Triple Chemotherapy Research Articles

Comparative Cost-Effectiveness of Gemcitabine and Cisplatin in Combination with S-1, Durvalumab, or Pembrolizumab as First-Line Triple Treatment for Advanced Biliary Tract Cancer.

The clinical effectiveness of triple chemotherapy consisting of gemcitabine, cisplatin plus either S-1 (GCS), durvalumab (DGC), or pembrolizumab (PGC) as first-line treatment for advanced biliary tract cancer (BTC) has been reported. However, their comparative cost-effectiveness is unclear. We conducted a model-based cost-effectiveness analysis from the perspective of Japanese healthcare payer. A 10-year partitioned survival model was constructed by comparing the time-dependent hazards of the KHBO1401-MITSUBA, TOPAZ-1, and KEYNOTE-966 trials. The cost and utility came from previously published reports. Quality-adjusted life years (QALY) were used to measure the effects on health. Costs for direct medical care were taken into account. There was a one-way analysis and a probability sensitivity analysis. A willingness-to-pay threshold of 7.5 million yen (57,034 USD) per QALY was defined. The incremental costs per QALY for GCS, DGC, and PGC in the base case study were 3,779,374 JPY (28,740 USD), 86,058,056 JPY (65,4434 USD), and 28,982,059 JPY (220,396 USD), respectively. No parameter had an influence beyond the threshold in a one-way sensitivity analysis. A probabilistic sensitivity analysis revealed that the probability of GCS, DGC, and PGC being cost-effective at the threshold was 85.6%, 0%, and 0%, respectively. Given the current circumstances, it is probable that triple therapy utilizing GCS will emerge as a plausible and efficient primary chemotherapy strategy for patients with advanced BTC in the Japanese healthcare system, as opposed to DGC and PGC.

Novel Effective Therapeutic Regimen for Recurrent/Metastatic Head and Neck Squamous Cell Cancer: Concurrent Triple Oral Metronomic Chemotherapy and Immunotherapy.

Novel Effective Therapeutic Regimen for Recurrent/Metastatic Head and Neck Squamous Cell Cancer: Concurrent Triple Oral Metronomic Chemotherapy and Immunotherapy.

Conversion surgery for BRCA-mutated pancreatic ductal adenocarcinoma with liver metastasis treated with platinum-based chemotherapy followed by olaparib

BackgroundWith recent dramatic developments in chemotherapy, attempts to incorporate surgery into the multidisciplinary treatment of unresectable pancreatic ductal adenocarcinoma with metastasis (UR-M PDAC) have emerged. Maintenance therapy with olaparib after chemotherapy including a platinum-based regimen, which inhibits the poly ADP-ribose polymerase (PARP) involved in DNA repair, was approved for UR-M PDAC with positive BRCA mutations.Case presentationA 47-year-old male patient with a high carbohydrate antigen 19-9 (CA19-9) level was diagnosed with PDAC in the pancreatic tail. Staging laparoscopy revealed occult liver metastasis. Because BRCA2 mutation was confirmed, triple combination chemotherapy with SOXIRI (S-1/oxaliplatin/irinotecan) was introduced and continued for 16 weeks, followed by 14 weeks of olaparib. After that, CA19-9 was normalized, and no obvious liver metastases of any size could be seen on imaging studies during chemotherapy. Since staging laparoscopy after chemotherapy proved that the liver metastasis had disappeared, laparoscopic distal pancreatectomy was performed, and curative resection was completed. After adjuvant chemotherapy with olaparib for 12 months, the patient is alive 36 months from his initial diagnosis and 27 months postoperatively without recurrence.ConclusionWe report a case of PDAC with liver metastasis and BRCA mutation-positivity who underwent conversion surgery and achieved long-term survival after irinotecan-based chemotherapy followed by maintenance therapy with olaparib.

Phase 3 randomized study for evaluation of physician choice Rx versus best supportive care as second-line or beyond therapy in head and neck cancer with poor performance status.

LBA6019 Background: Relapsed-recurrent head and neck squamous cell carcinoma (HNSCC) cancers have limited treatment options in the second line and beyond setting. Many of these patients have poor performance status (PS) and are subject to best supportive care (BSC). There is a lack of any level 1 evidence about the benefit of systemic therapy in HNSCC with poor PS. Methods: This was a randomized phase 3 superiority open-label multicentric study. Adult patients (age>=18 years) with relapsed-recurrent HNSCC, qualified to receive 2nd line or beyond systemic palliative therapy and had ECOG PS 2-3 were eligible. Such patients underwent central stratified random assignment 2:1 to either physician choice therapy either triple metronomic chemotherapy (tablet erlotinib 150 mg [fixed-dose] OD, capsule celecoxib 200 mg [fixed-dose] BD, and oral weekly methotrexate 9 mg/m2 orally or intravenous docetaxel [75 mg/m2 3 weekly]) or BSC. The chemotherapy was continued either till the progression of the disease or till the development of intolerable side effects. The primary endpoint was 6 month-overall survival (OS). The OS in the 2 arms was estimated using the Kaplan-Meier method and by log-rank test. A p-value of 0.05 was considered significant. Sample size: The 6-month OS assumed based on our previous data was 20%, we had assumed that it would increase to 50% in the intervention arm with a type 1 error of 5%, type 2 error of 20%, 2:1 allocation (1- BSC and 2- intervention) and 10% lost to follow up rate. The sample size required was 66. The events required for analysis were 47. Results: The study recruited 66 patients between 1st September 2022 to 27th December 2022 with 44 patients in physician choice therapy (PCT) and 22 in the BSC arm. The data was censored for analysis on 1st March 2024. The median age was 50 years (Range 25-75) with a predominantly male population (n=53;85%). The ECOG PS was PS 2 in 56 (84.8%) and PS 3 in 10 (15.2%) patients. The predominant site of primary was the oral cavity with 52 patients (78.8%). The previous number of systemic lines of therapy received were 1 in 41 (62.1%), 2 in 22 (33.3%), and >2 in 3 (4.5%) patients. Except for 2, all patients had a platinum refractory status (64;97%). The PCT was triple metronomic chemotherapy in 41 patients (93.2%; n=44) and docetaxel in 3 patients (6.8%; n=44). The 6-month OS was 9.09% (95% CI 1.56-25.1) in the BSC versus 53.8% (95% CI 37.9-67.2) in the PCT arm (P<0.0001). The median overall survival in PCT was 223.0 days (95% CI 129-283) versus 77.5 days (95%CI 58 -110) in the BSC arm. The corresponding hazard ratio was 0.333 (95%CI 0.187-0.593; P<0.0001). The data regarding adverse events will be presented at the conference. Conclusions: In this first-ever randomized study on poor PS HNSCC patients, warranting second-line and beyond therapy, the administration of systemic therapy led to a substantial improvement in OS. Clinical trial information: CTRI/2022/08/044733 .

Long term results of phase 3 randomized study evaluating the addition of low dose nivolumab to palliative chemotherapy in head and neck cancer.

LBA6054 Background: The addition of low-dose nivolumab to metronomic chemotherapy (MC) improved 1-year overall survival in relapsed and refractory head and neck squamous cell carcinoma (HNSCC). However, sustained benefit over the long term is an important aspect of immunotherapy and it has never been studied in a prospective randomized study for low-dose nivolumab. Methods: This was an open-label randomized phase 3 superiority study. Adult patients (age= or >18 years), ECOG PS (0-1), relapsed -recurrent or newly diagnosed advanced HNSCC, and normal organ functions were eligible. Patients were randomly assigned 1:1 to oral metronomic chemotherapy consisting of methotrexate 9 mg/m2 weekly, celecoxib 200 mg twice daily, and erlotinib 150 mg daily, with (TMC-I) or without (TMC) with intravenous nivolumab 20 mg flat dose once-every-3-weeks. Systemic therapy was continued till the development of intolerable side effects or progression of disease. The primary endpoint was overall survival (OS). Landmark analysis was performed to compare OS between 2 arms. Results: The median follow-up was 32.5 months (95% CI 29.6-32.7). The 1 year, 2 year and 2.5 year OS were 20% (95%CI 11.9-29.7) versus 35.5% (95%CI 25-46.2) {Hazard ratio (HR)= 0.6534, 95%CI 0.4473 -0.956: P=0.028}, 5.3% (95%CI 1.7-12.3) versus 18.4 %(95%CI 10.7-27.8) {HR= 0.6318, 95%CI 0.4476 -0.8919: P=0.009} and 5.3% (95%CI 1.7-12.3) versus 17.1 % (95%CI 9.66.-26.3) {HR= 0.6379, 95%CI 0.4524 -0.8993: P=0.01} in the TMC and the TMC-I arms respectively. The benefit of the addition of nivolumab was independent of other factors like age, gender, ECOG PS, Site of malignancy, time to failure, PDL1 score, and previous exposure to platinum (Table). Conclusions: The addition of low-dose nivolumab to triple metronomic chemotherapy leads to a tripling of OS thus suggesting that even low-dose nivolumab has sustainable benefits. The benefit observed is irrespective of known prognostic factors in HNSCC. Clinical trial information: CTRI/2020/11/028953 . [Table: see text]

Efficacy and safety of different chemotherapy regimens in patients with disseminated pancreatic cancer over 65 years old

Aim. To evaluate the effectiveness and tolerability of systemic chemotherapy in elderly patients with metastatic pancreatic cancer (mPC) in real clinical practice.Materials and methods. The study included patients with mPC over 65 years of age who received first-line chemotherapy at the N. N. Blokhin National Medical Research Center of Oncology for the period from 2004 to 2023. Any previous antitumor chemotherapy for mPC was an exclusion criterion. The primary endpoint was 1-year overall survival (OS), and the secondary endpoints were ORR, median progression-free survival, median OS, chemotherapy tolerability.Results. The study included 148 patients aged 65 to 86 years with mPC who received first-line chemotherapy. Median progression-free survival among the entire population was 5.2 months. One-year OS among all patients was 32 %. The 1-year OS in mFOLFIRINOX group was 43.4 % and in gemcitabine group – 19.6 %. In a subgroup analysis, median OS with combination treatment was higher than in the gemcitabine monotherapy group (median OS 8.4 months vs. 6.8 months, p = 0.009). Patients with ECOG 2–3 also benefited from combination chemotherapy. Median OS was 8.9 months versus 3.9 months in gemcitabine (p = 0.008). The frequency of an objective response with triple chemotherapy was 66.1 %. In 30.8 % of cases, grade 3–4 neutropenia developed with mFOLFIRINOX, but febrile neutropenia developed only in three patients (5.8 %). The incidence of grade 3–4 adverse events was low, and these chemotherapy regimens were well tolerated.Conclusion. Conducting a triple chemotherapy regimen in elderly patients with mPC is an effective treatment option with an acceptable range of toxicity.

Real world effectiveness and safety of low dose nivolumab with metronomic chemotherapy in patients with advanced platinum-resistant head and neck cancer: An Indian institutional experience.

6050 Background: Triple Metronomic chemotherapy (TMC) regimen of low-dose methotrexate, erlotinib, and celecoxib has been proven to improve overall survival (OS) of advanced platinum-resistant head and neck cancer (HNC) patients. The addition of low-dose nivolumab to metronomic chemotherapy is an alternative standard of care for those patients, who cannot access full-dose checkpoint inhibitors. In the present study, we aimed to assess the real world effectiveness and safety of low-dose nivolumab along with TMC. Methods: We performed a prospective analysis of advanced platinum-resistant HNC patients treated at our institute from June 2021 to June 2023 with TMC and low-dose immunotherapy consisting of capsule celecoxib (200 mg twice daily), tablet methotrexate (9 mg/m2/week), and erlotinib (150 mg once daily), along with intravenous nivolumab 20 mg (once every 2 weeks). Data was analysed descriptively and the Kaplan-Meier method was used to estimate OS, progression-free survival (PFS), and duration of response (DOR). Results: Overall, 85 patients of advanced platinum-resistant HNC were enrolled in this study. The median age of the patients was 54 years with male predominance. The most common primary sites were buccal mucosa (54%) and tongue (32%). The median follow-up was 6.5 months with 5 months of DOR to therapy. Median number of nivolumab doses received were 8 (IQR 2–48). The termination of therapy in the majority of patients was due to disease progression (55%). Most common adverse events reported were acneiform rash (62%), mucositis (52%), and fatigue (34%). Dose reduction for triple metronomic chemotherapy was required in 42% of patients for grade 3 and above adverse events. No grade 3/4 immune-related adverse events were reported throughout the study period. The median PFS and OS of the study population were observed to be 4.3 months and 8.8 months, respectively. Overall, 8 of 85 patients survived for ≥30 months and 20 (24%) patients were on treatment at the time of data analysis. Conclusions: Low-dose immunotherapy along with triple metronomic chemotherapy is a safe treatment option in real world advanced platinum-resistant HNC patients with acceptable outcomes.

A retrospective, descriptive analysis of a single-center experience with patients with metaplastic breast cancer.

e13173 Background: Metaplastic breast cancer (MpBC) is a subtype of breast cancer (BC) that is commonly triple negative (TN) and chemotherapy (CT) resistant. Despite CT resistance, standard of care therapy is administered according to receptor status, regardless of metaplastic histology. Randomized data regarding optimal treatment of this rare histologic subtype are lacking. Methods: This was a retrospective analysis of MpBC patients (pts) treated at Miami Cancer Institute (MCI) between 2017 and 2021. Pts were identified using COTA real-world Analytics, an analytics platform enabling rapid investigation of longitudinal real-world data. Pt demographics, pathologic characteristics, staging, treatment, and survival outcomes were collected and analyzed. Results: 46 pts with MpBC were identified. Median age at diagnosis was 60.5 years, and 83.7% were post-menopausal. 84.8% were White, 10.9% were Black, and 54.3% were Hispanic (all White). 80.4% (n=37) had TNBC (ER < 1% and HER2 negative by ASCO CAP guidelines). 13.0% of pts (n=6) had spindle cell morphology and these pts had numerically lower 5-yr overall survival (OS) compared to those with non-spindle cell morphology; (83.3%; 95% CI 53.5%-100% vs 91.7%; 95% CI 82.7%-100%). Of 21 pts (45.7%) who underwent germline genetic testing, a pathogenic variant was detected in 2 (9.5%); (BRCA2, PALBB2). At diagnosis, 93.5% (n=43) had early-stage disease, 2.2% (n=1) had de novo metastatic breast cancer (MBC), 2 were unknown. Of the early-stage pts, 12 (27.9%) had stage 1, 19 (44.1%) stage 2, and 6 (14.0%) stage 3 BC. Of 43 pts with treatment records available, 34 (79.1%) received CT and 20 (46.5%) received anthracycline-based CT in the early-stage setting. Of those who received CT, 50% (n=17) were treated in the neoadjuvant setting, and 2 pts (11.8%) achieved pathologic complete response (pCR). Median distant recurrence free survival (DRFS) and OS were not reached in the overall cohort. Two-year OS was 90.5% (95% CI 81.6%-99.4%) and two-year DRFS was 78.9% (95% CI 66.6%-91.2%). Of the 43 pts with early-stage MpBC at diagnosis, 11 (25.6%) developed MBC with lung as the most common site of metastasis. Only 15.2% (n=7) of tumors underwent somatic mutation analysis and 71.4% (5/7) were PIK3CA-mutated. Of the pts who developed MBC, median progression-free survival with cytotoxic chemotherapy was 9.0 months (95% CI 5.0-13.0). Conclusions: MpBC represents an aggressive phenotype of BC and optimal guidance regarding treatment is lacking. Consistent with published literature, a high proportion of MpBC in this study were TN (>80%). Our dataset represents the largest cohort to date of Hispanic pts with MpBC. Despite the poor outcomes historically reported with MpBC, median DRFS and OS were not reached in this cohort, with short follow up. Further prospective randomized data on the optimal treatment of MpBC is warranted and a larger multi-institution review is planned.

Abstract 5275: Celecoxib and chloroquine enhance the antitumor effect of immune checkpoint blockade therapy, in a syngeneic mouse model for pancreatic cancer

Abstract Immune checkpoint inhibitors (ICIs) have shown impressive clinical activities in some cancer types, but they have yet to demonstrate any meaningful clinical benefit in patients with pancreatic ductal adenocarcinoma (PDAC) except those with microsatellite instability high (MSI-H) tumors. Several recent studies showed that concomitant use of NSAIDs such as celecoxib by patients with certain cancers could improve the survival benefit of ICI treatment (e.g., Sebastian et al, Clin Lung Cancer, 2023;). Furthermore, autophagy inhibitors such as chloroquine were also reported to sensitize pancreatic tumors to the treatment of ICIs in mouse models for PDAC (Yamamoto, et al, Nature, 2020). We recently reported that the combination of chemotherapy (triple combination of nab-paclitaxel + gemcitabine + cisplatin) and a mouse surrogate of the IFc-enhanced anti-CTLA-4 antibody botensilimab, showed significantly improved antitumor activity in immune competent KPC syngeneic mouse model for PDAC [Tanne, et al, Cancer Res (13_Supplement), 2020]. In this study, we sought to determine whether or not the addition of celecoxib and/or chloroquine further improve the antitumor activity of triple chemotherapy and ICI in the syngeneic KPC model. We first found that celecoxib (30mg/kg P.O. QDx21) significantly enhanced the tumor growth inhibition when added to triple chemotherapy (Gemcitabine 70mg/kg I.P., Cisplatin 4mg/kg I.P., Nab-paclitaxel 25mg/kg I.V. days 1,4 and 7) plus the murine equivalents of botensilimab (100ug I.P. BIW for three weeks) and balstilimab (200ug I.P. BIW for three weeks) (p=0.004, N=10). We then performed a pilot study to assess if adding chloroquine could further improve the activity. While adding chloroquine (60mg/kg I.P. QDx21) alone did not significantly affect tumor growth the addition of both chloroquine and celecoxib greatly improve the tumor growth inhibition compared to just the triple chemotherapy and ICIs (p=0.009, N=5). Overall, our data showed that celecoxib or the combination of celecoxib and chloroquine could substantially sensitize the mouse pancreatic tumors to the treatment of chemotherapy and ICIs. (This work was supported in part by the Seena Magowitz Foundation and the Purple Pansies) Citation Format: Jaeger Moore, Dhan Chand, Daniel Levey, Daniel Von Hoff, Haiyong Han. Celecoxib and chloroquine enhance the antitumor effect of immune checkpoint blockade therapy, in a syngeneic mouse model for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5275.

DDX58 deficiency leads to triple negative breast cancer chemotherapy resistance by inhibiting Type I IFN-mediated signalling apoptosis.

Triple-negative breast cancer (TNBC) is characterized by its aggressive nature and absence of specific therapeutic targets, necessitating the reliance on chemotherapy as the primary treatment modality. However, the drug resistance poses a significant challenge in the management of TNBC. In this study, we investigated the role of DDX58 (DExD/H-box helicase 58), also known as RIG-I, in TNBC chemoresistance. The relationship between DDX58 expression and breast cancer prognosis was investigated by online clinical databases and confirmed by immunohistochemistry analysis. DDX58 was knockout by CRISPR-Cas9 system (DDX58-KO), knockdown by DDX58-siRNA (DDX58-KD), and stably over expressed (DDX58-OE) by lentivirus. Western blotting, immunofluorescence and qPCR were used for related molecules detection. Apoptosis was analyzed through flow cytometry (Annexin V/7AAD apoptosis assay) and Caspase 3/7 activity assay. Patients with lower expression of DDX58 led to lower rate of pathological complete response (pCR) and worse prognosis by online databases and hospital clinical data. DDX58-KD cells showed multiple chemo-drugs resistance (paclitaxel, doxorubicin, 5-fluorouracil) in TNBC cell lines. Similarly, DDX58-KO cells also showed multiple chemo-drugs resistance in a dosage-dependent manner. In the CDX model, tumours in the DDX58-KO group had a 25% reduction in the tumour growth inhibition rate (IR) compared to wild-type (WT) group after doxorubicin (Dox) treatment. The depletion of DDX58 inhibited proliferation and promoted the migration and invasion in MDA-MB-231 cells. The findings of our research indicated that DDX58-KO cells exhibit a reduction in Dox-induced apoptosis both in vivo and in vitro. Mechanistically, Dox treatment leads to a significant increase in the expression of double-stranded RNAs (dsRNAs) and activates the DDX58-Type I interferon (IFN) signaling pathway, ultimately promoting apoptosis in TNBC cells. In the process of TNBC chemotherapy, the deficiency of DDX58 can inhibit Dox-induced apoptosis, revealing a new pathway of chemotherapy resistance, and providing a possibility for developing personalized treatment strategies based on DDX58 expression levels.

109 Real world data on Low-Dose Nivolumab with Triple Metronomic Chemotherapy: Retrospective analysis of 50 consecutive patients from LMICs

109 Real world data on Low-Dose Nivolumab with Triple Metronomic Chemotherapy: Retrospective analysis of 50 consecutive patients from LMICs

Comparative Study on the Efficacy of Two Perioperative Chemotherapy Regimens for Lumbar Brucellosis.

The clinical efficacy of perioperative chemotherapy regimen (rifampicin, doxycycline, levofloxacin, ceftriaxone) was evaluated for lumbar brucellosis spondylitis patients with neurological injury. In Beijing Ditan Hospital affiliated with Capital Medical University, 32 patients with lumbar brucellosis spondylitis underwent surgery and triple perioperative chemotherapy (rifampicin, doxycycline, levofloxacin) between 2011 and 2021 due to neurological injury, and 34 patients matched up with the triple group underwent rifampicin, doxycycline, levofloxacin, and ceftriaxone. Both groups were compared in terms of changes in inflammation index, low back/leg pain, lumbar function, neurological function, and adverse drug reactions. There was no significant difference in erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), low back pain visualanalogue scale (VAS), leg pain VAS, lumbar Oswestry disability index (ODI) and nerve function injury rate between the two groups before chemotherapy (P>0.05). The ESR, CRP at 1 week and 2 weeks after chemotherapy and 1 week, 2 weeks, 1 month postoperatively in the quadruple group were significantly lower than those in the triple group, which is the same to ESR 3 months postoperatively (P<0.05). The low back pain VAS, leg pain VAS and lumbar ODI in the quadruple group were significantly lower than those in the triple group at 1 month and 3 months postoperatively (P<0.05). The recovery rate of neurological function in the quadruple group was significantly higher than that in the triple group at 3 and 6 months postoperatively (P<0.05). Both groups did not experience significantly different perioperative and postoperative adverse reactions (P>0.05). For lumbar brucellosis spondylitis with neurological injury, quadruple perioperative chemotherapy of rifampicin, doxycycline, levofloxacin and ceftriaxone can significantly reduce perioperative inflammation, and improve low back/leg pain, as well as promoting neurological function recovery in the short term.

Evaluation of standardized triple intrathecal therapy toxicity in oncohematological adult patients

ObjectiveTo assess the toxicity of a standardized triple intrathecal chemotherapy in onco- hematological adult patients and to establish risk factors of toxicity. MethodObservational and prospective study of standardized triple intrathecal chemotherapy administrations in onco-hematologic adult patients for 18 months. ResultsThere were some adverse events in 39.3% of the 56 administrations registered. 96.7% of the events were grade 1-2 and only 1 event was grade 3. The lower age of the patient and the greater difference between the administered drug volume and cerebrospinal fluid removed volume were shown as risk factors for toxicity. ConclusionsThe administration of standardized triple intrathecal chemotherapy was related to a low frequency of toxicity and most of adverse events were mild-moderate. The detection of adverse effects was significantly greater in young adults and in those administrations where the difference between cerebrospinal fluid remove volume and the administered drug was greater.

936P Triple oral metronomic chemotherapy (OMCT) versus physician choice chemotherapy after failure of platinum-based therapy in advanced head and neck squamous cell cancer (HNSCC): A phase III randomized open-label study

936P Triple oral metronomic chemotherapy (OMCT) versus physician choice chemotherapy after failure of platinum-based therapy in advanced head and neck squamous cell cancer (HNSCC): A phase III randomized open-label study

Survival Benefit from Multimodal Treatment for Patients with Atypical Teratoid Rhabdoid Tumor in a Surveillance, Epidemiology, and End Results Database Analysis

Introduction: Atypical teratoid rhabdoid tumor (ATRT) is among the most aggressive central nervous system malignancies. Although rare, this tumor typically afflicts young children and results in mortality within months. Here, we aim to determine key clinical features and treatment options that impact the survival of patients with ATRT. Methods: From the year 2000 to 2019, 363 patients with ATRT were identified from the Surveillance, Epidemiology, and End Results database. Univariate analysis was used to identify variables that had a significant impact on the primary endpoint of overall survival (OS). Multivariable analysis was then used to identify independent predictors of survival. Results: The median OS of the entire cohort was 13 months. Univariate analysis identified ages between 1 and 3 years, ages between 4 and 17 years, years of diagnosis between 2010 and 2019, and the receipt of treatment to have a significant impact on survival. In multivariable analysis, ages between 1 and 3 years and receipt of treatment were the only significant independent predictors of survival. The median OS was significantly greater in patients who received surgical treatment, chemotherapy, or radiation when compared to those who did not receive any treatment. In general, the receipt of any combination of therapies improved the median OS significantly. The receipt of triple therapy had the greatest impact on survival. Discussion: This study highlights the survival benefit of a multimodal approach in the treatment of ATRT. The use of triple therapy, including surgery, radiation, and chemotherapy, was found to have the greatest survival benefit for patients. Overall, these findings may guide future care for patients with ATRT.

Phase 3 randomized study for evaluation of physician choice Rx and triple metronomic as second-line therapy in head and neck cancer (CRSF 2021-HN-001).

LBA6004 Background: There are multiple options of treatment in second-line therapy in locally advanced head and neck squamous cell carcinoma (LAHNSCC) with recurrent or metastatic disease. However triple metronomic chemotherapy is oral, affordable, and requires minimal resources. Hence in this study, we compared NCCN-recommended physician choice of standard systemic therapy versus triple metronomic therapy in the second-line treatment of head and neck cancer. Methods: This was a phase 3, multicentric (16 sites), randomized study with a superiority design that was approved by the institutional ethics committees and registered with CTRI (CTRI/2021/08/036002) conducted in India under the aegis of Cancer Research Statistics Foundation. The study recruited LAHNSCC with a recurrent and metastatic disease that either was platinum-refractory or was planned for second-line chemotherapy. The key inclusion criteria were: Age ≥18 years, ECOG PS 0-2, and the presence of normal hematological and biochemical parameters. These patients underwent 1:1 central stratified randomization (Stratification - site of disease &amp; ECOG PS) to either triple metronomic chemotherapy (methotrexate 9 mg/m2 PO weekly, celecoxib 200 mg PO twice daily and erlotinib 150 mg PO once daily) or physician choice therapy ( nivolumab or pembrolizumab or cetuximab or taxane or afatinib or 5-FU or capecitabine). The study drugs were administered either till disease progression or the development of intolerable side effects. The primary endpoint of the study is overall survival (OS). The secondary endpoints are adverse events (CTCAE version 5.0), progression-free survival (PFS), and quality of life (EORTC). The sample size required was 114. The OS and PFS were estimated using Kaplan-Meier method and were compared using the log-rank test. Cox proportional hazard model was constructed for the calculation of the hazard ratio. The adverse events were compared using Fisher's test. A p-value of 0.05 was considered significant. Results: At a median follow-up of 258 (95% CI 209-306) days.The median overall survival of the triple metronomic chemotherapy was 181 days (95%CI 142.7-219.2) versus 123 days (95%CI 94-152) in the physician choice therapy arm (P=.0.002). The corresponding hazard ratio of death was 0.58 (95%CI 0.33-0.79, P=0.003). The 6-month OS was 52.9% (95%CI 36.9-65.1) versus 14.8% (95%CI 6.4-26.4). The median progression-free survival was 120 days (95%CI 89.2-150.8) versus 70 days (95% CI 58.2-81.8) in metronomic chemotherapy and in the physician choice therapy arms respectively (P=0.000). The corresponding hazard ratio of progression was 0.5 (95%CI 0.33-0.74, P=0.001). Conclusions: In this phase 3 multicentric study, triple metronomic chemotherapy as second-line therapy had an overall survival and progression-free survival advantage over NCCN-recommended physician choice therapy. Clinical trial information: CTRI/2021/08/036002 .

Advancements in super-selective catheterization and drug selection for intra-arterial chemotherapy for retinoblastoma: a 15-year evolution

BackgroundRetinoblastoma (Rb) is the most common primary ocular malignancy of childhood. Left untreated, it is 100% fatal and carries a substantial risk of impaired vision and removal of one or...

Long term outcomes of phase I/II study of palliative triple metronomic chemotherapy in platinum-refractory/early failure oral cancer.

Triple metronomic chemotherapy is one of the options of treatment in platinum-refractory/early failure oral cancer. However, long term outcomes with this regimen are unknown. Adult patients with platinum-refractory/early-failure oral cancer were enrolled in the study. Patients were administered triple metronomic chemotherapy ie erlotinib 150mg once daily celecoxib 200mg twice daily and methotrexate weekly (phase 1 in variable dose 15-6 mg/m2 & 9 mg/m2 in phase 2), all taken orally till progression of disease or development of intolerable adverse events. The primary objective was to estimate the long-term overall survival and factors impacting it. The Kaplan Meier method was used for time-to-event analysis. Cox proportional hazard model was used to identify factors impacting overall survival (OS) and progression-free survival (PFS). The factors included in the model were age, sex, Eastern Cooperative Oncology Group - performance status (ECOG PS), tobacco exposure and a subsite of primary and circulating endothelial cell levels at baseline. A p-value of 0.05 was considered significant. Clinical trials information: CTRI/2016/04/006834. A total of 91 patients were recruited (15 in phase 1 & 76 in phase 2), the median follow-up was 41 months and 84events of death had occurred. The median OS was 6.7 months (95% CI 5.4-7.4). The 1-year, 2-years and 3-year OS' were 14.1% (95% CI 7.8-22.2), 5.9% (95% CI 2.2-12.2) and 5.9% (95% CI 2.2-12.2) respectively. The only factor favorably impacting OS was the detection of circulating endothelial cells at baseline (HR=0.46; 95% CI 0.28-0.75, P=0.0020). The median PFS was 4.3 months (95% CI 4.1-5.1) and the 1-year PFS was 13.0% (95% CI 6.8-21.2). The factors with statistically significant impact on PFS were detection of circulating endothelial cells at baseline (HR=0.48; 95% CI 0.30-0.78, P=0.0020) and no tobacco exposure at baseline (HR=0.51; 95% CI 0.27-0.94, P=0.030). The long-term outcomes with triple oral metronomic chemotherapy ie erlotinib, methotrexate and celecoxib are unsatisfactory. Detection of circulating endothelial cells at baseline is a biomarker predicting efficacy of this therapy. The study was funded by an intramural grant from Tata Memorial Center Research Administration Council (TRAC) and Terry Fox foundation.

Impact of triple intrathecal prophylaxis in acute lymphoblastic leukemia adults receiving HyperCVAD: A COVID-19 practice change.

Treatment of acute lymphoblastic leukemia (ALL) requires both systemically and locally directed therapies to prevent central nervous system (CNS) recurrence. In response to restrictions brought on by the COVID-19 pandemic, our institution adopted triple intrathecal (IT) chemotherapy for CNS prophylaxis during HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine). We retrospectively reviewed records of newly diagnosed adult all patients who were consecutively treated with HyperCVAD between January 2011 and July 2022. Outcomes of patients who received triple IT chemotherapy and standard of care (SOC) CNS prophylaxis were compared. The primary endpoint was CNS relapse-free survival (RFS) while secondary endpoints included cumulative incidence of relapse, overall survival, number of outpatient, and total ITs per patient, and CNS treatment-related toxicities. A total of 37 patients including 21 in the triple IT and 16 in the SOC cohorts were evaluated. There were no differences between the triple IT and SOC cohorts with respect to CNS-RFS (89.6% vs. 80.4%; HR, 1.55; 95% CI, 0.45-5.39; p = .49), cumulative incidence of relapse (8.9% vs. 19.6%; HR, 1.14; 95% CI, 0.3-5.3; p = .87), and overall survival (89.6% vs. 85.7%; HR, 0.91; 95% CI, 0.20-4.21; p = .90) at 2-years. Significantly fewer IT doses were administered in the triple IT cohort (p = .011) and the number of additional outpatient appointments to administer IT chemotherapy were markedly reduced as 98.6% of IT doses were administered during scheduled admissions compared to 76.8% (p < .001). The adoption of triple IT chemotherapy did not increase CNS treatment-related toxicities but rather, the inverse was observed. Triple IT chemotherapy during HyperCVAD represents a feasible alternative to SOC CNS prophylaxis, especially during times of resource restriction and when minimization of patient exposures is desired.

Abstract 1689: The role of circular RNAs in triple negative breast cancer and chemotherapy resistance

Abstract Background: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death among women worldwide. Triple negative breast cancer (TNBC) represents 15-20% of all breast cancers and is an aggressive subtype. Chemotherapy-based treatments remain the standard of care for TNBC. Unfortunately, chemotherapy resistance is common, and for these patients, outcomes are poor and alternative treatment strategies remain an unmet need. circRNAs are a newly identified class of noncoding RNA molecules with covalently closed circular structures. An increasing number of recent studies including ours have indicated that circRNAs play crucial roles in regulating tumor development and chemoresistance. However, the role of circRNAs in the process of chemotherapy resistance and TNBC progression is not clear. Materials and Methods: As a first step towards identifying circRNAs that participate in the development of chemoresistance in TNBC cells, and to determine if targeting such circRNAs is a novel and efficacious therapeutic strategy, doxorubicin-resistant (Doxo-R), paclitaxel-resistant (PTX-R), and double-resistant (DP-R) cell lines were generated from MDA-MB-231. Human circRNA microarrays were utilized to profile the expression of approximately 14,000 known circRNAs in normal breast tissue, matched patient-derived xenografts (PDX) generated prior to and following neoadjuvant chemotherapy (NAC), and TNBC chemosensitive and chemoresistant cell lines. Top hits were validated using RT-PCR. Results: circRNA microarray profiling identified 429 and 310 transcripts differentially expressed in doxorubicin and paclitaxel resistant cells, respectively, compared to parental chemosensitive cell lines (|FC| ≥ 1.5; p value &amp;lt; 0.05). In comparison to pre-NAC derived xenografts, 1,396 circRNAs were dysregulated among post-NAC PDX models. Further, three circRNAs (hsa_circ_001388, hsa_circ_104652, and hsa_circ_061260) were upregulated in Doxo-R, PTX-R, and post-NAC PDX samples compared to their respective controls. Among these three circRNAs, hsa_circ_001388 (also known as circNSD2) was the only transcript also predicted to be translated into a novel and uncharacterized protein given the presence of a high confidence translation initiation site and IRES sequence. Ongoing studies are aimed at determining the role of circNSD2 protein in breast cancer carcinogenesis, progression, and response to standard of care chemotherapeutics and the mechanistic process by which this protein functions. Additionally, the efficacy of specifically targeting this circRNA as a novel therapeutic approach is being explored. Conclusions: Increasing knowledge of the important functions of circRNAs underlying drug resistance will provide new opportunities for developing efficacious therapeutic strategies and prognostic/predictive biomarkers for TNBC. Citation Format: Xiyin Wang, Michael J. Emch, Xiaojia Tang, Jia Yu, Krishna R. Kalari, Liewei Wang, Matthew P. Goetz, John R. Hawse. The role of circular RNAs in triple negative breast cancer and chemotherapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1689.