Systematic vitamin D supplementation is associated with improved outcomes and reduced thyroid adverse events in patients with cancer treated with immune checkpoint inhibitors: results from the prospective PROVIDENCE study.

BACKGROUND: Hypovitaminosis D can have a negative prognostic impact in patients with cancer. Vitamin D has a demonstrated role in T-cell-mediated immune activation. We hypothesized that systematic vitamin D repletion could impact clinical outcomes in patients with cancer receiving immune-checkpoint inhibitors (ICIs). METHODS: We planned a prospective observational study (PROVIDENCE) to assess serum vitamin D levels in patients with advanced cancer receiving ICIs (cohort 1 at treatment initiation, cohort 2 during treatment) and the impact of systematic repletion on survival and toxicity outcomes. In an exploratory analysis, we compared the clinical outcomes of cohort 1 with a control cohort of patients followed at the participating centers who did not receive systematic vitamin D repletion. RESULTS: Overall, 164 patients were prospectively recruited in the PROVIDENCE study. In cohort 1, consisting of 101 patients with 94.1% hypovitaminosis (≤ 30 ng/ml) at baseline, adequate repletion with cholecalciferol was obtained in 70.1% at the three months re-assessment. Cohort 2 consisted of 63 patients assessed for vitamin D at a median time of 3.7 months since immunotherapy initiation, with no patients having adequate levels (> 30 ng/ml). Even in cohort 2, systematic supplementation led to adequate levels in 77.8% of patients at the three months re-assessment. Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS, p = 0.013), time to treatment failure (TTF, p = 0.017), and higher disease control rate (DCR, p = 0.016). The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55, 95%CI: 0.34-0.90) and treatment discontinuation (HR 0.61, 95%CI: 0.40-0.91) for patients from PROVIDENCE cohort 1 in comparison to the control cohort. In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events (irAEs) was higher in the PROVIDENCE cohort 1 compared to the control cohort. Nevertheless, patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16, 95%CI: 0.03-0.85). CONCLUSION: The PROVIDENCE study suggests the potential positive impact of early systematic vitamin D supplementation on outcomes of patients with advanced cancer receiving ICIs and support adequate repletion as a possible prophylaxis for thyroid irAEs.

[Intercensal reconstruction of population and descriptive epidemiological measures in Italy: what is the impact on the cancer incidence rates?]. / La ricostruzione intercensuaria della popolazione e le misure di epidemiologia descrittiva in Italia: qual è l'impatto sui tassi di incidenza dei tumori?

OBJECTIVES: to test the effect on cancer incidence rates when using precensal computation (computed population) or intercensal reconstruction of population (reconstructed population). DESIGN: comparison between computed and reconstructed population by area and period in 2002-2011; evaluation of the effect on cancer rates using Italian cancer registries data. Setting e participants: population data from the Italian National Institute for Statistics, cancer data from Italian cancer registries; specific analysis involves data from Parma (Emilia-Romagna Region, Northern Italy) and Taranto (Apulia Region, Southern Italy) cancer registries. MAIN OUTCOME MEASURES: ratio between computed and reconstructed population by area, gender, age, and period; ratio between corresponding age-standardized incidence rates. RESULTS: Italian population estimates by precensal computation for years 2002-2011 was generally higher than that obtained by intercensal reconstruction especially in 2011, when this has been found in more than 86% of Italian Municipalities. In the same year a smaller proportion of Municipalities (11%) showed an inverse population ratio. Among the most populated Municipalities, the City of Milan showed the higher precensal to intercensal population ratio (1.076), while the City of Taranto showed the lower precensal to intercensal population ratio (0.956). The ratios between age standardized rates obtained with precensal population to those obtained with intercensal population show similar differences; in particular, for all cancer in males and females they were, respectively, 0.985 and 0.982 in the Province of Parma, 0.974 and 0.968 in the City of Parma, 1.023 and 1.013 in the Province of Taranto, and 1.08 and 1.051 in the City of Taranto. CONCLUSION: using precensal population as denominator for the year 2002- 2011 produces a remarkable distortion of both temporal trend and geographical comparisons. It is, therefore, necessary that researchers take into account this possible distortion when reporting descriptive measures in the years between the last two censuses in Italy.

[Evaluation of the cancer co-pay fee exemption data source (048 code) to estimate cancer incidence]. / Valutazione del flusso delle esenzioni ticket per neoplasia (codice 048) per stimare l'incidenza dei tumori.

OBJECTIVES: to assess whether the data source of cancer exemption ticket (code 048) correctly estimate the cancer incidence produced by Cancer registries (CR). DESIGN: comparison between incidence estimates produced by cancer exemptions ticket and cases registered by CR. SETTING AND PARTICIPANTS: six CRs provided incidence data for one year in the five-year period from 2007 to 2011 and for the previous five years, the exemptions provided for the same year and for the previous five years. MAIN OUTCOME MEASURES: incidence distribution by gender, age and tumour site, exemptions 048/incident cancers ratio, and trend estimates. RESULTS: out of 14,586 patients with 048 exemption, a first group was present in the CR database in the same reference year (No. 8,015) and a second group in the previous 6 months (No. 1,696). Of the remaining 4,875, only 2,771 were prevalent cases and 2,104 were manually re-valued: 514 non-cancer; 710 non-malignant/noninfiltrating tumours, 250 non-residents, 532 unknown, and 98 lost at CR. The exemption/ tumours ratio was 32%in males and 37% in females. Out of 27,632 cancer patients in CR, only 29% had a 048 exemption. Among linked cases, there is a case-mix problem: the exemptions overestimated the weight of some cancer sites (breast, prostate), but underestimate the weight of other sites (stomach, liver, lung) and the burden of tumours in the elderly.The trend estimated from the exemptions underestimates the true incidence of tumours and presents fluctuations, because of local administrative and organisational issues. CONCLUSIONS: the 048 codes are an accessory source for CRs, but when used as single flow they are not able to estimate the true incidence of tumours and, therefore, do not provide useful information on cancer trends.

Thyroid cancer incidence by histological type and related variants in a mildly iodine-deficient area of Northern Italy, 1998 to 2009.

BACKGROUND: The incidence of thyroid cancer is increasing in several countries. However, the issue of whether this applies to all different histological types and related variants is poorly addressed. METHODS: All incident thyroid cancers diagnosed between 1998 and 2009 in a mildly iodine-deficient area in northern Italy were derived from a population-based tumor registry. Stage of disease, size of the tumor, focality, and histological variants were recorded from a review of pathology reports and slides. The mean annual increase (MAI) of the standardized incidence rate was calculated over the entire 12-year period of observation and a standardized rate ratio was evaluated to compare the mean standardized incidence between 2 periods of 6 years each (1998-2003 vs 2004-2009). RESULTS: In total, 980 cases were considered. An increase in the incidence trend for all thyroid tumors was demonstrated; the increase was found to be continuous from 1998 to 2002 but not afterward. The cancer incidence increased in both male and female subjects. Papillary thyroid carcinoma (PTC), the follicular variant of PTC, the tall cell variant of PTC (TCV-PTC), and Hurthle cell carcinoma (HC) showed the most relevant changes in incidence whereas follicular carcinoma was not found to be significantly affected. TCV-PTC was the only histological type to demonstrated a significant (P < .01) proportional increase in the second 6-year period of observation. Only TCV-PTC and HC were found to display a significant MAI after 2002. CONCLUSIONS: The incidence of thyroid cancer has increased within the last decade, an increase that is accounted for mostly by differentiated tumors. The most significant increases were documented for aggressive variants of basic histotypes.

Cancer incidence in people with AIDS in Italy.

People with HIV/AIDS (PWHA) have increased risk of some cancers. The introduction of highly active antiretroviral therapies (HAART) has improved their life expectancy, exposing them to the combined consequences of aging and of a prolonged exposure to cancer risk factors. The aim of this study was to estimate incidence rates (IR) in PWHA in Italy, before and after the introduction of HAART, after adjusting for sex and age through direct standardization. An anonymous record linkage between Italian AIDS Registry (21,951 cases) and Cancer Registries (17.3 million, 30% of Italian population) was performed. In PWHA, crude IR, sex- and age-standardized IR and age-specific IR were estimated. The standardized IR for Kaposi sarcoma and non-Hodgkin lymphoma greatly declined in the HAART period. Although the crude IR for all non-AIDS-defining cancers increased in the HAART period, standardized IR did not significantly differ in the 2 periods (352 and 379/100,000, respectively). Increases were seen only for cancer of the liver (IR ratio = 4.6, 95% CI: 1.3-17.0) and lung (IR ratio = 1.8, 95% CI: 1.0-3.2). Age-specific IRs for liver and lung cancers, however, largely overlapped in the 2 periods pointing to the strong influence of the shift in the age distribution of PWHA on the observed upward trends. In conclusion, standardized IRs for non-AIDS-defining cancers have not risen in the HAART period, even if crude IRs of these cancers increased. This scenario calls, however, for the intensification of cancer-prevention strategies, notably smoking cessation and screening programs, in middle-aged HIV-patients.

[Cancer incidence estimation by hospital discharge flow as compared with cancer registries data]. / Stima dell'incidenza del carcinoma mammario attraverso il flusso dei ricoveri ospedalieri: confronto con i dati dei Registri tumori.

OBJECTIVE: the study evaluates the accuracy of an algorithm based on hospital discharge data (HDD) in order to estimate breast cancer incidence in three italian regions (Emilia-Romagna, Toscana and Veneto) covered by cancer registries (CR). The evolution of computer-based information systems in health organization suggests automatic processing of HDD as a possible alternative to the time-consuming methods of CR. The study intends to verify whether HDD quickly provides reliable cancer incidence estimates for diagnosis and therapy evaluations. DESIGN AND SETTING: an algorithm based on discharge diagnosis and surgical therapy of hospitalized breast cancer patients was developed in order to provide breast cancer incidence. Results were compared with the corresponding incidence data of cancer registries. The accuracy of the automatic method was also verified by a direct record-linkage between HDD output and registries' files. The overall survival of cases lost to "HDD method" was analyzed. RESULTS: in the period covered by the study (3,125,425 person/year) CR enrolled 6,079 incident cases, compared to 6,000 cases recorded through the HDD flow. Incidence rates of the two methods (CR 194.5; HDD 192.0 x 100.000) showed no statistical differences. However, matched cases by the two methods were only 5,038. The sensitivity of the HDD algorithm was 82.9% and its predictive positive value (PPV) was 84.0%. False positive cases were 9.9%. On the other hand, 12.3% CR incident cases were not identified by the algorithm: these were mainly made up of older women, not eligible for surgical therapy. Their three-years survival was 62.0% vs 88.8% of the whole incidence group. CONCLUSION: HDD flow performance was similar to observations reported in the literature. The agreement between HDD and CR incidence rates is a result of a cross effect of both sensitivity and specificity limitations of the HDD algorithm. This can seriously impair the reliability of the latter method with regard to the evaluation of diagnostic and therapeutic strategies in cohort studies (i.e. the most effective approach to health setting in oncology).s.

Impact of laterality and mucinous histology on relapse-free and overall survival in a registry-based colon cancer series.

Recent data suggest that tumor laterality and mucinous histology may be clinically relevant. We investigated how both variables impact on the prognosis and the response to therapies in a large population-based cohort of cancer patients. Incidence data, clinical and pathological features, and outcome were systematically collected from the Tumor Registry of Parma over the years 2004-2009. Survival data were modeled by multivariable analysis. 1358 patients affected by stage I-IV colon cancer were considered; 661 (49%) had right-sided and 697 (51%) left-sided tumors. 144 (11%) had mucinous (MAC) and 1214 (89%) non-mucinous (NMAC) histology. MACs and NMACs of the right colon showed no difference in stage distribution, whereas left colon MACs were more frequently in an advanced stage (stage IV) (p = 0.008). Stage IV right colon tumors had a poorer overall survival than stage IV left-sided colon cancers (75th percentile 20 vs 34 months, p < 0.001). At relapse, MACs were less responsive to systemic therapy and had worse survival compared with NMACs regardless of tumor side (7.1 vs 13.1 months, p = 0.018). Right-sided colon cancers had poorer survival compared to left-sided tumors; the effect was mainly attributable to NMACs. At relapse, MACs had unfavorable prognosis regardless of the primary tumor-side.

Size of thyroid carcinoma by histotype and variants: A population-based study in a mildly iodine-deficient area.

BACKGROUND: Data relating the size of thyroid cancer with histological types and variants are scarce. METHODS: All incident thyroid cancer diagnosed between 2003 and 2012 in a mildly iodine-deficient area were derived from a population-based tumor registry. Undifferentiated/anaplastic thyroid cancer and incidental cases were excluded. Major diameter of thyroid cancer, as assessed by pathological examination, was stratified in classes: ≤10 mm; 11-20 mm; 21-40 mm; and >40 mm. For each class, absolute and relative frequencies of histological types were calculated. RESULTS: Tumors >20 mm were more frequent among follicular thyroid carcinoma (FTC) and Hürthle cell carcinoma than in other histotypes, with median size of 22.50 mm (95% confidence interval [CI] 16.71-28.29) and 25.00 mm (95% CI 17.04-32.96) in FTC and Hürthle cell carcinoma, respectively. Odds ratio for tumors >20 mm was significant for FTC and Hürthle cell carcinoma only (P < .0001). CONCLUSION: Among the histotypes and variants of differentiated thyroid cancer, FTC and Hürthle cell carcinoma are characterized by the largest size.

Prognostic risk factors for treatment decision in pT1a,b N0M0 HER2-positive breast cancers.

Although outcomes for women with breast cancers may vary by biologic subtype, patients with T1a,b N0M0 tumors have an excellent prognosis across all subgroups. HER2 overexpression occurs in 15-20% of primary breast tumors, and is associated with diminished disease-free and overall survival. The anti-HER2 monoclonal antibody trastuzumab in combination with chemotherapy is an effective treatment for all stages of HER2 positive breast cancer (bc). However, the absolute benefit decreases as the risk of recurrence lessens and no available randomized adjuvant trial has evaluated the role of trastuzumab in women with pT1a,b N0M0, HER2-positive breast tumors. These findings may explain the debate about the appropriate indication for adjuvant chemotherapy plus trastuzumab in this setting of patients. The aim of this review was to describe known and novel prognostic risk factors to be used for tailored treatment decision in pT1a,b N0M0 HER2-positive tumors. Whether patients with small HER2-positive bc may be suitable for (chemo)therapy reduction strategies, the current available data cannot exclude the need for a more aggressive treatment in a small subset of these subjects. Novel clinical prognostic factors such as interval cancer (IC) detection may help to address this clinically important controversy. A multicenter population-based cancer registry study is currently evaluating whether IC detection may identify patients with pT1a N0M0 HER2-positive tumors in whom the rate of recurrence justifies consideration for use of conventional, trastuzumab-based chemotherapy regimens.

The changing distribution and survival of colorectal carcinoma: an epidemiological study in an area of northern Italy.

OBJECTIVE: This study analyses the inter-relations of anatomical tumour location, gender, age and incidence rates for colorectal cancer from 1978 to 1999 in an area of northern Italy: the Parma district. METHODS: Data were obtained from the Parma Cancer Registry. Age-adjusted incidence rates were analysed by gender, age and colorectal cancer subsites. In addition, 5 year observed survival rates were determined. RESULTS: In the Parma area, the incidence of colorectal cancer is rising. We have observed a true increase in the rate of the age standardized incidence of right colon cancer, linked to an increased incidence of left colon cancer, while the incidence of rectal cancer has remained constant. The frequency of right-sided colon cancer was higher in aged patients, and in women. Age-standardized relative survival of patients after diagnosis of colorectal cancer between 1992 and 1996 was found to be significantly higher than age-standardized relative survival after diagnosis between 1978 and 1982. CONCLUSIONS: In the Parma area there has been an increased incidence of right colon cancer, linked to an increased incidence of left colon cancer, while the incidence of rectal cancer has remained constant. We feel that this shift, whatever the reason for it, has important implications for the choice of screening techniques.

Human epidermal growth factor receptor 2 status and interval breast cancer in a population-based cancer registry study.

PURPOSE: To determine whether human epidermal growth factor receptor 2 (HER2) -positive status is associated with risk of breast cancer diagnosis in the interval between mammographic screening, we estimated the distribution of features of aggressive tumor behavior in a general population with newly diagnosed breast cancer and known screening status. PATIENTS AND METHODS: We evaluated all invasive breast cancers (N = 641) that were systematically collected by the Parma Province Cancer Registry and diagnosed in women age 50 to 69 years from 2004 to 2007. From this population, 292 screen-detected cancers and 48 interval cases with negative screening mammograms on expert rereading (true interval cancers) were selected for study purposes. Unconditional logistic regression adjusted for age and tumor size was used to determine whether interval cancers were associated with selected clinicobiologic characteristics. RESULTS: Tumors with a high histologic grade (odds ratio [OR], 1.8; 95% CI, 1.2 to 3.8), high proliferative rate (OR, 2.4; 95% CI, 1.2 to 4.5), negative estrogen receptor status (OR, 1.6; 95% CI, 1.1 to 3.1), or HER2-positive status (OR, 3.4; 95% CI, 1.7 to 7.1) were more likely to be diagnosed in the interval between screening. Women age less than 60 years with HER2-positive breast cancer were four times more likely to be diagnosed in the interval between screening compared with only a two-fold increased risk for older women. CONCLUSION: This population-based cancer registry study demonstrated that HER2-positive tumors account for a substantial proportion of mammographic screening failure. The distribution of biologic characteristics in screen-detected cancers differs from that observed in interval cancers and may account in part for the more aggressive behavior of interval-detected cases.