tbuckley/cabot-search huggingface dataset:
Retrospective analysis of outcomes of patients with bladder cancer when neoadjuvant chemotherapy is delayed.
Authors: Zakhar Kanyuka, Sandy Kassir, Nelson Leong, Osama Souied
Journal: Journal of Clinical Oncology (2024)

e16588 Background: Bladder (urothelial) cancer is the sixth most common form of cancer in the United States of America and results in significant morbidity and mortality. American Urological Association (AUA) guidelines recommend that muscle-invasive bladder cancer (MIBC) is treated with a course of cisplatin-based multi-agent neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC). The optimal timing of NAC is not well studied. Therefore, we aimed to evaluate the impact of timing NAC treatment to compare clinical outcomes among patients at the Saskatchewan Cancer Agency (SCA). Methods: We conducted a retrospective cohort study of the SCA electronic registry, reviewing the clinical and pathological data of 42 patients diagnosed with MIBC and treated with platinum-based NAC from January 2000 to December 2018. Patients with non-MIBC, metastatic bladder cancer, non-urothelial carcinoma histology, and charts with insufficient data were excluded. Survival analysis using Kaplan-Meier methods and log rank tests were utilized to compare overall survival (OS), disease recurrence, and post-RC surgical pathological staging of patients with respect to pre-specified time intervals between diagnosis, NAC and RC. Results: Patients who received NAC later than 8 weeks after diagnosis were more likely to have reduced OS (HR 1.25, 95% Confidence Interval (CI): 1.09-1.35, p=0.02). They also were more likely to have lymph node involvement (HR 1.63, 95% CI: 1.03-1.77, p=0.006). Patients who received RC more than 6 weeks after NAC completion were more likely to have more advanced primary tumour staging on pathology (HR 1.95, 95% CI: 1.3-2.09, p=0.01), but did not have significantly decreased OS (HR 1.88, 95% CI: 0.48-1.95, p=0.08). Delayed NAC (HR 2.77, 95% CI: 1.44-4.57, p&lt;0.001) and RC (HR 1.50, 95% CI: 1.08-3.10, p&lt;0.001) were associated with increased recurrence. Age, sex, body mass index, NAC regimen, and prior intravesical treatment were not statistically associated with OS upon analysis with univariate cox proportional hazard regression analysis. Conclusions: This review suggests an OS benefit by reducing the time from diagnosis to NAC in MIBC patients. This finding contrasts other studies that do not demonstrate any impact of delayed NAC on OS. These findings align with other works that do not show a survival detriment of delaying RC beyond 6 weeks after NAC completion. However, delaying surgery is associated with more advanced pathologic tumour staging. This study identifies the possibility of an association between delays in treatment delivery and worse clinical outcomes in some cohorts. Accordingly, further investigation of interval timing can better inform treatment planning and resource allocation in the management of patients with MIBC.
Efficacy and safety of axitinib in combination with sintilimab as neoadjuvant therapy for patients with locally advanced renal cell carcinoma: A phase II clinical study.
Authors: Yixin Huang, Zhiling Zhang, Xiangpeng Zou
Journal: Journal of Clinical Oncology (2024)

e16534 Background: NCCN, EAU and CUA guidelines recommend radical nephrectomy (RN) for patients with locally advanced renal cell carcinoma (RCC). However, some patients experience complex local invasion, resulting in the difficulty of operation and the high rate of postoperative recurrence. Preoperative neoadjuvant therapy has been shown to reduce tumor volume effectively, consequently increasing the success rate of RN. The objective of this study is to evaluate the effectiveness and safety of combining neoadjuvant Axitinib with sintilimab in these patients. Methods: This is a phase II study to assess the efficacy and safety of neoadjuvant Axitinib combined with sintilimab in RCC patients. Patients diagnosed with locally advanced RCC enrolled in this study received Axitinib (5 mg bid) plus sintilimab (200mg Q3W) until progressive disease or unacceptable toxicity, and then patients will withdraw from the study and explore the option of surgical resection or alternative targeted/immunotherapy. Surgical intervention will be conducted after patients complete four cycles of PD-1 therapy. Results: A total of 12 patients were enrolled in the study. All patients had computerized tomography at screening and after treatment. The median reduction rate of primary tumor volume and active volume in that study were 26.4% and 58.6%, respectively. Stable disease was observed in 10 patients, and partial response was observed in 2 patients and progressive disease was observed in 1 patient. All patients (100.0%) enrolled in the study experienced a treatment-related adverse event (TRAE) of any grade. TRAEs of any grade leading to discontinuation occurred in 2 patients. Only one patient experienced a Grade 3 TRAEs, manifested as increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Only one patient did not undergo RN due to cardiovascular disease. Conclusions: Most of the patients showed a certain degree of tolerance to the medication and underwent RN successfully. But, only a minority of patients can benefit from Axitinib in Combination with Sintilimab in neoadjuvant therapy for locally advanced RCC. The combination of AKI and PD-1 is still a potential choice for preoperative tumor reduction in locally advanced RCC. There is an urgent need to explore a more effective and safe neoadjuvant therapy for these patients.
Real-world survival outcomes associated with immunotherapy followed with anti-vascular targeted therapy for metastatic clear cell renal cell carcinoma.
Authors: Hui Zhang, Zhiwei Hou, Long Lai, Huaguo Wu
Journal: Journal of Clinical Oncology (2024)

e16507 Background: The Food and Drug Administration (FDA) has approved a variety of drugs for the treatment of advanced metastatic renal cell carcinoma, including anti-vascular tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). Options for initial therapy range from monotherapy to combination therapy. However, the challenge of choosing the most effective first- and second-line treatments to enhance overall survival persists. Methods: In this retrospective, propensity-matched cohort study, we included 135 patients with metastatic clear cell renal cell carcinoma (mRCC) treated at Shandong Cancer Hospital between January 1, 2017, and December 31, 2022. These patients received ICIs as part of their first or second line of therapy. Statistical analysis was conducted from June 1, 2023, to August 1, 2023. The primary endpoint was OS, measured from the date of diagnosis to death or the last follow-up. PFS was assessed during treatment. Survival analysis was performed using Cox proportional hazards regression and Kaplan-Meier estimates. Results: The final cohort comprised 135 patients, of whom 84 received first-line therapy with ICIs. The remaining 51 patients were treated with ICIs as second-line therapy following an initial regime of TKIs. Patients were initially categorized based on whether ICIs were used in the first-line treatment. It was observed that the OS for patients receiving first-line targeted therapy was higher than for those receiving first-line immunotherapy, with median OS figures of 33 months versus 15 months. To investigate this outcome, we further refined the patient groups based on the sequence of ICIs and TKIs in the treatment regimen. We discovered that the median PFS following first-line anti-vascular targeted therapy combined with immunotherapy was 3.5 months, compared to 14.5 months when immunotherapy followed first-line anti-vascular targeted therapy (p=0.0092). The median PFS for second-line treatments was 6.5 months versus 15 months (p=0.0014). Similarly, the median OS figures were 16.66 months and 31.88 months, respectively (p=0.008). Conclusions: This study suggests that administering immunotherapy after the progression of anti-vascular therapy significantly improves both OS and PFS compared to other sequences of immunotherapy. These findings offer valuable insights and strong empirical support for clinical decision-making regarding the sequencing of treatments for mRCC.
Phase 2 trial for sequential treatment of high dose cabozantinib (CABO) or CABO plus nivolumab (NIVO) on/after progression on CABO monotherapy in advanced renal cell carcinoma (RCC): Seq-Cabo.
Authors: Qian Qin, James Brugarolas, Hans J. Hammers, Waddah Arafat, Kevin Dale Courtney, Jue Wang, Changchuan Jiang, Song Zhang, Charles Lance Cowey, Thomas E. Hutson, Tian Zhang
Journal: Journal of Clinical Oncology (2024)

TPS4609 Background: Efficacy outcomes for advanced RCC have improved with vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (IO), and CABO has become an established treatment for both front-line and refractory, advanced RCC. However, most patients develop resistance to CABO. With each subsequent line of therapy, efficacy and survival benefits also shorten and treatment options become limited. It is thus important to explore ways to maximize each line of therapy. Methods: Based on previous studies suggesting 1) dose-dependent effect of VEGFR-TKIs with feasibility/efficacy of CABO dose escalation to 80mg and 2) immune-modulatory effects of CABO, we have designed a two-cohort phase 2 trial to salvage CABO response, either by escalating the dose of CABO to 80mg oral (PO) daily (cohort 1) or by combining CABO 40mg PO daily with NIVO 480mg intravenous (IV) every 4 weeks (cohort 2), based on investigator choice. Subjects will be treated until progression or unacceptable toxicity. Main inclusion criteria include progressive advanced RCC after prior CABO monotherapy for at least 6 months, able to tolerate CABO 60mg PO daily (cohort 1) and 40mg PO daily (cohort 2), radiographically measurable disease, ECOG &lt; 2, and adequate end-organ function. Main exclusion criteria include prior treatment with concurrent CABO/NIVO, uncontrolled co-morbidities, uncontrolled HIV, and concurrent malignancy (excepting completely excised skin cancers and organ-confined Gleason 6 prostate cancer). Primary endpoint is progression free survival (PFS) with key secondary endpoints including overall response rate, disease control rate, duration of response, and overall survival. The null hypothesis of median PFS 3 months will be tested against an alternative hypothesis of median PFS 6 months. Assuming a 2-sided significance level of 10% and 80% power, and estimating 10% drop out, 18 patients per cohort (36 patients total) will be enrolled.Pharmacokinetics, circulating biomarkers, and pre-/post-biopsies are planned for tissue-based analyses. The study is open for enrollment (NCT05931393). Clinical trial information: NCT05931393 .
Annotations-free survival prediction with WSIs using graph convolutional neural networks.
Authors: Qianqian Kong, Ruilei Li, Jiaran Zhang, Ke Li, Chunlei Ge, Xieqiao Yan, Hong Yao, Jun Guo, Chen LI
Journal: Journal of Clinical Oncology (2024)

e16501 Background: Survival prediction of cancer patients has always been an challenging problem.Tumor microenvironment (TME) Analyzation based on whole-slide-images (WSIs) has provide an effective perspective for survival prediction. However, most existing TME analyzation based on cell segmentation or classification relies heavily on labor-intensive cell-level annotations of pathologists. Furthermore, except for each individual cell or local pathological feature, survival prediction also involves local-level pathological features interactions in tumor microenvironments. This requires context-awareness based on histological features to fully infer the patient's survival risk. Therefore, we explored a model based on graph convolutional neural networks (GCNN) to perform survival prediction of cancer patients using WSIs. Methods: We utilized WSIs collected from The Cancer Genome Atlas (TCGA) to develop a graph convolutional neural network for survival prediction of cancer patients. The model leverages the advantages of graph structures to autonomously learn the histopathological contextual features in WSIs, and therefore can incorporate additional and crucial tumor microenvironment interaction information while avoiding the labor-intensive annotations. WSIs of two different cancers, KIRC and LUAD, were randomly divided into training, validation, and testing sets in a ratio of 7:1:2. The performance of the constructed model is evaluated using the test set and the results are compared with other state-of-art methods. Results: Our work is compared with other state-of-art weakly supervised learning methods for survival prediction in computational pathology. Abundant experimental results shown that our method outperformed previous methods on these two cancer types (achieving a 2.9% improvement compared to Multiple Instance Learning (MIL) and a 2.6% improvement compared to Attention MIL), with an overall c-index of 0.646. Additionally, we evaluated the interpretability of our model through attention heatmaps of low-risk and high-risk patients. Conclusions: We have developed a GCNN based model, combined with attention mechanisms, to learn features of heterogeneous tumor microenvironments and their contextual information from memory-efficient representations of highly correlated image patches for cancer patients survival prediction. This model is applicable to any weakly supervised learning task in computational pathology that involves slide-level or patient-level labels, making it an effective supplementary diagnostic tool for oncologists and pathologists.
Gemcitabine/paclitaxel/adriamycin (GTA) as a nephron-sparing regimen in urothelial carcinoma: The MD Anderson Cancer Center (MDACC) experience.
Authors: Mohammad Jad Moussa, Naveen G. Subramanian, Jaime Haro-Silerio, Lily Chen, Amishi Yogesh Shah, Jianjun Gao, Paul Gettys Corn, Sangeeta Goswami, Pavlos Msaouel, Jianbo Wang, Ashish M. Kamat, Charles C. Guo, Nizar M. Tannir, Arlene O. Siefker-Radtke, Omar Alhalabi, Matthew T Campbell
Journal: Journal of Clinical Oncology (2024)

e16576 Background: GTA (Gemcitabine 900 mg/m 2 IV; Paclitaxel 135 mg/m 2 IV and Adriamycin 30 mg/m 2 IV, with pegfilgrastim 6mg SQ on a 14-day cycle) was initially reported from a prospective phase II study of 39 patients (pts) by Siefker-Radtke et al. Urology (2016). We report real-world efficacy and survival outcomes with this nephron-sparing regimen in locally advanced or metastatic urothelial carcinoma (LA/mUC). Methods: We retrospectively reviewed records of n=76 pts with frontline (1L) GTA for LA/mUC between March 2016 and April 2023 at MDACC. Imaging-based best overall responses (BOR) using RECIST v1.1 were noted as partial (PR), stable (SD), progressive (PD) or non-evaluable (NE). We use Kaplan-Meier (KM) method to estimate overall survival (OS) and progression-free survival (PFS) from GTA start, and reverse KM for follow-up (FU). Results: Baseline characteristics (n=76) are shown in Table. Median age at diagnosis was 70.6 [IQR: 65.3 – 76.3]. The decision to start GTA was justified by tumor-related (55, 72.4%) or non-tumor-related (14, 18.4%) renal insufficiency, and general comorbidities (7, 9.2%).n=48 (63.2%) had percutaneous nephrostomy or ureteral stenting before GTA initiation. Pts had a median number of 3 cycles (IQR: 2-5). At GTA start, most pts (38, 50%) had one Barjorin risk factor (either bone/liver/lung mets or ECOG PS ≥2), 28 (36.8%) had none and 10 (13.2%) had both factors. Median OS was 11.3 mo (95% CI: 9.1 – 15.1 mo) with a median FU of 64.8 mo (95% CI: 26.2 – 83.6). Median PFS was 3.4 mo (95% CI: 3.03 – 4.5 mo). Overall response ratewas 26.3%, and BOR to 1L GTA included: PR 20/76 (26.3%), SD 25/76 (32.9%), PD 17/76 (22.4%) and NE 14/76 (18.4%). NE responses were due to transition to cisplatin-based regimens or other therapies in 8/14, toxicity in 3/14, pt death in 2/14 and pt preference in 1/14. GTA dose reduction was required in 15 (19.7%), and serious adverse events leading to hospitalization occurred in 18 (23.7%). Finally, among 69 pts with tumor or non-tumor related renal insufficiency, 16/69 (23.2%) were able to receive cisplatin post-GTA. In a paired t-test analysis of 76 GFR pairs, an improvement in GFR post-GTA was observed compared to pre-GTA GFR, with a significant difference of 11.2 mL/min [95% CI: 7.4 – 14.9, p &lt; 0.0001]. Conclusions: GTA shows modest efficacy as a 1L regimen in LA/mUC. The facilitation of cisplatin-based regimens after GTA in a subset of pts might be explained by restoring patency in partially obstructed collecting systems. This ‘GTA bridging’ strategy may be beneficial for pts for whom nephrostomy or ureteral stenting proves impractical or insufficient to address renal insufficiency. [Table: see text]
Estimated impact of novel immune checkpoint inhibitors on reducing cancer mortality in patients with locally advanced or metastatic urothelial carcinoma in Russia.
Authors: Boris Alekseev, Boris Alekseev, Nikolay Avxentyev, Yuliya Makarova, Irina Andreiashkina
Journal: Journal of Clinical Oncology (2024)

e16560 Background: The standard first-line treatment for patients with locally advanced or metastatic urothelial carcinoma (UC) is platinum-based chemotherapy. Other available therapeutic option are immune checkpoint inhibitors (ICIs) such as pembrolizumab, nivolumab, atezolizumab, and avelumab. However, unlike other drugs in this class, avelumab can be used as maintenance therapy in patients without disease progression after first-line platinum-based chemotherapy. Objective: In this study we sought to evaluate the effects of using ICIs in treating adult patients with locally advanced or metastatic urothelial UC on reducing overall and one-year cancer mortality in Russia. Methods: A mathematical model based on overall survival and progression-free survival data from clinical trials has been proposed. This model describes duration of therapy and treatment outcomes for treatment without ICIs (historical approach), with pembrolizumab and atezolizumab in first-line in cisplatin-ineligible PDL1-positive patients; nivolumab and pembrolizumab, atezolizumab in second-line therapy according to real-life clinical practice (current approach), and with avelumab as maintenance therapy after platinum-based chemotherapy (suggested approach). The model was applied to assess the healthcare expenses and the increase in saved lives when shifting from historical to current approaches and from current to suggested methods over a three-year timeframe. This analysis considered the annual population of patients in Russia with locally advanced or metastatic UC who might initiate platinum-based therapy. Results: Annually, up to 4,182 patients with locally advanced or metastatic UC in Russia can initiate platinum-based chemotherapy. Compared with historical approach, the use of pembrolizumab, nivolumab, and atezolizumab in the first and second lines of therapy according to real-life clinical practice, allows reducing mortality from malignant neoplasms by 553 cases over a 3-year horizon. Over the same period, avelumab-based treatment would additionally save 2,506 lives. Shifting to suggested practice with avelumab maintenance therapy may lead to decrease in one-year cancer mortality from 20.3% to 20.25% and one-year bladder cancer mortality from 13.8% to 12.12%. Furthermore, the cost of saving one life with avelumab amounts to 6.0 million rubles, which is 9% lower compared to the cost of saving one life with other ICIs (6.6 million rubles). Conclusions: The use of avelumab maintenance in advanced or metastatic UC patients without progression after platinum-based chemotherapy has a significant and quantifiable impact on reducing cancer-related mortality in Russia.
Neoadjuvant versus adjuvant chemotherapy in muscle-invasive bladder cancer: The RealBLADDER study—Results on behalf of the GOIRC.
Authors: Elisabetta Gambale, Roberta Giorgione, Irene De Gennaro Aquino, Federico Scolari, Giandomenico Roviello, Martina Catalano, Marinella Micol Mela, Laura Doni, Mikol Modesti, Ismaela Anna Vascotto, Virginia Rossi, Luca Galli, Francesco Atzori, Sarah Scagliarini, Valentina Baldazzi, Serena Pillozzi, Cristina Masini, Umberto Basso, Giuseppe Fornarini, Lorenzo Antonuzzo
Journal: Journal of Clinical Oncology (2024)

e16503 Background: In regard to resectable muscle-invasive bladder cancer (MIBC) patients, treatment with radical cystectomy (RC) and perioperative platinum-based chemotherapy (CT) (neoadjuvant or adjuvant) represents the standard of care. Perioperative treatment can improve overall survival (OS), and the most robust evidence are in favor of neoadjuvant CT. RealBLADDER is an observational study aiming to describe the use and the impact on survival of perioperative CT for patients with MIBC in an Italian real-world setting. Methods: RealBLADDER is a multicentric, observational, retrospective and prospective study, which enrolled patients with MIBC treated with perioperative CT from June 2018 up to June 2023. The primary endpoint was the rate of pathological complete response (pCR)(&lt;pT1), defined as the absence of residual tumor cells in bladder and nodes at the pathological examination after neoadjuvant CT. Secondary endpoints were disease-free survival (DFS), OS and surgical outcomes (morbidity and mortality rates). DFS and OS by setting of chemotherapy were determined. Results: 172 eligible patients were identified. One hundred and thirty-six patients (79.1%) received neoadjuvant and 36 (20.9%) received adjuvant CT. The rate of pCR was 43.3%. The rate of surgical morbidity and mortality were 20.9% and 0%, respectively. Compared to adjuvant chemotherapy, 12-months DFS was improved in patients treated with neoadjuvant CT (p=0.042). Notably, patients treated with neoadjuvant CT had 12-months OS longer in than those treated with adjuvant CT (p=0.043). Conclusions: This real-world analysis of Italian patients with MIBC confirmed that neoadjuvant chemotherapy is associated with a high rate of pCR and low rate of surgical morbidity and mortality supporting the use of neoadjuvant CT in MIBC prior to RC.