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Concurrent chemoradiotherapy has been the standard of care for locally advanced cervical cancer for over 20 years; however, 30–40% of treated patients have recurrence or progression within 5 years. Immune checkpoint inhibition has improved outcomes for patients with PD-L1 positive metastatic or recurrent cervical cancer. We assessed the benefit of adding durvalumab, a PD-L1 antibody, with and following chemoradiotherapy for locally advanced cervical cancer. The CALLA randomised, double-blind, phase 3 trial included 105 hospitals across 15 countries. Patients aged at least 18 years with previously untreated locally advanced cervical cancer (adenocarcinoma, squamous, or adenosquamous; International Federation of Gynaecology and Obstetrics [FIGO] 2009 stage IB2–IIB lymph node positive, stage ≥III any lymph node status) and WHO or Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) through an interactive web response system using a permuted block size of 4 to receive durvalumab (1500 mg intravenously once every 4 weeks) or placebo with and following chemoradiotherapy, for up to 24 cycles. Chemoradiotherapy included 45 Gy external beam radiotherapy at 5 fractions per week concurrent with intravenous cisplatin (40 mg/m2) or carboplatin (area under the concentration-time curve 2) once weekly for 5 weeks, followed by image-guided brachytherapy (high-dose rate, 27·5–30 Gy or low-dose/pulse-dose rate, 35–40 Gy). Randomisation was stratified by disease stage status (FIGO stage and node status) and geographical region. Chemoradiotherapy quality was continuously reviewed. The primary endpoint was progression-free survival, assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03830866. Between Feb 15, 2019, and Dec 10, 2020, 770 women were randomly assigned (385 to durvalumab and 385 to placebo; median age 49 years [IQR 41–57]). Median follow-up was 18·5 months (IQR 13·2–21·5) in the durvalumab group and 18·4 months (13·2–23·7) in the placebo group. At data cutoff, median progression-free survival had not been reached (95% CI not reached–not reached) for either group (HR 0·84; 95% CI 0·65–1·08; p=0·17); 12-month progression-free survival was 76·0% (71·3–80·0) with durvalumab and 73·3% (68·4–77·5) with placebo. The most frequently reported grade 3–4 adverse events in both groups were anaemia (76 [20%] of 385 in the durvalumab group vs 56 [15%] of 384 in the placebo group) and decreased white blood cells (39 [10%] vs 49 [13%]). Serious adverse events occurred for 106 (28%) patients who received durvalumab and 89 (23%) patients who received placebo. There were five treatment-related deaths in the durvalumab group (one case each of urinary tract infection, blood loss anaemia, and pulmonary embolism related to chemoradiotherapy only; one case of endocrine disorder related to durvalumab only; and one case of sepsis related to both durvalumab and chemoradiotherapy). There was one treatment-related death in the placebo group (pneumonia related to chemoradiotherapy). Durvalumab concurrent with chemoradiotherapy was well tolerated in participants with locally advanced cervical cancer, however it did not significantly improve progression-free survival in a biomarker unselected, all-comers population. Concurrent durvalumab plus chemoradiotherapy warrants further exploration in patients with high tumoral PD-L1 expression. Rigorous monitoring ensured high chemoradiotherapy compliance with advanced technology and allowed patients to receive optimal care. AstraZeneca.

The COVID-19 pandemic has led to the need for health services adjustments, which may have compromised management of other diseases. For cancer patients, delays may significantly impair outcomes in some situations. We aimed to assess the impact of the COVID-19 pandemic in breast and cervical cancer diagnosis and treatment compared to the same period prior to the pandemic. Data were collected from patients attending their first visit to a Brazilian cancer centre from 1 September 2020 to 31 January 2021 and from 1 September 2019 to 31 January 2020. The pandemic started in February 2020 in Brazil and is still ongoing. We considered this period (September/20-January/21) to be representative of the pandemic impact on cancer management. The primary endpoint was breast and cervical cancer stages at diagnosis. A total of 268 breast cancer patients and 44 cervical cancer patients had their first consult in our cancer centre from September/20 to January/21; 457 and 60, respectively, occurred from September/19 to January/20. Patients who attended their first visit during the pandemic (September/20-January/21) presented with more advanced-stage breast cancer ( < 0.001) and cervical cancer ( = 0.328) than those in the period prior to the pandemic (September/19-January/20), although the difference was not statistically significant for cervical cancer. The proportion of cervical cancer patients diagnosed with locally advanced disease (stages III-IVA) was 56.8% ( = 25) in September/20-January/21 compared to 43.3% ( = 26) in September/19-January/20. Similarly, 37.3% ( = 100) of breast cancer patients had stage III disease in September/20-January/21 compared to 23.2% ( = 106) in September/19-January/20. Fewer breast cancer patients (13.7%) were diagnosed due to screening tests during the pandemic than before it (25.5%) ( < 0.001). Breast and cervical cancer patients had more advanced-stage diseases in their first visit to a cancer centre during the COVID-19 pandemic compared to a similar period prior to the pandemic. Efforts should be made not to compromise essential cancer services since this results in long-term negative impacts for oncologic patients.

We evaluated the prevalence of pathogenic/likely pathogenic germline variants (PGV) in Brazilian pancreatic adenocarcinoma (PC) patients, that represent a multiethnic population, in a cross-sectional study. We included 192 PC patients unselected for family history of cancer. We evaluated a panel of 113 cancer genes, through genomic DNA sequencing and 46 ancestry-informative markers, through multiplex PCR. The median age was 61 years; 63.5% of the patients presented disease clinical stages III or IV; 8.3% reported personal history of cancer; 4.7% and 16.1% reported first-degree relatives with PC or breast and/or prostate cancer, respectively. Although the main ancestry was European, there was considerable genetic composition admixture. Twelve patients (6.25%) were PGV carriers in PC predisposition genes ( ATM , BRCA1 , BRCA2 , CDKN2A , MSH2 , PALB2 ) and another 25 (13.0%) were PGV carriers in genes with a limited association or not previously associated with PC ( ACD , BLM , BRIP1 , CHEK2 , ERCC4 , FANCA , FANCE , FANCM , GALNT12 , MITF , MRE11 , MUTYH , POLE , RAD51B , RAD51C , RECQL4 , SDHA , TERF2IP) . The most frequently affected genes were CHEK2 , ATM and FANC . In tumor samples from PGV carriers in ACD , BRIP1 , MRE11 , POLE , SDHA , TERF2IP , which were examined through exome sequencing, the main single base substitutions (SBS) mutational signature was SBS1+5+18, probably associated with age, tobacco smoking and reactive oxygen species. SBS3 associated with homologous repair deficiency was also represented, but on a lower scale. There was no difference in the frequency of PGV carriers between: (a) patients with or without first-degree relatives with cancer; and (b) patients with admixed ancestry versus those with predominantly European ancestry. Furthermore, there was no difference in overall survival between PGV carriers and non-carriers. Therefore, genetic testing should be offered to all Brazilian pancreatic cancer patients, regardless of their ancestry. Genes with limited or previously unrecognized associations with pancreatic cancer should be further investigated to clarify their role in cancer risk.

ObjectiveThe CIRCE trial (NCT 01973101) investigated the efficacy, safety, and quality of life of the addition of neoadjuvant chemotherapy with cisplatin and gemcitabine to standard chemoradiation for locally advanced cervical cancer (stages IIB–IVA). The impact of both treatment arms on quality of life is reported in the present study.MethodsPatients completed the European Organization of Research and Treatment of Cancer questionnaire QLQ-C30 and CX24 before treatment and at 3, 6, 9, and 12 months after treatment. Linear mixed models were fitted to analyze differences in quality of life over time and between groups. Differences in mean quality of life scales >10 points and p<0.05 were considered clinically relevant and statistically significant, respectively. Inclusion criteria were: (1) histological diagnosis of locally advanced invasive carcinoma of the uterine cervix, International Federation of Gynecology and Obstetrics stages IIB–IVA; (2) signed informed consent to participate in the CIRCE trial; and (3) answered at least one quality of life questionnaire. Excluded were patients who did not complete any quality of life questionnaire. Relevant exclusion criteria for the CIRCE trial included Eastern Cooperative Oncology Group performance status >2 and peripheral neuropathy >2. Mann–Whitney U tests were performed to assess differences between groups in quality of life at baseline. To evaluate differences between treatment arms, linear mixed models were fitted using the transformed quality of life scores as a dependent variable and time of follow-up and study arm as factors.ResultsA total of 107 patients were enrolled (n=55 neoadjuvant chemotherapy arm; n=52 chemoradiation arm). Quality of life compliance rates were higher for the chemoradiation group at every assessment time (ranging from 75–86.5% in the chemoradiation arm vs 55–81.8% in the neoadjuvant chemotherapy arm). For quality of life results at baseline, no statistically significant difference between the groups was seen. For both groups, most scales showed improvements over time, except for worsening of the summary score, sexual enjoyment, peripheral neuropathy, and menopausal symptoms. For chemoradiation, body image was lower (p<0.001) and patients presented more lymphedema (p<0.001) and sexual worry (p<0.001) at 12 months compared with baseline. Comparing study arms, neoadjuvant chemotherapy showed significantly lower scores in the menopausal symptoms scale (p=0.03) and higher scores for sexual/vaginal functioning (p=0.01). At 12 months, clinical differences were seen only for body image and menopausal symptoms scale, with neoadjuvant chemotherapy presenting better body image scores and a lower burden of menopausal symptoms.ConclusionAfter treatment for locally advanced cervical cancer, patients improved in most quality of life aspects. However, worsening was observed in sexual enjoyment, peripheral neuropathy, and menopausal symptoms. To improve patients’ quality of life, efforts should be made to prevent and treat these long term effects of locally advanced cervical cancer treatment.

Background Approximately 8–15% epithelial ovarian cancer patients are BRCA1 or BRCA2 germline mutation carriers. Brazilian inhabitants may have peculiar genetic characteristics associated with ethnic diversity, and studies focusing on the entire BRCA1/BRCA2 gene sequencing in Brazilian ovarian cancer patients are still lacking. The aim of this study was to evaluate BRCA1/2 mutations, through entire gene sequencing, in a Brazilian population of women with epithelial ovarian cancer. Methods In a cross sectional study performed in one reference centre for cancer treatment in São Paulo, Brazil, 100 patients diagnosed with epithelial ovarian cancer unselected for family history of breast and/or ovarian cancer were included. The complete coding sequence of BRCA1 /2 genes was evaluated through Next-Generation or capillary sequencing. Large deletions were investigated through Multiplex Ligation-dependent Probe Amplification (MLPA). Results Nineteen pathogenic mutations ( BRCA1 : n  = 17 and BRCA2 : n  = 2) featuring 14 different mutations, including two large deletions in BRCA1 (exon 1–2 deleted and exon 5–7 deleted) were identified. Three mutations were detected more than once (c.3331_3334delCAAG, c.5266dupC and c.4484G > T). Two novel frameshift mutations were identified, one in BRCA1 (c.961_962delTG) and one in BRCA2 (c.1963_1963delC). BRCA1/2 mutations were seen in 35.5% of the patients with first and/or second-degree relatives with breast and/or ovarian cancer. Nineteen variants of uncertain significance (VUS) were detected ( BRCA1 : n  = 2 and BRCA2 : n  = 17), including five distinct missense variants ( BRCA1 : c.5348 T > C; BRCA2 : c.2350A > G, c.3515C > T, c.7534C > T, and c.8351G > A). Conclusions Among epithelial ovarian cancer patients unselected for family history of cancer, 19% were BRCA1/2 germline mutation carriers. Almost ¾ of the BRCA mutations, including two large deletions, were detected only once. Our work emphasizes the need of entire gene sequencing and MLPA screening in Brazil.

In this article, we describe some practical aspects that promote the humanisation of clinical research. Actions are not limited to improving the communication skills of medical staff but also include maintenance of care continuity, accessible written information, and application of theoretic models such as shared decision-making and management of stress in decision-making under uncertainty. We believe that a comprehensive strategy will increase patients' motivation to participate in and adhere to clinical research.

ObjectiveTo investigate the efficacy and safety of hu3S193, a humanized anti-Lewis-Y monoclonal antibody, as a consolidation strategy in patients with platinum-sensitive recurrent epithelial ovarian cancer who achieved a second complete response after salvage platinum-doublet chemotherapy.MethodsThis single-arm phase II study accrued patients with recurrent epithelial ovarian cancer with Lewis-Y expression by immunohistochemistry who had achieved a second complete response after five to eight cycles of platinum-based chemotherapy. Patients received intravenous infusions of hu3S193, 30 mg/m2 every 2 weeks starting no more than 8 weeks after the last dose of chemotherapy and continuing for 12 doses, until disease progression, or unacceptable toxicity. The primary endpoint was progression-free survival of the second remission. Secondary objectives were safety and pharmacokinetics.ResultsTwenty-nine patients were enrolled. Most had a papillary/serous histology tumor (94%), stage III disease at diagnosis (75%), and five (17%) underwent secondary cytoreduction before salvage chemotherapy. Two patients were not eligible for efficacy but were considered for toxicity analysis. Eighteen patients (62%) completed the full consolidation treatment while nine patients progressed on treatment. At the time of analysis, 23 patients (85%) of the eligible population had progressed and seven of these patients (26%) had died. Median progression-free survival of the second remission was 12.1 months (95% CI: 10.6–13.9), with a 1-year progression-free survival of the second remission rate of 50.1%. The trial was terminated early since it was unlikely that the primary objective would be achieved. The most commonly reported treatment-related adverse events were nausea (55%) and vomiting (51%).ConclusionsHu3S193 did not show sufficient clinical activity as consolidation therapy in patients with recurrent epithelial ovarian cancer who achieved a second complete response after platinum-based chemotherapy.Trial registration NCT01137071.

During the COVID-19 pandemic, health services worldwide are going through important adaptations to assist patients infected with COVID-19, at the same time as continuing to provide assistance to other potentially life-threatening diseases. Although patients with cancer may be at increased risk for severe events related to COVID-19 infection, their oncologic treatments frequently cannot be delayed for long periods without jeopardising oncologic outcomes. Considering this, a careful consideration for treatment management of different malignancies is required. Cervical cancer is concentrated mainly in low-middle income countries (LMICs), which face particular challenges during the COVID-19 pandemic due to the scarcity of health resources in many places. Although cervical cancer is the fourth cause of cancer death among women, it receives little attention from international Oncology societies and scientific research studies. In this review paper, we discuss the cervical cancer landscape and provide specialists recommendations for its management during the COVID-19 pandemic, particularly focused on LMICs' reality.

Cervical cancer remains a prevalent and deadly disease in low-income countries, especially among young and otherwise healthy women. Multimodality treatment has led to a significant improvement in outcomes for patients with locally advanced disease, and this is mainly because of the incorporation of platinum-based chemoradiotherapy in current treatment protocols. However, locally advanced tumors are associated with a greater risk for para-aortic lymph node (PALN) involvement, which is an important adverse prognostic factor. Most staging techniques have low accuracy for detection of disease in this area, which could lead to understaging and undertreatment. Meanwhile, patients with PALN disease are underrepresented in trials addressing the treatment of advanced cervical cancer and a few studies have been directed at this population. The aim of this review is to analyze the current data regarding staging and treatment of cervical cancer with PALN disease to determine which strategy is best when managing these patients.

In recent years, the potential of multi-criteria decision analysis (MCDA) in the health field has been discussed widely. However, most MCDA methodologies have given little attention to the aggregation of different stakeholder individual perspectives. To illustrate how a paraconsistent theory-based MCDA reusable framework, designed to aid hospital-based Health Technology Assessment (HTA), could be used to aggregate individual expert perspectives when valuing cancer treatments. An MCDA methodological process was adopted based on paraconsistent theory and following ISPOR recommended steps in conducting an MCDA study. A proof-of-concept exercise focusing on identifying and assessing the global value of first-line treatments for metastatic colorectal cancer (mCRC) was conducted to foster the development of the MCDA framework. On consultation with hospital-based HTA committee members, 11 perspectives were considered in an expert panel: medical oncology, oncologic surgery, radiotherapy, palliative care, pharmacist, health economist, epidemiologist, public health expert, health media expert, pharmaceutical industry, and patient advocate. The highest weights were assigned to the criteria \"overall survival\" (mean 0.22), \"burden of disease\" (mean 0.21) and \"adverse events\" (mean 0.20), and the lowest weights were given to \"progression-free survival\" and \"cost of treatment\" (mean 0.18 for both). FOLFIRI and mFlox scored the highest global value score of 0.75, followed by mFOLFOX6 with a global value score of 0.71. mIFL was ranked last with a global value score of 0.62. The paraconsistent analysis (para-analysis) of 6 first-line treatments for mCRC indicated that FOLFIRI and mFlox were the appropriate options for reimbursement in the context of this study. The Paraconsistent Value Framework is proposed as a step beyond the current MCDA practices, in order to improve means of dealing with individual expert perspectives in hospital-based HTA of cancer treatments.