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Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. Methods: In this randomised, open-label, phase 3 study, patients aged 18–65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1–2, 4–5, 8–9, and 11–12 in the VTD regimen, and 40 mg on days 1–4 and 9–12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2–131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28–41) compared with 17% (13–23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50–0·77]; p

Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICI) are lacking.We performed a retrospective multicenter study to characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in advanced cancer patients. IrAEs were categorized into “early” (≤12 months) and “late” (>12 months).From September 2013 to October 2019, 436 consecutive patients were evaluated. 223 experienced any grade early-irAEs (51.1%), while 132 experienced any grade late-irAEs (30.3%) (p < 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, while 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced G3/G4 irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95%CI: 2.8-4.2), while 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 (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). Also the time-adjusted cumulative risk of death according to 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.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.

The novel severe acute respiratory syndrome coronavirus-2 pandemic is a global health problem, which started to affect China by the end of 2019. In Europe, Italy has faced this novel disease entity (named novel coronavirus disease [COVID-19]) first and severely. COVID-19 represents a significant hurdle for public health services and a potential harm for patients with cancer. The Collegio Italiano dei Primari Oncologi Medici (CIPOMO) is an Italian association of head physicians in oncology departments, which promotes working and research activities in oncology on a national basis. In the midst of the epidemic in Italy, the CIPOMO promoted a national survey aiming to evaluate the impact of COVID-19 on clinical activity of oncologists and the implementation of containment measures of COVID-19 diffusion. Overall, 122 head physicians participated in this survey, with a homogeneous distribution on the national territory. Results show that the following measures for oncologic patients have been promptly implemented through the whole country: use of protective devices, triage of patients accessing the hospital, delay of non-urgent visits and use of telemedicine. Results of this survey suggest that Italian oncology departments have promptly set a proactive approach to the actual emergency. Oncologists need to preserve the continuum of care of patients, as the benefit of ensuring a well-delivered anti-cancer treatment plan outweighs the risk of COVID-19 infection. International cooperation is an important starting point, as heavily affected nations can serve as an example to find out ways to safely preserve health activity during the pandemic.

Approximately 10% of metastatic colorectal cancer (mCRC) cases will harbor the BRAF p.V600E mutation (BRAF-mCRC) and have been associated with a poor prognosis. Although they are usually considered a unique clinical entity, biologic heterogeneity has been described. We performed an extensive clinicopathologic study of a multicenter series of BRAF-mCRC to highlight differences between tumors with microsatellite instability (MSI) and microsatellite stable tumors, focusing on both inflammatory profiles and neuroendocrine differentiation.We included 59 BRAF-mCRC cases and collected the clinical data (ie, surgery, treatment, and follow-up). We evaluated MSI status, budding, lympho-angioinvasion, neuroinvasion, extent of active stroma, CD3The 22 MSI BRAF-mCRC cases were associated with the right side (P .0001), an expansive grown pattern (P .01), programmed cell death ligand 1 expression (P .0001), high CD8 T-cell content (P = .0001), and lymph node metastases (P .029). The 37 MSS BRAF-mCRC cases were characterized by a greater stromal component (P = .0002), pulmonary metastases (P = .095), and p53 and synaptophysin immunoreactivity (P = .004 and P = .001, respectively). Univariate analysis demonstrated that MSI and a high CD8 T-cell content were associated with a 34% (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.34-1.28; P = .2) and 33% (HR, 0.67; 95% CI, 0.45-0.99; P = .04) reduction in the risk of death, respectively. The combined presence of MSI and CD8 T-cell content decreased the hazard of mortality ≤ 63% (HR, 0.37; 95% CI, 0.14-0.97; P = .2), which was slightly reduced after multivariate analysis.A simultaneous evaluation of MSI, CD8 T-cell content, and neuroendocrine markers could allow for the identification of subsets of BRAF-mCRC with a different prognosis and potential eligibility for specific treatments.

We analyzed the clinicopathological, immunohistochemical and cytogenetic features of 106 extranodal (EN) diffuse large B-cell lymphomas (DLBCLs) from stomach (34 cases), intestine (10), cervico-cephalic region (11), central nervous system (13), testes (21), skin (8), and miscellaneous sites (9). Hans’ algorithm and the immunohistochemical double expressor score (DES) for MYC and BCL2 were applied to all cases. A subset of fifty-eight cases were analyzed with fluorescent in situ hybridization (FISH) with specific break apart probes for BCL6, MYC, BCL2, CCND1, BCL10 and MALT1 genes. Clinical records were available for all patients. The immunohistochemical study showed that, in our series of EN-DLBCLs, the Hans’ subgroup and the DES differed significantly according to the site of origin. At FISH analysis, BCL6 and BCL2 were the most commonly rearranged genes in non-GC and in GC cases, respectively. Gastrointestinal lymphomas displayed the highest rate of gene rearrangements, often with MYC involvement. One testicular DLBCL showed BCL2/MYC double hit. At survival analysis, cerebral and testicular origin was associated with poor prognosis. In addition, Hans’ subgroup and other immunohistochemical markers influenced patients’ outcome. In conclusion, our data suggest that immunophenotypic, genetic and survival characteristics of EN-DLBCL are related to the specific primary site of the disease.

In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women.We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4-6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2·5 mg/day orally for 5 years) or intermittent use of letrozole (2·5 mg/day orally for 9 months followed by a 3-month break in years 1-4 and then 2·5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing.Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53-72), disease-free survival was 85·8% (95% CI 84·2-87·2) in the intermittent letrozole group compared with 87·5% (86·0-88·8) in the continuous letrozole group (hazard ratio 1·08, 95% CI 0·93-1·26; p=0·31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3-5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3-5 CNS cerebrovascular ischaemia, 16 (nine [1%] vs seven [1%]) had grade 3-5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3-5 cardiac ischaemia. In total, 23 (1%) of 4851 patients died while on trial treatment (13 [1%] of 2417 patients in the intermittent letrozole group vs ten [1%] of 2411 in the continuous letrozole group).In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them.Novartis and the International Breast Cancer Study Group.

Aim Little scientific evidence is available on the costs of targeted genetic testing and surveillance programmes for the identification of hereditary colorectal cancers (HCRC). The present study is a cost analysis of an intensive surveillance programme with and without the use of genetic testing, carried out in a province of northern Italy. Additionally, cancer care using an intensive surveillance programme for gene carrier subjects was compared to cancer care in subjects not selected for genetic testing who followed unselective clinical surveillance. Methods A model based on epidemiological factors was developed to estimate the incidence of gene carriers for Lynch Syndrome. A hypothetical cohort of 98 healthy people with a high cancer risk (due to being carriers of a pathogenetic MMR mutation) was followed over a period of ten years. To evaluate the economic burden of using genetic testing, a cost analysis was performed. Results Despite genetic testing causing an initial increase in costs, their use within an intensive surveillance programme generated a saving of 24%, thanks to a better selection of individuals at high risk of colorectal cancers (CRC). This resulted in reduced resource consumption and in an overall saving of 36%, when considering the treatment of patients developing a genetic cancer, as compared to an unselective clinical surveillance. Conclusions Identification of HCRC led to surveillance that is more effective and could prevent premature death of patients affected by the most common hereditary forms of CRC. This, in the long-term, could result in an overall reduction of cancer care costs.

Background Immunotherapy has become a standard of care for an increasing number of tumors. Patients have a chance of developing immune-related adverse events (irAEs). In general, irAEs occur quite early, mostly within weeks to 3 months after initiation of treatment. Being drugs relatively innovative, “late” irAEs are still unknown. Methods We conducted a multicenter retrospective study of advanced cancer patients (any histology, regardless of treatment line) treated with anti-PD-1/PD-L1 (mono)immunotherapy, with a minimum time to treatment failure (TTF) of 12 months. IrAEs were categorized into “early” ( Results We evaluated 318 consecutive patients treated with immunotherapy from September 2013 to August 2018. Median age was 68.6 years (32-90). 175 patients (55.5%) experienced any grade early-irAEs, while 110 (34.6%) experienced any grade late-irAEs (p = 0.0013); 13 patients (4.1%) experienced G3/G4 early-irAEs, while 12 (3.8%) G3/G4 late-irAEs (p = 0.8446). There was a significant association between the occurrence of any grade early-irAEs and late-irAEs (p = 0.0452), as well as between G3/G4 early-irAEs and late-irAEs (p = 0.0251). Among patients who experienced early-irAEs, 63 (36%) experienced “multiple-site” irAEs (multiple sites/organs), while 17 patients (15.4%) experienced multiple-site late-irAEs (p = 0.0040). The median period of follow-up was 22.2 months. The median time to irAEs onset were 3.1 and 16.1 months for early- and late-irAEs, respectively. Late irAEs were not significantly related to TTF; on the other hand, were significantly related to a prolonged OS. When adjusted for primary tumor, late-irAEs were confirmed to be significantly related to a prolonged OS (HR = 0.25 [95%CI:0.11-0.55]; p = 0.0006). Conclusion Late-irAEs among long responders seem to have a mild/moderate incidence. They are mostly non-serious and clinical manageable, with a low rate of treatment discontinuation. In this positive-selected population, the occurrence of any grade late-irAEs seems to be furtherly related to a prolonged OS. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Hyponatremia (serum sodium concentration [Na+] Methods ASSERT was a prospective, observational, non-interventional study conducted from October 2015 to June 2017 in cancer patients requiring treatment for hyponatremia secondary to SIADH at 18 Italian oncology centres. Management of hyponatremia primarily included water restriction, tolvaptan and hypertonic saline, in accordance with local standard of care/guideline recommendations. The primary endpoint was change in serum [Na+] from baseline visit to end of the first month of the observational period, or earlier discontinuation. Results The full analysis set (FAS) included 68 adult cancer patients (lung cancer, n = 48, SCLC, n = 33). Group 1 patients received ≥1 dose of tolvaptan during the observational period; Group 2 patients did not receive tolvaptan. Overall survival (FAS) was significantly higher in Group 1 vs Group 2 (median 123 vs 56 days; p = 0.001), as was mean survival (299.4 vs 74.9 days; p = 0.001). In a linear regression analysis of the relationship between sodium levels and tolvaptan dose intensity for the lung cancer and SCLC cohorts, dose intensity correlated significantly with clinical response after 6 months of treatment in both cohorts (p = 0.005 and p = 0.023, respectively). In the lung cancer cohort, a significantly higher percentage of patients achieved serum [Na+] ≥130 mmol/L in Group 1 vs Group 2 during 6 months of follow-up (Group 1, 87.5% vs Group 2, 62.5%; p = 0.033). These results were similar to those observed in the FAS. Conclusions Hyponatremia secondary to SIADH is a potentially modifiable risk factor, which might be implicated in the survival of lung cancer patients. Correction of hyponatremia may be preferentially achieved with pharmacological treatment, rather than the non-pharmacological approaches routinely used in clinical practice. Clinical trial identification NCT102573077. Editorial acknowledgement Sarah Stowell PhD, CMPP of Ashley Medical Communications, funded by Otsuka Pharmaceutical Europe Ltd. Legal entity responsible for the study Otsuka Pharmaceutical Italy Srl. Funding Otsuka Pharmaceutical Italy Srl. Disclosure R. Berardi: Honoraria (self), Advisory / Consultancy: Otsuka Pharmaceutical. C. Ferrara: Full / Part-time employment: Otsuka Pharmaceutical Italy. M.G. Giustra: Full / Part-time employment: Otsuka Pharmaceutical Italy. R. Evans: Full / Part-time employment: Otsuka Pharmaceutical Europe. All other authors have declared no conflicts of interest.

Background: This clinical trial assessed the efficacy of pemetrexed combined with oxaliplatin (PEMOX) in patients with advanced gastric cancer (AGC). Patients and methods: Forty-four patients with untreated AGC were enrolled to evaluate response rate (RR). Patients received pemetrexed (500 mg/m2) with vitamin supplementation and oxaliplatin (120 mg/m2) every 21 days for six cycles or until disease progression occurred. Results: Median age was 62 years (range 26–76). The majority of patients (93%) had metastatic disease. Sixteen of the 44 patients achieved confirmed response [RR 36%; 95% confidence interval (CI) 22% to 52%]; four complete responses and 12 partial responses (complete and partial responses according to the RECIST guidelines are the confirmed-responses observed in the study population). Median time to tumor progression (TTP) was 6.2 months (95% CI 4.3–7.5) and median survival was 10.8 months (95% CI 7.7–17.2). A total of 220 cycles were administered, with a median of six cycles. Most common grade 3/4 toxic effects were neutropenia in 41% of patients (19% of cycles) and thrombocytopenia in 11% of patients (4% of cycles). Treatment delays or dose reductions for toxicity occurred in 10% and 5% of cycles, respectively. Conclusions: PEMOX is active and well tolerated in AGC. RR, TTP, and survival were comparable to those achieved in studies using different 5-fluorouracil (5-FU)–oxaliplatin combinations, without the inconvenience of prolonged 5-FU schedules.

sOncologia,Ospedale 'Infermi', Rimini, Italy Summary Background: The definition of prognostic parameters in early stages of gastric lymphoma is still controversial. The aim of this retrospective analysis was to assess the value of the stagemodified international prognostic index (IPI) in predicting the outcome of a large, consecutive series of patients with PGL of diffuse large B-cell histology (DLCL). Patients and methods: Three hundred twelve consecutive, newly-diagnosed, patients with localized PGL (stages I-IIE according to the 'Lugano staging system for GI lymphomas') referred from April 1972 to December 1997 to eight Italian and one Swiss centers were reviewed and their outcomes updated to June 1998. One hundred three patients were treated with single-modality therapy, while two hundred four received combined-modality treatment, most of which included surgery and short-term chemotherapy. Results: After a median follow-up of 66 months (range 0.6300 months), 195 (64%) were alive in first continuous complete remission (CCR). The five-year estimates of overall survival (OS) and event-free survival (EFS) were 75% and 67%, respectively. OS and EFS varied according to IPI, from, respectively, 90% and 82% for patients with 0-1 risk factors, to 40% and 35% for patients with ^3 risk factors (P = 0.00001). Cox regression analysis showed that IPI was the strongest predictor of survival. Conclusions: This study shows that stage-modified IPI is an effective predictive model in patients with primary DLCL of the stomach, enabling identification of patients with significantly different outcomes.

BACKGROUND The term mantle cell lymphoma (MCL) describes a subtype of non-Hodgkin's lymphoma that includes those lymphomas previously defined as centrocytic lymphoma, intermediate lymphocytic lymphoma, and mantle zone lymphoma. Since MCL has only recently been recognised as a distinct entity, the clinical literature is sparse and very little information is available about its treatment. PATIENTS AND METHODS We retrospectively attempted to analyse the clinical features and outcome of 65 patients with mantle cell lymphoma (MCL) treated from 1979 to 1993 at two institutions in the same geographic area. Univariate (Log-rank test) and multivariate (Cox regression) analyses of the major prognostic factors were performed. RESULTS At the time of analysis the median follow-up was 49 months. Median age was 64 years with a range of 27-85 years. The male to female ratio was 2:1. Forty-seven patients (72%) had stage IV at presentation and 20 (31%) had B-symptoms at presentation. The patients usually presented with generalised adenopathy (78% of cases) and bone marrow involvement (58%). Serum LDH were analysed at diagnosis in 61 patients and found to be elevated in 30%. beta 2-Microglobulin was determined at presentation in 42 patients and was higher than normal in 54% of them. In comparison with the other subtypes of NHLs in our series, MCL appears to have a very poor survival pattern. The median overall survival was 42 months. The CR rate was 51% with a median DFS of 44 months. Good performance status, normal LDH, normal beta 2-microglobulin, younger age (< 65 years), and a low prognostic risk according to the International Index were significantly associated (p < 0.05) with a better outcome. CONCLUSIONS The characteristics of the patients in this study appear to be in general agreement with those in most of the previously reported series except for the somewhat lower rate of bone marrow infiltration observed in this series. Despite the limitations of a retrospective analysis and the lack of randomization between the treatment options, this study seems to suggest a survival advantage with anthracycline-containing regimens in some patients with MCL. However, this benefit was evident only for the patients with favourable International Index prognostic scores (i.e., low- and to low-intermediate-risk disease) who may already have a better prognosis. Patients with intermediate-high and high-risk disease according to the International Index have a poor prognosis regardless of the type of therapy given.

Various reports have documented the efficacy of the combination of etoposide, doxorubicin and cisplatin (EAP) in the treatment of advanced gastric cancer, although other studies have not confirmed such results. This multicentre phase II study was designed to try to define the efficacy and tolerability of the original EAP regimen. From January 1990 to May 1992, 96 patients with locally advanced or metastatic gastric cancer were treated every 3 weeks with etoposide (120 mg/m2) on days 4, 5 and 6, doxorubicin (20 mg/m2) on days 1 and 7, and cisplatin (40 mg/m2) on days 2 and 8. All of the patients had measurable lesions, and were to receive a maximum of six cycles. A total of 416 courses was given (median four/patient), 27% with a delay of > or = 2 weeks. Objective responses were achieved in 34 of the 91 evaluable patients (37%: confidence interval 27-47%), with complete response (CR) in 11 (12%) and partial response (PR) in 23 (25%). The median duration of response was 6 months (range 1-19), and the median survival of the 96 eligible patients was 9 months. Side-effects (WHO grade 3-4) were leucopenia (30%), thrombocytopenia (9%) and mucositis (10%). We conclude that the EAP regimen is active in inducing major objective responses (12% of CR), and that treatment is feasible in patients with good performance status.

P084 Feasibility study to examine underlying mechanisms for “Chemo Fog” V. Jenkins *, H. Harder, M. Cercingani, H. Whiteley-Jones, R. Thwaites, L. Mullen, N. Harrison, K. Davies, C. Zammit, S. Sacre. SHORE-C Brighton & Sussex Medical School, University of Sussex, Brighton, United Kingdom, CISC Brighton & Sussex Medical School, University of Sussex, Brighton, United Kingdom, Brighton & Sussex Medical School, University of Sussex, Brighton, United Kingdom, Breast Surgery, Brighton & Sussex University Hospitals, Brighton, United Kingdom