Optimal Treatment Sequence Research Articles

Navigating therapeutic sequencing in the metastatic castration-resistant prostate cancer patient journey.

Novel therapies for metastatic castration-resistant prostate cancer (mCRPC) have improved patient outcomes. However, there is uncertainty on the optimal selection of therapeutic agents for subsequent lines of therapy. We conducted a comprehensive review of published evidence from pivotal clinical trials and recent guidelines for the treatment of mCRPC. We further identify gaps in knowledge and areas for future research. Key considerations to help guide treatment selection for patients with mCRPC include personal treatment history, individual clinical characteristics, symptoms, prognosis, availability of clinical trials, and other patient-specific factors. Genetic testing and prostate-specific membrane antigen-targeted imaging are important tools to evaluate candidacy for newer therapeutic options such as poly (ADP-ribose) polymerase inhibitors, alone or in combination with androgen receptor pathway inhibitors, and [177Lu]Lu-PSMA-617. This article provides an overview of the evolving treatment landscape of mCRPC, discussing guideline-recommended treatment options and data from key clinical trials, while highlighting ongoing trials that may impact the future treatment landscape. Recommendations for optimal treatment sequencing based on individual patient factors are provided.

Review article: Novel therapies in inflammatory bowel disease - An update for clinicians.

Several new treatments including small molecules and biologics have been approved for the treatment of inflammatory bowel diseases in recent years. Clinicians and patients now have a wide variety of therapeutic options to choose from and these novel therapies provide several advantages including oral administration, lower immunogenicity, better selectivity and arguably better safety profiles. An increase in treatment options has increased the complexity of decision-making. Both patients and clinicians have had to become rapidly familiar with efficacy of new medications balanced against a range of pre-initiation requirements, dosing schedules and adverse event profiles. To provide a simple guide to practising clinicians on recently approved and emerging therapies and address key challenges around treatment strategies such as optimal sequencing and timing of treatment. We comprehensively searched the published literature and major conference abstracts to identify phase III placebo-controlled and active comparator trials for Crohn's disease and ulcerative colitis. Data for recently approved therapies including selective Janus kinase inhibitors, sphingosine-1 receptor modulators and p19 interleukin (IL)-23 inhibitors have demonstrated improved patient outcomes in both Crohn's disease and ulcerative colitis. Further comparative head-to-head studies have improved our understanding of when and how to optimally use newer therapies, specifically for IL-23 inhibitors. Data for emerging treatment options and novel treatment strategies such as early effective treatment, combinations of treatments and implications for sequencing are continuing to transform IBD care continually. Recently approved novel therapies have expanded the range of medical options available to treat IBD. However, further data from long-term extension studies, real-world studies and head-to-head trials are warranted to better inform the long-term safety and optimal sequencing of treatments for patients living with IBD.

Update on Neoadjuvant and Adjuvant BRAF Inhibitors in Papillary Craniopharyngioma: A Systematic Review

Background/Objectives: The recent discovery of BRAF mutation in papillary craniopharyngiomas opened new avenues for targeted therapies to control tumour growth, decreasing the need for invasive treatments and relative complications. The aim of this systematic review was to summarize the recent scientific data dealing with the use of targeted therapies in papillary craniopharyngiomas, as adjuvant and neoadjuvant treatments. Methods: The PRISMA guidelines were followed with searches performed in Scopus, MEDLINE, and Embase, following a dedicated PICO approach. Results: We included 21 pertinent studies encompassing 53 patients: 26 patients received BRAF inhibitors (BRAFi) as adjuvant treatment, while 25 received them as neoadjuvant treatment. In the adjuvant setting, BRAFi were used to treat recurrent tumours after surgery or adjuvant radiation therapy. The most common regimen combined dabrafenib (BRAFi) with trametinib (MEK1 and 2 inhibitor) in 81% of cases. The mean treatment length was 8.8 months (range 1.6 to 28 months) and 32% were continuing BRAFi. A reduction of tumour volume variable from 24% to 100% was observed at cerebral MRI during treatment and volumetric reduction ≥80% was described in 64% of cases. Once the treatment was stopped, adjuvant treatments were performed to stabilize patients in remission in 11 cases (65%) or when a progression was detected in three cases (12%). In four cases no further therapies were administered (16%). Mean follow-up after the end of targeted therapy was 17.1 months. As neoadjuvant regimen, 36% of patients were treated with dabrafenib and trametinib with a near complete radiological response in all the cases with a mean treatment of 5.7 months. The neoadjuvant use of verumafenib (BRAFi) and cometinib (MEK1 inhibitor) induced a near complete response in 15 patients (94%), with a median volumetric reduction between 85% and 91%. Ten patients did not receive further treatments. Side effects varied among studies. The optimal timing, sequencing, and duration of treatment of these new therapies should be established. Moreover, questions remain about the choice of specific BRAF/MEK inhibitors, the optimal protocol of treatment, and the strategies for managing adverse events. Conclusions: Treatment is shifting to a wider multidisciplinary management, where a key role is played by targeted therapies, to improve outcomes and quality of life for patients with BRAF-mutated craniopharyngiomas. Future, larger comparative trials will optimize their protocol of use and integration into multimodal strategies of treatment.

Current National Treatment Trends for Gastric Adenocarcinoma in the United States.

The treatment of gastric adenocarcinoma (GA) continues to evolve. While neoadjuvant chemotherapy (NAC) has demonstrated emerging benefit, the optimal treatment regimen, and sequence remain to be firmly established. Patients with nonmetastatic GA who underwent resection were identified within the 2020 National Cancer Database. Patients were compared between the mutually exclusive treatment groups of NAC, neoadjuvant chemoradiotherapy (NCRT), adjuvant chemotherapy, adjuvant chemoradiotherapy (CRT), and surgery only. The primary endpoint was receipt of NAC or NCRT. Patients were 1-to-1 propensity score matched for receiving any neoadjuvant therapy. Multivariable logistic regression was used to identify predictors of receipt of any neoadjuvant therapy and receipt of any adjuvant therapy. Twenty-five thousand and seventy-three patients were included in the analysis. Patients were treated with NAC (25.0%), NCRT (31.4%), adjuvant chemotherapy (6.5%), adjuvant CRT (12.6%), and surgery only (24.5%). Compared to 2006-2011, patients diagnosed between 2012 and 2017 experienced the greatest increases in NAC (18.6% vs. 29.0%; p < 0.001) and NCRT (25.0% vs. 35.5%; p < 0.001). Median OS was 44.9 months. OS was longest for patients who received any neoadjuvant therapy compared to those receiving adjuvant or surgery only (51.0 vs. 42.4 vs. 38.0 months, respectively; p < 0.001). Patients who were Black, in the lowest income quartile or treated at lower volume facilities were less likely to receive NAT (all p < 0.001). There has been significant acceleration in the use of neoadjuvant therapy for GA. Currently, NCRT followed by surgery are the most common treatment sequences in the United States. Additional trials are needed to further define the optimal treatment sequence.

Immune Checkpoint Inhibitors in the Management of Brain Metastases from Non-Small Cell Lung Cancer: A Comprehensive Review of Current Trials, Guidelines and Future Directions

Background: Brain metastases (BM) are a common, severe complication in patients with non-small cell lung cancer (NSCLC) and are difficult to treat due to their complex tumor biology and the intricate microenvironment of the brain. Objectives: This review examines the current role of immune checkpoint inhibitors (ICIs) in treating NSCLC with BM, focusing on the latest clinical trials, emerging strategies, current guidelines, and future directions. We highlight the efficacy of ICIs as monotherapy and in combination with other treatments such as radiotherapy, stereotactic radiosurgery, chemotherapy, and anti-VEGF agents. Results: While no single treatment sequence is universally accepted, combining ICIs with traditional therapies forms the core of the current treatment protocols. ICIs targeting the PD-1/PD-L1 pathway have significantly advanced NSCLC treatment, demonstrated by improved overall and progression-free survival in various settings. However, optimizing these benefits requires careful consideration of potential side effects, including cognitive decline and radiation necrosis, and the impact of steroid use on ICI efficacy. Conclusion: The review underscores the necessity for a personalized, integrated multidisciplinary treatment approach. Future research should focus on refining combination therapies and understanding the optimal sequence and timing of treatment.

Real-World Treatment Patterns, Sequencing, and Outcomes in Patients with Locally Advanced or Metastatic Urothelial Carcinoma Receiving Avelumab First-Line Maintenance in the United States.

For patients with locally advanced/metastatic urothelial carcinoma (la/mUC), first-line (1L) treatment with platinum-based chemotherapy (PBC) followed by avelumab 1L maintenance (1LM) is a recommended therapy per treatment guidelines in patients without disease progression. However, contemporary real-world (rw) data among patients receiving this treatment are necessary to understand clinical outcomes and optimal treatment sequencing. This retrospective cohort study analyzed rw treatment patterns and clinical outcomes, including overall survival (rwOS) and progression-free survival (rwPFS), in patients with la/mUC receiving avelumab 1LM. From the Flatiron Health database, 214 patients who received avelumab 1LM following 1L PBC were included. From the start of avelumab 1LM, median rwOS was 23.8 months (95% CI: 18.2-not estimable [NE]) and median rwPFS was 5.1 months (95% CI: 4.1-7.0). A total of 96 patients received second-line (2L) therapy, with 53 receiving enfortumab vedotin (EV). From the start of 2L EV, median rwOS was 11.2 months (95% CI: 6.8-NE) and median rwPFS was 4.9 months (95% CI: 3.9-8.8). Treatment patterns and clinical outcomes in this study align with guidelines and outcomes observed in the JAVELIN Bladder 100 and EV-301 clinical trials and other rw studies, supporting the use of 1L PBC followed by avelumab 1LM and 2L EV for eligible patients.

Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 Study

Immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors are cornerstones of first-line treatment for advanced renal cell carcinoma; however, optimal treatment sequencing after progression is unknown. This study aimed to assess clinical outcomes of tivozanib-nivolumab versus tivozanib monotherapy in patients with metastatic renal cell carcinoma who have progressed following one or two lines of therapy in the post-ICI setting. TiNivo-2 is a multicentre, randomised, open-label, phase 3 trial at 190 sites across 16 countries, in Australia, Europe, North America, and South America. Patients with advanced renal cell carcinoma and progression during or after one to two previous lines of therapy (including one ICI) were randomised 1:1 to tivozanib (0·89 mg per day, orally) plus nivolumab (480 mg every 4 weeks, intravenously) or tivozanib (1·34 mg per day, orally). Randomisation was stratified by immediate previous therapy (ICI or non-ICI) and International Metastatic Renal Cell Carcinoma Database Consortium risk category. The primary endpoint was progression-free survival (PFS), defined as the time from randomisation to first documentation of objective progressive disease according to RECIST 1·1 or death from any cause, whichever came first, by independent radiology review. Efficacy was evaluated in the intention-to-treat population, and safety was assessed in patients who received one or more doses of the study drug. This trial was registered on ClinicalTrials.gov (NCT04987203) and is active and not recruiting. From Nov 4, 2021, to June 16, 2023, 343 patients were randomly assigned to tivozanib-nivolumab (n=171) or tivozanib monotherapy (n=172). Median follow-up was 12·0 months. Median PFS was 5·7 months (95% CI 4·0-7·4) with tivozanib-nivolumab and 7·4 months (5·6-9·2) with tivozanib monotherapy (hazard ratio 1·10, 95% CI 0·84-1·43; p=0·49). Among those with an ICI as their immediate previous therapy (n=244), median PFS was 7·4 months (95% CI 5·6-9·6) with tivozanib-nivolumab and 9·2 months (7·4-10·0) with tivozanib monotherapy. With non-ICIs as the most recent therapy, lower median PFS was observed, with no difference between groups (tivozanib-nivolumab 3·7 months [95% CI 2·7-5·4] and with tivozanib monotherapy 3·7 months [1·9-7·2]). Serious adverse events occurred in 54 (32%) of 168 patients receiving tivozanib-nivolumab and 64 (37%) of 171 patients receiving tivozanib monotherapy. One (<1%) treatment-related death occurred (tivozanib group). These data further support that ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma. Furthermore, these data suggest that tivozanib monotherapy has efficacy in the post-ICI setting. Aveo Pharmaceuticals.

797. A COMPARATIVE ANALYSIS ON THE EFFECTIVENESS OF DIFFERENT TREATMENT MODALITIES FOR ESOPHAGEAL CARCINOMA; A SYSTEMATIC REVIEW

Abstract Background Esophageal carcinoma; sixth most common cancer worldwide, presents a significant clinical challenge due to its aggressive nature and often late-stage diagnosis, resulting in poor prognosis and limited treatment options. Various treatment modalities, including surgery, chemotherapy, radiation therapy, immunotherapy, and targeted therapy, are utilized in clinical practice. However, the optimal treatment strategy remains uncertain, as the comparative effectiveness of these modalities is not well-defined. Past studies have provided conflicting evidence, necessitating a comprehensive evaluation to guide clinical decision-making. Therefore, this systematic review aims to compare the efficacy and safety of different treatment modalities for esophageal carcinoma, with the objective of informing evidence-based treatment approaches and improving patient outcomes. Methods Total 350 publications from PubMed, EMBASE, Cochrane, Google Scholar and Semantic Scholar databases were identified on the effectiveness of different treatment modalities for esophageal carcinoma between 2000 and 2024. Following deduplication, two independent reviewers initially screened the articles for eligibility with titles and abstracts, and then, with complete articles. Bias assessment using GRADE guidelines for observational studies was done. Non-English studies, case-series/case-reports/essays/book-chapters/conference-abstracts/editorials/thesis/dissertations and studies without full-texts were excluded. Results Overall, the effectiveness of each treatment modality for esophageal carcinoma depends on various factors, including tumor stage, histology, patient characteristics, and treatment regimen. Combination approaches, such as chemoradiotherapy or multimodal therapy, are often used to maximize treatment efficacy and improve patient outcomes. Conclusion Multidisciplinary collaboration, personalized treatment approach, integration of novel therapies, such as immunotherapy and targeted therapy, into standard treatment regimens, survivorship care and advocate for further research to identify optimal treatment sequencing, identify predictive biomarkers of treatment response, and explore novel therapeutic targets to improve outcomes for patients with esophageal carcinoma is recommended.

Determining Clinicopathologic Factors That Influence Treatment in Advanced Breast Cancer in Argentina After CDK4/6 Inhibitors.

The optimal treatment sequence for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) after progression on first-line cyclin-dependent kinase 4/6 inhibitor (CDKi) and endocrine therapy is unclear. Clinical and biological factors influencing treatment choices and outcomes in the second-line setting need to be elucidated. This is a retrospective analysis of a real-world cohort including patients with HR+/HER2- ABC who received CDKi and endocrine therapy in the first-line setting and progressed, requiring second-line treatment. Clinical and biological factors were analyzed to evaluate their association with daily treatment decisions and the prognostic role of progression-free survival (PFS) in the second-line setting. Two hundred thirty-five patients were included. Second-line treatments were hormone therapy (HT) based in 60% and chemotherapy based in 40% of patients. The second-line median PFS was 6.6 months, with no difference between treatment types. In multivariable analysis, postmenopausal status, lower Ki-67 expression, and non-de novo stage IV disease were associated with improved second-line (2L) PFS. Menopausal status significantly interacted with treatment type, with reduced PFS in premenopausal patients receiving HT-based treatments (4.7 v 8.7 months, P = .00045). In our study, treatment decisions reflected the current algorithm incorporated in our clinical guidelines, and prior treatment response was the most relevant factor to determine 2L treatment decision. Menopausal status interacted with the subsequent therapy efficacy in this setting. Hence, we consider that menopausal status should be routinely evaluated in the subgroup analysis of clinical trials.

Reduced Efficacy of Behavior Therapy Following Initial Multimodal Treatment of ADHD

ABSTRACT Background Evidence-based treatments for childhood attention-deficit/hyperactivity disorder (ADHD) include behavioral treatment and psychostimulants, preferably in combination. Research on the treatment of ADHD underscores a gap in the literature regarding the optimal sequencing of treatments (Pelham et al. 2020). Emerging evidence supports starting with behavioral treatment before psychostimulants, though the mechanisms of this sequencing effect are not entirely understood. Objective This study explores one plausible mechanism – that psychostimulants reduce behaviors targeted by behavioral treatment, thereby reducing opportunities for children to learn and practice self-regulation skills. The article reports post hoc findings from a triple-masked, AB/BA crossover study, conducted in the Summer Treatment Program (STP). Method Two-hundred forty-eight children diagnosed with ADHD; 77% male; 85% Hispanic) were randomized to receive either (a) intensive behavior therapy plus medication (“COMB”) or (b) intensive behavior therapy plus placebo (“BT”) for 3 weeks, then crossed over to the other condition for 3 weeks. Behavior in recreational settings was systematically recorded and analyzed as a function of medication status and order of treatments. Results We found evidence that initial medication reduced the efficacy of subsequent behavior therapy. That is, children exhibited significantly more misbehaviors when unmedicated if they started with combined treatment, then had medication withdrawn, than if they started with behavior therapy alone. Conclusion These findings suggest that starting with a combined treatment approach had an unintended adverse impact on children’s behavioral functioning when medication was withdrawn. The results support current clinical recommendations, which are to start treatment of ADHD with behavior therapy alone and to add medication as necessary.

The role of radiotherapy in the treatment of sinonasal undifferentiated carcinoma: A population-based analysis.

Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive disease with ambiguous management and poor prognosis. This study aimed to evaluate the role of radiation therapy (RT) and explore the optimal treatment sequence. Retrospective analysis of survival trends of 410 SNUC patients between 1973 and 2015. The 5-year cancer-specific survival (CSS) rate (45.1%) and overall survival (OS) rates (38.1%) were reported in the 84-month median follow-up. Radiotherapy was a prognosticator for improving CSS (hazard ratio [HR] = 0.425, 95% confidence interval [CI]: 0.299-0.603, p = 0.000) and OS (HR = 0.415, 95% CI: 0.303-0.570, p = 0.000), either with surgery (p = 0.000) or without surgery (p = 0.000). However, in a combined therapy of surgery and RT, preoperative and postoperative RT (5-year OS rates were 47.1% and 45.6%, respectively, p = 0.486) were not significantly different. Radiotherapy plays a key role in improving SNUC survival rates. No significant difference in survival rates was observed in preoperative and postoperative RT treatment.

Timing of stereotactic radiosurgery within the first-line systemic treatment in non-small cell lung cancer brain metastases: a retrospective single-center cohort study.

Stereotactic radiosurgery/radiotherapy (SRS/SRT) and novel systemic treatments, such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), have demonstrated to be effective in managing brain metastases in non-small cell lung cancer (NSCLC). However, the optimal treatment sequence of SRS/SRT and TKI/ICI remains uncertain. This retrospective monocentric analysis addresses this question by comparing the outcomes of patients with NSCLC brain metastases who received upfront SRS/SRT versus those who were initially treated with TKI/ICI. All patients treated with SRS/SRT and TKI/ICI for NSCLC brain metastases were collected from a clinical database. The patients who received first-line TKI or ICI for the treatment of brain metastases were then selected for further analysis. Within this cohort, a comparative analysis between upfront SRS/SRT and patients initially treated with TKI/ICI was conducted, assessing key parameters such as overall survival (OS), intracranial progression-free survival (iPFS) and treatment-related toxicity. Both OS and iPFS were defined as the time from SRS/SRT to either death or disease progression, respectively. The analysis encompassed 54 patients, of which 34 (63.0%) patients received SRS/SRT and TKI/ICI as their first-line therapy. Of the latter, 17 (50.0%) patients received upfront SRS/SRT and 17 (50.0%) were initially treated with TKI/ICI; 24 (70.6%) received SRS/SRT and ICI, and 10 (29.4%) received SRS/SRT and TKI. The cohorts did not significantly differ in the univariable analyses for the following parameters: sex, age, histology, molecular genetics, disease stage at study treatment, performance status, number of brain metastases, treatment technique, tumor volume, target volume, disease progression, radiation necrosis, dosimetry. While no significant differences were found in terms of iPFS and OS between patients treated with upfront SRS/SRT and patients initially treated with TKI, upfront SRS/SRT demonstrated significantly superior OS when compared to patients initially treated with ICI (median OS not reached vs. 17.5 months; mean 37.8 vs. 23.6 months; P=0.03) with no difference in iPFS. No significant differences in treatment-related toxicity were observed among the cohorts. In this retrospective, single-center cohort study, patients treated with upfront SRS/SRT demonstrated significantly longer OS compared to patients initially treated with ICI in the cohort receiving first-line therapy for brain metastases. However, given the retrospective design and the limited cohort size, definitive conclusions cannot be drawn from these findings. Nevertheless, the results suggest that the timing of SRS/SRT may play an important role in treatment outcomes. Further investigation, preferably through prospective randomized trials, is warranted to provide more conclusive answers to this important question.

Sequence of Contact X-ray Brachytherapy (CXB) and External Beam Radiation (EBRT) in organ-preserving treatment for small rectal cancer

Background and purposeExternal Beam Radiotherapy (EBRT) followed by Contact X-ray Brachytherapy (CXB) and vice versa are viable alternatives to surgery for selected rectal cancer patients who have small tumours (≤3 cm). However, the optimal sequence of treatment needs to be established. We compared two approaches using Propensity Score (PS) matching and inverse probability treatment weighting (IPTW) analyses to investigate whether the sequence of treatment affected patient outcomes. Materials and methodsThis retrospective analysis (2008–2019) included patients with rectal adenocarcinoma (cT1-3,N0-1,M0, grade 1–2, size ≤ 3 cm) who received both EBRT and CXB, irrespective of treatment sequence. PS matching and IPTW were conducted to balance covariate standardised mean differences between groups. Oncological outcomes and rate of post-treatment rectal bleeding were assessed. ResultsFollowing PS matching and IPTW analyses from 251 eligible patients; 103 starting with EBRT (median follow-up: 37 [IQR:18–56] months) and 148 with CXB (median follow-up: 32 [IQR:16–54] months, a significant improvement in 3-year overall survival (77% vs 85%, p = 0.02, [HR:0.58 (95% CI:0.37–0.91)]) and a higher risk of post-treatment rectal bleeding (grade 1 (26%) and grade 2 (6%)) were found in patients who started with CXB (p = 0.08). No significant differences were observed in local regrowth (18% vs 12%, p = 0.47), distant relapse (10% vs 6%, p = 0.53), 3-year organ preservation rates (70% vs 75%, p = 0.20, [HR:0.66 (95% CI: 0.35–1.26)]), or disease-free survival (78% vs 82%, p = 0.17, [HR: 0.47 (95% CI: 0.16–1.38)]) ConclusionIn patients with rectal cancer (≤3 cm), commencing with CXB rather than EBRT, was associated with improved overall survival, but had a higher risk of G1/2 rectal bleeding. No statistically significant differences were observed in other oncological outcomes.

Head-to-head comparison of treatment sequences in advanced pancreatic cancer-Real-world data from the prospective German TPK clinical cohort study.

There are no clear guidelines regarding the optimal treatment sequence for advanced pancreatic cancer, as head-to-head phase III randomised trials are missing. We assess real-world effectiveness of three common sequential treatment strategies by emulating a hypothetical randomised trial. This analysis included 1551 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer receiving FOLFIRINOX (n = 613) or gemcitabine/nab-paclitaxel (GEMNAB; n = 938) as palliative first-line treatment. We used marginal structural modelling to compare overall survival (OS) and time to deterioration (TTD) of health-related quality of life (HRQoL) between three common first- to second-line treatment sequences, adjusting for time-varying potential confounding. The sequences were: FOLFIRINOX→GEMNAB, GEMNAB→FOLFOX/OFF and GEMNAB→nanoliposomal irinotecan (NALIRI) + 5-fluorouracil. Outcome was also calculated stratified by patients' prognostic risk according to the Pancreatic Cancer Score. Median OS and TTD of HRQoL independent of risk were 10.7 [8.9, 11.9] and 6.4 [4.8, 7.7] months for FOLFIRINOX→GEMNAB, 8.4 [7.4, 9.7] and 5.8 [4.6, 7.1] months for GEMNAB→FOLFOX/OFF and 8.9 [7.8, 10.4] and 4.6 [4.1, 6.1] months for GEMNAB→NALIRI+5-fluorouracil. Compared to FOLFIRINOX→GEMNAB, OS and TTD were worse for poor-risk patients with GEMNAB→FOLFOX/OFF (OS: HR 2.09 [1.47, 2.98]; TTD: HR 1.97 [1.19, 3.27]) and those with GEMNAB→NALIRI+5-fluorouracil (OS: HR 1.35, [0.76, 2.39]; TTD: HR 2.62 [1.56, 4.42]). Brackets denote 95%-confidence intervals. The estimated real-world effectiveness of the three treatment sequences evaluated were largely comparable.Poor-risk patients might benefit from intensified treatment with FOLFIRINOX→GEMNAB in terms of clinical and patient-reported outcomes. Future randomised trials on sequential treatments in advanced pancreatic cancer are warranted.

To establish a prognostic model of epidermal growth factor receptor mutated non-small cell lung cancer patients based on Least Absolute Shrinkage and Selection Operator regression.

There is currently a shortage of effective diagnostic tools that are used for identifying long-term survival among non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. This research utilized the development of a prognostic model to assist clinicians in forecasting the survival over 24 months. In Phase III and IV those patients who were diagnosed with EGFR mutation from January 2018 to June 2022 were enrolled into the lung cancer group of Thoracic Surgery Department of Hebei Provincial People's Hospital. Long-run survival was stated as survival for 24 months after being diagnosed. A multivariate prognostic pattern was constructed by means of internal validation and binary logistic regression by bootstrapping. One nomogram was created with a view to boosting the explanation and applicability of the pattern. A total of 603 patients with EGFR mutation were registered. Elements linked to the whole survival beyond 24 months were age (OR 6.15); female (OR 1.79); functional status (ECOG 0-1) (OR 5.26); Exon 20 insertion mutation deletion (OR 2.08); No central nervous system metastasis (OR 2.66), targeted therapy (OR 0.43); Immunotherapy (OR 0.24). The model has good internal validation. Seven pretreatment clinicopathological variables predicted survival over 24 months. That pattern owns a great discriminative capability. It is hypothesized that this pattern is capable of assisting in selecting the optimal treatment sequence for NSCLC patients with EGFR mutations.

International multicenter real-world REGistry for patients with metastatic renAL cell carcinoma – Meet-URO 33 study (REGAL study)

BackgroundNowadays, different therapeutic options are available for the first-line treatment of metastatic renal cell carcinoma (mRCC). Immuno-combinations are the standard first-line therapy in all mRCC patients regardless of the International Metastatic RCC Database Consortium (IMDC) risk category, even though TKI monotherapy is still a therapeutic option in selected patients. However, comparisons between the different first-line treatment strategies are lacking and few real-world data are available in this setting. For this reason, the regimen choice represents an important issue in clinical practice and the optimal treatment sequence remains unclear.MethodsThe REGAL study is a multicentric prospective observational study enrolling mRCC patients treated with first-line systemic therapy according to clinical practice in a real-world setting. A retrospective cohort of mRCC patients who received first-line systemic therapy from the 1st of January 2021 will also be included. The primary objective is to identify potential prognostic and predictive factors that could help guide the treatment choice; secondary objectives included the assessment of the prognostic performance of the novel prognostic Meet-URO score (IMDC score + neutrophil-to-lymphocyte ratio + bone metastases) compared with the IMDC score and the comparison between treatment strategies according to response and survival outcomes and toxicity profile.DiscussionConsidering the high number of therapeutic first-line strategies available for mRCC, the identification of clinical prognostic and predictive factors to candidate patients to a preferable systemic therapy is still an unmet clinical need. The Meet-URO 33 study aims to provide a large-scale real-world database on mRCC patients, to identify the clinical predictive and prognostic factors and the different performances between the ICI-based combinations according to response, survival and toxicity.Trial RegistrationCESC IOV 2023-78.

What is the best salvage therapy for Hodgkin lymphoma?

Historically, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (HDT/ASCT) was the mainstay approach for relapsed or refractory classic HL. The emergence of novel agents for HL, such as brentuximab vedotin and programmed death-1 (PD-1) blockade has revolutionized therapeutic strategies, yielding excellent results. This review aims to provide a comprehensive overview of new salvage therapies and offer insights into forthcoming therapeutic options. The incorporation of brentuximab vedotin and PD-1 blockade into salvage therapy before HDT/ASCT has led to markedly improved outcomes. Notably, PD-1 based salvage studies yield posttransplant 2-year progression-free survival rates approaching 90%, marking a significant advancement in the treatment of Hodgkin lymphoma (HL). Studies are beginning to explore nontransplant treatment approaches following front-line treatment failure and may identify certain risk groups eligible for these strategies. The landscape of HL treatment is rapidly evolving, leading to significant changes in the standard of care. Novel agents are now administered earlier in the disease course, resulting in higher cure rates. The focus of treatment is shifting towards achieving cure with minimal toxicity, reducing exposure to various agents, and advancing research in optimizing treatment sequencing and patient selection for less intensive therapies.

Survival Benefit of Synchronous Lenvatinib Combined PD-1 Inhibitors for Advanced Hepatocellular Carcinoma Beyond Oligometastasis.

Strategies therapy for hepatocellular carcinoma (HCC) beyond oligometastasis are limited. The optimal sequence of systemic treatment for advanced HCC is not yet clear. Our study aims to evaluate the effectiveness of simultaneous lenvatinib combined PD-1 inhibitor on advanced HCC beyond oligometastasis. A total of 232 patients were enrolled in our retrospective study. Patients divided into three groups. (a) Lenvatinib plus simultaneous PD-1 inhibitor (Simultaneous group, n=58); (b) patients received PD-1 inhibitor before the tumor progression with continued lenvatinib administration (Before PD group, n=77); (c) patients received PD-1 inhibitor after the tumor progression (After PD group, n=97). To analyze overall survival (OS) and progression-free survival (PFS) among the three groups. The estimated 6-, 12-, 18- and 24-mon OS for Simultaneous group patients were 100%, 93.1%, 63.4%, 48.3%, whereas the OS rates were 100%, 78%, 36.3%, 23.6% in Before PD group, and 99%, 61.2%, 22.1%, 7.5% in After PD group. The OS rates were obviously improved with the use of simultaneous PD-1 inhibitor among the three groups (P <0.001). The estimated 3-, 6-, 9- and 12-month PFS rates for patients were 89.6%, 44.8%, 24.6%, 6% in After PD group, 90.9%, 59.7%, 27.3%, 12.4% in Before PD group and 98.3%, 81%, 51.7%, 39.7% in Simultaneous group, respectively. PFS rate was significantly different among the three groups (P <0.001). Synchronous administration of lenvatinib and PD-1 inhibitors improved survival rate significantly. The synchronous combination could represent a promising strategy in HCC beyond oligometastasis.

Clinical and molecular characteristics and targeted therapy of pediatric non-infantile fibrosarcoma NTRK rearrangement–related tumors.

10048 Background: Neurotrophic tyrosine receptor kinase (NTRK) rearrangement is rare in tumors and relevant to targeted therapy. Pediatric NTRK rearrangement-related tumors have distinct clinical and molecular features compared to adults, and previous studies on pediatric NTRK rearrangement-related tumors has focused on infantile fibrosarcoma (IFS), the most common subtype. However, the clinical behaviors and molecular profiles of other subtypes of pediatric NTRK rearrangement-related tumors are largely unknown. Methods: In this study, we evaluated the molecular features, treatment response, and prognosis of 28 pediatric patients with non-IFS NTRK rearrangement-related tumors. Next-generation sequencing was performed in 21 patients to identify the NTRK fusion types and their co-occurring alterations, and pathway enrichment analysis was performed to explore the potential mechanisms involving NTRK rearrangement and resistance to tyrosine receptor kinase (TRK) inhibitors. Results: The NTRK fusion partners were diverse and tumor-specific. Several novel NTRK fusions were identified, including SNIP1-NTRK1, AGAP1-NTRK2, CRCT1-NTRK1, ZBTB7B-NTRK1, and SLC6A15-NTRK3. RTK-RAS, NOTCH, TP53, and WNT pathways were top 4 significantly enriched in tested samples. Twelve of 17 patients (70.6%) received TRK inhibitors as salvage treatment achieved complete or partial response. Patients who did not develop DDR, NOTCH, or TP53 pathway-related gene mutations had a high objective response rate of 82%, 82%, and 83%, respectively. Conclusions: Our findings may have important implications for the diagnosis and treatment of non-IFS NTRK fusion-positive tumors in pediatric patients. We also provide potential therapeutic targets for tumors resistant to TRK inhibitors. Clinical trials with TRK inhibitors, either alone or in combination, are required to establish the optimal treatment regimen and sequence in large-cohort pediatric patients with non-IFS NTRK rearrangement-related tumors. Clinical trial information: NCT05076071 .

Evolving Standards of Care in the Management of Localized Colorectal Cancer.

The treatment of patients with localized rectal cancer is complex and requires input from a multidisciplinary team. Baseline local staging and mismatch repair protein testing are vital to develop individualized treatment plans. There are multiple options in terms of treatment modalities and sequencing, including transanal excision, short-course radiation, long-course chemoradiation, chemotherapy doublet or triplet, nonoperative management, and immune checkpoint blockade for patients with mismatch repair deficient tumors. While localized colon cancer is typically treated with surgical resection and consideration of adjuvant chemotherapy, emerging data suggest that neoadjuvant chemotherapy may be beneficial in patients with higher-risk disease. Quality-of-life considerations are imperative to prevent potential chronic effects on psychosocial health, neuropathy, fertility, and bowel, bladder, and sexual function. The omission of radiation or surgery can mitigate these toxicities without diminishing oncologic outcomes. The optimal treatment plan and sequence is not a one-size-fits-all approach but rather should be personalized to the patient's disease burden, tumor location, comorbidities, and preferences.