Improvement In Overall Survival Research Articles

The peritumoral edema index and related mechanisms influence the prognosis of GBM patients.

Peritumoral brain edema (PTBE) represents a characteristic phenotype of intracranial gliomas. However, there is a lack of consensus regarding the prognosis and mechanism of PTBE. In this study, clinical imaging data, along with publicly available imaging data, were utilized to assess the prognosis of PTBE in glioblastoma (GBM) patients, and the associated mechanisms were preliminarily analyzed. We investigated relevant imaging features, including edema, in GBM patients using ITK-SNAP imaging segmentation software. Risk factors affecting progression-free survival (PFS) and overall survival (OS) were assessed using a Cox proportional hazard regression model. In addition, the impact of PTBE on PFS and OS was analyzed in clinical GBM patients using the Kaplan-Meier survival analysis method, and the results further validated by combining data from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA). Finally, functional enrichment analysis based on TCIA and TCGA datasets identified several pathways potentially involved in the mechanism of edema formation. This study included a total of 32 clinical GBM patients and 132 GBM patients from public databases. Univariate and multivariate analyses indicated that age and edema index (EI) are independent risk factors for PFS, but not for OS. Kaplan-Meier curves revealed consistent survival analysis results between IE groups among both clinical patients and TCIA and TCGA patients, suggesting a significant effect of PTBE on PFS but not on OS. Furthermore, functional enrichment analysis predicted the involvement of several pathways related mainly to cellular bioenergetics and vasculogenic processes in the mechanism of PTBE formation. While these novel results warrant confirmation in a larger patient cohort, they support good prognostic value for PTBE assessment in GBM. Our results indicate that a low EI positively impacts disease control in GBM patients, but this does not entirely translate into an improvement in OS. Multiple genes, signaling pathways, and biological processes may contribute to the formation of peritumoral edema in GBM through cytotoxic and vascular mechanisms.

Long-term real-world evidence of CPX-351 of high-risk patients with AML identified high rate of negative MRD and prolonged OS

AbstractCPX-351 has been approved for patients with therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). No extensive data are available on measurable residual disease (MRD) and long-term clinical outcome using CPX-351 in AML in real life. We retrospectively collected data from 168 patients in 36 centers in France and Italy who had received 1 or 2 cycles of induction with CPX-351. All patients were aged >18 years and had newly diagnosed, untreated t-AML or MRC-AML. With a median follow-up of 3 years, the median overall survival (OS) was 13.3 months. The median OS was 20.4 months vs 12.9 months for patients with MRD below or above 10–3, respectively (P = .006). In a multivariate analysis, only MRD >10–3 was associated with a poorer OS (hazard ratio, 2.6; 95% confidence interval, 1.2-5.5; P = .013). We also observed a trend toward a better median OS in patients who underwent hematopoietic stem cell transplantation with MRD <10–3 (not reached vs 26.0 months; P = .06). Achievement of MRD negativity contributed to the improvement of OS in the overall population and, maybe, in patients receiving transplant. These data provide the rationale for the 2 ongoing studies evaluating CPX-351 vs 7+3 in non–MRC-AML and non–t-AML using MRD as the primary end point for ALFA-2101 phase 2 clinical trial and event-free survival for AMLSG 30-18 phase 3 clinical trial.

Comparative analysis of hypofractionated short-course versus standard radiation therapy in elderly patients with glioblastoma: analysis of nationwide database.

Hypofractionated short-course radiation therapy (SCRT) is an alternative treatment option for elderly or frail patients with newly diagnosed glioblastoma (GBM) post-surgery. This study compares survival outcomes and treatment costs between patients receiving SCRT and those undergoing standard long-course radiation therapy (LCRT). This retrospective study utilized health insurance claims and national cancer registry data from Korea to compare overall survival (OS) and treatment costs between patients receiving SCRT and LCRT across all ages and sub-group analysis within the subgroup of cases aged 65 and older from 2016 onwards, a period when intensity-modulated radiotherapy (IMRT) was widely adopted. A total of 1,598 patients were included. Median OS since the first day of radiation therapy was 10.4 months (95% CI [9.6; 12.8]) for SCRT (n = 197) versus 16.2 months (95% CI [15.5; 16.9]) for LCRT (n = 1401) respectively. Subgroup analysis using stabilized inverse probability of treatment weighting (S-IPTW) showed indicating non-inferiority in elderly patients in median OS for elderly patients (≥ 65) with 10.6 months (95% CI [8.9; 14.0]) for SCRT (n = 147) versus 13.2 months (95% CI [8.9; 14.0]) for LCRT (n = 541). The median treatment cost of SCRT is about 6,000 USD lower, 25% less than LCRT. Compliance with the standard TMZ regimen post-radiation improved OS across all age groups. Considering comparable OS and shorter treatment duration, SCRT offers a viable, cost-effective option for elderly GBM patients. Adhering to standard TMZ also contributes to OS improvement. Further research reflecting key prognostic factors is essential to refining the role of SCRT.

Therapeutic strategies for mobile spine chordoma: en bloc Versus intralesional surgery with adjuvant charged-particle therapy.

The aim of this retrospective study is to analyze the impact of en bloc resection with negative margins versus intralesional resection plus adjuvant hadron-therapy (HT) on local control (LC) and overall survival (OS) in patients with mobile spine chordomas. Mechanical complications incidence as well as risk factors, and outcome differences are investigated as secondary endpoints. 33 patients in a period from January 2013 to December 2021 were enrolled for the final analysis. The inclusion criteria were: lesions located in the mobile spine (C1-L5), age ≥ 15 years, minimum follow-up of 2 years, en bloc or intralesional surgical resection, virgin or recurrent chordomas, with only one previous surgical treatment. No difference was found in terms of LC between the two groups. The presence of pathologic fracture at pre-operative imaging and the presence of macroscopic residual tumor after surgery, independently from its entity, seemed to be associated with an increased risk of LR. No difference was found between planned en bloc and planned intralesional surgery in terms of mechanical complications occurrence. Eight patients (24.24%) had mechanical complications during the follow up period: male sex, presence of pathologic fracture at baseline, a combined surgical approach, the use of carbon fiber-only hardware appeared to be associated with an increased risk of mechanical complications after the primary surgery. En bloc resection, whenever possible, is always to be preferred for its widely recognized potential in LC and OS improvement. However, technology advances in high-dose conformal charged-particle therapy have allowed improvement of local control rates as an adjuvant therapy of intralesional surgery for mobile spine chordoma, with acceptable acute and chronic toxicity.

A 14-year retrospective of HER2 + metastatic breast cancer treatment at one comprehensive cancer center: Impact of the trastuzumab/pertuzumab and trastuzumab-emtansine sequence versus trastuzumab on overall survival.

Introduction: Monoclonal antibodies represent a significant improvement in the treatment of the HER2 + metastatic cancer, which is associated with a worse prognosis. The objective of this study was to compare overall survival (OS) data in patients treated with trastuzumab + pertuzumab followed by trastuzumab-emtansine (T-DM1) in the second line of metastatic treatment (Arm A) versus patients treated with trastuzumab alone (Arm B). Progression-free survival (PFS) in first-line metastatic patients was also compared in both arms. Methods: This single-center retrospective study included patients from February 2008 to August 2022. OS and PFS of both arms were described and estimated using the Kaplan-Meier method. Data were extracted from electronic medical records and CHIMIO prescribing software. Results: The total duration of metastatic treatment of the 82 patients was significantly longer in the arm A (43.2 ± 28 months vs 33.6 ± 28.9 months), as was the median time to death (59 vs 52 months). The OS data showed a significant reduction in the risk of death in the arm A (Hazard Ratio = 0.59; 95% Confidence Interval [0.37-0.94]; p = 0.02). No difference was shown for PFS. Conclusion: The trastuzumab/pertuzumab/T-DM1 combination showed a significant improvement in OS. Our results are in line with the CLEOPATRA and EMILIA studies, but long-term responders in the arm A may have impacted our results. The absence of difference in term of PFS in first metastatic line may be explained by a selection bias, as patients in the arm A potentially have more aggressive forms.

Spinal chordoma and chondrosarcoma treatment experiences - a 20-year retrospective study from databases of two medical centers

The research retrospectively analyzed cases of spinal chordoma and chondrosarcoma involving patients who received treatment at the two hospitals between 2001 and 2023. Among the 48 patients studied (39 chordoma and 9 chondrosarcoma cases), the average age was 53.9 ± 15.8 years, with a range of 17 to 86 years. Out of these patients, 43 underwent excision surgery and were categorized based on tumor margin into negative (R0) or microscopically positive (R1) margin (n = 14) and macroscopically positive (R2) margin (n = 29) groups. The mean overall survival (OS) for R0/R1 and R2 groups was 156.5 ± 19.3 and 79.2 ± 11.9 months, respectively (p value = 0.012). The mean progression-free survival (PFS) for R0/R1 and R2 was 112.9 ± 24.4 and 25.5 ± 5.5 months (p value < 0.001). The study showed that regardless of whether patients in the R0/R1 or R2 groups received radiation therapy (RT) or not, there was no significant improvement in OS or PFS. Specifically, the OS and PFS for the RT only group were 75.9 ± 16.6 and 73.3 ± 18.0 months. In conclusion, the recommended treatment approach for spinal chordoma and chondrosarcoma remains en bloc resection surgery with an appropriate margin. Patients who are unsuitable for or decline surgery may find a beneficial disease control rate with traditional external beam photon/proton therapy.

First-line treatment of EGFR-mutated non-small cell lung cancer with brain metastases: a systematic review and meta-analysis

This systematic review and network meta-analysis evaluates first-line treatment options for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases. We analyzed 24 randomized controlled trials (RCTs) involving 2,682 patients, comparing various EGFR tyrosine kinase inhibitors (TKIs) and combination therapies. Direct comparisons showed that the addition of bevacizumab or chemotherapy to first-generation (1G) EGFR-TKIs improved overall survival (OS) compared to 1G TKIs alone, with HRs of 0.704 (95% CI: 0.433–0.973) and 0.682 (95% CI: 0.464–0.899), respectively. However, third-generation (3G) TKI monotherapy did not significantly improve OS compared with 1G TKIs, with an HR of 0.855 (95% CI: 0.511–1.198). Indirect comparisons suggested that the combination of 3G TKIs with chemotherapy provided the most significant improvements in OS and progression-free survival (PFS), significantly outperforming 3G TKIs, with HRs of OS 1.69 (95% CI: 1.14–3.4) and PFS 2.13 (95% CI: 1.28–3.54). Intracranial PFS was best with 1G TKIs plus bevacizumab. Our findings suggest that 3G EGFR-TKIs in combination with chemotherapy may be the most effective strategy for patients with EGFR-mutant NSCLC and brain metastases, though further head-to-head trials are needed for validation.

Characteristics and Survival Outcomes of Male Breast Cancer in Brazil: A Large Population-Based Study

AimsThis study evaluated the clinicopathological characteristics, treatment trends, and overall survival (OS) in male breast cancer (BC) in Sao Paulo State of Brazil. Materials and methodsMen diagnosed with invasive breast cancer between January 2000 and June 2020 were identified from Fundação Oncocentro de Sao Paulo database encompasses data pertinent to 46 million residents of the Sao Paulo State of Brazil. Patients were described according to age, education level, clinical stage, treatment modalities, and medical practice. Categorical variables were described as percentages and frequencies. Demographic, treatment factors, and OS were associated using a Cox proportional hazard regression model while accounting for different lengths of participant follow-up. The Kaplan-Meier curves were used to display survival curves. ResultsA total of 907 male BC patients were included. The age distribution at diagnosis was <51 years, 51–70 years, and >70 years in 21.5%, 51.5% and 27.0% of patients, respectively. The proportions of stages I, II, III, and IV were 19.5%, 36.6%, 31.5%, and 12.3%. For each stage I, II, III, and IV, 5- and 10-years OS were 87.9% and 77.8%, 79.9% and 58.9%, 51.6% and 24.5%, 20.0% and 5.6%, respectively. Patients who received postoperative radiotherapy experienced a significant improvement in OS (HR 0.67; 95% CI 0.53–0.84; p < 0.001). In the multivariable analysis adjusted for practice (public or private), education (low or medium/high), age, stage at diagnosis, and treatment modalities, the significant independent predictor for OS was stage at diagnosis. ConclusionMale BC tends to be diagnosed at a more advanced stage and older age at the time of diagnosis. Age and educational level did not influence survival outcomes. Stage at diagnosis and the use of postoperative radiotherapy were factors associated with improved OS.

Concurrent Chemoradiotherapy versus Radiotherapy Alone in the Treatment of Stage II and T3N0M0 Nasopharyngeal Carcinoma: A Systematic Review and Meta-Analysis

AimsThe efficacy of concurrent chemoradiotherapy (CCRT) for Stage II and T3N0 nasopharyngeal carcinoma (NPC), particularly during the shift from two-dimensional conventional radiotherapy (2DCRT) to intensity-modulated radiotherapy (IMRT) is debated.Therefore this study aims to systematically evaluate and meta-analyze survival benefits of CCRT versus radiotherapy alone for Stage II and T3N0 NPC, stratified by radiotherapy techniques. Materials and methodsAs of April 1, 2024, we conducted an exhaustive literature search across databases such as PubMed, Embase, Cochrane Library, and Web of Science, with the aim of identifying and screening studies that compare the efficacy of CCRT versus radiotherapy alone in the treatment of Stage II and T3N0 NPC. ResultsA total of 10 studies encompassing 5015 patients were included in this comprehensive analysis. The findings indicate that, apart from progression-free survival (PFS), CCRT did not improve survival outcomes, including overall survival (OS), distant metastasis-free survival (DMFS), local recurrence-free survival (LRRFS), and failure-free survival (FFS), with all P values exceeding 0.05. Concurrently, the incidence of grade ≥3 adverse events associated with CCRT was significantly elevated (odds ratio [OR] = 3.77, 95% confidence interval [CI] = 2.75–5.15, P < 0.0001). Subgroup analysis revealed that, compared with RT, the combination of 2DCRT with concurrent chemotherapy significantly improved OS (hazard ratio [HR] = 0.57, 95% CI = 0.46–0.71, P < 0.00001), PFS (HR = 0.65, 95% CI=0.53–0.78, P < 0.00001), DMFS (HR = 0.54, 95% CI = 0.37–0.79, P = 0.002), and LRRFS (HR = 0.63, 95% CI = 0.49–0.82, P = 0.0005). In contrast, the combination of IMRT with concurrent chemotherapy failed to demonstrate improvements in OS, PFS, DMFS, or LRRFS, with all P values exceeding 0.05. ConclusionIn contrast with RT, CCRT did not enhance survival in stage II and T3N0 NPC patients, yet caused more adverse reactions. 2DCRT combined with concurrent chemotherapy significantly improved OS, PFS, DMFS, and LRRFS, while IMRT with concurrent chemotherapy showed no clinical benefits.

Immunotherapy in Stage III-IV Colon Cancer: A Propensity Score-Matched Analysis of the National Cancer Database.

Immunotherapy for the systemic treatment of cancer offers new treatment possibilities for advanced malignancies. Despite promising initial results, evidence on efficacy of immunotherapy for colon cancer is lacking. Thus, we aimed to assess short-term and long-term outcomes of immunotherapy in patients with advanced colon cancer. A US National Cancer Database was searched for patients with stage III-IV colonic adenocarcinoma between 2010 and 2019. Propensity score matching was used to classify the cohort into 2 groups: patients who received immunotherapy and controls. Main outcome measures were primary outcome was overall survival (OS). A total of 23,778 patients with stage III-IV colonic adenocarcinoma were treated with immunotherapy during the study period compared to 114,753 controls. Immunotherapy treated patients were younger (median age 61 vs. 67 y; P <0.001), more often male (57.3% vs. 50.7%, P <0.001), had more private insurance (44.1% vs. 33.7%; P <0.001), had more left-sided tumors (49.5% vs. 39.1%; P <0.001) and liver metastasis (80.2% vs. 61.7%; P <0.001) than controls. Immunotherapy patients received more standard chemotherapy (49.8% vs. 41.6%; P <0.001). After propensity-score matching, mean OS was significantly shorter in the immunotherapy group compared with controls (34.7 vs. 36.2 mo; P =0.008). Cox regression analysis demonstrated that immunotherapy was associated with increased risk for mortality (HR: 1.1; 95% CI: 1.02-1.18; P =0.005). Patients who received immunotherapy had lower 90-day mortality rates compared with controls (2.3% vs. 3.6%; P =0.004), but the groups had equivalent 30-day mortality rates (0.7% vs. 0.8%; P =0.76). Immunotherapy showed no improvement in OS in patients with stage III-IV colon cancer.

Analysis of progression-free and overall survival in ovarian cancer: Bevacizumab treatment outcomes using historical cohort.

Background: The incorporation of bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has redefined therapeutic strategies for advanced ovarian cancer. This study evaluates the efficacy of bevacizumab combined with standard chemotherapy by comparing progression-free survival (PFS) and overall survival (OS) outcomes with a historical cohort of patients treated with standard chemotherapy alone. Methods: We conducted an analysis of 71 patients with advanced epithelial ovarian cancer treated at the University Clinical Center in Niš, Serbia, from April 2017 to March 2023. All patients received standard chemotherapy paired with bevacizumab and were monitored for progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier estimates. Subgroup analyses were performed based on age, ECOG performance status, presence of metastases, and pleural effusion. Additionally, a historical cohort of 30 patients treated with standard chemotherapy alone was used for comparison, and Cox regression analysis was conducted to identify factors influencing treatment outcomes. Results: The study findings indicate significant improvements in median PFS (20 months vs. 15 months) and OS (58 months vs. an undetermined upper limit) compared to the historical cohort. Subgroup analysis of the bevacizumab-treated group revealed that younger patients (<65 years) and those without metastases or pleural effusion exhibited notably better survival outcomes. The hazard ratio for PFS in patients younger than 65 was 0.65 (95% CI: 0.45-0.93), suggesting a substantial reduction in disease progression risk compared to older patients. Conclusion: Bevacizumab, when used alongside standard chemotherapy, significantly extends both PFS and OS in patients with advanced ovarian cancer. These benefits are particularly pronounced in younger patients. The results underscore the necessity of integrating bevacizumab into the treatment regimen for advanced ovarian cancer, advocating for tailored therapeutic strategies based on individual risk profiles and clinical characteristics. This study reinforces the pivotal role of bevacizumab in enhancing the current ovarian cancer treatment landscape and highlights the potential for further personalizing oncological care.

Sacituzumab govitecan in HR+HER2− metastatic breast cancer: the randomized phase 3 EVER-132-002 trial

Sacituzumab govitecan (SG) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+HER2−) metastatic breast cancer (mBC) in the global TROPiCS-02 study. TROPiCS-02 enrolled few Asian patients. Here we report results of SG in Asian patients with HR+HER2− mBC from the EVER-132-002 study. Patients were randomized to SG (n = 166) or chemotherapy (n = 165). The primary endpoint was met: PFS was improved with SG versus chemotherapy (hazard ratio of 0.67, 95% confidence interval 0.52–0.87; P = 0.0028; median 4.3 versus 4.2 months). OS also improved with SG versus chemotherapy (hazard ratio of 0.64, 95% confidence interval 0.47–0.88; P = 0.0061; median 21.0 versus 15.3 months). The most common grade ≥3 treatment-emergent adverse events were neutropenia, leukopenia and anemia. SG demonstrated significant and clinically meaningful improvement in PFS and OS versus chemotherapy, with a manageable safety profile consistent with prior studies. SG represents a promising treatment option for Asian patients with HR+HER2− mBC (ClinicalTrials.gov identifier no. NCT04639986).

Evolution of overall survival (OS) after curative-intent lung cancer surgery in a population-based Mississippi Delta cohort.

278 Background: Surgical resection is the most important curative modality for patients with lung cancer, with long-term OS influenced by both surgical quality and cancer biology. We compared surgical care and outcomes over 4 eras in the population-based Mid-South Quality of Surgical Resection (MS-QSR) cohort, an ongoing regional surgical and pathologic quality improvement (QI) dissemination and implementation project. Methods: We implemented a surgical lymph node collection kit and a novel pathology gross dissection method across 12 hospitals encompassing &gt;95% of lung cancer resections in 5 contiguous Dartmouth Hospital Referral Regions. We analyzed the MS-QSR cohort at 5-year intervals characterized by stepped-wedge implementation of specific QI interventions: Era 1 (2004-2008; baseline, no QI), Era 2 (2009-2013; quality feedback, surgical QI pilot), Era 3 (2014-2018; surgical QI implementation), and Era 4 (2019-2023; combined surgical QI and pathology QI implementation). We used standard statistical methods to compare surgical quality; Kaplan-Meier plot, log-rank test, and Cox proportional hazards model with Era 1 as reference to compare OS across eras. Results: Of 7240 resections, 14%, 31%, 29%, and 26% were performed in Eras 1-4, respectively (Table). Attainment of the stringent International Association for the Study of Lung Cancer (IASLC) definition of complete resection increased from 0% in Era 1 to 32% in Era 4; attainment of the American College of Surgeons Operative Standard 5.8 (ACS_OS 5.8), the current US definition of surgical quality, improved from 4% in Era 1 to 67% in Era 4; 120-day mortality rate decreased from 10% to 4% (p&lt;0.0001 for all comparisons). With median follow-up of 4.7, 5.5, 5.6, and 2 years for Eras 1-4, 3-year OS rates were 60%, 64%, 70%, and 79%; 5-year OS rates were 48%, 52%, 58%, and 70%, respectively (p&lt;0.0001). The Hazard Ratio (HR) for mortality decreased from 0.91 (95% CI: 0.8-0.99) in Era 2 to 0.49 (95% CI: 0.43-0.56) in Era 4. Conclusions: Surgical quality and OS sequentially improved in this diverse, high-risk population-based Mississippi Delta surgical resection cohort. We are evaluating the full range of factors associated with this striking OS improvement. Ongoing work is exploring biologic correlates to this improvement. Variable Era 1 N= 988 Era 2 N=2235 Era 3 N=2107 Era 4 N=1910 Median age (Q1, Q3) 68 (62, 74) 68 (62, 74) 68 (61, 74) 68 (61, 74) Male sex (%) 514 (52%) 1234 (55%) 1082 (51%) 977 (51%) Black race 221 (22%) 416 (19%) 450 (21%) 451 (24%) Attained ACS_OS 5.8 40 (4%) 533 (24%) 1050 (50%) 1272 (67%) IASLC complete resectionUncertain completeness 0 (0%)930 (94%) 194 (9%)1932 (86%) 435 (21%)1594 (76%) 606 (32%)1227 (64%) 120-day mortality 100 (10%) 197 (9%) 139 (7%) 72 (4%) 5-year OS 48 (45-51) 52 (50-55) 58 (56-60) 70 (66-74) HR (95% CI) Reference 0.91 (0.83-0.99) 0.75 (0.69-0.83) 0.49 (0.43-0.56)

Are Palliative Interventions Worth the Risk in Advanced Gastric Cancer? A Systematic Review.

Background: Less than 25% of gastric cancers (GC) are discovered early, leading to limited treatment options and poor outcomes (27.8% mortality, 3.7% 5-year survival). Screening programs have improved cure rates, yet post-diagnosis treatment guidelines remain unclear (systemic chemotherapy versus surgery). The optimal type of palliative surgery (palliative gastrectomy (PG), surgical bypass (SB), endoscopic stenting (ES)) for long-term outcomes is also debated. Methods: A literature review was conducted using PubMed, MEDLINE, and EMBASE databases along with Google Scholar with the search terms "gastric cancer" and "palliative surgery" for studies post-1985. From the initial 1018 articles, multiple screenings narrowed it to 92 articles meeting criteria such as "metastatic, stage IV GC", and intervention (surgery or chemotherapy). Data regarding survival and other long-term outcomes were recorded. Results: Overall, there was significant variation between studies but there were similarities of the conclusions reached. ES provided quick symptom relief, while PG showed improved overall survival (OS) only with adjuvant chemotherapy in a selective population. PG had higher mortality rates compared to SB, with ES having a reported 0% mortality, but OS improved with chemotherapy across both SB and PG. Conclusions: Less frail patients may experience an improvement in OS with palliative resection under limited circumstances. However, operative intervention without systemic chemotherapy is unlikely to demonstrate a survival benefit. Further research is needed to explore any correlations.

Breast cancer drugs: FDA approval, development time, efficacy, clinical benefits, innovation, trials, endpoints, quality of life, value, and price

ObjectiveThis study analyzes the development, benefits, trial evidence, and price of new breast cancer drugs with US Food and Drug Administration (FDA) approval.MethodsWe identified 26 drugs with 42 FDA-approved indications for early and metastatic breast cancer (2000–2023). Data were collected from FDA labels, clinicaltrials.gov, and Medicare and Medicaid. Overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) and tumor response’s relative risk (RR) alongside objective response rate (ORR) were meta-analyzed.ResultsThe median development time for breast cancer drugs was 7.8 years (95% CI 6.2–10.8). 26% of treatments were considered innovative (“first-in-indication”) with 88% acting via a targeted mechanism. 64% were small molecules, 19% antibodies, and 18% antibody-drug conjugates. 38% were approved for HR + and 31% for HER2 + breast cancer. 6 indications were for early and 36 for metastatic breast cancer. Indications utilized FDA’s special programs: orphan (2%), fast track (24%), accelerated approval (19%), priority review (74%), breakthrough therapy (44%). Approval was predominantly supported by phase 3 trials (88%) of randomized controlled design (66%), enrolling a median of 585 patients (IQR 417–752) at 181 centers (IQR 142–223) across 19 countries (IQR 17–20). New drugs’ HR were 0.78 for OS (95% CI 0.74–0.82) and 0.59 for PFS (95% CI 0.54–0.64) with a RR for tumor response of 1.61 (95% CI 1.46–1.76). Median improvements of OS were 2.8 months (IQR 1.8–5.8) and PFS were 4.4 months (IQR 2.2–7.1). In single-arm trials, the average ORR was 31% (95% CI 10–53). In meta-regressions, the correlation between OS/PFS was 0.34 (p = 0.031) and OS/response was 0.01 (p = 0.435). 60% of treatments had a ‘high-value’ ESMO-MCBS score with 14% demonstrating improvements in quality of life. The median price was $16,013 per month (95% CI 13,097–17,617). There was no association between prices and patient benefit. The median value per life year gained was $62,419 (IQR 25,840–86,062).ConclusionsOver the past two decades, the development of innovative and effective drugs transformed the treatment landscape for breast cancer patients. Yet, investigators and regulators must safeguard that highly-priced new drugs demonstrate improvements in patient-centered clinical endpoints: overall survival and quality of life.

Efficacy and safety of PARP inhibitor maintenance therapy for ovarian cancer: a meta-analysis and trial sequential analysis of randomized controlled trials.

The landscape of poly (ADP-ribose) polymerase (PARP) inhibitor treatment for ovarian cancer (OC) is continually evolving. This research aimed to evaluate the efficacy and safety of PARP inhibitors compared to placebo as a maintenance therapy for OC patients. We conducted a search of PubMed, Embase, Web of Science, and the Cochrane Library databases for randomized controlled trials (RCTs) involving the use of PARP inhibitors as maintenance therapy in OC patients, up to 16 June 2024. Data regarding progression-free survival (PFS), overall survival (OS), chemotherapy-free interval (CFI), time to first subsequent therapy or death (TFST), time to second subsequent therapy or death (TSST), and treatment-emergent adverse events (TEAEs) were aggregated. Pooled hazard ratio (HR) and their corresponding 95% confidence intervals (CI) were calculated for PFS, OS, CFI, TFST, and TSST. Additionally, the relative risk (RR) and 95% CI for TEAEs were determined. This meta-analysis encompassed 20 RCTs involving 7,832 participants. The overall analysis demonstrated that maintenance therapy with PARP inhibitors led to significant improvements in PFS (HR: 0.398, 95% CI = 0.339-0.467, 95% PI = 0.219-0.724), OS (HR: 0.677, 95% CI = 0.582-0.788, 95% PI = 0.546-0.839), CFI (HR: 0.417, 95% CI = 0.368-0.472, 95% PI = 0.265-0.627), TFST (HR: 0.441, 95% CI = 0.391-0.498, 95% PI = 0.308-0.632), and TSST (HR: 0.574, 95% CI = 0.507-0.649, 95% PI = 0.488-0.674) compared with placebo. Subgroup analyses further indicated that PARP inhibitor maintenance treatment significantly improved PFS, regardless of homologous recombination status (all p < 0.05). However, the risks of any grade (RR = 1.046, 95% CI = 1.032-1.059, 95% PI = 1.028-1.055) and grade ≥3 TEAEs (RR = 2.931, 95% CI = 2.641-3.253, 95% PI = 2.128-3.792) were increased by PARP inhibitor maintenance therapy compared to placebo. Our research elucidated the benefits of maintenance therapy with PARP inhibitors in patients with OC, showing improvements in PFS, OS, CFI, TFST, and TSST. Vigilance regarding TEAEs is paramount for clinicians implementing PARP inhibitor maintenance therapy in clinical practice. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024560286.

The Role of Local Prostate and Metastasis-Directed Radiotherapy in the Treatment of Oligometastatic Prostate Cancer.

Background/Objectives: Oligometastatic prostate cancer (OMPC) represents an early stage of metastatic disease characterized by a limited number of lesions. Recent advancements in imaging and treatment have revived interest in personalized therapies, including metastasis-directed radiotherapy (OMDRT) and primary prostate radiotherapy (PPR). This study evaluates the impact of OMDRT timing and the role of PPR on survival outcomes in OMPC patients; Methods: In this retrospective cohort study, 82 patients with OMPC who underwent OMDRT between 2010 and 2019 were analyzed. Patients were classified based on OMDRT timing (early vs. late) and disease type (synchronous vs. metachronous). Progression-free survival (PFS) and overall survival (OS) were the primary endpoints, assessed via Kaplan-Meier analysis and Cox proportional hazards models; Results: Among the patients, 36 (43.9%) had synchronous and 46 (56.1%) had metachronous OMD. With a median follow-up of 32 months, the 5-year PFS and OS rates were 77.5% and 88.5%, respectively. Early OMDRT significantly improved PFS (HR 0.461, 95% CI: 0.257-0.826, p = 0.009) and OS (HR 0.219, 95% CI: 0.080-0.603, p = 0.003). Subgroup analysis showed the most favorable outcomes for synchronous OMD patients receiving early OMDRT, with a median PFS of 22.2 months and a 5-year survival rate of 42.1%. The treatment of the primary prostate provided a survival benefit in the OS of synchronous OMD patients (5-year 83.1% vs. 50%, p = 0.025), and there was a further improvement in OS after PPR (5-year 87.7% vs. 50%, p = 0.015). Conclusions: Early OMDRT significantly enhances survival outcomes in OMPC, in both synchronous and metachronous cases. The integration of PPR can further improve results, emphasizing the importance of early intervention and personalized treatment strategies. To more definitively clarify our findings across various clinical situations, further studies with larger cohorts or prospective designs are necessary.

Results from the randomized KEYNOTE-355 study of pembrolizumab plus chemotherapy for Asian patients with advanced TNBC

In the phase 3 KEYNOTE-355 study (NCT02819518), pembrolizumab plus chemotherapy demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy among patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) and programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 10 tumors. We analyzed outcomes for the subgroup of patients enrolled in Asia in KEYNOTE-355. Patients received pembrolizumab 200 mg or placebo (2:1 randomization) every 3 weeks for 35 cycles plus investigator’s choice chemotherapy. Primary endpoints were PFS per Response Evaluation Criteria in Solid Tumors version 1.1 and OS. Among patients enrolled in Hong Kong, Japan, Korea, Malaysia and Taiwan (pembrolizumab plus chemotherapy, n = 113; placebo plus chemotherapy, n = 47), 117 (73.1%) had PD-L1 CPS ≥ 1 and 56 (35.0%) had PD-L1 CPS ≥ 10. Median time from randomization to data cutoff (June 15, 2021) was 43.8 (range, 36.8‒53.2) months (intent-to-treat [ITT] population). Hazard ratios (HRs [95% CI]) for PFS in the CPS ≥ 10, CPS ≥ 1, and ITT populations were 0.48 (0.24‒0.98), 0.58 (0.37‒0.91), and 0.66 (0.44‒0.99), respectively. Corresponding HRs (95% CI) for OS were 0.54 (0.28‒1.04), 0.62 (0.40‒0.97), and 0.57 (0.39‒0.84). Grade 3/4 treatment-related adverse events (AEs) occurred in 77.9% versus 78.7% of patients with pembrolizumab plus chemotherapy versus placebo plus chemotherapy. No grade 5 AEs occurred. Clinically meaningful improvement in PFS and OS with manageable toxicity were observed with pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients enrolled in Asia with previously untreated, inoperable or metastatic TNBC.Trial registration: ClinicalTrials.gov, NCT02819518.

Impact of Adjuvant Chemotherapy on Resected Intraductal Papillary Mucinous Neoplasm-Derived Pancreatic Cancer: Results From an International Multicenter Study.

The benefit of adjuvant therapy for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) remains unclear because of severely limited evidence. Although biologically distinct entities, adjuvant therapy practices for IPMN-derived PDAC are largely founded on pancreatic intraepithelial neoplasia-derived PDAC. We aimed to evaluate the role of adjuvant chemotherapy in IPMN-derived PDAC. This international multicenter retrospective cohort study (2005-2018) was conceived at the Verona Evidence-Based Medicine meeting. Cox regressions were performed to identify risk-adjusted hazard ratios (HR) associated with overall survival (OS). Kaplan-Meier curves and log-rank tests were employed for survival analysis. Logistic regression was performed to identify factors motivating adjuvant chemotherapy administration. A decision tree was proposed and categorized patients into overtreated, undertreated, and optimally treated cohorts. In 1,031 patients from 16 centers, nodal disease (HR, 2.88, P < .001) and elevated (≥37 to <200 µ/mL, HR, 1.44, P = .006) or markedly elevated (≥200 µ/mL, HR, 2.53, P < .001) carbohydrate antigen 19-9 (CA19-9) were associated with worse OS. Node-positive patients with elevated CA19-9 had an associated 34.4-month improvement in median OS (P = .047) after adjuvant chemotherapy while those with positive nodes and markedly elevated CA19-9 had an associated 12.6-month survival benefit (P < .001). Node-negative patients, regardless of CA19-9, did not have an associated benefit from adjuvant chemotherapy (all P > .05). Based on this model, we observed undertreatment in 18.1% and overtreatment in 61.2% of patients. Factors associated with chemotherapy administration included younger age, R1-margin, poorer differentiation, and nodal disease. Almost half of patients with resected IPMN-derived PDAC may be overtreated or undertreated. In patients with node-negative disease or normal CA19-9, adjuvant chemotherapy is not associated with a survival benefit, whereas those with node-positive disease and elevated CA19-9 have an associated benefit from adjuvant chemotherapy. A decision tree was proposed. Randomized controlled trials are needed for validation.

High-dose chemotherapy for patients with stage III breast cancer with homologous recombination deficiency: a discrete choice experiment among healthcare providers.

High-dose chemotherapy with autologous stem cell rescue (HDCT) is currently under investigation as a potential therapy for patients with stage III HER2-negative breast cancer with homologous recombination deficiency (HRD). In addition to survival, the impact on short- and long-term side effects might influence the uptake of HDCT by healthcare professionals. As part of the SUBITO trial, we investigated healthcare professionals' treatment (outcome) preferences for patients with HRD stage III HER2-negative breast cancer and established how healthcare professionals make trade-offs between these treatment outcomes. We conducted a discrete choice experiment in which healthcare professionals were asked to choose repeatedly between scenarios with two treatment options (HDCT or standard of care (SOC)) that varied in outcome with respect to 10-year overall survival (OS), short-term toxicity, long-term cognitive impairment, and premature menopause. We analysed treatment preferences, relative importance, and trade-offs using a multinomial logistic model. Thirty-five of the 151 dedicated breast cancer professionals with extensive experience in treating breast cancer patients completed the survey. The 10-year OS and long-term cognitive impairment were the most important attributes. The results indicate a requirement of 10.4% and 25.1% absolute additional improvement in the 10-year survival rate to justify accepting moderate or severe long-term cognitive impairment as a trade-off, respectively. Therefore, we found in our dataset that healthcare professionals expected a large improvement in 10-year OS to accept moderate to severe cognitive impairment. This information calls for further research into chemotherapy-related cognitive impairment, shared decision-making, and treatment preferences for patients with stage III breast cancer.