Treatment Of Metastatic Cancer Research Articles

Comparison between different therapeutic sequences in patients affected by metastatic pancreatic ductal adenocarcinoma.

674 Background: The first-line treatment of metastatic pancreatic cancer involves different therapeutic regimens, among them, mFOLFIRINOX and gemcitabine-nabpaclitaxel. However, it remains to be clarified which sequence might correlate with better outcomes. The aim of our work was to evaluate which sequence leads to better overall survival in this setting. Methods: We retrospectively collected data from 358 patients affected by stage IV pancreatic ductal adenocarcinoma from 3 different Italian Institutions. Patients received mFOLFIRINOX or gemcitabine plus nabpaclitaxel as first-line chemotherapy, followed by a second-line non-cross-resistant chemotherapy (gemcitabine or fluoropyrimidine-based combinations). Survival distribution was assessed by Kaplan-Meier curves. The primary endpoint was median overall survival. Statistical analysis was performed with MedCalc package. Results: The median age was 66 (± 9), 195 (54,4%) were male and 163 (45,6%) were female. 292 (81,5%) patients start gemcitabine plus nabpaclitaxel as first line treatment, while 66 (18,5%) patients start mFOLFIRINOX first-line therapy. No statistically significant differences in terms of mOS were observed between the two mFOLFIRINOX and gemcitabine-nabpaclitaxel groups: 16 versus 15 months, respectively, p = 0,2). No significant differences were found in terms of mPFS either: 7 versus 8 months, respectively, p = 0,3). Conclusions: The results of our retrospective study showed no statistically significant survival advantage between the sequences starting with mFOLFIRINOX or with gemcitabine-nabpaclitaxel. Further studies will be necessary to establish the effectiveness of new therapeutic schemes to be introduced into clinical practice in order to define a better therapeutic algorithm.

Alternating application of gemcitabine/nab-paclitaxel (Gem/nab-Pac) and Gem monotherapy or continuous application of Gem/nab-Pac after induction treatment for first-line treatment of metastatic pancreatic cancer (mPC): First results from the randomized phase 2 ALPACA study from the German AIO study group (AIO-PAK-0114).

605 Background: The aim of the ALPACA study was to investigate whether improved overall tolerability accompanied by prolonged treatment duration and increased efficacy can be achieved by alternating treatment cycles of Gem/nab-Pac and Gem monotherapy compared to standard continuous Gem/nab-Pac after a 3-month induction phase in patients with mPC. Methods: The randomized, multicenter phase 2 ALPACA trial of the German AIO study group enrolled patients with confirmed mPC in the first-line setting. After an induction phase with 3 cycles of standard dose Gem/nab-Pac (Gem 1000 mg/m2 and nab-Pac 125 mg/m2 on d1, 8, 15 of each 28-day cycle), patients were randomized (1:1) either to continue treatment with standard Gem/nab-Pac, or to receive alternating cycles of standard dose Gem/nab-Pac combination therapy and Gem monotherapy (Gem 1000 mg/m2 on d1, 8, 15 of each 28-day cycle). Primary study endpoint was overall survival (OS) after randomization. The trial was registered with ClinicalTrials.gov, NCT02564146. Results: Between May 2016 and May 2021, 325 patients were enrolled from 29 German centers. 6 of the enrolled patients did not start treatment within the study. Following 3 cycles of induction treatment, 174 patients (53.5%) could be randomized. Main reasons for premature dropout were death (24.8%), progression of disease (22.8%), and adverse events (15.9%). Median OS after randomization in the alternating treatment arm was comparable to the standard treatment arm (10.5 vs. 10.4 months; HR 0.903, 80% CI 0.723-1.128, p=0.5551). Likewise, median progression-free survival was comparable in both arms (5.5 vs. 5.3 months; HR 0.767, 95% CI 0.556-1.056, p=0.1017). Tolerability was improved for mPC patients treated with alternating cycles compared to standard therapy, especially regarding peripheral neuropathy (all grades, 44.7% vs. 52.5%), and occurrence of infections (all grades, 29.4% vs. 47.5%). Treatment duration after randomization was similar in both arms (3.25 vs. 3.02 months). Fewer patients receiving alternating treatment cycles dropped out of the study due to adverse events compared to patients treated with continuous Gem/nab-Pac (14.9% vs 27.5%). In return, these patients terminated the study slightly more often due to progression of disease (48.3% vs 42.5%). Conclusions: The ALPACA trial suggests that a dose-reduced regimen with alternating cycles of Gem/nab-Pac and Gem monotherapy after 3 induction cycles of standard Gem/nab-Pac is feasible and associated with an OS comparable to standard treatment while resulting in improved tolerability. Clinical trial information: NCT02564146 .

A randomized phase II/III study to evaluate the safety and efficacy of disitamab vedotin (DV) plus toripalimab and chemotherapy/trastuzumab as first-line treatment for HER2-expressed, locally advanced, or metastatic gastric cancer.

TPS427 Background: For HER2-positive (IHC 2+/FISH-, IHC 3+) advanced gastric cancer/gastroesophageal junction cancer (GC/GEJ), trastuzumab in combination with chemotherapy is the standard first-line treatment. Adding pembrolizumab to trastuzumab and chemotherapy significantly improves objective response rate. However, the overall survival results did not meet statistical significance. DV, a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E (MMAE) via a cleavable linker. We aimed to evaluate DV combined with toripalimab and chemotherapy/ trastuzumab as first-line treatment for HER2-expressed (IHC 1+, 2+ or 3+) locally advanced or metastatic GC/GEJ. Methods: This is a randomized, seamless phase II/III trial. Key eligibility criteria include participants confirmed GC/GEJ and systemic treatment naïve. In phase II period, participants will be divided into two cohorts. Ninety participants with HER2-positive (IHC2+ FISH+ or IHC3+) will be randomly (1:1:1) assigned to receive DV every 2 weeks (Q2W) plus toripalimab Q2W and oxaliplatin and capecitabine (CAPOX) every 3 weeks (Q3W), or DV plus toripalimab and trastuzumab Q3W, versus toripalimab plus trastuzumab and CAPOX. Forty participants with HER2-low (IHC1+ or IHC2+/FISH-) will be randomly (1:1) assigned to receive DV plus toripalimab and CAPOX, versus toripalimab and CAPOX. In phase III period, HER2-positive participants will be randomly (1:1) assigned to receive DV plus toripalimab and CAPOX or trastuzumab versus CAPOX plus trastuzumab±anti-PD-1 antibody, based on results from phase II, and evolution of treatment landscape. HER2-low participants will be randomly (1:1) assigned to receive DV plus toripalimab and CAPOX versus CAPOX±anti-PD-1 antibody based on evolution of stand of care. The primary endpoint is PFS by IRC in PD-L1 CPS ≥5 population. To the best of our knowledge, this is the first Phase III clinical trial exploring the combination of anti-HER2 ADC with trastuzumab and chemotherapy in first-line GC/GEJ. This trial began in August 2023 and has enrolled 4 patients at the time of submission. Clinical trial information: NCT05980481 .

Metastatic Pancreatic Cancer: Where Are We?

Pancreatic cancer is one of the most lethal neoplasms worldwide; it is aggressive in nature and has a poor prognosis. The overall survival rate for pancreatic cancer is low. Most patients present non-specific symptoms in the advanced stages, which generally leads to late diagnosis, at which point there is no option for curative surgery. The treatment of metastatic pancreatic cancer includes systemic therapy, in some cases radiotherapy, and more recently, molecular targeted therapies, which can positively impact cancer control and improve quality of life. This review provides an overview of the molecular landscape of pancreatic cancer based on the most recent literature, as well as current treatment options for patients with metastatic pancreatic cancer.

Abstract C084: iExplore: A phase I study of mesenchymal stem cell derived exosomes with KrasG12D siRNA for metastatic pancreas cancer patients harboring the KrasG12D mutation

Abstract Introduction The safety, target engagement, and benefit of iExosomes, short interfering RNA targeting KrasG12D encapsulated within exosomes and intravenously administered, were explored in patients with advanced pancreatic cancer harboring a KrasG12D mutation. Methods The initial phase I protocol was a conventional 3+3 design with three escalating dose levels (levels 1-3) of iExosomes, defined as exosomal protein levels and containing equal amounts of siRNA. Lack of toxicity at the highest dose level subsequently guided protocol amendment to an adaptive design exploring further dose escalation, with one patient treated at each additional dose level (levels 4-6). The highest dose level safely tolerated would be considered the optimal biological dose (OBD). Treatments were administered over three consecutive 14-day cycles. Blood was collected from all patients to assess changes in KrasG12D circulating DNA in response to treatment. Pre and post treatment biopsies were obtained from patients treated at dose levels 4-6 to evaluate target engagement, including changes in phosphorylated ERK levels by immunohistochemistry. Results Twelve patients received multiple iExosome treatments at specified dose levels, and none experienced any related adverse events of any grade. No dose limiting toxicities were observed, and the OBD was determined to be 28.8 mg of iExosome protein, administered in 6 infusions. Levels of circulating KrasG12D DNA decreased over the course of therapy. Levels of phosphorylated ERK in tumor biopsies decreased while on treatment, dropping to undetectable levels in higher dose levels. Clinically, the best response observed was stable disease as per RECISTv1.1 criteria in three patients, one each at dose levels 1-3. Conclusions iExosome therapy targeting KrasG12D is a safe and well-tolerated treatment for metastatic pancreatic cancer. Decrease in levels of circulating KrasG12D DNA and suppression of downstream Kras signaling phosphorylated ERK in tissue biopsies support effective target engagement of iExosomes in patients. Considering preclinical studies that indicate iExosome treatment enhances immune mediated anti-tumor responses, a future trial design will explore iExosomes at the OBD in combination with immune checkpoint inhibition for the treatment of pancreatic cancer. Citation Format: Brandon G. Smaglo, Valerie S. LeBleu, J. Jack Lee, Anirban Maitra, Raghu Kalluri, Katy Rezvani, Luisa M. Solis Soto, Mark Hurd, Indreshpal Kaur, Mayela C. Mendt Vilchez, Michelle L. Kirtley, Stacy L. Shaftoe, Maria Pia Morelli, Michael J. Overman, Dan Zhou, Robert A. Wolff, Janet Tu, Jason A. Willis, Ryan W. Huey, Michael S. Lee, Priya R. Bhosale, Suzanne W. Dworsky, Li Xu, Shubham Pant, Elizabeth J. Shpall. iExplore: A phase I study of mesenchymal stem cell derived exosomes with KrasG12D siRNA for metastatic pancreas cancer patients harboring the KrasG12D mutation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C084.

Metastases-directed local therapies (MDT) beyond genuine oligometastatic disease (OMD): Indications, endpoints and the role of imaging

To further personalise treatment in metastatic cancer, the indications for metastases-directed local therapy (MDT) and the biology of oligometastatic disease (OMD) should be kept conceptually apart. Both need to be vigorously investigated. Tumour growth dynamics – growth rate combined with metastatic seeding efficiency – is the single most important biological feature determining the likelihood of success of MDT in an individual patient, which might even be beneficial in slowly developing polymetastatic disease. This can be reasonably well assessed using appropriate clinical imaging. In the context of considering appropriate indications for MDT, detecting metastases at the edge of image resolution should therefore suggest postponing MDT. While three to five lesions are typically used to define OMD, it could be argued that countability throughout the course of metastatic disease, rather than a specific maximum number of lesions, could serve as a better parameter for guiding MDT. Here we argue that the unit of MDT as a treatment option in metastatic cancer might best be defined not as a single procedure at a single point in time, but as a series of treatments that can be delivered in a single or multiple sessions to different lesions over time. Newly emerging lesions that remain amenable to MDT without triggering the start of a new systemic treatment, a change in systemic therapy, or initiation of best supportive care, would thus not constitute a failure of MDT. This would have implications for defining endpoints in clinical trials and registries: Rather than with any disease progression, failure of MDT would only be declared when there is progression to polymetastatic disease, which then precludes further options for MDT.

Cost-Effectiveness Analysis of Systemic Therapy for Intensification of Treatment in Metastatic Hormone-Sensitive Prostate Cancer in India.

Androgen-deprivation therapy is the mainstay of treatment for patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC). However, the intensification of treatment with either docetaxel or novel anti-androgens (abiraterone-acetate plus prednisone [AAP], enzalutamide, and apalutamide) is being recommended based on the improved clinical outcomes and quality of life among patients. This study aimed to determine the most cost-effective drug for treatment intensification for patients with mHSPC in India. A Markov model was developed with four health states: progression-free survival, progressive disease, best supportive care, and death. Lifetime costs and consequences were estimated for four treatment sequences: AAP-first, enzalutamide-first, apalutamide-first, and docetaxel-first. Incremental cost per quality-adjusted life-year (QALY)gained with a given treatment option was compared against the next best alternative and assessed for cost effectiveness using a willingness to pay threshold of 1 × per capita gross domestic product in India. We estimated that the total lifetime cost per patient was ₹1,367,454 (US$17,487), ₹2,168,885 (US$27,735), ₹7,678,501 (US$98,190), and ₹1,358,746 (US$17,375) in the AAP-first, enzalutamide-first, apalutamide-first, and docetaxel-first treatment sequence, respectively. The mean quality-adjusted life-years lived per patient were 4.78, 5.03, 3.22, and 2.61, respectively. The AAP-first sequence incurs an incremental cost of ₹4014 (US$51) per quality-adjusted life-year gained as compared with the docetaxel-first sequence, with a 87% probability of being cost effective at the willingness-to-pay threshold of 1 × per-capita gross domestic product of India. The use of AAP-first also incurs an incremental net monetary benefit of ₹396,491 (US$5070) as compared with the docetaxel-first treatment sequence. Nearly a 48% reduction in the price of enzalutamide is required to make it a cost-effective treatment sequence as compared with AAP-first in India. We concur with the inclusion of standard-dose AAP in India's publicly financed health insurance scheme for the intensification of treatment in mHSPC as it is the only cost-effective sequence among the various novel anti-androgens when compared with the docetaxel-first treatment sequence. Furthermore, a systematic reduction in the price of enzalutamide would further help to improve clinical outcomes among patients with mHSPC.

Carboplatin and Etoposide for the Treatment of Metastatic Prostate Cancer with or without Neuroendocrine Features: A French Single-Center Experience.

Chemotherapy using carboplatin and etoposide (CE) is frequently pragmatically proposed to treat metastatic prostate cancer (mPC), both primary small-cell neuroendocrine (PSC-NE) carcinoma and adenocarcinoma with or without neuroendocrine (NE) marker elevation. However, the real benefit of CE is poorly reported in the recent therapeutic context. We retrospectively analyzed the efficacy and tolerance of CE chemotherapy in these three different groups of mPC patients. Efficacy endpoints included radiological response, progression-free survival (PFS), and overall survival (OS), as well as PSA response and PFS2/PFS1 ratio in patients with adenocarcinoma. Sixty-nine patients were included in this single-center study (N = 18 with PSC-NE carcinoma and 51 with adenocarcinoma with (N = 18) or without (N = 33) NE marker elevation). Patients with adenocarcinoma were highly pretreated with next-generation hormonal agents (NHAs) and taxanes. In patients with adenocarcinoma, a PSA response ≥50% was observed in six patients (15.8%), four of whom had NE marker elevation. The radiological response was higher in PSC-NE and tended to be higher in adenocarcinoma when NE marker elevation was present. Comparing patients with adenocarcinoma with vs. without NE marker elevation, the median PFS was 3.7 and 2.1 months and the median OS was 7.7 and 4.7 months, respectively. Overall, 62.3% of patients experienced grade 3-4 adverse events (mainly hematological), and three treatment-related deaths were recorded. Reports of the clinical results of CE suggest that we should not mix PSC-NE and castration-resistant adenocarcinoma of the prostate. In patients with heavily pretreated adenocarcinoma, the benefit/risk ratio of CE chemotherapy seems unfavorable due to poor response and high toxicity.

Evaluating Policies of Expanding Versus Restricting First-Line Treatment Choices: A Cost-Effectiveness Analysis Framework

ObjectivesHealthcare payers often implement coverage policies that restrict the utilization of costly new first-line treatments. Cost-effectiveness analysis can be conducted to inform these decisions by comparing the new treatment with an existing one. However, this approach may overlook important factors such as treatment effect heterogeneity and endogenous treatment selection, policy implementation costs, and diverse patient preferences across multiple treatment options. We aimed to develop a cost-effectiveness analysis framework that considers these real-world factors, facilitating the evaluation of alternative policies related to expanding or restricting first-line treatment choices. MethodsWe introduced a metric of incremental cost-effectiveness ratio (ICER) that compares an expanded choice set (CS) including the new first-line treatment with a restricted CS excluding the new treatment. ICER(CS) accounts for treatment selection influenced by heterogeneous treatment effects and policy implementation costs. We examined a basic scenario with 2 standard first-line treatment choices and a more realistic scenario involving diverse preferences toward multiple choices. To illustrate the framework, we conducted a retrospective evaluation of including versus excluding abiraterone acetate plus prednisone (AAP) (androgen deprivation therapy [ADT] + AAP) as a first-line treatment for metastatic hormone-sensitive prostate cancer. ResultsThe traditional ICERs for ADT + AAP versus ADT alone and ADT+ docetaxel were $104 269 and $206 324/quality-adjusted life-year, respectively. The ICER(CS) for comparing an expanded CS with ADT + AAP with a restricted CS without ADT + AAP was $123 179/quality-adjusted life-year. ConclusionsThe proposed framework provides decision makers with policy-relevant tools, enabling them to assess the cost-effectiveness of alternative policies of expanding versus restricting patients’ and physicians’ first-line treatment choices.

Metastatic Hormone-Sensitive Prostate Cancer in the Era of Doublet and Triplet Therapy.

Treatment for metastatic hormone-sensitive prostate cancer has undergone significant evolution in recent years, leading to substantial improvements in overall survival. Men are living longer than ever before with a median survival now which is almost 6 years. The timing and extent of metastatic disease combined with individual patient factors helps treatment recommendation of doublet therapy including androgen deprivation (ADT) plus either chemotherapy or androgen receptor signaling inhibition (ARSI) or triplet therapy with ADT+ARSI+chemotherapy. New treatments must continue to be developed to enhance survival with goals of cure. Better biomarkers that allow for more effective treatments will enhance disease control, quality of life, and survival.

EIF4A3-mediated biogenesis of circSTX6 promotes bladder cancer metastasis and cisplatin resistance

BackgroundCisplatin (CDDP)-based chemotherapy is a standard first-line treatment for metastatic bladder cancer (BCa) patients, and chemoresistance remains a major challenge in clinical practice. Circular RNAs (circRNAs) have emerged as essential regulators in carcinogenesis and cancer progression. However, the role of circRNAs in mediating CDDP chemosensitivity has yet to be well elucidated in BCa.MethodsCircSTX6 (hsa_circ_0007905) was identified by mining the public circRNA datasets and verified by Sanger sequencing, agarose gel electrophoresis, RNase R treatment and qRT-PCR assays. Then, function experiments were performed to evaluate the effects of circSTX6 on BCa metastasis. Luciferase reporter assay, RNA pull-down, RNA immunoprecipitation (RIP), RNA stability assay, Fluorescence in situ hybridization (FISH) and Immunofluorescence (IF) were conducted to evaluate the interaction among circSTX6, miR-515-3p, PABPC1 and SUZ12. Animal experiments were performed to explore the function of circSTX6 in tumor metastasis and CDDP sensitivity.ResultsWe identified that circSTX6 was significantly upregulated in clinical samples and cells of BCa. Functionally, circSTX6 promoted cell migration and invasion both in vitro and in vivo. Mechanistically, circSTX6 could act as a miR-515-3p sponge and abolish its effect on SUZ12. Moreover, circSTX6 was confirmed to increase the stability of SUZ12 mRNA by interacting with a mRNA stabilizer PABPC1 and subsequently promote the expression of SUZ12. Importantly, silencing of circSTX6 improved the chemosensitivity of CDDP-resistant bladder cancer cells to CDDP. Furthermore, in vivo analysis supported that knockdown of circSTX6 attenuated CDDP resistance in BCa tumors.ConclusionThese studies demonstrate that circSTX6 plays a pivotal role in BCa metastasis and chemoresistance, and has potential to serve as a therapeutic target for treatment of BCa.

Definitive Local Treatment for Metastatic Prostate Cancer: A National Cancer Database Analysis

Introduction: Prostate cancer (PCa) is the second leading cause of cancer mortality in US males, with metastatic disease (mPCa) comprising 5% of cases. This represents an incurable and uniformly lethal disease. Thus, novel therapeutic approaches are needed. Cytoreductive surgery in the metastatic setting has become commonplace for renal cell carcinoma, and definitive local radiotherapy has been employed in the oligometastatic setting for prostate cancer via the STAMPEDE trial. This study further explores the use of definitive local treatment via pelvic radiotherapy or radical prostatectomy along with androgen deprivation therapy (ADT) vs. ADT alone in the setting of metastatic prostate cancer. Methods: The 2019 National Cancer Database (NCDB) was queried to conduct a retrospective cohort analysis of cT1-4N0-3M1 PCa who received local therapy in conjunction with ADT vs. ADT alone. Clinicopathologic variables were compared between the two groups using Wilcoxon signed rank and Chi-square for continuous and categorical variables, respectively. Overall survival (OS) analysis was performed using Cox Proportional Hazards and the Kaplan-Meier method. Comparisons were made between local therapy + ADT vs. ADT alone and between radical prostatectomy + ADT vs. radiation therapy + ADT vs. ADT alone. Results: A total of n=36,635 patients with cM1 were identified, with 3197 (8.7%) patients receiving local therapy + ADT. Among local therapy + ADT, 2884 (90.2%) patients received radiation therapy + ADT, and 313 (9.8%) received radical prostatectomy + ADT. The median follow-up was 2.8 years. Kaplan-Meier analysis showed significant improvement in 5-year OS for patients who received local therapy + ADT vs. ADT alone. For ADT alone, 5-year OS was 31.3% (CI= 30.7-31.8%) vs. 54.2%. (CI= 52.4-56.1%) for local therapy +ADT. Furthermore, comparing the type of local therapy on Kaplan-Meier analysis: radical prostatectomy + ADT showed better 5-yr OS, 74.0% (CI= 67.5-79.1%) vs. 52.2% (CI= 50.2-54.2%) for radiation therapy +ADT (p<0.001). Conclusion: Definitive local treatment, in addition to ADT, may improve 5-year OS for well-selected patients with metastatic prostate cancer. Patient outcomes are significantly improved for those treated with radical prostatectomy vs. radiation therapy. These findings support multimodal treatment for metastatic prostate cancer, and further studies are needed to optimize criteria for patient selection and choice of definitive localized therapy in this setting.

Efficacy of bevacizumab combined with apatinib in the treatment of advanced metastatic gastric cancer.

To evaluate the clinical efficacy and safety of bevacizumab combined with apatinib in the treatment of advanced metastatic gastric cancer, providing insights for treatment decisions. We conducted a single-center retrospective study involving patients with metastatic gastric cancer treated with apatinib, with or without bevacizumab, between August 2018 and April 2021 at Nanchang Medical College. Data on efficacy, adverse events, response rates, and quality of life were collected and compared. No significant differences were observed in complete remission, partial response, stable disease, disease progression, objective response rate, or disease control rate between the groups (all P>0.05). The median progression-free survival was 9.23 months in the control group and 9.94 months in the observation group (P=0.587). Median overall survival (OS) was 19.64 months in the control group and 26.44 months in the observation group (P=0.187). Univariate and multivariate analyses identified combination therapy with apatinib and bevacizumab, primary lesion resection, and number of metastatic organs as independent prognostic factors for OS. Scores for role, emotional, somatic, cognitive, and social functions were significantly higher in the observation group post-intervention (all P<0.05). In patients with advanced metastatic gastric cancer, combined therapy with bevacizumab and apatinib significantly improved OS, enhanced response rates, and increased rates of early and maximal tumor shrinkage.

Clinical practice guidelines for cervical cancer: the Korean Society of Gynecologic Oncology guidelines.

This fifth revised version of the Korean Society of Gynecologic Oncology practice guidelines for the management of cervical cancer incorporates recent research findings and changes in treatment strategies based on version 4.0 released in 2020. Each key question was developed by focusing on recent notable insights and crucial contemporary issues in the field of cervical cancer. These questions were evaluated for their significance and impact on the current treatment and were finalized through voting by the development committee. The selected key questions were as follows: the efficacy and safety of immune checkpoint inhibitors as first- or second-line treatment for recurrent or metastatic cervical cancer; the oncologic safety of minimally invasive radical hysterectomy in early stage cervical cancer; the efficacy and safety of adjuvant systemic treatment after concurrent chemoradiotherapy in locally advanced cervical cancer; and the oncologic safety of sentinel lymph node mapping compared to pelvic lymph node dissection. The recommendations, directions, and strengths of this guideline were based on systematic reviews and meta-analyses, and were finally confirmed through public hearings and external reviews. In this study, we describe the revised practice guidelines for the management of cervical cancer.

Study protocol: phase II study to evaluate the effect of cetuximab monotherapy after immunotherapy with PD-1 inhibitors in patients with head and neck squamous cell cancer.

Immunotherapy with programmed death receptor-1 (PD-1) inhibitors, as a single agent or in combination with chemotherapy, is the standard first-line treatment for recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC). Unfortunately, there is no established second-line treatment for the many patients who fail immunotherapy. Cetuximab is the only targeted therapy approved in HNSCC but historically has a low response rate of 13%. We hypothesize that cetuximab monotherapy following an immune checkpoint inhibitor (ICI) will lead to increased efficacy due to a potential synergistic effect on the antitumor immune response, as a result of activation effects of both treatments on innate and adaptative immune responses. To the authors' knowledge, this is the only ongoing prospective clinical study that evaluates the combination of cetuximab and ICIs administered sequentially. In this non-randomized, open-label, phase II trial, 30 patients with R/M HNSCC who have previously failed or could not tolerate a PD-1 inhibitor as a single agent or in combination with chemotherapy will subsequently be treated with cetuximab monotherapy. Outcomes of interest include overall response rate, duration of response, progression-free survival, overall survival, and treatment toxicity, as well as treatment outcome measured by a patient-reported outcome questionnaire. Saliva and blood will be collected for correlative studies to investigate the immune response status at the end of therapy with an ICI and the effect of cetuximab on the antitumor immune response. The results will be correlated with the response to cetuximab and the time window between the last administration of an ICI and the loading dose of cetuximab. The clinical study is actively recruiting. This study was approved by the Wake Forest Comprehensive Cancer Center Institutional Review Board: IRB00065239. This study is registered on ClinicalTrials.gov: NCT04375384.

The cost-effectiveness of germline BRCA testing-guided olaparib treatment in metastatic castration resistant prostate cancer.

Olaparib targets the DNA repair pathways and has revolutionized the management of metastatic castration resistant prostate cancer (mCRPC). Treatment with the drug should be guided by genetic testing; however, published economic evaluations did not consider olaparib and genetic testing as codependent technologies. This study aims to assess the cost-effectiveness of BRCA germline testing to inform olaparib treatment in mCRPC. We conducted a cost-utility analysis of germline BRCA testing-guided olaparib treatment compared to standard care without testing from an Australian health payer perspective. The analysis applied a decision tree to indicate the germline testing or no testing strategy. A Markov multi-state transition approach was used for patients within each strategy. The model had a time horizon of 5years. Costs and outcomes were discounted at an annual rate of 5 percent. Decision uncertainty was characterized using probabilistic and scenario analyses. Compared to standard care, BRCA testing-guided olaparib treatment was associated with an incremental cost of AU$7,841 and a gain of 0.06 quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio (ICER) was AU$143,613 per QALY. The probability of BRCA testing-guided treatment being cost effective at a willingness-to-pay threshold of AU$100,000 per QALY was around 2 percent; however, the likelihood for cost-effectiveness increased to 66 percent if the price of olaparib was reduced by 30 percent. This is the first study to evaluate germline genetic testing and olaparib treatment as codependent technologies in mCRPC. Genetic testing-guided olaparib treatment may be cost-effective with significant discounts on olaparib pricing.

Liquid biopsy to personalize treatment for metastatic prostate cancer.

Liquid biopsy is an innovative approach that provides a more complete understanding of treatment response and prognosis in monitoring metastatic prostate cancer. It complements invasive tissue biopsy and involves the assessment of various biomarkers in body fluids such as blood, semen, and urine. Liquid biopsy analyzes circulating tumor cells, extracellular vesicles, circulating tumor DNA, and the secretome. This is particularly important given the heterogeneity of prostate cancer and the need for better prognostic biomarkers. Liquid biopsy can personalize the treatment of homonosensitive and castration-resistant metastatic prostate cancer by acting as a predictive and prognostic tool. This review discusses various biomarkers, assay techniques, and potential applications in daily clinical practice, highlighting the exciting possibilities that this emerging field holds for improving patient outcomes.

DNA-encoded chemical libraries enable the discovery of potent PSMA-ligands with substantially reduced affinity towards the GCPIII anti-target.

Prostate-specific membrane antigen (PSMA) is a tumor-associated protein that has been successfully targeted with small organic ligands and monoclonal antibodies. Pluvicto™ is a PSMA-targeted radioligand therapeutic (RLT) recently approved by the FDA for the treatment of metastatic castration-resistant prostate cancer (2022 FDA marketing authorization). Although a large Phase III clinical trial (VISION trial) demonstrated clinical benefits in patients treated with Pluvicto™, the therapeutic window of the drug is narrowed by its undesired accumulation in healthy organs. Glutamate carboxypeptidase III (GCPIII), an enzyme sharing 70% identity with PSMA, may be responsible for the off-target accumulation of PSMA-RLTs in salivary glands and kidneys. In this work, we designed and synthesized affinity and selectivity maturation DNA-encoded chemical libraries (ASM-DELs) comprising 18'284'658 compounds that were screened in parallel against PSMA and GCPIII with the aim to identify potent and selective PSMA ligands for tumor-targeting applications. Compound A70-B104 was isolated as the most potent and selective ligand (KD of 900 pM for PSMA, KD of 40 nM for GCPIII). 177Lu-A70-B104-DOTA, a radiolabeled derivative of compound A70-B104, presented selective accumulation in PSMA-positive cancer lesions (i.e., 7.4% ID g-1, 2 hour time point) after systemic administration in tumor-bearing mice. The results of autoradiography experiments showed that 177Lu-A70-B104-DOTA selectively binds to PSMA-positive cancer tissues, while negligible binding on human salivary glands was observed.

Simple and Epididymal-Sparing Orchiectomy for Surgical Castration in Stage IV Prostate Cancer.

Background: Androgen deprivation therapy, the mainstay of treatment for patients with advanced prostate cancer, can be either medical or surgical. Surgery has cost benefits compared to medical treatment. In this study, we evaluated the use of simple and epididymal-sparing orchiectomy in 2 different practice settings for the treatment of metastatic prostate cancer. Methods: We reviewed patients who underwent surgical castration for metastatic prostate cancer between 2011 and 2022. The primary outcome was achieving castration-level total testosterone of <50 ng/dL. We also compared the characteristics of patients who were seen at a public academic teaching hospital vs those who were seen at a private community hospital (oncology group practice), and we evaluated the impact of orchiectomy approach (simple vs epididymal-sparing orchiectomy) on patient outcomes. Results: We analyzed 101 patients who underwent orchiectomy: 40 (39.6%) at a public academic teaching hospital and 61 (60.4%) at a private community hospital (oncology group practice). Of these patients, 81 (80.2%) underwent simple orchiectomy and 20 (19.8%) underwent epididymal-sparing orchiectomy. Forty-nine patients (48.5%) had previously received medical androgen deprivation therapy, 9 (18.4%) of whom had medication adherence issues. Patient age, race, and marital status differed significantly between hospital facilities. The overall surgical complication rate was 3.0%. Postoperative total testosterone levels were available for 81 patients, drawn a median of 57 days after surgery [IQR 30, 123]. All patients had castrate-level total testosterone (median 10 ng/dL [IQR 9, 19]) postoperatively, with no differences seen between surgery location (P= 0.84) or surgical technique (P= 0.90). Conclusion: Simple or epididymal-sparing orchiectomy is safe and effective for surgical castration and is an alternative to medical androgen deprivation therapy for patients diagnosed with metastatic prostate cancer regardless of the practice demographics.

The Financial Burden of Guideline-recommended Cancer Medications for Metastatic Urothelial Carcinoma

Bladder cancer is a significant global health concern owing to its prevalence, negative impact on quality of life, and high treatment costs. Treatment for metastatic urothelial carcinoma (mUC) traditionally relies on platinum-based chemotherapy regimens. However, clinical trial results have led to the approval of immune checkpoint inhibitors (ICIs) as viable treatment options. We assessed the escalating costs and economic viability of mUC treatment guidelines in Europe. We used a pragmatic approach that involved: (1) collection of the costs of the recommended medications in the five most populous European countries; (2) conversion of the costs into international dollars to account for differences in purchasing power parity among countries; (3) evaluation of the cost trends over time; and (4) comparison of the medication costs to World Health Organization thresholds. Introduction of ICIs in European guidelines substantially increased the cost of medications for mUC. Intriguingly, important differences across European countries emerged: the annual cost of medications was twofold higher in Italy than in France and the UK. Despite limitations, our study sheds light on the escalating costs and economic challenges of mUC treatment, and highlights the need for assessments of sustainable and cost-effective management approaches. Patient summaryWe looked at the costs of treatments for metastatic bladder cancer and found that costs have been rising over time, especially with the introduction of new immune therapies, with notable differences among European countries. While these new treatments improve patient outcomes, they also come with a high price tag, which could strain health care budgets. Our results suggest that cost-effectiveness studies will be essential in determining the best and most sustainable treatment strategies in the future.