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Brief Report: Clinical Characteristics and Outcomes of Patients with Thoracic SMARCA4-Deficient Undifferentiated Tumors

IntroductionThoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs) are a recently-defined group of aggressive cancers in which the effectiveness of standard treatments for lung cancer is unknown. MethodsWe collected clinical, pathological, and demographic variables from 5 institutions for patients whose tumors met criteria for SMARCA4-UTs (undifferentiated morphology and loss of SMARCA4/BRG1 by immunohistochemistry). ResultsWe identified 92 patients with SMARCA4-UTs; 58 (63%) had stage IV disease at diagnosis, and 16 (17%) developed recurrent/metastatic disease after initial diagnosis. Median overall survival (OS) from metastatic diagnosis was 7.3 (95% CI: 4.6-12.8) months. Of patients with metastatic disease, 58 (78%) received first-line systemic treatment. Most commonly, patients received chemo/immunotherapy combination (41%), chemotherapy alone (33%), or immunotherapy alone (16%). Median progression-free survival (PFS) from start of systemic therapy was 1.9 (95%CI: 1.4-14.5) months for chemo/immunotherapy, 1.6 (95%CI: 1.1-5.8) months for chemotherapy, and 3.3 (95%CI: 1.2-undefined) months for immunotherapy alone. Five patients had durable responses (≥ 2 years); all received immunotherapy as part of first-line regimens. Nine (16%) of 55 tumor samples tested had PD-L1 expression ≥50%, with 24 (44%) negative samples. Tumor mutational burden was available in 48 cases (52%), median was 10.5 (range 2-48) mutations/megabase. ConclusionsThis multi-institution retrospective cohort analysis revealed a population of patients with short PFS to standard therapies and poor OS. A few patients demonstrated remarkable response to regimens including immunotherapy. Prospective clinical studies are urgently needed to identify better therapeutic approaches to treat this aggressive malignancy and this analysis may serve as a benchmark for future clinical trial design.

Tailored management of advanced thyroid cancer patients treated with lenvatinib or vandetanib: the role of a multimodal approach.

In differentiated/poorly differentiated (DTC/PDTC) or medullary thyroid cancer (MTC) treated with kinase inhibitors (KIs), additional treatments (ATs) can be performed in selected cases. We retrospectively analysed all the ATs performed in our center in KI-treated TC patients, evaluating the subsequent KI modulation, the local PD in case of loco-regional procedure (LRP) and the AT-related complications. DTC/PDTC patients with or without progressive disease before the first AT (PD and NO PD GROUP, respectively) were analysed separately. In our center, 32 ATs (30 LRPs and 2 radioactive iodine treatments) were performed in 14 DTC/PDTC patients and 4 MTC subjects after the start of systemic therapy with lenvatinib or vandetanib (27 and 5 ATs, respectively). Brain was the most treated site (11/30 LRPs) and external beam radiation was the most employed LRP (18/30 LRPs). KIs dose reduction or discontinuation of KI therapy (at least transient) was performed after 50% of ATs in DTC/PDTC NO PD GROUP. The KI was maintained at the same dosage after 75% and 50% of the ATs performed in DTC/PDTC PD GROUP and MTC, respectively. During the follow-up, local PD was detected after 14 LRPs. Local progression-free survival (LPFS) was significantly shorter in DTC/PDTC PD GROUP in comparison to NO PD GROUP (12 month-LPFS 91.7% versus 15.2%); in patients with MTC, 12 month-LPFS was 50%. AT-related AEs were mostly G1-G2. In selected DTC/PDTC without previous PD and treated with a multimodal strategy, local disease control is generally maintained regardless the KI dose modulation. In DTC/PDTC patients with previous limited PD and in MTC subjects, the choice of performing a LRP and continue the ongoing KI therapy must consider the risk of early local progression. AT-related AEs in KI treated patients were mild in most cases.

Outcomes of extracranial stereotactic body radiation therapy for induced oligometastatic non-small cell lung cancer on novel systemic therapy.

Stereotactic body radiation therapy (SBRT) is often delivered in patients with oligometastatic disease (OMD). However, the specific subset of patients with polymetastatic non-small cell lung cancer (NSCLC) on novel systemic therapies who develop induced oligopersistant disease (OpersisD) or oligoprogressive disease (OprogD), as defined by the European Organisation for Research and Treatment of Cancer (EORTC) OMD classification, has not been well described. This study explores the outcomes of patients treated with this strategy. Patients with stage IV NSCLC being treated with osimertinib or immune checkpoint inhibitors (ICIs) who received extracranial SBRT for OpersisD or OprogD were identified in our retrospective analysis. Outcomes reported include progression-free survival (PFS), time to change of systemic treatment (TTCST), overall survival (OS), local control (LC) and treatment-related toxicity. Forty-nine patients received SBRT for OpersisD (34.7%) or OprogD (65.3%) at a median of 5.8 and 15.3 months after start of systemic therapy, respectively. 55.1% received concurrent osimertinib and 44.9% received ICI. Seventy-seven extracranial lesions were treated with various fractionation schemas. At a median of 18.8 months follow-up from first SBRT, LC was achieved in 92.2% of total lesions treated (71). The 1-year OS was 91.7% for OpersisD and 83.3% for OprogD. OpersisD compared to OprogD had a longer median PFS (18.3 vs. 6.1 months) and longer median TTCST (23.6 vs. 13.5 months), median OS was not reached for either cohort. On multivariate analysis, patients treated with osimertinib had shorter PFS (HR: 2.20; 95% CI: 1.01-4.82; P=0.048) and shorter TTCST (HR: 2.83; 95% CI: 1.09-7.33; P=0.032). One patient (2%) experienced grade 3 pneumonitis after SBRT, and no grade 4-5 toxicities were reported with SBRT treatment. This study indicates that SBRT for OpersisD or OprogD in Stage IV NSCLC patients on osimertinib or ICIs is safe, very well tolerated, and may prolong the time before needing a shift in systemic therapy. Further prospective research is needed to validate and expand upon these findings.

Systemic and surgical treatment in renal cell carcinoma: Does timing matter?

417 Background: Today, targeted systemic therapy is standard 1st line treatment of advanced/metastatic renal cell carcinoma (aRCC). Upfront cytoreductive nephrectomy (CN) has been an important treatment option. Recently its role is under debate, especially in combination with the new 1st line treatments. Our study evaluated the current relevance of initial surgical intervention and the role of inductive systemic therapy in aRCC. Methods: We included 33 patients with aRCC from the University Hospitals in Essen and Münster initiating 1st line treatment from 03/18 to 01/23 pre or post surgery. We retrospectively formed two cohorts, either CN followed by systemic therapy (cohort 1; 13 patients) or vice versa (cohort 2; 20 patients). Patients received either Ipilimumab/Nivolumab (Ipi/Nivo) (42.4%) or a checkpoint inhibitor and tyrosine kinase inhibitor (CPI/TKI) combination (57.6%). Progression-free survival (PFS) was estimated with Kaplan-Meier-method from initiation of systemic therapy or CN to progression or death. In Cohort 2, we additionally analyzed the radiologic response of the primary measured by change of the longest diameter. The radiographic response was analysed according to RECIST1.1. Results: Patients’ age ranged from 44 to 80 years with a median of 63 years. Intermediate and poor prognosis occurred in 61.3% and 38.7% of cases. The two cohorts did not differ significantly regarding baseline characteristics. Median PFS was 8 vs. 23 months (p=0.03) in cohort 1 (95% CI 0.9-15.1) compared to cohort 2 (95% CI 18.8-27.2). In cohort 2 the time between start of systemic therapy and surgery was in median 8.5 months (95% CI 3.3-21.1), the primary had a median diameter of 10.7 cm (95% CI 4.5-13.3). Median reduction of the primary was in total 32.2%, 28.9% in the Ipi/Nivo and 34.7% in the CPI/TKI group (p=0.74). In seven patients (35%) response led to modification of the surgical approach, enabling partial instead of radical nephrectomy. Conclusions: The sequence of systemic therapy followed by surgery was associated with a significant PFS benefit. In addition, prior systemic therapy led to a primary reduction and better operability, in some cases even to kidney sparing surgery. Major limitation is the retrospective nature of our analysis and a potential selection bias. However, the sequence of prior systemic therapy followed by surgery in aRCC was associated with notably better outcomes.

MR-Guided Stereotactic Ablative Body Radiotherapy for Pancreatic Oligometastases from Renal Cell Carcinoma

Patients with pancreatic metastases from renal cell carcinoma (RCC) have been reported to have an unusually favorable prognosis. Traditionally, treatment for these pancreatic oligometastases comprises either surgical resection or systemic therapy. However, stereotactic ablative body radiotherapy (SAbR) may be an effective, non-invasive alternative strategy, provided that it shows acceptable toxicity and high local control rates among treated patients. We reviewed all patients treated with MR-guided SABR for pancreatic oligometastases from renal cell carcinoma at a single institute. We explored adverse events (AE), freedom from local progression (FFLP), progression-free survival (PFS), and freedom from start of systemic therapy (FFST) among treated patients. The Kaplan-Meier method was used to describe the time-to-event endpoints. From June 2019 to September 2022, we identified 11 patients treated with MR-guided SAbR to 31 pancreatic oligometastases from RCC. Patients had a mean age of 65.6 years (±6.8) and had a median of 3 irradiated pancreatic metastases (range 1-7). Metastases were treated with 5 fractions of 7 Gy (n = 1 metastasis) or 8 Gy (n = 30 metastases) per fraction. One grade 3 adverse event (bleeding) was observed. At a median follow-up of 10.5 months (range 5-46 months), estimated FFLP at 1 year was 100%. 1y-PFS was 83% (95% CI 58-100%), and 1y-FFST was 91% (95% CI 75-100%). First exploration of MR-guided SAbR to pancreatic oligometastases from RCC indicates that it can be an effective and safe treatment option. Moreover, MR-guided SAbR may facilitate deferral of systemic therapy initiation in this select group of patients with favorable prognosis.

Outcomes Following Different Thermal Ablation Strategies in Patients with Unresectable Colorectal Liver Metastases.

Background For patients with unresectable colorectal liver metastases (CRLM), clinical guidelines recommend imaging-guided thermal ablation combined with systemic therapy. However, the optimal thermal ablation strategy remains unclear. Purpose To compare long-term outcomes between patients who underwent upfront ablation or delayed ablation for unresectable CRLM. Materials and Methods This retrospective study included patients with unresectable CRLM (three or fewer lesions; diameter, <3 cm) admitted to one of seven hospitals between October 2009 and December 2020. Upfront ablation was performed 2-4 weeks before the start of systemic therapy, and delayed ablation was performed 2-3 months after the start of systemic therapy. Propensity score matching was applied to adjust for differences in baseline variables between groups. Disease-free survival (DFS) was the primary outcome. Overall survival (OS), complications, and adverse events were secondary outcomes. Outcomes were compared between groups by using the log-rank test. Results In total, 255 patients who underwent delayed ablation (mean age, 57 years ± 11 [SD]; 184 men [72%]) and 103 patients who underwent upfront ablation (mean age, 56 years ± 12; 72 men [70%]) were included. After propensity score matching (n = 100 in both groups), the 5-year DFS for patients who underwent upfront ablation was better compared with patients who underwent delayed ablation (36% vs 21%; P = .02). For 5-year OS, no evidence of a difference was observed between ablation strategies (delayed ablation, 59% vs upfront ablation, 64%; P = .49). Additionally, no differences were observed between ablation strategies with respect to the rates of ablative complications (delayed ablation, 6% vs upfront ablation, 5%; P = .76) or drug-related adverse events (delayed and upfront ablation both 9%; P = .99). Conclusion In patients with relatively few (three or fewer) and small (<3 cm) unresectable CRLM, upfront thermal ablation combined with adjuvant systemic therapy led to better DFS compared with delayed ablation. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Georgiades in this issue.

Reduced symptom burden after implementation of an electronic symptom management program.

12006 Background: The SIMPRO consortium implemented an electronic patient reported outcomes (ePRO) symptom management program as part of routine clinical care for patients (pts) receiving systemic cancer therapy or surgery across six health systems including rural and community cancer centers. To evaluate impact of the Epic-integrated electronic symptom management (eSyM) program on quality of life, pre- and post-implementation surveys were sent to a subset of gastrointestinal, thoracic, and gynecologic medical oncology (MO) and surgical (Surg) patients at all sites. Methods: A survey assessing symptom burden, health literacy, and self-efficacy was administered to separate groups of MO and Surg pts before (Pre-Implementation) and after (Post-Implementation) eSyM deployment. A waiver of documentation of consent was obtained for participation. Questions were derived from validated instruments including PROMIS, a standardized measurement tool for patient-reported symptoms. Surveys were completed 30-90 days after surgery or start of systemic therapy. PROMIS item responses were scored individually then translated into standardized T-scores with a mean of 50 based on an established reference population. Mean T-scores for PROMIS depression, anxiety, fatigue, and pain interference were calculated. Higher T-score correlated with greater symptom burden. Comparison between groups utilized non-parametric Kruskal-Wallis testing. Results: The number of survey responses were 498 MO Pre-Implementation, 518 MO Post-Implementation, 566 Surg Pre-Implementation, and 507 Surg Post-Implementation. MO pts reported significantly lower PROMIS mean T-scores for depression, anxiety, fatigue, and pain interference after eSyM compared to a similar group of MO pts prior to eSyM. Surg pts reported lower T-scores for depression, anxiety, fatigue, and pain interference after eSyM compared to a similar group of Surg pts prior to eSyM, although reduction in pain interference was not statistically significant. Conclusions: eSyM deployment in MO was associated with a significant reduction in patient reported depression, anxiety, fatigue, and pain interference. Surgical pts after eSyM deployment reported significantly lower rates of depression, anxiety, and fatigue. External validation with PROMIS based surveys demonstrated small but meaningful benefits of ePRO symptom monitoring as part of routine clinical care across six diverse health systems. Clinical trial information: NCT03850912 . [Table: see text]

Serum immuno-oncology markers carry independent prognostic information in patients with newly diagnosed metastatic breast cancer, from a prospective observational study

BackgroundMetastatic breast cancer (MBC) is a challenging disease, and despite new therapies, prognosis is still poor for a majority of patients. There is a clinical need for improved prognostication where immuno-oncology markers can provide important information. The aim of this study was to evaluate serum immuno-oncology markers in MBC patients and their respective relevance for prediction of survival.Patients and methodsWe investigated a broad panel of 92 immuno-oncology proteins in serum from 136 MBC patients included in a prospective observational study (NCT01322893) with long-term follow-up. Serum samples were collected before start of systemic therapy and analyzed using multiplex proximity extension assay (Olink Target 96 Immuno-Oncology panel). Multiple machine learning techniques were used to identify serum markers with highest importance for prediction of overall and progression-free survival (OS and PFS), and associations to survival were further evaluated using Cox regression analyses. False discovery rate was then used to adjust for multiple comparisons.ResultsUsing random forest and random survival forest analyses, we identified the top nine and ten variables of highest predictive importance for OS and PFS, respectively. Cox regression analyses revealed significant associations (P < 0.005) of higher serum levels of IL-8, IL-10 and CAIX with worse OS in multivariable analyses, adjusted for established clinical prognostic factors including circulating tumor cells (CTCs). Similarly, high serum levels of IL-8, IL-10, ADA and CASP8 significantly associated with worse PFS. Interestingly, high serum levels of FasL significantly associated with improved OS and PFS. In addition, CSF-1, IL-6, MUC16, TFNSFR4 and CD244 showed suggestive evidence (P < 0.05) for an association to survival in multivariable analyses. After correction for multiple comparisons, IL-8 still showed strong evidence for correlation to survival.ConclusionTo conclude, we found six serum immuno-oncology markers that were significantly associated with OS and/or PFS in MBC patients, independently of other established prognostic factors including CTCs. Furthermore, an additional five serum immuno-oncology markers provided suggestive evidence for an independent association to survival. These findings highlight the relevance of immuno-oncology serum markers in MBC patients and support their usefulness for improved prognostication.Trial registration Clinical Trials (NCT01322893), registered March 25, 2011.

Differences in the tumor transcriptomic profile of patients (pts) with advanced prostate cancer (PCa) with and without diabetes mellitus (DM).

244 Background: Pre-existing DM is associated with increased PCa specific and all-cause mortality in men with prostate cancer (PMID: 27652121). However, the underlying reasons are unclear. We hypothesized that transcriptomic profile of metastatic PCa pts with diagnosis of DM prior to the diagnosis of metastatic disease and start of systemic therapy will be different from those without DM. Methods: In this IRB-approved retrospective study, advanced PCa pts with available RNA profiling of treatment naïve tumor tissue through a CLIA-certified laboratory were included. Based on pre-existing DM prior to onset of metastatic disease, pts was grouped into DM and non-DM. Differential gene expression analysis between the two groups was performed using DeSeq2. These results were subjected to Gene Set Enrichment software analysis (GSEA) to identify pathways enriched in each cohort. Gene ontology analysis using TopGO software was done to identify the biological process occurring at the molecular level of these differentially expressed genes. All bioinformatic analysis was conducted in R studio, version 4.1.1. Results: 75 pts were eligible and included: 20 DM vs 55 non-DM. Baseline characteristics (DM vs non-DM): median age 63.5 vs 64 years; median PSA at diagnosis 20 vs 18.85ng/mL; de novo disease: 55% vs 43.6%; Gleason score ≥8: 60% vs 74.5%. DM pts had upregulation of the following pathways: TNF alpha signaling, inflammatory response, IL-6 JAK STAT3 signaling, heme metabolism, and the p53 pathway vs non-DM pts. Gene ontology analysis and individual differential gene expression profiles will be reported at the meeting. Conclusions: Our study found that pre-existing DM is associated with upregulation of inflammatory pathways in pts with PCa These hypothesis-generating results need external validation. Identification of transcriptomic biomarkers in these subsets of pts may help with further drug development. [Table: see text]

Responses to first-line systemic therapies in patients with hepatocellular carcinoma with TERT promoter mutations.

589 Background: The treatment landscape of advanced hepatocellular carcinoma (HCC) has made significant advances with the use of oral multikinase inhibitors and immunotherapy-containing regimens. However, there is minimal data with regards to which biomarkers may predict treatment responses in this population. The increased use of next-generation sequencing (NGS) has identified the most frequent mutations in HCC, including TERT promoter mutations which are found in up to 65% of patients. With the high frequency of these mutations, additional studies are needed to investigate their associations with treatment outcomes. Methods: Our team performed a retrospective study to determine the association between TERT promoter mutations in HCC and responses to first-line systemic therapies. All patients in this study underwent NGS testing on tumor tissue or peripheral blood samples. Responses to treatment were determined by imaging at least 6 weeks after the start of systemic therapy. Results: There were 128 HCC patients included in this study with TERT promoter mutations found in 72 patients (56.3%). All patients received first-line therapy with either an immunotherapy-based regimen or oral multikinase inhibitor monotherapy (lenvatinib or sorafenib). When looking at responses to all first-line therapies, patients with TERT promoter mutations were found to have significantly higher rates of disease progression (PD) compared to those without TERT promoter mutations (34.7% vs 17.9%, p = 0.04). In addition, when stratifying responses by type of systemic therapy, the TERT promoter-mutated population had notably higher rates of PD with immunotherapy regimens compared to patients without TERT mutations (34.6% vs 10.8%, p = 0.01). In contrast, there was no significant difference in rates of PD with oral multikinase inhibitor monotherapy between TERT mutated and TERT non-mutated individuals (35% vs 31.6%, p = 1). See table for further details. Conclusions: In this study, HCC patients with TERT promoter mutations were found to have significantly higher rates of PD to first-line therapies and, specifically, immunotherapy-containing regimens. Given the prevalence of these mutations in the HCC population, further investigation is needed to clarify this association and its impact on patient survival.[Table: see text]

The impact of nutritional status and changes of body composition on the prognosis of metastatic renal cell carcinoma patients

This study aimed to analyze the impact of patients' nutritional status and changes in body composition on the prognosis of metastatic renal cell carcinoma (mRCC) patients who received systemic therapy with tyrosine kinase inhibitors (TKIs).A total of 57 mRCC patients who received systemic therapy with TKIs as first-line therapy at our facility between November 2004 and October 2018 were included. The Prognostic Nutritional Index (PNI) was used to evaluate their nutritional status. The volumes of skeletal muscle mass and fat tissue were calculated using the SYNAPSE VINCENT system. The effects of nutritional status and body composition of mRCC patients on progression-free survival (PFS) and overall survival (OS) were analyzed using Cox regression methods.Low PNI at the start of systemic therapy was a significant prognostic predictor for OS (HR 3.807 [95% CI 1.205-12.027], P=0.046), and it was related to loss of muscle mass three months after systemic therapy. Although the loss of muscle mass at the start of systemic therapy was not associated with OS, loss of muscle mass during treatment predicted worse OS.Nutritional status of mRCC patients may predict changes in body composition and be associated with their prognosis. J. Med. Invest. 70 : 80-87, February, 2023.

Analysis of Lenvatinib's Efficacy against Intermediate-Stage Unresectable Hepatocellular Carcinoma.

Transarterial chemoembolization (TACE) has been the standard treatment for intermediate-stage, unresectable hepatocellular carcinoma (u-HCC). However, with recent advances in systemic therapy and the emergence of the concept of TACE-refractory or -unsuitable, the effectiveness of systemic therapy, as well as TACE, has been demonstrated for patients judged to be TACE-refractory or -unsuitable. In this study, the efficacy of lenvatinib and its combination with TACE after lenvatinib was investigated in 140 patients with intermediate-stage u-HCC treated with lenvatinib mainly because of being judged to be TACE-refractory or -unsuitable. Median overall survival (OS) and progression-free survival (PFS) were 24.4 and 9.0 months, respectively, indicating a good response rate. In multivariate analysis, modified albumin-bilirubin (mALBI) grade and up to seven criteria were identified as independent factors for OS, and mALBI grade and tumor morphology were identified as independent factors for PFS. While 95% of all patients were TACE-refractory or -unsuitable, the further prognosis was prolonged by the combination with TACE after lenvatinib initiation. These findings suggest that systemic therapy should be considered for intermediate-stage u-HCC, even in patients judged to be TACE-refractory or -unsuitable. The use of TACE after the start of systemic therapy may further improve prognosis.

Disparities in timely treatment among lung cancer patients.

e18515 Background: NSCLC is the leading cause of cancer-related deaths in the US. There are no federal standardized guidelines regarding timely treatment (TT) of NSCLC care and little is known regarding the sociodemographic differences in TT of anticancer therapies among NSCLC patients. This is particularly notable among Black Americans, who are less likely to receive lung cancer screening, more likely to be diagnosed with advanced or metastatic NSCLCL, and less likely to receive NCCN-concordant targeted therapy relative to their white counterparts. The objective of this retrospective study is to assess racial differences in TT and related outcomes among patients with advanced or metastatic NSCLC (aNSCLC). Methods: We identified 3,603 patients from ConcertAI’s Real-world data (RWD) sources, including CancerLinQ Electronic Medical Records. Patient demographics included: a) aged 18 to 64 years; b) confirmed diagnosis of aNSCLC between January 1, 2010, and December 31, 2019; and c) self-identify as White or African American. For this study the primary endpoint was receipt of TT, defined as start of systemic therapy within 30 days after diagnosis of aNSCLC. Logistic regression was leveraged to obtain adjusted odds ratios of comparisons between White and Black American populations on receipt of TT, controlling for demographic and baseline characteristics such as type of setting, ECOG score and smoking status. Results: Descriptive analyses revealed 79.1% of Black aNSCLC patients did not receive TT, as compared to 71.4% of White aNSCLC patients. When controlling for associated confounding factors, Black aNSCLC patients had a 21.4% less chance of receiving TT as compared to White patients, and the same was evident from the predicted probabilities of TT for Black vs. White aNSCLC patients. When evaluating institutional setting type, 76.1% of community hospitals provided TT vs. 61.3% of academic centers. Conclusions: This real-world study shows Black aNSCLC patients were associated with treatment delay. While present findings suggest improving access to effective screening and timely access to NCCN-concordant targeted therapies may be used as a means through which to lessen NSCLC disparities, further investigation is required to assess how it may improve overall outcomes for minorities. [Table: see text]

Fumarate hydratase-deficient renal cell carcinoma: The real-world experience at Dana-Farber Cancer Institute and Moores Cancer Center.

e16522 Background: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare and aggressive tumor with limited clinical trials dedicated to therapeutics for this disease. This retrospective study aimed to report a multi-center experience in the systemic treatment of FH-deficient RCC. Methods: The medical records of patients undergoing systemic therapy for advanced or metastatic FH-deficient RCC at Dana-Farber Cancer Institute and Moores Cancer Center were reviewed from 2012 to 2021. Demographic, histologic, molecular, and survival parameters were collected. Response was assessed using RECIST 1.1 criteria. A confirmative initial diagnosis of FH-RCC was made utilizing FH/2SC immunohistochemistry (n = 12) and/or the presence of an FH mutation (n = 6). The primary endpoint of this study was to characterize patients with FH-deficient RCC in the modern era. Results: 18 patients were included; median age at diagnosis was 45 (interquartile range [IQR]: 40-55) years. All patients had a Karnofsky Performance Status (KPS) ≥ 80. Among 14 patients with evaluable IMDC criteria, 1 (7.4%) had favorable-risk disease, while 10 (71.4%) and 3 (21.4%) had intermediate- and poor-risk disease, respectively. Tumors at diagnosis were stage III (n = 6, 33.3%), and IV (n = 12, 66.7%). Median time from diagnosis to the start of systemic therapy was 2.8 months. Six types of regimens were given as first-line therapy (Table). Fourteen patients (78%) developed disease progression on frontline therapy and received subsequent therapy; two patients, initially treated with an mTOR inhibitor and combined vascular endothelial growth factor (VEGF) inhibitor and immune checkpoint inhibitor (ICI), are off therapy and still under surveillance with no recurrence to date; one patient passed away while on frontline therapy; and one patient has limited follow-up. For a median follow-up of 22 months (IQR:6.4-49), the 18-month-overall survival estimate was 81% (95% confidence interval [CI]: 53%-94%) and median progression-free survival (PFS) was 6.7 months (95%CI: 5.0-17.0). Conclusions: This study shows considerable heterogeneity in the treatment for FH deficient-RCC, with disparate clinical outcomes. Dedicated trials and guidelines on the management of FH-deficient RCC are needed.[Table: see text]

Active Surveillance in Metastatic Renal Cell Carcinoma: Results From the Canadian Kidney Cancer Information System.

Active surveillance (AS) is a commonly used strategy in patients with slow-growing disease. We aimed to assess the outcomes and safety of AS in patients with metastatic renal cell carcinoma (mRCC). We used the Canadian Kidney Cancer information system (CKCis) to identify patients with mRCC diagnosed between January 1, 2011, and December 31, 2016. The AS strategy was defined as (1) the start of systemic therapy ≥ 6 months after diagnosis of mRCC, or (2) never receiving systemic therapy for mRCC with an overall survival (OS) of ≥1 year. Patients starting systemic treatment <6 months after diagnosis of mRCC were defined as receiving immediate systemic treatment. OS and time until first-line treatment failure (TTF) were compared between the two cohorts. A total of 853 patients met the criteria for AS (cohort A). Of these, 364 started treatment >6 months after their initial diagnosis (cohort A1) and 489 never started systemic therapy (cohort A2); 827 patients received immediate systemic treatment (cohort B). The 5-year OS probability was significantly greater for cohort A than for cohort B (70% vs. 33.6%; P < .0001). After adjusting for International Metastatic RCC Database Consortium risk criteria and age, both OS (hazard ratio [HR]=0.58; 95% confidence interval [CI], 0.47-0.70; P < .0001) and TTF (HR=0.72; 95% CI, 0.60-0.85; P=.0002) were greater in cohort A1 compared with B. For cohort A1, the median time on AS was 14.2 months (range, 6-71). Based on the largest analysis of AS in mRCC to date, our data suggest that a subset of patients may be safely observed without immediate initiation of systemic therapy.

Overall survival improvement in patients with metastatic clear-cell renal cell carcinoma between 2000 and 2020: a retrospective cohort study

Background Only a few recent phase III trials with targeted therapies or immune checkpoint inhibitors (ICIs) in metastatic clear-cell renal cell carcinoma (m-ccRCC) demonstrated an overall survival (OS) benefit compared to standard of care. We aimed to study the evolution of OS since the start of systemic therapy from 2000 to 2020. Patients and methods Retrospective study on all consecutively treated m-ccRCC patients in three Belgian hospitals starting with systemic therapy. The study outcome was OS since the start of systemic therapy. We used a univariable Cox model for OS with year of the start of therapy as a predictor, and a multivariable analysis including known prognostic factors. Linear and non-linear trends of time were tested. Results Five hundred patients were included. In a linear model, the HR for OS depending on the year of the start of therapy was 0.95 (95%CI 0.93–0.97; p < 0.0001), estimated for an increase with 1 year in time. In a non-linear model, OS started to improve from 2006 on, when vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) replaced interferon alfa (IFNa) as a standard of care and continued to increase steadily during the following years. On multivariable analysis, the year of the start of therapy remained an independent prognostic factor for OS. Two-year OS after the start of systemic therapy was 23%, 34%, 50% and 59% for patients who started treatment in 2000–2005, 2006–2011, 2012–2017, and 2018–2020, respectively. The five-year OS of the first three groups was 7%, 14% and 24%. The mean number of administered lines of therapy increased over time, with an incidence rate ratio of 1.07 (95%CI 1.05–1.08; p < 0.0001) per year increase for the period 2000–2016. Conclusion OS of m-ccRCC patients has been improving significantly over the last 15 years since the introduction of VEGFR-TKIs and ICIs.

The unfavorable effects of COVID-19 on Dutch advanced melanoma care.

The COVID‐19 pandemic had a severe impact on medical care. Our study aims to investigate the impact of COVID‐19 on advanced melanoma care in the Netherlands. We selected patients diagnosed with irresectable stage IIIc and IV melanoma during the first and second COVID‐19 wave and compared them with patients diagnosed within the same time frame in 2018 and 2019. Patients were divided into three geographical regions. We investigated baseline characteristics, time from diagnosis until start of systemic therapy and postponement of anti‐PD‐1 courses. During both waves, fewer patients were diagnosed compared to the control groups. During the first wave, time between diagnosis and start of treatment was significantly longer in the southern region compared to other regions (33 vs 9 and 15 days, P‐value <.05). Anti‐PD‐1 courses were postponed in 20.0% vs 3.0% of patients in the first wave compared to the control period. Significantly more patients had courses postponed in the south during the first wave compared to other regions (34.8% vs 11.5% vs 22.3%, P‐value <.001). Significantly more patients diagnosed during the second wave had brain metastases and worse performance status compared to the control period. In conclusion, advanced melanoma care in the Netherlands was severely affected by the COVID‐19 pandemic. In the south, the start of systemic treatment for advanced melanoma was more often delayed, and treatment courses were more frequently postponed. During the second wave, patients were diagnosed with poorer patient and tumor characteristics. Longer follow‐up is needed to establish the impact on patient outcomes.

Outcomes of Patients With HER2-Positive Breast Cancer Metastatic to Brain Treated With HER2-Targeted Systemic Therapy and Stereotactic Radiosurgery

For patients with HER2-positive breast cancer metastatic to brain, HER2-directed systemic therapies are increasingly used with stereotactic radiosurgery (SRS), with a goal to avoid or delay whole brain radiotherapy. These include monoclonal antibodies such as trastuzumab (Herceptin, H) and pertuzumab (Perjeta, P), antibody-drug conjugates such as ado-trastuzumab emtansine (T-DM1), and tyrosine kinase inhibitors such as lapatinib. Limited data exist regarding appropriate timing with SRS and outcomes of this treatment regimen for HER2-positive breast cancer metastatic to the brain.A single-institution retrospective review was performed to identify and collect clinical data on patients with biopsy-proven breast cancer metastatic to the brain who were treated with SRS. Outcomes analyses were performed using the Kaplan-Meier method, and the chi-square statistic was used to compare different treatment groups.Of 82 patients with breast cancer metastatic to the brain treated with SRS from 2009-2020, 33 (40%) had positive HER2 status, 18 of whom had hormone receptor positivity. At brain metastasis diagnosis, 15 patients (45%) had > 1 intracranial metastasis (range 2-7), and the median maximal brain metastasis dimension was 2.0 cm. Fifteen patients had uncontrolled extracranial disease. After brain metastasis diagnosis, 9 patients (27%) were treated with systemic therapy first (3 with T-DM1, 1 with T-DM1+HP, 1 with lapatinib+HP, 3 with chemotherapy+HP, 1 with chemotherapy) with a median of 18.6 months between the start of systemic therapy and SRS. Seven patients (21%) were treated with SRS first, followed by systemic therapy in 6 of these patients (these were multi-agent regimens with 4 including T-DM1 or lapatinib). Seventeen (52%) received concurrent systemic therapy and SRS upfront (3 with T-DM1, 2 with T-DM1+chemotherapy, 2 with lapatinib, 4 with HP, 5 with hormone therapy, 1 with chemotherapy). Median follow-up time was 21.1 months. Median overall survival was 24.8 months and not statistically different between treatment groups (table). Four patients (12%) developed symptomatic radionecrosis; 3 were on T-DM1 concurrent with SRS (of a total of 10 patients treated with this combination whether upfront or following initial systemic therapy).In this small patient sample, we noted favorable survival outcomes for patients with HER2-positive breast cancer metastatic to the brain when treated with HER2-targeted therapies together with SRS. The sequence of systemic therapy and SRS does not appear to impact survival outcomes. Concurrent treatment with T-DM1 and SRS may be associated with higher rates of radionecrosis.

Time Interval to Initiation of Whole-Brain Radiation Therapy in Patients With Small Cell Lung Cancer With Brain Metastasis

PurposePatients with small cell lung cancer (SCLC) who have brain metastases require whole-brain radiation therapy (WBRT). When there is no emergent indication for WBRT, patients may receive systemic therapy first and WBRT afterward. In scenarios when systemic therapy is initiated first, it has not been previously investigated whether delaying WBRT is harmful. Methods and MaterialsThe National Cancer Database was queried (2004-2016) for patients with SCLC with brain metastases who received 30 Gy in 10 fractions of WBRT. Patients were divided into groups based on whether they received early WBRT (3-14 days after initiation of chemotherapy) or late WBRT (15-90 days after initiation of chemotherapy). Demographic and clinicopathologic categorical variables were compared between those who had early WBRT (3-14 days) and those who had late WBRT (15-90 days). Factors predictive for late WBRT were determined. Overall survival (OS), which was defined as days from diagnosis to death, was evaluated and variables prognostic for OS were determined. ResultsA total of 1082 patients met selection criteria; 587 (54%) had early WBRT and 495 (46%) received late WBRT. Groups were similarly distributed aside from days from initiating chemotherapy to initiating WBRT (P < .001). The early WBRT group had a median of 7 days (interquartile range [IQR], 5-10 days) from initiating chemotherapy to initiating WBRT and the late WBRT group had a median of 34 days (IQR, 21-57 days). On binary logistic regression analysis, a longer time interval between diagnosis and the start of systemic therapy was predictive for later WBRT. Median OS was 8.7 months for early WBRT and 7.5 months for late WBRT (hazard ratio [HR], 1.165; P = .008). Early WBRT (P = .02), female sex (P = .045), and private insurance (P = .04) were favorable prognostic factors for OS on multivariable analysis, whereas older age (P = .006) was an unfavorable prognostic factor. ConclusionsPatients with SCLC and brain metastases who received early WBRT were found to have a modest improvement in OS compared with patients who received late WBRT. These findings suggest that early WBRT should be offered to patients who have brain metastases, even in the absence of an indication for emergent WBRT.

Stereotactic Ablative Radiation Therapy for Oligoprogressive Renal Cell Carcinoma

PurposeOligoprogression, defined as limited sites of progression on systemic therapy, in patients with metastatic renal cell carcinoma (mRCC) is not uncommon, possibly because of inter- and intratumoral heterogeneity. We evaluated the effect of stereotactic ablative radiation therapy (SAbR) for longitudinal control of oligoprogressive mRCC. Methods and MaterialsPatients with extracranial mRCC were included in this retrospective analysis if they progressed in ≤3 sites on systemic therapy while demonstrating response/stability at other sites and received SAbR to all progressing sites without switching systemic therapy. Our primary endpoint was modified progression-free survival (mPFS), which we calculated from the start of SAbR to the start of a subsequent systemic therapy, death, or loss to follow-up. ResultsWe identified 36 patients with a median follow-up of 20.4 months (interquartile range, 10.9-29.4). Forty-three sites were treated with SAbR with a median dose of 36 Gy (range, 18-50) in 3 fractions (range, 1-5). Median time to SAbR from the start of systemic therapy was 11.4 months (interquartile range, 6.1-17.1). Median mPFS was 9.2 months (95% confidence interval [CI], 5.9-13.2). Patients receiving SAbR while on immunotherapy exhibited a longer median mPFS (>28.4 months, log-rank P = .0001) than patients not on immunotherapy (9.2 months). Median overall survival from SAbR administration was 43.4 months (95% CI, 21.5-not Reached). The 1-year local control rate was 93% (95% CI, 78.7-97.5). Most SAbR-related toxicities were grade 1 to 2 (33% of patients), with one grade 5 hemoptysis event possibly related to SAbR or disease progression. ConclusionsSAbR has the potential to extend the the duration of current systemic therapy for selected patients with mRCC, preserving subsequent therapies for later administration possibly enabling longer treatment duration.