Triplet Chemotherapy Regimens Research Articles

261. CONVERSION ESOPHAGECTOMY FOR CT4B ESOPHAGEAL CANCER - MIE VS OPEN -

Abstract Background and Aims The standard treatment for locally advanced unresectable esophageal cancer is definitive chemoradiotherapy (dCRT), however, after induction chemotherapy with a triplet chemotherapy regimen (docetaxel, cisplatin, and 5-FU: DCF) or dCRT, conversion surgery could be performed if esophageal cancer is considered resectable. Furthermore, minimally invasive surgery such as robot-assisted or thoracoscopic procedures are expected to improve the outcome of patients with advanced esophageal cancer. We investigated the feasibility of minimally invasive esophagectomy (MIE) in conversion surgery. Materials and Methods Sixty-six patients who underwent conversion thoracic esophagectomy for cT4b esophageal cancer from 2007 to 2023 were included. The short-term outcomes of 25 open esophagectomy group and 41 MIE group (8 robot-assisted and 33 thoracoscopic) were compared. Results No differences in age, gender, PS, tumor location, histology, cN, or cM were observed between the two groups. cT4b organs tended to be in the airway in the MIE group (airway 70.7% vs 44%, major vessels 19.5% vs 24%, both 9.7% vs 32%, p=0.04) and DCF therapy was significantly performed in the MIE group for induction therapy (DCF 87.8% vs 56%, dCRT 12.2% vs 44%, p<0.001). On the other hand, salvage surgery was significantly associated with open esophagectomy (24.3% vs. 52%, p=0.003). There was no difference in surgical outcomes regarding thoracic operation time (157 min vs. 180 min, p=0.09), whereas the total operation time was significantly shorter in the MIE group (392 min vs. 439 min, p=0.02). Blood loss was significantly lower in the MIE group (79 ml vs. 470 ml, p<0.001), and R0 resection rate did not differ (82.9% vs. 72%, p=0.357). There were no significant differences in postoperative complications including pneumonia (26.8% vs. 44%, p=0.183) and recurrent nerve palsy (21.9% vs. 36%, p=0.260), but anastomotic leakage was significantly lower in the MIE group (4.8% vs. 24%, p=0.04). There was no difference in median postoperative hospital stay (16 [11-20] vs. 16 [14-29] days), however, median ICU stay (3 [3-4] vs. 4 [3-4] days, p=0.03) and readmission within 1 month after discharge (2.4% vs. 16%, p=0.04) were significantly lower in the MIE group. In-hospital mortality was observed in 1 case in the MIE group and 3 in the open esophagectomy group. Conclusion Despite the bias associated with the transition of treatment modalities and surgical techniques, MIE may contribute to improved short-term outcomes in conversion surgery.

Abstract PO2-05-07: Which treatment is done in patients with metastatic breast cancer who received a prior treatment with CDK4/6 inhibitors? A real-world experience in a single italian Institution

Abstract Patients with HR positive (HR+) and c-erb-b2 negative (HER2-) advanced breast cancer are treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with hormone therapy (HT). At the time of disease progression with these treatments, no established guidelines are defined for the subsequent therapeutic options.Treatment options after progression can be different, in terms of use of chemotherapy or ET alone, or the combination of the two, or of other biological agents (such as everolimus) or the HT combined with other therapies. We aimed to verify in our Institute (IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy) how HR+ mBC patients are treated after having received a treatment with HT plus CDK4/6 inhibitors (ribociclib, palbociclib, abemaciclib). 105 mBC patients, 32 of whom were treated with CD4/6 inhibitors plus letrozole and 73 treated with CDK4/6 inhibitors and fulvestrant were included in the study. 83 were treated with palbociclib, 16 with ribociclib and 6 with abemaciclib. The median age was 65 years (range 40-86), 58 were younger than 65 years. 90 were in postmenopausal status. On the total 105 patients, 46 (43.8%) were treated with a single chemotherapy regimen while 25 (23.8%) with a combined schedule of chemotherapies (Table 1). Only 9 (8.6%) have been treated with HT alone. 22 (20.95%) patients received combined treatments with ET or chemotherapy+targeted therapy or chemotherapy +immune checkpoint inhibitor. 1 (0.95%) patients was treated with a triplet chemotherapy regimen (cyclophosphamide+capecitabine +vinorelbine), 2 (1.9%) for whom the re-biopsy of the tumor resulted HER2 + were treated with taxol +pertuzumab +trastuzumab. 82/105 (78%) patients performed more lines of therapies after CDK4/6 inhibitors. In conclusion, patients with mBC were treated heterogeneously. The major part of them have been treated with chemotherapy alone or with combination of more chemotherapies. The evaluation of the patient response in relation to the different therapies is still ongoing as well as the effect of all the other therapies beyond the first line of treatment. Table 1. Type of treatments done in mBC patients (Nf105) after treatment with HT+ CDK4/6 inhibitors *1 performed only 1 cycle ** 1 was treated also with a metronomic schedule of therapy Citation Format: Sara Bravaccini, William Balzi, Andrea Roncadori, Alessandra Virga, Paola Ulivi, Giovanni Martinelli, Roberta Maltoni. Which treatment is done in patients with metastatic breast cancer who received a prior treatment with CDK4/6 inhibitors? A real-world experience in a single italian Institution [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-07.

Ganoderma spore lipid ameliorates docetaxel, cisplatin, and 5-fluorouracil chemotherapy-induced damage to bone marrow mesenchymal stem cells and hematopoiesis

BackgroundA triplet chemotherapy regimen of docetaxel, cisplatin, and 5-fluorouracil (TPF) is used to treat head and neck squamous cell carcinoma; however, it is toxic to bone marrow mesenchymal stem cells (BMSCs). We previously demonstrated that Ganoderma spore lipid (GSL) protect BMSCs against cyclophosphamide toxicity. In this study, we investigated the protective effects of GSL against TPF-induced BMSCs and hematopoietic damage.MethodsBMSCs and C57BL/6 mice were divided into control, TPF, co-treatment (simultaneously treated with GSL and TPF for 2 days), and pre-treatment (treated with GSL for 7 days before 2 days of TPF treatment) groups. In vitro, morphology, phenotype, proliferation, senescence, apoptosis, reactive oxygen species (ROS), and differentiation of BMSCs were evaluated. In vivo, peripheral platelets (PLTs) and white blood cells (WBCs) from mouse venous blood were quantified. Bone marrow cells were isolated for hematopoietic colony-forming examination.ResultsIn vitro, GSL significantly alleviated TPF-induced damage to BMSCs compared with the TPF group, recovering their morphology, phenotype, proliferation, and differentiation capacity (p < 0.05). Annexin V/PI and senescence-associated β-galactosidase staining showed that GSL inhibited apoptosis and delayed senescence in TPF-treated BMSCs (p < 0.05). GSL downregulated the expression of caspase-3 and reduced ROS formation (p < 0.05). In vivo, GSL restored the number of peripheral PLTs and WBCs and protected the colony-forming capacity of bone marrow cells (p < 0.05).ConclusionsGSL efficiently protected BMSCs from damage caused by TPF and recovered hematopoiesis.

The efficacy of chemotherapy re-challenge in third-line setting for metastatic colorectal cancer patients: a real-world study

Objective: To explore the efficacy of chemotherapy re-challenge in the third-line setting for patients with metastatic colorectal cancer (mCRC) in the real world. Methods: The clinicopathological data, treatment information, recent treatment efficacy, adverse events and survival data of mCRC patients who had disease progression after treatment with oxaliplatin-based and/or irinotecan-based chemotherapy and received third-line chemotherapy re-challenge from January 2013 to December 2020 at Tianjin Medical University Cancer Institute and Hospital were retrospectively collected. Survival curves were plotted with the Kaplan-Meier method, and the Cox proportional hazard model was used to analyze the prognostic factors. Results: A total of 95 mCRC patients were included. Among them, 32 patients (33.7%) received chemotherapy alone and 63 patients (66.3%) received chemotherapy combined with targeted drugs. Eighty-three patients were treated with dual-drug chemotherapy (87.4%), including oxaliplatin re-challenge in 35 patients and irinotecan re-challenge in 48 patients. The remaining 12 patients were treated with triplet chemotherapy regimens (12.6%). Among them, as 5 patients had sequential application of oxaliplatin and irinotecan in front-line treatments, their third-line therapy re-challenged both oxaliplatin and irinotecan; 7 patients only had oxaliplatin prescription before, and these patients re-challenged oxaliplatin in the third-line treatment. The overall response rate (ORR) and disease control rate (DCR) reached 8.6% (8/93) and 61.3% (57/93), respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.9 months and 13.0 months, respectively. The most common adverse events were leukopenia (34.7%) and neutropenia (34.7%), followed by gastrointestinal adverse reactions such as nausea (32.6%) and vomiting (31.6%). Grade 3-4 adverse events were mostly hematological toxicity. Cox multivariate analysis showed that gender (HR=1.609, 95% CI: 1.016-2.548) and the PFS of front-line treatments (HR=0.598, 95% CI: 0.378-0.947) were independent prognostic factors. Conclusion: The results suggested that it is safe and effective for mCRC patients to choose third-line chemotherapy re-challenge, especially for patients with a PFS of more than one year in front-line treatments.

Najnoviji stavovi o prednostima primjene neoadjuvantne terapije kod pacijenata s uznapredovalim rakom želuca

Treatment for gastric cancer has multiple approaches and options across the world. Standard treatment for the Asian population comprises D2-gastrectomy and adjuvant chemotherapy. However, in Europe and North America, clinical trials have shown that perioperative chemotherapy, given to patients before surgery, could improve resection and survival rates significantly. Most recent studies have also discussed the advantages of doublet vs. triplet chemotherapy regimens. Furthermore, researchers have been comparing the effects of perioperative chemoradiotherapy as opposed to chemotherapy alone. The specific advantages of previously stated therapy options, as well as any novel treatments, should be researched more thoroughly in the future.

Recurrence Pattern Comparing Preoperative Chemoradiotherapy and Preoperative Chemotherapy with Docetaxel plus 5-Fluorouracil and Cisplatin for Advanced Esophageal Cancer

Background: Preoperative chemoradiation therapy (CRT) or chemotherapy (CT) followed by surgery is currently being administered for advanced esophageal cancer. However, few studies have directly compared CRT and CT for treating locally advanced esophageal carcinoma. This study aimed to assess postoperative recurrence patterns and post-recurrence outcomes in patients with radical esophagectomy after CRT or triplet CT regimen with docetaxel, cisplatin, and 5-fluorouracil (DCF). Methods: This study included 325 consecutive patients with thoracic esophageal cancer who received preoperative CRT or DCF followed by curative esophagectomy between January 2010 and December 2019. We compared recurrence patterns after surgery and post-recurrence treatments between CRT and DCF. Locoregional recurrence was defined as recurrences at the primary tumor site or regional lymph nodes. Distant recurrence was defined as non-regional lymph node recurrences, systemic metastases, malignant pleural effusions, or peritoneal metastases. Results: Among 325 patients, 74 received preoperative CF + RT and 251 received preoperative DCF. A propensity score-matched cohort of 53 with CRT and 53 with DCF was included. CRT patients had tumors located in the upper esophagus and had more advanced cancer than DCF patients; however, no differences in patient characteristics were observed in the matched cohort. CRT patients had better histopathological responses and control of locoregional recurrence than DCF patients. On the other hand, distant recurrence, especially in the non-regional lymph node, lung, and pleural dissemination, significantly developed more frequently in CRT patients. Furthermore, CRT patients may have received insufficient post-recurrence treatment, owing to fewer treatment options. Therefore, although there was no difference in recurrence rate in the two groups, CRT patients had significantly poorer post-recurrence survival than DCF patients. Conclusions: Preoperative DCF could reduce distant recurrence after surgery compared to preoperative CRT. The differences in recurrence patterns can be related to the selection of post-recurrence treatment and their prognosis after recurrence.

Abstract 2566: Pre-clinical efficacy of the Wnt pathway inhibitor RXC004 in combination with anti-cancer therapies

Abstract Background: RXC004, a potent and selective inhibitor of the Wnt pathway regulator Porcupine, is being investigated in phase 2 studies in patients with advanced cancers (NCT04907851 and NCT04907539). Wnt pathway alterations, including loss-of-function RNF43 mutations and RSPO gene fusions, result in higher levels of the Wnt receptor Frizzled (Fzd) on the cell surface increasing Wnt-ligand dependent signaling. These alterations, which have been shown to be sensitive to Porcupine inhibitors, are implicated in colorectal, gastric and pancreatic cancer. Pre-clinical in vivo data on the effects of RXC004 in combination with clinically relevant anti-cancer therapies have not previously been described in genetically-defined models of cancer. Methods: RXC004 was evaluated as a monotherapy, and in combination with clinically relevant chemotherapy regimens, in an RSPO-fusion colorectal xenograft model (SNU-1411). RXC004, dosed at 5mg/kg QD (5 days on/2 days off), was evaluated in combination with either the clinically relevant colorectal triplet chemotherapy regimen (5-fluorouracil 5-FU (25mg/kg), irinotecan (50mg/kg) and oxaliplatin (5mg/kg)) or doublet chemotherapy regimen (5-FU (25mg/kg), irinotecan (50mg/kg)). Each chemotherapy regimen was dosed once a week for 3 to 4 weeks either alone or in combination with RXC004, which was dosed from day 8 onwards at 5mg/kg QD (5 days on/2 days off). Efficacy was measured by tumor volume and survival endpoint. In addition, RXC004 was studied in vitro, as monotherapy and in combination with a PARP inhibitor in genetically selected cell lines with both RSPO-fusion and RNF43 mutation. Combination and monotherapy effects on proliferation and effects on downstream signaling were investigated. Results: RXC004 in combination with the triplet chemotherapy regimen led to significantly increased survival compared to either treatment alone (p&amp;lt;0.005) and significant tumor volume reduction measured at Day 22 (p&amp;lt;0.001). RXC004 in combination with the doublet chemotherapy also increased survival compared to either treatment alone (p&amp;lt;0.05), and the combination led to significantly decreased tumor volume measured at Day 25 (p&amp;lt;0.05). RXC004 treatment in genetically defined cell lines with RSPO fusions or RNF43 mutations led to a significant reduction in BRCA1 and BRCA2 gene expression. In in vitro proliferation studies a synergistic effect of RXC004 and a PARP inhibitor was demonstrated in genetically defined cell lines. Conclusion: These data demonstrate that RXC004 in combination with clinically relevant standard of care chemotherapy regimens can lead to potential benefit over chemotherapy alone. The RXC004 induced downregulation of DNA repair pathway genes observed in vitro could contribute to the beneficial effect seen in combination with a PARP inhibitor in vitro as well as the combination effect observed in vivo with standard of care chemotherapy agents. Citation Format: James Kelly, Simon Woodcock, Inder Bhamra, Cliff Jones, Richard Armer, Jane Robertson, Caroline Phillips. Pre-clinical efficacy of the Wnt pathway inhibitor RXC004 in combination with anti-cancer therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2566.

Abstract CT549: Randomized Phase II trial of two different nutritional approaches for patients receiving treatment for their advanced pancreatic cancer

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by stromal fibrosis, hypoxia, and nutritional deprivation. PDAC tumors grow aggressively, diagnosis is typically made after metastasis and the disease remains associated with poor outcomes. The triplet chemotherapy regimen of gemcitabine, nab-paclitaxel with cisplatin was associated with a median overall survival of 16.4 months in patients with metastatic pancreatic cancer in the first-line setting (Jameson et al., 2020). Nutritional, metabolic interventions offer an opportunity to fundamentally change the tumor microenvironment and improve outcomes for patients. A medically supervised ketogenic diet (MSKD) defined as lower carbohydrate, lower protein, and higher fat can significantly reduce glucose and insulin and increase metabolically active ketone bodies. A ketogenic diet combined with triplet chemotherapy (gemcitabine, nab-paclitaxel, cisplatin) was shown to inhibit murine pancreatic KPC tumor growth and to triple the survival benefit of chemotherapy alone. The ketogenic diet combined with triple chemotherapy was associated with glucose depletion, altered TCA substrate usage, and NADH elevation. Methods: In this Phase II randomized clinical trial (NCT04631445), we are evaluating a medically supervised ketogenic diet (MSKD) versus a standard diet when combined with the triplet therapy in patients with treatment-naive advanced pancreatic cancer. The primary endpoint is progression free survival for triplet therapy while on MSKD or non-MSKD. Secondary endpoints include disease control rate (PR+ CR+ SD for at least 9 weeks), change in CA 19-9 (or CA125, or CEA if not expressers of CA 19-9), average insulin levels, HbA1c, body weight, a comparison of gut microbial diversity, changes in serum metabolites and quality of life via the EORTC QLQ-C30 assessment. Unlike prior ketogenic intervention studies, the MSKD is being supported by a continuous care nutrition intervention through Virta Health Corp, that offers tracking of daily ketone and glucose levels, a web-based software application, education, and communication with a remote care team to ensure sustained nutritional ketosis. A total of 40 patients with untreated metastatic PDAC are planned for enrollment, 20 randomized to each arm. The trial opened for accrual November 2020. Citation Format: Diana Hanna, Gayle S. Jameson, Drew W. Rasco, Angela Alistar, Richard C. Frank, Anthony B. El-Khoueiry, Julia E. Wiedmeier, Caroline Roberts, Brandon Fell, Sarah Hallberg, Denise Roe, Derek Cridebring, Joshua Rabinowitz, Stephen Thomas Gately, Daniel D. Von Hoff. Randomized Phase II trial of two different nutritional approaches for patients receiving treatment for their advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT549.

Elevated levels of CA125 (MUC16) in metastatic gastric cancer as a strong predictor of poor survival

Introduction: CA125 is an extracellular domain of MUC16 glycoprotein. The clinical significance of serum CA125 has been most extensively studied in ovarian cancer. The significance of serum CA125 in gastric cancer has not been fully elucidated. There is evidence that MUC16 overexpression is associated with poor survival in patients with metastatic gastric cancer. We have not found any research papers on the correlation between the levels of serum CA125 and MUC16 overexpression.Objective: The objective of the study was to assess the effects of elevated CA125 levels in patients with metastatic cancer on the long‑term results (time to disease progression and overall survival).Materials and methods: CA125 was determined in the serum before the start of first‑line chemotherapy in 75 patients (45 males and 30 females) with metastatic gastric cancer. The mean age of the patients was 61,3 (26,7–84,9) years. Synchronous metastases were observed in 85 % of patients: 57,3 % in the peritoneum, 37,3 % in the liver, 5,4 % at other sites. Palliative gastrectomy and metastasectomy were performed in 28 % and 20 % of patients, respectively. Monotherapy, doublet and triplet chemotherapy regimens were used in 6,7 %, 58,7 % and 36,0 % of patients, respectively.Results: the analysis showed that elevated levels of CA125 (&gt; 37 IU/mL) were associated with a significant reduction in median time to progression (3,5 months (CI 2,87–9,53) vs 6,2 months, р = 0.001 (CI 2,02–4,9)) and overall survival (5,1 months (CI 6,07–28,1) vs 17,1 months (CI 3,5–6,67), р = 0.001). One‑factor ANOVA showed that factors with the strongest effects on the survival rates included the location of metastases (peritoneum), tumor histology (adenocarcinoma/signet ring cell carcinoma), the use of palliative gastrectomy and metastasis resection. A multi‑factor ANOVA showed that the only favorable prognostic factors in terms of overall survival rates were normal CA125 levels (HR 0,39 (95 % CI 0,18–0,84), р = 0.001) and the use of palliative gastrectomy (HR 0,23 (95 % CI 0,1–0,58), р = 0.001). The use of triplet chemotherapy regimens allowed to slightly improve the overall survival rates in the group of patients with elevated CA125 levels; however, the differences were not statistically significant (6,7 months vs 4Ю0 months, p = 0.29).Conclusion: Elevated levels of CA125, which reflect MUC16 overexpression to a certain extent, is a strong independent predictor of poor outcome in metastatic gastric cancer. Currently, a possible way to overcome this negative impact is to use more intensive chemotherapy regimens. However, further research should be aimed at finding adequate targets and ways of neutralizing the negative impact of MUC16 overexpression in patients with metastatic gastric cancer.

Randomized phase II trial of two different nutritional approaches for patients receiving treatment for their advanced pancreatic cancer.

TPS637 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by stromal fibrosis, hypoxia, and nutritional deprivation. PDAC tumors grow aggressively, diagnosis is typically made after metastasis and the disease remains associated with poor outcomes. The triplet chemotherapy regimen of gemcitabine, nab-paclitaxel with cisplatin was associated with a median overall survival of 16.4 months in patients with metastatic pancreatic cancer in the first-line setting (Jameson et al., 2020). Nutritional, metabolic interventions offer an opportunity to fundamentally change the tumor microenvironment and improve outcomes for patients. A ketogenic diet defined as lower carbohydrate, lower protein, and higher fat can significantly reduce glucose and insulin and increase metabolically active ketone bodies and has been evaluated in patients with a variety of solid tumors (Weber et al, 2020). Recently, a ketogenic diet combined with triplet chemotherapy was shown to inhibit murine pancreatic KPC tumor growth and significantly prolong animal survival over chemotherapy alone. Tumor growth inhibition was associated with glucose depletion, altered TCA substrate usage, and NADH elevation. Methods: In this Phase II randomized clinical trial (NCT04631445), we are evaluating a medically supervised ketogenic diet (MSKD) versus a standard diet when combined with the triplet therapy in patients with treatment-naive advanced pancreatic cancer. The primary endpoint is progression free survival for triplet therapy while on MSKD or non-MSKD. Secondary endpoints include disease control rate (PR+ CR+ SD for at least 9 weeks), change in CA 19-9 (or CA125, or CEA if not expressers of CA 19-9), average insulin levels, HbA1c, body weight, a comparison of gut microbial diversity, changes in serum metabolites and quality of life via the EORTC QLQ-C30 assessment. Unlike prior ketogenic intervention studies, the MSKD is being supported by a continuous care nutrition intervention through Virta Health Corp, that offers tracking of daily ketone and glucose levels, a web-based software application, education, and communication with a remote care team to ensure sustained nutritional ketosis. A total of 40 patients with untreated metastatic PDAC are planned for enrollment, 20 randomized to each arm. The trial opened for accrual November 2020. Clinical trial information: NCT04631445.

Gastric cancer: Russian clinical guidelines

Gastric cancer remains one of the most common malignancies in Russia. Despite steady decrease of gastric cancer incidence it still reaches 24.65 per 100 000 population (crude rate) in 2019 with about 36 000 new cases annually. More than 29 000 people die of gastric cancer every year. High mortality rate is mostly caused by an extremely significant proportion of patients with metastatic disease which reached 40.1% in 2019. The majority of cases is related to Helicobacter pylori infection, salty diet, tobacco exposure as well as hereditary syndromes. Staging of locally advanced gastric cancer includes contrast-enhanced computed tomography of the thorax, abdomen and pelvis as well as diagnostic laparoscopy with peritoneal washings. In patients with inoperable or disseminated cancer of the stomach additional analysis for HER2, microsatellite instability and PD-L1 status is recommended. Endoscopic or laparoscopic resection remains the mainstay of treatment in patients with early cancer. Laparoscopic gastrectomy in patients with locally advanced cancer is reserved for high-volume centers with extensive experience with the procedure. Recently, perioperative cytotoxic therapy became the standard of treatment in patients with locally advanced gastric cancer. FLOT regimen is recommended while FOLFOX6 or XELOX are considered possible in the elderly or frail patients. Drug therapy includes standard doublet or triplet chemotherapy regimens for metastatic disease with trastuzumab for HER2(+++) patients. Patients with MSI-H tumors can be treated with pembrolizumab starting with 2nd line while nivolumab is reserved for the 3rd and further lines regardless of PD-L1 status. Importantly, this year guidelines include multimodal prehabilitation including physical exercise, nutritional support and psychological counselling as a possibility in all patients in need of surgery. Also standardized enhanced recovery protocols are recommended for usage during the perioperative period.

Triplet versus doublet neoadjuvant chemotherapy regimens for locally advanced gastric cancer: a propensity score matching analysis

BackgroundTo investigate the differences between doublet and triplet neoadjuvant chemotherapy (NAC) regimens in efficacy and safety profile.MethodsA total of 227 locally advanced gastric cancer (LAGC) patients who received NAC and sequential radical gastrectomy were reviewed. After propensity score matching (PSM), 140 patients with similar baseline characteristics were selected. Among them, 70 received doublet NAC regimens consisted of platinum and fluorouracil; the other 70 received triplet NAC regimens consisted of docetaxel, platinum, and fluorouracil.ResultsThe efficacy of doublet and triplet regimens was comparable after propensity score matching in terms of tumor regression (pathological complete response, Doublet 11.4% vs. Triplet 15.7%, p = 0.642), achieving of R0 resection (Doublet 88.6% vs. Triplet 88.6%, p = 1), 1-year disease-free survival (DFS) (Doublet 77.1% vs. Triplet 68.6%, p = 0.178), 3-years overall survival (OS) (Doublet 54.3% vs. Triplet 60.9%, p = 0.941). Post-surgery complications were more common in the triplet cohort (Doublet 5.7% vs. Triplet 27.1%, p = 0.001), especially abdominal infection (Doublet 0% vs. Triplet 11.1%, p = 0.001).ConclusionsA more intense preoperative triplet NAC regimen does not bring extra downstage effect and survival benefit compared to a doublet regimen. It may even result in a higher risk of post-surgery complications.

Multimodality approaches to control esophageal cancer: development of chemoradiotherapy, chemotherapy, and immunotherapy

Esophageal cancer has a poor prognosis despite the fact that surgical techniques have been advanced and optimized, and systemic multimodality approaches have progressed recently. Adding chemotherapy, radiotherapy, and immunotherapy to the basic surgical approach have been shown to have therapeutic benefit for esophageal cancer. This review describes the latest development of chemoradiotherapy, chemotherapy, and immunotherapy, which have contributed to the reduction in esophageal cancer growth and improved the survival of patients. Chemoradiation is a treatment option for resectable esophageal cancer to preserve the esophagus for patients who cannot tolerate surgery. Moreover, a combination of chemoradiotherapy and salvage surgery could extend the survival of patients. The effects of a triplet chemotherapy regimen are currently being verified in some Phase III studies for unresectable advanced/recurrent esophageal cancer. In addition, with the great promise of immune checkpoint inhibitors, strategies that incorporate the use of immunotherapy may shift from the metastatic setting to the neoadjuvant/adjuvant setting as a result of clinical trials. More precise comprehension of the molecular biology of esophageal cancer is expected to further control disease progression using multimodality treatments in the future.

The real-world practiсe of surgery in patients with metastatic gastric cancer (mGC).

363 Background: According to recent studies the results of treatment patients with initially mGC are still not sufficient: median overall survival varies between 6.1 and 12.4 months. The triplet-chemotherapy regimens demonstrate high efficacy and allow to downstage the disease and perform surgical treatment. Conversion treatment in stage IV GC is a modern trend and still an area of ongoing research. Methods: We analyzed the efficacy of first line chemotherapy (6-9 courses) for patients with mGC (n = 55) including the following regimens: 1) mFOLFIRINOX; 2) douplet: oxaliplatin/irinotecan + fluoropyrimidine; 3) triplet variations: docetaxel, platinum and fluoropyrimidine. 27/55 patients had &gt; 2 metastatic sites, 2/55 patient - 5 metastatic sites. The most common localizations of metastases were peritoneum (n = 34) and retroperitoneal lymph nodes (n = 11). Unlike in REGATTA trial all patients underwent surgical treatment with curative intent followed by complete response of distant metastases after chemotherapy. For patients with ovarian metastases ovariectomy was also perfomed. Results: Median progression-free survival and median overall survival were 18.5 and 33.27 months, respectively and the 3-year survival rate was 43.5%. Multivariate analysis showed that clinically determined ascites (p = 0.023), linitis plastica (p = 0.022), tumor grade 3 (p = 0.014), present of lymphovascular invasion (p = 0.037), absence of grade III-IV pathomorphosis (p = 0.037) and treatment free interval before surgery &lt; 3.4 month (p = 0.046) were poor independent prognostic factors. Conclusions: Surgery after effective combination chemotherapy may have significant clinical efficacy for selected patients with initially unresectable gastric cancer. According to our data the optimal time for surgery is a 3.4 and more months treatment-free interval in the absence of disease progression.

Optimizing Therapies in the Perioperative Management of Gastric Cancer.

Gastric cancer is a major health burden worldwide. Only about one-third of all the gastric cancer patients survive beyond 5-years. Management of this deadly disease has evolved over the last few decades due to the incorporation of better staging techniques, surgical approach, effective systemic treatment, and sequencing of different therapeutic modalities. There are some global differences in how local-regional gastric cancer is managed and treated. In the USA and some parts of Europe, perioperative chemotherapy is a preferred management approach. Adjuvant chemoradiation is considered if the surgical resection is performed upfront. However, in Asia, postoperative chemotherapy alone after D2 surgical resection is considered standard of care treatment. Based on recent evidence, perioperative treatment with triplet chemotherapy regimen FLOT (5FU, leucovorin, oxaliplatin, docetaxel) is the preferred regimen. However, doublet fluoropyrimidine/platinum combination is a reasonable alternative if triplet regimen cannot be given. At present, there are no approved targeted or immunotherapy agents in perioperative setting; however, there are a number of ongoing trials designed to examine the efficacy of targeted therapy and checkpoint inhibitors in various combinations with systemic therapy in perioperative setting.

Multimorbidity patterns and their association with survival in a large national cohort of older veterans with multiple myeloma.

8033 Background: The majority of older adults carry two or more chronic conditions (multimorbidity). Although comorbidity in multiple myeloma (MM) has often been described with comorbidity counts, the impact of multimorbidity clusters has yet to be investigated. Methods: In a national cohort of 7815 patients aged ≥60 years diagnosed with and treated for MM in Veterans Affairs Healthcare System, we extracted 53 chronic conditions from claims in the 3 years preceding diagnosis using the Centers of Medicare and Medicaid Services-defined chronic and disabling conditions. We performed latent class analysis to identify patterns of multimorbidity that coexisted with MM at diagnosis. We then assessed whether these multimorbidity patterns were associated with survival in 5992 non-transplanted patients initially treated with either doublet or triplet chemotherapy regimens, adjusting for MM stage, sociodemographic factors, and prognostic lab values. Results: Mean follow up time was 3.1 years (SD, 2.6). We identified 6 multimorbidity clusters at the time of MM diagnosis: minimal disease (1302 patients, 16.7%), cardiovascular disease (2011, 25.7%), diabetes and complications (1820, 23.3%), psychiatric and substance use disorders (931, 11.9%), chronic lung disease (759, 9.7%), and multisystem impairment (992, 12.7%). In patients initially treated with doublet or triplet chemotherapy, survival varied across multimorbidity patterns (p &lt; 0.001); patients with minimal disease had the best survival (median survival [MS] = 4.5 years, 5-year survival = 47.5%), and patients with multisystem impairment had the worst (MS = 2.4 years, 5-year survival = 24.3%). After adjustment for covariates, patients with clusters of chronic lung disease (HR = 1.40 [1.22-1.60]), psychiatric and substance use (HR = 1.57 [1.37-1.79]), and multisystem impairment (HR = 1.71 [1.50-1.94]) had higher hazards of death than patients with minimal disease. Conclusions: We found higher-impact and lower-impact multimorbidity clusters among older veterans with newly-diagnosed MM treated with chemotherapy. Unique combinations of chronic diseases may interact with MM itself to drive differences in mortality.

Oxaliplatin in perioperative chemotherapy for gastric and gastroesophageal junction (GEJ) adenocarcinoma

ABSTRACTIntroduction: Platinum-based chemotherapy remains standard-of-care for gastric and gastroesophageal junction (GEJ) adenocarcinoma. For locally advanced resectable disease, perioperative treatment with cisplatin-based doublet or triplet chemotherapy regimens had been the predominant approach in Europe and the US, based on pivotal phase III trials including the MAGIC study. Results from more recent landmark studies including the German FLOT4 and the Asian CLASSIC trials have, however, triggered a shift from cisplatin towards oxaliplatin-based chemotherapy protocols in the perioperative setting.Areas covered: This drug profile summarizes current state-of-the-art of perioperative and adjuvant treatment for locally advanced resectable gastric/GEJ cancers with a special focus on the increasingly predominant role of oxaliplatin over cisplatin in this setting. We review pharmacology, clinical efficacy, and safety profile of oxaliplatin and oxaliplatin combination regimens. We highlight recent advances and ongoing developments in the field.Expert opinion: While the adoption of oxaliplatin-containing combination regimens for perioperative therapy of gastric/GEJ cancers represents a significant step ahead, many pivotal questions remain unanswered. At the sample time, the evolution of molecular subtyping and immunotherapy is likely to dramatically change clinical practice in the foreseeable future.

Histological changes of superficial esophageal squamous cell carcinoma after preoperative chemotherapy.

We aimed to analyze the clinical and histological effects of chemotherapy in superficial esophageal squamous cell carcinoma (SESCC). We analyzed tumor samples from five patients with cT1bN1M0 who underwent subtotal esophagectomy following two courses of a new triplet chemotherapy regimen including docetaxel, cisplatin, and 5-fluorouracil (DCF). To assess the histological effects of chemotherapy, resected specimens were analyzed by macroscopic examination, hematoxylin & eosin (HE) staining, immunohistochemical (IHC) staining (p53, Ki-67 and cytokeratin) and periodic acid-Schiff (PAS) staining. All five patients had a pathological T stage of T0/1a-LPM/1a-MM/1b (1/2/1/1) and histological grade of grade1a/1b/2/3 (1/1/2/1). Endoscopic examination revealed substantial shrinkage of lugol-voiding lesions (LVLs) in all cases. One case showed complete LVL disappearance, and resected specimen examination confirmed pathological complete response (pCR). IHC and PAS staining revealed that most initial LVLs were PAS-negative. Obvious viable cells were confirmed in two cases. The other three cases exhibited nuclear atypia and strong expression of p53 and Ki-67 in the basal layer of mucosa or lamina propria mucosae, even though the superficial layer of mucosa showed no obvious LVLs with PAS-positive. p53-positive lesions were also observed in Ki-67-positive. This indicated discordance between the endoscopic findings and histopathological evaluation. DCF chemotherapy alone had a substantial therapeutic effect on SESCC in all cases. However, despite the normal appearance of the mucosal surface, viable cancer cells remained below the basal layer of mucosa. Careful attention should be paid when diagnosing clinical CR, or securing a resection margin of SESCC after DCF chemotherapy.

A comparison of doublet versus triplet chemotherapy regimens for esophagogastric adenocarcinoma (EGC): Is more always better?

124 Background: Recent data showed that a taxane-containing triplet regimen (FLOT) was superior to an anthracycline-containing regimen (ECX/ECF). However, there is no comparison between more costly and toxic triplet (T) regimens versus doublets (D) in the perioperative setting (periCT) of EGC. Methods: A retrospective analysis of patients (pts) with newly diagnosed EGC was carried out at AC Camargo Cancer Center from 2007 to 2015. Pts received either a D with a fluopyrimidine and platin or T with addition of epirubicin or docetaxel. Variables used in the Cox model were age, site, TNM, Lauren subtype and periCT (T versus D). The selection between T and D was at physician's choice. Endpoints were Relapse Free Survival (RFS) and Overall Survival (OS). Results: A total of 128 pts were included. Median age was 59.5y (56.5y for T and 67y for D, respectively). Male/female ratio was 82/46. Sixty-six received T (DCF 26 pts, EOX 28, ECX 8, 4 others) and 62 received D (FOLFOX 47 pts, CF 13, 2 others). Primary site: gastric in 93 pts and 35 EGJ. Main clinical staging cT3 N = 81 (63.3%), cN+ 84 (65.4%). Lauren subtype: intestinal N = 48, diffuse N = 54. Regarding surgery: 114 pts were resected and median lymph nodes removed 30. Pathologic complete response was seen in N = 9 (14.5%) and N = 4 (6.1%) considering D and T regimens, respectively (p = 0.14). In multivariate analysis there was no advantage of T over D regarding RFS (HR = 1.65, 0.87 – 3.11, p = 0.12) or OS (HR = 1.29, 0.65 – 2.57, p = 0.45). The 3y RFS rate was 63.2% for D and 40.6% for T and the 3y OS was 69.4% for D and 56.1% for T. Conclusions: In our analysis outcomes of pts treated with T regimen was not superior to D. Our main T was DCF and D was FOLFOX. We consider that doublet regimens may still have a role in periCT in EGC and could be an option for frail or elderly pts. Future trials are needed to confirm our data.

Outcome of Autologous Hematopoietic Stem Cell Transplantation in Relapsed and Refractory Multiple Myeloma

Introduction: Despite the introduction of highly effective novel agents, the outcome of patients with relapsed and refractory multiple myeloma (RRMM) remains poor, particularly in those with disease refractory to both proteasome inhibitors (PI) and immunomodulatory agents (IMiDs). Limited available data suggests that autologous hematopoietic stem cell transplantation (auto-HCT) may be an effective therapy in this patient population.Methods: We retrospectively analyzed all patients with RRMM who underwent first auto-HCT at our center between March 2000 and October 2015. RRMM was defined as never achieving a response (stable disease [SD]) or having progressed while on therapy or within 60 days after discontinuation of therapy. Patients with disease refractory to at least one PI and at least one IMiD either in combination or administered separately were classified as double refractory (DR-MM).Results: 233 patients with RRMM were identified. Of these, 105 (45%) had DR-MM. The remaining 128 (55%) patients were classified as refractory (R)-MM and included all patients with RRMM but without history of being double refractory. Median age at auto-HCT was 59 years (DR-MM 60 vs. 56 years in R-MM, p=0.005). High-risk cytogenetics (IMWG criteria) were noticed in 67 of 140 (48%) patients (DR-MM, 35/89 [39%] vs. R-MM, 32/51 [63%], p=0.009). Median number of prior lines of therapy was 2 (range 1 - 7) (DR-MM, 2 (1 - 7) vs. R-MM, 1 (1 - 5), p<0.001). Eighty-two (35%) patients received induction with triplet chemotherapy regimens (DR-MM, n=55 [52%] vs. R-MM, n=27 [21%], p<0.001). Chemomobilization was used in 94 (40%) patients (DR-MM, n=54 [51%] vs. R-MM, n=40 [31%], p=0.002). Median time from diagnosis to auto-HCT was 9.4 months (DR-MM 12 vs. 8 months in R-MM, p<0.001). Conditioning regimen consisted of melphalan alone in 168 (72%) and various combinations with melphalan in 65 (28%) patients with no significant difference between DR-MM and R-MM. Maintenance therapy was used in 113 (49%) patients (DR-MM, n=63 [60%] vs. R-MM, n=50 [39%], p=0.001). With a median follow up of 36 months post auto-HCT, at least partial response was seen in 188 (81%) patients (DR-MM, n=83 [79%]; R-MM, n=105 [82%], p=0.50). Near complete remission or better was seen in 52 (22%) patients (DR-MM, n=25 (24%); R-MM, n=27 (21%), p=0.64). The cumulative incidence of non-relapse mortality (NRM) at day 100 and 6 months was 1% and 2% (DR-MM, 0% and 1%; R-MM 2% each at day 100 and 6 months, p=0.56), respectively. The median progression-free survival (PFS) was 17.6 months (14.4 months in the DR-MM and 18.2 months in the R-MM, p=0.40) (Figure 1). Median overall survival (OS) was 48 months (39 months in DR-MM and 57 months in R-MM, p=0.27) (Figure 2). When accounting for other significant measures (i.e., hemoglobin level and β2 microglobulin), having high-risk chromosomal abnormalities was significantly associated with worse PFS (p=0.006) while worsening of PFS for patients with ISS stage II or III disease approached significance (p=0.06). A significant association between OS and hemoglobin level, β2 microglobulin, high risk cytogenetics, ISS stage, and induction treatment was observed, however, none of these measures remained significant in the multivariable model.Conclusions: Our findings highlight that auto-HCT is an effective and safe therapy in patients with RRMM including those who are refractory to an IMiD and PI [Display omitted] [Display omitted] DisclosuresCiurea:Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board.