Platinum Research Articles

Breast squamous cell carcinoma: Case report and review of the literature

Squamous cell carcinoma (SCC) of the breast is a rare and aggressive form of breast cancer, classified as a metaplastic carcinoma. Diagnosis of this carcinoma is challenging due to the absence of distinctive clinical or radiological features. Histopathological conformation is essential, and immunochemistry typically shows negativity for hormone receptors and HER2, with positive markers such as CK5/6 and P40. Treatment strategies are not well defined, but platinum-based chemotherapy has shown promising results in some cases. Radiotherapy can serve both curative and palliative purposes depending on disease stage. We report the case of a 57-year-old patient treated in our department with chemotherapy and radiotherapy.

TROPION-Lung07: Phase III study of Dato-DXd+pembrolizumab±platinum-based chemotherapy as 1L therapy for advanced non-small-cell lung cancer.

For patients with advanced/metastatic non-small-cell lung cancer (NSCLC) without actionable genomic alterations and low (<50%) PD-L1 expression, pembrolizumab plus pemetrexed and platinum chemotherapy is a preferred first-line treatment. These patients have comparatively worse outcomes than those with higher PD-L1 expression, underscoring the need for new combination strategies. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, has demonstrated encouraging antitumor activity and safety in this patient population. We describe the rationale and design of TROPION-Lung07, a randomized, open-label Phase III study assessing Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pembrolizumab plus pemetrexed and platinum-based chemotherapy in patients with advanced/metastatic non-squamous NSCLC without actionable genomic alterations and <50% PD-L1 expression. Primary study objectives are progression-free survival and overall survival.Clinical Trial Registration: NCT05555732 (ClinicalTrials.gov).

Platinum Resistance in Ovarian Cancer: Is This the End of the Line?

Approximately 80% of females with ovarian cancer are diagnosed with advanced disease, and around 70% of these females relapse within 3 years of first-line treatment. Five-year survival for newly diagnosed advanced ovarian cancer is less than 50%. Platinum-based chemotherapy is the cornerstone of systemic treatment; however, it is not appropriate for patients with relapsed ovarian cancer who had disease progression during previous platinum treatment, early symptomatic progression post-platinum treatment, or who are platinum intolerant. New drugs are needed to address the unmet need in patients with relapsed ovarian cancer who are not eligible for platinum-based chemotherapy. This article presents highlights from a satellite symposium conducted as part of the European Society for Medical Oncology (ESMO) Congress 2024, which took place from 13th–17th September 2024 in Barcelona, Spain. The objectives of the symposium were to improve understanding of the current treatment pathways and unmet needs for patients with ovarian cancer who are ineligible for platinum-based therapies, to raise awareness of the rationale for targeting folate receptor α (FRα) in a variety of novel therapeutics for platinum-resistant ovarian cancer (PROC), and to review the efficacy outcomes and side effects from recent clinical trials involving antibody–drug conjugates (ADC) in PROC. In this symposium, Ana Oaknin, Vall d’Hebron University Hospital, Barcelona, Spain, described the current landscape in advanced ovarian cancer and the unmet need in relapsed disease; Philipp Harter, Evangelische Kliniken Essen-Mitte, Germany, explored FRα-targeted therapeutics in PROC; and Kathleen Moore, Stephenson Cancer Center, University of Oklahoma, Norman, USA, discussed ADC development beyond FRα in PROC. The symposium concluded with a lively discussion, including questions from the audience, key examples of which are included in this article.

Efficacy and safety of pembrolizumab in patients with advanced urothelial carcinoma deemed potentially ineligible for platinum-containing chemotherapy: Post hoc analysis of KEYNOTE-052 and LEAP-011.

First-line pembrolizumab monotherapy is a standard of care for platinum-ineligible patients with advanced urothelial carcinoma (UC). No global standardized definition of platinum ineligibility exists. This study aimed to evaluate the efficacy and safety of pembrolizumab monotherapy in patients with UC who met various criteria for platinum ineligibility. Patients from KEYNOTE-052 and LEAP-011 deemed potentially platinum ineligible were pooled for this post hoc exploratory analysis as follows: group 1: Eastern Cooperative Oncology Group performance status (ECOG PS) 2; group 2: ECOG PS 2 and age ≥80 years, renal dysfunction, or visceral disease; and group 3: any two other factors regardless of ECOG PS. Patients received pembrolizumab 200 mg intravenously every 3 weeks. End points included objective response rate (ORR), progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1, by blinded independent central review, overall survival (OS), and safety. A total of 612 patients treated with pembrolizumab from KEYNOTE-052 (n=370) and LEAP-011 (n=242) were included; the median (range) follow-up was 56.3 months (51.2-65.3 months) and 12.8 months (0.2-25.1 months), respectively. For group 1, ORR was 26.2%, median PFS was 2.7 months, and median OS was 10.1 months. For group 2, ORR ranged from 23.5% to 33.3%, median PFS ranged from 2.1 to 4.4 months, and median OS ranged from 9.1 to 10.1 months. For group 3, ORR ranged from 25.7% to 27.9%, median PFS ranged from 2.1 to 2.8 months, and median OS ranged from 9.0 to 10.6 months. Treatment-related adverse event rates were consistent across groups. Frontline pembrolizumab has consistent antitumor activity and safety in patients with advanced UC categorized as potentially ineligible for platinum-based chemotherapy, regardless of the variable definitions of platinum ineligibility used.

Perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy for resectable non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 2 trial (TD-NeoFOUR trial)

This open-label, single-arm, phase 2 trial evaluated the efficacy and safety of neoadjuvant sintilimab combined with anlotinib and chemotherapy, followed by adjuvant sintilimab, for resectable NSCLC. Forty-five patients received anlotinib (10 mg, QD, PO, days 1–14), sintilimab (200 mg, day 1), and platinum-based chemotherapy of each three-week cycle for 3 cycles, followed by surgery within 4–6 weeks. Adjuvant sintilimab (200 mg) was administered every 3 weeks. The primary endpoint was achieving a pathological complete response (pCR). From June 10, 2021 through October 10, 2023, 45 patients were enrolled and composed the intention-to-treat population. Twenty-six patients (57.8%) achieved pCR, and 30 (66.7%) achieved major pathological response (MPR). Forty-one patients underwent surgery. In the per-protocol set (PP set), 63.4% (26/41) achieved pCR, and 73.2% achieved MPR. The median event-free survival was not attained (95% CI, 25.1-NE). During the neoadjuvant treatment phase, grade 3 or 4 treatment-related adverse events were observed in 25 patients (55.6%), while immune-related adverse events were reported in 7 patients (15.6%). We assessed vascular normalization and infiltration of immune-related cells by detecting the expression of relevant cell markers in NSCLC tissues with mIHC. Significant tumor microenvironment changes were observed in pCR patients, including reduced VEGF+ cells and CD4+Foxp3+ Treg cells, and increased perivascular CD4+ T cells, CD39+CD8+ T cells, and M1 macrophages. In conclusion, perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy achieved pCR in a notable proportion of patients with resectable NSCLC and were associated with profound changes in the tumour microenvironment (ClinicalTrials.gov NCT05400070).

Risk factors for treatment-related sensorineural hearing loss and hearing aid use in medulloblastoma patients: an observational cohort study.

This study aimed to analyze treatment-related risk factors for sensorineural hearing loss (SNHL) and an indication for hearing aids (IHA) in medulloblastoma patients after craniospinal radiotherapy (CSRT) and platin-based chemotherapy (PCth). Atotal of 58patients (116 ears) with medulloblastoma and clinically non-relevant pre-treatment hearing thresholds were included. Cranial radiotherapy and PCth were applied sequentially according to the HIT 2000 study protocol or post-study recommendations, the NOA-07 protocol, or the PNET (primitive neuroectodermal tumor) 5MB therapy protocol. Audiological outcomes up to amaximum post-therapeutic follow-up of 4years were assessed. The incidence, post-treatment progression, and time-to-onset of SNHL, defined as Muenster classification grade ≥MS2b, were evaluated. Risk factors for IHA were analyzed separately. While 39patients received conventionally fractionated RT (CFRT; group1), 19patients received hyperfractionated RT (HFRT; group2). Over amedian follow-up of 40months, 69.2% of ears in group1 experienced SNHL ≥MS2b compared to 89.5% in group2 (p = 0.017). In multivariable Cox regressions analysis, younger age and increased mean cochlear radiation dose calculated as the equivalent dose in 2‑Gy fractions (EQD2) were associated with time-to-onset of SNHL ≥MS2b (p = 0.019 and p = 0.023, respectively) and IHA (p < 0.001 and p = 0.016, respectively). Tomotherapy and supine positioning were associated with alower risk for IHA in univariable modelling only (p = 0.048 and p = 0.027, respectively). Young age and cochlear EQD2 Dmean ≥40 Gy are significant risk factors for the incidence, degree, and time-to-event of SNHL as well as for IHA in medulloblastoma patients.

Real-world treatment patterns, biomarker testing, and clinical outcomes of metastatic non-small cell lung cancer patients in the immunotherapy era

BackgroundTreatment for first-line (1L) metastatic non-small cell cancer (mNSCLC) changed with the introduction of immunotherapy. We describe treatment utilization and clinical outcomes in a real-world mNSCLC cohort in a 2.7-million-member state-mandated health provider.MethodsNewly diagnosed mNSCLC patients initiating systemic anti-cancer treatment (January 2017–December 2020) were identified from the National Cancer Registry. Real-world time on treatment (rwToT) was defined as the length of time between the first and last administration date of treatment. Real-world overall survival (rwOS) was estimated using Kaplan–Meier analysis. Outcomes were assessed at a minimum of 6 months’ follow-up (cutoff: 30 June 2021).ResultsAmong 843 patients, 85% had adenocarcinoma (NSQ) and 15% had squamous cell carcinoma (SQ) histology: of these, 43% and 26% were women, median age was 67 and 69 years, and 55% and 48% had 0–1 ECOG performance status, respectively (missing: 27% and 30%, respectively). Median follow-up for the entire cohort was 27.1 months (95% CI: 24.7–29.6). NSQ patients with no known EGFR/ALK/ROS1 aberrations received PD-1 inhibitor monotherapy (PDM) (N = 147) or combination (PDC) (N = 194) or platinum-based chemotherapy (PBC, N = 133). Median rwToT was 4.5 (95% CI: 3.5–7.6), 5.2 (95% CI: 4.6–7.6), and 2.3 (95% CI: 2.1–3.0) months, respectively; for the subgroup of patients with ECOG PS 0–1, rwToT was 9.4 (95% CI: 5.0–20.8), 7.1 (95% CI: 5.0–10.1), and 2.9 (95% CI: 2.2–4.1) months, respectively. Median rwOS from 1L was 12.5 (95% CI: 9.9–17.9), 14.8 (95% CI: 10.5–19.4), and 9.1 (95% CI: 7.1–11.5) months; for the subgroup of patients with ECOG PS 0–1, median rwOS was 25.1 [95% CI: 14.9–not reached (NR)], 17.6 (95% CI: 14.3–NR), and 11.3 (95% CI: 9.2–21.3) months, respectively. For ECOG PS 0–1 and PD-L1 ≥50% patients, median rwOS was 25.1 months (95% CI: 13.9–NR) and NR for PDM and PDC, respectively. For ECOG PS 0–1 and PD-L1 &amp;lt;50% patients, median rwOS was 14.3 (95% CI: 10.1–NR) and 11.2 (95% CI: 9.1–21.3) months for PDC and PBC, respectively.ConclusionOur real-world data support the benefit of single-agent PD-1 inhibitor monotherapy for patients with PD-L1 high expression or PD-1 inhibitor combination for all patients diagnosed with mNSCLC with no known EGFR/ALK/ROS1 aberrations, initiating 1L treatment.

Treatment Strategies for Advanced Endometrial Cancer According to Molecular Classification

The management of advanced endometrial cancer (EC) has changed in the last few years due to the introduction of a new molecular classification and the approval of immunotherapy. For a long time, carboplatin plus paclitaxel was considered the standard treatment for first-line advanced EC, since the approval of the combination of chemotherapy plus immunotherapy. For patients with recurrent EC, with previous platinum-based chemotherapy, single-agent immunotherapy or in combination with tyrosine-kinase inhibitor (TKI) has been approved according to mismatch repair status. Ongoing trials are exploring the possibility of a chemo-free future for mismatch repair-deficient (dMMR) EC and new molecular targets are under investigation. The treatment paradigm for advanced EC has shifted from standard chemotherapy for all to a more personalized approach. The aim of this review is to provide an updated therapeutic landscape for the management of patients with advanced/metastatic EC according to their disease history and molecular biology.

The VALTIVE1 study protocol: a study for the validation of Tie2 as the first tumour vascular response biomarker for VEGF inhibitors

BackgroundAnti-angiogenic, VEGF inhibitors (VEGFi) increase progression-free survival (PFS) and, in some cases, overall survival in many solid tumours. However, their use has been compromised by a lack of informative biomarkers. We have shown that plasma Tie2 is the first tumour vascular response biomarker for VEGFi in ovarian, colorectal and gall bladder cancer: If plasma Tie2 concentrations do not change after 9 weeks of treatment with a VEGFi, the patient does not benefit, whereas a confirmed reduction of at least 10% plasma Tie2 defines a vascular response with a hazard ratio (HR) for PFS of 0.56. The aim of the VALTIVE1 study is to validate the utility of plasma Tie2 as a vascular response biomarker and to optimise the Tie2-definition of vascular response so that the subsequent randomised discontinuation VALTIVE2 study can be powered optimally.MethodsVALTIVE1 is a multi-centre, single arm, non-interventional biomarker study, with a sample size of 205 participants (176 bevacizumab-treated participants + 29 participants receiving bevacizumab and olaparib/PARPi), who are 16 years or older, have FIGO stage IIIc/IV ovarian cancer on treatment with first-line platinum-based chemotherapy and bevacizumab. Their blood plasma samples will be collected before, during, and after treatment and the concentration of Tie2 will be determined. The primary objective is to define the PFS difference between Tie2-defined vascular responders and Tie2-defined vascular non-responders in patients receiving bevacizumab for high-risk Ovarian Cancer. Secondary objectives include defining the relationship between Tie2-defined vascular progression and disease progression assessed according to RECIST 1.1 criteria and assessing the impact of PARPi on the plasma concentration of Tie2 and, therefore, the decision-making utility of Tie2 as a vascular response biomarker for bevacizumab during combined bevacizumab-PARPi maintenance.DiscussionThere is an urgent need to establish a test that tells patients and their doctors when VEGFi are working and when they stop working. The data generated from this study will be used to design a second trial aiming to prove conclusively the value of the Tie2 test.Trial registrationClinicalTrials.gov identifier: NCT04523116. Registered on 21 Aug 2020.

Comparison of survival outcomes and safety between early and late initiation of niraparib maintenance in newly diagnosed advanced epithelial ovarian cancer

ObjectiveThis multicenter retrospective cohort study aimed to compare survival outcomes and adverse events between early and late initiation of niraparib maintenance therapy in patients with newly diagnosed advanced ovarian cancer.MethodsWe...

Association Between Chemotherapy-Induced Peripheral Neuropathy and Low Anterior Resection Syndrome

Introduction: Low anterior resection syndrome (LARS) can be a debilitating condition that develops after undergoing sphincter-preserving surgery for rectal cancer. Chemotherapy-induced peripheral neuropathy is a common side effect of platinum-based chemotherapy agents used as systemic therapy for rectal cancer treatment. The purpose of this study was to determine the potential relationship between CIPN and LARS. Methods: This was a retrospective review of patients who underwent a low anterior resection for rectal cancer and received systemic therapy contacted at least six months from the most recent surgery. Eligible patients were called and completed the relevant surveys over the phone or email. Results: There was a total of 42 patients who completed the surveys with 33 (79%) having major LARS. Presence of a diverting ileostomy was the only significantly differentcharacteristic in those with major LARS versus those without. CIPN was independently associated with LARS (p = 0.046) on linear regression when controlling for neoadjuvant chemoradiation, diverting ileostomy and tumor distance from the anal verge. Conclusions: Developing severe CIPN is associated with developing LARS. Further studies evaluating the etiology behind this relationship should be conducted.

New tumor markers for testicular cancer - in the here and now and in the future

Germ cell tumors of the testis are the most common tumor entities in young men. Since the introduction of platinum-based chemotherapy in the 1970s, most patients can be cured despite the aggressiveness of germ cell tumors. Optimal serum tumor markers are required for diagnostics, therapy monitoring and aftercare, and these are subject to high requirements. The conventional testicular tumor markers human chorionic gonadotropin (hCG), alpha fetoprotein (AFP) and lactate dehydrogenase (LDH) only meet these requirements with insufficient sensitivity (30-70%). The markers investigated in recent decades, such as PLAP, CEA and NSE, have not become established. Currently, miRNA-371 is being researched in particular. Reliable findings are available for initial staging with significantly better specificities of miRNA-371 compared to conventional tumor markers. Further prospective studies are being conducted for other possible clinical applications, such as follow-up care, therapy monitoring or residual tumors, in order to investigate the revolutionary potential of miRNA-371 in these areas as well. Research is also currently being conducted on circulating tumor cells (CTCs) and cell-free DNA (cfNA) in various areas of application. With regard to germ cell tumors of the testis, however, these analyses are still in their infancy, but it is hoped that this will provide a further sufficient opportunity to use serum tumor markers.

Osimertinib (Tagrisso)

Canada’s Drug Agency (CDA-AMC) recommends that Tagrisso in combination with pemetrexed and platinum-based chemotherapy should be reimbursed by public drug plans for the first-line treatment of patients with locally advanced (not amenable to curative therapies) or metastatic non–small cell lung cancer (NSCLC) which harbours epidermal growth factor receptor (EGFR) exon 19 deletions (Ex19del) or exon 21 (L858R) substitution mutations if certain conditions are met. Tagrisso plus chemotherapy should only be covered to treat adult patients (aged ≥ 18 years) who have nonsquamous NSCLC; whose tumours have spread to other parts of the body, returned after treatment, or cannot be removed by surgery or radiation; whose tumours harbour EGFR Ex19del or L858R substitution mutations; and who are in relatively good health. Tagrisso should not be covered to treat patients who have a history of breathing difficulties caused by scarring and inflammation in the lung tissue; who have a history of heart problems associated with their heart taking longer to recharge between beats or their heart beating too fast, too slow, or in an irregular way; or, who have already been treated for NSCLC with treatments affecting their entire body (except for treatments given at least 6 months before the tumour returned, as a first step to shrink a tumour before the primary treatment, or as an additional treatment after the primary treatment to lower the risk of the tumour returning). Tagrisso should only be reimbursed if it is prescribed in combination with pemetrexed and platinum-based (i.e., cisplatin or carboplatin) chemotherapy by clinicians with expertise in treating NSCLC, and the cost of Tagrisso is reduced. Reimbursement of Tagrisso plus chemotherapy should be discontinued if a patient’s cancer grows or spreads, or if treatment is unacceptably toxic to the patient.

Anti-ovarian cancer migration and toxicity characteristics of a platinum(IV) pro-drug with axial HDAC inhibitor ligands in zebrafish models.

Ovarian cancer is the fifth leading cause of cancer related death in the United States. Cisplatin is a platinum-based anti-cancer drug used against ovarian cancer that enters malignant cells and then damages DNA causing cell death. Typically, ovarian cancer cells become resistant to cisplatin making it necessary to increase subsequent dosage, which usually leads to side-effects including irreversible damage to kidney and auditory system tissue. Ovarian cancer resistance is often associated with upregulation of histone deacetylase (HDAC) enzymes that cause DNA to adopt a closed configuration which reduces the ability of cisplatin to target and damage DNA. Compound B, a platinum(IV) complex with two axial phenylbutyrate (PBA) HDAC inhibitor ligands attached to a cisplatin core, can simultaneously inhibit HDAC activity and damage DNA causing decreased cancer cell viability in cisplatin-sensitive (A2780) and -resistant (A2780cis) ovarian cancer cell lines. However, compound B was not previously evaluated in vivo. As simultaneously inhibiting HDAC-mediated resistance with cisplatin treatment could potentiate the platinum drug's effect, we first confirmed the anti-cancer effect of compound B in the A2780 and A2780cis cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide spectrophotometric assay. Then, we used zebrafish embryo and transgenic animal models to comparatively analyze the effect of cisplatin, compound B, and controls on general organismal, auditory, and renal system toxicity, and cancer metastasis. We found that lower dosages of compound B (0.3 or 0.6 µM) than of cisplatin (2.0 µM) could cause similar or decreased levels of general, auditory, and renal tissue toxicity, and at 0.6 µM, compound B reduces cancer metastasis more than 2.0 µM cisplatin.

A real-world retrospective study to assess efficacy and safety of alectinib as adjuvant therapy in IB-IIIB NSCLC patients harboring ALK rearrangement

BackgroundAlectinib has demonstrated promising disease-free survival (DFS) benefit for early-stage non-small cell lung cancer (NSCLC) patients with ALK rearrangement positive in phase 3 ALINA trial. However, real-world evidence for the efficacy and safety of alectinib in early-stage ALK-positive NSCLC is limited.Materials and methodsWe retrospectively reviewed 68 patients with stage IB-IIIB ALK-positive NSCLC who underwent complete pulmonary resections from April 2010 to July 2023 at a single institution. 38 (55.9%) enrolled patients had N2 lymph node metastasis, and 17 (24.9%) patients had multi-station N2 metastasis. Patients were stratified into two groups according to the adjuvant treatment regimen, with 19 patients in the alectinib group and 49 patients in the chemotherapy group. There were no significant differences in clinicopathological characteristics between the two groups. After curative resection surgery, patients in alectinib group received oral alectinib at a dose of 600 mg twice daily and patients in chemotherapy group received platinum-based doublet chemotherapy regimen every 3 weeks for 4 cycles. The primary endpoint was 3-year DFS. The Kaplan-Meier method was used to estimate DFS and overall survival (OS). Safety analyses were conducted by comparing the incidence of adverse events between the two groups.ResultsAt the last follow-up date (January 22th, 2024), A total of 1 (5.3%) and 28 (57.1%) DFS events were observed in alectinib group and chemotherapy group respectively. The 3-year DFS showed significant improvement in the alectinib group compared with chemotherapy group (91.7% vs 60.7%, P=0.051). In the IIIAN2 subgroup, the 3-year DFS rate in the alectinib group reached a satisfactory 87.5%. In both groups, the majority of AEs were graded as level 1 or 2, No grade 3-4 AEs were observed in alectinib group.ConclusionAlectinib, as adjuvant therapy, demonstrated favorable efficacy and manageable safety in patients with completely resected ALK-positive stage I B-IIIB non-small cell lung cancer. A limitation of this study is the small sample size, and a larger-scale real-world sample study is needed to further evaluate the efficacy and safety of alectinib as adjuvant therapy.

Predictive markers of response to immune checkpoint inhibitor rechallenge in metastatic non-small cell lung cancer.

The present study aims to evaluate the efficacy of rechallenge with immune checkpoint inhibitors (ICIs) compared to chemotherapy and the predictive role of clinical parameters in non-small cell lung cancer (NSCLC) patients who were rechallenged. The study included 113 metastatic NSCLC patients who had initially responded to ICIs and platinum-based chemotherapy, either in combination in the first line or sequentially in the first and second line, but later experienced disease progression. Of those patients, 52 later received ICI rechallenge and 61 were exposed to chemotherapy. In the rechallenge cohort, the median age was 67 years, 38 patients were men (73.1%), 26 (50.0%) had squamous cell carcinoma. Patients who underwent ICI rechallenge had longer overall survival (OS) compared to those who received chemotherapy (12.9 months vs. 9.6 months, P = 0.008). Multivariate analysis for progression-free survival (PFS) and OS revealed that poor Eastern Cooperative Oncology Group Performance Status (ECOG PS; PFS: P = 0.013 and OS: P = 0.037), absence of objective response during initial ICI therapy (PFS: P = 0.014 and OS: P = 0.028), and baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3.8 (PFS: P = 0.001 and OS: P = 0.003) were negative predictive factors of ICI rechallenge. The three parameters were included in a risk model named as the NEO score, which stratified patients who received ICI rechallenge into two predictive groups. Patients with ECOG PS 0-1, objective response during initial ICI treatment, and NLR < 3.8 (favorable group) had longer PFS (8.6 months vs. 3.0 months, P < 0.001) and OS (16.6 months vs. 5.5 months, P < 0.001) compared to those with absence of all three markers (poor group). There was no association between the NEO score and survival outcomes in patients who did not undergo rechallenge. ICI rechallenge showed a survival benefit, particularly in NSCLC patients with NLR < 3.8, good ECOG PS, and objective response.

Minimizing overtreatment and maximizing oncologic outcomes in upper tract urothelial carcinoma

Purpose of review An update on the latest advances in the management of upper tract urothelial carcinoma (UTUC), with an emphasis on strategies to optimize oncologic outcomes while minimizing overtreatment. Recent findings Recent high-quality trials have changed the landscape of UTUC treatment. Emerging tools including 3D histology and measurement of cell free tumor DNA may improve diagnostic accuracy of disease grading and staging, and be used in monitoring treatment response. Novel therapies show promise of reducing low-grade UTUC disease recurrence at the cost of significant side-effects. Platinum-based neoadjuvant chemotherapy in high-grade/muscle-invasive disease showed complete pathological response in a subset of patients, but difficult to predict responders. Adjuvant platinum-based chemotherapy exhibited a clear survival benefit, but immunotherapy did not, suggesting possible overtreatment with these agents. Molecularly-targeted therapies in metastatic UTUC have shown the greatest recent oncologic advances, but exhibit a high adverse event-rate. Summary Low-grade UTUC has the potential for overtreatment, as it exhibits low metastatic-potential and excellent survival. For high-grade and advanced-stage UTUC, these carry high mortality rates and require more aggressive treatment, but studies are limited by inaccurate grading and staging which can lead to overtreatment especially in the neoadjuvant setting. Emerging technologies will help improve diagnostic accuracy and noninvasive monitoring of treatment response.

Does maximal effort cytoreductive surgery after 6-cycles of chemotherapy play a role in the management of advanced ovarian cancer?

The current gold standard in the surgical management of advanced ovarian cancer recommended by ESGO and ASCO is complete resection of all visible disease. If this is not deemed possible in the upfront setting, then interval cytoreductive surgery should be undertaken after 3-4-cycles of neo-adjuvant chemotherapy. Occasionally, surgery in the interval setting may not be possible either due to factors associated with patient fitness, or due to persistence of disease in sites deemed unresectable on interval scanning. Limited published data assessing outcomes from surgery delayed to after 6-cycles of NACT (delayed cytoreductive surgery) suggests a potential benefit over no surgery and suggests that if interval cytoreductive surgery is not possible, then the clinician might consider delayed surgery on a case by case basis. We sought to review the outcomes of patients with Advanced Ovarian Cancer presenting to the Northern Gynaecological Oncology Centre who underwent delayed surgery. This study is a retrospective analysis looking at patients with epithelial ovarian cancer of FIGO stage IIIC and above, who were not deemed suitable to undergo either primary or interval cytoreductive surgery, referred to the Northern Gynaecological Oncology Centre Gateshead, UK, between January 2014 and December 2020. We compared survival outcomes in women receiving non-standard treatment for advanced ovarian cancer, comparing two groups of patients; those completing at least six cycles of platinum-based chemotherapy as part of their first-line treatment and not having surgery with those who received delayed cytoreductive surgery after completing of 6-cycles of primary chemotherapy. A total of 89 cases were included in the analysis and 78/89 patients had completed at least 6-cycles of primary chemotherapy in the first-line treatment setting without any attempt at surgical cytoreduction. 11/89 patients underwent DDS after completion of 6-cycles of primary chemotherapy. The majority of included cases 87/89 (98%) were high-grade serous ovarian cancer (HGSOC). Surgery and no-surgery groups were well matched in terms of stage comparison at presentation with an overall stage distribution of 62% FIGO stage IIIC, 10% stage IVA and 28% stage IVB. The surgery group were significantly younger than the no-surgery group with median age of 68 (interquartile range (IQR) 59-71years) and 77years (IQR 70-82years) (p < 0.01), respectively. The overall survival (OS) of the surgery and no-surgery groups was 25months and 23months, respectively (p = 0.38) with a median follow-up of 20months (IQR 11-29months). The 1year disease-specific mortality for both groups was 18%. Maximal effort cytoreductive surgery after 6-cycles is not associated with a survival benefit (even with complete cytoreduction) but may be considered in the context of symptomatic disease or for palliation of symptoms amenable to surgery.

Unlocking the potential of immunotherapy in platinum-resistant ovarian cancer: rationale, challenges, and novel strategies

Ovarian cancer is a significant global health challenge, with cytoreductive surgery and platinum-based chemotherapy serving as established primary treatments. Unfortunately, most patients relapse and ultimately become platinum-resistant, at which point there are limited effective treatment options. Given the success of immunotherapy in inducing durable treatment responses in several other cancers, its potential in platinum-resistant ovarian cancer (PROC) is currently being investigated. However, in unselected advanced ovarian cancer populations, researchers have reported low response rates to immune checkpoint inhibition, and thus far, no validated biomarkers are predictive of response. Understanding the intricate interplay between platinum resistance, immune recognition, and the tumour microenvironment (TME) is crucial. In this review, we examine the research challenges encountered thus far, the biological rationale for immunotherapy, the underlying mechanisms of immune resistance, and new strategies to overcome resistance.

AptBCis1, An Aptamer-Cisplatin Conjugate, Is Effective in Lung Cancer Leptomeningeal Carcinomatosis.

Treatment of lung cancer leptomeningeal carcinomatosis (LM) remains challenging partly due to the biological nature of the blood-brain barrier (BBB). Cisplatin has limited effects on LM, and it is notorious for neurotoxicity. Aptamers are small oligonucleotides considered as antibody surrogates. Here we report a DNA therapeutics, AptBCis1. AptBCis1 is a cisplatin-conjugated, BBB-penetrating, and cancer-targeting DNA aptamer. Its backbone, AptB1, was identified via in vivo SELEX using lung cancer LM orthotopic mouse models. The AptB1 binds to EAAT2, Nucleolin, and YB-1 proteins. Treatment with AptBCis1 1 mg/kg (equivalent to cisplatin 0.35 mg/kg) showed superior tumor suppressive effects compared to cisplatin 2 mg/kg in mice with lung cancer LM diseases. The cerebrospinal fluid platinum concentration in the AptBCis1 group was 10% of that in the cisplatin group. The data suggested the translational potential of AptBCis1 in lung cancer with LM and in cancers in which platinum-based chemotherapy remains as the standard of care.