Incidence of thyroid cancer in Italy, 1991-2005: time trends and age-period-cohort effects.

BACKGROUND: In Italy, some of the highest incidence rates (IRs) of thyroid cancer (TC) worldwide have been reported. PATIENTS AND METHODS: TC cases <85 years of age reported to Italian cancer registries during 1991-2005 were included. Age-standardized IRs were computed for all TC and age-period-cohort effects were estimated for papillary TC. RESULTS: IRs of TC were twofold higher in 2001-2005 than in 1991-1995 (18 and 8 per 100,000 women, 6 and 3 per 100,000 men, respectively). Increases were similar in the two sexes and nearly exclusively due to papillary TC. Increases of papillary TC by birth cohort were found in both sexes and among all age groups between 20 and 79 years. Age-period-cohort models showed a strong period effect in both sexes (rate ratio for 2001-2009 versus 1991-1995 = 2.5 in women and 2.3 in men), although IRs peaked at an earlier age in women (45-49 years) than men (65-69 years). CONCLUSION: The strength of the period effect in both sexes and the earlier onset in women than men strongly implicated increased medical surveillance in the upward trends of papillary TC incidence in Italy. The consequences of the current intense search for TC on morbidity and possible overtreatment, especially among young women, should be carefully evaluated.

Pattern of cancer risk in persons with AIDS in Italy in the HAART era.

A record-linkage study was carried out between the Italian AIDS Registry and 24 Italian cancer registries to compare cancer excess among persons with HIV/AIDS (PWHA) before and after the introduction of highly active antiretroviral therapy (HAART) in 1996. Standardised incidence ratios (SIR) were computed in 21951 AIDS cases aged 16-69 years reported between 1986 and 2005. Of 101 669 person-years available, 45 026 were after 1996. SIR for Kaposi sarcoma (KS) and non-Hodgkin lymphoma greatly decreased in 1997-2004 compared with 1986-1996, but high SIRs for KS persisted in the increasingly large fraction of PWHA who had an interval of <1 year between first HIV-positive test and AIDS diagnosis. A significant excess of liver cancer (SIR=6.4) emerged in 1997-2004, whereas the SIRs for cancer of the cervix (41.5), anus (44.0), lung (4.1), brain (3.2), skin (non-melanoma, 1.8), Hodgkin lymphoma (20.7), myeloma (3.9), and non-AIDS-defining cancers (2.2) were similarly elevated in the two periods. The excess of some potentially preventable cancers in PWHA suggests that HAART use must be accompanied by cancer-prevention strategies, notably antismoking and cervical cancer screening programmes. Improvements in the timely identification of HIV-positive individuals are also a priority in Italy to avoid the adverse consequences of delayed HAART use.

Effectiveness of service screening: a case-control study to assess breast cancer mortality reduction.

The aim of this study was the evaluation of the impact of service screening programmes on breast cancer mortality in five regions of Italy. We conducted a matched case-control study with four controls for each case. Cases were defined as breast cancer deaths occurred not later than 31 December 2002. Controls were sampled from the local municipality list and matched by date of birth. Screening histories were assessed by the local, computerised, screening database and subjects were classified as either invited or not-yet-invited and as either screened or unscreened. There were a total of 1750 breast cancer deaths within the 50 to 74-year-old breast cancer cases and a total of 7000 controls. The logistic conditional estimate of the cumulative odds ratios comparing invited with not-yet-invited women was 0.75 (95% CI: 0.62-0.92). Restricting the analyses to invited women, the odds ratio of screened to never-respondent women corrected for self-selection bias was 0.55 (95% CI: 0.36-0.85). The introduction of breast cancer screening programmes in Italy is associated with a reduction in breast cancer mortality attributable to the additional impact of service screening over and above the background access to mammography.

Mastectomy rates are decreasing in the era of service screening: a population-based study in Italy (1997-2001).

We enrolled all 2162 in situ and 21 148 invasive cases of breast cancer in 17 areas of Italy, diagnosed in 1997-2001. Rates of early cancer increased by 13.7% in the screening age group (50-69 years), and breast conserving surgery by 24.6%. Advanced cancer rates decreased by 19.4%, and mastectomy rates by 24.2%. Service screening did not increase mastectomy rates in the study population.

Screen-detected vs clinical breast cancer: the advantage in the relative risk of lymph node metastases decreases with increasing tumour size.

Screen-detected (SD) breast cancers are smaller and biologically more indolent than clinically presenting cancers. An often debated question is: if left undiagnosed during their preclinical phase, would they become more aggressive or would they only increase in size? This study considered a registry-based series (1988-1999) of 3329 unifocal, pT1a-pT3 breast cancer cases aged 50-70 years, of which 994 were SD cases and 2335 clinical cases. The rationale was that (1) the average risk of lymph node involvement (N+) is lower for SD cases, (2) nodal status is the product of biological aggressiveness and chronological age of the disease, (3) for any breast cancer, tumour size is an indicator of chronological age, and (4) for SD cases, tumour size is specifically an indicator of the duration of the preclinical phase, that is, an inverse indicator of lead time. The hypothesis was that the relative protection of SD cases from the risk of N+ and, thus, their relative biological indolence decrease with increasing tumour size. The odds ratio (OR) estimate of the risk of N+ was obtained from a multiple logistic regression model that included terms for detection modality, tumour size category, patient age, histological type, and number of lymph nodes recovered. A term for the detection modality-by-tumour size category interaction was entered, and the OR for the main effect of detection by screening vs clinical diagnosis was calculated. This increased linearly from 0.05 (95% confidence interval: 0.01-0.39) in the 2-7 mm size category to 0.95 (0.64-1.40) in the 18-22 mm category. This trend is compatible with the view that biological aggressiveness of breast cancer increases during the preclinical phase.

Classic Kaposi's sarcoma in Italy, 1985-1998.

To evaluate incidence rates (IRs) of classic Kaposi's sarcoma (CKS) in Italy after the spread of AIDS, we distinguished CKS from AIDS-related KS (AKS) using an 'ad hoc' record linkage procedure between 15 Cancer Registries (CRs) (21% of the Italian population) and the national AIDS Registry. Between 1985 and 1998, 874 cases of CKS and 634 cases of AKS were diagnosed in the study areas. CKS accounted for 16 and 27% of KS cases below 55 years of age in men and women, respectively, but for 91 and 100% of those above age 55. The IRs for CKS were 1.0/ in men and 0.4/100,000 in women, but they varied between 0.3 in Umbria and 4.7 in Sassari in men, and between 0.1 in Parma and 1.7 in Sassari in women. IRs of CKS in both genders were stable between 1985-1987 and 1993-1998. In Northern and Central CRs the IR (adjusted for age and gender) for CKS was 0.5 in individuals born in the same area, but 1.6 in individuals born in Southern Italy or in the Islands (rate ratio = 3.2) suggesting that KS-associated herpesvirus, the cause of KS, is acquired early in life.

The impact of organised screening programmes on the stage-specific incidence of breast cancer in some Italian areas.

The aim of this study was to examine the effects of mammographic screening programmes on stage-specific incidence of breast cancer. The study compared prescreening and screening periods in seven areas in Italy, primarily evaluating the first screening round. All 17617 breast cancers (16554 invasive, 1063 in situ) registered in women aged 40-79 years between 1988 and 1999 were analysed through age-standardised rates and Poisson regression models. For all areas, independent of the baseline rates, the introduction of screening increased incidence for invasive cancers overall and, more markedly, for early cancers (screening/prescreening ratio: range 1.07-1.47 and 1.23-1.82, respectively), modifying the pattern of age-specific rates. The multiple regression analysis showed that the percentage of cases diagnosed at screening explained most of the increase; a residual effect of diagnosis period (screening versus prescreening) suggested a role for 'spontaneous' early detection in ages outside of the screening programme. Advanced cases did not show consistent variations across the registries for those aged 40-79 years (range: 0.91-1.21), whereas a more coherent picture was observed for those aged 50-69 years. In one area, a moderate reduction in the number of 'advanced' cases in the second screening period was observed. For all stages, the age-specific incidence rates of cases diagnosed outside of the screening programme for the age groups 50-69 years were lower than the corresponding rates in the prescreening period, suggesting a shift from the usual clinical services to the screening programme. Our results confirmed the increase in early-stage cancers occurring at the start of screening, and substantially explained the rise in breast cancer incidence. In addition, our study confirms the importance of cancer registries in monitoring the effect of breast cancer screening and the validity, for this purpose, of the linkage between cancer registries and screening programme databases.

Net survival: comparison between relative and cause-specific survival estimates.

This paper presents a comparison between cause-specific survival and relative survival calculated according to the Hakulinen method. The data are from the Tuscany Cancer Registry and we analysed the following cancer sites: stomach, colon, rectum, cervix and corpus uteri, female breast and skin melanoma. When cause-specific survival was calculated including among the deceased only those subjects whose death certificate reported strictly the same neoplasm as cause of death (three digits ICD-9), very good agreement between the two methods was found for stomach, lung, and skin melanoma and a good agreement was found for female breast. For cancer of the colon and rectum, in order to obtain similar estimates, deaths coded as caused by cancer in other sites of the large bowel and partially the not specified intestine had to be included. For cancer of the cervix and corpus uteri, in order to obtain similar estimates, but with cause-specific remaining higher than the relative estimates, deaths coded as not specified uteri cancer had to be included. In conclusion, cause-specific survival may be used also with overall mortality data, providing the death causes by cancers most susceptible to misclassification are to be included. However, using cause-specific survival creates some difficulties in comparative studies due to the different reliability of mortality data and to the different criteria used to identify the main cause of death.

Non-Hodgkin lymphoma among young adults with and without AIDS in Italy.

To compare the presentation and prognosis of non-Hodgkin lymphoma (NHL) in people with AIDS (PWA) and in the general Italian population, a record linkage study was carried out. The fraction of NHLs attributable to HIV/AIDS was also estimated. Information from the National AIDS Registry (RAIDS) was linked with records from 13 cancer registries (CR), covering about 15% of the Italian population. During the period 1985--94, among PWA ages 15--49, 136 NHLs were identified (8% of all NHLs) and were compared with 1,481 concurrent incident NHL cases of the same age group among non-PWA. Percentages above 13% of all NHLs were registered in the northern areas of Genoa and Varese, i.e., the most heavily affected by the AIDS epidemic. Between 1 year prior to and 3.5 years after AIDS diagnosis, PWA showed an overall standardised incidence ratio (SIR) for NHL of 302. SIR was particularly high (394) within 3 months after AIDS diagnosis and subsequently declined to 170. SIR was somewhat higher in females (428) than in males (280) but similar among intravenous-drug users (299) and other HIV-transmission groups (309). High-grade NHL, particularly immunoblastic and Burkitt's lymphoma, were twice as frequent among PWA than non-PWA. Conversely, low-grade NHL were less frequent. Except for the high proportion of brain localisation, no clear difference emerged in the pattern of NHL presentation site in PWA compared with non-PWA. At variance with NHL in the general population, among PWA histological grade had little impact on survival, which overall appeared to be very poor (2-year survival: 10%; 95% confidence interval: 3%--17%). Our present linkage of RAIDS and CRs represents an efficient tool for the surveillance of trends in incidence and survival of NHL among PWA in Italy.

Three new active cisplatin-containing combinations in the neoadjuvant treatment of locally advanced and locally recurrent breast carcinoma: a randomized phase II trial.

We designed three new four-drug cisplatin-containing combinations and evaluated their activity in a randomized phase II study including patients with locally advanced (stage III) and locally recurrent breast carcinoma. All combinations included methotrexate (M) on day 1 and cisplatin (P) on day 2 (MVAC-like combinations) and differed from one another by the addition of Epirubicin (Epi), Vincristine (V), Etoposide (E), Mitomycin (Mi). Based on the administered agents, they were named MPEMi, MPEpiE, MPEpiV. The combinations were randomly assigned to 101 patients, 57 with locally advanced and 44 with locally recurrent breast carcinoma. Response was evaluated after 4 cycles. The complete response (CR) rates were 7% and 43% and the CR plus partial response (PR) rates were 84% and 89% in locally advanced and in locally recurrent disease, respectively. In locally advanced disease, a pathologic CR (pCR) was assessed in seven of 57 patients (12%). There were no significant differences among the three combinations. The toxicities were at times severe, but generally tolerable, as demonstrated by the high cumulative doses of the drugs received by the patients. In conclusion, these three innovative chemotherapy regimens induced high CR plus PR rates in the neoadjuvant treatment of stage III and of locally recurrent breast carcinoma, and a high rate of pCR in stage III disease. These regimens warrant testing in phase III trials.

Bolus versus 5-day continuous infusion of cisplatin with mitomycin and vindesine in the treatment of advanced non-small cell lung cancer (NSCLC): a phase III prospective randomised trial of the Italian Oncology Group for Clinical Research (GOIRC).

The aim of this randomised trial was to compare the efficacy of bolus versus continuous infusion cisplatin combined with mitomycin C and vindesine (MVP) for chemotherapy-naive patients with stage IIIB-IV non-small cell lung cancer (NSCLC). 97 patients (49 given bolus cisplatin-arm A and 48 given continuous infusion cisplatin--arm B) were evaluable for response. In arm A, 2 patients achieved a complete response (CR), 21 achieved a partial response (PR), whilst in arm B, 14 patients achieved a PR (29%) (P = 0.07). Median survival was 8 months in both arms. Myelosuppression was the most frequent and severe toxicity, with a higher incidence of grade 3-4 leucopenia in arm A when compared with arm B (44% versus 25%). In conclusion, there is no advantage for a cisplatin 5 day infusion in the MVP regimen.

Intraperitoneal carboplatin with or without interferon-alpha in advanced ovarian cancer patients with minimal residual disease at second look: a prospective randomized trial of 111 patients. G.O.N.O. Gruppo Oncologic Nord Ovest.

From June 1990 to October 1994, 111 advanced ovarian cancer patients with minimal (less than 2 cm) residual disease after platinum-based front-line chemotherapy and second-look laparotomy entered a cooperative randomized study aimed at evaluating the effectiveness and the toxicity of the addition of interferon-alpha2 to carboplatin, both intraperitoneally (ip) administered. Patients were randomized to receive either 3 courses of ip Carboplatin 400 mg/m2 Day 1 q 28 days (54 pts) (CBDCA) or ip interferon-alpha 25 x 10(6) U Day 1 + ip carboplatin 400 mg/m2 Day 2 q 28 days (57 pts) (CBDCA + IFN). Patients treated with interferon experienced more severe (WHO grade 3-4) leukopenia (28% vs 17.1%) and anemia (14% vs 4.2%). Fever (P = 0.000) and flu-like syndrome (P = 0.02) were significantly more frequent in the combination arm. No difference in gastroenteric, neurologic, or renal toxicity was observed. At a median follow-up time of 13 months (range 1-72) 71 patients showed a disease progression (31 CBDCA, 40 CBDCA + IFN) and 44 patients died (21 CBDCA, 23 CBDCA + IFN). Median progression-free survival was 11 months in the CBDCA group and 10 months in the CBDCA + IFN arm. Median survival was 22 and 29 months in CBDCA and CBDCA + IFN arm, respectively. In conclusion, intraperitoneal interferon-alpha does not seem to improve the results achievable with intraperitoneal carboplatin in this subset of patients, while the toxicity and the costs of the combination are consistently higher than with chemotherapy alone.

Variations in the survival of adult cancer patients in Italy.

AIMS: As part of the ITACARE project, the present study analyzed and compared population-based data on the survival of adult cancer patients in Italy, according to sex, age, period of diagnosis and geographical area. METHODS: Nine Italian population-based cancer registries provided data on all their cancer patients (total 90,431 cases) followed for at least 5 years and diagnosed during the period 1978-1989. About 10% of the Italian population is covered by these registries. The data was analyzed by means of a multivariate model. RESULTS: The major findings were that there was a general improvement in 5-year relative survival over the study period (from 33% to 39%) and that there were significant differences in survival between different areas of the country, particularly for cancer sites which respond well to treatment. In general, the area covered by the Ragusa (Sicily) registry was characterized by significantly worse survival than other registry populations. Other important findings were that for all malignant cancer sites 5-year relative survival decreased with age from 50% for the youngest age class (15-44 years) to 27% for the oldest age class (75+ years) and that women have a better prognosis for most cancer sites (overall 5-year relative survival in women 48% vs 32% in men). CONCLUSIONS: The significant regional differences in survival may reflect unequal provision of care, particularly between northern-central Italy and the south. The reasons for the general survival improvement with time are not completely understood, whereas the marked overall sex difference is related to the fact that the commonest cancer in women (breast cancer) is eminently more treatable than the commonest malignancy in men (lung cancer). The unfavorable trend with increasing age may be due to increasing difficulty in applying complete therapy protocols as general health declines, sometimes in relation to an advanced cancer stage at diagnosis.

The combination of cisplatin, doxorubicin, and mitomycin (PAM) compared with the FAM regimen in treating advanced gastric carcinoma. A phase II randomized trial of the Italian Oncology Group for Clinical Research.

BACKGROUND: In a randomized Phase II study, the authors evaluated the activity and toxicity of the new cisplatin, doxorubicin, and mitomycin C (PAM) combination, that includes cisplatin (P) instead of 5-fluorouracil as in the 5-fluorouracil, doxorubicin, and mitomycin C (FAM) combination, in patients with advanced gastric carcinoma. FAM was utilized as a control treatment arm. METHODS: Fifty eligible patients were assigned to the FAM (5-fluorouracil 600 mg/m2 intravenous (i.v.) on Days 1, 8, 29, 36; doxorubicin 30 mg/m2 i.v. on Days 1 and 29; mitomycin C 10 mg/m2 i.v. on Day 1; every 8 weeks) and 52 to the PAM combination (cisplatin 60 mg/m2 i.v. on Days 1 and 29; doxorubicin 30 mg/m2 i.v. on Days 1 and 29; mitomycin C 10 mg/m2 i.v. on Day 1; every 8 weeks). All eligible patients were included in the evaluation of response, toxicity and survival. RESULTS: The PAM combination complete response (CR) rate was 8%, and the CR plus partial response (PR) rate was 21% (95% confidence interval [CI] from 10% to 32%). The median time to progression, duration of response, and duration of survival were 15, 26, and 29 weeks, respectively. The FAM combination CR rate was 2% and the CR plus PR rate was 26% (95% CI from 14% to 38%). The median time to progression, duration of response, and duration of survival were 17, 27, and 23 weeks, respectively. Hematologic and nonhematologic toxicity were mild with both regimens. CONCLUSIONS: This study shows that this new combination, that does not include 5-fluorouracil, is active in patients with advanced gastric carcinoma. Since treatment with 5-fluorouracil alone is still considered the standard according to some authors, the PAM combination may be included among the sequential clinical options before or after treatment with 5-fluorouracil alone.

Cancer Incidence and Mortality in the Elderly: Profile of the Italian Problem.

In Italy, 28% of all deaths are due to cancer. Of the 15% of the population that is 65 years or older, 65% of cancer deaths occur in men and 69.5% in women. The proportional mortality and incidence of cancer in Italy varies with increasing age. All patients over 65 years are found to be at increased risk for intestinal cancers. In older men, the proportion of lung and urinary tract cancers decreases, while prostate, intestinal and gastric cancers increases. Prostate cancer predominates in men over 85 years and intestinal and gastric cancers are relatively more common than lung cancer. In women over age 74, intestinal cancer is most common. Breast, genital and lung cancers decrease rapidly with age, while stomach, liver, gallbladder and pancreatic cancers increase with age. The ratio of incidence to mortality for all cancers studied is shown to equalize with increased age, the probable result of lower hospitalization rates and less adequate cancer therapy for the elderly.

Fluorouracil, doxorubicin, and mitomycin combination versus PELF chemotherapy in advanced gastric cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research.

PURPOSE: The combination of cisplatin, epirubicin, and leucovorin preceding fluorouracil (PELF) includes three novel agents compared with the standard combination of fluorouracil, doxorubicin, and mitomycin (FAM) in the treatment of advanced gastric carcinoma. We report the results of a prospective randomized comparison of the two combinations in previously untreated patients. PATIENTS AND METHODS: One hundred thirty assessable patients were entered onto the trial; 52 received FAM and 85 PELF. A 1:2 unbalanced randomization in favor of the experimental treatment was chosen. Approximately 90% of patients had measurable tumor masses. RESULTS: The overall response rates (complete responses [CRs] and partial responses [PRs]) were 15% and 43% for the FAM and the PELF regimens, respectively, with a statistically significant advantage for the experimental treatment (P = .001). Time to progression (median, 2.6 and 4.7 months), duration of response (median, 10.7 and 10.2 months), and survival durations (median, 5.6 and 8.1 months) were not significantly different between the FAM and PELF regimens, respectively. The PELF combination was more toxic compared with FAM, but generally tolerable. CONCLUSION: This study showed that the PELF combination is about three times more effective than the FAM combination in inducing objective responses. Due to tolerability, it is not recommended for routine clinical use. However, it should be considered, among other second-generation chemotherapy combinations, in future randomized studies aimed to improve the therapeutic outcome in gastric carcinoma.

M-VAC combination in locally advanced, locally recurrent or metastatic breast carcinoma. A phase II study.

BACKGROUND: The M-VAC combination is very effective in bladder carcinoma, as are all four drugs, as single-agent, in advanced breast carcinoma. PATIENTS AND METHODS: M-VAC was given in 27 patients, 4 with locally advanced breast carcinoma, 3 with local recurrence and 20 with distant metastases. The median age was 51 (range 25; 70). Eleven of the 20 patients with metastatic disease has been previously treated with a different chemotherapy. RESULTS: 15 of 26 evaluable patients responded, with 9 (35%) complete remissions and 6 partial responses. The overall response rate (CR plus PR) was 57% (95% confidence interval 38% to 76%). In patients with metastatic disease the median duration of response was 7 months (range 4+; 36+), median time to progression 5 months (range 1; 36+) and median duration of survival 17 months (range 1; 40+). CONCLUSION: The M-VAC combination is very effective in locally advanced, locally recurrent and metastatic breast carcinoma. Further trials are warranted to evaluate whether the activity of this combination is partially schedule-dependent.

Cisplatin and etoposide as first-line chemotherapy for metastatic breast carcinoma: a prospective randomized trial of the Italian Oncology Group for Clinical Research.

In this prospective randomized study, first-line treatment with the combination of cisplatin (P) and etoposide (E) was compared with the standard cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in 140 patients. Complete remissions were obtained in 11% of 65 assessable patients on CMF and in 12% of 65 assessable patients on PE. Complete plus partial remission rates were 48% on CMF and 63% on PE (P = .08). Time to progression (median, 32 v 31 weeks), duration of response (48 v 39 weeks), and survival (75 v 76 weeks) were not different. Hematologic toxicity was significantly higher with PE, and gastrointestinal side effects were frequent with this treatment. This study demonstrated that the PE combination is effective as front-line chemotherapy. As far as response rate is concerned, a trend of superiority over CMF was observed, which was of borderline significance. Due to the lack of survival advantage and to toxicity, this combination is not recommended for routine clinical use. However, its high level of activity should be taken into account for further research.

A comparison of continuation versus late intensification followed by discontinuation of chemotherapy in advanced breast cancer. A prospective randomized trial of the Italian Oncology Group for Clinical Research (G.O.I.R.C.).

One hundred ninety-eight postmenopausal women with metastatic breast carcinoma were entered in this study. After six induction cycles with cyclophosphamide, methotrexate and 5-fluorouracil (CMF), patients with at least stable disease were randomized to the "continuation arm" (continuation of CMF until progression) (A, 49 evaluable patients) or to the "intensification-discontinuation arm" (addition of adriamycin and vincristine to two of the three drugs of CMF for six more cycles; i.e., CMAV, CFAV, MFAV, twice; discontinuation of chemotherapy; radiotherapy to pre-study sites of disease in patients prospectively considered as candidates to receive this treatment) (B, 46 evaluable patients). After randomization, escalation of response category occurred in five patients on A (10%) and in five on B (11%). Time to progression was transiently delayed in arm B within 6 months after randomization. There were no significant differences in the overall time to progression, duration of response or survival. On arm B, after discontinuation of chemotherapy, median time to relapse was 22 weeks. This time was significantly longer in patients who were candidates for radiation therapy (36 weeks, P = 0.005), or with a disease-free interval greater than 1 year (32 weeks, P = 0.004) or who achieved complete remission (60 weeks, P = 0.0001). On arm B, three patients (7%) are still alive in complete remission in excess of three, five and six years following discontinuation of therapy. This study indicates that late intensification of chemotherapy followed by discontinuation of treatment may maintain palliation, and allow a long treatment-free period in responding patients with advanced breast carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)