Total neoadjuvant therapy (TNT) incorporates (chemo)-radiotherapy ((C)RT) and chemotherapy (ChT) prior to surgery for locally advanced rectal cancer (LARC). Recent phase 3 trials reported that this approach improves pathologic complete response rate and disease-specific survival by reducing the risk of metastatic progression. We report real-world data on tolerability and early outcome data of patients treated with TNT in our institution. Patients with LARC diagnosed and treated using the TNT approach at the Royal Free London between August 2017 and October 2022 were retrospectively identified from the radiotherapy planning system. Baseline demographic, clinic, imaging, and follow-up data were collated from electronic patient records. 43 patients were identified. Median age was 62 years (range 43-83). All patients had ECOG performance status 0-1. Rectal cancer staging was T3/T4 in 37 patients (86%) and 17 (40%) had N2 involvement on MRI. The majority of patients had high-risk features with 33 (77%) having threatened circumferential resection margin and 26 (60%) with radiological extramural vascular invasion. 5 patients (12%) had pelvic side wall lymph node disease. All except 3 patients had the RT-ChT sequence. 37 patients (86%) had long course CRT 45-50.4Gy in 25-28 fractions with concurrent capecitabine and 6 (14%) had short course RT 25Gy in 5 fractions. ChT regimens used were CAPOX (39 patients), FOLFOX (2), FOLFOXIRI (1) and 5-FU (1). Median number of cycles was 4 (range 3-8). 35 (81%) patients had a dose-reduction of ChT. Majority of dose reductions were for oxaliplatin due to concerns about long-term neurotoxicity. Grade 3+ toxicity occurred in 2 patients due to enterocolitis. Post-treatment MRI was done at median of 13 weeks and 23 weeks from start of radiotherapy. 22 patients (51%) had TRG1 (radiologic complete response (CR)) on post-TNT MRI. 9 patients opted to defer surgery and began active surveillance. Of these, 1 patient had a successful salvage surgery due to local progression. 26 surgical outcomes were available at point of analysis. Surgery was performed after a median of 11 weeks after the last chemotherapy. Median post-operative hospital stay was 11 days. 25 patients (96%) had an R0 resection and 8 patients (31%) had a pathologic CR. 5 patients received adjuvant ChT. At point of analysis 4 patients with MRI TRG1 without evidence of luminal disease on flexible sigmoidoscopy had surgery (including the patient with local progression following surveillance). Excluding the patient with progressive disease, 1 of 3 patients had evidence of residual disease on post-operative histology. After a median follow up of 17 months (range 7-59), 2 (5%) patients had local progression and 9 (21%) patients had distant metastatic progression. TNT approach for LARC was generally well-tolerated in this UK cohort with good completion rate of neoadjuvant treatment. In patients who underwent surgery, a high rate of R0 resection and complete pathologic response was seen despite majority of patients having a dose reduction of chemotherapy. Early outcomes in this high-risk rectal cancer cohort are similar to those reported in recent trials. Further follow-up is required to assess long-term oncological outcomes.

Evidence is lacking as to the impact of SARS-CoV-2 Omicron (B.1.1.529) variant in oncological patients. Capitalizing on OnCovid study data (NCT04393974), we analysed COVID-19 morbidity and case fatality rate at 28 days (CFR28) of unvaccinated patients across 3 phases defined following the evolution of the pandemic in Europe, according to date of COVID-19 diagnosis: "Pre-vaccination" phase (27/02/2020-30/11/2020), "Alpha-Delta variant" phase (01/12/2020-14/12/2021), "Omicron variant" phase (15/12/2021-31/01/2022). By the data lock of 04/02/2022, 3820 patients from 37 institutions across 6 countries were entered. Out of 3473 eligible patients, 2033 (58.6%), 1075 (30.9%) and 365 (10.5%) were diagnosed during the Pre-vaccination, Alpha-Delta and Omicron phases. In total 659 (61.3%) and 42 (11.5%) were unvaccinated in the Alpha-Delta and Omicron. Unvaccinated patients across the Omicron, Alpha-Delta and Pre-vaccination phases experienced similar CFR28 (27.5%, 28%, 29%). Following propensity score matching, 42 unvaccinated Omicron patients were matched with 122 and 121 patients from the Pre-vaccination and Alpha-Delta phases respectively, based on country of origin, sex, age, comorbidity burden, primary tumour, cancer stage and status, and the receipt of systemic anticancer therapy at COVID-19. Unvaccinated Omicron patients experienced improved COVID-19 outcomes in comparison to patients diagnosed during the Pre-vaccination phase. Morbidity and mortality were comparable to those of unvaccinated patients diagnosed during the Alpha-Delta phase.Table: 504POmicron vs Pre-vaccination OR (95%CI)Omicron vs Alpha-Delta OR (95%CI)CFR280.43 (0.19-0.94)0.56 (0.25-1.24Hospitalization0.30 (0.12-0.72)1.07 (0.46-2.51)Oxygen therapy0.39 (0.18-0.84)0.77 (0.35-1.66)COVID-19 complications0.47 (0.22-1.01)0.84 (0.39-1.79) Open table in a new tab Despite time-dependent improvements in outcomes reported in the Omicron phase, patients with cancer remain highly vulnerable to SARS-CoV-2 in absence of vaccinal protection. This study provides unequivocal evidence in support of universal vaccination of patients with cancer as a protective measure against morbidity and mortality from COVID-19.

Early reports from registry studies demonstrated high vulnerability of cancer patients from COVID-19, with case-fatality rates (CFR) >30% at the onset of the pandemic. With advances in disease management and increased testing capacity, the lethality of COVID-19 in cancer patients may have improved over time. The OnCovid registry lists European cancer patients consecutively diagnosed with COVID-19 in 35 centres from Jan 2020 to Feb 2021. We analysed clinical characteristics and outcomes stratified in 5 trimesters (Jan-Mar, Apr-Jun, Jul-Sep, Oct-Dec 2020 and Jan-Feb 2021) and studied predictors of mortality across 2 semesters (Jan-Jun 2020 and Jul 2020-Feb 2021). At data cut-off, the 2634 eligible patients demonstrated significant time-dependant improvement in 14-days CFR with trimestral estimates of 29.8%, 20.3%, 12.5%, 17.2% and 14.5% (p<0.0001). Compared to the 2nd semester, patients diagnosed in the Jan-Jun 2020 time period were ≥65 (60.3% vs 56.1%, p=0.031) had ≥2 comorbidities (48.8% vs 42.4%, p=0.001) and non-advanced tumours (46.4% vs 56.1%, p<0.001). COVID-19 was more likely to be complicated in Jan-Jun 2020 (45.4% vs 33.9%, p<0.001), requiring hospitalization (59.8% vs 42.1%, p<0.001) and anti-COVID-19 therapy (61.7% vs 49.7%, p<0.001). The 14-days CFR for the 1st and 2nd semester was 25.6% vs 16.2% (p<0.0001), respectively. After adjusting for gender, age, comorbidities, tumour features, COVID-19 and anti-cancer therapy and COVID-19 complications, patients diagnosed in the 1st semester had an increased risk of death at 14 days (HR 1.68 [95%CI: 1.35-2.09]), but not at 3 months (HR 1.10 [95%CI: 0.94-1.29]) compared to those from the 2nd semester. We report a time-dependent improvement in the mortality from COVID-19 in European cancer patients. This may be explained by expanding testing capacity, improved healthcare resources and dynamic changes in community transmission over time. These findings are informative for clinical practice and policy making in the context of an unresolved pandemic.

BACKGROUND:Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study. METHODS:In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets. RESULTS:We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p<0.01), recovering in survivors to pre-COVID-19 levels. Patients in poorer risk categories for each index except the PLR exhibited higher mortality rates (p<0.001) and shorter median overall survival in the training and validation sets (p<0.01). Multivariable analyses revealed the OIS to be most independently predictive of survival (validation set HR 2.48, 95% CI 1.47 to 4.20, p=0.001; adjusted concordance index score 0.611). CONCLUSIONS:Systemic inflammation is a validated prognostic domain in SARS-CoV-2-infected patients with cancer and can be used as a bedside predictor of adverse outcome. Lymphocytopenia and hypoalbuminemia as computed by the OIS are independently predictive of severe COVID-19, supporting their use for risk stratification. Reversal of the COVID-19-induced proinflammatory state is a putative therapeutic strategy in patients with cancer.

Background: The incidence and clinical significance of electrolyte abnormalities (EAs) in phase I studies is not well documented. The objective of this study is to evaluate the incidence of EAs, graded according to CTCAE v4.03, and its correlation with factors influencing them. Methods: A retrospective chart review was performed of 1088 cases in 82 phase 1 clinical trials consecutively treated from 2011 to 2015 at the Drug Development Unit, The Royal Marsden Hospital. Cox regression was used to examine the relationship between overall survival and baseline characteristics, treating the occurrence of grade 3/4 EAs as a time-varying covariate. Results: The most common EAs in all grades during trials are: hyponatremia 62%, hypokalemia 40%, hypophosphatemia 32%, hypomagnesemia 17% and hypocalcemia 12%. Overall, grade 3/4 EAs occurred in 19% of cases. More specifically, grade 3/4 EAs were observed, as follow: hyponatremia 10%, hypophosphatemia 6%, hypokalemia 5%, hypomagnesemia 1%, hypermagnesemia 1%. Grade 3/4 EAs occurred during the dose-limiting toxicity window in 8.73% of cases. Overall, diarrhea was associated with hypomagnesemia in all grades (HR 1.78, 95% CI: 1.32-2.39, p < 0.001), with G3/G4 hypokalemia (HR 1.93, 95% CI: 1.09-3.43, p = 0.02) and hyponatremia in all grades (HR 0.79, 95% CI: 0.67-0.93, p = 0.006). Vomiting was also associated with hypomagnesemia in all grades (HR 1.45, 95% CI: 1.08-1.95, p = 0.01) and G3/4 hypokalemia (HR 2.91, 95% CI: 1.62-5.23, p < 0.001). Baseline hypoalbuminemia, hyponatremia and female gender are associated with higher risk of developing other EAs during trial in the univariate analysis. Patients who developed G3/4 EAs during follow-up had a poorer median overall survival (OS) (26 weeks vs 37 weeks, HR = 1.61; 95% CI: 1.37-1.90; p < 0.001). Conclusions: Baseline EAs are common in patients with advanced cancers participating in phase I trials. This is the first study to demonstrate the clinical significance of baseline hypoalbuminemia and hyponatremia, which are predictors of development of other EAs in phase 1 patients. G3/4 EAs are adverse prognostic factors of OS independent of serum albumin levels. Legal entity responsible for the study: The Royal Marsden Hospital NHS Foundation Trust Funding: None Disclosure: J. de Bono: Consulting or advisory role: Astex, AstraZeneca, Genentech, Genmab, GSK, Merck, Pfizer, Sanofix. Research funding: AstraZeneca, Genentech, GSK, Sanofi, Janssen. U. Banerji: Receipt of grants/research supports: AstraZeneca, Chugai, Onyx, BTG. Receipt of honoraria or consultation fees: Astex, Karus Therapeutics, Novartis, Vernalis. All other authors have declared no conflicts of interest.

Background: BAL101553 is the prodrug of BAL27862, a novel small-molecule microtubule-targeting agent (MTA) with potent activity in tumor models refractory to conventional MTAs. It exerts antiproliferative effects and dose-dependent vascular disruption. A NSCLC xenograft mouse model demonstrated similar BAL27862 tumor exposure (AUC) at the MTD and a sub-MTD dose, with 11-fold higher peak intratumoral levels at the lower dose. Objectives of this first-in-human clinical trial were to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and to evaluate PK, PD and anti-tumor activity.

PURPOSETo investigate the prognostic significance of smoking in addition to established risk factors in patients with Dukes stage B and C colorectal cancer (CRC).METHODS291 consecutive non-selected CRC patients were studied retrospectively. Twenty-three variables were examined using a regression statistical model to identify relevant prognostic factors related to disease free survival (DFS) and overall survival (OS).RESULTSOn multivariate analysis DFS was found to be negatively affected in patients with a smoking history of ≤10 pack-years vs. non-smokers (p<0.016). Additionally, performance status (PS)<90 (p<0.001), Dukes stage C (p<0.001) and elevated tumor markers (p<0.001) at the time of diagnosis were found to adversely affect DFS. Smoking also had a significant association with relapse. Patients with a smoking history of ≤10 pack-years had 2.45 (p<0.018) higher risk of recurrence compared to patients with no smoking history. OS was influenced by Karnofsky performance status (PS), Dukes stage, and elevated tumor markers. In particular patients with PS< 90 had a 4.69-fold higher risk of death (p<0.001) than patients with better PS. Stage C disease was associated with 2.27-fold higher risk of death (p<0.001) than stage B disease, and patients with elevated tumor markers at the time of diagnosis had 2.74-fold higher risk of death (p<0.014) when compared to those whose tumor markers were normal at presentation.CONCLUSIONOur study associates smoking and relapse incidence in non-clinical- trial CRC patients and reiterates the prognostic significance of PS, stage and tumor markers at the time of diagnosis.

PURPOSE To investigate the overall survival (OS) of patients developing breast cancer (BC) after curative chemotherapy for non-Hodgkin's lymphoma (NHL) and to evaluate the possible effect on the patients' outcome of the expression of drug resistance-related proteins (P-glycoprotein-Pgp, multidrug resistance-associated protein-MRP, and multidrug resistance-related vault lung resistance protein-LRP) in BC issue. PATIENTS AND METHODS STUDY GROUP 25 female patients (median age 60 years, range 37-70) who developed BC after chemotherapy for high/intermediate grade B-cell NHL, treated with CHOP and achieving complete remission (CR). This group was further subdivided in subgroups A and B, according to the time interval between NHL and BC development (=24 and > 24 months, respectively). A matched-pair group of de novo BC patients formed the control group. BC tissue was immuno-histochemically stained for Pgp, MRP and LRP. RESULTS The median interval between NHL diagnosis and BC development was 26 months (range 9-49). In both groups 14 patients had tumor grade II; 16 were negative for steroid receptors; 17 overexpressed c-erbB-2; 14 were stage IIIA/B, and 11 stage IV. CMF or CNF (mitoxantrone instead of doxorubicin) were given for BC. Early progression was noticed in all study group patients for which second-line chemotherapy was instituted. There was a better response for stage IV patients in the control versus the study group (p=0.07). More prolonged OS was demonstrate for patients with stage III in the control group (median 51 months) and in subgroup B (median 47 months) than in subgroup A (median 16 months; p=0.00012), as well as for patients with advanced disease (p=0.0045). Development of BC < 24 months after NHL resulted in reduced OS (p=0.017). No difference was noticed in the expression of drug resistance proteins between the study and control group or between subgroups A and B. CONCLUSION BC developing shortly after a CR to NHL is an aggressive disease variant with minimal potential for response to conventional chemotherapy. Analysis of Pgp, MRP and LRP failed to demonstrate significant difference between the study and control group, although indications exist that drug resistance mechanisms might be part of the aggressive disease phenotype, contributing to the poor outcome.

PURPOSE To evaluate the effectiveness of 6-month therapy with leucovorin (LV)+5-fluorouracil (5-FU) versus 12-month therapy with levamisole (LVS)+5-FU, as adjuvant chemotherapy in patients with completely resected Aster-Coller stage B(2) or C(1)/C(2) rectal cancer (RC). PATIENTS AND METHODS One hundred and fifty patients with surgically resected RC were enrolled. Seventy patients with stage B(2) and 80 with stage C were randomly assigned to adjuvant chemotherapy with 5-FU+LXx6 months or 5-FU+LVSx12 months. Patient characteristics were equally balanced between the examined groups. Adjuvant chemotherapy consisted of LV 20 mg/m(2) intravenously (i.v.) plus 5-FU 450 mg/m(2) i.v. bolus every week plus LVS tablets 50 mg t.i.dx3 days every 2 weeks for 1 year. RESULTS After a median follow up for survivors of 8.7 years (range 1.8-10.5), all of the patients were evaluable. There were no significant differences between the two treatment groups with respect to the recurrence rates (p=0.821). Moreover, there were no significant differences between the two tratment groups in disease-free survival (DFS) (p=0.84) [B(2)(p=0.805) and C (p=0.978)] and overall survival (OS) rates for patients of either stage B(2) or C (p=0.78). Toxicities were more frequent in the 5-FU+LVS versus 5-FU+LV group: myelosuppression (grade 3 leucopenia, 12 versus 4%, p<0.04), diarrhea (grade 0, 60 versus 76%, p<0.02), and liver toxicity (increase of transaminases >3-fold, 12 patients versus 2, p<0.03.). No patient stopped chemotherapy because of toxicity, and there were no treatment-related deaths. CONCLUSION Adjuvant chemotherapy in RC with LV+5-FU for 6 months is equally effective and less toxic than LVS+5-FU for 12 months.