Early Treatment Discontinuation Research Articles

Menopausal hormone therapy for breast cancer survivors.

The global incidence of breast cancer continues to increase and increasing efficacy of treatments has improved overall prognosis and survival with a resulting requisite focus on improving quality of life after cancer. Treatment inevitably results in symptoms of menopause and these symptoms may be more severe after cancer treatment compared to natural menopause and may pose a potential risk of early treatment discontinuation. Consequently, the global burden of successfully managing these symptoms is significant. There is a discordance between randomized and observational data regarding the risk of systemic menopausal hormone therapy and breast cancer recurrence; hormone receptor status is significant to recurrence risk in this setting. The systemic absorption of local oestrogen is not a consistent surrogate marker for cancer recurrence and clinical data has not demonstrated a consistent increase in the risk of cancer recurrence with local therapy. Nonhormonal treatments remain first-line management of menopause symptoms in breast cancer survivors to minimize the risk of cancer recurrence. However, severe symptoms not responding to nonhormonal interventions require a multidisciplinary, patient-centred approach to discuss the evidence base for hormonal treatments.

TRLR-01 THE PROGNOSTIC UTILITY OF TEMPORALIS MUSCLE THICKNESS MEASURED ON MAGNETIC RESONANCE SCANS IN PATIENTS WITH INTRA-AXIAL MALIGNANT BRAIN TUMOURS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract OBJECTIVE Sarcopenia is associated with worsened outcomes in solid cancers. Temporalis muscle thickness (TMT) has emerged as a measure of sarcopenia. Hence, this study aims to evaluate the relationship between TMT and outcome measures in patients with malignant intra-axial neoplasms. METHODS Following the PRISMA guidelines, we systematically searched PubMed, Embase, Scopus, and Cochrane databases for relevant studies from inception until June 17, 2022. Event ratios with 95% confidence intervals (CI) were analyzed using the RevMan 5.4 software. Where meta-analysis was impossible, vote counting was used to determine the effect of TMT on outcomes. The GRADE framework was used to determine the certainty of the evidence. RESULTS Four outcomes were reported for three conditions across 17 studies involving 4430 patients. Glioblastoma: thicker TMT was protective for overall survival (OS) (HR 0.59; 95% CI 0.46–0.76) (GRADE low), progression-free survival (PFS) (HR 0.40; 95% CI 0.26–0.62) (GRADE high), and early discontinuation of treatment (OR 0.408; 95% CI 0.168–0.989) (GRADE high); no association with complications (HR 0.82; 95% CI 0.60–1.10) (GRADE low). Brain Metastases: thicker TMT was protective for OS (HR 0.73; 95% CI 0.67–0.78) (GRADE moderate); no association with PFS (GRADE low). Primary CNS Lymphoma: TMT was protective for overall survival (HR 0.34; 95% CI 0.19–0.60) (GRADE moderate) and progression-free survival (HR 0.23; 95% CI 0.09–0.56) (GRADE high). CONCLUSION TMT has significant prognostic potential in intra-axial malignant neoplasms, showing a moderate to high certainty for its association with outcomes following GRADE evaluation. This will enable shared decision-making between patients and clinicians.

Tolerability and Safety of Miltefosine for the Treatment of Cutaneous Leishmaniasis.

Miltefosine, an orally administered drug, is an important component of the therapeutic arsenal against visceral and mucosal forms of leishmaniasis. However, data regarding the safety and tolerability of miltefosine treatment for cutaneous leishmaniasis (CL) are relatively limited. The aim of this study was to evaluate the tolerability, safety, and adverse events (AEs) of miltefosine treatment in patients with CL. In this cohort study, we reviewed the medical records of all miltefosine-treated patients between 1 January 2016 and 31 December 2022, at Israel Defense Forces military dermatology clinics and the dermatology and Tropical Medicine Clinics at Chaim Sheba Medical Center, Ramat-Gan, Israel. A total of 68 patients (54 males, 79%) with a median age of 30.3 ± 15.6 years (range: 18-88) were included in this study. Leishmania species were identified as L. major (n = 37, 54.4%), L. tropica (n = 12, 17.6%), L. braziliensis (n = 18, 26.5%), and L. infantum (n = 1, 1.5%) using polymerase chain reaction (PCR). Miltefosine tablets were administered orally at a dose of 50 mg, three times daily, for 28 days. Overall, 44 patients (65%) completed the 28-day treatment, and the remaining patients required dose reduction or early discontinuation of treatment. AEs (of any degree) were common, reported in 91% of patients. Both previously reported and previously unreported AEs were documented. Gastrointestinal symptoms (66.1%) and malaise (23.5%) typically occurred during the first two weeks of treatment and tended to subside. Other AEs, including acute renal failure (20.6%), sudden and severe pleuritic chest pain (7.6%), acne exacerbation (11.8%), suppuration of CL lesions (17.8%), and AEs related to the male genitourinary system (39.6% of males), typically occurred towards the end of treatment. The latter included testicular pain, epididymitis, diminution or complete absence of ejaculate, inability to orgasm, and impotence. Severe AEs necessitated treatment discontinuation (29.4%) or hospitalization (10.3%). URTI-like symptoms, arthritis, cutaneous eruption, pruritus, and laboratory abnormalities were also observed. Overall, the cure rate (for all patients combined) evaluated 3 months after the completion of treatment was 60%. The tolerability of miltefosine treatment for CL is low. Close clinical and laboratory monitoring is required during treatment, as severe AEs are not uncommon. As new insights regarding its toxicities emerge, further studies are required to define the role of miltefosine in the treatment of CL.

540P Early treatment discontinuation (ETD) in dMMR/MSI-H metastastic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICIs)

540P Early treatment discontinuation (ETD) in dMMR/MSI-H metastastic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICIs)

Early therapeutic drug monitoring helps to identify inflammatory bowel disease patients with a high risk to fail thiopurine treatment.

Conventional thiopurines (azathioprine and mercaptopurine) remain standard therapy to maintain steroid sparing remission in inflammatory bowel disease (IBD), but are regularly discontinued due to adverse drug reactions (ADRs). Measurement of the metabolites 6-thioguanine nucleotides (6-TGN), 6-methylmercaptopurine ribonucleotides (6-MMPR) and the 6-MMPR/6-TGN ratio, may predict the development of these ADRs. Our aim was to evaluate whether early thiopurine metabolite measurements were associated with clinical outcomes. A post-hoc analysis was conducted of a multicentre, prospective, observational study on thiopurine-induced hepatotoxicity. IBD patients who initiated thiopurine therapy were included and thiopurine metabolite concentrations were assessed after 7days (±1) (T1). Patients were monitored for 12 weeks to document the occurrence of ADRs, early treatment discontinuation and effectiveness. In total, 181 patients were evaluated. At T1, 6-MMPR concentrations and 6-TGN/6-MMPR ratios were independently related to treatment discontinuation within 12 weeks after correction for sex, age and body mass index (BMI) (P= .034 and .002, respectively). The largest effects were observed for 6-MMPR ≥3000pmol/8 × 108 RBC and 6-TGN/6-MMPR ratio ≥17. Furthermore, 6-MMPR concentrations and 6-TGN/6-MMPR ratios at T1 were independently related to skewed metabolism at steady state (Week 8, 6-MMPR/-6TGN ratio ≥11 and ≥20) (both P< .001). The occurrence of ADRs and effectiveness were not independently related to T1 thiopurine metabolite concentrations. Thiopurine metabolite concentrations at T1 were related to early treatment discontinuation and skewed metabolism at steady state, but not to effectiveness, helping to identify patients with a high risk of thiopurine treatment failure.

Clinical Outcomes of Elective Early Discontinuation of Immunotherapy Based on Objective Response in Microsatellite Instability-High Metastatic Colorectal Cancer

BackgroundPatients with microsatellite-high (MSI-H) metastatic colorectal cancers (CRC) may experience long-lasting benefit from immune checkpoint inhibitors (ICI) upon stopping therapy. However, optimal timing and patient selection criteria for early treatment withdrawal remain undefined. In this single-center retrospective study, we characterized the clinical response and associated survival outcomes of patients who received elective early versus late treatment discontinuation. MethodsWe retrospectively analyzed patients with MSI-H metastatic CRC treated with ICI therapy from May 2015 to April 2024. Early ICI discontinuation was defined as treatment withdrawal before 2 years, and late ICI discontinuation as after 2 years. Response was assessed using Response Evaluation Criteria in Solid Tumors. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. Efficacy outcomes between early and late ICI discontinuation groups were compared using a log-rank test. ResultsOf 36 patients with MSI-H metastatic CRC, 12 underwent elective early ICI discontinuation and 9 experienced late ICI discontinuation. After a median follow-up of 32 months post-treatment, 91.7% (11/12) in the early discontinuation group remain off therapy without progression. PFS and OS outcomes between the early and late discontinuation groups were similarly favorable (P = .88 and P = .85, respectively), despite a 12-month difference in median duration of ICI therapy (13.3 and 25.6 months, respectively). The most common reason for elective early treatment discontinuation was clinical remission (n = 10), defined as a complete response, or a partial response with negative PET and/or ctDNA testing. ConclusionsEarly ICI discontinuation guided by response criteria resulted in low rates of recurrence. Survival outcomes between early and late ICI discontinuation groups were comparable, suggesting that treatment duration can be individualized based on clinical response without compromising favorable long-term prognosis.

Exploring early discontinuation of mental health outpatient treatment: language, demographics and clinical characteristics among migrant populations in Japan

BackgroundThe fast-growing migrant population in Japan and globally poses challenges in mental healthcare, yet research addressing migrants’ mental health treatment engagement remains limited.ObjectiveThis study examined language proficiency, demographic and clinical...

Dose delay, dose reduction, and early treatment discontinuation in Black and White women receiving chemotherapy for nonmetastatic breast cancer.

To describe reasons for deviations from planned chemotherapy treatments in women with nonmetastatic breast cancer that contribute to less-than-planned receipt of chemotherapy. Electronic medical records for patients receiving chemotherapy were reviewed for adverse events and treatment modifications. Log-binomial regression models were used to estimate relative risks (RRs) with 95% CIs to examine associations between chemotherapy modifications, patient characteristics, and treatment modalities. Delays in chemotherapy initiation (7%) were for surgical complications (58%), personal reasons (16%), and other (26%; port malfunction, infections, and obtaining extra imaging). Delays during chemotherapy (38%) were for infections (20%), neutropenia (13%), and personal reasons (13%). Dose reductions (38%) were for neuropathy (36%), unknown causes (9%), anemia (9%), and neutropenia (8%). Early treatment discontinuations (23%) were for neuropathy (29%). Patients receiving paclitaxel/nab-paclitaxel (RR 2.05; 95% CI, 1.47-2.87) and an anthracycline (RR 1.89; 95% CI, 1.39-2.57) reported more dose delays during chemotherapy. Black race (RR 1.46; 95% CI, 1.07-2.00), stage 3 (RR 1.79; 95% CI, 1.09-2.93), and paclitaxel/nab-paclitaxel receipt (RR 1.39; 95% CI, 1.02-1.90) increased the likelihood of dose reduction. Both Black race (RR 2.06; 95% CI, 1.35-3.15) and receipt of paclitaxel/nab-paclitaxel (RR 1.93; 95% CI, 1.19-3.13) increased the likelihood of early discontinuation. Patients receiving anthracyclines had higher rates of hospitalizations during chemotherapy (RR: 1.79; 95% CI, 1.11-2.89). Toxicities are the most common reason for treatment modifications and need close monitoring in high-risk groups for timely intervention. Dose reductions and early treatment discontinuations occurred more for Black patients and need further study.

Analysis of Treatment Discontinuation in Orthokeratology: Studying Efficacy, Safety, and Patient Adherence Over Six Months.

This study aimed to evaluate the efficacy, safety, and participant compliance of orthokeratology treatment for the correction of myopic refractive errors over a six-month prospective study and to define the potential reasons for early treatment discontinuation. A total of 32 participants with low-to-moderate myopia were fitted with the spherical model of corneal refractive therapy (CRT) orthokeratology lenses (Paragon Vision Sciences) and followed over six months, with specific attention to alterations in refractive error, corneal topography, and epithelial thickness. Concurrently, participant feedback and reasons for any treatment discontinuation were documented. Significant changes in refractive error and in corneal topography were observed, with approximately 50% of the refractive error being corrected on the first night of use and 100% by the first two weeks ( P <0.001). Central epithelial thickness experienced substantial thinning, reducing to 15.65±4.49 μm (67.38%) ( P <0.001) after 6 months of lens use. Six participants withdrew from this study for varied reasons, including unmet visual expectations and difficulty adhering to the lens-wearing regimen. Notably, the dropout group exhibited higher baseline low-order aberrations and less prolate corneas than those who persisted with the treatment ( P <0.05). Orthokeratology with CRT is efficacious and safe for the correction of low-to-moderate myopia in adults, but a portion of patients discontinue the treatment in the first 6 months of contact lens wear. Special care should be taken when recommending orthokeratology in patients with higher levels of myopia and corneas with less prolate shape, providing more realistic expectations and even changing to dual axis or more sophisticated designs.

PRGN-2012, a novel gorilla adenovirus-based immunotherapy, provides the first treatment that leads to complete and durable responses in recurrent respiratory papillomatosis patients.

LBA6015 Background: Recurrent respiratory papillomatosis (RRP) is a rare, neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11. Significant morbidity can occur due to airway obstruction and, although rare, transformation into malignant cancer. There are no approved therapeutics. RRP is currently managed with frequent ablative procedures that can lead to irreversible laryngotracheal scarring and disability. PRGN-2012 is a gorilla adenovirus-based gene therapy/immunotherapy designed to generate HPV6/11-specific T cell immunity. The FDA has granted PRGN-2012 Breakthrough Therapy Designation for the treatment of RRP recognizing that this single arm study can serve as pivotal to support a licensing application. Methods: This pivotal trial (NCT04724980) evaluates the safety and efficacy of PRGN-2012 in patients with RRP requiring a minimum of 3 surgeries in the 12 months prior to treatment. Eligible patients received 4 subcutaneous (SC) injections of PRGN-2012 at dose level (DL) 1 (1x1011 Particle Units (PU) per injection; n=3) or DL2 (5x1011 PU per injection; n=35) over 12 weeks. The primary endpoint was the rate of complete response (CR), defined as no requirement for surgery in the 12 months following completion of treatment. Other key endpoints include duration of response, change in extent of papilloma growth (anatomic Derkay score) and vocal function. Results: PRGN-2012 was well-tolerated, with no serious adverse events, grade &gt; 2 treatment-related adverse events, or early treatment discontinuations. The most common adverse events were injection-site reaction, fatigue, chills, fever, and myalgia. PRGN-2012 treatment at DL2 significantly (p&lt;0.0001) decreased the requirement for surgery, with a median number of surgeries in the 12 month period decreasing from 4 (3-10) prior to treatment to 0 (0-7) surgeries post-treatment. Approximately 90% of patients experienced a decrease in the number of surgeries in the 12 months post-treatment compared to pre-treatment with PRGN-2012. The primary endpoint evaluation demonstrated a confirmed complete response in 17/31 (55%) of evaluable patients. The median duration of complete response has yet to be reached with a median follow up of 15 months (12 - 30) at the time of data cutoff (March 6, 2024). Additionally, PRGN-2012 treatment resulted in a significant reduction in Derkay score, improvement in vocal function and generation of HPV-specific immune responses. Conclusions: These data demonstrate the overall favorable safety profile and significant clinical benefit of PRGN-2012 in adult RRP patients. These findings support PRGN-2012 as a potential therapeutic option for this patient population where no FDA-approved therapeutics exist. Clinical trial information: NCT04724980 .

A phase IV study of ApricityCARE program for cancer adverse events rapid evaluation to improve treatment outcomes of ethnic/racial minority patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICI).

TPS1642 Background: ICI have changed the treatment landscape of NSCLC, with many now FDA approved in not just advanced, but even early-stage disease. With the increase in ICI use, the incidence of immune-related adverse effects (irAEs) has also risen, occurring in up to 16% of ICI-treated patients. Prompt recognition and timely management are necessary to avert potential poor outcomes from direct toxicity and/or early treatment discontinuation. However, existing barriers to access care that disproportionately impact racial and ethnic minority patients may amplify challenges in early, effective management of irAEs. Using technology-enabled health interventions in a culturally competent manner can improve access to health care resources and reduce health disparities. These platforms need to be optimized at the technology and health literacy level of underserved minority communities and adapted to meet the community's needs. Methods: We have designed a multi-center phase IV clinical trial to 1) assess factors related to suboptimal and optimal use of the ApricityCARE, a virtual first-response clinical support (or coverage) to provide 24/7 symptom monitoring and side effect management and 2) determine the impact of the program on ICI toxicity management for NSCLC patients receiving ICIs in a highly diverse community. Eligible patients are those with a confirmed diagnosis of NSCLC who self-identify as a member of an ethnic minority or underserved population, prescribed for any treatment regimen that includes an ICI. The study entails a 50-patient run-in phase with two focus group discussions, stratified on a Likert-type scale based on the frequency of utilization, to determine factors impacting usability of the ApricityCare program. This data will inform optimal implementation of ApricityCare for the randomized phase of the study, where 230 patients will be assigned 1:1 to use of ApricityCare versus standard of care. The run-in phase of the study is currently accruing at Columbia University, and is planned to open at NYU, Mount Sinai, and Montefiore (NCT05812274). Clinical trial information: NCT05812274 .

Start low, go slow: A systematic review and meta-analysis of upfront tailored treatment dosing in older adults with advanced cancer.

1625 Background: Older adults aged ≥65 with advanced cancer are underrepresented in treatment trials. This gap limits informed decision-making regarding the dose and tolerability of proposed therapies. Standard chemotherapy is associated with &gt;50% serious adverse event rate among older adults, with frequent dose reduction and early treatment discontinuation. A "start low, go slow" (SLGS) approach begins systemic therapy at lower-than-standard doses and increases the dose if well-tolerated. This alternative dosing strategy has shown value in minimizing adverse events and functional decline without compromising the overall effectiveness of treatments. We conducted the first systematic review and meta-analysis of SLGS effectiveness among older adults across advanced cancers. Methods: This review, was registered with PROSPERO and adhered to PRISMA criteria, covering PubMed, Journal of Geriatric Oncology and EMBASE from January 2000 until December 15, 2024. Eligible study designs were randomized controlled trials, retrospective trials, and non-randomized clinical trials with patients with advanced cancers who underwent systemic therapy. We reported all studies that studied the SLGS approach. Our studied outcomes were overall survival (OS), progression-free survival (PFS), treatment discontinuation, and toxicity. Data extraction included author, patient, cancer type, treatment, and survival outcomes. A meta-analysis using fixed effects and risk ratios (RR) was performed when sufficient data was available; significant outcomes had α&lt;0.05. Results: Our search identified 13 studies testing SLGS strategies in oncology, including 3,508 patients, with a median age 63-78 years. The -represented cancers included colorectal (6 studies, 3059 patients total), lung (2 studies, 113 pts), chronic myeloid leukemia (2 studies, 127 pts), non-Hodgkin lymphoma (1 study, 45 pts), and prostate (2 studies, 164 pts) cancers. Ten (77%) studies assessed OS and PFS. Five studies (39%) compared SLGS against standard doses, finding no significant differences in PFS and OS across all trials. Dose escalation rates for SLGS ranged from 5% to 60%. The ability to complete planned cycles was higher with SLGS compared to standard dose (1 study, 43% vs 26%, p=0.04). Treatment discontinuation was not different for SLGL vs. standard dose (5 studies, meta-analysis RR 1.07, 95% CI 0.90-1.27, p=0.42). Toxicity ranged from 5% to 89% across studies; SLGS had lower grade ≥3 adverse events compared to standard dose (4 studies, meta-analysis RR 0.88, 95% CI 0.80-0.94, p &lt; 0.001). Conclusions: This is the first systematic review and meta-analysis analyzing the SLGS approach to systemic therapy dosing in older adults with advanced cancer. Compared to standard-dose systemic therapy, older adults pursuing a SLGS strategy had greater completion of planned cycles, reduced toxicity, and similar survival.

Real world impact of pembrolizumab availability for deficient mismatch repair metastatic colorectal cancer.

e15569 Background: Keynote 177 was a practice changing study, with pembrolizumab versus dealers’ choice chemotherapy +/- biologic significantly improving progression free survival in patients (pts) with previously untreated deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC). A high rate (29.4%) of pembrolizumab treated pts had stopped treatment at or before first response evaluation due to progressive disease as best response. Pembrolizumab availability in routine care is anticipated to benefit individual pts otherwise treated with chemotherapy. Additional pts not fit for chemotherapy, but fit for first line (1L) pembrolizumab, may be able to receive active treatment, which could increase the dMMR mCRC population benefit. Pembrolizumab availability may also drive increased MMR testing, which may impact the proportion of pts with dMMR mCRC. Methods: We analysed data from the TRACC registry of pts with mCRC in Australia comparing patient treatment across two cohorts. The first cohort was pts diagnosed from 1/1/2015 to 31/7/2021 when immunotherapy was only available via trial, self-funding or through a limited access program and the second cohort was pts diagnosed from 1/8/2021 to 23/1/2024, following the government’s Pharmaceutical Benefits Scheme reimbursement (PBSr) of pembrolizumab as 1L treatment for dMMR mCRC. We also examined early treatment discontinuation rates for pembrolizumab treated pts after PBSr. Results: Of 2819 mCRC pts overall, 2344 (83%) had known MMR status. Of pts tested 163 (7%) were dMMR. Pts with dMMR mCRC were older (mean age 66.6 vs 62.2, p &lt; 0.01) and had more co-morbidities (59% vs 47% for modified Charlson Comorbidity Index ≥ 3, p &lt; 0.01). They were also more likely to have a right side primary (67% vs 31%, p &lt; 0.01), BRAF V600E mutation (49% vs 11%, p &lt; 0.01) and peritoneal or brain metastases (34% vs 22%, p &lt; 0.01). Before PBSr of pembrolizumab, 85 of 117 (73%) dMMR mCRC pts received 1L treatment; 62/85 (73%) chemotherapy, 19/85 (22%) immunotherapy and 4/85 (5%) combination BRAF inhibitor and EGFR inhibitor. Following PBSr, an increased proportion (40 of 46) of dMMR mCRC pts received any 1L treatment (87% vs 73%, p = 0.05), with 1/40 (2.5%) receiving chemotherapy and 39/40 (97.5%) pembrolizumab. In a landmark analysis of these 39 pts, 12 of 19 (63%) that had started treatment ≥ 6 months ago remained on pembrolizumab. Conclusions: A high proportion of Australian pts with mCRC are undergoing dMMR testing. Increasing testing, including of more elderly pts, may increase the proportion of mCRC pts that are dMMR compared to that reported for trial populations. dMMR mCRC pts have multiple adverse prognostic features. The broad availability of pembrolizumab, such as through the Australian PBSr, looks likely to lead to an increased proportion of pts receiving any 1L therapy. Early data suggests the expected clinical benefit, with a low rate of early treatment discontinuation.

Real-world clinical outcomes and economic burden of early discontinuation of taxane therapy among patients with metastatic castration-resistant prostate cancer.

e17043 Background: Despite comprising an important part of the treatment paradigm for metastatic castration-resistant prostate cancer (mCRPC) for over a decade, real-world use of taxanes is hindered by adverse events (AEs). AEs may lead to early treatment discontinuation, which may adversely affect outcomes. The two goals of this study were to determine the proportion of mCRPC patients who discontinue taxanes early (defining the early discontinuation threshold relative to efficacy results associated with androgen receptor pathway inhibitors [ARPIs]) and to evaluate the impact of early discontinuation on clinical outcomes, AEs, and healthcare costs. Methods: This was a retrospective, observational study of adult men with mCRPC treated with an ARPI as their first-line (1L) therapy and who initiated second-line (2L) therapy with another ARPI or a taxane. The Flatiron Health electronic health record database (07/01/2012–06/30/2020) was used to estimate Kaplan-Meier overall survival (OS) curves for the taxane cohort by the number of cycles received; these were compared with patients who received ARPI at 2L. Cox regression modeling and median PFS and OS values were used to identify the number of taxane cycles needed to achieve comparable OS to ARPI. The number of taxane cycles with similar OS outcomes to ARPI was then considered the threshold for early discontinuation. In addition, the IQVIA PharMetrics Plus claims database (01/01/2013–08/31/2021) was used to estimate taxane-related AEs (based on product information) and associated healthcare costs among patients who did and did not discontinue taxanes early. Results: From Flatiron, 473 2L ARPI patients and 214 2L taxane patients were included. Similar clinical characteristics – e.g., prostate-specific antigen level, ECOG performance status, and Gleason score – were observed between the two cohorts. Overall, 2L ARPI was associated with longer median OS (15.4 vs. 13.6 months) than 2L taxane. The number of taxane cycles needed to reach comparable OS to ARPI was determined to be 8. Patients receiving &gt;8 cycles (n=48; 22%) compared to those receiving ≤8 cycles (n=166; 78%) had longer median OS (18.4 vs. 11.9 months, respectively) and PFS (9.0 vs. 4.3 months, respectively). From PharMetrics, 158 2L taxane patients were included. Patients receiving &gt;8 cycles (n=20; 13%) were more likely to experience an AE (95% vs. 88%) than those receiving ≤8 cycles (n=138; 87%) but had lower mean AE-related total healthcare costs per patient per month ($3,429 vs. $6,334). Conclusions: These results suggest that mCRPC patients need to receive &gt;8 cycles of taxane at 2L to receive more clinical benefit than 2L ARPI. However, the vast majority of patients in the study discontinued taxane early, resulting in shorter survival outcomes compared to ARPI.

A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer (GIANT): ECOG-ACRIN EA2186.

4003 Background: Evidence-based data is lacking to guide the care of vulnerable older adults with newly diagnosed metastatic pancreatic ductal adenocarcinoma (mPDAC) resulting in extrapolation of the treatment approach utilizing data from younger patients. EA2186 is a phase II randomized controlled trial, and the first prospective study aiming to define the optimal treatment approach for vulnerable older adults with newly diagnosed mPDAC. Methods: EA2186 enrolled vulnerable patients ≥70 years of age with histologically confirmed mPDAC, ECOG PS 0-2 and adequate organ function. Vulnerability was defined by a screening geriatric assessment (GA) demonstrating mild abnormalities in functional status, comorbidities, cognition, or age ≥80 years. Patients were randomized to Arm A: Gemcitabine (1000mg/m2) and Nab-Paclitaxel (125mg/m2) every 14 days or Arm B: 5-Fluorouracil (2400mg/m2 over 46hr) Leucovorin (400mg/m2) and Liposomal Irinotecan (50mg/m2) every 14 days. A comprehensive GA and quality of life (QOL) evaluation were completed at baseline and 3 time points. Primary endpoint was overall survival (OS); secondary endpoints included progression free survival (PFS), response rate (RR), safety, and QOL. The study had 90% power to detect a difference in median OS of 7.7 vs. 10.7 months (HR of 0.72) using a one-sided log-rank test at the 0.10 significance level. Stratification factors included age 70-74 vs ≥75, and ECOG PS 0-1 vs 2. The study met the planned futility boundary for OS at its single interim analysis (60.6% information) and was closed early by the DSMC. Results: 176 patients were enrolled at 92 US sites between 6/2020 – 10/2023, 88 patients per arm. Median age of enrolled patients was 77 (range 70-90), 49% females, 24% ECOG-0, 64% ECOG-1 and 12% ECOG-2. Majority of patients were deemed vulnerable by cognition (46%), age (36%) or co-morbidities (31.4%), with some patients meeting vulnerability criteria in multiple domains. No significant difference was seen in median OS between the arms (4.7 vs. 4.4 months in Arms A and B respectively; p = 0.72). PFS, RR, and factors contributing to early treatment discontinuation and affecting the lower-than-expected survival will be presented at the meeting. At the time of data cut off rates of ≥grade 3 toxicity was 45.6% in Arm A and 58.7% in Arm B (p = 0.10); rates of ≥grade 4 toxicity were 7.6% in Arm A vs 14.7% in Arm B (p = 0.16). Most common ≥grade 3 toxicities included anemia, neutropenia, fatigue in both Arms, and diarrhea in Arm B. Conclusions: EA2186 did not demonstrate a significant difference in efficacy or overall toxicity between two attenuated regimens tested in vulnerable older adults with mPDAC. These results provide important data to guide treatment decisions and goals of care discussions in this vulnerable patient population. Clinical trial information: NCT04233866 .

Real-world outcomes following adverse events and dose reduction of first-line ibrutinib in Medicare beneficiaries with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

e19017 Background: Dose reduction (DR) has been used to manage treatment-related adverse events (AEs) effectively and avoid early treatment discontinuation in patients (pts) with CLL/SLL receiving ibrutinib (ibr) in the first-line (1L) setting. This study evaluated DR and time to next treatment (TTNT) following AE in Medicare pts with CLL/SLL who were initiating ibr. Methods: Medicare Fee-for-Service (FFS) closed claims and enrollment data were used to identify pts with CLL/SLL who initiated 1L single-agent ibr (420 mg/day) from January 2014 to September 2020 with an incident AE following treatment initiation. Ibr DR was defined as reduction of starting dose following the first reported incident AE. Demographics, clinical characteristics, time to first incident AE, TTNT, and Healthcare Resource Utilization (HCRU) were analyzed among pts with and without DR (time to event measured in months). TTNT was defined as time from first incident AE to initiation of a new agent (≤90 days of ibr discontinuation) or death and was compared in pts with and without DR using Kaplan-Meier analysis and a time-varying Cox proportional hazards model. Results: Of 3575 pts included in the analysis (median age: 76 years; male: 63.4%), 459 (12.8%) had a DR. Duration of 1L ibr, time to first incident AE, time to DR, and TTNT varied among study cohorts. Median TTNT (standard deviation [SD]) for pts with and without DR was 49.8 months (1.4) and 22.0 months (0.6), respectively. After 6 and 12 months of follow-up, significantly fewer pts with DR discontinued treatment than pts without DR (6 months: 8.3% vs 27.3%, P = 0.0062; 12 months: 13.8% vs 38.2%, P = 0.0003). A total of 51 pts discontinued treatment immediately after the first incident AE; 414 deaths were reported within 90 days of the first incident AE. After controlling for baseline demographics and clinical characteristics as well as time-varying HCRU and costs, pts with DR were not significantly likely to discontinue treatment compared with pts without DR (hazard ratio [95% CI], DR vs no DR: 0.89 [0.71–1.12]). Increased age, comorbidity index score, healthcare costs, and number of hospitalizations were significant predictors of treatment discontinuation. Conclusions: Among Medicare FFS pts with CLL/SLL and an AE following initiation of 1L ibr, pts with DR remained on therapy significantly longer than pts without DR. Ibr DR may be an effective strategy to manage tolerability while maintaining clinical efficacy.

The Polypill: A New Alternative in the Prevention and Treatment of Cardiovascular Disease.

Cardiovascular disease (CVD) is the primary cause of death and disability worldwide. Although age-standardized CVD mortality rates decreased globally by 14.5% between 2006 and 2016, the burden of CVD remains disproportionately higher in low- and middle-income countries compared to high-income countries. Even though proven, effective approaches based on multiple-drug intake aimed at the prevention and treatment of CVD are currently available, poor adherence, early discontinuation of treatment, and suboptimal daily execution of the prescribed therapeutic regimes give rise to shortfalls in drug exposure, leading to high variability in the responses to the prescribed medications. Wald and Law, in their landmark paper published in BMJ 2003, hypothesized that the use of a fixed-dose combination of statins, β-blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and aspirin (classic Polypill composition) may increase adherence and decrease CVD by up to 80% when prescribed as primary prevention or in substitution of traditional protocols. Since then, many clinical trials have tested this hypothesis, with comparable results. This review aims to describe the available clinical trials performed to assess the impact of fixed-dose combinations on adherence, cost-effectiveness, and the risk factors critical to the onset of CVD.

Safe Stop IPI-NIVO trial: early discontinuation of nivolumab upon achieving a complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab – study protocol

BackgroundPatients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy.MethodsThe Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life.DiscussionFrom a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response.Trial registrationClinicalTrials.gov ID NCT05652673, registration date: 08–12-2022.

Elevated pretreatment lactate dehydrogenase and albumin-to-alkaline phosphatase ratio predict poor prognosis and early treatment discontinuation in head and neck cancer patients with preexistent diabetes mellitus.

Increased serum lactate dehydrogenase (LDH) activity is considered as amarker of cellular necrosis and serves as ametabolomic diagnostic marker in several types of cancer including head and neck squamous cell carcinoma (HNSCC). LDH, an enzyme involved in the glycolytic cycle, is correlated not only with the activation of oncogenes such as HIF-α and Myc, but also with effects such as tumor proliferation and metastasis. Serum alkaline phosphatase (ALP) is amarker of cell differentiation and tumor induction. Albumin-to-alkaline phosphatase ratio (AAPR) could be an advantageous biomarker due to its easily accessible dynamics and cost-effectiveness. Elevated values of AAPR could be associated with longer overall survival (OS) in cases with solid tumors. Diabetes mellitus (DM) could influence the outcome of patients with HNSCC by contributing to insulin resistance and chronic inflammation, and by being involved in various aspects of carcinogenesis, disease progression and metastasis. However, the use of antihyperglycemic medications (metformin) can have beneficial effects by inhibiting tumor metabolic pathways. The biomarker role of LDH and AAPR in HNSCC patients with DM has been less evaluated. The purpose of the study was to assess the prognostic value of pretreatment serum lactate dehydrogenase (LDH) and albumin-to-alkaline phosphatase ratio (AAPR) in predicting the duration of non-surgical oncological treatment and glycemic control in cases of head and neck cancers patients with DM, including cases selected from the database of the oncology clinic and oncology outpatient clinic of the Craiova County Hospital. Both LDH and AAPR can be used as pre-treatment biomarkers predictive of treatment response, or prognostic tools included in complex multi-parametric models in HNC associated with DM. However, given the impact of short-term glycemic control on the LDH level, it is necessary to evaluate these biomarkers after assessing and controlling for DM, and with the recommended cut-off value set around 0.5. Due to the limited number of cases, it is necessary to validate the results in multicentric trials with alarger number of patients (Tab. 5, Ref. 50). Keywords: diabetes mellitus, HNC, LDH, AAPR, biomarkers, predictive, head and neck cancers, lactate dehydrogenase, albumin-to-alkaline phosphatase ratio.

The prognostic utility of temporalis thickness measured on MRI scans in patients with intra-axial malignant brain tumours: a systematic review and meta-analysis

Sarcopenia is associated with worsened outcomes in solid cancers [1].Temporalis muscle thickness (TMT) has emerged as a measure of sarcopenia[2]. Hence, this study aims to evaluate the relationship between TMTand outcome measures in patients with malignant intra-axial neoplasms.We searched Medline, Embase, Scopus, and Cochrane databases for relevantstudies. Event ratios with 95% confidence intervals (CI) were analysedusing the RevMan 5.4 software. Where meta-analysis was impossible, votecounting was used to determine the effect of TMT on outcomes. TheGRADE framework was used to determine the certainty of the evidence. Four outcomes were reported for three conditions across 17 studiesinvolving 4430 patients. Glioblastoma: thicker TMT was protective foroverall survival (OS) (HR 0.59; 95% CI 0.46–0.76) (GRADE low), progressionfree survival (PFS) (HR 0.40; 95% CI 0.26–0.62) (GRADE high),and early discontinuation of treatment (OR 0.408; 95% CI 0.168–0.989)(GRADE high); there was no association with complications (HR 0.82;95% CI 0.60–1.10) (GRADE low). Brain Metastases: thicker TMTwas protective for OS (HR 0.73; 95% CI 0.67–0.78) (GRADE moderate);there was no association with PFS (GRADE low). Primary CNSlymphoma: TMT was protective for overall survival (HR 0.34; 95%CI 0.19–0.60) (GRADE moderate) and progression free survival (HR0.23; 95% CI 0.09–0.56) (GRADE high).Across various intracranial intra-axial malignancies, patients withthicker TMT have better survival outcomes and are less prone to discontinuingtreatment secondary to drug toxicity. TMT has the potential tobe a valuable prognostic tool for risk-benefit considerations in the managementof these patients.