•Liquid biopsy has several advantages as compared with tissue biopsy.•Liquid biopsy showed prognostic and predictive value in different CRC stages.•Studies of liquid biopsy in CRC have several ...limits.•Prospective studies are required to transfer liquid biopsy in clinical practice.•Analysis of multiple biomarkers might improve liquid biopsy sensitivity/specificity.
The term liquid biopsy refers to the analysis of biomarkers in any body fluid, including blood, urine and cerebrospinal fluid. In cancer, liquid biopsy testing allows the analysis of tumor-derived DNA, RNA, miRNA and proteins that can be either cell-free or contained in circulating tumor cells (CTC), extracellular vesicles (EVs) or platelets. A number of studies suggest that liquid biopsy testing could have a relevant role in the management of colorectal cancer (CRC) patients at different stages of the disease. Analysis of cell-free DNA (cfDNA), CTC and/or miRNA can provide relevant information for the early diagnosis of CRC and the identification of minimal residual disease and, more generally, the evaluation of the risk of recurrence in early CRC patients. In addition, liquid biopsy testing might allow the assessment of prognostic and predictive biomarkers in metastatic CRC patients, and the monitoring of the response to treatment and of the clonal evolution of the disease. While a number of elegant studies have shown the potential of liquid biopsy in CRC, the possibility to use this approach in the daily clinical practice is still limited. The use of non-standardized methods, the small cohorts of patients analyzed, the lack of demonstration of a clear clinical benefit are the main limitations of the studies with liquid biopsy in CRC reported up to now. The potential of this approach and the steps that need still to be taken to translate these preliminary findings in the clinic are discussed in this review.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer.
Seven hundred forty-seven patients with resectable, locally ...advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m(2)/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m(2) weekly × 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here.
Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014).
Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.
In cancer patients, malnutrition is associated with treatment toxicity, complications, reduced physical functioning, and decreased survival. The Prevalence of Malnutrition in Oncology (PreMiO) study ...identified malnutrition or its risk among cancer patients making their first medical oncology visit. Innovatively, oncologists, not nutritionists, evaluated the nutritional status of the patients in this study.
PreMiO was a prospective, observational study conducted at 22 medical oncology centers across Italy. For inclusion, adult patients (>18 years) had a solid tumor diagnosis, were treatment-naive, and had a life expectancy >3 months. Malnutrition was identified by the Mini Nutritional Assessment (MNA), appetite status with a visual analog scale (VAS), and appetite loss with a modified version of Anorexia-Cachexia Subscale (AC/S-12) of the Functional Assessment of Anorexia-Cachexia Therapy (FAACT).
Of patients enrolled (
1,952), 51% had nutritional impairment; 9% were overtly malnourished, and 43% were at risk for malnutrition. Severity of malnutrition was positively correlated with the stage of cancer. Over 40% of patients were experiencing anorexia, as reported in the VAS and FAACT questionnaire. During the prior six months, 64% of patients lost weight (1-10 kg).
Malnutrition, anorexia, and weight loss are common in cancer patients, even at their first visit to a medical oncology center.
Abstract Background The attitude towards malnutrition varies considerably among oncologists and many malnourished cancer patients receive inadequate nutritional support. Methods Between January and ...July 2015, the Italian Society of Medical Oncology (AIOM) and the Italian Society of Artificial Nutrition and Metabolism (SINPE) conducted a national web-based exploratory survey, to investigate the attitude of oncologists towards malnutrition, and the management of nutritional support, before publication of an inter-society consensus document. Results Of the 2375 AIOM members, 135 (5.7%) participated in the survey, with a satisfactory distribution across all Italian regions. Nutritional assessment and support were routinely integrated into patient care for 38 (28%) responders. According to 66 (49%) participants, nutritional assessment was carried out only upon patients’ request (n=62), or not at all (n=4). Clinical nutritionists were reported to be available by 88 (65%) participants. For 131 responders (97%), nutritional status was decisive (n=63) or often crucial (n=68) in assessing whether anti-cancer treatment was practicable or would be tolerated. Conclusions The low response rate may reflect the lack of awareness and consideration of nutritional issues among Italian oncologists. Although malnutrition and nutritional support seemed to be perceived by the responders as relevant factors for the efficacy of oncologic treatments, it seems that nutritional care practices may well be inappropriate. The lack of collaboration between oncologists and clinical nutritionists may be the first obstacle to overcome. Educational inter-society initiatives aimed at improving nutritional support management for cancer patients in Italy appear urgently needed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We sought to develop criteria for ERBB2-positivity (HER2) in colorectal cancer to ensure accurate identification of ERBB2-amplified metastatic colorectal cancer patients suitable for enrollment in a ...phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2-positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test (N=256) and clinical validation (N=830) cohorts, a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2-positive according to the colorectal cancer-specific ERBB2 scoring criteria. ERBB2-positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2 amplification, in >50% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2-positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximab-resistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Right-sided colorectal cancer (CRC) has worse survival than does left-sided CRC. The objective of this study was to further assess the impact of right-side location on survival and the role of the ...extent of lymphadenectomy.
All CRCs diagnosed between 2000 and 2012 in Emilia-Romagna Region, Italy, were included. Data for stage, grade, histology, screening history, and number of removed lymph nodes (LN) were collected. Multivariable Cox regression models were used to estimate hazard ratios (HR), with relative 95% confidence intervals (95%CI), of right vs. left colon and of removing < 12, 12-21 or > 21 lymph nodes by cancer site.
During the study period, 29,358 patients were registered (8828 right colon, 18,852 left colon, 1678 transverse). Patients with right cancer were more often older, females, with advanced stage and high grade, and higher number of removed LNs. Five-year survival was lower in the right than in the left colon (55.2% vs 59.7%). In multivariable analysis, right colon showed a lower survival when adjusting for age, sex, and screening status (HR 1.12, 95%CI 1.04-1.21). Stratification by number of lymph nodes removed (12-21 or > 21) was associated with better survival in right colon (HR 0.54, 95%CI 0.40-0.72 and HR 0.40, 95%CI 0.30-0.55, respectively) compared to left colon (HR 0.89, 95%CI 0.76-1.06 and HR 0.83, 95%CI 0.69-1.01, respectively).
This study confirms that right CRC has worse survival; the association is not due to screening status. An adequate removal of lymph nodes is associated with better survival, although the direction of the association in terms of causal links is not clear.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Deleterious polymorphisms in the gene encoding DPD (DPYD) may result in severe reduction of DPD enzymatic activity that causes life-threatening toxicities when the standard dose of fluorouracil is ...used. The best panel of single-nucleotide polymorphism (SNPs) of DPYD is not well defined.
In 2011, we began screening DPYD*2A in patients candidate for fluoropyrimidine-based chemotherapy. We planned a case-control study with all cases of DPYD*2A wild type who developed toxicity ≥G3 and with a cohort of patients who did not present severe toxicities. Then, we tested the additional SNPs: c.2846A>T, c.1679T>G, c.2194G>A.
From 2011 to 2016, we screened 1827 patients for DPD deficiency; of those, 31 subjects (1.7%) showed DPYD*2A SNP. We selected 146 subjects who developed severe toxicities (Cases) and 220 patients who experienced no or mild toxicities (Controls); 53 patients carried one of the additional SNPs: 35 subjects (66%) fell into the Cases and 18 (34%) into the Controls (p < 0.0001). c.2194G>A was the most frequent SNP (12.5%) and showed a correlation with neutropenia. We confirmed that c.2846A>T and c.1679T>G were related to various toxicities.
The additional DPYD polymorphisms could enhance the prevention of fluoropyrimidine toxicity. c.2194G>A is the most frequent polymorphism and it was found to be associated with neutropenia.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The aim of this study is to present the 5-year relative survival by stage of breast and colorectal cancer patients in a northern Italian province. For the period 2013-2015, cases were selected from ...the Reggio Emilia Cancer Registry. Breast cancer patients were divided into 3 age groups: <45, 45-74 (the target screening population) and 74+. Colorectal cancers patients were classified into <50, 50-69 (the target screening population), and over 69 years. Carcinomas
in situ
and unknown stage were both excluded from the survival analyses. The five-year relative survival was estimated using the Pohar Perme method. During the period examined, 1,450 breast cancers and 992 colorectal cancer cases were registered. Analyzing in detail the patients with breast cancer for the entire 2013-2015 period, we noted that 50.4% were in stage I, 33.6% in stage II, 10.8% in stage III and 3.8% in stage IV. The stage was unknown in only 1.3% of patients (19 cases). The stage data of patients with colorectal cancer showed 24.5% were in stage I, 26.1% in stage II, 23.4% in stage III, and 24.6% in stage IV, and 1.4% unknown. Breast cancer 5-year survival was 100%, 89.7%, 71.4%, and 29.1% for stages I, II, III and IV, respectively and for colon cancer 96.7%, 83.4%, 70.8% and 16.2%, respectively.The presence of cancer screening, associated with effective treatments, account for the high survival rate of early-stage breast and colon cancers.
The present paper illustrates the definition of unmet need provided by the peer-reviewed literature and the Health Technology Assessment (HTA) authorities across Europe in the assessment and ...appraisal process and within the early access schemes for medicines.
The analysis relied on a descriptive review of the peer-reviewed literature and HTA documents on the definition of need (disease severity) and the way it is satisfied (existence and validity of alternatives).
HTA agencies were found using (i) a narrow definition of need, focused on the clinical impact and the impact on health-related quality of life of the disease and (ii) a broad definition of comparators, including treatments used off-label in the clinical practice. Most of the contributions of the literature advocated for a broader definition of need, including additional dimensions (for example, the socio-economic impact of the disease) and the effects of existing treatments beyond their risk-benefit profile (for example, acceptability to patients).
On the one hand, these contributions should be considered by HTA agencies, considering its multi-disciplinary and multi-stakeholder nature. On the other one, the explicit inclusion of the unmet need domains, at present disregarded, should depend on the decisions taken on the ground of the assessment.
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