Salvage Setting Research Articles

Real World Data on Treatment of Acute Myeloid Leukemia (AML) in a Private Healthcare Institution in Brazil, a Low-Middle Income Country - Importance of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Introduction: Treatment of patients with AML has evolved in the past decade, with development of novel drugs and increased knowledge about the genetic basis of disease. However, results of therapy in AML in LMICs have lagged those seen in more developed countries. A recently published paper highlighted the worse outcome of pts with AML treated in two public healthcare hospitals in Brazil compared with pts treated at an academic center at Oxford, UK, with lower overall survival (OS), lower rates of HSCT and a longer time to HSCT. 1 We hypothesized, however, that better outcomes could be seen in private healthcare institutions in Brazil with a higher rate of HSCT in first remission. Methods: We reviewed medical records of 122 patients with a diagnosis AML treated at Hospital Israelita Albert Einstein in São Paulo, Brazil, from 2010 until 2023. OS was defined as time from diagnosis until death from any cause and estimated by the Kaplan-Meier method. Risk was evaluated by the ELN 2022 risk classification. Results: A total of 122 consecutive patients were included. Median age was 63 years (range 24-91 years), and 45% were female. Per the ELN 2022 risk classification, 17% of patients were low risk, 33% were intermediate risk and 50% were considered high risk cases. Intensive chemotherapy was used in 62.5% of cases, while low-intensity regimens were employed in 37.5% of cases, including venetoclax in 21.4% of patients. After a median follow-up of 36 months, median OS of the whole cohort is 25.2 months (95% CI 19.2-83.8 months), and 3-years OS is 44% (95% CI 34-55%). As expected, patients in the high 2022 ELN risk category had lower 3-years OS probability (15.6% vs. 47.3%/91.6% for intermediate- and low-risk, respectively). Eighty-two patients (67.2% of the cohort) underwent HSCT, and 59% were in MRD-negative complete remission (CR) prior to HSCT. We next analyzed outcomes in patients younger than 60 years of age who received intensive chemotherapy, the subset of patients analyzed by Silveira et al. 1 Results are summarized in Table 1 and figure 1. The outcomes of our patients compare favorable to what has been reported here in Brazil and, like the data from the UK center, has a high rate of HSCT with a low time to transplant. Conclusion: Our results demonstrate that it is feasible to obtain favorable outcomes in patients with AML in a LMIC with a high rate of HSCT in first CR. It is also important to mention that our results also reflect the reality of a private healthcare institution in Brazil. However, even after considering this, our results carry an important message. There is limited availability of clinical trials and novel medications for AML in LMICs compared to the developed world, and options in the salvage setting are usually limited to intensive chemotherapeutic regimes. Allogeneic HSCT is a technique that is readily available in most countries and has the potential to cure AML, particularly when employed in first CR. We believe that physicians and institutions treating patients with AML in a LMIC should primarily focus on strategies that improve access to HSCT in first CR for these patients.

Comparison of Hematopoietic Stem Cell Transplantation and Repeated Immunosuppressive Therapy As Second-Line Treatment for Relapsed/Refractory Severe Aplastic Anemia

The optimal treatment for patients with severe aplastic anemia (SAA) who fail or have relapse after an initial course of immunosuppressive therapy (IST) has not been established. We conducted a retrospective study to compare the effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n = 36) with repeated IST (n = 33) as salvage therapy for relapsed/refractory SAA between 2007 and 2022. In the repeated IST group, patients were treated with antithymocyte globulin (ATG) (n = 16) or high-dose cyclophosphamide (HD-CTX) (n = 17). The overall response rate was 42.4% at 6 months, and 60.6% at 12 months. In the HSCT group, 6 were matched sibling donor (MSD), 7 were matched unrelated donor (MUD), and 23 were haploidentical donor (HID). All patients achieved neutrophil engraftment and no primary graft failure was observed. The rate of platelet engraftment was 88.9%, with a median time of 16 days. The cumulative incidences of grade II-IV, III-IV acute GVHD was 36.1% ± 0.7%, 13.9% ± 0.3% at day +100, and chronic GVHD was 36.2% ± 0.7% at 5 years. Compared with IST, HSCT recipients showed much higher hematologic recovery rate at 3-, 6- and 12-months post treatment (63.9%, 83.3% and 86.1%, respectively, P < 0.001). The estimated 5-year overall survival (OS) (79.8% ± 6.8% vs. 80.0% ± 7.3%, p = 0.957) were similar; however, the estimated 5-year failure-free survival (FFS) was significantly better in the HSCT group (79.8% ± 6.8% vs. 55.2% ± 9.2%, p = 0.049). In multivariate analysis, age ≤ 35 years at salvage HSCT was the only favorable factor for OS and FFS ( p = 0.019, 95% CI 0.019-0.706). These results suggest that HSCT and repeated IST are both effective for refractory/relapsed SAA in the salvage setting. Considering the superior FFS in the HSCT cohort, especially in younger patients (age ≤ 35 years), we recommend HSCT instead of a second IST for these patients.

Cladribine-Based Chemotherapy for Patients with Secondary Acute Myeloid Leukemia (AML) Arising after Myeloproliferative Neoplasms (MPNs)

Introduction: Patients with acute myeloid leukemia (AML) evolving from myeloproliferative neoplasms (MPN) have poor survival with median of 4-6 months and limited therapeutic options that could induce up to 60% of overall responses, but they are usually transient. Cladribine added to a backbone regimen of high dose cytarabine [≥ 1 gram per m2 intravenously (IV) for up to 5 days] and idarubicin (CLIA; further HD-clad) or low dose cytarabine [LDAC; 20 mg twice daily subcutaneously (SQ) for up to 10 days] alternating every two cycles with hypomethylating agent (HMA; regimen referred as LD-clad) have been routinely used in the treatment of AML at our institution. Objectives: We sought to investigate the efficacy and outcome of using HD-clad or LD-clad in patients with AML arising from MPN at our center. Methods: This is a retrospective chart review of patients with AML after previous MPN who were treated with clad-based regimen at our center and had comprehensive clinical data, including next generation molecular sequencing at AML diagnosis (≥ 28-gene myeloid panel). Since HMA-based therapy is often utilized early in MPN patients with accelerated (blasts up to 20%) or blast phase (blasts ≥20 %), and since HMA-treatment can affect outcomes, we separately evaluated patient's outcomes based on their prior exposure to HMA. Responses were according to the 2007 ELN criteria for AML and overall survival was measured from therapy initiation for AML (Kaplan-Meier method with log-rank test). Results: The cohort includes 50 patients (median age 68 years, range 28-83; 66% males); 72%, 18%, and 10% received clad-based therapy as induction (frontline, FL), salvage 1 and salvage 2+, respectively. Among the 36 FL patients, 23 (64%) received LD-clad and 13 (36%) HD-clad regimen. 30% and 38% of patients treated with FL LD-clad and FL HD-clad were previously exposed to HMA therapy; the remaining patients were HMA-naïve. All patients in the salvage (S) setting were pre-treated with HMA. Patients' characteristics at the time of AML therapy initiation are depicted in Table 1. Median time between the diagnosis of MPN and clad-based AML therapy was 62 months (range, 1-299) for FL and 137 months (range, 26-263) for S settings. 64% of patients on FL therapy had advanced grade of reticulin fibrosis, 44% had complex cytogenetics and 56% had JAK2 mutation. Additional co-mutations were detected in 78% of FL patients, the most common (in descending order) being ASXL1, RAS, RUNX1 and TP53. Patients treated with FL HD-clad were significantly younger (median age of 61 vs 72 years for patients on FL LD-clad, p = 0.03, respectively). LD-clad was more common as FL therapy, and was used in 67% of HMA-naïve and 58% of HMA-exposed patients. The complete remission rate with and without count recovery (CR & CRi) for FL HD-clad was 62%: 75% in HMA naïve and 40% in HMA-exposed patients. CR/CRi for FL LD-clad was 43%; 50% in HMA naïve and 29% in HMA-exposed patients. 75% and 50% of patients without previous HMA-exposure were able to proceed with allogeneic stem cell transplantation (SCT) after FL HD-clad and FL LD-clad, respectively. The median OS of 30 months (95% CI, 7-unreached) was the longest in HMA-naïve patients treated with FL HD-clad regimen (Figure; median OS censored for SCT was 15 months, range: not estimated - 24). The median OS for salvage pts treated with LD-clad and HD-clad were 3.25 and 1.85 months, respectively. Among 38 patients without SCT, 10 (26%) lived for more than 12 months since therapy initiation, including 2 patients in the salvage setting. Conclusion: Cladribine added to chemotherapy is an effective approach in patients with AML from MPN, either as an induction therapy for those eligible for SCT or acceptable long-term therapy for non-eligible patients. Noticeably, almost 40% of patients without SCT were alive past 12 months since the initiation of LD-clad therapy. HMA pretreated patients had lower response rates and poor survival even in the frontline setting.

Percutaneous CT-Guided Cryoablation for Locally Recurrent Prostate Cancer: Technical Feasibility, Safety, and Effectiveness

PurposeTo assess the feasibility and safety of using computed tomography (CT) guidance for ablation of prostate cancer in the salvage setting. Materials and MethodsThis institutional review board–approved retrospective study of consecutive patients who presented with prostate cancer recurrence and underwent percutaneous CT-guided cryoablation was conducted between July 2020 and September 2022. A total of 18 patients met the inclusion criteria, and a total of 19 procedures were performed. Demographic details; preablation and postablation urinary, rectal, and erectile function assessment; procedure details; and preoperative and postoperative imaging findings and prostate-specific antigen (PSA) values were recorded. ResultsThe mean treated tumor size was 15.7 mm ± 6.2. Technical success was achieved in 18 of the 19 procedures (94.7%), with 1 procedure aborted due to inability to obtain a safe plane. The mean follow-up time was 10.0 months (range, 2.3–26.7 months) at the time of manuscript preparation. The mean PSA before ablation was 8.1 ng/mL ± 9.3, and postablation PSA nadir was 2.6 ng/mL ± 4.0 (P = .002). Of the 18 patients who had postoperative imaging, 16 (88.9%) had a complete response (ie, no evidence of residual disease), and 2 (11.1%) patients had residual disease. Overall, 16 (88.9%) of the 18 treated patients demonstrated a PSA and/or imaging response to ablation. Mild adverse events occurred in 4 (22%) of the 18 cases. ConclusionsCT-guided cryoablation appears to be a technically feasible, safe option for treating locally recurrent prostate cancer.

Immunohistochemistry-Based Biomarkers and Impact on Outcomes Following Salvage Radiotherapy for Prostate Cancer.

Salvage radiation therapy (SRT) is a mainstay of treatment for prostate cancer patients who experience biochemical relapse following radical prostatectomy. We sought to characterize the prognostic impact of previously identified deleterious molecular phenotypes-loss of PTEN, ERG expression, and p53 mutation- upon survival in patients undergoing SRT. We analyzed an institutional database of 320 patients treated with SRT for whom prostatectomy tissue was available; tissue microarrays (TMAs) were constructed and used for genetically validated immunohistochemistry assays for PTEN, ERG, and p53. Chi-squared and Mann-Whitney's tests were used to assess association between molecular expression and clinical risk factors for adverse survival. Uni- and multivariate Cox-proportional hazards models were constructed to determine effects on biochemical (bRFS) and metastasis-free survival (MFS), calculated from end of SRT to event. Loss of PTEN (n = 123, 50%) and ERG expression (n = 118, 39.1%) were common, while p53 overexpression (signifying TP53 missense mutation) was less common (n = 21, 6.6%). On univariate Cox regression, loss of PTEN portended worse bRFS [HR 1.86; 95% CI 1.36-2.57] and MFS [HR 1.89; 1.21-2.94], with homogeneous loss associated with particularly worse MFS [HR 2.47; 1.54-3.95]. Similarly, p53 overexpression predicted worse bRFS [HR 1.95; 1.14-3.32] and MFS [HR 2.79; 1.50-5.19]. ERG expression was associated with only worse MFS [HR 1.6; 1.03-2.48]. On multivariate analysis adjusting for known prognostic features (grade, nodal involvement, pathologic stage, androgen deprivation therapy (ADT), and PSA velocity), homogeneous PTEN loss remained predictive of adverse bRFS [HR 1.73; 1.06-2.82] and MFS [HR 2.35; 1.04-5.34]. PTEN loss identified by immunohistochemistry is an independent adverse prognostic factor for both biochemical and metastasis-free survival in prostate cancer patients treated with SRT. Although clinically validated RNA expression assays also exist which are prognostic for outcomes following SRT, stromal contamination in bulk RNA could mask "loss" signals specific to tumor cells, such as PTEN. Further work is necessary to determine the optimal approach to treating patients with poor molecular prognostic features in a salvage setting.

The Role of Radiation Therapy in the Management of Gray Zone Lymphoma.

Gray zone lymphoma (GZL) is a relatively rare disease predominantly affecting young adults with purportedly poor outcomes with current treatment approaches. The role of radiation therapy (RT) in the management of GZL is not well established. This is the largest study to report on the outcomes of GZL patients treated with and without RT. A retrospective review of 30 patients with GZL treated across 3 institutions from 2009 to 2021 was performed. Event-free survival (EFS) was defined from initiation of frontline chemotherapy (CHT) to disease progression/relapse, initiation of salvage therapy, or death. Local control (LC) was defined from RT start date to in-field recurrence. The median age was 32 (range: 18-86) years, and 16 (53%) patients had early stage (I-II) disease. Bulky mediastinal disease was present in 63% of patients, and the median tumor diameter was 10 (range: 1.5-18) cm. Patients received ABVD (20%), RCHOP (33%), or REPOCH (47%) as frontline CHT. Among 25 patients with interim PET/CT scan, there were 6 rapid early responders and 14 slow early responders (SER), with 2-year EFS of 33% and 24%, respectively (p = 0.13). After the completion of CHT, 15 (50%) patients achieved complete response (CR) and 10 (33%) achieved partial response (PR), with 2-year EFS of 46% and 10%, respectively (p = 0.004). RT was given to 9 patients in CR (n = 3) or in PR (n = 6). The median RT dose was 36 (30.6-48.6) Gy, at 1.8-2 Gy/fraction. Those receiving RT had bulkier disease at diagnosis (p = 0.049) and lower rates of CR following CHT (p = 0.03). After RT, 3/6 (50%) PR patients converted to CR. At a median follow-up of 4 years, the 2-year EFS was 26% for all patients, 33% for RT and 23% for noRT (p = 0.44). Among patients who did not receive upfront RT and experienced progression (n = 17), 16 (94%) relapsed in pre-existing sites. The 5-year OS was 80% for all patients, 88% for RT and 78% for no RT (p = 0.63). Patients who achieved PR to CHT and received RT had better 2-year EFS (17% vs 0%, p = 0.007) compared to patients who did not receive RT. Similarly, patients with SER who received RT had superior 2-year EFS (33% vs 13%, p = 0.038). Patients with bulky mediastinal disease had a 2-year EFS of 43% with RT and 11% without RT (p = 0.08). After 1st line treatment, 22 (73%) patients relapsed and 18 were successfully salvaged with a sustained CR. The most common salvage regimen involved high dose CHT followed by hematopoietic cell transplantation (HCT) (n = 15). RT was given for 7 patients in the relapsed/refractory setting (consolidative peri-HCT n = 4; definitive salvage n = 3) and 5 (71%) achieved a sustained CR. Among the 16 patients who received RT in the upfront (n = 9) or salvage (n = 7) setting, 3 patients experienced in-field recurrence translating to 2-year LC of 79%. GZL patients have high risk of relapse and maximal upfront combined modality therapy should be considered. RT provides good local control and improves EFS particularly for SER, PR, and bulky mediastinal disease.

Focal Brachytherapy for Localized Prostate Cancer: Systematic Review and Meta-Analysis

Advances in image-guided brachytherapy have increased the interest in focal brachytherapy (F-BT) approaches to optimize disease control, while reducing the toxicities associated whole gland treatments for prostate cancer (PCa). In this study we performed a systematic review to report biochemical control (BC), and genitourinary (GU) and gastrointestinal (GI) toxicity rates in patients with localized prostate cancer treated with F-BT as a definitive or salvage modality. This project was registered in the PROSPERO database (ID CRD42022320921). A comprehensive literature search was conducted in Cochrane Central databases, Cochrane Database of Systematic Reviews, Embase Classic +Embase, and Medline ALL, all from the OvidSP platform and Web of Science from Clarivate, from each database's inception to July 2022. Search was restricted to English and included terms: focal brachytherapy/prostate cancer, partial brachytherapy/prostate cancer. In total, 14862 articles were identified. Manuscripts that not related to focal or partial prostate brachytherapy, review papers and studies not reporting BC were excluded. After eliminating duplicates, and studies deemed irrelevant by consensus among three independent reviewers, 44 articles remained for in-depth review and data extraction. Thirty studies that included BC outcomes were included for this analysis, comprising 1556 patients treated with F-BT for PCa. Of these, 1094 (70%) and 462 (30%) underwent F-BT as definitive monotherapy or salvage, respectively; while 585 (38%) and 971 (62%) received HDR or LDR, respectively. For F-BT as monotherapy, the most commonly prescribed dose for HDR was 19 Gy in 1 fraction (range 19-24 Gy), and for LDR, 145 Gy (90-160Gy). Whereas for salvage F-BT, most common dose schedule of HDR was 19Gy in 1 fraction (19-27GY) and LDR 145Gy (144-145Gy). BC random effects estimate for F-BT monotherapy at 1-, 2-, 3-, and 5-years were 100% (P = 1.0), 96% (P = 0.45), 91% (P = 0.45) and 87% (P< 0.01), respectively. Whereas BC random effects estimate for salvage at 1-, 2-, 3-, and 5-years were 91% (P = 0.86), 68% (0.17), and 57% (P = 0.20), respectively. GI and GU grade 3-4 crude toxicity rates for monotherapy and salvage ranged from 0-3.33% and 0-17%, respectively. Over the last decade, there has been increasing interest in F-BT approaches, both as monotherapy and in the salvage setting. BC and toxicity profiles of F-BT appear favorable, and future studies directly comparing with whole-gland treatments are warranted.

Holmium-166 Radioembolization of Hepatic Metastases in Salvage Setting: Preliminary Findings from a Single Center Experience

Abstract Purpose The aim of this study is to report the early outcomes of holmium-166 (166Ho) radioembolization in the treatment of liver metastases. Methods Nine patients with liver metastases originating from different primary sites were treated with 166Ho radioembolization between January 2019 and February 2020. The patients were assessed for pain using a visual analog scale (VAS) and quality of life (QoL) at various intervals during hospitalization and follow-up. Toxicity that may be attributable to radioembolization was graded according to CTCAE v5.0. The tumor dosimetry and tumor response were assessed with anatomic and metabolic imaging. Results The mean tumor dose was 150 Gy, 95% confidence interval (CI) was 135.2 to 164.8, with a range of 100 to 200 Gy based on single-photon emission computed tomography (SPECT)/CT, and distribution verified with inline T2/R2* magnetic resonance imaging (MRI) maps. No early (30-day) mortality or grade greater than 2 toxicities were noted, but one patient had chylous ascites. QoL assessed with the European Quality of Life 5-Dimensions 3-Level version (EQ-5D-3L) revealed mean index scores of 0.748 (range: 0.5–1), 95% CI of 0.6 to 0.9, before the procedure, and 0.7 (range: 0.5–1) and 95% CI of 0.6 to 0.8, at 1 month. The mean VAS was 70.6, 95% CI was 65.5 to 75.6, immediately after the procedure, and decreased to the mean VAS of 65.7 and 95% CI of 55.9 to 75.5 after 1 month. Five patients showed a partial response, three showed a stable disease, and one showed progressive disease at the first 2- to 3-month imaging follow-up. Conclusion Radioembolization with 166Ho microspheres for liver metastases appears to be safe, tolerable, and effective during the short term in this small-scale study.

Fms-like tyrosine kinase 3 positive acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) mutations are common in newly diagnosed patients with acute myeloid leukemia (AML). They are associated with a high risk of relapse. The identification of FLT3 mutations has important implications for the management of AML. FLT3 inhibitors have shown improved outcomes in FLT3-positive AML when used as a single agent in the salvage setting. However, the combination of inhibitors and chemotherapy in the first-line setting is the real game changer in FLT3mutant AML. The introduction of these drugs has improved the prognosis of FLT3-mutant AML, but the development of resistance is common. There are still many unanswered questions about FLT3-mutant AML. This article will analyze recent advances for FLT3-mutant AML, focusing on front-line therapy and post-transplant maintenance. Novel drug combinations and strategies against FLT3 mutated AML are currently under investigation and will be the focus of future studies. The development of more selective and potent FLT3 inhibitors may further improve outcomes for patients with FLT3-positive AML. Monitoring minimal residual disease and overcoming resistance are key issues for the future.

Randomized phase II trial of MRI-guided salvage radiotherapy for prostate cancer in 4 weeks versus 2 weeks (SHORTER)

BackgroundUltra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment.MethodsA total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator’s discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival.DiscussionThe SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions.Trial registrationClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020.

Early Mortality as a Quality Indicator in Frontline and Salvage Acute Myeloid Leukemia

BackgroundEarly mortality is a historical measure of the quality of care incorporated into many quality measure algorithms that mostly account for patient comorbidities but do not incorporate disease characteristics and treatment status which independently increase early mortality. This is particularly significant in leukemia, especially in the refractory and salvage settings. Study AimTo define the independent adverse effect of leukemia salvage vs. frontline therapy on early mortality in acute myeloid leukemia (AML) after accounting for the pretreatment independent adverse effects associated with early mortality. Patients and MethodsA total of 4151 patients with AML were analyzed, 2893 newly diagnosed and 1258 in salvage. Univariate and multivariate analyses (MVA) were conducted to determine the independent adverse effects associated with 8-week mortality. ResultsThe 8-week mortality was 13% in frontline therapy and 18% in salvage therapy. By MVA, older age; therapy-related AML; prior history of myelodysplastic syndrome; poorer performance status; high white blood cell count; lower platelet count; higher percent of peripheral blasts; lower albumin levels; higher bilirubin, creatinine, and lactate dehydrogenase levels; and adverse cytogenetic risk groups were independently associated with a higher 8-week mortality rate. Adding treatment status after accounting for the independent adverse variables still selected salvage status as significantly adverse for 8-week mortality (hazard ratio 1.954; P-value < .001). ConclusionsQuality measure algorithms should incorporate a risk mortality index related to leukemia vs. other tumors and benign conditions and a risk mortality index related to the treatment status of leukemia (salvage vs. frontline therapy).

Complications following salvage transoral robotic surgery with and without reconstruction: A systematic review of the literature

BackgroundTransoral robotic surgery (TORS) has been used in the salvage setting for head and neck cancers both with and without reconstruction. The complications of salvage TORS and the effect of reconstruction on complications has not been studied. ObjectiveTo study the complications of salvage TORS and examine the effect of reconstruction on complication rates.Method:An electronic search of the English- language literature using PubMed, Medline, and the Cochrane database was conducted and a systematic review performed in accordance with PRISMA guidelines (CRD42020181057). ResultsA total of 23 studies including 533 patients have been published on salvage TORS.The average patient age was 61.2 years.Prior treatment was described for 420 patients.205 (48.8%) underwent prior definitive radiotherapy (RT).160 (38.1%) underwent definitive chemoradiotherapy (CRT).Only 55 (13.1%) had prior surgery.Overall, there were 158 complications with a pooled rate of 33.6% (95%CI: 25.4–42.3%).77 were major complications requiring surgical intervention with a pooled rate of 18.9% (95% CI: 14.8–23.3%).The number of patients undergoing reconstruction among salvage cases in the literature is 59 (9.19%), with 24 local flaps and 25 microvascular free flaps.Reconstruction was associated with lower overall hemorrhage rates but had no impact on major hemorrhage rates. ConclusionsThe pooled incidence rates of major complications, major POH and emergency tracheostomy following salvage TORS are 18.9%, 10.5%, and 4.4%.The rate of death following salvage TORS is 3.6%. Reconstruction was associated with lower overall hemorrhage rate after salvage TORS but had no impact on major postoperative hemorrhage rates.

Radical cystectomy in bladder cancer patients previously treated for prostate cancer: Insights from a large European multicentric series

IntroductionPrevious radical prostatectomy (RP) for prostate cancer (PCa) might impair feasibility of radical cystectomy (RC) for bladder cancer (BCa). The current study addressed morbidity, operative time (OT), and length of stay (LOS) of RC, within the largest available series of patients with history of previous RP. Materials and methodsAll patients previously submitted to RP for PCa and subsequently submitted to RC for BCa, at six high-volume European institutions between 2010 and 2019, were identified. Presence of either PCa or BCa metastases, RT as primary treatment for PCa, and palliative RC represented exclusion criteria.The quality criteria for accurate and comprehensive reporting of intra- and post-operative surgical outcomes, recommended by the European Association of Urology guidelines, were fulfilled. Multivariable logistic and Poisson regression analyses were performed. ResultsOverall, 140 RC patients with history of RP were identified. After RP, 69 (49%) patients received radiotherapy (RT) for PCa, either in adjuvant (n = 50, 36%) or salvage setting (n = 19, 13%). Median age-adjusted Charlson comorbidity index was 6 (IQR 5, 7). Median OT, estimated blood loss and LOS were, respectively, 300 min, 500 ml, and 16 days. Intra-operative transfusions rate was 47% (n = 65). One intra-operative complication occurred (EAUiaiC grade 2, perforation of the rectum managed with immediate repair). Eighty-two (59%) patients experienced a total of 107 post-operative complications during the hospital stay, and seven (5%) patients required hospital readmission. In multivariable regression analyses, RT for PCa was associated with higher risk of post-operative complications (odds ratio 1.82, p = 0.039), longer OT (incidence rate ratio 1.09, p < 0.001), and longer LOS (incidence rate ratio 1.24, p < 0.001). ConclusionsRC in patients with history of RP is feasible, albeit burdened by remarkable morbidity, even in centers of excellence. RT after RP for PCa portends worse surgical outcomes.

Can salvage Retzius-sparing robotic-assisted radical prostatectomy improve continence outcomes? A systematic review and meta-analysis study.

Salvage Radical Prostatectomy is challenging and associated with high rates of incontinence. The novel Retzius-sparing RARP (RS-RARP) approach has shown impressive high immediate and 1-year continence rates (> 90%) when applied as primary treatment. The purpose of this study is to evaluate the impact of salvage Retzius-sparing RARP (sRS-RARP) on continence outcomes in the salvage scenario. Using PRISMA guidelines, a systematic review and meta-analysis of articles was conducted on Medline through PubMed and on Cochrane through Central Register of Controlled Trials databases. Inclusion and exclusion criteria were used to select 17 retrospective cohort studies published until April 2023 about sRS-RARP and continence. Data were extracted independently by at least two authors. The International Prospective Register of Systematic Reviews (PROSPERO) was registered. Retrospective studies were subjected to a domain-based risk of bias assessment in accordance with the Newcastle-Ottawa quality assessment scale cohort studies (NOS). Prostate cancer patients were chosen from prospective nonrandomized or randomized sRS-RARP or sS-RARP studies that examined continence outcomes. Seventeen studies were included: 14 were retrospectives only and 3 described retrospective comparison cohorts (sRS-RARP vs sS-RARP). All the retrospective studies were of "fair" quality using the NOS. sRS-RARP may increase recovery of urinary continence after surgery compared to sS-RARP [OR 4.36, 95% CI 1.7-11.17; I2 = 46.8%; studies = 4; participants = 87]. sRS-RARP approach has potential to improve continence outcomes in the salvage setting. sRS-RARP approach has potential to positively impact continence function on patients who underwent salvage surgery.

Phase 2 trial of intravesical cabazitaxel, gemcitabine, and cisplatin (CGC) for the treatment of non-muscle invasive BCG unresponsive urothelial carcinoma of the bladder.

TPS4616 Background: For patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacille Calmette-Guerin (BCG), multi-agent intravesical trials have been limited. The goal of this Phase 2 study is to investigate the efficacy of intravesical chemotherapy consisting of sequential cabazitaxel, gemcitabine, and cisplatin (CGC) in the salvage setting. Phase 1 results reporting on 18 subjects demonstrated adverse events limited to local Grade 1 and 2 toxicities. Partial funding support for the trial was provided by a pharmaceutical company. Methods: This is a Phase 2 trial (NCT02202772) presently enrolling patients with BCG unresponsive NMIBC as defined by the FDA who refuse or are ineligible for radical cystectomy. All patients undergo pre-treatment transurethral resection of bladder tumor (TURBT) and a 6-week regimen of intravesical cisplatin (100mg), gemcitabine (2gm), and cabazitaxel (5mg). Each drug is instilled weekly except for cisplatin, which is given every other week. Complete response is defined as having no evidence of cancer on post-induction biopsy and negative urine cytology at 3 months. Complete responders proceed with monthly and bimonthly maintenance therapy without cisplatin in the first and second years, respectively, for a total of 24 months. Results: To date thirty-one patients have been enrolled (with target accrual of 33), of whom seven are female. One patient withdrew consent before first evaluation cystoscopy. Mean age thus far is 72 years. All patients have previously received at least two prior induction cycles of BCG, and meet FDA criteria for BCG unresponsive disease. All patients have biopsy proven high grade disease at enrollment; 8 (27%) have high grade T1 disease; and 20 (67%) patients have CIS. Conclusions: Salvage options for BCG unresponsive NMIBC are limited. The CGC protocol has been demonstrated to be safe in a previous Phase 1 study, and accrual for this Phase 2 is near completion. Clinical trial information: NCT02202772 .

RADIATION THERAPY AS A BRIDGING AND SALVAGE STRATEGY IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA UNDERGOING BCMA‐TARGETED CAR T‐CELL THERAPY

Introduction: Radiation therapy (RT) may be a useful bridging and/or salvage approach prior to and following B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory multiple myeloma (MM). Thus, we sought to report our early experience evaluating the potential role of RT in bridging and salvage settings in MM patients undergoing CAR T-cell therapy. Methods: A multi-institutional retrospective study was conducted for consecutive MM patients who received CAR T-cell therapy between 2018 and 2022. Patients who were administered bridging RT pre-CAR T and salvage RT post-CAR T failure were identified and analyzed using descriptive and statistical analysis. Results: We retrospectively reviewed 13 patients who have been treated with RT pre- and/or post-CAR T-cell therapy infusion at two tertiary care centers [5 patients received bridging RT pre-CAR T, 4 patients received salvage RT post-CAR T failure, and 4 patients received both bridging and salvage RT]. A total of 17 sites were treated with bridging-RT with a median dose of 20 Gy (range, 4–24 Gy) and a median of 5 fractions (range, 1–12 fractions). Twelve sites were treated with salvage RT with a median dose/fractionation of 20 Gy (range, 4–30 Gy) and 5 fractions (range, 1–12 fractions). No worsening in CAR T-related toxicities occurred among the patients who were treated with bridging RT, and no significant RT-related toxicities were observed post-bridging or salvage RT. For the entire cohort, the median overall survival was 16.2 months (95% CI: 8.6 months-not reached), and the median progression-free survival was 4.1 months (95% CI: 1.07 months-not reached). The local control rate for patients receiving bridging RT and/or salvage RT was 100%, with a median follow-up after each RT course of 7.3 months. Conclusion: Our findings suggest that using RT as a bridging and salvage strategy is safe and feasible, and offers excellent local control among relapsed/refractory MM patients treated with CAR T-cell therapy infusion. Future larger studies with translational correlatives are required to assess the optimal role of RT in these settings. Keywords: Cellular therapies, Multiple Myeloma No conflicts of interests pertinent to the abstract.

Doxorubicin, paclitaxel, and cisplatin (ATP) for refractory germ cell tumors.

e17028 Background: Patients with refractory germ cell tumor (GCT) have limited treatment options and poor prognosis. We describe our institutional experience with doxorubicin, paclitaxel, and cisplatin (ATP) as an outpatient chemotherapy regimen for patients with refractory GCT. Methods: We performed a retrospective chart review of all patients who received ATP at our institution between August 2017 and August 2022. ATP consisted of doxorubicin 30 mg/m2, paclitaxel 100 mg/m2 over one hour, and cisplatin 30 mg/m2 every 2-3 weeks. We reviewed patient and disease characteristics including staging, histology, prior therapies, tumor marker and imaging responses. Progression free survival (PFS) and overall survival (OS) were respectively calculated from the first ATP dose date to disease progression/death and to death/last follow up. Results: A total of 39 patients with refractory GCT received ATP. Patients were 95% male, 54% white, with a mean age of 30 years (range 18-63). Prior to ATP administration, 92% of GCTs had elevated tumor markers, including 54% with elevated AFP, 56% with elevated HCG, and 18% with elevated both tumor markers. 8% of GCTs did not have elevated tumor markers at baseline. Further disease characteristics are described in table 1. Patients received a median of 2 lines of prior systemic therapies (range 1-6), including 97% with prior cisplatin-based regimens and 21% with prior high dose chemotherapy with stem cell rescue transplant. Patients received a median of 3 doses of ATP (range 1-8) with 31% for palliative intent and the rest as a bridge to transplant or other therapies. After ATP administration, 77% patients had decreased tumor markers, including 18% with tumor marker normalization. Of the 19 patients with imaging post-ATP, 53% had complete or partial response, 16% had stable disease, and 32% had disease progression. By December 2022, 79% patients had progression or death, with a median PFS of 3.8 months (95% CI: 1.94, 7.16) and median OS of 10.7 months (95% CI: 6.37, 32.69). 18% of patients experienced toxicities requiring admissions. Conclusions: Based on our retrospective single institution experience, ATP has clinical activity in refractory GCT and is associated with decreased tumor markers and imaging response in most patients. ATP is a convenient and feasible outpatient regimen and can be used in the salvage setting and as a bridge to other therapies. [Table: see text]

Primary analysis of STARTAR: A phase 2 salvage trial of androgen receptor (AR) inhibition with androgen deprivation therapy (ADT) and apalutamide with radiation therapy (RT) followed by docetaxel in men with PSA recurrent prostate cancer (PC) after radical prostatectomy (RP).

5016 Background: ADT with salvage RT improves survival for men with PSA recurrence after RP. For high risk PSA recurrence, current standard ADT duration is up to 2 years with RT; shortening but intensifying systemic therapy may improve outcomes. The STREAM trial showed 6 mo enzalutamide with ADT/RT had 3-year progression free survival (PFS) of 53% in a high risk population, including lymph node (LN) positive. Given docetaxel (doce) improves survival in mHSPC, we evaluated the combination of salvage RT, ADT/apalutamide (apa) and doce in this setting. Methods: STARTAR is a multicenter investigator initiated phase 2 trial for salvage treatment of PSA recurrent PC post-RP, conducted in the DOD Prostate Cancer Clinical Trials Consortium. Key inclusion criteria included Gleason 7 with T3/positive margin/N1 or Gleason 8-10 PC, PSA relapse &lt;4 years post-RP (inclusion PSA 0.2-4 ng/mL), and &lt;4 positive LNs, standard imaging negative. Patients (pts) received ADT with apa for 9 months, RT (66-74 Gy to the prostate bed +/- pelvic LNs over 6-8 wks) starting wk 8, and then completed 6 cycles of concurrent doce 75mg/m2 q3 wks. The primary endpoint was 36 month PFS, defined as composite of freedom from PSA&gt;0.2 + post-RT nadir with subsequent rise, clinical progression, other therapy start, or death, among pts with testosterone (T) recovery (&gt;100ng/dL). Kaplan-Meier estimates for PFS were used to determine landmark 24 mo and 36 mo rates and compared to PFS rates from prior trials using a binomial test. Results: From 3/2018 to 2/2020, 39 pts were enrolled. As of 12/2022 data cutoff, median follow up was 36 months. Baseline characteristics: Gleason 7 in 54%; Gleason 8-10 in 46%; 23% LN positive; median PSA 0.58 ng/mL (range 0.21-3.40), and median time from RP 7.6 mo (range 2-98). 37 pts (95%) and 23 pts (62%) completed at least 1 and all 6 cycles doce, respectively. All pts achieved undetectable PSA nadirs. At 24mo and 36mo, PFS rates were 84% and 72%, respectively, with 95% pts recovering T at 36 mo. Compared to 40% historical PFS and 53% STREAM PFS rates, the 72% 36-mo PFS rate was statistically significantly improved (p&lt;0.001 and p=0.013, respectively). Common any-grade adverse events (AEs) included 98% hot flashes, 88% fatigue, 77% alopecia, 57% dysgeusia, and 53% rash (28% grade 1; 15% grade 2, 10% grade 3), with 5% febrile neutropenia. Conclusions: In this first phase 2 trial of ADT, apa, salvage RT, and 6 cycles of doce for high risk PSA recurrence, the primary endpoint 3-year PFS rate improved to 72%, indicating durable remissions beyond historic controls. Intensifying systemic treatments in the non-metastatic hormone sensitive but high risk salvage setting may be feasible and efficacious, with fewer pts experiencing cancer progression over time. Clinical trial information: NCT03311555 .

Water soluble swallow for leak detection after total laryngectomy post radiotherapy.

Pharyngeal leak (PL) and pharyngocutaneous fistula (PCF) are serious complications following total laryngectomy and their incidence is higher in the salvage setting. The aim of this study is to describe the accuracy of water soluble swallow (WSS) to rule out salivary postoperative leak after salvage total laryngectomy (STL) to expedite start of oral intake. Retrospective study including patients undergoing STL between 2008 and 2021 at Guy's Hospital. WSS was routinely performed within 15days post operation. Sixty-six patients underwent STL. Nine developed clinically diagnosed PCF; one died before having WSS. Fifty-six patients underwent WSS post STL. WSS was performed within 15days after STL when no postoperative complications occurred (76.8%). Among patients undergoing WSS with no clinical suspicion for fistula (56), PL was identified in 15 cases (26.8%). They were managed conservatively; PCF was avoided in 7(46.7%) cases. Three patients (7.3%) developed PCF after having started oral intake with a negative WSS. These three cases were further analysed, 2 cases where recorded at the beginning of the studied period when less experience was available possibly leading to incorrect results. Sensitivity and negative predictive value (NPV) for fistula prediction were 72.7% and 92.7%, respectively. Taking into account the high NPV of WSS, it is safe to start oral intake after negative WSS. Further studies to evaluate its accuracy earlier on after SLT are justified taking into account the results and the impact that delayed feeding has on patient's quality of life.

Outcomes of Salvage Therapy for Oropharyngeal Cancer Recurrence Following Upfront Radiation Therapy and Prognostic Factors.

This study aimed to investigate the oncologic outcomes and prognostic factors of salvage treatments in patients with recurrent oropharyngeal squamous cell carcinoma (OPSCC) after radiotherapy (RT)-based treatment. A cancer registry was used to retrieve the records of 337 patients treated with definitive RT or concurrent chemoradiotherapy (CRT) from 2008 to 2018 at a single institution. The poor-responder group (PRG) was defined as patients with residual or recurrent disease after primary treatment, and the oncologic outcomes for each salvage treatment method were analyzed. In addition, prognostic indicators of recurrence-free survival (RFS) and overall survival (OS) were identified in patients who underwent salvage treatment. After initial (C)RT, the PRG comprised 71 of the 337 patients (21.1%): 18 patients had residual disease, and 53 had recurrence after primary treatment (mean time to recurrence 19.5 months). Of these, 63 patients received salvage treatment (surgery 57.2%, re-(C)RT 23.8%, and chemotherapy 19.0%), and the salvage success rate was 47.6% at the last follow-up. The overall 2-year OS for salvage treatments was 56.4% (60.8% for the salvage surgery group and 46.2% for the salvage re-(C)RT). Salvage surgery patients with negative resection margins had better oncologic outcomes than those with close/positive resection margins. Using multivariate analyses, locoregional recurrence and residual disease after primary surgery were associated with poor outcome after salvage treatment. In Kaplan-Meier analyses, p16 status was significantly associated with OS in the initial treatment setting but not in the salvage setting. In recurrent OPSCC after RT-based treatment, successful salvage was achieved in 56.4% patients who had undergone salvage surgery and radiation treatment. Salvage treatment methods should be selected carefully, given recurrence site as a prognostic factor for RFS.