Treatment Of Localized Tumors Research Articles

A novel microbubble platform for cancer immunotherapy

The innate immune sensor cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS-STING) has recently emerged as a potential therapeutic target to boost antitumor immune responses. However, STING is a cytoplasmic protein, and its natural activator cGAMP is a negatively charged dinucleotide that is difficult to deliver intracellularly. We have developed a new platform called Microbubble-assisted UltraSound (US)-guided Immunotherapy of Cancer (MUSIC) to activate STING with spatio-temporal control to treat cancer. MUSIC showed greater STING activation compared to cGAMP alone in vitro. In murine models, MUSIC showed dramatic tumor growth inhibition and increased survival in both syngeneic breast cancer models. The absence of antitumor immune responses in STING-/- mice shows that MUSIC action is STING-dependent. Furthermore, 6/10 MUSIC-treated mice were tumor-free versus 2/10 cGAMP-treated mice. All the rechallenged MUSIC-treated mice remained tumor-free 30 days after rechallenge. MUSIC also resulted in a 7-fold decrease in metastatic burden when compared to cGAMP alone. In summary, MUSIC showed efficient STING activation invitro. In addition, local MUSIC treatment of primary tumors produced systemic antitumor immune responses in vivo as well as anticancer immune memory preventing tumor growth upon rechallenge. We are now exploring the use of nanobubbles for systemic administration. [Work supported by CPRIT Grants RR150010 and RP190233. R.F.M. is a CPRIT Established Investigator.]

A Nomogram for the Prediction of Intermediate Significant Renal Function Loss After Robot-assisted Partial Nephrectomy for Localized Renal Tumors: A Prospective Multicenter Observational Study (RECORd2 Project)

BackgroundRobot-assisted partial nephrectomy (RAPN) is increasingly adopted for the treatment of localized renal tumors; however, rates and predictors of significant renal function (RF) loss after RAPN are still poorly investigated, especially at a long-term evaluation. ObjectiveTo analyze the predictive factors and develop a clinical nomogram for predicting the likelihood of ultimate RF loss after RAPN. Design, setting, and participantsWe prospectively evaluated all patients treated with RAPN in a multicenter series (RECORd2 project). Outcome measurements and statistical analysisSignificant RF loss was defined as >25% reduction in estimated glomerular filtration rate (eGFR) from preoperative assessment at 48th month follow-up after surgery. Uni- and multivariable logistic regression analyses for RF loss were performed. The area under the receiving operator characteristic curve (AUC) was used to quantify predictive discrimination. A nomogram was created from the multivariable model. Results and limitationsA total of 981 patients were included. The median age at surgery was 64.2 (interquartile range [IQR] 54.3–71.4) yr, and 62.4% of patients were male. The median Charlson Comorbidity Index (CCI) was 1 (IQR 0–2), 12.9% of patients suffered from diabetes mellitus, and 18.6% of patients showed peripheral vascular disease (PVD). The median Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) score was 7 (IQR 7–9). Imperative indications to partial nephrectomy were present in 3.6% of patients. Significant RF loss at 48th month postoperative evaluation was registered in 108 (11%) patients. At multivariable analysis, age (p = 0.04), female gender (p < 0.0001), CCI (p < 0.0001), CCI (p < 0.0001), diabetes (p < 0.0001), PVD (p < 0.0001), eGFR (p = 0.02), imperative (p = 0.001) surgical indication, and PADUA score (p < 0.0001) were found to be predictors of RF loss. The developed nomogram including these variables showed an AUC of 0.816. ConclusionsWe developed a clinical nomogram for the prediction of late RF loss after RAPN using preoperative and surgical variables from a large multicenter dataset. Patient summaryWe developed a nomogram that could represent a clinical tool for early detection of patients at the highest risk of significant renal function impairment after robotic conservative surgery for renal tumors.

Ultrasound-Guided Radiofrequency Ablation Versus Thyroid Lobectomy for Low-Risk Papillary Thyroid Microcarcinoma: A Propensity-Matched Cohort Study of 884 Patients.

Background: Thermal ablation (TA) has been applied in patients with low-risk papillary thyroid microcarcinoma (PTMC) who refuse surgery or active surveillance (AS). Recently, TA has been proposed as a potential therapeutic option for patients who are suitable for surgery or AS. However, the clinical outcomes of TA versus surgery remains controversial because of a lack of sufficient data. This study aimed to compare the clinical outcomes between radiofrequency ablation (RFA) versus thyroid lobectomy (TL) for low-risk PTMC in a large cohort. Methods: This retrospective study evaluated 884 patients with unifocal low-risk PTMC treated with TL or RFA from June 2014 to March 2018. Among them, 460 patients underwent TL (TL group) and 424 patients, who refused surgery or AS, underwent RFA (RFA group). Patients were regularly followed up after treatment. Local tumor progression, recurrence-free survival (RFS), complications, and treatment variables, including procedure time, estimated blood loss, hospitalization, and cost, were compared after propensity score matching (PSM). Results: After PSM, a total of 332 patients underwent TL (mean ages 43.8 ± 9.5 years) and 332 underwent RFA (mean ages 44.1 ± 9.5 years). During the follow-up (median [interquartile ranges], 48.3 [23.2] months), no significant differences were observed in local tumor progression (1.8% vs. 3.3%, p = 0.209), lymph node metastasis (0.6% vs. 0.6%, p = 1.000), recurrent PTMC (1.2% vs. 2.4%, p = 0.244), persistent lesion (0% vs. 0.3%, p = 0.317), and 4-year RFS rates (98.2% vs. 97.0%, p = 0.223) between the TL and RFA groups. Distant metastasis was not detected. None of the patients who were treated by RFA underwent delayed surgery. Patients undergoing RFA had shorter procedure time (3.4 [2.5] vs. 86.0 [37.0] minutes, p < 0.001), lower estimated blood loss (0 vs. 20 [10.0] mL, p < 0.001), shorter hospitalization (0 vs. 7.0 [3.0] days, p < 0.001), lower cost ($2035.7 [254.0] vs. $2269.1 [943.4], p < 0.001) and lower complication rate (0% vs. 4.5%, p < 0.001) than those treated by TL. The association between treatment modality and recurrence remained nonsignificant after Cox analysis (p = 0.247). Conclusions: This large matched study revealed comparable four-year clinical outcomes between RFA and TL for low-risk PTMC. As a minimally invasive modality, RFA may be a promising alternative to the existing treatment options for low-risk PTMC.

Development of biocompatible electrostatic‐repulsive microparticles for local tumor treatment

AbstractIn this study, we reported pH‐responsive microparticles consisting of poly(D,L‐lactide‐co‐glycolide) (PLGA), aminated hyaluronic acid (aHA) conjugated with 2,3‐dimethylmaleic anhydride (DMA, as a pH‐responsive cleavable molecule) (aHA‐DMA), and doxorubicin (DOX, as an antitumor drug) for local tumor treatment. The DOX‐loaded microparticles, denoted as PLGA(aHA‐DMA)/DOX MPs, were fabricated using the W1/O/W2 multi‐emulsification method. These PLGA(aHA‐DMA)/DOX MPs (~10 μm in diameter) accelerated the rate of DOX release at pH 6.8 due to the acidic pH‐responsive cleavage of the DMA moieties followed by electrostatic‐repulsion between aHA and DOX. This event caused the structural destabilization and collapse of the MPs, leading to the rapid release of DOX. Consequently, the PLGA(aHA‐DMA)/DOX MPs resulted in significant inhibition of tumor growth, demonstrating their ability for acidic tumor‐specific treatment.

An Avascular Niche Created by Axitinib-Loaded PCL/Collagen Nanofibrous Membrane Stabilized Subcutaneous Chondrogenesis of Mesenchymal Stromal Cells.

Engineered cartilage derived from mesenchymal stromal cells (MSCs) always fails to maintain the cartilaginous phenotype in the subcutaneous environment due to the ossification tendency. Vascular invasion is a prerequisite for endochondral ossification during the development of long bone. As an oral antitumor medicine, Inlyta (axitinib) possesses pronounced antiangiogenic activity, owing to the inactivation of the vascular endothelial growth factor (VEGF) signaling pathway. In this study, axitinib‐loaded poly(ε‐caprolactone) (PCL)/collagen nanofibrous membranes are fabricated by electrospinning for the first time. Rabbit‐derived MSCs‐engineered cartilage is encapsulated in the axitinib‐loaded nanofibrous membrane and subcutaneously implanted into nude mice. The sustained and localized release of axitinib successfully inhibits vascular invasion, stabilizes cartilaginous phenotype, and helps cartilage maturation. RNA sequence further reveals that axitinib creates an avascular, hypoxic, and low immune response niche. Timp1 is remarkably upregulated in this niche, which probably plays a functional role in inhibiting the activity of matrix metalloproteinases and stabilizing the engineered cartilage. This study provides a novel strategy for stable subcutaneous chondrogenesis of mesenchymal stromal cells, which is also suitable for other medical applications, such as arthritis treatment, local treatment of tumors, and regeneration of other avascular tissues (cornea and tendon).

8-Hydroxyquinoline-5-Sulfonic Acid-Containing Poly(Vinyl Alcohol)/Chitosan Electrospun Materials and Their Cu2+ and Fe3+ Complexes: Preparation, Antibacterial, Antifungal and Antitumor Activities.

Novel poly(vinyl alcohol) (PVA)/chitosan (Ch)-based fibrous materials containing an ionizable model drug, 8-hydroxyquinoline-5-sulfonic acid (SQ), were successfully fabricated by electrospinning. Complexes between the components of the crosslinked PVA/Ch/SQ mats and Cu2+ and Fe3+ ions were formed. The coordination of these ions in the mats was examined by electron paramagnetic resonance spectroscopy (EPR). The microbiological screening against S. aureus and C. albicans revealed that both the incorporation of SQ in the mats and the complexation with Cu2+ and Fe3+ imparted to these materials antibacterial and antifungal activities. Moreover, the SQ-containing mats and their complexes displayed good cytotoxicity against human cervical HeLa tumor cells. The most prominent was the cytotoxicity of the Cu2+ complex of the mats. The combined antibacterial, antifungal and in vitro antitumor activities render these novel materials promising candidates for wound dressing applications and for application in the local treatment of cervical tumors.

Incorporation of Layered Rectorite into Biocompatible Core-Sheath Nanofibrous Mats for Sustained Drug Delivery.

Searching for drug carries with controlled release and good biocompatibility has always been one of the research hotspots and difficulties. Herein, core-sheath nanofibrous mats (NFs) consisting of biocompatible poly(ethylene oxide) (PEO, core) and poly(l-lactic acid) (PLLA, sheath) for drug delivery were fabricated via coaxial electrospinning strategy. The nontoxic layered silicate rectorite (REC) with 0.5-1 wt % amount was introduced in the sheath for sustained drug delivery. Layered REC could be intercalated with PLLA macromolecule chains, leading to the densified structure for loading and keeping doxorubicin hydrochloride (DOX) while reversibly capturing and releasing DOX to delay the drug migration due to its high cation activity. The addition of REC in NFs could delay the initial burst release of DOX and prolong the residence time from 12 to 96 h. Moreover, DOX-loaded core-sheath NFs had in vitro culture with strong antitumor activity, which was confirmed by cytotoxicity results and live and dead assay. HepG2 tumor-bearing xenograft further demonstrated the tumor-suppression effect and the excellent safety of the DOX-loaded core-sheath NFs in vivo. The constructed NFs as drug carriers showed great potential in the local treatment of solid tumors.

A removable bio-orthogonal catalytic patch: A local “landmine”

Recently, Zhejiang University scientists developed a local "landmine." They engineered a patch device consisting of microneedle arrays integrated with palladium nanoparticles supported by TiO₂ nanosheets to catalyze a local prodrug-into-drug conversion via bio-orthogonal reaction for tumor inhibition. This study provides a novel paradigm for biological application of bio-orthogonal chemistry in local tumor treatment.

New aspects and innovations in the local treatment of renal and urogenital pediatric tumors

Local treatment plays a key role for patients’ outcome in tumors of the urogenital tract in children. Despite a great variety of different etiologies, the specific localization of pediatric urogenital tumors renders several characteristic demands to the treating personnel. Surgery and radiotherapy are the main elements of local treatment in this group of neoplasms. Numerous new guidelines and innovative technical developments of surgery and radiotherapy have recently been integrated into treatment concepts for pediatric urogenital tumors. Due to the broadness of the field it is not possible to give a full overview over all aspects. Therefore, this article highlights the most important innovations and new guidelines of surgery and radiotherapy of pediatric urogenital tumors.

Combined liver resection and radiofrequency ablation for bilobar multiple colorectal liver metastasis

Combined liver resection and radiofrequency ablation for bilobar multiple colorectal liver metastasis

Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles

Extracellular vesicles (EVs) play important roles in various intercellular communication processes. The abscopal effect is an interesting phenomenon in cancer treatment, in which immune activation is generally considered a main factor. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), and occasionally observed therapeutic effects on distal tumors after local treatment in immunodeficient mice. In this study, we hypothesized that EVs may be involved in the abscopal effect of OBP-301. EVs isolated from the supernatant of HCT116 human colon carcinoma cells treated with OBP-301 were confirmed to contain OBP-301, and they showed cytotoxic activity (apoptosis and autophagy) similar to OBP-301. In bilateral subcutaneous HCT116 and CT26 tumor models, intratumoral administration of OBP-301 produced potent antitumor effects on tumors that were not directly treated with OBP-301, involving direct mediation by tumor-derived EVs containing OBP-301. This indicates that immune activation is not the main factor in this abscopal effect. Moreover, tumor-derived EVs exhibited high tumor tropism in orthotopic HCT116 rectal tumors, in which adenovirus E1A and adenovirus type 5 proteins were observed in metastatic liver tumors after localized rectal tumor treatment. In conclusion, local treatment with OBP-301 has the potential to produce abscopal effects via tumor-derived EVs.

Consolidative radiotherapy for metastatic urothelial bladder cancer patients without progression and with no more than three residual metastatic lesions following first line systemic therapy: A prospective randomized comparative phase II trial (BLAD RAD01/GETUG-AFU V07).

TPS4588 Background: Consolidative local treatment of the primary tumor in the treatment of metastatic malignancies has shown promising results in several types of tumors, mostly relying on the seed-and-soil theory. Furthermore, the local treatment of the residual metastases following systemic treatment is a promising approach, in part due to the high incidence of progression at prior sites of disease in patients who had initially responded to chemotherapy. To date, no prospective data exists on such consolidative approach in metastatic urothelial bladder cancer (mUBC). The phase II trial BLAD-RAD01 GETUG-AFU V07 was designed to investigate the role of local consolidative radiotherapy in patients with limited mUBC and without progression following the initial phase of first-line systemic therapy. Methods: This is a phase II, multicenter, randomized open-label and comparative study. Patients with mUBC (excluding brain and liver metastases), without progression following standard first-line systemic therapy according to RECIST v1.1, and with no more than 3 residual metastatic lesions on 18FDG-PET scanner and/or contrast-enhanced CT-scanner are eligible for the study. After the completion of systemic treatment, an estimated 130 patients will be randomized in a 1:1 ratio between consolidative local treatment (pelvic radiotherapy +/- previous transurethal resection of bladder tumor, associated with stereotactic body radiotherapy (SBRT) to the residual metastases) plus standard of care (arm B) and standard of care only (arm A). Stratification is performed based upon: the center, the ECOG performance status, the administration of immunotherapy or not, the number of residual metastatic lesions and the imaging modality for assessment of the number of residual lesions. To date, standard of care for this population is maintenance treatment with avelumab. Radiotherapy regimens consist in conventionally fractionated (64Gy in 32 fractions) or hypofractionated (55Gy in 20 fractions) irradiation of the bladder, optional pelvic nodes irradiation, and 3 to 5 fractions of 6 to 18 Gy in SBRT for metastases, depending on the location. The main objective is to detect an increase in 20-month overall survival rate following chemotherapy from 50% (based upon the JAVELIN 100 trial) to 66%; this corresponds to a hazard ratio of 0.6. A total of 83 events are necessary for 85% power to detect this difference if it is true using a one-sided logrank test at the 10% of significance. Target difference, type I and II error rates are relaxed and compatibles with recommendations for comparative phase II trials. Key secondary endpoints are progression free survival, safety and quality of life. To date, one patient has been enrolled and eight centers are open for accrual. Clinical trial information: NCT04428554.

Retroperitoneal Robot-Assisted Partial Nephrectomy (rRAPN): Surgical Technique and Review.

We aim to offer a description of the surgical technique and to review the current state retroperitoneal robot-assisted partial nephrectomy (rRAPN). Partial nephrectomy is the standard treatment for localized kidney tumours. rRAPN is especially useful for kidney tumours of posterior location. It offers advantages such as direct access to the renal artery and no need for bowel mobilization. The disadvantages are the small working space and the less familiar anatomical landmarks. It is a reproducible technique that achieves similar oncological and functional results to the more traditional transperitoneal route (tRAPN). High-quality randomized studies are needed to ascertain the role of new technologies as modern high-flow insufflation systems, intracavitary ultrasound, 3D planning, and augmented reality (AR), in the performance of this operation. rRAPN is especially useful for kidney tumours of posterior location. Robotic surgeons ideally should become familiar with both approaches, transperitoneal or retroperitoneal.

MK-6482 as a potential treatment for von Hippel-Lindau disease-associated clear cell renal cell carcinoma

ABSTRACT Introduction Von Hippel-Lindau (VHL) disease is an inherited autosomal dominant syndrome caused by a germline mutation and/or deletion of the VHL gene. Inappropriate hypoxia-inducible factor (HIF)-mediated transcription of proangiogenic and metabolic genes leads to the development of tumors and cysts in multiple organs. Surgery is a standard treatment for localized tumors with a risk of metastasis or organ dysfunction. Repeated surgeries cause substantial morbidity and have a major impact on quality of life. There is an urgent need to develop effective and safe systemic treatments for VHL disease manifestations. The small-molecule HIF 2 alpha inhibitor MK-6482 (belzutifan) has demonstrated significant efficacy in VHL disease related renal cell carcinomas, hemangioblastomas, and pancreatic neuroendocrine tumors while demonstrating an acceptable safety profile. Areas covered This paper reviews the development of the HIF-2 alpha inhibitor, MK-6482, and discusses preliminary results of ongoing phase I/II studies in renal cell carcinoma (RCC) and VHL disease. An examination of ongoing clinical development of MK-6482 and perspectives on potential future developments and challenges are offered. Expert opinion Because of its favorable safety profile, its clear efficacy in VHL disease, promising findings in sporadic, advanced RCC, and convenient oral formulation, MK-6482 is expected to become a leading treatment for VHL disease. Among other currently available oral agents, we believe that MK-6482 will be a preferred treatment for VHL-associated RCC.

Effective Treatment for Primary Locally Aggressive Intermediate and Malignant Soft Tissue Tumors of the Breast

ObjectiveThis study aimed to examine the rare locally aggressive intermediate tumors and malignant primary breast mesenchymal tumors in patients receiving surgical treatment.Summary of background dataLocally aggressive intermediate tumors were subdivided into nonmetastasizing and rarely metastasizing, and the malignant group was subdivided as a single subgroup called able to metastasize. A retrospective examination of surgical notes and clinical charts was carried out reviewing gender, age, symptoms, duration of symptoms, tumor size, clinical presentation, radiation history, kind of surgery undergone, adjuvant radiotherapy, adjuvant chemotherapy, local recurrences, systemic metastases, and mortality.ResultsMitotic index and Ki-67 were statistically different between locally aggressive and malignant groups (P &amp;lt; 0.001). One local recurrence occurred in only 1 patient diagnosed as dermatofibrosarcoma protuberans among all patients. None of the entities showed distant metastasis or mortality. In this result, clear margin of surgery in locally aggressive intermediate group and combination of surgery with radiation therapy in the malignant group was the most important determinant for the prospect of the patients with mean follow-up of 28 months.ConclusionThe main treatment for localized mesenchymal breast tumors is surgery. When the disease is locally advanced or malignant with high mitotic index, radiotherapy with surgery is predominantly used. Targeted therapies are promising with the limited place of chemotherapy.

Combining Gold Nanoparticles with Other Radiosensitizing Agents for Unlocking the Full Potential of Cancer Radiotherapy.

About half of cancer patients (50%) receive radiotherapy (RT) for the treatment of local tumors. However, one of the main obstacles in RT is the close proximity of adjacent organs at risk, resulting in treatment doses being limited by significant tissue toxicity, hence preventing the necessary dose escalation that would guarantee local control. Effective local cancer therapy is needed to avoid progression of tumors and to decrease the development of systemic metastases which may further increase the possibility of resection. In an effort to do so, radiosensitizing agents are introduced to further increase damage to the tumor while minimizing normal tissue toxicity. Cisplatin and docetaxel (DTX) are currently being used as radiation dose enhancers in RT. Recent research shows the potential of gold nanoparticles (GNPs) as a radiosensitizing agent. GNPs are biocompatible and have been tested in phase I clinical trials. The focus will be on exploring the effects of adding other radiosensitizing agents such as DTX and cisplatin to the GNP-RT platform. Therefore, a combined use of local radiosensitizing agents, such as GNPs, with currently available radiosensitizing drugs could make a significant impact in future RT. The ultimate goal is to develop treatments that have limited or nonexistent side effects to improve the quality of life of all cancer patients.

Oncolytic adeno-immunotherapy modulates the immune system enabling CAR T-cells to cure pancreatic tumors

High expression levels of human epidermal growth factor receptor 2 (HER2) have been associated with poor prognosis in patients with pancreatic adenocarcinoma (PDAC). However, HER2-targeting immunotherapies have been unsuccessful to date. Here we increase the breadth, potency, and duration of anti-PDAC HER2-specific CAR T-cell (HER2.CART) activity with an oncolytic adeno-immunotherapy that produces cytokine, immune checkpoint blockade, and a safety switch (CAdTrio). Combination treatment with CAdTrio and HER2.CARTs cured tumors in two PDAC xenograft models and produced durable tumor responses in humanized mice. Modifications to the tumor immune microenvironment contributed to the antitumor activity of our combination immunotherapy, as intratumoral CAdTrio treatment induced chemotaxis to enable HER2.CART migration to the tumor site. Using an advanced PDAC model in humanized mice, we found that local CAdTrio treatment of primary tumor stimulated systemic host immune responses that repolarized distant tumor microenvironments, improving HER2.CART anti-tumor activity. Overall, our data demonstrate that CAdTrio and HER2.CARTs provide complementary activities to eradicate metastatic PDAC and may represent a promising co-operative therapy for PDAC patients.

Intravesical Recurrence After Radical Nephroureterectomy of Upper Urinary Tract Urothelial Carcinoma: A Large Population-Based Investigation of Clinicopathologic Characteristics and Survival Outcomes.

Background: Of patients with upper urinary tract urothelial carcinoma (UTUC), 22–47% developed bladder recurrence after radical nephroureterectomy. Furthermore, the effect of surgery for UTUC-bladder cancer (BC) has not been well validated. The aim of this study was to assess the impact of standard primary BC surgical strategy on survival of patients diagnosed with UTUC-BC.Patients and Methods: A total of 676 UTUC-BC patients and 197,753 primary BC patients diagnosed from 2004 to 2016, were identified based on the SEER database. The Kaplan-Meier method and the Fine and Gray competing risks analysis were performed to assess overall survival (OS) and cancer-specific mortality (CSM). Multivariate Cox regression model and competing risks regression model were used to identify independent risk factors. Propensity score matching (PSM) was also performed to adjust potential confounding factors.Results: The baseline characteristics and survival outcomes of the two BC patient cohorts are quite different. For UTUC-BC patients, no significant difference in OS (NMIBC: p = 0.88; MIBC: p = 0.98) or cumulative incidence of CSM (NMIBC: p = 0.12; MIBC: p = 0.96) were noted for various surgical procedures. Local tumor treatment and partial cystectomy for UTUC-NMIBC patients produced lower 1-year (6.1%) and 3-year CSM (16.2%). Radical cystectomy for UTUC-MIBC patients produced lower 1-year (11.8%) but higher 3-year CSM (62.7%). After PSM for covariates, UTUC-BC patients still had a worse prognosis after surgery compared with primary BC patients. Based on regression models, older age, advanced T stage, N positive disease, M positive disease, and shorter interval between UTUC and BC were identified as independent risk factors for UTUC-BC patients.Conclusion: Standard primary BC surgical strategy did not provide significant survival benefit for UTUC-BC patients. Compared with primary BC patients, UTUC-BC patients had a worse prognosis after surgery, suggesting that current primary BC surgical guidelines are not entirely appropriate for UTUC-BC patients. Our findings underscore the continued importance and need for better prognosis and improved guidelines for management of UTUC-BC patients.

Correction: High intensity focused ultrasound: a future alternative to surgery for the treatment of localized pancreatic tumors?

Correction: High intensity focused ultrasound: a future alternative to surgery for the treatment of localized pancreatic tumors?

Role of consolidative radiotherapy for metastatic urothelial bladder cancer patients without progression and with no more than five residual metastatic lesions following first line systemic therapy: A retrospective analysis.

454 Background: Consolidative local treatment of the primary tumor and metastases in the treatment of metastatic malignancies has shown promising results in several types of primary tumors. The aim of this study is to assess consolidative radiotherapy to the bladder and to residual metastases among metastatic urothelial bladder cancer with no progression following first line systemic therapy, hypothesizing an increase in overall survival and in progression free survival. Methods: Between January 2005 and December 2018, patients who received standard first-line chemotherapy for the treatment of metastatic urothelial bladder cancer (mUBC) were retrospectively identified through the database of four Comprehensive Cancer Centers in France. Among them, patients with no disease progression following chemotherapy and with no more than 5 residual metastases were analyzed: patients who received subsequent radiotherapy (of EQD2Gy &gt; 50Gy) to the bladder and residual metastases were included in the consolidative group (RT group), and the other patients were included in the observation group (OBS group). PFS and OS were determined from the start of the first-line chemotherapy using the Kaplan-Meier method. To account for the delay from chemotherapy initiation to consolidative radiotherapy, a Cox model with time-dependant covariates, and a 6-month landmark analyses were performed to examine OS and PFS. Results: A total of 91 patients with at least stable disease following chemotherapy and with no more than 5 residual metastases were analyzed: 51 in the RT group and 40 in the OBS group. Metachronous metastatic disease (following definitive treatment of localized UBC) was more frequent in the OBS group (19% vs 5%, p = 0.02); the median number of metastases in the RT group vs in the OBS group was: 2 (1-9) vs 3 (1-5) (p = 0.04) at metastatic presentation, and 1 (0-5) vs 2 (0-5) (p = 0.18) after completion of chemotherapy (residual lesions), respectively. Two grade 3 toxicities (3.9%) and no grade 4 toxicity were reported in the RT group. With a median follow up of 85.9 months (95% IC [36.7; 101.6]), median OS and PFS were 21.7 months (95% IC [17.1; 29.7]) and 11.1 months (95% IC [9.9; 14.1]) for the whole cohort, respectively. In multivariable analysis: consolidative RT in comparison with observation was associated with improved OS in both the standard analysis (HR = 0.47, p = 0.015) and in the 6-month landmark analysis (HR = 0.48, p = 0.026); and with improved PFS only in the standard analysis (HR = 0.49, p = 0.007). Conclusions: Consolidative radiotherapy for mUBC patients who have not progressed after chemotherapy and with limited residual disease seems to confer both OS and PFS advantage. Prospective data in that field with addition of avelumab are needed.