Atezolizumab and chemotherapy for advanced or recurrent endometrial cancer (AtTEnd): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: At the time of AtTEnd trial design, standard treatment for advanced or recurrent endometrial cancer included carboplatin and paclitaxel chemotherapy. This trial assessed whether combining atezolizumab with chemotherapy might improve outcomes in this population. METHODS: AtTEnd was a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done in 89 hospitals in 11 countries across Europe, Australia, New Zealand, and Asia. Enrolled patients were aged 18 years or older, and had advanced or recurrent endometrial carcinoma or carcinosarcoma, an Eastern Cooperative Oncology Group performance status of 0-2, and received no previous systemic chemotherapy for recurrence. Patients were randomly assigned (2:1) using an interactive web response system (block size of six) to either atezolizumab 1200 mg or placebo given intravenously with chemotherapy (carboplatin at area under the curve of 5 or 6 and paclitaxel 175 mg/m2 intravenously on day 1 every 21 days) for 6-8 cycles, then continued until progression. Stratification factors were country, histological subtype, advanced or recurrent status, and mismatch repair (MMR) status. Participants and treating clinicians were masked to group allocation. The hierarchically tested co-primary endpoints were progression-free survival (in patients with MMR-deficient [dMMR] tumours, and in the overall population) and overall survival (in the overall population). Primary analyses were done in the intention-to-treat population, defined as all randomly assigned patients who gave their full consent to participation in the study and data processing. Safety was assessed in all patients included in the intention-to-treat population who received at least one dose of study treatment. Here, we report the primary progression-free survival and the interim overall survival results. This study is ongoing and is registered with ClinicalTrials.gov, NCT03603184. FINDINGS: Between Oct 3, 2018, and Jan 7, 2022, 551 patients were randomly assigned to atezolizumab (n=362) or placebo (n=189). Two patients in the atezolizumab group were excluded from all analyses due to lack of consent. Median follow-up was 28·3 months (IQR 21·2-37·6). 81 (23%) patients in the atezolizumab group and 44 (23%) patients in the placebo group had dMMR disease by central assessment. In the dMMR population, median progression-free survival was not estimable (95% CI 12·4 months-not estimable [NE]) in the atezolizumab group and 6·9 months (6·3-10·1) in the placebo group (hazard ratio [HR] 0·36, 95% CI 0·23-0·57; p=0·0005). In the overall population, median progression-free survival was 10·1 months (95% CI 9·5-12·3) in the atezolizumab group and 8·9 months (8·1-9·6) in the placebo group (HR 0·74, 95% CI 0·61-0·91; p=0·022). Median overall survival was 38·7 months (95% CI 30·6-NE) in the atezolizumab group and 30·2 months (25·0-37·2) in the placebo group (HR 0·82, 95% CI 0·63-1·07; log-rank p=0·048). The p value for the interim analysis of overall survival did not cross the stopping boundary; therefore, the trial will continue until the required number of events are recorded. The most common grade 3-4 adverse events were neutropenia (97 [27%] of 356 patients in the atezolizumab group vs 51 [28%] of 185 in the placebo group) and anaemia (49 [14%] vs 24 [13%]). Treatment-related serious adverse events occurred in 46 (13%) patients in the atezolizumab group and six (3%) patients in the placebo group. Treatment-related deaths occurred in two patients (pneumonia in one patient in each group). INTERPRETATION: Atezolizumab plus chemotherapy increased progression-free survival in patients with advanced or recurrent endometrial carcinoma, particularly in those with dMMR carcinomas, suggesting the addition of atezolizumab to standard chemotherapy as first-line treatment in this specific subgroup. FUNDING: F Hoffmann-La Roche.

Immunogenicity of two doses of BNT162b2 and mRNA-1273 vaccines for solid cancer patients on treatment with or without a previous SARS-CoV-2 infection.

Previous studies on the immunogenicity of SARS-CoV-2 mRNA vaccines showed a reduced seroconversion in cancer patients. The aim of our study is to evaluate the immunogenicity of two doses of mRNA vaccines in solid cancer patients with or without a previous exposure to the virus. This is a single-institution, prospective, nonrandomized study. Patients in active treatment and a control cohort of healthy people received two doses of BNT162b2 (Comirnaty, BioNTech/Pfizer, The United States) or mRNA-1273 (Spikevax, Moderna). Vaccine was administered before starting anticancer therapy or on the first day of the treatment cycle. SARS-CoV-2 antibody levels against S1, RBD (to evaluate vaccine response) and N proteins (to evaluate previous infection) were measured in plasma before the first dose and 30 days after the second one. From January to June 2021, 195 consecutive cancer patients and 20 healthy controls were enrolled. Thirty-one cancer patients had a previous exposure to SARS-CoV-2. Cancer patients previously exposed to the virus had significantly higher median levels of anti-S1 and anti-RBD IgG, compared to healthy controls (P = .0349) and to cancer patients without a previous infection (P < .001). Vaccine type (anti-S1: P < .0001; anti-RBD: P = .0045), comorbidities (anti-S1: P = .0274; anti-RBD: P = .0048) and the use of G-CSF (anti-S1: P = .0151) negatively affected the antibody response. Conversely, previous exposure to SARS-CoV-2 significantly enhanced the response to vaccination (anti-S1: P < .0001; anti-RBD: P = .0026). Vaccine immunogenicity in cancer patients with a previous exposure to SARS-CoV-2 seems comparable to that of healthy subjects. On the other hand, clinical variables of immune frailty negatively affect humoral immune response to vaccination.

The emotional impact of the COVID-19 outbreak on cancer outpatients and their caregivers: results of a survey conducted in the midst of the Italian pandemic.

INTRODUCTION: The study investigates the emotional discomfort of cancer patients and their caregivers, who need to access the oncology day hospital to receive treatment during the COVID-19 pandemic in Italy. METHODS: This is a single-institution, prospective, cross-sectional study. From May to June 2020, the points of view of both patients and caregivers were compared through 2 different multiple-choice questionnaires, enquiring demographic characteristics, changes in emotional status, interpersonal relationships with health professionals (HCPs) and self-perception of treatment outcomes. RESULTS: Six hundred twenty-five patients and 254 caregivers were enrolled. Females were prevalent and patients were generally older than caregivers. Forty percent of patients and 25.6% of caregivers thought they were at a greater risk of contagion because lived together with a cancer patient or accessed the hospital. Both patients (86.3%) and caregivers (85.4%) considered containment measures a valid support to avoid the spread of infection. People with a lower education level were less worried about being infected with SARS-COV-2. Waiting and performing visits/treatments without caregivers had no impact on the emotional status of patients (64.4%), but generated in caregivers greater anxiety (58.8%) and fear (19.8%) of not properly managing patients at home. The majority of patients (54%) and caregivers (39.4%) thought the pandemic does not influence treatment outcomes. The relationship with HCPs was not negatively impacted for majority of patients and caregivers. CONCLUSIONS: Starting from these data, we can better understand the current psychological distress of patients and their families in order to develop potential strategies to support them in this strenuous period of crisis.

Increased incidence of interstitial pneumonia detected on [18F]-FDG-PET/CT in asymptomatic cancer patients during COVID-19 pandemic in Lombardy: a casualty or COVID-19 infection?

PURPOSE: The study aimed to compare the incidence of interstitial pneumonia on [18F]-FDG PET/CT scans between two 6-month periods: (a) the COVID-19 pandemic peak and (b) control period. Secondly, we compared the incidence of interstitial pneumonia on [18F]-FDG PET/CT and epidemiological data from the regional registry of COVID-19 cases. Additionally, imaging findings and the intensity of [18F]-FDG PET/CT uptake in terms of maximum standardized uptake value (SUVmax) were compared. METHODS: We retrospectively analyzed [18F]-FDG PET/CT scans performed in cancer patients referred to nuclear medicine of Humanitas Gavazzeni in Bergamo from December 2019 to May 2020 and from December 2018 to May 2019. The per month incidence of interstitial pneumonia at imaging and the epidemiological data were assessed. To evaluate the differences between the two symmetric groups (period of COVID-19 pandemic and control), the stratified Cochran-Mantel-Haenszel test was used. Chi-square test or Fisher's exact test and t test or Wilcoxon test were performed to compare the distributions of categorical and continuous variables, respectively. RESULTS: Overall, 1298 patients were included in the study. The two cohorts-COVID-19 pandemic (n = 575) and control (n = 723)-did not statistically differ in terms of age, disease, or scan indication (p > 0.05). Signs of interstitial pneumonia were observed in 24 (4.2%) and 14 patients (1.9%) in the COVID-19 period and the control period, respectively, with a statistically significant difference (p = 0.013). The level of statistical significance improved further when the period from January to May was considered, with a peak in March (7/83 patients, 8.4% vs 3/134 patients, 2.2%, p = 0.001). The curve of interstitial pneumonia diagnosis overlapped with the COVID-19 incidence in the area of Lombardy (Spearman correlation index was equal to 1). Imaging data did not differ among the two cohorts. CONCLUSIONS: Significant increase of interstitial lung alterations at [18F]-FDG PET/CT has been demonstrated during the COVID-19 pandemic. Additionally, the incidence curve of imaging abnormalities resulted in resembling the epidemiological data of the general population. These data support the rationale to adopt [18F]-FDG PET/CT as sentinel modality to identify suspicious COVID-19 cases to be referred for additional confirmatory testing. Nuclear medicine physicians and staff should continue active surveillance of interstitial pneumonia findings, especially when new infection peak is expected.

Early-stage clear cell ovarian cancer compared to high-grade histological subtypes: An outcome exploratory analysis in two oncology centers.

OBJECTIVE: advanced stage clear cell ovarian cancer (CCOC) carries a higher risk of relapse and death compared to other histological subtypes. The prognosis of early-stage CCOC is controversial. METHODS: Early-stage high-grade OC patients from two Italian oncologic centers were included. Patients with early-stage CCOC were compared with those with high-grade endometrioid (HGE) and serous (HGS) OC in terms of relapse-free interval (RFI), cancer-specific survival (CSS) and post relapse cancer-specific survival (prCSS). The Cox proportional hazard model and the restricted mean survival time were used. RESULTS: Between 1981 and 2012, 134 patients with CC, 152 with HGE and 160 with HGS were treated at two referral centers. Median follow-up was 11.5 years. Ten years RFI rates were 80.6%, 72.1%, 60.6%, and CSS rates were 84.3%, 82.6%, 81.7% respectively. Adjuvant chemotherapy significantly improved RFI (aHR 0.61, 95%CI 0.40 to 0.91, P = 0.015). In the multivariable analysis HGS histotype was associated with a shorter RFI compared to CC, (Hazard Ratio [HR]: 1.81; 95%CI: 1.12-2.93; P = 0.016), whereas CSS was not statistically different. prCSS was longer in HGS compared to CCOC (HR, 0.36; 95% CI, 0.17-0.74; P = 0.006). According to the stage, IA/IB/IC1 HGSOC had a shorter RFI (HR, 2.13; 95% CI, 1.14-3.99; P = 0.018) compared to IA/IB/IC1 CCOC, but similar CSS. For prCSS, CC compared to HGS conferred a worse prognosis regardless of the initial stage. CONCLUSIONS: Early-stage CCOC is associated with a longer RFI, similar CSS and a shorter prCSS compared to HGSOC. No prognostic differences were observed between CC and HGE OC. The relapse risk was the lowest in IA/IB/IC1 CC compared to HGS, whereas CC displayed poor sensitivity to chemotherapy after relapse.

Predictive Impact of Mucinous Tumors on the Clinical Outcome in Patients with Poorly Differentiated, Stage II Colon Cancer: A TOSCA Subgroup Analysis.

BACKGROUND: Although American Society of Clinical Oncology and European Society for Medical Oncology guidelines have identified the negative prognostic factors that clinicians have to consider when treating their patients with stage II colon cancer (CC), the role of histological subtype is controversial. SUBJECTS, MATERIALS, AND METHODS: The randomized, multicenter, phase III TOSCA trial compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy in 3,759 patients with high-risk stage II or stage III CC. The objective of this substudy was to evaluate the influence of histological subtypes on the impact of the treatment duration of adjuvant chemotherapy in terms of relapse-free survival (RFS) and overall survival (OS) in 85 mucinous adenocarcinoma (MUC) and 389 nonmucinous adenocarcinoma (NMUC) patients with high-risk stage II, grade 3 CC. RESULTS: A significant interaction between treatment duration and histology was observed in both RFS (p = .027) and OS (p = .017). In the subgroup of patients with MUC, worse RFS (adjusted hazard ratio [HR], 3.95; 95% confidence interval [CI], 1.03-15.17; p = .045) and OS (HR, 9.56; 95% CI, 1.14-79.98; p = .037) were detected for patients treated in the 3-month arm. No statistically significant differences were found in the subgroup of patients with NMUC. CONCLUSION: Patients with MUC, grade 3, stage II CC require special attention and may need 6 months of oxaliplatin-based chemotherapy. Larger studies are required to assess the combined use of histology and other prognostic/predictive factors to define the administration of chemotherapy in patients with stage II CC and to improve their prognosis. IMPLICATIONS FOR PRACTICE: Although ASCO and ESMO guidelines define the prognostic factors for patients with stage II colon cancer to establish the use of adjuvant chemotherapy, the influence of histological subtypes is controversial in this population. This study underscores that patients with grade 3 mucinous adenocarcinomas may need adjuvant chemotherapy with oxaliplatin and fluoropyrimidines for a duration of 6 months rather than 3 months.

Multicenter, randomised, open-label, non-comparative phase 2 trial on the efficacy and safety of the combination of bevacizumab and trabectedin with or without carboplatin in women with partially platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Trabectedin, in addition to its antiproliferative effect, can modify the tumour microenvironment and this could be synergistic with bevacizumab. The efficacy and safety of trabectedin and bevacizumab ± carboplatin have never been investigated. METHODS: In this phase 2 study, women progressing between 6 and 12 months since their last platinum-based therapy were randomised to Arm BT: bevacizumab, trabectedin every 21 days, or Arm BT+C: bevacizumab, trabectedin and carboplatin every 28 days, from cycles 1 to 6, then trabectedin and bevacizumab as in Arm BT. Primary endpoints were progression-free survival rate (PFS-6) and severe toxicity rate (ST-6) at 6 months, assuming a PFS-6 ≤35% for BT and ≤40% for BT+C as not of therapeutic interest and, for both arms, a ST-6 ≥ 30% as unacceptable. RESULTS: BT+C (21 patients) did not meet the safety criteria for the second stage (ST-6 45%; 95%CI: 23%-69%) but PFS-6 was 85% (95%CI: 62%-97%). BT (50 patients) had 75% PFS-6 (95%CI: 60%-87%) and 16% ST-6 (95%CI 7%-30%). CONCLUSIONS: BT compared favourably with other platinum- and non-platinum-based regimens. The combination with carboplatin needs to be assessed further in a re-modulated safer schedule to confirm its apparent strong activity. CLINICAL TRIAL REGISTRATION: NCT01735071 (Clinicaltrials.gov).

Impact of Metformin Use and Diabetic Status During Adjuvant Fluoropyrimidine-Oxaliplatin Chemotherapy on the Outcome of Patients with Resected Colon Cancer: A TOSCA Study Subanalysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with increased risk of colon cancer (CC), whereas metformin use seems to be protective. However, the impact of metformin use on the risk of death or disease recurrence after radical surgery for CC remains uncertain. MATERIALS AND METHODS: This is a substudy conducted in patients with high-risk stage II or stage III CC randomized in the TOSCA trial, which compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy. Objective of the study was to investigate the impact of metformin exposure during adjuvant chemotherapy on overall survival (OS) and relapse-free survival (RFS). We also evaluated the impact of T2DM or metformin dosage on clinical outcomes. RESULTS: Out of 3,759 patients enrolled in the TOSCA trial, 133 patients with diabetes (9.2%) and 1,319 without diabetes (90.8%) were recruited in this study. After excluding 13 patients with diabetes without information on metformin exposure, 76 patients with T2DM (63.3%) were defined as metformin users and 44 (36.7%) as metformin nonusers. After a median follow-up of 60.4 months, 26 (21.7%) patients relapsed and 16 (13.3%) died. Metformin use was neither associated with OS (adjusted hazard ratio [HR], 1.51; 95% confidence interval [CI], 0.48-4.77; p = .4781) nor with RFS (HR, 1.56; 95% CI, 0.69-3.54; p = .2881). Similarly, we found no association between T2DM or metformin dosage and OS or RFS. CONCLUSIONS: Metformin use and T2DM did not impact on OS or RFS in patients with resected CC treated with adjuvant fluoropyrimidine-oxaliplatin chemotherapy. Larger studies and longer follow-up are required to clarify the potential efficacy of metformin in improving the prognosis of patients with CC. IMPLICATIONS FOR PRACTICE: The role of the antidiabetic drug metformin in colon cancer prevention and treatment is highly debated. While low-dose metformin reduced the incidence of colorectal adenomas in two prospective studies, its effect in patients with already established colon cancer remains unclear. In this study, the potential impact of metformin on the survival of resected colon cancer patients who received adjuvant chemotherapy was investigated in the context of the TOSCA study. We did not find any association between metformin use or dosages and patient survival. Prospective studies are required to draw definitive conclusions about metformin impact on colon cancer recurrence and survival.

Ovarian function, fertility, and menopause occurrence after fertility-sparing surgery and chemotherapy for ovarian neoplasms.

BACKGROUND: The effect of chemotherapy exposure (CE) on ovarian function in young women with ovarian neoplasms undergoing fertility-sparing treatment (FST) remains unclear. We investigated whether CE is correlated with the outcomes (1) during-treatment and (2) post-treatment amenorrhea, (3) conception rate, (4) pregnancy outcome, and (5) spontaneous menopausal age. PATIENTS AND METHODS: Eligibility criteria were patients with a diagnosis of epithelial (EOC) or nonepithelial (no-EOC) invasive ovarian neoplasm, premenopausal age, undergoing FST ±â€¯CE, histopathology confirmation, and adequate follow-up. The groups' outcomes were compared by logistic and linear regression analysis. RESULTS: A total of 548 patients diagnosed during 1980 and 2014 were included, 198 in the EOC group and 350 in the no-EOC group, and 44% received chemotherapy, with a median follow-up of 15.9 years. In no-EOC patients, CE conferred a higher risk for Outcomes 1 (adjusted OR [aOR] 27; 95% CI 12 to 61; P < .0001) and 2 (aOR 5.42; 95% CI 1 to 24; P = .0256) and was associated with a younger menopausal age (adjusted ß -5.52; 95% CI -10.53 to -0.52; P = .0313). Overall, 57% of patients attempted pregnancy, with a conception rate of 89%. In EOC patients, no association between CE and a decreased fertility was demonstrated (aOR, 3.05; 95% CI 0.72 to 12.88; P = .1298). CONCLUSIONS: CE in no-EOC was associated with an increased risk of during-treatment amenorrhea, post-treatment amenorrhea, and earlier spontaneous menopausal age; CE in EOC was not associated with any item at study. Patients undergoing FST had reassuringly high conception rates and low premature ovarian failure rates; however, in pretreatment counseling, the risks of this approach in such young population should be discussed.

Prognostic impact of regression in patients with primary cutaneous melanoma >1 mm in thickness.

BACKGROUND: The impact of histologic regression on sentinel lymph node biopsy (SLNB) status and on clinical outcome is uncertain. OBJECTIVE: To investigate whether and to what extent regression <75% is able to predict SLNB status and clinical outcome of patients with melanoma >1-mm thick. METHODS: The study included patients with diagnoses given at 4 centers of the Italian Melanoma Intergroup. Univariate and multivariate Cox proportional hazard models stratified by center were used to analyze the effect of regression on disease-free interval and melanoma-specific survival. RESULTS: Out of 1182 patients given primary cutaneous melanoma diagnoses during 1998-2015 with a Breslow thickness >1 mm, 954 (304 with and 650 without regression) were included in the analysis. The proportion of patients with a positive SLNB was lower in patients with regression than without (24.4% vs 31.6%, chi-squared test P = .0368). At multivariate analysis, no association was detected between regression and disease-free interval (hazard ratio 1.11, 95% confidence interval 0.85-1.46; P = .4509) or melanoma-specific survival (hazard ratio 1.05, 95% confidence interval 0.77-1.44; P = .7600). LIMITATION: Retrospective analysis. CONCLUSION: In our series, regression was not an independent prognostic factor in primary cutaneous melanoma patients with Breslow thickness >1 mm whereas it was associated with a lower incidence of SLNB positivity.