Clinical and pharmacological phase I study with accelerated titration design of a daily times five schedule of BBR3464, a novel cationic triplatinum complex.

OBJECTIVES: To define the maximum tolerated dose (MTD), the toxicity and pharmacokinetic profile of BBR3464, a novel triplatinum complex. PATIENTS AND METHODS: Fourteen patients with advanced solid tumors not responsive to previous antitumor treatments received BBR 3464 on a daily x 5 schedule every twenty-eighth day. The drug was given as a one-hour infusion with pre-and post-treatment hydration (500 ml in one hour) and no antiemetic prophylaxis. The starting dose was 0.03 mg/m2/day. A modified accelerated titration escalation design was used. Total and free platinum (Pt) concentrations in plasma and urine were assessed by ICP-MS on days 1 and 5 of the first cycle. RESULTS: Dose was escalated four times up to 0.17 mg/m2/day. Short-lasting neutropenia and diarrhea of late onset were dose-limiting and defined the MTD at 0.12 mg/m2. Nausea and vomiting were rare, neither neuro- nor renal toxic effects were observed. BBR3464 showed a rapid distribution phase of 1 hour and a terminal half-life of several days. At 0.17 mg/m2 plasma Cmax and AUC on day 5 were higher than on day 1, indicating drug accumulation. Approximately 10% of the equivalent dose of BBR3464 (2.2%-13.4%) was recovered in a 24-hour urine collection. CONCLUSIONS: The higher than expected incidence of neutropenia and GI toxicity might be related to the prolonged half-life and accumulation of total and free Pt after daily administrations. Lack of nephrotoxicity and the low urinary excretion support the use of the drug without hydration. The single intermittent schedule has been selected for clinical development.

Phase II studies of 4'-iodo-4'-deoxydoxorubicin in advanced non-small cell lung, colon and breast cancers.

The new anthracycline analogue, 4'-iodo-4'-deoxydoxorubicin (I-DOX), was administered at 70 mg/m2 as first chemotherapy in 61 patients with advanced NSCL (19), colon (20) and breast cancers (22). Treatment was repeated every 3 weeks; the dose was decreased to 60 mg/m2 (19% of the cycles) or increased to 80 mg/m2 (17% of the cycles) according to the granulocyte count nadir. Partial responses were observed in 6% of the patients with NSCL, in 5.5% of those with colon and in 10% of those with breast cancers. The main toxicity was a selective granulocytopenia characterized by a duration of about 1 week, and a high inter-patient variability. Non-haematological toxicities were mild. The negative results obtained in breast cancer might be related to the dose administered. Further studies in this tumour type should be performed with a more aggressive schedule.

Smoking in pregnancy: a survey from northern Italy.

The prevalence of smoking in pregnancy was analyzed in a survey of women delivering between January and March 1989 in a large maternity clinic in Milan, Northern Italy. Out of the 528 women interviewed, 183 (35%) were current smokers before pregnancy and 99 stopped smoking during pregnancy. The probability of stopping smoking decreased with increasing age and was lower in less educated women, but these findings were not statistically significant. Considering persistent smokers only, the mean number of cigarettes per day fell from 13 before to 8 during pregnancy; this reduction was generally consistent in various subgroups of age and education. The reductions, however, are probably overestimated, since they are based on the women's reports only. Thus, there still appears to be ample scope for intervention on smoking in pregnancy, particularly in older and less educated women.

Critical review of the quality and development of randomized clinical trials (RCTs) and their influence on the treatment of advanced epithelial ovarian cancer.

Trials on chemotherapy of advanced ovarian cancer published between 1975-88 were systematically reviewed for quality (according to the method of Chalmers) and consistency of tested hypotheses with a view to a meta-analysis of all published studies in the field. Median overall, internal and external validity scores were 47%, 43% and 53%, respectively. No association was found between scores and key features of trials, such as percentage studies with significant results in response or survival or percentage studies with high or low follow-up retention (withdrawal rates less than or greater than or equal to 15%). Only 21% of trials reported a fully blind randomization procedure and only in 13% were drop-outs accounted for by the intent-to-treat method. Only 4 trials entered more than 150 patients per arm, a sample size consistent with detection of an absolute difference of 11% in mortality. The majority of trials (58%) investigated the role of combination regimens versus a single-agent control arm. The remaining trials tested different polychemotherapies. However, within these two general issues, treatment options were quite heterogeneous: seven subgroups were identified by whether cisplatin was present in either the treatment or the control arm. We conclude that the internal coherence and development of randomized clinical trials in advanced ovarian cancer and their methodologic soundness are quite poor. In this situation meta-analysis cannot go beyond a systematic attempt to answer a very general "treatment effectiveness" question.

[Assessment of the use of Pap test in a sample of pregnant women]. / Valutazione della pratica del Pap-test in un campione di donne gravide.

Four hundred and ninety-nine women were interviewed who gave birth in the "L. Mangiagali" Obstetrics-Gynaecological Clinic between March and April 1989. 22% of these women had never had a Pap-test, 37% reported having had 1-2 cervical smears and 41% 3 or more. In the group of patients that contacted a private gynaecologist during pregnancy, the percentage of women who had never had a Pap-test was 18% versus 30% in the group of subjects followed in the public health service. Although pluriparas reported a greater number of Pap-test than primiparas, this difference was not statistically significant. Youth is significantly related to the probability of never having had a cervical smear. Social and economic factors were also clearly important. In particular, women with a low educational level represented the group with the highest risk for the lack of cervical screening. The role of the gynaecologist and preventive programmes aimed at the higher risk levels play an important role in terms of heightening awareness.

Quality of care of colorectal cancer patients in general hospitals: diffusion and impact of management guidelines.

Over the last ten years the Italian National Research Council (C.N.R.) has launched an educational program aimed at favoring the delivery of the most up to date care for cancer patients in community hospitals. Among various tumors for which this effort was undertaken, management guidelines for colorectal cancer were developed in 1978 by a multidisciplinary team of national experts and reported in booklets distributed nationwide under the aegis of the Colorectal Cancer Task Force. In 1988, the C.N.R. funded an evaluation to learn whether: a) the guidelines were widely diffused in the target physician populations; b) their content was accepted by those who received them and, c) practice patterns were consistent with the recommendations in the guidelines. Overall results indicate only a limited effect. Despite clear evidence of a positive self-selection in the physicians' survey, guidelines were familiar to only 47% of responders. Although acceptance of at least some specific recommendations was good among doctors aware of the guidelines (greater than or equal to 60% responders), this finding loses relevance since a not negligible proportion of those not aware of them had the same convictions. Finally, analysis of practice patterns showed serious deficiencies (mostly in terms of thoroughness of operative staging) even in centers where more widespread knowledge of the guidelines should have led to better quality of care. The paper also discusses the comparability of our findings to results of a similar evaluation carried out in the U.S.A. Our results underscore the importance of analyzing the process of diffusion in any assessment of interventions based on knowledge dissemination.

Trends in patterns of care for breast cancer in Italy (1979-1987).

We reviewed care delivered to about 2,500 breast cancer patients in general hospitals over the period 1979-1987 using data from three surveys. The most important and consistent failure was in diagnostic timeliness: about one out of four patients was diagnosed six or more months after the first symptom leading to an almost doubled probability of being diagnosed with more advanced disease. Acceptance of treatment recommendations seemed less satisfactory for surgery than for adjuvant treatments. Conservative surgery still appeared to have limited acceptance for patients with small primary tumor (21 and 23% in 1983 and 1987, respectively) although, starting 1983, there was a shift from the Halsted to the Patey type of radical mastectomy. Follow-up was routine in most node-negative patients and adjuvant chemotherapy was already well established treatment for most pre-menopausal node-positive women (64, 79 and 76% in 1979, 1983 and 1987, respectively). Some form of adjuvant treatment in post-menopausal node-positive women was already present in 1983 but became more widespread in 1987 (82%): this being mostly accounted for by the increase in the use of tamoxifen (delivered alone or in combination with chemotherapy to 53% of women). Overall, our results suggest that areas of care more dependent on organization or doctors' and patients' education (i.e. diagnostic timeliness and accessibility) are those where deficiencies seen to be least amenable to change in the absence of concerted intervention. Among more narrowly defined clinical issues, there appeared to be some dissonance between the rapid acceptance of adjuvant treatments and the still slow pace of acceptance of less aggressive procedures by surgeons.

[The smoking habit in pregnancy: results of a survey conducted in Milan]. / L'abitudine al fumo in gravidanza: risultati di una sorveglianza condotta a Milano.

The prevalence of smoking in pregnancy has been analyzed in a surveillance of women delivering between February and March 1989 in a large maternity clinic in Milan, Northern Italy. Out of the 411 interviewed women, 133 (32%) were current smokers before and 71 quit smoking during pregnancy. The probability to quit smoking decreased with increasing age and was lower in less educated women; these findings were however not statistically significant. Considering persistent smokers only, the mean number of cigarettes per day decreased from 13 before pregnancy to 8 during gestation; this finding was generally consistent in various subgroups of age and education. These reduction, however, are probably overestimated, since they are based on women's report only. Thus, these findings indicate that there is still ample scope for intervention on smoking in pregnancy, particularly in older and less educated women.

Short-term reproductive prognosis when no cause can be found for recurrent miscarriage.

The short-term reproductive prognosis of recurrent miscarriage for which no cause was found has been evaluated in 95 couples investigated between 1980 and 1986 at the First Obstetric and Gynaecological Clinic of the University of Milan. The actuarial overall 3-year livebirth delivery rate was 64%, increasing constantly with time. The reproductive success rate decreased with the number of previous miscarriages from 80% in women with two, to 60% with three and 46% with four or more miscarriages. No effect of age and socio-economic status emerged. There was a positive association between the number of previous miscarriages and the risk of miscarriage in the next pregnancy. Compared with women with two miscarriages the relative risk of another miscarriage was 2.3 for those with three previous miscarriages and 5.0 for those with four or more (chi 2 1 for trend adjusted for age = 5.2, P = 0.02).

The problem of identification of prognostic factors for persistent trophoblastic disease.

The role of anamnestic and clinical factors in defining the high group at risk of developing persistent trophoblastic disease (PTD) has been analyzed in 301 cases of hydatidiform mole. Patients age 40 or more years with AB blood, and a previous history of molar pregnancy had an elevated risk of developing PTD. The presence of various risk factors increased the frequency of PTD. However, with discriminant analysis, correct classification of outcome was obtained for only 69% of cases. Despite the magnitude of risk of PTD for women with three or more risk factors, the clinical relevance of prognostic variables in the prediction of outcome was limited by the low proportion of women classified in the low- and high-risk groups, making the identification at diagnosis of the women who could benefit of prophylactic chemotherapy extremely difficult and hence of little clinical importance.

Coffee consumption and risk of pancreatic cancer.

The relationship between pancreatic cancer and coffee, decaffeinated coffee and tea drinking habits was evaluated using data from a hospital-based case-control study conducted in Northern Italy on 150 histologically confirmed cases and 605 controls with acute, non-neoplastic, other than digestive tract diseases unrelated to coffee consumption or to any of the known or potential risk factors for cancer of the pancreas. Compared with subjects who did not drink coffee, the multivariate relative risks were 1.7 for those who drank less than 2 cups per day, but only 1.4, and 1.1 respectively for drinkers of 3 or 4 and 5 or more cups. Likewise, there was no association with duration of consumption of coffee, decaffeinated coffee or tea. These findings were reviewed together with published evidence from other case-control studies (or cohort studies analyzed as case-control) of coffee and pancreatic cancer. When appropriate statistical methods were used to pool information, and the data from the first study which was the basis of the hypothesis were omitted, the relative risk of pancreatic cancer based on 1,464 cases was 1.2 for moderate coffee drinkers and 1.4 for heavy drinkers, and we suspect that at least part of this moderate residual association is confounded by cigarette smoking. Thus, although the present investigation and a general overview of published epidemiological evidence are compatible with a small effect of coffee on pancreatic carcinogenesis, interpretation of these findings is not obvious on account of the possibility of residual confounding and other sources of bias.

Vitamin A and other dietary factors in the etiology of esophageal cancer.

The risk of esophageal cancer, in relation to the frequency of consumption of selected dietary items, was evaluated in a hospital-based case-control study; this study was of 105 histologically confirmed cases and 348 control subjects with acute conditions unrelated to any of the established or potential risk factors for esophageal cancer. The frequency of consumption of carrots, green vegetables, or fresh fruits was lower in cases. Further, cases tended to eat meat and fish less frequently and eggs more frequently. The estimated multivariate relative risks were 0.6 for regular (more than once a week) carrot consumption and 0.6 and 0.3, respectively, for the highest levels of vegetable or fruit consumption (compared with the lowest ones). Consequently, a strong negative association emerged between estimated beta-carotene (but not retinol) intake and esophageal cancer risk. The risk of cancer of the esophagus was not significantly related to subjective scores of fat and whole-meal food intake; however, a strong positive association did emerge with measures of alcohol consumption. Although the information collected does not allow precise definition of specific micro-nutrient(s) causally related with esophageal cancer risk, the confirmation of marked differences in reported diet between esophageal cancer cases and controls is still of interest; this is mostly in consideration of the strength and persistence of the associations after allowing for alcohol and tobacco use in addition to indicators of socioeconomic status.

Tar yields of cigarettes and the risk of oesophageal cancer.

The relationship between cigarettes with varying tar yields and the risk of oesophageal cancer was evaluated using data from a hospital-based case-control study conducted in Northern Italy on 129 histologically confirmed cases and 426 controls with acute, non-neoplastic of digestive diseases unrelated to tobacco or alcohol consumption. Compared with never-smokers, the relative risks of developing cancer of the oesophagus were 2.9 for subjects who smoked mainly middle- or low-tar (less than 22 mg) cigarettes and 8.9 for those smoking high-tar cigarettes (greater than or equal to 22 mg). The difference between the two categories was evident among ever-smokers and only current smokers, was not explained by adjustment for the major covariates of interest (social class, alcohol consumption and dietary indicators), and persisted when allowance was made for duration of smoking and number of cigarettes smoked per day by means of multiple regression analysis. The present findings suggest that the relation between tar deliveries of cigarettes and risk may be even more marked for oesophageal than for lung cancer. Further, they have important public health implications, in consideration of the current relatively high tar yields of Italian cigarettes, particularly in a few areas of north-eastern Italy where death certification rates from cancer of the oesophagus are among the highest in Europe. Nonetheless, in this study, smokers of prevalently low- to mid-tar cigarettes still did experience a significantly higher oesophageal cancer risk than life-long non-smokers.

Coffee drinking and the risk of epithelial ovarian cancer.

The relation between ovarian cancer and coffee drinking habits was evaluated in a case-control study of 247 histologically confirmed epithelial ovarian cancers and 494 age-matched controls, admitted to hospital for acute conditions apparently unrelated to coffee consumption. Compared to rates for women who had never drunk coffee, the crude relative risk estimates for those who drank less than two, two or three, and four or more cups per day were 1.3, 1.5 and 1.4 respectively; however, when allowance was made for smoking habits, these risk estimates became 1.3, 1.7 and 1.8 respectively, and a significant linear trend of increasing risk with more elevated coffee consumption was evident. These results were not explained by various other potential confounding factors, including the major risk factors for ovarian cancer, but we had no information on dietary variables. The relative risk, however, did not increase with increasing duration of use. The findings of this study give apparent support in favour of the hypothesis that coffee consumption, or related dietary variables, may be associated with the risk of epithelial ovarian cancer. Further studies in different settings, however, are required in order to establish whether this association is real, and if so, whether it is causal.