[What patients with cancer think about the dehospitalization. A survey of Cipomo.] / Cosa pensano i pazienti oncologici circa le cure di prossimità. Risultato della survey del Cipomo.

BACKGROUND: Ministerial Decrete 77 (DM 77) promotes dehospitalization for chronic patients and defines out-of-hospital health facilities at this purpose. It has never been investigated how much patients with cancer know and judge this decree law. MATERIAL AND METHODS: The Collegio italiano dei primari oncologi medici ospedalieri (Cipomo) carried out a survey with a dedicated questionnaire on oncological patients attending public hospital to investigate the liking of DM 77. RESULTS: Anonymous responses were obtained from 1.443 patients. Median age 64ys, 42% males, 21% live alone, 70% have a companion. 19% thinks that oral chemotherapy could be managed outside the hospital, 26.68% carried out follow-up (FU),19.15% parenteral therapy, 32.16% basic examinations. Home is preferred by 21.8%, a health facility close to home by 36.3%, hospital by 37.54%. 59.67% would like FU in hospital by their personal oncologist, 5.47% by GP, 35.41% by both together and 9.45% by oncologist outside the hospital. Asked what they might feel about being followed out of the hospital, 29.94% say of not being treated at its best, 12.68% of not being able to be visited in hospital anymore, 5.27% of being abandoned, 30.7% of being freer and 10.88% of feeling less sick. Regarding the use of new technical tools to favor dehospitalisation, 44.15% answered yes, 15.88% no and 30.07% did not know. About the distance or traveling time from home to the therapy administration side, 20.26% answered this should be no more than 15 km or 30 mins, 9.91% no more than 30 km or 45 mins, 5.47% no more than 50 km or 60 mins but 39.5% say that the distance does not matter to them but only the continuity of care. The question related to the inconveniences with going to hospital for therapy: 40.81% waiting time, 20.47% lack of parking, 17.02% rotation of doctors,12.76% travel time and 5.62% bureaucracy. CONCLUSIONS: The patients' answers suggest that dehospitalization could improve their quality of life, but at the condition of being able to maintain a close relationship with the personal oncologist.

Real-world outcomes of Italian patients with advanced non-squamous lung cancer treated with first-line pembrolizumab plus platinum-pemetrexed.

PURPOSE: The aim of this multi-center, retrospective/prospective cohort observational study was to evaluate outcomes in routine clinical practice of first-line chemo-immunotherapy with cis/carboplatin, pemetrexed and pembrolizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) in 33 Italian centers. METHODS: The outcome measure was to evaluate overall survival (OS) in a real-world patient population. Secondary endpoints were: progression-free survival (PFS), objective response rate (ORR), duration of response (DoR) and incidence of treatment-related adverse events (AEs). RESULTS: 1068 patients were enrolled at the time of data cut-off (January 31st, 2023), and 812 (76.0%) belonged to the retrospective cohort. Median age was 66 years (27-85), ECOG PS was ≥ 2 in 91 (8.6%) patients; 254 (23.8%) patients had brain metastases at baseline; 38 (3.6%) patients had tumor with PD-L1 expression ≥ 50%. After a median follow-up of 17.0 months (95% CI, 16.1-17.9), median OS was 16.1 months (95% CI, 14.4-18.8) and PFS was 9.9 months (95% CI, 8.8-11.2). Median DoR (n = 493) was 14.7 months (95% CI, 13.6-17.1). ORR was 43.4% (95% CI, 40.4-46.4). Any-grade AEs occurred in 636 (59.6%) patients and grade ≥ 3 in 253 (23.7%) patients. Most common grade ≥ 3 AEs were neutropenia (6.3%) and anemia (6.3%). CONCLUSIONS: First-line chemo-immunotherapy was effective and tolerable in this large, real-world Italian study of patients with advanced non-squamous NSCLC. Our results were in line with the KEYNOTE-189 registration study, also considering the low number of PD-L1 ≥ 50% patients included in our study.

Implementation of Precision Oncology in Clinical Practice: Results of a National Survey for Health Care Professionals.

BACKGROUND: Two main aspects lead the implementation of precision oncology into clinical practice: the adoption of extended genome sequencing technologies and the institution of the Molecular Tumor Boards (MTBs). CIPOMO (Italian Association of Heads of Oncology Department) promoted a national survey across top health care professionals to gain an understanding of the current state of precision oncology in Italy. METHODS: Nineteen questions were sent via the SurveyMonkey platform to 169 heads of oncology departments. Their answers were collected in February 2022. RESULTS: Overall, 129 directors participated; 113 sets of answers were analyzed. Nineteen regions out of 21 participated as a representative sample of the Italian health care system. The use of next-generation sequencing (NGS) is unevenly distributed; informed consent and clinical reports are managed differently, as the integration of medical, biologic, and informatics domains in a patient-centered workflow is inconsistent. A heterogeneous MTB environment emerged. A total of 33.6% of the responding professionals did not have access to MTBs while 76% of those who have did not refer cases. CONCLUSIONS: NGS technologies and MTBs are not homogeneously implemented in Italy. This fact potentially jeopardizes equal access chances to innovative therapies for patients. This survey was carried out as part of an organizational research project, pursuing a bottom-up approach to identify the needs and possible solutions to optimize the process. These results could be a starting point for clinicians, scientific societies, and health care institutions to outline the best practices and offer shared recommendations for precision oncology implementation in current clinical practice.

Late immune-related adverse events in long-term responders to PD-1/PD-L1 checkpoint inhibitors: A multicentre study.

BACKGROUND: Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICIs) are lacking. METHODS: We performed a retrospective multicenter study to characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in patients with advanced cancer. IrAEs were categorized into 'early' (≤12 months) and 'late' (>12 months). RESULTS: From September 2013 to October 2019, 436 consecutive patients were evaluated. Two hundred twenty-three experienced any grade early-irAEs (51.1%), whereas 132 experienced any grade late-irAEs (30.3%) (p < 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, whereas 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced GIII/GIV irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95% confidence interval [CI]: 2.8-4.2), whereas the median time to onset of late-irAEs was 16.6 months (95% CI: 15.8-17.6). Cumulative time-adjusted risk of disease progression according to both the early-irAEs (hazard ratio [HR] = 0.63 [95% CI: 0.30-1.29], p = 0.204) and late-irAEs occurrence revealed no statistically significant differences (HR = 0.75 [95% CI: 0.37-1.56], p = 0.452). In addition, the time-adjusted cumulative risk of death in accordance with both early-irAEs (HR = 0.79 [95% CI: 0.34-1.86], p = 0.598) and late-irAEs (HR = 0.92 [95% CI: 0.49-1.74], p = 0.811) did not show statistically significant differences. CONCLUSION: Although less frequent than early-irAEs, late-irAEs are quite common in long responders to PD-(L)1 ICIs and are different in terms of spectrum and grade. Time-adjusted analysis revealed that the cumulative risk of disease progression and death were not significantly reduced in patients who experienced late-irAEs.

Another side of the association between body mass index (BMI) and clinical outcomes of cancer patients receiving programmed cell death protein-1 (PD-1)/ Programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors: A multicentre analysis of immune-related adverse events.

BACKGROUND: Several studies have found an association between higher body mass index (BMI) and improved clinical outcomes in cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors. In a previous study, we found that overweight/obese patients were significantly more likely to experience any grade immune-related adverse events (irAEs) compared to non-overweight patients. PATIENTS AND METHODS: We conducted a 'real-life', multi centre, retrospective observational study aimed at comparing the incidence of irAEs among cancer patients treated with PD-1/PD-L1 inhibitors according to baseline BMI. RESULTS: One thousand and seventy advanced cancer patients were evaluated. The median age was 68 years (range: 21-92), male/female ratio was 724/346. Primary tumours were: non-small-cell lung carcinoma (NSCLC) (653 patients), melanoma (233 patients), renal cell carcinoma (RCC) (152 patients) and others (29 patients). Median BMI was 25 (13.6-46.6); according to World Health Organisation (WHO) classification, 44 patients (4.1%) were defined as underweight, 480 patients (44.9%) as having a normal weight, 416 patients (38.9%) as overweight and 130 patients (12.1%) as obese. Higher BMI was significantly related to higher occurrence of any grade immune-related adverse events [irAEs] (p < 0.0001), G3/G4 irAEs (p < 0.0001) and irAEs leading to discontinuation (LTD) (p < 0.0001). Overweight and obesity were confirmed predictors for irAEs of any grade at both univariate and multivariate analysis. The adjusted odds ratios (ORs) (compared to normal-weight) were 10.6; 95% confidence interval (95%CI): 7.5-14.9 for overweight, and 16.6 (95%CI: 10.3-26.7) for obese patients. Obesity was the only factor significantly related to a higher incidence of G3/G4 irAEs (OR = 11.9 [95%CI: 6.4-22.3], p < 0.0001) and LTD irAEs (OR = 8.8 [95%CI: 4.3-18.2], p < 0.0001). Overweight and obese patients experienced a significantly higher occurrence of cutaneous, endocrine, gastro-intestinal (GI), hepatic and 'others' irAEs, compared to normal-weight patients. Only obese patients experienced a significantly higher occurrence of pulmonary and rheumatic irAEs, compared to normal-weight patients. CONCLUSIONS: Considering the previously evidenced association between higher BMI and better outcome, the current finding about the relationship between BMI and irAEs occurrence can contribute to consideration of these findings as the upside of the downside, which underlies an 'immunogenic phenotype'.

Evaluating the role of FAMIly history of cancer and diagnosis of multiple neoplasms in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: the multicenter FAMI-L1 study.

Background: We investigate the role of family history of cancer (FHC) and diagnosis of metachronous and/or synchronous multiple neoplasms (MN), during anti-PD-1/PD-L1 immunotherapy. Design: This was a multicenter retrospective study of advanced cancer patients treated with anti-PD-1/PD-L1 immunotherapy. FHC was collected in lineal and collateral lines, and patients were categorized as follows: FHC-high (in case of cancer diagnoses in both the lineal and collateral family lines), FHC-low (in case of cancer diagnoses in only one family line), and FHC-negative. Patients were also categorized according to the diagnosis of MN as follows: MN-high (>2 malignancies), MN-low (two malignancies), and MN-negative. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and incidence of immune-related adverse events (irAEs) of any grade were evaluated. Results: 822 consecutive patients were evaluated. 458 patients (55.7%) were FHC-negative, 289 (35.2%) were FHC-low, and 75 (9.1%) FHC-high, respectively. 29 (3.5%) had a diagnosis of synchronous MN and 94 (11.4%) of metachronous MN. 108 (13.2%) and 15 (1.8%) patients were MN-low and MN-high, respectively. The median follow-up was 15.6 months. No significant differences were found regarding ORR among subgroups. FHC-high patients had a significantly longer PFS (hazard ratio [HR] = 0.69 [95% CI: 0.48-0.97], p = .0379) and OS (HR = 0.61 [95% CI: 0.39-0.93], p = .0210), when compared to FHC-negative patients. FHC-high was confirmed as an independent predictor for PFS and OS at multivariate analysis. No significant differences were found according to MN categories. FHC-high patients had a significantly higher incidence of irAEs of any grade, compared to FHC-negative patients (p = .0012). Conclusions: FHC-high patients seem to benefit more than FHC-negative patients from anti-PD-1/PD-L1 checkpoint inhibitors.

Clinical and psychometric validation of the BreSAS questionnaire module for symptom assessment among breast cancer survivors.

BACKGROUND: The large number of women surviving many years post breast cancer (BC) diagnosis has heightened interest in studying long-term effects of cancer on quality of life (QoL). Several cancer-specific health-related measures have been developed, but these may not be appropriate for long survivors. This study evaluates the reliability and clinical and psychometric validity of the BreSAS questionnaire (BQ) among BC survivors. METHODS: The BQ is a quick, simple ten-item module for the assessment of long-term physical, psychological, sexual, and cognitive effects that may influence QoL. The total BreSAS score ranks from 0 to 100, with a low score indicating a better QoL. Patients complete the BQ, the FACT-ES questionnaire, and case report forms for clinical and socio-demographic data during follow-up visits. Reliability and clinical and psychometric validity of the questionnaires are assessed by correlation analyses and exploration of known group comparisons. RESULTS: From September 2015 to February 2016, 149 patients from three Italian oncology units were enrolled. Baseline questionnaires were returned from all, and 134 patients (89%) completed the BQ and FACT-ES in less than 15 min. For reliability, Cronbach's alpha coefficients for each scale were greater than 0.70 in all analyzed symptoms. Convergent validity of BQ showed by Pearson's r demonstrated a high correlation between intensity of symptoms and QoL, especially for pain and depression. No data were provided about reproducibility with test-retest study. CONCLUSION: The BQ demonstrates sufficient validity and reliability to support its use to assess patient-reported symptoms during planned follow-up clinical visits among BC survivors. Further full validation studies are needed.

Early fatigue in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: an insight from clinical practice.

BACKGROUND: Fatigue was reported as the most common any-grade adverse event (18.3%), and the most common grade 3 or higher immune-related adverse event (irAE) (0.89%) in patients receiving PD-1/PD-L1 checkpoint inhibitors in clinical trial. METHODS: The aim of this retrospective multicenter study was to evaluate the correlations between "early ir-fatigue", "delayed ir-fatigue", and clinical outcomes in cancer patients receiving PD-1/PD-L1 inhibitors in clinical practice. RESULTS: 517 patients were evaluated. After the 12-weeks landmark selection, 386 (74.7%) patients were eligible for the clinical outcomes analysis. 40.4% were NSCLC, 42.2% were melanoma, 15.3% renal cell carcinoma and 2.1% other malignancies. 76 patients (19.7%) experienced early ir-fatigue (within 1 month from treatment commencement), while 150 patients (38.9%) experienced delayed ir-fatigue. Early ir-fatigue was significantly related to shortened PFS (HR = 2.29 [95% CI 1.62-3.22], p < 0.0001) and OS (HR = 2.32 [95% CI 1.59-3.38], p < 0.0001) at the multivariate analysis. On the other hand, we found a significant association between the occurrence of early ir-fatigue, ECOG-PS ≥ 2 (p < 0.0001), and disease burden (p = 0.0003). Delayed ir-fatigue was not significantly related to PFS nor OS. CONCLUSIONS: Early ir-fatigue seems to be negative prognostic parameter, but to proper weight its role we must to consider the predominant role of performance status, which was related to early ir-fatigue in the study population.

Correlations Between the Immune-related Adverse Events Spectrum and Efficacy of Anti-PD1 Immunotherapy in NSCLC Patients.

BACKGROUND: Immune-related adverse events (irAEs) developed during immunotherapy with anti-PD-1 agents, could be a predictive surrogate marker of clinical benefit in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Patients with NSCLC, treated with anti-PD-1 agents, were retrospectively evaluated. Univariate and multivariate analyses were performed to evaluate the relationships between types of irAEs (differentiated according to system/organ involved and to single-site/multiple-site), overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). We further performed a 6-week landmark analysis. RESULTS: A total of 559 patients were enrolled; 231 patients (41.3%) developed irAEs of any grade and 50 patients (8.9%) G3/G4 events; 191 of them (82.6%) developed "single-site" irAEs and 40 (17.4%) "multiple-site" irAEs. At multivariate analysis, higher ORR was related to irAEs of any grade (P < .0001), "single-site" irAEs (P < .0001), endocrine (P = .0043) and skin irAEs (P = .0005). Longer PFS was related to irAEs of any grade (P < .0001), "single-site" irAEs (P < .0001), "multiple-site" irAEs (P = .0374), endocrine irAEs (P = .0084) and skin irAEs (P = .0001). Longer OS was related to irAEs of any grade (P < .0001), "single-site" irAEs (P < .0001), endocrine irAEs (P = .0044), gastrointestinal irAEs (P = .0437), skin irAEs (P = .0006), and others irAEs (P = .0378). At the 6-week landmark analysis, irAEs of any grade was confirmed an independent predictor of higher ORR, longer PFS, and longer OS. CONCLUSION: Our study confirmed that irAEs are concordantly related to higher ORR, longer PFS, and longer OS with anti-PD-1 immunotherapy in patients with NSCLC.

A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable.

BACKGROUND: Recent evidence suggested a potential correlation between overweight and the efficacy of immune checkpoint inhibitors (ICIs) in cancer patients. PATIENTS AND METHODS: We conducted a retrospective study of advanced cancer patients consecutively treated with anti-PD-1/PD-L1 inhibitors, in order to compare clinical outcomes according to baseline BMI levels as primary analysis. Based on their BMI, patients were categorized into overweight/obese (≥ 25) and non-overweight (< 25). A gender analysis was also performed, using the same binomial cut-off. Further subgroup analyses were performed categorizing patients into underweight, normal weight, overweight and obese. RESULTS: Between September 2013 and May 2018, 976 patients were evaluated. The median age was 68 years, male/female ratio was 663/313. Primary tumors were: NSCLC (65.1%), melanoma (18.7%), renal cell carcinoma (13.8%) and others (2.4%). ECOG-PS was ≥2 in 145 patients (14.9%). PD-1/PD-L1 inhibitors were administered as first-line treatment in 26.6% of cases. Median BMI was 24.9: 492 patients (50.6%) were non-overweight, 480 patients (50.4%) were overweight/obese. 25.2% of non-overweight patients experienced irAEs of any grade, while 55.6% of overweight/obese patients (p < 0.0001). ORR was significantly higher in overweight/obese patients compared to non-overweight (p < 0.0001). Median follow-up was 17.2 months. Median TTF, PFS and OS were significantly longer for overweight/obese patients in univariate (p < 0.0001, for all the survival intervals) and multivariate models (p = 0.0009, p < 0.0001 and p < 0.0001 respectively). The significance was confirmed in both sex, except for PFS in male patients (p = 0.0668). CONCLUSIONS: Overweight could be considered a tumorigenic immune-dysfunction that could be effectively reversed by ICIs. BMI could be a useful predictive tool in clinical practice and a stratification factor in prospective clinical trials with ICIs.

Clinical Outcomes of Patients with Advanced Cancer and Pre-Existing Autoimmune Diseases Treated with Anti-Programmed Death-1 Immunotherapy: A Real-World Transverse Study.

BACKGROUND: Patients with a history of autoimmune diseases (AIDs) have not usually been included in clinical trials with immune checkpoint inhibitors. MATERIALS AND METHODS: Consecutive patients with advanced cancer, treated with anti-programmed death-1 (PD-1) agents, were evaluated according to the presence of pre-existing AIDs. The incidence of immune-related adverse events (irAEs) and clinical outcomes were compared among subgroups. RESULTS: A total of 751 patients were enrolled; median age was 69 years. Primary tumors were as follows: non-small cell lung cancer, 492 (65.5%); melanoma, 159 (21.2%); kidney cancer, 94 (12.5%); and others, 6 (0.8%). Male/female ratio was 499/252. Eighty-five patients (11.3%) had pre-existing AIDs, further differentiated in clinically active (17.6%) and inactive (82.4%). Among patients with pre-existing AIDs, incidence of irAEs of any grade was significantly higher when compared with patients without AIDs (65.9% vs. 39.9%). At multivariate analysis, both inactive (p = .0005) and active pre-existing AIDs (p = .0162), female sex (p = .0004), and Eastern Cooperative Oncology Group Performance Status <2 (p = .0030) were significantly related to a higher incidence of irAEs of any grade. No significant differences were observed regarding grade 3/4 irAEs and objective response rate among subgroups. Pre-existing AIDs were not significantly related with progression-free survival and overall survival. CONCLUSION: This study quantifies the increased risk of developing irAEs in patients with pre-existing AIDs who had to be treated with anti-PD-1 immunotherapy. Nevertheless, the incidence of grade 3/4 irAEs is not significantly higher when compared with control population. The finding of a greater incidence of irAEs among female patients ranks among the "hot topics" in gender-related differences in immuno-oncology. IMPLICATIONS FOR PRACTICE: Patients with a history of autoimmune diseases (AIDs) have not usually been included in clinical trials with immune checkpoint inhibitors but are frequent in clinical practice. This study quantifies the increased risk of developing immune-related adverse events (irAEs) in patients with pre-existing AIDs who had to be treated with anti-programmed death-1 immunotherapy. Nevertheless, their toxicities are mild and the incidence of grade 3/4 irAEs is not significantly higher compared with those of controls. These results will help clinicians in everyday practice, improving their ability to offer a proper counselling to patients, in order to offer an immunotherapy treatment even to patients with pre-existing autoimmune disease.

A Delphi consensus and open debate on the role of first-line bevacizumab for HER2-negative metastatic breast cancer.

To gain consensus on the role of bevacizumab plus paclitaxel as first-line treatment for HER2-negative metastatic breast cancer, a panel of expert oncologists experienced in treating patients with metastatic breast cancer in Italy participated in a Delphi consensus study. The panel reached a full consensus on the efficacy of bevacizumab plus paclitaxel and the clinical meaningfulness of the progression-free survival benefit compared with paclitaxel alone, despite the lack of an overall survival effect in clinical trials. The participants agreed that real-world data support the effectiveness and well-defined safety profile of the regimen. Views on the use of bevacizumab plus paclitaxel in specific patient populations were not unanimous and clinical judgment remains important. Nevertheless, a high level of agreement was reached.

Patient and caregiver needs in oncology. An Italian survey.

AIMS AND BACKGROUND: Cancer is a disease that has far-reaching consequences for patients and their families. The present study targets unmet caregiver needs so that better support can be provided and planned for. METHODS: The first phase of the study was to conduct a survey designed to explore basic needs (medical and nursing information, psychological support, social welfare). The survey also investigated the caregiver's personal details (age, sex, degree of kinship). The survey was distributed to caregivers coming to the day hospitals of the 4 oncology departments involved in the study. RESULTS: A total of 137 relatives of cancer patients completed the survey. Among the explored needs, the most recurrent was the availability of a doctor who provides full information on the treatment choices. A further important request was for consistency between the information provided by doctors and that provided by other health-care workers, with specific reference to a patient-centered approach that can be easily and fully understood, available therapeutic options especially at home, and prognosis. CONCLUSIONS: The study showed that the need for exhaustive and simple information provided by a referral physician is still an unmet need in the Internet age.

Compliance with breast and cervical cancer screening programs in women: results from a population-based study.

AIMS AND BACKGROUND: Women's adherence to mammography and PAP test screening guidelines is a fundamental topic regarding women's health. The aim of the study was to evaluate the knowledge and compliance to breast and cervical cancer screening programs in women living in three Italian towns, where a public screening program, consisting of free mammography every two years and free PAP test every three years, is ongoing. METHODS: An anonymous survey was mailed to a random sample of women. Eight 120-min focus discussions with groups of women exploring perceptions, knowledge and practices were carried out after analysis of the returned surveys. RESULTS: Replies were received from 1345 women (response rate, 27%). Almost every woman knew of the screening program, but women's practice of mammography was age-dependent: up to 72% of the women performed it before the age of 50. Conversely, the age of the first PAP test was rather late: up to 70% of the women performed it at over 30 years of age. Women with a lower educational level reported being screened less than those with a higher level. During the group discussions, women's perceptions, knowledge and beliefs regarding cancer and screening, together with aspects of the health care system, appeared to strongly influence the preventive practices. Many women deplored being infrequently instructed by health professionals. CONCLUSIONS: Despite the limitations of the study due to the low response rate, we believe that health professionals should invest on encouraging factors and reduce the deterring factors to optimize screening practices.

Phase II study of pharmacogenetic-tailored therapy in elderly colorectal cancer patients.

BACKGROUND: Retrospective analyses suggested that a pharmacogenetic approach may allow a tailored selection of chemotherapy for metastatic colorectal cancer. AIM: We conducted a phase II study of pharmacogenetic-selected first-line chemotherapy in elderly patients with advanced colorectal cancer, with the aim to improve efficacy and to reduce toxicity in this group of patients. METHODS: 24 patients were enrolled in this study. Chemotherapy regimen was prospectively assigned based on TS, DPD, ERCC-1 and UGT1A1 genotyping results. Twelve patients (50%) were treated with modified FOLFIRI, 11 patients (46%) with modified FOLFOX6 and 1 (4%) with De Gramont regimen. RESULTS: A partial remission was obtained in 4 cases (17%), stable disease in 8 cases (33%) and progressive disease in 12 cases (50%). Grade 3-4 neutropenia was observed in 7 patients (29%) and diarrhoea in 3 cases (12%). The trial was then interrupted according to study design requiring 13 partial remissions out of the first 24 patients enrolled as the necessary response rate level in order to continue. CONCLUSION: Prospective selection of chemotherapy based on TS, DPD, ERCC-1 and UGT1A1 expression in elderly advanced colorectal cancer patients failed to confirm previous results. A more accurate validation of retrospective findings is warranted before these molecular markers can be used for treatment selection in the clinical practice.

The role of HER-3 expression in the prediction of clinical outcome for advanced colorectal cancer patients receiving irinotecan and cetuximab.

Preclinical data suggested that, in the presence of human epidermal growth factor receptor (HER)-3-altered activation, colorectal cancer cells may escape anti-epidermal growth factor receptor (EGFR)-mediated cell death. HER-3 overexpression may then represent a key factor for resistance to anti-EGFR antibodies in colorectal cancer. The aim of our analysis was to investigate a possible correlation between HER-3 expression and clinical outcome in wild-type K-RAS advanced colorectal cancer patients receiving cetuximab and irinotecan. We retrospectively analyzed immunoreactivity for HER-3 in wild-type K-RAS advanced colorectal cancer patients receiving irinotecan and cetuximab. Eighty-four advanced wild-type K-RAS colorectal cancer patients were available for HER-3 analysis. Forty patients (48%) had a HER-3(-) colorectal tumor, whereas the remaining 44 cases (52%) were deemed HER-3(+). In patients with HER-3(-) and HER-3(+) tumors, we observed a partial response in 17 (42%) and eight (18%) patients respectively; progressive disease occurred in 11 (35%) and 26 (53%) patients with HER-3(-) and HER-3(+) tumors, respectively (p = .003). The median progression-free survival time was 6.3 months in patients with HER-3(-) tumors and 2.8 months for those who had HER-3-overexpressing tumors (p < .0001). The median overall survival time was 13.6 months in patients showing HER-3(-) tumors and 10.5 months for those who had HER-3-expressing tumors (p = .01). HER-3 proved to be a predictive factor for clinical outcome in wild-type K-RAS colorectal cancer patients treated with cetuximab. Combined HER-3 and K-RAS analysis may represent an effective strategy for better selection of responding colorectal cancer patients.

Pegylated liposomal doxorubicin, 5-fluorouracil and cisplatin versus mitomycin-C, 5-fluorouracil and cisplatin for advanced gastric cancer: a randomized phase II trial.

PURPOSE: Clinical data suggested that a regimen incorporating doxorubicin to 5-fluorouracil (5-FU) and cisplatin may be more effective but probably quite toxic for advanced gastric cancer patients. With the aim to maintain efficacy while reducing toxicity, we compared the activity and safety of a combination of 5-FU, cisplatin and pegylated liposomal doxorubicin with a combination of 5-FU, cisplatin and mitomycin-C. PATIENTS AND METHODS: Seventy-eight patients were randomised to receive 5-FU (400 mg/m(2) bolus, 600 mg/m(2) 22 h continuous infusion day 1 and 2) and cisplatin (50 mg/m(2) day 1) every 2 weeks, combined either with pegylated liposomal doxorubicin (20 mg/m(2) day 1 every two weeks) (arm A) or mitomycin-C (7 mg/m(2) every 6 weeks) (arm B). RESULTS: The overall response rate was 64.1% in arm A and 38.5% in arm B (P = 0.041). The median time to tumour progression and overall survival were 7.93 and 5.14 months (P = 0.04) and 12.1 and 8.3 months (P = 0.02) in arm A and B, respectively. Fourteen patients in arm A and 18 patients in arm B experienced a grade 3/4 toxic effect. CONCLUSIONS: A combination of pegylated liposomal doxorubicin, cisplatin and 5-FU can be safely administered in gastric cancer patients with a promising efficacy profile.

Insulin-like growth factor 1 expression correlates with clinical outcome in K-RAS wild type colorectal cancer patients treated with cetuximab and irinotecan.

Seventy to 40% of K-RAS wild type colorectal tumors does not seem to benefit from treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies. Recent data suggested that in presence of IGF-1 system, altered activation colorectal cancer cells may escape anti-EGFR mediated cell death. The interaction between IGF-1 expression and K-RAS mutational analysis was tested to verify the ability of IGF-1 to identify a subgroup of patients more likely to benefit from EGFR-targeted antibodies treatment. IGF-1 expression and K-RAS mutational status was assessed in advanced colorectal cancer patients receiving irinotecan/cetuximab. One hundred twelve patients were analyzed. IGF-1 was negative in 30 patients (27%) and overexpressed in the remaining 82 cases (73%). In IGF-1 negative and IGF-1 positive tumors, we observed progressive disease in 9 (30%) and 55 (67%) patients, respectively (p = 0.001). Median progression-free survival was 7.5 mo in patients showing IGF-1 negative tumors and 3 mo for IGF-1 expressing tumors (p = 0.002). Among K-RAS wild type patients, IGF-1 negative and positive tumors showed a partial response to cetuximab-irinotecan in 13 (65%) and 11 (22%) cases, respectively (p = 0.002). Median progression-free survival in IGF-1 negative tumors was 10 mo and 3.2 mo in IGF-1 positive colorectal cancers (p = 0.02). IGF-1 proved to be a possible predictive factor for resistance to anti-EGFR monoclonal antibodies in K-RAS wild type colorectal cancer. Combined IGF-1 and K-RAS analysis may represent an effective strategy for a better selection of responding colorectal cancer patients.

COX-2 and NF-KB overexpression is common in pancreatic cancer but does not predict for COX-2 inhibitors activity in combination with gemcitabine and oxaliplatin.

OBJECTIVE: The attempt to improve therapeutic results in pancreatic carcinoma has recently focused on the emerging role of molecular biology. We investigated the role of COX-2 and NF-KB expression in relation to the use of a COX-2 inhibitor (celecoxib) associated to gemcitabine and oxaliplatin in pancreatic cancer. METHODS: Forty-four patients with histologically or cytologically verified, locally advanced unresectable and/or metastatic pancreatic carcinoma were eligible for the study. RESULTS: Thirty-three patients (75%) assumed celecoxib for all their treatment period. Treatment was repeated every 2 weeks, until there was evidence of disease progression, patient refusal, or unacceptable toxicity. Efficacy was assessed according to tumor response, clinical benefit, and time-related parameters. Five patients had a partial response, 24 had a stable disease, and 15 had a disease progression, for an overall response rate of 11%. Biochemical response rate based on CA 19.9 levels showed 2 complete and 10 partial responses, whereas 31 patients presented no changes of CA 19.9 levels. COX-2 protein expression was found in 30 tumors, while a moderate or weak/absent expression was present in 10 patients. Sixteen tumors showed a strong expression for NF-KB, 4 a moderate expression, and 5 a weak/absent expression. CONCLUSION: The use of a COX-2 inhibitor does not add any valuable activity to a gemcitabine/oxaliplatin combination, even in patients with COX-2 and NF-KB overexpressing tumors.