Alternative Systemic Therapies Research Articles

Tislelizumab: a promising alternative first-line systemic therapy in unresectable advanced hepatocellular carcinoma

Tislelizumab: a promising alternative first-line systemic therapy in unresectable advanced hepatocellular carcinoma

Spinal Meningiomas: A Comprehensive Review and Update on Advancements in Molecular Characterization, Diagnostics, Surgical Approach and Technology, and Alternative Therapies.

Spinal meningiomas are the most common intradural, extramedullary tumor in adults, yet the least common entity when accounting for all meningiomas spanning the neuraxis. While traditionally considered a benign recapitulation of their intracranial counterpart, a paucity of knowledge exists regarding the differences between meningiomas arising from these two anatomic compartments in terms of histopathologic subtypes, molecular tumor biology, surgical principles, long-term functional outcomes, and recurrence rates. To date, advancements at the bench have largely been made for intracranial meningiomas, including the discovery of novel gene targets, DNA methylation profiles, integrated diagnoses, and alternative systemic therapies, with few exceptions reserved for spinal pathology. Likewise, evolving clinical research offers significant updates to our understanding of guiding surgical principles, intraoperative technology, and perioperative patient management for intracranial meningiomas. Nonetheless, spinal meningiomas are predominantly relegated to studies considering non-specific intradural extramedullary spinal tumors of all histopathologic types. The aim of this review is to comprehensively report updates in both basic science and clinical research regarding intraspinal meningiomas and to provide illustrative case examples thereof, thereby lending a better understanding of this heterogenous class of central nervous system tumors.

Natural history and patterns of progression for dMMR/MSI-H colorectal cancer treated with immune checkpoint blockade: A single center retrospective analysis.

145 Background: Deficiency in mismatch repair or high microsatellite instability (dMMR/MSI-H), occurring in approximately 20% of all colorectal cancer (CRC) cases and approximately 4% of metastatic CRC (mCRC), predicts clinical benefit of immune checkpoint blockade (ICB). With response rates of about 50% in mCRC and higher in localized cases, ICB is providing durable benefit and even cure in a meaningful portion of cases. However, further understanding of those patients who progress and treatment options following progression are needed. Methods: A single institution retrospective review was performed on 151 dMMR/MSI-H CRC patients receiving ICB at MD Anderson Cancer Center from 2014 to 2023. Data was collected including patient demographics, tumor and mutational data, ICB treatment data, progression patterns, and treatment following progression. Progression patterns were classified as intrinsic (progression at initial restaging with pseudoprogression excluded) or adaptive progression and oligometastatic (3 or less sites of metastatic disease regardless of organs involved) or systemic progression. Results: The median time to progression (TTP) of all patients treated with ICB was 88 months (m). Median follow up was 40 m. Of the 151 patients, 59 (39%) progressed on ICB. The majority of these were treated with monotherapy anti-PD1 (49, 83%) while only 10 (17%) were treated with combination ICB. Of those that progressed, 29 (49%) were considered intrinsic while 30 (51%) were considered adaptive. In the adaptive group, average TTP was 21 m. The majority progressed at a metastatic site (51, 86%) and at a prior site of disease (47, 80%). Progression was oligometastatic in 30 (51%) patients and systemic in 29 (49%) patients. The median TTP for oligometastatic progression was 9 m while median TTP for systemic progression was 4 m (p=0.005). The median OS for those with systemic progression was 17 m while the median OS for oligometastatic progression was not reached (p=0.027). Of those with progression, 12 (20%) had non-surgical local therapy to progressing sites, 6 (10%) underwent surgery to progressing sites, and 31 (52%) received alternative systemic therapy (chemotherapy or ICB). Of the 16 patients who received local therapy (non-surgical, surgical, or both), 7 (44%) remain with no evidence of disease. Conclusions: This is one of the largest reviews of dMMR/MSI-H CRC progressors on ICB. Adaptive progression represented approximately one half of all progression events and local-modality therapy was utilized in 27% of patients. Long-term disease control was seen in oligometastatic adaptive progressors who received local modality therapy.

GLOBRYTE: A Phase III, Open-Label, Multicenter, Randomized Trial Evaluating Glofitamab Monotherapy in Patients with Relapsed or Refractory Mantle Cell Lymphoma

Background and Significance: There is currently no standard of care for patients (pts) with relapsed or refractory (R/R) mantle cell lymphoma (MCL). Although Bruton tyrosine kinase inhibitors (BTKi) have improved clinical outcomes in R/R MCL, there is a high unmet need for new treatment options for pts who do not respond to, or progress through, BTKi therapy. Chimeric antigen receptor (CAR) T-cell therapies, such as brexucabtagene autoleucel, have shown promising outcomes, but alternative systemic therapies are still needed in this pt population. Glofitamab is a CD20xCD3 T-cell-engaging bispecific antibody that redirects T cells to eliminate B cells. A Phase I/II trial of glofitamab monotherapy with step-up dosing (SUD) and obinutuzumab pretreatment (Gpt; 1000 or 2000mg) to mitigate the risk of cytokine release syndrome (CRS) showed high and durable complete response (CR) rates (73.0%) and manageable, mostly low-grade CRS in heavily pretreated pts with R/R MCL (n=37), most of whom had failed prior BTKi therapy (Phillips et al. ASH 2021, Phillips et al. ASH 2022). Study Design and Methods : The GLOBRYTE study (GO43878; EU CT: 2023-503206-37-00) is a Phase III, open-label, multicenter, randomized, controlled trial that will evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (biomarkers) of glofitamab monotherapy in pts with R/R MCL, in comparison with an investigator's choice of rituximab + bendamustine (BR) or rituximab + lenalidomide (R-Len). Pts with histologically confirmed R/R MCL who have received ≥1 prior line of systemic therapy (including a BTKi) and have an Eastern Cooperative Oncology Group performance status of 0-2 are eligible for enrollment. Exclusion criteria include leukemic, non-nodal MCL; prior CAR T-cell therapy or CD20xCD3 bispecific antibodies; primary or secondary central nervous system (CNS) lymphoma or history of CNS lymphoma; and current or prior CNS disease (including stroke or transient ischemic attack in the past 2 years and residual neurologic deficits, epilepsy, or CNS vasculitis). Eligible pts will be randomly assigned (1:1) to receive glofitamab or investigator's choice of BR or R-Len stratified by line of therapy (1 vs ≥2) and response to last therapy (relapsed vs refractory). Pts will receive intravenous (IV) Gpt (2000mg) on Day (D) 1 of Cycle (C) 1, 7 days prior to the first glofitamab dose (Gpt may be split over 2 days as 1000mg doses if needed: the second 1000mg dose must be administered ≥1 day before initial glofitamab treatment). Pts will receive glofitamab for a fixed duration of 12 cycles, unless progressive disease (PD) or unacceptable toxicity occurs earlier. Glofitamab IV SUD will be given on C1D8 (2.5mg), C1D15 (10mg), and then the target dose (30mg) on D1 of C2-12 (21-day cycles). Pts randomized to the investigator's choice will receive 375mg/m 2 IV rituximab on D1 in combination with either 90mg/m 2 IV bendamustine on D1-2 of each cycle (BR for six cycles) or 20mg/day oral lenalidomide on D1-21 of each cycle (R-Len until PD); the cycle length for BR or R-Len is 28 days. Crossover to glofitamab from the investigator's choice is permitted in pts with radiologic confirmation of PD ( Figure). The primary endpoint is progression-free survival (PFS) determined by independent review committee (IRC). Treatment comparisons will be made with a 2-sided, level 0.05 stratified log-rank test. Secondary endpoints include overall survival (OS); IRC- and investigator-assessed CR rate, objective response rate, duration of response, and duration of CR; PFS (investigator-assessed); safety; health-related quality of life including time to deterioration in physical functioning or fatigue evaluated by the EORTC QLQ-C30; glofitamab PK; and immune response to glofitamab (including presence of anti-drug antibodies). Response will be determined according to Lugano criteria (Cheson et al. J Clin Oncol 2014). Stratified hazard ratios with 95% confidence intervals (95% CI) will be calculated for PFS and OS, and odds ratios (95% CI) will be calculated for the difference in CR rate and overall response rate between treatment arms. Predictive and prognostic biomarkers (to characterize high-risk subgroups and minimal residual disease kinetics) will also be explored. An estimated 80 sites globally will enroll approximately 182 pts with R/R MCL (glofitamab n=91; BR or R-Len n=91 total) starting in Oct-Nov 2023 (APAC, US, and EU regions).

Oral minocycline as systemic therapy for uncomplicated venous access device-related bloodstream infection with coagulase-negative staphylococci after allogeneic hematopoietic cell transplantation

BackgroundVenous access device-related bloodstream infection (VAD-BSI) with coagulase-negative staphylococci (CoNS) is a common complication after allogeneic hematopoietic cell transplantation (alloHCT). Standard systemic antimicrobial therapy for uncomplicated VAD-BSI with methicillin-resistant CoNS consists of intravenous (IV) vancomycin (vanco). This requires hospitalization, needs new competent venous access, exposes patients to potential toxicity (mainly renal) and increases the risk of commensal flora dysbiosis with selection of vanco-resistant enterococci. Combined with VAD management (removal or antibiotic locks), oral minocycline (mino) has been evaluated as an alternative systemic therapy for the treatment of uncomplicated VAD-BSIs with CoNS at our center, primarily when the reference treatment with IV vanco was not possible (renal failure or allergy) or when hospitalization was refused by patients. Here, we retrospectively report our single center experience with this mino-based approach. Patients and methodsFrom January 2012 to December 2020, 24 uncomplicated VAD-BSIs with CoNS in 23 alloHCT patients were treated with oral mino as systemic antibiotic therapy in combination with VAD management. VAD were implantable ports (n = 17), tunneled catheter (n = 1) or PIC-lines (n = 6). Staphylococci were S. epidermidis (n = 21) or S. haemolyticus (n = 3). Mino was administered with a loading dose of 200 mg followed by 100 mg BID for 7–14 days. For 8 VAD-BSIs, patients were initially treated with IV vanco for the first 1–3 days followed by oral mino, while 16 VAD-BSIs were treated with oral mino as the sole antimicrobial agent for systemic therapy. VAD management consisted of catheter removal (for tunneled catheters and PIC-lines, n = 7) or antibiotic locks with vanco (n = 15) or gentamicin (n = 2) administered at least 3 times a week for 14 days (for ports). ResultsOverall, clearance of bacteremia (as assessed by negativity for the same CoNS of surveillance peripheral blood cultures drawn between day+ 3 and +30 after initiation of systemic therapy) was achieved in all but 1 patient (with port) who had persistent bacteremia at day +9. No complication such as suppurative thrombophlebitis, endocarditis, distant foci of infection or BSI-related death was observed in any patient during the 3-month period after initiation of treatment. Regarding the 17 port-BSI cases for which VAD conservative strategy was attempted, failure of 3-month VAD preservation was documented in 7/17 cases and 3-month recurrence of VAD-BSI was observed in 3/17 cases (with 1 patient with cellulitis). Treatment with mino was well tolerated except for a mild skin rash in one patient. ConclusionFurther prospective studies are needed to evaluate efficacy and safety of this approach.

Transitioning to Pegylated Interferon for the Treatment of Cutaneous T‐Cell Lymphoma: Meeting the Challenge of Therapy Discontinuation and a Proposed Algorithm

Cutaneous T‐cell lymphoma (CTCL) is an uncommon non‐Hodgkin lymphoma characterized by skin involvement, with the most recognized subtypes being mycosis fungoides (MF) and Sezary syndrome (SS). Interferon has been an established treatment for MF/SS since 1984 and is integrated into management guidelines internationally. In 2019, manufacturers abruptly discontinued interferon‐α2b and interferon‐α2a. Many alternative systemic therapies in MF/SS remain unfunded or unavailable in Canada, presenting a unique challenge. Although off‐label use of pegylated interferon is a logical substitute, there are no established dosing guidelines and limited published experience. This case series provides a single‐center experience on pegylated interferon‐α2b for treatment of MF/SS, a suggested management algorithm, and a review of the literature. All patients identified in the Calgary Cutaneous Lymphoma Program with stage IIB–IVB MF/SS treated with interferon‐α2b (4.5–9 MU/week) were switched to once weekly pegylated interferon (90 μg, 0.5 mL) between February and July 2021. Response was monitored using the mSWAT and SkinDex‐29 tools. Eight patients were switched to pegylated interferon, with a median disease duration of 69 months (range: 8–275 months). Five out of eight patients remain on pegylated interferon, with the remainder having switched to preplanned therapies. Two patients required dose reduction due to side effects, including grade II anemia and mood changes. The remaining patients had normal laboratory investigations and no additional side effects. Uncommon lymphomas like MF/SS have limited treatment options, and the impact of abrupt product discontinuation is substantial. We propose a management algorithm for the transition of patients from interferon to pegylated interferon.

Cutaenous Leishmaniasis In Libya

Cutaneous Leishmaniasis is wide spread in northwestern of Libya with increasing of incidence in the last years, as well as with appearance of new foci in Tawarga, Sirte, and Zliten, to become also endemic areas, and added to old known endemic areas like Jabal Nafusa. Different clinical manifestations and atypical presentations of skin lesions necessitate more clinical alertness as well as use of laboratory diagnostic procedures. Leishmania major was the main cause of cutaneous Leishmaniasis in Libya, followed by L. tropica, which was less frequent cause in less than one-third of all molecularly investigated patients. Some of main used therapies in Libya were cryotherapy, and intralesional antimony for patients with few and small lesions, although, in some patients; with large number as well as large size of lesions or patients with appearance of lesions at face or ears; made systemic treatment with sodium stibogluconate or meglumine antimoniate more suitable and mandatory treatment. In Libya, low doses of antimony as intramuscular injection were the followed regime that was recommended by national guidelines. Oral rifampicin and isoniazid were also successful alternative systemic therapy when systemic antimony was unsuitable or not effective.

Molecular analysis of endometrioid and non-endometrioid uterine cancer and response to treatment (246)

<b>Objectives:</b> Carboplatin and Paclitaxel are the recommended first-line regimens for uterine cancer patients requiring systemic treatment. In light of promising new alternative systemic therapies, we aimed to identify biomarkers that may predict response to carboplatin. <b>Methods:</b> Uterine cancer tumor samples were analyzed using next-generation sequencing (NGS: NextSeq, 592 Genes) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). Real-world overall survival (OS) was obtained from insurance claims data, and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts from the first treatment of carboplatin to the last day of contact. The median survival of carboplatin-associated survival (CAS) was determined after the first carboplatin treatment. Two cohorts were created and compared: <i>1)</i> OS after carboplatin-based treatment that was less than the median CAS of the whole cohort (Non-Responders, "NR"); and <i>2)</i> OS after carboplatin-based treatment that was longer than the median CAS (Responders, "R"). NGS and IHC results of the tumor samples of these cohorts were compared. Statistical significance was calculated using Mann-Whitney U and Chi-square test and adjusted for multiple comparisons (adjusted p-value = q-value). <b>Results:</b> Total 2436 uterine cancer patients who received carboplatin treatment with molecular data were included in this analysis: 578 (23.7%) were of endometrioid histology, and 1051 (43.1%) serous, carcinosarcoma, or clear cell histology. Irrespective of histology, 20 genes were significantly altered (q<0.05) between R and NR, including genes related to the pathways involved in Base/Nucleotide Excision Repair, Cell Cycle Control, Chromatin Remodeling, RTK RAS, HR, PI3K, VEGF, and WNT signaling (Table 1). Of note, <i>KMT2C,</i> a histone methyltransferase, was more frequently mutated in Rs compared to NRs (8.44% vs 3.73% mutated, p=0.01). But <i>HOOK3</i> and <i>NSD3</i> were more frequently amplified in NRs compared to Rs (1.19% vs 0.12%, q=0.047; 2.14% vs 0.73%, q=0.11). <i>NSD3,</i> a gene involved in the regulation of tumorigenesis, was amplified in 1.07% of patients and was associated with a median difference in survival of 661 fewer days (HR: 2.75, 95% CI: 1.70-4.45, p<0.00001). Among endometrioid and serous uterine histology, ER positivity was seen significantly more frequently in Rs compared to NRs (83% vs 66.2%, q=0.03; 60.1% vs 45.8%, q=0.03). However, <i>CCNE1</i> amplification was less frequent in Rs compared to NRs (4.80% vs 16.4%, q=0.01). There were no molecular differences seen between Rs and NRs in carcinosarcoma and clear cell histologies treated with carboplatin. <b>Conclusions:</b> There are significant differences in the molecular profiles of endometrial cancers that have longer median CAS compared to those with shorter median CAS. Further investigation into biomarkers that may predict response to carboplatin-based therapy in endometrial cancer is needed.

MP27-10 CLINICAL UTILITY OF NEXT-GENERATION SEQUENCING FOR PROSTATE CANCER IN THE CONTEXT OF A CHANGING TREATMENT LANDSCAPE

You have accessJournal of UrologyCME1 May 2022MP27-10 CLINICAL UTILITY OF NEXT-GENERATION SEQUENCING FOR PROSTATE CANCER IN THE CONTEXT OF A CHANGING TREATMENT LANDSCAPE Jacqueline R. Griffin, Tomi Jun, Sunny Guin, Bobby Chi-Hung Liaw, Vaibhav G. Patel, Che-Kai Tsao, Michael R. Rossi, Rong Chen, Xiang Zhou, Feras Hantash, and William K. Oh Jacqueline R. GriffinJacqueline R. Griffin More articles by this author , Tomi JunTomi Jun More articles by this author , Sunny GuinSunny Guin More articles by this author , Bobby Chi-Hung LiawBobby Chi-Hung Liaw More articles by this author , Vaibhav G. PatelVaibhav G. Patel More articles by this author , Che-Kai TsaoChe-Kai Tsao More articles by this author , Michael R. RossiMichael R. Rossi More articles by this author , Rong ChenRong Chen More articles by this author , Xiang ZhouXiang Zhou More articles by this author , Feras HantashFeras Hantash More articles by this author , and William K. OhWilliam K. Oh More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002570.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The clinical utility of next-generation sequencing (NGS) depends on the availability of sequencing-directed therapies (SDT). There were no FDA-approved SDTs in prostate cancer (PCa) until 2020, when PARP inhibitors olaparib and rucaparib were approved for tumors bearing homologous recombination repair (HRR) genes. We assessed the clinical utility of NGS in PCa before and after the approval of these agents in a single academic medical center. METHODS: For PCa patients seen at Mount Sinai Hospital (New York, NY: 2018–2021) receiving NGS (161-gene Sema4 Signal Solid Tumor Panel), data were extracted from Mount Sinai electronic medical record using a proprietary automated pipeline with limited manual curation (Sema4 PRODB). The primary outcome was clinical utility in metastatic PCa, defined as proportion of metastatic PCa patients receiving SDT. Secondary outcomes included time-to-next-treatment (TTNT, time from SDT start to the start of next systemic therapy) and the proportion of patients with clinically actionable (as of 9/2021) alterations, defined as either Tier 1 (FDA-approved treatments in prostate cancer) or Tier 2 (either off-label or investigational agents). RESULTS: Of 332 PCa patients; 51% (N=170) were sequenced 2020 or later. Median age at diagnosis was 65 (IQR 12). Of which, 39% (N=129) were localized and 61% (N=203) metastatic. We identified 167 actionable alterations in 125 patients (38% of cohort). Of actionable alterations, 31% (N=51) were Tier 1 and 69% (N=116) Tier 2. Of the 44 patients with Tier 1 alterations, 8 (18%) received SDT (all received olaparib). Proportion of metastatic patients receiving olaparib increased from 1% (2/145) before 2020 to 10% (6/58) during or after 2020 (p=0.008). Of the 36 patients not receiving olaparib: 20 were sequenced before FDA approval and treated with an alternative systemic therapy; 8 had localized disease and were not eligible; 8 had limited follow-up or unknown treatment status. For those who received olaparib, the median TTNT was 5 months. CONCLUSIONS: Clinical utility of NGS was linked to treatment landscape. Increases in NGS test volume and olaparib use coincided with approval of PARP inhibitors for HRR-mutated PCa patients. Notably, NGS was used to match patients to off-label/investigational olaparib before its FDA approval. Source of Funding: Sema4 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e453 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jacqueline R. Griffin More articles by this author Tomi Jun More articles by this author Sunny Guin More articles by this author Bobby Chi-Hung Liaw More articles by this author Vaibhav G. Patel More articles by this author Che-Kai Tsao More articles by this author Michael R. Rossi More articles by this author Rong Chen More articles by this author Xiang Zhou More articles by this author Feras Hantash More articles by this author William K. Oh More articles by this author Expand All Advertisement PDF DownloadLoading ...

Beware clonal haematopoiesis following chronic lymphocytic leukaemia treatment

Clonal myeloid haematopoiesis co-existing with chronic lymphocytic leukaemia (CLL) is not rare and is associated with high risks for development of therapy-related myeloid neoplasms (t-MNs) after cytotoxic chemotherapy. This has serious implications for the use of these therapies in newly diagnosed CLL patients. Therapy-related myeloid neoplasms are devastating conditions. Their development following cytotoxic chemotherapy for various neoplasms often ultimately leads to treatment-refractory acute myeloid leukaemia and is usually lethal for afflicted patients. These neoplasms often develop following exposure to alkylating agents or anthracyclines,1 but they have been reported following single-agent fludarabine.2 T-MNs typically present after prior cytotoxic therapy given in an adjuvant context or for relatively indolent neoplasms, and thus their development is particularly distressing for many otherwise cancer-free or cancer-controlled patients. Effective long-term control of t-MNs is difficult to achieve, and at present always requires allogeneic haematopoietic transplant. The paper by Voso et al.3 regarding clonal haematopoiesis of indeterminant potential (CHIP) as a risk factor for t-MNs following chemotherapy for CLL is thus timely and worthy of attention from all physicians who manage CLL. CHIP has (unsurprisingly) been associated with increased risks of t-MN. The current report is, however, the first reported study of t-MN following therapy for CLL. It is worth noting that this experience is based upon 15 patients who were selected only for the availability of pretreatment genomic material. Amongst the relevant 13 patients whose t-MN followed the use of cytotoxic therapy, a prior mutation consistent with myeloid CHIP was present in 10, or 77%. Mutations compatible with CHIP were found in 34 of 285 cases of CLL not developing t-MN. The authors thus appropriately conclude that CHIP seems to be a significant risk factor for the development of t-MN following cytotoxic therapy for CLL. This work presents a detailed description of the mutations found in prechemotherapy haematopoietic material. The authors are conservative in terms of attributing these mutations to the CLL or the myeloid elements found in the available pretreatment cells. They correctly observe that mutations of TP53 and SF3B1 could in principle arise either from clonal CLL cells or from a myeloid CHIP clone, and thus cannot be firmly identified as having driven the development of the t-MN. Data found in their table S4, however, show that in two patients (#6 and #8), mutations in TP53 (two cases) and in SF3B1 (one case), were identical in pretreatment samples of CLL containing cells and in the t-MN material. The same mutated sequences were found in these two paired samples in both cases and for both genes. Thus, although we cannot be completely certain, it seems very likely that in fact the pretreatment mutation was found in myeloid cells that were subsequently transformed in response to the exposure to cytotoxic agents, leading to the t-MN. These findings have important implications for the management of CLL and other neoplasms. First, CHIP is reasonably common in patients who are candidates to receive cytotoxic agents. Pre-existing CHIP clearly poses very significant risks for the development of t-MN and most of these secondary neoplasms will prove to be lethal for affected patients. Thus, particularly in older patients with higher risks of CHIP, it seems reasonable to consider screening patients for myeloid clonal states prior to offering cytotoxic therapy for management. Notably, there are now alternative systemic therapies available for CLL (and many other neoplasms) which do not involve cytotoxic therapy and thus should not pose the same risk of potential secondary neoplasm. Another and potentially provocative conclusion is that mutations of TP53 or SF3B1 found in pretreatment blood or other tissues from CLL patients may not necessarily represent changes in the CLL clone but may be situated in associated myeloid cells. This issue in it itself may affect decisions concerning CLL management, as TP53 mutations are associated with poor prognosis and as this finding in a CLL patient may potentially increase the desire for aggressive therapy. Finally, in such patients the use of cytotoxic chemotherapy in disease management might have disastrous downstream consequences, leading to a lethal t-MN. The development of effective systemic targeted therapies for CLL not employing cytotoxic or mutagenic agents has revolutionized the therapy of CLL. The application of these agents has already greatly reduced the use of potentially leukaemogenic therapies. Recently, however, it has been asserted that “In fit patients with immunoglobulin heavy chain mutation, it is still acceptable to use the chemotherapy regimen with fludarabine, cyclophosphamide, and rituximab (FCR) and, in those who [are] not fit or are not IgVH-mutated, bendamustine-rituximab regimen”.4 Given the availability of effective non-cytotoxic agents for management of essentially all CLL patients, haematologists and oncologists managing this group of highly treatable but fragile patients should take pause, and note the findings described by Voso et al.

Clinical utility of next-generation sequencing for prostate cancer in the context of a changing treatment landscape.

112 Background: Next-generation sequencing (NGS) is increasingly common in clinical practice, but its clinical utility may depend on the availability of sequencing-directed therapies (SDT). There were no FDA-approved SDTs in prostate cancer (PCa) until 2020, when PARP inhibitors olaparib and rucaparib were approved for tumors bearing alterations in certain homologous recombination repair (HRR) genes. We assessed the clinical utility of NGS in PCa before and after the approval of these agents in a single academic medical center. Methods: This was a retrospective single-center study including all PCa patients seen at Mount Sinai Hospital (New York, NY) between 2018–2021 who received NGS via the 161-gene Sema4 Signal Solid Tumor Panel. Clinical data were extracted from the Mount Sinai electronic medical record using a proprietary automated pipeline with limited manual curation (Sema4 PRODB). The primary outcome was clinical utility in metastatic PCa, defined as the proportion of metastatic PCa patients who received SDT. Secondary outcomes included time-to-next-treatment (TTNT, defined as time from SDT start to the start of next systemic therapy) and the proportion of patients with clinically actionable (as of 9/2021) alterations, defined as either Tier 1 (associated with FDA-approved treatments in prostate cancer) or Tier 2 (associated with either off-label or investigational agents). Results: The cohort consisted of 332 PCa patients; 51% (N = 170) were sequenced in 2020 or later. The median age at diagnosis was 65 (IQR 12). The most advanced stage documented was localized for 39% (N = 129) and metastatic for 61% (N = 203). Overall, 167 actionable alterations were identified in 125 patients (38% of cohort). Of the actionable alterations, 31% (N = 51) were Tier 1 and 69% (N = 116) were Tier 2. Of the 44 patients with Tier 1 alterations, 8 (18%) received SDT (all received olaparib). The proportion of metastatic patients receiving olaparib increased from 1% (2/145) before 2020 to 10% (6/58) during or after 2020 (p = 0.008). Of the 36 patients not receiving olaparib: 20 were sequenced before FDA approval and were treated with an alternative systemic therapy; 8 had localized disease and were not eligible; 8 had limited follow-up or unknown treatment status. For those who received olaparib, median TTNT was 5 months. Conclusions: In this single-center retrospective cohort, clinical utility of NGS was linked to treatment landscape. Increases in NGS test volume and olaparib use coincided with the approval of PARP inhibitors for patients with HRR-mutated prostate cancers. Notably, NGS was used to match patients to off-label/ investigational olaparib before its FDA approval.[Table: see text]

Inoperable Early-Stage Non-Small-Cell Lung Cancer: Stereotactic Ablative Radiotherapy and Rationale for Systemic Therapy.

Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable, early-stage non-small-cell lung cancer. SABR results in high rates of in-field tumor control, but among larger and more biologically aggressive tumors, regional and distant failures are problematic. Cytotoxic chemotherapy is rarely used in this patient population and the benefit is unclear. Alternative systemic therapy options with a milder side-effect profile are of considerable interest, and several randomized phase III trials are currently testing immune checkpoint inhibitors in this setting. We review the rationale, data, and ongoing studies evaluating systemic therapy in medically inoperable, early-stage non-small-cell lung cancer treated with SABR.

SWI/SNF-deficiency defines highly aggressive undifferentiated endometrial carcinoma.

Dedifferentiated/undifferentiated endometrial carcinoma (DDEC/UEC) is an endometrial cancer characterized by the presence of histologically undifferentiated carcinoma. Genomic inactivation of core switch/sucrose nonfermentable (SWI/SNF) complex proteins was recently identified in approximately two‐thirds of DDEC/UEC. The aim of this study was to delineate the clinical behavior of SWI/SNF‐deficient DDEC/UEC in comparison to SWI/SNF‐intact DDEC/UEC. The study cohort consisted of 56 SWI/SNF‐deficient DDEC/UEC (2 POLE‐mutated), which showed either SMARCA4 (BRG1) loss, ARID1A/1B co‐loss, or SMARCB1 (INI1) loss in the undifferentiated tumor, and 26 SWI/SNF‐intact DDEC/UEC (4 POLE‐mutated). The average age at diagnosis was 61 years for patients with SWI/SNF‐deficient tumors and 64 years for SWI/SNF‐intact tumors. Mismatch repair (MMR) protein deficiency was seen in 66% of SWI/SNF‐deficient and 50% of SWI/SNF‐intact tumors. At initial presentation, 55% of patients with SWI/SNF‐deficient tumors had extrauterine disease spread in contrast to 38% of patients with SWI/SNF‐intact tumors. The 2‐year disease specific survival (DSS) for stages I and II disease was 65% for SWI/SNF deficient tumors relative to 100% for SWI/SNF‐intact tumors (p = 0.042). For patients with stages III and IV disease, the median survival was 4 months for SWI/SNF‐deficient tumors compared to 36 months for SWI/SNF‐intact tumors (p = 0.0003). All six patients with POLE‐mutated tumors, including one with stage IV SWI/SNF‐deficient tumor were alive with no evidence of disease. Among the patients with advanced stage SWI/SNF‐deficient tumors, 68% (21 of 31) received adjuvant or neoadjuvant chemotherapy (platinum/taxane‐based) and all except the patient with a POLE‐mutated tumor (20 of 21) experienced disease progression either during chemotherapy or within 4 months after its completion. These findings show that core SWI/SNF‐deficiency defines a highly aggressive group of undifferentiated cancer characterized by rapid disease progression that is refractory to conventional platinum/taxane‐based chemotherapy. This underscores the importance of accurate clinical recognition of this aggressive tumor and the need to consider alternative systemic therapy for these tumors.

Barriers to prescribing targeted therapies for NSCLC patients with highly actionable gene variants in the VA National Precision Oncology Program.

2005 Background: Next-Generation Sequencing (NGS) gene panels are often completed to guide therapeutic decisions for patients with advanced stage non-small cell lung cancer (NSCLC). Patients with highly-actionable gene variants may experience improved therapeutic treatments and reduced toxicities with use of targeted agents. Ensuring appropriate prescription of targeted therapies is therefore of high importance. We sought to identify barriers to targeted agent use within the Veterans Health Affairs’ (VHA) National Precision Oncology Program (NPOP). Methods: A retrospective evaluation examined the cohort of NSCLC patients who underwent NGS multi-gene panels through NPOP between July 2015 and February 2019. A level of evidence for drug actionability was assigned to each observed oncogenic gene variant using an artificial intelligence offering (IBM Watson for Genomics: WfG). WfG level 1 and 2A evidence was reviewed by NPOP staff to exclude gene variants that did not conform to NPOP level 1 and 2A definitions. Anti-neoplastic drug prescriptions and oncology provider notes were obtained for all included patients from the VHA Corporate Data Warehouse. Review of clinical notes of patients who did not receive targeted agents was performed to categorize the reason(s). Results: Of 1764 NSCLC patients who successfully underwent NGS gene panel testing, 156 (8.9%) received therapeutic level 1 (7.3%) or 2A (1.6%) options for targeted agents based on WfG evidence analysis. In total, 117 (6.6%) patients had NPOP level 1 and 2A gene variants, all within ALK, BRAF, EGFR, ERBB2, MET, and RET. Of these, 49 (41.2%) patients were not prescribed available targeted agents. The three most common reasons were: (1) treating provider did not comment on NGS results (30.7%), (2) patient did not carry a diagnosis of advanced stage disease (18.4%), and (3) patient had begun an alternative systemic therapy prior to completion of sequencing (16.3%). No patient was denied access to a level 1 or 2A targeted drug due to utilization-management review. Conclusions: A substantial minority of patients with advanced NSCLC bearing highly-actionable gene variants are not prescribed available targeted agents. Further provider- and pathologist-directed educational effort are needed, as well as implementation of health informatics systems to provide near real-time decision support for test ordering and interpretation.

Analysis of AR/ARV7 Expression in Isolated Circulating Tumor Cells of Patients with Metastatic Castration-Resistant Prostate Cancer (SAKK 08/14 IMPROVE Trial).

Despite several treatment options and an initial high response rate to androgen deprivation therapy, the majority of prostate cancers will eventually become castration-resistant in the metastatic stage (mCRPC). Androgen receptor splice variant 7 (ARV7) is one of the best-characterized androgen receptor (AR) variants whose expression in circulating tumor cells (CTCs) has been associated with enzalutamide resistance. ARV7 expression analysis before and during enzalutamide treatment could identify patients requiring alternative systemic therapies. However, a robust test for the assessment of the ARV7 status in patient samples is still missing. Here, we implemented an RT-qPCR-based assay for detection of AR full length (ARFL)/ARV7 expression in CTCs for clinical use. Additionally, as a proof-of-principle, we validated a cohort of 95 mCRPC patients initiating first line treatment with enzalutamide or enzalutamide/metformin within a clinical trial. A total of 95 mCRPC patients were analyzed at baseline of whom 27.3% (26/95) had ARFL+ARV7+, 23.1% (22/95) had ARFL+ARV7−, 23.1% (22/95) had ARFL−ARV7−, and 1.1% (1/95) had ARFL−ARV7+ CTCs. In 11.6% (11/95), no CTCs could be isolated. A total of 25/95 patients had another CTC analysis at progressive disease, of whom 48% (12/25) were ARV7+. Of those, 50% (6/12) were ARV7− and 50% (6/12) were ARV7+ at baseline. Our results show that mRNA analysis of isolated CTCs in mCRPC is feasible and allows for longitudinal endocrine agent response monitoring and hence could contribute to treatment optimization in mCRPC.

Comparing high-dose cisplatin with cisplatin-based combination chemotherapy in definitive concurrent chemoradiation setting for locally advanced head and neck squamous cell carcinoma (LAHNSCC).

BackgroundHigh‐dose cisplatin (Cis) is a preferred systemic agent for concurrent chemoradiation (CRT) in locally advanced head and neck squamous cell cancer (LAHNSCC) patients. As some patients are unable to tolerate Cis, this study compares the toxicity and efficacy of weekly cisplatin‐paclitaxel (CP) regimen with Cis.MethodsPatients with LAHNSCC receiving definitive chemoradiation either with Cis (Cisplatin—100 mg/m2 q3w x 3) or CP (Cisplatin—20 mg/m2; Paclitaxel—30 mg/m2qw x7) were included.ResultsCis and CP groups were comprised of 114 and 111 subjects, respectively. Complete response for Cis versus CP groups was 88% versus 88%, respectively. Median follow‐up for the study was 58.5 months. After adjusting for potential treatment selection bias, no significant differences were evident between Cis and CP groups for overall survival (hazard ratios [HR] 0.85, 95% CI 0.59‐1.21, P = 0.36), progression free survival (HR 0.88, 95% CI 0.62‐1.24, P = 0.46), locoregional control (HR 0.77, 95% CI 0.52‐1.15, P = 0.21), and distant control (HR 0.87, 95% CI 0.61‐1.23, P = 0.42). Patients in the CP group had less acute and chronic toxicities.ConclusionsWeekly CP regimen can serve as an alternative systemic therapy with radiation in patients with LAHNSCC who are not fit for Cis.

The Past, Present and Future of Pulmonary Metastasectomy: A Review Article.

Pulmonary metastases are a sign of advanced malignancy and an omen of poor prognosis. Once primary tumors metastasize, they become notoriously difficult to treat and interdisciplinary management often involves a combination of chemotherapy, radiotherapy, and surgery. Over the last 25 years, the emerging body of evidence has recognized the curative potential of pulmonary metastasectomy. Surgical resection of pulmonary metastases is now commonly considered for patients with controlled primary disease, absence of widely disseminated extrapulmonary disease, completely resectable lung metastases, sufficient cardiopulmonary reserve, and lack of a better alternative systemic therapy. Since the development of these selection criteria, other prognostic factors have been proposed to better predict survival and optimize the selection of surgical candidates. Disease-free interval (DFI), completeness of resection, surgical approach, number and laterality of lung metastases, and lymph node metastases all play a dynamic role in determining patient outcomes. There is a definite need to continue reviewing these prognosticators to identify patients who will benefit most from pulmonary metastasectomy and those who should avoid unnecessary loss of lung parenchyma. This literature review aims to explore and synthesize the last 25 years of evidence on the long-term survival, prognostic factors, and patient selection process for pulmonary metastasectomy.

Vaginal estrogen and mammogram results: case series and review of literature on treatment of genitourinary syndrome of menopause (GSM) in breast cancer survivors.

To examine mammographic density before and after at least 1 year of vaginal estrogen use in a small cohort of healthy postmenopausal women and women with a personal history of breast cancer. We extracted data via chart review of patients from a single practitioner's menopause specialty clinic in Baltimore, MD. Mammographic change was primarily determined via the Bi-RADS scoring system, including the Bi-RADS density score. In addition, we conduct a narrative review of the current literature on the usage of local estrogen therapy, and systemic and local alternatives in the treatment of genitourinary syndrome of menopause (GSM) in breast cancer survivors. Twenty healthy postmenopausal women and three breast cancer survivors fit our inclusion criteria. Amongst these two groups, we did not find an increase in mammographic density after at least 1 year and up to 18 years of local vaginal estrogen. Ospemifene use in one patient did not appear to be associated with any change in Bi-RADS score. Our narrative review found little data on the effects of vaginal estrogen therapy or newer alternative systemic therapies such as ospemifene on mammographic density. Low-dose vaginal estrogen use for 1 or more years in a small cohort of women with GSM did not appear to be associated with any changes in breast density or Bi-RADS breast cancer risk scores in the majority of study participants, including three breast cancer survivors. Larger long-term controlled clinical trials should be conducted to examine the effects of low-dose vaginal estrogen on mammographic density in women with and without a personal history of breast cancer. Furthermore, relative efficacy and risk of vaginal estrogen compared with other forms of treatment for GSM should also be studied in long-term trials.

ORAL ISOTRETINOIN IN THE TREATMENT OF LARGE BENIGN CONDYLOMA ACUMINATA OF ANOGENITAL AREA – A CASE REPORT

Condyloma acuminata is a gross, exophytic cutaneous lesion most commonly occurring in the anogenital region. It is caused mostly by sexually transmitted human papilloma virus. Genital human papilloma virus infection is the most common sexual transmited disease worldwide and a leading cause of mortality among young women. Conventional topical therapy is generally ineffective, in large and extensive lesions, whereas a wide and sometimes mutilating surgical excision is necessary in many cases. We aim to present the case of a 26 year-old HIV-negative woman presenting with a four-month history of large benign Condyloma acuminata on the anogenital area, which has been treated successfully with oral isotretinoin without surgery. As a result, low dose oral isotretinoin monotherapy may represent an efficacious, safe, fairly well tolerated, noninvasive and cost effective alternative systemic therapy for anogenital Condyloma acuminata. Key words: condyloma acuminata, oral isotretinoin, large benign Condyloma acuminata. Cite this article : Cikim Ahu Ciler, Duysak Sibel, Terzi Erdinc. Oral isotretinoin in the treatment of large benign condyloma acuminata of anogenital area – a case report. RoJCED 2017;4(4):214-216 https://doi.org/10.26574/rojced.2017.4.4.214

Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial

Transarterial chemoembolisation (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma, while the multikinase inhibitor sorafenib improves survival in patients with advanced disease. We aimed to determine whether TACE with sorafenib improves progression-free survival versus TACE with placebo. We did a multicentre, randomised, placebo-controlled, phase 3 trial (TACE 2) in 20 hospitals in the UK for patients with unresectable, liver-confined hepatocellular carcinoma. Patients were eligible if they were at least aged 18 years, had Eastern Cooperative Oncology Group performance status of 1 or less, and had Child-Pugh A liver disease. Patients were randomised 1:1 by computerised minimisation algorithm to continuous oral sorafenib (400 mg twice-daily) or matching placebo combined with TACE using drug-eluting beads (DEB-TACE), which was given via the hepatic artery 2-5 weeks after randomisation and according to radiological response and patient tolerance thereafter. Patients were stratified according to randomising centre and serum α-fetoprotein concentration (<400 ng/mL and ≥400 ng/mL). Only the trial coordinator was unmasked to treatment allocation before patient progression during the study. The primary endpoint was progression-free survival defined as the interval between randomisation and progression according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) or death due to any cause, and was analysed by intention-to-treat. Safety was analysed by intention-to-treat. The trial has been completed and the final results are reported. The trial is registered at EudraCT, number 2008-005073-36, and ISRCTN, number ISRCTN93375053. Between Nov 4, 2010, and Dec 7, 2015, the trial enrolled 399 patients and was terminated after a planned interim futility analysis. 86 patients failed screening and 313 remaining patients were randomly assigned: 157 to sorafenib and 156 to placebo. The median daily dose was 660 mg (IQR 389·2-800·0) sorafenib versus 800 mg (758·2-800·0) placebo, and median duration of therapy was 120·0 days (IQR 43·0-266·0) for sorafenib versus 162·0 days (70·0-323·5) for placebo. There was no evidence of difference in progression-free survival between the sorafenib group and the placebo group (hazard ratio [HR] 0·99 [95% CI 0·77-1·27], p=0·94); median progression-free survival was 238·0 days (95% CI 221·0-281·0) in the sorafenib group and 235·0 days (209·0-322·0) in the placebo group. The most common grade 3-4 adverse events were fatigue (29 [18%] of 157 patients in the sorafenib group vs 21 [13%] of 156 patients in the placebo group), abdominal pain (20 [13%] vs 12 [8%]), diarrhoea (16 [10%] vs four [3%]), gastrointestinal disorders (18 [11%] vs 12 [8%]), and hand-foot skin reaction (12 [8%] and none). At least one serious adverse event was reported in 65 (41%) of 157 patients in the sorafenib group and 50 (32%) of 156 in the placebo group, and 181 serious adverse events were reported in total, 95 (52%) in the sorafenib group and 86 (48%) in the placebo group. Three deaths occurred in each group that were attributed to DEB-TACE. Four deaths were attributed to study drug; three in the sorafenib group and one in the placebo group. The addition of sorafenib to DEB-TACE does not improve progression-free survival in European patients with hepatocellular carcinoma. Alternative systemic therapies need to be assessed in combination with TACE to improve patient outcomes. Bayer PLC and BTG PLC.