Oncologic Concerns regarding Laparoscopic Cytoreductive Surgery in Patients with Advanced Ovarian Cancer Submitted to Neoadjuvant Chemotherapy.

BACKGROUND: Presently, the use of laparoscopy in advanced ovarian cancer (AOC) is extremely controversial. In the era of neoadjuvant chemotherapy (NACT), endoscopic debulking surgery could be a reasonable alternative for selected patients with primarily unresectable disease. OBJECTIVES: To evaluate the feasibility as well as the operative and oncologic safety of laparoscopic debulking surgery in patients with AOC submitted to NACT. METHODS: This is a pilot observational study on initially unresectable, high-grade serous ovarian cancer treated with a sequence of 6 cycles of carboplatin and paclitaxel followed by debulking surgery performed by laparoscopy (group 1) or laparotomy (group 2). The inclusion criteria were clinical complete response, CA-125 normalization, imaging without disease in critical areas, and optimal cytoreduction. RESULTS: From January 2011 to March 2014, 21 patients were included. Ten women underwent laparoscopy and 11 laparotomy. No epidemiological or oncologic differences were observed between the groups. No surgery-related casualties, intraoperative complications, conversion to laparotomy, or excessive blood loss or transfusion was detected in the laparoscopic procedures. The mean time of operation was 292 min. The length of hospital stay averaged 3.6 days. Two women in group 1 developed relevant complications. After a mean follow-up of 20 months, the recurrence rates were similar, i.e. 80% in group 1 versus 88% in group 2. Although statistical significance was not reached, the mortality related to cancer was considerably higher (20 vs. 0%; p = 0.086) and the mean chemotherapy-free interval was markedly shorter in group 1 (13.3 vs. 20.5 months; p = 0.288). CONCLUSION: Laparoscopic optimal debulking surgery after NACT is feasible and effective in selected patients. Nevertheless, laparoscopy was substantially associated with inferior oncologic results. Endoscopic cytoreduction in AOC should be cautiously suggested until larger prospective trials confirm the observed results.

Unplanned Hospital Admissions in Patients With Solid Tumors in Brazil: Causes and Progressive Disease's Impact on Outcomes.

PURPOSE: Most patients with cancer will be hospitalized throughout the disease course. However, most evidence on the causes and outcomes of these hospitalizations comes from administrative data or small retrospective studies from high-income countries. METHODS: This study is a retrospective cohort of patients with solid tumors hospitalized from February 1, 2021, to December 31, 2021, in a tertiary cancer center in São Paulo, Brazil. We collected data on cancer diagnosis, symptoms at admission, hospitalization diagnosis, and survival clinical outcomes during in-hospital stay (in-hospital mortality) and after discharge (readmission rates and overall survival [OS]). Progressive disease (PD) diagnosis during admission was retrieved from manual chart review if explicitly stated by the attending physician. We modeled in-hospital mortality and postdischarge OS with logistic regression and Cox proportional hazards models, respectively. RESULTS: A total of 3,726 unique unplanned admissions were identified. The most common symptoms at admission were pain (40.6%), nausea (16.8%), and dyspnea (16.1%). PD (34.0%), infection (31.1%), and cancer pain (13.4%) were the most frequent reasons for admission. The in-hospital mortality rate was 18.9%. Patients with PD had a high in-hospital mortality rate across all tumor groups and higher odds of in-hospital death (odds ratio, 3.5 [95% CI, 3.0 to 4.2]). The 7-, 30-, and 90-day readmission rates were 11.9%, 33.5%, and 54%, respectively. The postdischarge median OS (mOS) was 12.6 months (95% CI, 11.6 to 13.7). Poorer postdischarge survival was observed among patients with PD (mOS, 5 months v 18 months; P < .001; hazard ratio, 2.4 [95% CI, 2.1 to 2.6]). CONCLUSION: PD is a common diagnosis during unplanned hospitalizations and is associated with higher in-hospital mortality rates and poorer OS after discharge. Oncologists should be aware of the prognostic implications of PD during admission and align goals of care with their patients.

Hereditary cancer risk assessment: essential tools for a better approach.

Hereditary cancer risk assessment (HCRA) is a multidisciplinary process of estimating probabilities of germline mutations in cancer susceptibility genes and assessing empiric risks of cancer, based on personal and family history. It includes genetic counseling, testing and management of at-risk individuals so that they can make well-informed choices about cancer surveillance, surgical treatment and chemopreventive measures, including biomolecular cancer therapies. Providing patients and family members with an appropriate HCRA will contribute to a better process of making decisions about their personal and family risks of cancer. Following individuals at high risk through screening protocols, reassuring those at low risk, and referring those at increased risk of hereditary cancer to a cancer genetics center may be the best suitable approach of HCRA.

A matched case-control study of the prognosis of early breast cancer in patients with Li-Fraumeni syndrome (BREAST TP53).

INTRODUCTION: Breast cancer (BC) is the most common type of cancer in premenopausal women with germline TP53 pathogenic variants (mTP53) (Li Fraumeni syndrome - LFS). However, little is known about the BC prognosis in these patients. This study analyzed the BC-related oncologic outcomes of patients with LFS. METHODS: We evaluated a cohort of LFS patients with BC in comparison with a control cohort of BC patients with no pathogenic variant in a hereditary cancer panel. The primary endpoint was recurrence-free survival (RFS). Due to the risk of second malignancies in LFS, only locoregional and distant recurrences were considered events for RFS. Secondary endpoints included rates of contralateral BC, overall survival (OS), and breast cancer-specific survival (BCSS). RESULTS: Forty-one patients were evaluated in the mTP53 group and 82 in the control group. Median age at BC diagnosis was 40 and 41 years, respectively. The mTP53 group received less adjuvant radiotherapy than the control group (63.4% vs 93.9%, P < 0.001). Other relevant baseline characteristics and treatment received were similar between groups. 5y-RFS rates were 79.4% in the mTP53 versus 93.6% in the control group (HR 2.43, 95%CI 0.74-8.01, P = 0.143); and were not impacted by the use of adjuvant radiotherapy. 5y-BCSS rates were 92.2% and 98.6%, respectively (HR 1.87, IC95% 0.25-13.48, P = 0.534). CONCLUSIONS: Our results showed no statistically significant difference in BC-related RFS and BCSS between patients with mTP53 and a control group with no pathogenic variant. Larger multicentric studies are warranted to confirm these results.

Cost-effectiveness analysis of trastuzumab for early breast cancer in Brazil.

BACKGROUND: Adjuvant chemotherapy with trastuzumab for HER2 positive breast cancers has brought considerable benefits to disease-free survival and overall survival. OBJECTIVE: To conduct a cost-effectiveness analysis of the treatment of patients with early and locally advanced HER2 positive breast cancer, within the scope of the Brazilian public health system, comparing adjuvant chemotherapy with and without trastuzumab, for 1 year of treatment. METHODS: A 4-state Markov model was developed to estimate strategy costs and outcomes. RESULTS: Based on the proposed model, we verified an incremental benefit of trastuzumab therapy compared to treatment without trastuzumab with 0.84 quality-adjusted life years (QALY) and 1.16 life years gained (LYG). The use of adjuvant chemotherapy with trastuzumab has an ICER of US$19,599.26 for each quality-adjusted life year and US$14,180.68 for each life year gained in relation to chemotherapy without trastuzumab. CONCLUSION: In Brazil, adjuvant chemotherapy with trastuzumab may be considered cost-effective only if a cost-effectiveness threshold is stipulated with the value starting at three times the Brazilian GDP per capita for QALY or two times the Brazilian GDP per capita for LYG, from health system perspective.

Multiple Criteria Decision Analysis (MCDA) for evaluating cancer treatments in hospital-based health technology assessment: The Paraconsistent Value Framework.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Perspectives on PARP Inhibitor Combinations for Ovarian Cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors constitute an important treatment option for ovarian cancer nowadays. The magnitude of benefit from PARP inhibitors is influenced by the homologous recombination status, with greater benefit observed in patients with BRCA mutated or BRCA wild-type homologous recombination deficient (HRD) tumors. Although some PARP inhibitor activity has been shown in homologous recombination proficient (HRP) ovarian tumors, its clinical relevance as a single agent is unsatisfactory in this population. Furthermore, even HRD tumors present primary or secondary resistance to PARP inhibitors. Strategies to overcome treatment resistance, as well as to enhance PARP inhibitors' efficacy in HRP tumors, are highly warranted. Diverse combinations are being studied with this aim, including combinations with antiangiogenics, immunotherapy, and other targeted therapies. This review discusses the rationale for developing therapy combinations with PARP inhibitors, the current knowledge, and the future perspectives on this issue.

Impact of the COVID-19 pandemic on breast and cervical cancer stage at diagnosis in Brazil.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (p < 0.001) and cervical cancer (p = 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% (N = 25) in September/20-January/21 compared to 43.3% (N = 26) in September/19-January/20. Similarly, 37.3% (N = 100) of breast cancer patients had stage III disease in September/20-January/21 compared to 23.2% (N = 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%) (p < 0.001). CONCLUSIONS: 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.

Challenge of Incorporating New Drugs for Breast Cancer in Brazil: A Proposed Framework for Improving Access to Innovative Therapies.

PURPOSE: The objective of this review is to address the barriers limiting access to treatment of advanced metastatic breast cancer (mBC) in Brazil, specifically for patients in the public health care system, arguably those with the least access to innovation. MATERIALS AND METHODS: A selected panel of Brazilian experts in BC were provided with a series of relevant questions to address in a multiday conference. During the conference, responses were discussed and edited by the entire group through numerous drafts and rounds of discussion until a consensus was achieved. RESULTS: The authors propose specific and realistic recommendations for implementing access to new drugs in cancer care in Brazil. Moreover, in creating these recommendations and framework, the authors strive to address the most important barriers and impediments for technology incorporation. A feasible and specific multidisciplinary process is proposed, which is based on the collective participation of all involved stakeholders. CONCLUSION: Given the current benefits and likely future developments, there is a great need to expand treatments for mBC not only in Brazil but also in most other countries in the world where access issues remain an unresolved demand. Adapting the current framework is essential for accomplishing this goal. The recommendations in this review can serve as a framework for adoption of new technologies in countries with limited resources.

Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants.

Young breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR-]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I-III invasive early BC at age ≤40 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P < 0.001). Median follow-up was 7.9 years. Second primary BC (P = 0.009) and non-BC malignancies (P = 0.02) were more frequent among mBRCA1 patients while distant recurrences were less frequent (P = 0.02). Irrespective of hormone receptor status, mBRCA1 patients had worse disease-free survival (DFS; adjusted HR = 0.76, 95% CI = 0.60-0.96), with no difference in distant recurrence-free interval (DRFI) and overall survival (OS). Patients with HR+ disease had more frequent distant recurrences (P < 0.001) and less frequent second primary malignancies (BC: P = 0.005; non-BC: P = 0.18). No differences in DFS and OS were observed according to hormone receptor status, with a tendency for worse DRFI (adjusted HR = 1.39, 95% CI = 0.94-2.05) in patients with HR+ BC. Type of mBRCA gene and hormone receptor status strongly impact BC clinical behavior and outcomes in mBRCA young patients. These results provide important information for patients' counseling on treatment, prevention, and surveillance strategies.

Ovarian cancer risk assessment in the era of next-generation sequencing.

Ovarian cancer is one of the cancers most influenced by hereditary factors. Testing for hereditary susceptibility genes is recommended for every woman with epithelial ovarian cancer (EOC). Pathogenic germline variants in BRCA1 and BRCA2 genes are responsible for a substantial fraction of hereditary ovarian cancer. However, alterations in other genes, such as BRIP1, RAD51C, RAD51D, and mismatch repair genes, also enhance ovarian cancer risk. Other genes may also participate in ovarian carcinogenesis, but their role as ovarian cancer susceptibility genes still needs to be clarified. With several genes involved, the complexity of genetic testing increases. In this context, next-generation sequencing (NGS) allows testing for multiple genes simultaneously, with rapid turn-around time. However, the incorporation of this technology into clinical practice faces some challenges. In this review, we will discuss the ovarian cancer risk assessment in the era of NGS.

Radiotherapy-induced malignancies in breast cancer patients with TP53 pathogenic germline variants (Li-Fraumeni syndrome).

The risk of radiotherapy-induced malignancies (RIMs) is a concern when treating Li-Fraumeni syndrome (LFS) or Li-Fraumeni Like (LFL) patients. However, the type of TP53 pathogenic germline variant may possibly influence this risk. TP53 p.R337H mutation is particularly prevalent in Brazil. We aimed to evaluate the outcomes of patients with pathogenic TP53 variants treated for localized breast cancer in a Brazilian cohort. We evaluated retrospectively a cohort of patients with germline TP53 pathogenic variants treated for localized breast cancer between December 1999 and October 2017. All patients were followed by the Hereditary Cancer Group of an academic cancer center. Our primary objective was to evaluate the occurrence of RIMs after adjuvant radiotherapy. Sixteen patients were evaluated; 10 (62.5%) had a germline TP53 p.R337H pathogenic variant. Median age was 39.8 years. Thirteen patients had invasive ductal carcinoma: 8 (61.5%) were hormone receptor-positive; 6 (46.1%), human epithelial growth factor receptor 2 (HER2)-amplified. Three patients had ductal carcinoma in situ. Most patients (N = 12/16, 75%) received adjuvant radiotherapy. After a median follow-up of 52.5 months, 2 patients (2/12, 16.6%) had RIMs. One had a fibrosarcoma and the other, a low-grade leiomyosarcoma. In the group treated with radiotherapy, one distant recurrence was diagnosed (1/12), and no loco-regional recurrence occurred. Among 4 patients who did not receive radiotherapy, 2 presented with loco-regional recurrence. In this cohort of patients with LFS enriched in TP53 p.R337H pathogenic variant, the incidence of RIMs after treatment of localized breast cancer was lower than previous literature. Nevertheless, rates of RIMs were still alarming. Early molecular diagnosis and careful evaluation of treatment risks and benefits are essential for these patients.

Pregnancy After Breast Cancer in Patients With Germline BRCA Mutations.

PURPOSE: Young women with germline BRCA mutations have unique reproductive challenges. Pregnancy after breast cancer does not increase the risk of recurrence; however, very limited data are available in patients with BRCA mutations. This study investigated the impact of pregnancy on breast cancer outcomes in patients with germline BRCA mutations. PATIENTS AND METHODS: This is an international, multicenter, hospital-based, retrospective cohort study. Eligible patients were diagnosed between January 2000 and December 2012 with invasive early breast cancer at age ≤ 40 years and harbored deleterious germline BRCA mutations. Primary end points were pregnancy rate, and disease-free survival (DFS) between patients with and without a pregnancy after breast cancer. Pregnancy outcomes and overall survival (OS) were secondary end points. Survival analyses were adjusted for guarantee-time bias controlling for known prognostic factors. RESULTS: Of 1,252 patients with germline BRCA mutations (BRCA1, 811 patients; BRCA2, 430 patients; BRCA1/2, 11 patients) included, 195 had at least 1 pregnancy after breast cancer (pregnancy rate at 10 years, 19%; 95% CI, 17% to 22%). Induced abortions and miscarriages occurred in 16 (8.2%) and 20 (10.3%) patients, respectively. Among the 150 patients who gave birth (76.9%; 170 babies), pregnancy complications and congenital anomalies occurred in 13 (11.6%) and 2 (1.8%) cases, respectively. Median follow-up from breast cancer diagnosis was 8.3 years. No differences in DFS (adjusted hazard ratio [HR], 0.87; 95% CI, 0.61 to 1.23; P = .41) or OS (adjusted HR, 0.88; 95% CI, 0.50 to 1.56; P = .66) were observed between the pregnancy and nonpregnancy cohorts. CONCLUSION: Pregnancy after breast cancer in patients with germline BRCA mutations is safe without apparent worsening of maternal prognosis and is associated with favorable fetal outcomes. These results provide reassurance to patients with BRCA-mutated breast cancer interested in future fertility.

Neoadjuvant Chemotherapy With Cisplatin and Gemcitabine Followed by Chemoradiation Versus Chemoradiation for Locally Advanced Cervical Cancer: A Randomized Phase II Trial.

PURPOSE: Although chemoradiation therapy (CRT) with cisplatin remains the standard treatment of patients with locally advanced cervical cancer (LACC), 40% of patients present with disease recurrence. Additional treatment strategies are required to improve outcomes. We conducted a trial to evaluate the efficacy and safety of neoadjuvant chemotherapy (NAC) with cisplatin and gemcitabine followed by CRT. METHODS: In this phase II trial, patients with LACC (International Federation of Gynecology and Obstetrics stage IIB to IVA or with positive lymph nodes) were randomly assigned to three cycles of NAC with cisplatin and gemcitabine followed by standard CRT with weekly cisplatin plus pelvic radiotherapy or to standard CRT alone. The primary end point was 3-year progression-free survival (PFS). Secondary end points were response rate, 3-year locoregional control, 3-year overall survival (OS), safety, and quality of life. RESULTS: From 107 patients enrolled in the trial, 55 were randomly assigned to the NAC arm and 52 to the CRT-alone arm. The majority of patients had squamous cell carcinoma (87.8%). After a median follow-up of 31.7 months, NAC was associated with an inferior PFS, with 3-year PFS rates of 40.9% v 60.4% in the CRT arm (hazard ratio, 1.84; 95% CI, 1.04 to 3.26; P = .033). NAC also was associated with a lower OS (3-year OS rate, 60.7% v 86.8%; hazard ratio, 2.79; 95% CI, 1.29 to 6.01; P = .006). After treatment completion, complete response rates were 56.3% in the NAC arm and 80.3% in the CRT arm (P = .008). Toxicities were similar in both arms, with the exception of hypomagnesemia and neuropathy being more common with NAC. CONCLUSION: This study shows that the addition of NAC consisting of cisplatin and gemcitabine to standard CRT is not superior and is possibly inferior to CRT alone for the treatment of LACC.

Phase II consolidation trial with anti-Lewis-Y monoclonal antibody (hu3S193) in platinum-sensitive ovarian cancer after a second remission

Objective To 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. Methods This 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. Results Twenty-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%). Conclusions Hu3S193 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.

Câncer de colo uterino: fatores de risco, prevenção, diagnóstico e tratamento / Carcinoma of the cervix: risk factors, prevention, diagnosis and treatment

O câncer de colo uterino é o segundo tipo de câncer mais frequente entre as mulheres de todo o mundo e também no Brasil. Sua maior incidência se dá em mulheres entre 45 e 49 anos de idade e estima-se que o rastreamento sistemático e o tratamento de lesões precursoras possam reduzir a mortalidade pela doença em até 80 por cento...

The cervical cancer is the second leading cause of cancer between women around the world, as in Brazil. The highest incidence is in women aged 45-49 years and the mortality can be reduced by 80 per cent with the systematic screening and treatment of precursor lesions.