Salvage Therapy Research Articles

A Phase II Trial of Bevacizumab in Patients with Recurrent/Progressive Solid Tumor Brain Metastases That Have Progressed Following Whole-Brain Radiation Therapy.

Patients with solid tumor brain metastases that progress after whole-brain radiation have limited options. This prospective trial investigated the efficacy, safety, and tolerability of bevacizumab as salvage therapy in this population. Eligible patients received bevacizumab 10 mg/kg intravenously every 2 weeks until progression. The primary endpoint was radiologic response using Response Assessment in Neuro-Oncology (RANO) criteria. The secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response, and safety. Quality of life (QOL) was studied using the Functional Assessment of Cancer Therapy-Brain (FACT-Br) scale. Twenty-seven patients were enrolled, with twenty-four having evaluable data for response. The majority of histologies (n = 21, 78%) were breast cancer. The remaining histologies were non-small-cell lung cancer (n = 4, 15%), neuroendocrine cancer (n = 1, 3%), and papillary fallopian serous adenocarcinoma (n = 1, 3%). Eighteen patients had radiologic response, with two patients demonstrating partial response (8.33%) and sixteen patients demonstrating stable disease (66.7%). The median duration of response was 203 days. PFS at 6 months was 46%, median PFS was 5.3 m, and median OS was 9.5 m. Treatment was well tolerated, with six patients experiencing grade 3 lymphopenia and hypertension. There was one grade 3 thromboembolism. QOL was not negatively impacted. Bevacizumab is a safe and feasible salvage treatment with durable response and favorable overall survival for patients with progressive brain metastases after whole-brain radiation.

Olanzapine Plus Triple Antiemetic Therapy for the Prevention of Carboplatin-Induced Nausea and Vomiting: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial.

We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone for preventing chemotherapy-induced nausea and vomiting in patients receiving carboplatin-containing chemotherapy. Chemotherapy-naïve patients scheduled to receive carboplatin (AUC ≥5) were randomly assigned to receive either olanzapine 5 mg once daily (olanzapine group) or placebo (placebo group) in combination with aprepitant, a 5-HT3 RA, and dexamethasone. The primary end point was the complete response (CR; no vomiting and no rescue therapy) rate in the overall phase (0-120 hours). Secondary end points included the proportion of patients free of nausea and safety. In total, 355 patients (78.6% male, median age 72 years, 100% thoracic cancer), including 175 and 180 patients in the olanzapine and placebo groups, respectively, were evaluated. The overall CR rate was 86.9% in the olanzapine group versus 80.6% in the placebo group. The intergroup difference in the overall CR rate was 6.3% (95% CI, -1.3 to 13.9). The proportions of patients free of chemotherapy-induced nausea in the overall (88.6% in the olanzapine group v 75.0% in the placebo group) and delayed (89.7% v 75.6%, respectively) phases were significantly higher in the olanzapine group than in the placebo group (both P < .001). Somnolence was observed in 43 (24.6%) and 41 (22.9%) patients in the olanzapine and placebo groups, respectively, and no events were grade ≥3 in severity. The addition of olanzapine was not associated with a significant increase in the overall CR rate. Regarding the prevention of nausea, adding olanzapine provided better control in patients receiving carboplatin-containing chemotherapy, which needs further exploration.

A Case of Olfactory Neuroblastoma Developing Bilateral Retropharyngeal Lymph Node Metastasis 14-years After Skull Base Surgery.

Olfactory neuroblastoma (ONB) is an uncommon malignant tumor and is usually treated by a multidisciplinary approach includes surgery, radiotherapy, and chemotherapy. A 62 years-old male had a tumor in the nasal cavity and diagnosed as ONB with Kadish A stage. Anterior skull base surgery was performed as radical treatment. Since the surgical margin was negative, no postoperative radiotherapy was administered. 14 years after the surgery, bilateral otitis media with effusion (OME) was occurred, we found the recurrence tumor at bilateral retropharyngeal lymph node (RPLN) which surrounded the internal carotid arteries. Since these were unresectable, we planned chemoradiotherapy which was 70Gy of intensity modulated radiotherapy combined with two courses of carboplatin and etoposide. The tumor volume was reduced and bilateral OME were improved. He has been alive for 3 years after salvage treatment. Although ONB has a relatively good prognosis, it is known to often cause cervical lymph node metastasis. Grades III and IV of Hyams classification are considered high risk. This case, initial tumor was limited in the nasal cavity and its clinical classification was early stage, but Hyams classification was grade III. In reference to this case, considering that RPLN metastasis are difficult to radically resect at the salvage surgery, including this area in postoperative radiotherapy was considered an option.

Endoscopic Plastic Pigtail Stents for Leak after Bariatric Surgery: Effective as Primary and Rescue Therapy

Bariatric procedures are increasingly being performed to manage obesity. Postoperative leak is one of the serious complications after bariatric surgery. The management of leaks includes surgery and endoscopic interventions. Endoscopic interventions are less invasive and have shown good efficacy in treating leaks. This includes placement of stents (plastic or metal) or closure of leak by stitching or clipping. Among these, internal drainage by placement of plastic stents is probably the least expensive intervention. In this case series, we show the effectiveness of plastic stents in the management of postbariatric surgery leak in three different scenarios – early postoperative leak, delayed postoperative leak, and prior failed metal stent for treatment of leak.

Management of acute severe ulcerative colitis-an update for generalist and specialist clinicians.

Acute severe ulcerative colitis (ASUC) is a potentially life-threatening medical emergency that occurs in up to 25% of patients with ulcerative colitis. Although intravenous corticosteroids remain the cornerstone of therapy, 30-40% of patients will not respond and need timely consideration of rescue therapy with (currently) either infliximab or ciclosporin or indeed colectomy, underscoring the importance of multidisciplinary care to ensure favourable outcomes for patients. We discuss the current evidence and present an approach to the management of ASUC for general and specialist clinicians caring for patients with ASUC. The information in this review is derived from data published in peer- reviewed academic journals and registered clinical trials. Management of acute severe colitis requires a multidisciplinary approach with early initiation with steroids and timely escalation of treatment to either medical rescue therapy or surgery. Balancing the risks of delayed surgery vs. optimizing medical therapy, including accelerated dosing schedules for biologics, remains ambiguous. The position on newer molecules like Janus Kinase inhibitors, such as tofacitinib, is a growing area with early real-world data showing promise for steroid refractory ASUC. Developing predictive biomarkers and clinical risk scores for personalized rescue therapy selection is an evolving area of research.

Neoadjuvant tislelizumab plus chemotherapy followed by salvage surgery and adjuvant tislelizumab for recurrent head and neck squamous cell carcinoma after radiotherapy: A single-arm, phase II trial.

6070 Background: Locoregional recurrence remains a significant challenge in head and neck squamous cell carcinoma (HNSCC) after surgery and radiotherapy. Salvage surgery is the best option if negative margins can be achieved, and this can be strengthened in the era of immunotherapy. However, some relevant questions remain unanswered. The objectives of this prospective study were to evaluate the efficacy and safety of neoadjuvant tislelizumab plus chemotherapy followed by salvage surgery and adjuvant tislelizumab for recurrent HNSCC after radiotherapy. Methods: In this phase II, single-arm study, eligible pts 18 years of age or older with locoregional recurrent HNSCC after radiotherapy received neoadjuvant therapy with tislelizumab (200 mg), albumin-bound paclitaxel (260 mg/m2), and cisplatin (60-75 mg/m2) Q3W for 2 cycles, followed by salvage surgery and adjuvant tislelizumab (200 mg) Q3W for 6 cycles. The primary endpoint was major pathologic response (MPR) rate. Secondary endpoints included pathological complete response (pCR) rate, objective response rate (ORR), event-free survival (EFS), overall survival (OS) and safety. Results: Between March 2022 and September 2023, 34 pts were enrolled. Median age was 56 (30-75) yrs, 20.6% smoking history, 20.6% alcohol history and 61.8% male. All pts completed neoadjuvant therapy with an ORR of 35.3% (12/34) and DCR of 94.1% (32/34). Twenty-six pts (23 OSCC, 3 OPSCC) successfully underwent surgery with MPR rate 19.2% (5/26), of which the pCR rate was 15.4% (4/26). At median follow-up of 15.1 months, 1-year EFS was 63.4% and 1-year OS was 82.5% for per-protocol population. Twenty-five pts complained symptoms included pain, trismus, dysphagic, and speech disorders at baseline visit, and 84% (21/25) achieved remission after 2 cycles of neoadjuvant therapy. Grade 1-2 adverse events (AEs) with an incidence greater than 10% include 94.1% alopecia, 38.2% fatigue, 35.3% anorexia, 17.6% hypothyroidism and 14.7% anemia. Grade 3-4 adverse events (AEs) occurred in 1 pts (2.9%) with G3 hyperglycemia. Conclusions: Neoadjuvant and adjuvant tislelizumab with salvage surgery is well tolerated. The 1-year EFS and OS compared favorably with historical data. These encouraging results warrant further investigations. Clinical trial information: ChiCTR2100054296.

Total neoadjuvant therapy with split-course hypofraction radiotherapy combined with CAPOX and envafolimab followed by local excision for locally advanced very low rectal cancer (TRACE-LE): An open-label, single-arm, multicenter, phase II trial.

TPS3647 Background: In the treatment of patients with locally advanced very low rectal cancer, neoadjuvant chemoradiotherapy followed by total mesorectal excision (TME) is considered a standard therapeutic approach. Short-course hypofractionated radiotherapy, in combination with subsequent chemotherapy, has been shown to be comparable to long-term chemoradiotherapy in terms of neoadjuvant therapy effects in rectal cancer. Additionally, it has been observed that hypofractionated radiotherapy, when combined with programmed death L-1 (PD-L1) blockade, can enhance the immune response. This study aims to investigate efficacy and safety of organ preservation in patients with locally advanced very low rectal cancer by utilizing total neoadjuvant therapy involving split-course hypofraction radiotherapy in conjunction with CAPOX and Envafolimab (a humanized single-domain anti-PD-L1 antibody fused to an Fc fragment). Methods: TheTRACE-LE trail is an open-label, single-arm, multicenter, phase II trial. The target sample is 72 participants. Key eligibility criteria include individuals aged 18-75, confirmed rectal adenocarcinoma, cT3-4N0/cT1-4N1-2 with lower margin ≤ 2cm from anorectal ring's upper edge (MRI) and ECOG performance status of 0-2. The treatment protocol include preoperative split-course hypofractionated radiotherapy (5×7Gy), in conjunction with 6 cycles of CAPOX chemotherapy and Enverolimab (300 mg subcutaneous injections) administered in a 3-week treatment cycle. The primary outcome measure is organ preservation, specifically the rectum intact, owing to no radical total mesorectal excision (TME), no locoregional regrowth unless amenable to limited, curative (R0) salvage surgery by local excision (LE) and no permanent stoma (including a never reversed protective stoma, or a stoma owing to toxicities and/or poor functional outcomes). The secondary outcome measures encompass ypT0-1 rate, pathological complete response (pCR) rate, acute and late toxicity as per NCICTCAE V.5.0, local recurrence rate, local regional recurrence rate, disease-free survival, quality of life, and anorectal function. Clinical trial information: NCT05970900 .

Contact x-ray brachytherapy for the treatment of rectal cancer: A systematic review and meta-analysis.

e15628 Background: Rectal cancer is a highly prevalent disease, particularly among the elderly and frail populations. While surgical resection has traditionally been the primary management approach, it carries inherent risks, including operative mortality, morbidity, and poor long-term functional outcomes. These risks are particularly pronounced in older, co-morbid individuals. Evidence presented in the 2023 phase III OPERA randomised trial suggests that Contact X-ray Brachytherapy (CXB) is a viable organ-preserving alternative to radical surgery. We conducted a systematic review and meta-analysis to assess the clinical effectiveness of CXB in the treatment of rectal cancer. Methods: This systematic review was prospectively registered (CRD42021284969) and reported in accordance with PRISMA guidelines. PubMed, EMBASE, SCOPUS and Cochrane CENTRAL Libraries were interrogated using the search terms “Rectal cancer”, “Contact Brachytherapy”, and synonym terms. Literature search and data extraction were conducted by two reviewers, with recourse to a senior author for resolution of conflicts. Clinical complete response (cCR) was the primary outcome. Secondary outcomes include local regrowth, regional recurrence, salvage surgery rates, long-term disease control post-salvage surgery and survival outcomes. Proportional meta-analyses were conducted and presented as forest plots with summary proportions and 95% confidence intervals. The Higgins I2 statistic was used to assess for heterogeneity. The random effects model was employed in studies reporting substantial heterogeneity (I2&gt; 50%). Results: The literature search identified 973 studies, of which 48 studies encompassing 5,447 patients were included in the meta-analysis. Pooled estimates of outcomes were as follows: cCR rate = 80% (95% CI 76-88%), local regrowth = 15% (95% CI 12-18%), regional failure rate = 3% (95% CI 2-4%), salvage surgery rate = 14% (95% CI 11-18%), long-term disease control post-salvage surgery rate = 88% (95% CI 78-96%) and organ preservation 82% (95% CI 75-88%). A subgroup analysis was conducted and stratified by concomitant therapy (CXB alone, CXB &amp; EBRT, CXB &amp; EBCRT). CXB, in conjunction with EBCRT, leads to a statistically significant reduction in both local regrowth and regional failure. The local regrowth rates were 16% (95% CI 11-21%), 17% (95% CI 11-23%), and 10% (95% CI 8-13%) respectively, with a p-value of 0.05. The regional failure rates were 4% (95% CI 2-8%), 4% (95% CI 2-5%), and 1% (95% CI 0-2%), p = 0.02. Conclusions: CXB, combined with EBCRT, in the appropriately selected patient can achieve long-term disease control whilst avoiding major surgery. Salvage surgery is a viable option for patients who experience disease regrowth, with excellent long-term disease control. CXB may be considered a safe alternative to surgery in the appropriately selected patient.

Long term outcome of patients with rectal cancer with complete clinical response or near complete clinical response after neoadjuvant therapy: A multicenter registry study by Chinese Watch and Wait Database.

e15597 Background: To report the long-term outcomes of Chinese rectal cancer patients after Watch and Wait (W&amp;W) following neoadjuvant therapy(NAT). Methods: Collecting real-world multicenter retrospective data, including the Chinese W&amp;W Database group (CWWD) and data from centers that initiated this work earlier in China. Patients with a follow-up time of no less than 2 years were included. Analyzing and reporting on their oncological outcomes and comparing differences between cCR and near-cCR groups. Results: The study included 318 rectal cancer patients from 8 institutions who received NAT and underwent W&amp;W. Among them, 291 initially achieved cCR, and 27 had near-cCR. The median follow-up time was 48.4 months (10.2-110.3 months). The 5-year OS and CSS were 92.4% (95% CI 86.8-95.7%) and 96.6% (95% CI 92.2-98.5%), respectively. The 5-year OP-DFS(organ preservation adapted DFS) was 86.6% (95% CI 81.0-90.7%), and the 5-year OPR was 85.3% (95% CI 80.3-89.1%). The overall 5-year local regrowth rate and distant metastasis rate were 18.5% (95% CI 14.9-20.8%) and 8.2% (95% CI 5.4-12.5%), respectively. The 5-year local regrowth rate in the near-cCR group was higher than in the cCR group (41.6% vs. 16.4%, p&lt;0.01), with a lower OPR rate (69.2 vs. 88.0%, p&lt;0.001). However, there were no significant differences in OS, CSS, and OP-DFS between the two groups. 91% of local regrowths occurred within the intestinal lumen, 7.2% (4/56) occurred simultaneously in the intestinal lumen and mesentery, and 1.8% (1/56) occurred only in the mesentery. 82.1% of local regrowths occurred within 2 years, 91.0% occurred within 3 years, with a median regrowth time of 11.7 months (2.5-66.6 months). Among cases with local regrowth beyond 2 years, 30% (3/10) had mesenteric regrowth. The salvage success rate after local regrowth (conversion to disease-free status after salvage surgery) was 82.1% (46/56). 60.8% of distant metastases occurred within 2 years, 73.9% occurred within 3 years. Common sites included lung metastasis (65.2%), liver metastasis (34.8%), and bone metastasis (30.4%), with 26% involving multiple organs. 83.3% (5/6) of liver metastases occurred within 2 years, while lung and bone metastases spread out over 5 years follow-up. Among patients with local regrowth, 16.0% (9/56) developed distant metastases. The salvage success rates for local regrowth and distant metastasis were 82.1% (46/56) and 12.5% (3/23), respectively. Conclusions: Rectal cancer patients who achieve cCR or near-cCR after NAT and undergo W&amp;W have favorable oncological outcomes and a high rate of organ preservation. Local regrowth and distant metastasis during W&amp;W follow certain patterns, with a relatively high salvage rate for local regrowth. It emphasizes the importance of close follow-up and timely intervention during the W&amp;W process.

Veno-arterial ECMO ventricular assistance as a direct bridge to heart transplant: A single center experience in a low-middle income country.

The use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) as a direct bridge to heart transplantation (BTT) is not common in adults worldwide. BTT with ECMO is associated with increased early/mid-term mortality compared with other interventions. In low- and middle-income countries (LMIC), where no other type of short-term mechanical circulatory support is available, its use is widespread and increasingly used as rescue therapy in patients with cardiogenic shock (CS) as a direct bridge to heart transplantation (HT). To assess the outcomes of adult patients using VA-ECMO as a direct BTT in an LMIC and compare them with international registries. We conducted a single-center study analyzing consecutive adult patients requiring VA-ECMO as BTT due to refractory CS or cardiac arrest (CA) in a cardiovascular center in Argentina between January 2014 and December 2022. Survival and adverse clinical events after VA-ECMO implantation were evaluated. Of 86 VA-ECMO, 22 (25.5%) were implanted as initial BTT strategy, and 52.1% of them underwent HT. Mean age was 46 years (SD 12); 59% were male. ECMO was indicated in 81% for CS, and the most common underlying condition was coronary artery disease (31.8%). Overall, in-hospital mortality for VA-ECMO as BTT was 50%. Survival to discharge was 83% in those who underwent HT and 10% in those who did not, p<.001. In those who did not undergo HT, the main cause of death was hemorrhagic complications (44%), followed by thrombotic complications (33%). The median duration of VA-ECMO was 6 days (IQR 3-16). There were no differences in the number of days on ECMO between those who received a transplant and those who did not. In the Spanish registry, in-hospital survival after HT was 66.7%; the United Network of Organ Sharing registry estimated post-transplant survival at 73.1%±4.4%, and in the French national registry 1-year posttransplant survival was 70% in the VA-ECMO group. In adult patients with cardiogenic shock, VA-ECMO as a direct BTT allowed successful HT in half of the patients. HT provided a survival benefit in listed patients on VA-ECMO. We present a single center experience with results comparable to those of international registries.

Adjuvant or rescue disitamab vedotin (RC48-ADC) for high-risk non-muscle invasive bladder cancer with HER2 overexpression: A phase II multi-center study.

TPS4625 Background: Non-muscle invasive bladder cancer (NMIBC) comprises approximately three-quarters of newly diagnosed cases of bladder cancer. Based on the risk of disease progression, NMIBC is categorized into low, intermediate, and high risk, with high-risk NMIBC patients facing a 5-year disease progression rate of up to 40%. The current standard treatment for high-risk NMIBC involves transurethral resection of the bladder tumor (TURBT) combined with intravesical Bacillus Calmette-Guérin (BCG) instillation as adjuvant therapy. In cases of BCG instillation treatment failure, the standard approach is radical cystectomy. Multiple studies have reported HER2 positivity in 20-44% of NMIBC cases, and HER2 overexpression (immunohistochemistry ≥2+) is closely linked to the progression and adverse prognosis of bladder cancer. Consequently, HER2 may serve as a novel therapeutic target for bladder cancer. Disitamab Vedotin (DV; RC48-ADC) is an antibody-drug conjugate (ADC) comprising a fully humanized HER2-directed monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. Results from a Phase II clinical trial (NCT03507166) suggest that Disitamab Vedotin exhibits favorable efficacy and safety in HER2-positive metastatic urothelial carcinoma patients who have previously failed chemotherapy. This clinical trial aims to investigate the efficacy and safety of RC48-ADC as adjuvant or rescue therapy for high-risk NMIBC with HER2 overexpression and to explore molecular biomarkers predicting the efficacy of RC48-ADC. Methods: This multicenter, Phase II clinical trial will enroll two cohorts: Cohort A, consisting of 52 patients undergoing first-line adjuvant therapy, and Cohort B, with 25 patients receiving rescue therapy after BCG instillation failure, both exhibiting HER2 overexpression in high-risk NMIBC. Following the Simon two-stage optimal design, the first stage will involve enrolling 19 patients in Cohort A and 12 patients in Cohort B. After safety and baseline assessments, both cohorts will undergo six cycles of treatment with RC48-ADC (120 mg intravenous infusion every two weeks), totaling 12 weeks of treatment. Primary endpoints include safety, 12-month recurrence-free rate (Cohort A), and 3-month clinical complete response rate (Cohort B). Secondary endpoints encompass the 6-month recurrence-free rate (Cohort A), duration of response (Cohort B), recurrence-free survival, progression-free survival, overall survival, and quality of life (assessed through eEuroQoL EQ-5D and FACT-BI). Additionally, exploratory endpoints will investigate the relationship between biomarkers in tumor tissues, blood, and urine, and treatment efficacy. Clinical trial information: NCT05996952 .

A phase ib-II study of dabrafenib, trametinib, cetuximab plus irinotecan in patients with BRAF mutant metastatic colorectal cancer: Subgroup analysis and biomarker identification.

e15581 Background: About 5%-12% of patients with metastatic CRC (mCRC) have BRAF mutations in which BRAF V600E mutated was most common, accounts for approximately 90% of cases of BRAF mutation mCRC. Therefore, multi-drug combination therapy with BRAF inhibitor has been tried. The efficacy results of this study have been reported in 2023 ASCO GI (#156). The ORR was 30% (3/10), the DCR was 80% (8/10). After a median follow-up of 19.7 months, the median PFS was 7.5 months. Here, we reported the results of subsequent analyses. Methods: In this phase Ib-II trial, 15 patients with BRAF-mutant mCRC received Dabrafenib, trametinib, cetuximab plus irinotecan combination therapy. Whole exome sequencing was conducted in 8 proficient mismatch repair (pMMR) mCRC patients with BRAF V600E-mutant. Patients were followed up clinically and radiographically. Response was defined as Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) were defined according to the response definitions of the RECIST criteria. Results: 3 mCRC patients (CR or PR) were divided into response group, 5 mCRC patients (SD or PD) were divided into non-response group. Age (59.6±4.22 vs 39.0±9.93), Gender (male 66.67% vs 80%), ECOG score (0.67 vs 0.60), ALT flare rate (66.67% vs 60%) were similar in the two group. Patients in response group have better 2-year survival rate (66.7% vs 0%, P &lt; 0.05). Furthermore, response-related Differential Expression Genes (DEGs) (log2fc &gt; 1, P &lt; 0.05) were analyzed. Meanwhile, GO and KEGG pathway analysis was conducted based on DEGs. Results showed that MAPK signaling pathway related genes were down-regulated in response group such as EGF, FGF18, HGF, IGF1, MAPK10, NGF. While Apoptosis related genes were up-regulated in response group such as BCL2L1, AIFM1, DAXX. Moreover, Antigen processing and presentation related genes such as CALR, CANX, HSPA8 were enriched in response group, which indicated a more active immune microenvironment. On the contrary, Hedgehog signaling pathway related genes such as GLI1, HHIP, BOC were enriched in non-response group. Next, we verified the clinical significance of DEGS in TCGA CRC cohort database using Cox-regression analysis. Results showed that expression of IGF1, NGF, CAMK2B, CCNA1 were associated with poor prognosis and CANX, HSPA8 were associated with better prognosis, which is in accordance with our sequencing results. Conclusions: Inhibition of MAPK signaling and promoted Apoptosis was found in BRAF V600E-mutant mCRC patients who were response to Dabrafenib, trametinib, cetuximab plus irinotecan. It's worth noticing that immune activation occurred in responsive patients, indicated a potential benefit from immunotherapy combination therapy. Moreover, Hedgehog signaling pathway may be target in rescue therapy in mCRC patients. Clinical trial information: ChiCTR2200063316.

Response to therapy in patients with chronic inflammatory demyelinating polyradiculoneuropathy: An observational study

Background &amp; Objective: The existing practice in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is to initiate therapy with steroids, intravenous immune globulin (IVIg), or plasma exchange (PLEX) followed by period of immunosuppression. The objective of this study is to assess disability outcomes at 6 months after starting therapy. Methods: Patients who were diagnosed as having CIDP from the Army Hospital of Research and Referral, Delhi; who were initiated and maintained on therapy by treating neurologists with a six month follow up were included in this study. They were retrospectively divided into three groups based on initial therapy received. The primary outcome was comparison of the Inflammatory Neuropathy Cause and Treatment (INCAT) group overall disability sum score (INCAT-ODSS) at 6 months. Secondary outcomes were difference in score at 1 and 3 months, proportion with at least 20% response at 3 and 6 months (“responders”) and proportion who needed “rescue” therapy during the 6 months. Results: Sixty patients (26 retrospective, 34 prospective) were included in this study. They were treated with IVIg (33), steroid (19) and PLEX (8). Baseline INCAT-ODSS score (±SD) was 7.2(2.2), 7.2(1.5) and 7.5(1.9) respectively. All received some form of oral immune suppression during follow up. Twenty one (35%) needed additional rescue therapy. There was an overall significant reduction in the mean INCAT-ODSS disability score from 7.2 to 3.1 (Mean difference 4.2; CI 3.6-4.8); p&lt;0.01). Nearly 88% of patients (51/58) showed at least 20% improvement from baseline. Two were lost to follow up (1 IVIg, 1 steroid). There was no difference in the ODSS at 6 months [2.9(2.4), 3.5(2.7) and 2.7(1.3)] respectively. No difference in ODSS at 1 and 3 months. Proportion of responders at 6 months and proportion who needed rescue therapy were also similar. Conclusion: Irrespective of initial therapy and maintenance oral immunosuppression used, the overall disability reduction in treatment with IVIg, steroid or PLEX is significant; however the three modalities are comparable in terms of disability reduction at 6 months. At least a third may need additional rescue therapy.

Visual Outcomes after Proton Therapy for Recurrent Uveal Melanoma

Proton beam reirradiation remains an effective and globe-preserving alternative to enucleation in the treatment of local recurrence in uveal melanoma. The study aimed to assess visual outcomes and prognostic factors in visual acuity following proton beam salvage therapy. Retrospective study SUBJECTS: A retrospective study evaluated patients with recurrent uveal melanoma treated with proton beam irradiation (PBI) from 1984 through 2019 at a single academic tertiary center. Patient and tumor characteristics were collected from the medical record, as well as best visual acuity (BVA) and ocular outcomes following treatment of recurrent uveal melanoma with PBI. The primary outcome of the study was the visual acuity of patients following proton beam irradiation for recurrent uveal melanoma. Additional outcome measures included enucleation rate of patients following salvage PBI and analysis of tumor and patient characteristics in the prognostication of visual acuity. The study comprised 67 patients who received PBI for recurrent uveal melanoma. The median age at recurrence was 67.6 years (range 31.6-91.0 years) and median follow-up from the time of recurrence to last examination was 4.4 years (range 0.23-17.1 years). The median final BVA was hand motion (range 20/20-no light perception) and 6 (9.1%) patients maintained a Snellen VA 20/40 or better. The 5-year probability of visual acuity retention of 20/200 or better was 19%. In a multivariable Cox model, VA at tumor recurrence of less than 20/40 was found to be significantly associated with a VA of 20/200 or worse following retreatment with PBI. Twelve (18%) patients underwent enucleation following retreatment with PBI. PBI allows for ocular preservation and functional vision in the treatment of recurrent uveal melanoma in select patients.

Paradigm Shifts in Hodgkin Lymphoma Treatment: From Frontline Therapies to Relapsed Disease.

Combination chemotherapy with or without radiation has served as the primary therapeutic option for classic Hodgkin lymphoma (cHL), leading to durable remission in a majority of patients with early- and advanced-stage cHL. Patients with relapsed/refractory (RR) cHL could still be cured with salvage chemotherapy and autologous stem-cell transplantation. Brentuximab vedotin (BV) and the anti-PD-1-blocking antibodies, nivolumab and pembrolizumab, are highly effective treatments for cHL and have revolutionized the management of the disease. Recent studies incorporating BV and PD-1 blockade into salvage therapy for RR cHL and into frontline treatment regimens have changed the cHL treatment paradigm. The novel agents are also useful in the treatment of older patients who have poor outcomes with traditional therapy. This manuscript will review current strategies for approaching the management of previously untreated, RR, and challenging populations with cHL, including how to incorporate the novel agents.

Carfilzomib plus rituximab, ifosfamide, carboplatin and etoposide (C-RICE) led to higher response, OS, and PFS in patients with transplant-eligible relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

7042 Background: The CORAL study highlighted the need to develop novel salvage regimens for R/Rr/r DLBCL previously treated with R+CHOP. Overall response rate (ORR) to second line immuno-chemotherapy was 51% with a 3-year progression free survival (PFS) of 30% following high-dose chemotherapy and autologous stem cell support (HDC-ASCS). Optimal disease control (complete remission [CR] or partial remission [PR]) prior to HDC-ADCS and more recently to chimeric antigen receptor T-cell therapy (CAR T), correlates with improved outcomes. Dysregulation of Bcl-2 family members has been associated with acquired resistance to rituximab and chemotherapy which we have previously shown may be mitigated by co-treatment with proteasome inhibition in pre-clinical model. Subsequently, we conducted a Phase I/II clinical trial evaluating the safety and efficacy of CRICE as salvage therapy for R/R DLBCL (Blood Adv. 2023 7:1146-1155). Methods: Here we retrospectively compared the clinical outcomes of R/R DLBCL patients treated with CRICE (N=28) versus RICE (N=38) on our prior clinical trial (NCT01959698). Demographic, clinical, and pathological characteristics were collected for both groups (Table). Study endpoints consisted of differences in overall response rate (ORR), CR/PR rates, median progression free survival (PFS) and overall survival (OS) between the two cohorts. Results: The addition of Carfilzomib to RICE resulted in improved clinical outcomes. A higher ORR (92.9 vs 76.3, P=0.073) and CR rates (82.1 vs. 44.7, P=0.002) were observed in CRICE vs. RICE treated patients. Multivariate analysis confirmed the higher CR rates in CRICE vs. RICE when adjusted by DLBCL subtype (GCB vs. nNon-GCB, P=0.003). More CRICE patients proceeded to HDC-ASCS (52.6% vs. 47.4%, P=0.618). The 3yr PFS rate was higher in CRICE (54%, 32-72%) vs. RICE treated patients (35%, 19-51%). While the median PFS was longer in CRICE treated patients 36.8m (0.8, 73.2) vs. 3.2m (0.5, 54.2) (RICE), it did not reach statistical significance (P=0.714). No differences in OS were observed between CRICE &amp; RICE patients, median OS 67.3m vs. 71.8m. Conclusions: The CRICE outcomes were more striking in patients with non-GCB r/r DLBCL (ORR 85%, mPFS and OS not reached). CRICE led to high CR rates and longer PFS among r/r DLBCL patients, especially in non-GCB DLBCL patients. CRICE could be an attractive regimen to achieve disease control in r/r DLBCL patients undergoing consolidation therapy with HDC-ASCT or CAR T-cell therapy. [Table: see text]

Real world outcomes of 2,339 patients with early-stage triple-negative breast cancer (TNBC) treated in British Columbia.

e23274 Background: TNBC represents 15-20% of all breast cancers, and tends to exhibit more aggressive features, more frequent distant metastasis and overall worse prognosis than other breast cancer subtypes. The treatment landscape for early-stage TNBC has changed considerably in the last decade, with new additions to neoadjuvant therapy (NAT) aimed at improving pathologic responses and outcomes. In this study, we assess real world data regarding treatment and outcomes in those with early-stage TNBC. Methods: The BC Cancer Breast Cancer Outcomes Unit database contains prospectively collected data on patients residing in British Columbia and diagnosed with breast cancer since 1989. This retrospective study evaluated patients diagnosed with stage I-III TNBC from 2010 to 2019. During this era, regimens containing anthracyclines and taxanes were routinely used. TNBC was defined as per ASCO-CAP guidelines as ER≤1%, PR≤1% and negative HER 2 (0, 1+ by immunohistochemistry, or 2+ ISH negative). Outcomes of interest included event free survival (EFS), overall survival (OS), and pathologic complete response (pCR). Results: 2,339 patients withstage I-III TNBC were identified with a mean follow up of 6.5 years. OS was 87% (95% CI 85-88%) at 3-years and 79% (95% CI 77-80%) at 5-years. The presenting stage was a significant prognostic factor, with 5-year EFS of 89%, 81% and 51%- and 5-year OS of 90%, 80%, and 53% for stages I, II, and III, respectively. There was an increase in NAT use in 2019 (n = 82/230,35.7%) when compared to 2010 (n = 20/227, 8.8%). The most common neoadjuvant regimens used included anthracycline and taxane chemotherapies (n = 343,81.4%), with only a small number receiving neoadjuvant platinum chemotherapy (n = 52, 12.4%). Pathological complete response (pCR) was achieved in 24.5% (103/421) of patients who received NAT. Patients with pCR had improved 5- year EFS (91% vs. 57%, HR 0.26 [95% CI 0.15-0.45]) and 5-year OS (90% vs. 59%, HR 0.26 [95% CI 0.15-0.45]) compared to those with residual disease. The subgroup that received salvage capecitabine had a poor 3-year EFS at 22% but was enriched for patients with residual nodal disease after NAT (n = 77/130, 59.2%). Conclusions: This real-world study of TNBC in the era prior to routine immunotherapy (IO), highlights the poor prognosis of TNBC, particularly patients with locally advanced disease and those who did not achieve pCR, despite adjuvant capecitabine. This stresses the need for advances in NAT and salvage therapies for TNBC with residual disease at high risk of recurrence. [Table: see text]

Results from METIS (EF-25), an international, multicenter phase III randomized study evaluating the efficacy and safety of tumor treating fields (TTFields) therapy in NSCLC patients with brain metastases.

2008 Background: For non-small cell lung cancer (NSCLC) with brain metastases (BM) stereotactic radiosurgery (SRS) is the current preferred therapy. Due to frequent intracranial failures, there is a high unmet need for salvage therapies. Whole brain radiotherapy (WBRT) reduces intracranial failure but used less frequently due to cognitive consequences. Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell division and have shown improved survival and safety in patients with glioblastoma and metastatic NSCLC. Phase 3 METIS trial [NCT02831959] aimed to evaluate the efficacy and safety of TTFields therapy in NSCLC patients with BM treated with SRS, specifically in terms of lengthening time to intracranial progression without cognitive decline. Methods: Mutation negative (M-) NSCLC patients with 1–10 BM were randomized 1:1 to receive stereotactic radiosurgery (SRS) followed by Tumor Treating Fields (TTFields; 150 kHz) therapy with best supportive care (BSC) or SRS followed by BSC. Patients with Karnofsky Performance Status (KPS) ≥70, newly diagnosed with one inoperable or 2–10 supra-/infratentorial brain metastases suitable for SRS and receiving optimal extracranial disease therapy were included. Exclusions were prior WBRT and single operable or recurrent brain metastases. Primary endpoint was time to first intracranial progression (RANO-BM) based on cumulative risk. Patients were followed every two months until second intracranial progression. Cognition and patient quality of life (QoL) were evaluated. Results: Between July 2016 and September 2022, 298 patients were randomized. Baseline characteristics were balanced: median age was 63.5 (range 37-84) years, 37.6% females, majority of patients had a KPS ≥ 80, median time from initial NSCLC diagnosis was 1.8 months (range: 0.2-55.7), 77% had adenocarcinoma. Median treatment duration of TTFields was 16 weeks, with a median usage time of 67%. Primary endpoint, time to intracranial progression from SRS, was significantly prolonged with SRS followed by TTFields therapy with BSC vs. TTFields plus BSC arm (median of 21.9 vs. 11.3 months); HR=0.67 [0.48-0.93], p=0.02. TTFields-related AEs were mainly dermatological, and Grade ≤2. TTFields therapy also improved deterioration-free survival of global health status, physical functioning, and fatigue according to QoL, and did not negatively impact cognition. Conclusions: METIS study met its primary endpoint, demonstrating that TTFields therapy following SRS in mutation negative NSCLC patients with BM, significantly prolongs time to intracranial progression and could postpone WBRT, without QoL and cognition decline. Clinical trial information: NCT02831959 .

Clinical utility and accessibility of functional precision medicine for relapsed/refractory pediatric and adult cancers.

1551 Background: Pediatric and adult patients with rare, relapsed, or refractory cancers often have few treatment options. Precision medicine approaches are often the first strategy used to identify salvage therapy options when standard treatments fail. Despite the significant clinical benefit to advanced cancer patients, multiple genomics precision medicine trials have revealed important constraints for patients that lack treatments matched to mutations or biomarkers and have highlighted challenges in drug accessibility associated with novel targeted therapies identified through genomics precision medicine. Current clinical findings from large-scale studies demonstrate ~10% of cancer patients receive clinical benefit from genomics-guided therapies - in part due to limited insight into the complex relationship between tumor molecular characteristics and patient response. Methods: We implemented a functional precision medicine (FPM) approach combining genomic tumor profiling with high-throughput drug sensitivity testing (DST) of FDA-approved agents on patient-derived tumor cells to identify treatment options when standard-of-care is exhausted. Clinical utility and benefit of this program was investigated via a clinical trial (NCT03860376) at Nicklaus Children’s Hospital in Miami, FL. Results: We were returned DST data on 21 of 24 patients DST (median = 102 agents per sample) and genomic profiling on 20 of 24 patients. DST turnaround time was significantly below the 14 days required for clinical use (median = 10 days, p = 0.0012). FPM recommendations were returned to 19 (76%) patients, of which 14 patients underwent therapeutic intervention. Six patients received FPM-guided treatments, and five (83%) patients experienced a &gt;1.3-fold improved progression-free survival over their previous therapy, significantly above the rate from physician’s choice (p = 0.0104). We subsequently opened pan-cancer FPM clinical studies for adults (n = 36 patients) and children (n = 65 patients). A key objective in these trials is optimizing our DST protocol for tissue samples of various sizes. Here, we report preliminary efforts to optimize our DST approach for tissue samples from resections, core biopsies, and fine-needle biopsies from primary and metastatic lesions. Conclusions: The findings from our feasibility study illustrate the potential for FPM to positively impact clinical care for pediatric/adolescent patients with relapsed/refractory cancers, and have supported initiation of currently enrolling clinical studies. An NIMHD-funded expansion cohort now enrolling at Nicklaus Children’s Hospital (NCT05857969, n = 65 patients), and a rare/relapsed/refractory adult patient cohort at Cleveland Clinic Florida (NCT06024603, n = 36 patients). These studies aim to further investigate the impact on clinical outcomes through the use of FPM to recommend treatment options. Clinical trial information: NCT06024603 , NCT05857969 , NCT04956198 , NCT03860376 .

Impact of breaks in therapy on survival for pediatric patients with relapsed or refractory solid tumors: A single-center study.

10021 Background: Relapsed or refractory (R/R) solid tumors remain a significant cause of mortality for children. While upfront therapies have been well-studied, the cumulative effects of multiple relapses and salvage regimens is unknown. We describe the disease trajectory in these patients, from the time of first R/R event (on-therapy progression/refractoriness or off-therapy relapse) to time of death or last follow-up. We also analyze whether breaks ( &gt; 30 days) between diagnosis of events and initiation of subsequent therapies have an impact on survival. Methods: We reviewed data from electronic medical records for patients with primary, malignant R/R extracranial solid tumors treated at Texas Children’s Hospital between 2005-2023. Descriptive analysis was performed along with univariate chi-square, one-way ANOVA, and independent sample t-tests. Cox regression analysis was used to evaluate time from first event to death or last known follow-up for each variable described. Analysis was performed with SPSS v29. Results: We reviewed data for 466 patients with R/R solid tumors (female: 47%; median age: 8.66 years; median follow-up after first event: 12.9 months). Most common diagnoses were neuroblastoma (21.5%), rhabdomyosarcoma (19.1%), and osteosarcoma (16.1%). Patients had a median of 3 (interquartile range [IQR]: 1-4) R/R events with a median of 93 (IQR 52-200) days between each event. The most common post-event therapy regimens were intravenous chemotherapy alone (21.4%) or in combination with surgery and/or radiotherapy (19.9%). Deceased patients (n = 339) had a median of 291 (IQR: 127-549) days from first event to death. Increased time from first R/R event to death was associated with a break in disease-directed therapy; type of diagnosis; non-metastatic stage at original diagnosis; type of first event; type of first salvage regimen; and receiving phase 1 therapy. Of 438 patients who received ≥1 salvage therapy regimen, 116 (26.5%) took ≥1 break between an R/R event and subsequent therapy. Reasons for breaks varied relatively evenly between intentional/goal-concordant (e.g., to seek second opinion, to focus on quality of life), and unintentional (e.g., care coordination, care access issues). In a multivariable Cox regression model, taking a &gt; 30 day break in disease-directed therapy was associated with prolonged survival, even after adjusting for number of events and significant covariates (p &lt; 0.05). Conclusions: The prognosis for children with R/R solid tumors is poor. Most children experience multiple R/R events and therapy regimens without a break in therapy. Presence of a &gt; 30 day break between an R/R event and subsequent therapy did not negatively impact survival, implying that time between therapy regimens can safely be offered to some patients to promote quality of life, exploration of goals of care, and thoughtful decision-making, without compromising survival.