ cytofluorimetric analysis, WBC count and clonogenic assays were employed to monitor circulating cells and to analyze the PBPC harvest. Correlation between different PBPC doses and hematologic toxicity as well as leukocyte and platelet recovery time was attempted. Patients received a median number of 16 (4-25.1) x 10(6)/kg CD34+ cells, 81.3 (30.8-228) x 10(4)/kg CFU-GM and 4.2 (1.3-7.3) x 10(8)/kg nucleated cells (NC) after HD-L-PAM. The number of days with fewer than 1 x 10(9)/l leukocytes and 20 x 10(9)/l platelets were 6 (range 4-9) and 0 (range 0-3), respectively. The CD34+ cell dose significantly correlated with both platelet count nadir (r = 0.73) and time to 50 x 10(9)/l platelets (r = 0.7), but did not correlate with time to reach more than 1 x 10(9)/l WBC count (r = 0.2). In particular, we found that in 12 patients given very large amounts of CD34+ cells, ranging between 15.8 and 25. 1 x 10(6)/kg (V-LA-CD34+), the platelet nadir count never fell below 20 x 10(9)/l and platelet transfusions were not required. Conversely, nine patients who received only large amounts of CD34+ cells, ranging between 4 and 12 x 10(6)/kg (LA-CD34+), experienced a platelet nadir lower than 20 x 10(9)/l and required 2 days (range 1-4) to achieve independence from platelet transfusions (P = 0.001 and P = 0. 0005). The requirement for packed red blood cells (RBC) was 1.5 vs 3 units in the V-LA-CD34+ and LA-CD34+ groups respectively (P = 0.063). The analysis of 44 PBPC collections demonstrated that 29 aphereses performed with a WBC count <20 x 10(9)/l yielded a mean of 312 +/- 43 x 10(6) CD34+ cells and 1831 +/- 201 x 10(4) CFU-GM, whereas 15 collections performed with WBC count >20 x 10(9)/l yielded 553 +/- 64 x 10(6) CD34+ cells and 3190 +/- 432 x 10(4) CFU-GM (P = 0.004). In conclusion, our data suggests that V-LA-CD34+ eliminates severe thrombocytopenia and platelet transfusion requirements in breast cancer patients subjected to HD-L-PAM, and higher PBPC collections seems to coincide with WBC count higher than 20 x 10(9)/l after HD-Cy and G-CSF mobilization. These results justify a prospective study to establish whether large doses of CD34+ cells result in significant clinical benefits.

Intravenous itasetron: establishing the effective dose range for the prophylactic control of acute emesis in cancer patients undergoing high-dose cisplatin chemotherapy.

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.

A 4-week, double-blind, parallel-group study to compare the gastrointestinal effects of meloxicam 7.5 mg, meloxicam 15 mg, piroxicam 20 mg and placebo by means of faecal blood loss, endoscopy and symptom evaluation in healthy volunteers.

Meloxicam is a new non-steroidal anti-inflammatory drug (NSAID) which preferentially inhibits cyclooxygenase-2 (COX-2) over cyclooxygenase-1 (COX-1). Gastrointestinal (GI) tolerability of meloxicam 7.5 and 15 mg vs piroxicam 20 mg was evaluated in a 4-week, double-blind, parallel group, placebo-controlled study in 51 healthy male volunteers, using a combination of oesphago-gastro-duodenal endoscopy, faecal blood loss measurement and symptom evaluation. Analysis of covariance found no significant difference in faecal blood loss between the groups. However, significantly higher bleeding was found with piroxicam 20 mg compared with placebo using a Student's t-test on the weighted means. Endoscopy score were significantly higher with piroxicam than with meloxicam 7.5 mg or placebo (P < 0.01). A significant difference from baseline was observed in the meloxicam 15 mg and piroxicam groups (P < 0.05), but not in the meloxicam 7.5 mg and placebo groups. Six piroxicam-treated volunteers were withdrawn following a poor endoscopic score, but no such withdrawals occurred in the meloxicam and placebo groups (P < 0.01). Meloxicam 7.5 mg caused less GI damage compared with piroxicam 20 when administered to healthy young volunteers for 28 days; a possible dose dependency effect in GI tolerability was also suggested for meloxicam 7.5 and 15 mg, in relation to endoscopic findings.

Severe gastric mucosal damage induced by NSAIDs in healthy subjects is associated with Helicobacter pylori infection and high levels of serum pepsinogens.

Helicobacter pylori infection and NSAIDs are considered the two most important exogenous factors in ulcer disease. The interrelation between the two factors is not, however, clear. Moreover, serum pepsinogen has been suggested as a risk marker for the development of NSAID-induced gastrointestinal lesions. Fifty-one healthy volunteers, enrolled in a prospective, double-blind study carried out to evaluate gastrointestinal side effects of meloxicam and piroxicam, were analyzed to determine whether: (1) the prevalence of H. pylori correlates with the occurrence and severity of NSAID-induced gastrointestinal lesions, and (2) serum pepsinogen A and C levels could be used as markers of NSAID-induced mucosal damage. Upper endoscopy was performed by the same investigator before and after 28 days of treatment with placebo, meloxicam (7.5 mg/day and 15 mg/day), or piroxicam (20 mg/day). NSAID-induced damage was graded separately for hemorrhages and erosion ulcers according to Lanza's scale. There were no statistically significant differences in the prevalence of H. pylori in subjects with and without NSAID-induced mucosal lesions. However, there was a positive association between H. pylori infection and the severity of mucosal damage: total mean endoscopic score was 2.9 +/- 0.3 in H. pylori-positive subjects versus 1.6 +/- 0.5 in H. pylori-negative subjects (P < 0.05). Pepsinogen A and C levels increased from 55.3 +/- 3 to 149.4 +/- 15 and from 6.3 +/- 0.5 to 11.5 +/- 2.2, respectively (P < 0.05) in subjects who developed severe endoscopic injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and tolerability of teicoplanin in healthy volunteers after single increasing doses.

In this double-blind, randomized study, five healthy subjects per group received doses of 15, 20, or 25 mg of teicoplanin per kg of body weight, and one subject per group received a 0.9% NaCl placebo as single intravenous infusion over 30 min. Serial blood samples and urine were collected for 13 days postadministration, and concentrations of teicoplanin were determined by microbiological assay. The pharmacokinetic data were analyzed by noncompartmental and compartmental analyses. Laboratory safety tests, audiometry, and serum creatinine clearance measurements were done prior to day 1 and on days 2 and 14. In the three groups, peak levels at the end of the infusion averaged 194, 197, and 253 mg/liter, respectively. Mean concentrations in plasma 24 h after the administration were 10.5, 13.6, and 19.8 mg/liter, respectively. Mean values of volume of distribution at steady state were 0.80, 0.87, and 0.87 liters/kg, respectively. Terminal half-lives averaged 88, 83, and 92 h. Mean total clearance values were 10.9, 11.0, and 11.3 mg/h/kg, respectively, with renal clearance accounting for 75, 81, and 78%, respectively, of the total. The 13-day cumulative mean urinary recovery ranged from 71 to 78% of the dose within the groups. The pharmacokinetics of teicoplanin appears to be linear in the range of administered doses. Teicoplanin was generally well tolerated. Side effects, appearing in five subjects, were represented by fevers, chills, and skin reactions; these adverse reactions were mild, but one episode of rash necessitated the interruption of infusion, and one episode of chills necessitated treatment with corticosteroids. There was no indication of drug-related modifications of laboratory test results.

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.

Effects of parenteral diclofenac sodium on upper gastrointestinal motility after food in man.

In experimental animal models nonsteroidal anti-inflammatory drugs may influence gastrointestinal motility, but as evidence is lacking in man. The effect of diclofenac sodium 75 mg i.m. on the motor response of the upper gastrointestinal tract to food has been studied by manometry in 9 healthy volunteers. Diclofenac had no effect on the motor activity of the stomach, duodenum, or jejunum after a 605 kcal meal.

[Adverse effects of corticosteroids]. / Effetti indesiderati dei corticosteroidi.

Due to their anti-inflammatory and immunosuppressive properties, as well as their action on the hematopoietic system and the calcium phosphate turnover, corticosteroids are widely employed in the treatment of many diseases. However, the therapeutic use of these compounds is frequently associated with unwanted, mainly type A, effects that are directly dependent on the wide spectrum of their pharmacological activities. In this study these side effects are critically reviewed and classified on the basis of the organs and systems involved. Where possible, the incidence, pathogenesis, type of steroid, dose and schedule are reported, and the precautions that should prove useful in reducing the incidence and gravity of the side effects are given.

Ceftriaxone versus aztreonam plus cefazolin for infections in cancer patients with adequate neutrophil counts.

In a prospective randomized trial, 154 febrile episodes in cancer patients with adequate neutrophil counts (greater than 1,000 cells/mm3) were treated with either ceftriaxone (72 episodes) or aztreonam plus cefazolin (82 episodes). Documented infections represented almost half of the febrile episodes. The overall response rates among the 144 evaluable episodes were similar for the two regimens: 76% (51/67) with ceftriaxone versus 82% (63/77) with aztreonam plus cefazolin (p = 0.41, not significant). Although not statistically significant, the response rate of the microbiologically documented infections was slightly better in patients treated with the double beta-lactam combination (85% vs. 65%, p = 0.16) and clinically documented infections showed a better response in the group of patients receiving monotherapy (87% vs. 59%, p = 0.12). No serious adverse effects were observed during this study and both regimens were well tolerated. Ceftriaxone or the combination of aztreonam plus cefazolin showed a similar efficacy as empirical therapy for infections in cancer patients with adequate neutrophil counts.

Assessment of nausea.

In a standardized way three different methods of measuring nausea have been assessed in 849 patients enrolled in 4 double blind, randomized, clinical trials, and 2 observational studies. Nausea was measured before and 2, 4, 6, 8 and 24 hours after cancer chemotherapy by using a discrete scale (DS), a visual analogue scale (VAS) and a continuous chromatic analogue scale (ACCS), and it was evaluated according to 4 different dimensions: maximal intensity (MI) entity (E) duration (D) and quantity (Q). The distributions of nausea measurements in the population, agreement between the scales and their sensitivity, and agreement between dimensions and their sensitivity were analyzed. A uniform distribution of nausea measurements was found only in patients receiving chemotherapy without any antiemetic treatment. There was substantial equivalence of the different scales, and no advantage was shown an using an analogue (VAS) than a discrete (DS) scale. A trend toward increasing sensitivity in detecting differences as the dimensions of nausea considered became more inclusive of the various aspects of this symptom (Q more sensible than E more sensible than MI) was observed.

Protection from nausea and vomiting in cisplatin-treated patients: high-dose metoclopramide combined with methylprednisolone versus metoclopramide combined with dexamethasone and diphenhydramine: a study of the Italian Oncology Group for Clinical Research.

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.

Non-steroidal anti-inflammatory drugs: seven year's experience in preparing an annual review.

Since 1980 a yearly review of the world literature on NSAID side effects has been compiled. The review looks for new information on four main topics: (1) previously unrecognized side effects of old and new drugs; (2) new information on known side effects (i.e. their frequency and the identification of "high risk" groups of patients); (3) convalidation of previously recognized side effects; and (4) comparative evaluation of the comparative side effects of NSAIDs. Our knowledge of NSAID side effects, which is improving, depends on many sources of information. Research on the mechanism of action of NSAIDs and ad hoc studies, often based on preliminary data from single case reports, have proved to be, and will probably continue to be, the most valuable sources of information. Despite the large number of articles published on this subject the information available for an appropriate comparative evaluation of the benefit/risk risk profile of NSAIDs is, at best, scanty. Many of the trials show basic design faults, the main ones being the number of patients studied, the length of treatment, the dosages employed and the subgroups of patients examined. Too much stress is laid on new "me-too" drugs and too little time and effort is dedicated to learning more about the comparative merits of old drugs. This aspect cries out urgently for appropriate research. More adequate clinical trials are required on new drugs. It is of prime importance that both available data and incoming new data be brought to the attention of all prescribing doctors to help them in the difficult task of selecting the most appropriate anti-rheumatic drug for each particular patient.

Comparison of faecal blood loss, upper gastrointestinal mucosal integrity and symptoms after piroxicam beta-cyclodextrin, piroxicam and placebo administration.

In order to evaluate the gastric tolerance of the new piroxicam formulation CHF 1194 (piroxicam complexed with beta-cyclodextrin), a double-blind randomized trial was carried out in 21 young healthy volunteers comparing CHF 1194 with piroxicam and placebo. Faecal blood loss measurement by the Cr-51 labelled red blood cell technique, upper gastrointestinal endoscopic evaluation, titration of gastric pH and gastric biopsies before, during and after treatment were used to assess drug tolerability. Four out of 7 volunteers in the piroxicam-treated group withdrew because of severe gastrointestinal symptoms and oesophageal and/or gastroduodenal lesions, while all subjects treated with CHF 1194 or placebo completed the treatment. There was a significant difference between the endoscopic scores of the piroxicam and placebo groups, whereas no differences were found between CHF 1194 and placebo, nor between piroxicam and CHF 1194. Daily mean gastrointestinal blood loss was greater in the piroxicam group than in either the CHF 1194 or placebo groups, but the difference was not significant, due to the small number of piroxicam-treated subjects who completed the study. When administered for a short period to healthy young subjects, CHF 1194 caused less gastric damage and was better tolerated than piroxicam.

Leukopenia with neutropenia associated with teicoplanin therapy.

The first case report of leukopenia with neutropenia due to the new glycopeptide antibiotic teicoplanin is described. The side effect occurred in a 73-year-old man hospitalized because of subacute bacterial endocarditis caused by Streptococcus faecalis. Leukopenia with neutropenia (white blood cells 2000/mm3, neutrophils 46%) developed after 20 days of teicoplanin therapy. After stopping teicoplanin white blood cell and neutrophil counts reverted to normal, but dropped again on rechallenge. A review of 1500 records of patients treated with teicoplanin alone or in combination with other drugs was also performed. Five cases were found in which leukopenia was possibly (four cases) or probably (one case) related to teicoplanin therapy. From these preliminary data the incidence of leukopenia related to teicoplanin seems to be low.

Imipenem/cilastatin in the treatment of severe hospital infections.

Imipenem/cilastatin as a single agent or in combination with amikacin was used as empirical treatment of severe hospital infections. Twenty-five patients were evaluable for efficacy and the overall response rate was 62% with imipenem/cilastatin alone and 80% with imipenem/cilastatin in combination with amikacin. The highest response rate was obtained in urinary tract infection (75%) and in pneumonia (70%) and the lowest response rate (50%) was observed in bacteremia of unknown origin and in skin and soft tissue infections. Eight failures were observed and seven of them occurred in patients treated with imipenem/cilastatin alone. Two deaths occurred, both in patients with bacteremia. Imipenem/cilastatin treatment was interrupted early in 3 patients because the pathogen developed resistance during therapy and in 2 other patients because of side effects. In our study imipenem/cilastatin proved to be efficacious and well tolerated. The addition of an aminoglycoside to imipenem/cilastatin might improve its efficacy and prevent pathogens from becoming resistant during therapy. Therefore this association would seem to be advisable for the therapy of bacteremic infections and for those caused by difficult pathogens.

Pharmacokinetics of 14C-teicoplanin in healthy volunteers.

Five healthy male volunteers received over 60 sec a single intravenous injection of 400 mg of teicoplanin labelled with 41 microCi of 14C. Plasma and urine total radioactivity was measured up to 10 and 16 days, respectively. Teicoplanin was assayed in plasma and urine also by a microbiological method, with similar results. Pharmacokinetic parameters were estimated by model-independent analysis and the following mean values were obtained: elimination half-life 77 h; total body clearance 9.8 ml/h/kg; renal clearance 7.81 ml/h/kg; volume of distribution at steady-state 0.759 l/kg. Similar estimates were obtained by a compartmental analysis. A total of 80% of the administered dose was recovered in urine in 16 days; 2.7% of the dose was recovered in faeces collected for eight days after administration. The mean total recovery of the drug was 83 +/- 0.6%. The plasma and urine concentrations of teicoplanin observed after a single 400 mg iv dose exceeded the MIC for most pathogens for at least one day, and this suggests that a daily dosage regimen would be satisfactory for patients with normal renal function.