Systemic Combination Chemotherapy Research Articles

Blastic plasmacytoid dendritic cell neoplasm or CD4+ CD56+ acute myeloid leukemia: A case report.

Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an extremely rare disease that originates from dendritic cells, characterized by co-expression of CD4 and CD56 without any other lineage-specific markers. It is associated with a poor prognosis. Previously, it was referred to by several names, including blastic NK-cell lymphoma, agranular CD4+ natural killer cell leukemia, and agranular CD4+CD56+ hematodermic neoplasm. The various nomenclatures and its evolution reflect the uncertainty of its histogenesis and the challenges involved in describing this hematopoietic neoplasm. Diagnosis challenge is due to similarities with CD4+CD56+ acute myeloid leukemia (AML) and histiocytic sarcoma (HS) immunophenotypic and histopathological features. We report a case of a 42-year-old male who presented with skin lesions and pancytopenia. While biologists suspected the diagnosis of BPDCN or CD4+ CD56+ AML based on the flow cytometry (FCM), anatomic pathologists retained the diagnosis of HS. The patient didn't respond to a systemic combination chemotherapy regimen and passed away rapidly. BPDCN diagnosis requires careful and exhaustive analyses in order to formulate the most appropriate therapeutic plan and to improve its prognosis.

Benefits of adjuvant treatment with the Pingxiao capsule in patients with early breast cancer: A single‑center retrospective cohort study.

Early breast cancer (EBC) is cancer that has not spread beyond the breast or the axillary lymph nodes. The present retrospective cohort study investigated the efficacy and safety of the Pingxiao capsule (PXC), which contains a formula of traditional Chinese herbs, as adjuvant therapy in patients with EBC in a single Chinese academic medical center. Patients with EBC who had received surgery and chemotherapy were analyzed and divided into the PXC and non-PXC groups. Disease-free survival (DFS) time, overall survival (OS) time, demographic characteristics and adverse events were examined. Kaplan-Meier survival curves were used to compare the differences in DFS and OS. A total of 371 participants with a median age of 54 years were included in this study. The median DFS time of all patients was 101 months. The overall DFS rate was 72.1% in the PXC group compared with 63.6% in the non-PXC group. For women with hormone receptor-negative tumors, the DFS rate in the PXC group was significantly higher than that in the non-PXC group, irrespective of node status. Adjuvant treatment with PXC for ≥3 months was associated with significantly longer median DFS time compared with that in the non-PXC group. In addition, the incidence of neutropenia rated to be grade 2 or higher was significantly lower in the PXC group compared with that in the control group, and a markedly, but non-significantly, lower prevalence of nausea was observed in PXC group (0 vs. 4.1%). In conclusion, PXC as an adjuvant therapy along with chemotherapy is associated with prolonged DFS times in patients with EBC when compared with chemotherapy alone. The therapeutic value of combined PXC and systemic chemotherapy should be further elucidated by rigorous prospective clinical trials.

Prognostic factors for patients with sarcoma with brain metastases.

e23542 Background: Sarcomas arise in mesenchymal tissue occurring anywhere in the body with a propensity to metastasize often to the lung, liver, and bones. The brain is a rare site of metastasis with increasing incidences found in those relapsing after prolonged disease control with treatment. Brain metastases development has been associated with dismal prognoses, and more data is necessary to assess factors for improved outcomes of patients. Methods: The retrospective cohort includes 81 patients diagnosed with sarcomas metastasizing to the brain treated at five sarcoma centers between 1/1998 and 12/2021. Demographic data, characteristics and presentation of brain metastases, and treatment modalities for malignancy were identified and analyzed. Results: In total, there were 45 men and 36 women with the mean age of diagnosis being 43 years. Upon presentation, 89% of patients were symptomatic with the most common presenting symptom being focal neurological deficits (37.9%) and headaches (22.1%). At the time of analysis, 58 patients (71.6%) had died of metastatic sarcoma, 16 patients (19.8%) were alive with disease, and 3 patients (3.7%) were alive without evidence of disease. The most frequent histologies were leiomyosarcoma (12.3%) and undifferentiated pleomorphic sarcoma (12.3%). In 70.4% of patients, the tumor also had metastasized to the lung. Median time from sarcoma diagnosis to brain metastases was 1.9 years (range: 0-34.6 yrs). Median time from diagnosis of brain metastases until death was 6 months (range: 0.5-330 mo). Treatment modalities of brain metastasis varied widely with 18 patients (22.2%) undergoing whole brain radiation therapy (WBRT), 11 (13.6%) undergoing systemic chemotherapy and WBRT, and 10 (12.3%) undergoing combined surgery, systemic chemotherapy, and stereotactic radiosurgery. In multivariate analysis, the variables identified as statistically significant for predicting improved survival outcomes included surgery (HR 0.30) and chemotherapy (HR 0.24), but not radiation therapy. In patients undergoing surgery or chemotherapy, the median survival time after brain metastasis diagnosis was markedly improved, with 13.9 months and 12 months respectively versus the overall patient median of 6 months. In patients undergoing radiation therapy, there was significantly improved survival with stereotactic radiosurgery (SRS, mOS 11.6mo) as opposed to whole brain radiation therapy (WBRT, mOS 8.3mo) probably due to decreased mean number of brain metastases found in those necessitating SRS (3.2) compared to WBRT (5.7). Conclusions: Together, our findings identify that patients with metastatic sarcoma to the brain have poor prognoses, often have concurrent metastasis, and have median survival of only 6 months. However, there were significantly improved outcomes with interventions such as surgery, chemotherapy, or SRS, suggesting that aggressive treatments are warranted despite the overall poor prognosis.

Peritoneal Carcinomatosis from Ovarian Cancer: A Case Report

Epithelial ovarian cancer is one of the most common causes of cancer-related death in women. More than half of patients are diagnosed at an advanced stage, usually due to the locoregional spread of peritoneal carcinomatosis. We present the case of a 49-year-old woman who suffered from constitutional syndrome and abdominal distention. The imaging tests revealed two large, vascularized, and heterogeneous masses that depended on both ovaries. Bilateral adnexectomy was performed and the result of the anatomopathological study was endometrioid carcinoma moderately differentiated. The patient was treated according to the latest recommendations of the NCCN guidelines. A combination of systemic chemotherapy and cytoreductive surgery has been the standard treatment since the mid-1990s. However, a combination of hyperthermic intravenous and intraperitoneal chemotherapy may reduce plasma toxicity and increase therapeutic effectiveness.

УЧЕТ ИНДЕКСА КОМОРБИДНОСТИ ПРИ ПРОВЕДЕНИИ ПРОТИВООПУХОЛЕВОЙ ЛЕКАРСТВЕННОЙ ТЕРАПИИ У ПАЦИЕНТОВ ПОЖИЛОГО И СТАРЧЕСКОГО ВОЗРАСТА С КОЛОРЕКТАЛЬНЫМ РАКОМ (ОБЗОР ЛИТЕРАТУРЫ)

The problem of treating elderly patients is one of the most pressing in modern clinical medicine. Colorectal cancer is one of the main causes of mortality from malignant neoplasms in Russia and other developed countries. At the same time, the incidence of tumors of the colon and rectum steadily increases with age. Before starting treatment for elderly patients, it is necessary to carefully weigh the potential risks and the possibility of achieving positive results of antitumor therapy. Objective: To summarize the literature on the use of a comprehensive geriatric assessment, including the Cancer and Aging Research Group (CARG) toxicity assessment, to predict the risk of adverse events during anticancer drug treatment in elderly patients diagnosed with colorectal cancer. Materials and methods: The search for scientific sources was carried out in PubMed / Medline / UpToDate using the following keywords: “malignant tumors”, “metastatic colorectal cancer”, “senile age”, “antitumor drug therapy”. The time horizon covered 2016–2023. Using a time filter, the most relevant and innovative research papers on the issues of chemotherapy treatment of elderly and senile patients were selected. Results: Most current evidence demonstrates the importance of performing a comprehensive geriatric assessment (CGA), Cancer and Aging Research Group (CARG) toxicity assessment in elderly and geriatric patients. Information obtained from geriatric assessment should be used to predict and manage treatment toxicity. And also for assessing and predicting overall survival. Activities based on CGA can reduce the toxicity of chemotherapy, improve the quality of life of patients, and increase compliance with medical recommendations. Undoubtedly, a comprehensive geriatric assessment (CGA) can help achieve the necessary balance between the potential effectiveness and adverse events of chemotherapy. The choice of treatment tactics for an elderly and senile cancer patient should be based on the patient’s functional status (PS), general somatic status according to the ECOG scale, and the risk of toxicity according to the CARG scale. In the presence of colorectal cancer, patients with good functional status who need antitumor systemic effects can be prescribed polychemotherapy with FOLFOX, XELOX, FOLFIRI doublets with the addition of targeted drugs: bevacizumab or cetuximab (depending on the results of gene profiling of the tumor). Patients who are not candidates for polychemotherapy in standard doses, who have a general somatic status on the ECOG scale of 1-2 and an average risk of developing toxicity of grade 3 on the CARG scale, can undergo PCT with FOLFOX, XELOX, FOLFIRI doublets with a reduction in the starting dose by 20%, or monochemotherapy with antimetabolites: capecitabine, 5-fluorouracil; topoisomerase I inhibitor irinotecan. Patients with poor functional status, general somatic status on the ECOG scale 3-4, and a high risk of developing toxicity on the CARG scale are not candidates for systemic combination chemotherapy. Particular attention should be paid to maintenance therapy in this subgroup of patients. However, if the decrease in PS level is directly related to malignancy and PS ≥2, the possibility of monochemotherapy by infusion of a combination of 5-fluorouracil and leucovorin FU/LV can be evaluated.

Abstract 3835: Clinicopathologic determinants of survival in malignant histiocytic neoplasms: Analysis of a pooled database

Abstract Background: Malignant histiocytosis, also known as the M-group per the Histiocyte Society classification, represents a rare, aggressive malignant group of histiocytic neoplasms. It includes histiocytic neoplasms that occur de novo (pMHN) and those that develop in association with other malignant diseases (aMHN). However, little is known about factors that impact MHN clinical outcomes. We conducted this pooled database analysis to delineate key clinicopathological characteristics, prognostic indicators, and treatment modalities that affect survival in these rare diseases. Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 281 cases of MHN. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Results: A total of 281 patients with confirmed MHN were identified, with 77% pMHN and 23% aMHN. The median age was 45, with bimodal peaks between 0-13 and 52-65. There was a male preponderance with M:F of 1.6. Primary sites of involvement were liver (15%), CNS and spleen (13% each), thoracic, GI, and soft tissues (12% each), bones (11%), skin (10%), H&N (8%), and breast, heart, gonads, pancreas, and kidney (1% each). Lymphadenopathy and bone marrow (BM) were involved in 28% and 18%, respectively. Constitutional symptoms occurred in 12% and hemophagocytic syndrome (HPS) in 6%. The median OS of the whole group was 12 months. BM involvement had a worse median OS (5 vs. 60 months, p=0.0002). Stage 1 disease had better median OS than higher stages (p=0.0008). Furthermore, unifocal had better median OS than multifocal/multicentric disease (60 vs. 7 months, p=0.0001). The presence of inflammatory background positively impacted OS (p=0.01). The occurrence of HPS adversely affected OS (p<0.0001). Compared to no treatment, localized therapies such as surgery (S) and/or radiation therapy (RT) and systemic combination chemotherapy (CT) were statistically superior, with a median OS of 3, 24, and 16 months, respectively (p=0.009). Among systemic therapies, SCT and BRAF/MEK inhibitors were superior to conventional chemotherapy (p=0.02). Having CNS or splenic-lymphatic primary involvement tended to have a numerical but non-significant worse median OS than soft tissue or visceral disease. While female sex, size<10cm, and pMHN seemed to have numerically better OS, they did not reach statistical significance. There was no difference in median OS for age. Conclusion: This study presents updated clinicopathologic data from a pooled cohort of patients with MHN. It identifies BM involvement, stage, extent of the disease, the inflammatory background status, occurrence of HPS, and treatment approach as critical determinants of OS. Citation Format: Philip A. Haddad, Dinesh Keerty. Clinicopathologic determinants of survival in malignant histiocytic neoplasms: Analysis of a pooled database [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 3835.

Efficacy and safety of the combination of cisplatin plus nab-paclitaxel and nivolumab with radiotherapy after maximal tumor resection in non-metastatic muscle invasive bladder cancer (CNN-BC trial).

TPS723 Background: The therapeutic gold standard for muscle invasive bladder cancer (MIBC) is radical cystectomy (RC) preceded by neoadjuvant chemotherapy when appropriate. However, RC is a major surgery procedure with 13% rate of severe complication and a perioperative mortality rate of about 1.5 - 5 %. Trimodal therapy (TMT) is a “bladder sparing” option alternative to RC. TMT consists of complete transurethral bladder tumor resection (TURBT) followed by a combination of systemic chemotherapy and locoregional radiotherapy (RT), with the option of “salvage” cystectomy in case of local treatment failure. Immunotherapy with anti-PD1/PD-L1 monoclonal antibody significantly improves survival of metastatic BC patients, and it seems to potentiate the activity of RT without increased toxicity. Therefore, we investigate the role of a multimodal TMT strategy to increase the disease-free survival (DFS) and avoid or delay RC in non-metastatic MIBC pts. Methods: CNN-BC trial (NCT05203913) is a phase 2, open-label, mono-institutional study evaluating the activity and safety of TMT with cisplatin, nab-paclitaxel and nivolumab as systemic therapy in non-metastatic MIBC pts. Eligible pts should have undergone complete TURBT with diagnosis of T2-T3 N0M0 urothelial carcinoma, and no evidence of lymph nodes or metastatic disease at FDG-PET within 6 weeks from the start of treatments. TMT consists of nivolumab (480 mg IV every 4 weeks for a total of 13 doses), weekly nab-paclitaxel (60mg/m2) plus cisplatin (20mg/m2) administered concurrently with RT (60Gy in 25 fractions over 5 weeks on original bladder tumor, plus a concomitant boost of 50Gy in 25 fractions on whole bladder and pelvic nodes). The primary endpoint is the 1-year DFS rate, defined as the rate of survival free of recurrence in pelvic nodes or bladder, or appearance of distant metastases. Secondary endpoints include: the rate of pts who require salvage cystectomy, the rate of locoregional complete response (CR) and of locoregional DFS, median DFS, safety, and quality of life. Exploratory biomarkers analysis will be performed. The trial is actively recruiting. Clinical trial information: NCT05203913 .

Multidisciplinary treatment for small cell carcinoma of the bladder: a case report.

Small cell carcinoma (SCC) of the urinary bladder is a rare and highly aggressive subtype of bladder cancer. Most cases are diagnosed at advanced stages, and its therapeutic strategy remains unestablished. Here, we report a case of bladder SCC in which multidisciplinary treatment has resulted in relatively long-term survival. A 68-year-old man presented with gross hematuria. A cystoscopy revealed an invasive bladder tumor. A transurethral resection of bladder tumor (TURBT) was performed, and the pathological diagnosis was SCC. After systemic chemotherapy using etoposide and carboplatin and subsequent TURBT, a radical cystectomy and ileal conduit were performed. Three months postoperatively, the patient had a recurrence in the para-aortic lymph node. Systemic combination chemotherapy with carboplatin plus irinotecan (CBDCA + CPT-11) was administered, followed by amrubicin and an immune checkpoint inhibitor. In addition to this treatment, radiation therapy for the metastatic region led to the reduction of pain and shrinkage of the metastatic lesion. The patient survived for 2years after the initial diagnosis. Our report indicates that multidisciplinary treatment can be effective for SCC of the bladder, and a therapeutic strategy including the identification of novel biomarkers should be established.

Combined Intraperitoneal Paclitaxel and Systemic Chemotherapy for Patients with Massive Malignant Ascites Secondary to Pancreatic Cancer: A Report of Two Patients.

The prognosis of patients with peritoneal metastases from pancreatic cancer is poor, largely due to massive ascites, which precludes systemic treatment. Two patients with a poor performance status and malignant ascites were treated with cell-free and concentrated ascites reinfusion therapy followed by combined chemotherapy with intraperitoneal paclitaxel, intravenous gemcitabine, and nab-paclitaxel. These patients achieved a survival of 19 and 36 weeks with a relatively good quality of life. Combined intraperitoneal paclitaxel and systemic chemotherapy may provide effective palliative management for some patients with peritoneal metastases from pancreatic cancer.

Malignant Histiocytic Neoplasms' Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database

Background: Malignant histiocytosis, also known as the M-group per the Histiocyte Society classification, represents a rare, aggressive malignant group of histiocytic neoplasms. It includes histiocytic neoplasms that occur de novo (pMHN) and those that develop in association with other malignant diseases (aMHN). However, little is known about factors that impact MHN clinical outcomes. We conducted this pooled database analysis to delineate key clinicopathological characteristics, prognostic indicators, and treatment modalities that affect survival in this rare histiocytic group. Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 270 cases of MHN. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Results: A total of 270 patients with confirmed MHN were identified, with 77% pMHN and 23% aMHN. The median age was 45, with bimodal peaks between 13-26 and 52-65. There was a male preponderance with M:F of 1.6. The most common primary sites of involvement were liver (15%), CNS and spleen (13% each), thoracic, GI, and soft tissues (12% each), bones (11%), skin (10%), and H&N (8%). Lymphadenopathy and bone marrow (BM) were involved in 28% and 18%, respectively. Constitutional symptoms occurred in 12% and hemophagocytic syndrome (HPS) in 6%. The median time of MHN onset in aMHN was 12 months. The median OS of the whole group was 12 months. BM involvement had a worse median OS (p = 0.003). Stage 1 disease had better median OS than higher stages (p = 0.01). Furthermore, unifocal had better median OS than multifocal/multicentric disease (p = 0.0005). The presence of inflammatory background positively impacted OS (p = 0.01). The occurrence of HPS adversely affected OS (p < 0.0001). Compared to no treatment, localized therapies such as surgery (S) and/or radiation therapy (RT) and systemic combination chemotherapy (CT) were statistically superior, with a median OS of 3, 24, and 18 months, respectively (p = 0.02). When MHN was not amenable to complete resection, CT and CT+/-S+/-RT were superior to RT+S (p = 0.03). Having CNS or splenic-lymphatic primary involvement tended to have a numerical but non-significant worse median OS than soft tissue or visceral disease. While female sex, size<10cm, and pMHN seemed to have numerically better OS, they did not reach statistical significance. There was no difference in median OS for age. Conclusions: This study presents updated clinicopathologic data from a pooled cohort of patients with MHN. It identifies BM involvement, stage, extent of the disease, the inflammatory background status, occurrence of HPS, and treatment approach as critical determinants of OS.

Circulating Tumor DNA and Risk of Venous Thromboembolism in Locally Advanced Rectal Cancer

Venous thromboembolism (VTE) is a common complication in cancer patients, which negatively affects treatment delivery and, consequently, prognosis. The pathophysiology of cancer-associated thrombosis (CAT) is extremely complex, relying on cytokine release in response to interactions between tumor cells and macrophages, thus leading to endothelial damage and activation of coagulation. Several risk factors may contribute to VTE risk, including tumor types, advanced stage, and anti-cancer treatments. Anti-angiogenic agents or combination of systemic chemotherapy and concomitant radiotherapy (CT-RT), for instance, are well-established risk factors across different malignancies. Colorectal cancer (CRC) is not listed as a high-risk VTE tumor according to pivotal risk assessment models, although retrospective studies showed a VTE rate of around 20%. Consequently, considering the high prevalence of the disease, VTE in CRC represents a main burden in terms of morbidity, increased healthcare costs, and mortality. Rectal cancer (RC) comprises approximately 30% of all CRC. The treatment of locally advanced disease (LARC) consists of a multimodal approach which includes chemotherapy, radiotherapy, and surgery. In the context of CRC management, circulating tumor DNA (ctDNA) is a fast-growing tool able to detect minimal residual disease, useful for improving patients' stratification and prognosis. Moreover, its determination at the time of diagnosis may represent a surrogate of tumor burden, potentially increasing the risk of VTE compared to ctDNA negative patients. Due to the paucity of prospective data of VTE in LARC, the aim of this analysis is to describe the rate of VTE and the potential association between ctDNA levels at baseline and VTE occurrence. We conducted a prospective observational study enrolling patients with LARC managed with neoadjuvant CT-RT (capecitabine 1650 mg/m2 concomitant with 50,4 Gy pelvic long course radiotherapy), surgery, plus/minus adjuvant chemotherapy at European Institute of Oncology (IEO) between November 2014 and November 2019. Blood samples for ctDNA were obtained at pre-planned timepoints: baseline (T0), end of CT-RT (T1), after surgery (T2), end of adjuvant chemotherapy (T3). ctDNA was extracted from plasma and mutations detected on tumor biopsy (KRAS, NRAS, BRAF, PIK3CA) were evaluated on ctDNA. Among other clinical information, VTE events were collected, including pulmonary embolism (PE), deep vein thrombosis (DVT) and visceral venous thrombosis (VVT). VTE was counted when occurred after or whitin 30 days before LARC diagnosis. The ctDNA value, defined as variant allele frequency (VAF) in a targeted mutation, was analyzed for correlation with clinical outcomes and VTE events. Median baseline ctDNA value was set as threshold to subdivide patients in VAF high and VAF low. We enrolled 111 patients. Sixty-one (55%) patients harboring tumoral tissue mutations underwent liquid biopsy. KRAS mutation was the most frequent one (42%), followed by NRAS (7%) and PIK3CA (5%). Fifty-one patients (83%) had a clinical node positive disease. Baseline Khorana Score (KS) was 0 in 54 patients (88%) and 1 in 7. Median ctDNA value at T0 was 0.11 ng/2ml (range: 0.00 - 17.40). After a median follow up of 82 months, 9 VTE events (15%) were diagnosed, 4 PE, 3 DVT and 2 VVT. The median time from diagnosis to VTE event was 14 months (IQR 6 - 51). VTE occurrence was associated with VAF high at baseline, even though not statistically significant (Hazard Ratio [HR]: 2.85; 95% CI: 0.71-11.4, p value = 0.14). Looking specifically at KRAS mutant patients, 6 VTE events were observed, all experienced by VAF high patients (HR not estimable, p value = 0.001). Considering the overall population, VTE rate was 14% and no statistical differences were observed for VTE development according to mutational profile. In our prospective study on LARC patients, VTE was associated with high levels of ctDNA at diagnosis, although not statistically significant. However, the association was significant in KRAS mutant tumors, which may represent a subset of patients with higher risk of thromboembolic complications. Prospective translational studies using deeper molecular techniques and wider populations are required to define the role of ctDNA as additional predictive tool to stratify VTE risk in cancer patients.

Prognosis, Risk Factors, and Clinical Features of Intraocular Recurrence in Primary Vitreoretinal Lymphoma

PurposeTo investigate the clinical features, risk factors, and prognosis of the intraocular recurrence in primary vitreoretinal lymphoma (PVRL). DesignRetrospective case-control study. Participants97 eyes of 51 patients diagnosed with PVRL between 2011/12 and 2021/1 were enrolled in this study. 14 patients among them had experienced intraocular recurrence. MethodsDate on demographic and ophthalmic characteristics, results of diagnostic tests, treatments, prognosis of intraocular recurrence and non-recurrence PVRL patients were collected and compared. Multivariate logistic regression was used to identify independent risk factors. And receiver operating characteristic curve was conducted to determine the cut-off values. Main Outcome MeasuresClinical features and risk factors. Results14 (19 eyes) of 51 PVRL patients had intraocular recurrences, resulting in a recurrence rate of 27.5% over a mean follow-up period of 42.5 months. No difference was observed in central nervous system lymphoma (CNSL) relapse rate (54.3% vs. 64.3%, p=0.523) and median time to CNSL (36.5 95%CI [24.6-48.3] vs. 37.3 95%CI [24.8-49.8], p=0.777) between intraocular non-recurrence and intraocular recurrence groups. Furthermore, there were no statistically significant difference in the survival outcomes, such as mortality (28.6% vs. 29.7%, p=1.000) and median overall survival (70.8 95%CI [54.0-87.7] vs. 59.2 95%CI [44.8-73.6], p=0.297), between these two groups. Younger onset age (odds ratio [OR] 0.90, 95% confidence intervals [CI] 0.84-0.98, p=0.010), isolated PVRL (OR 35.3, 95%CI 2.08-600.0, p=0.014), and no history of intravitreal chemotherapy (OR 7.72, 95%CI 1.37-43.6, p=0.021) were identified as independent risk factors for intraocular recurrences. Of the patients with intraocular recurrence, 23.6% were asymptomatic and were diagnosed during routine follow-up. The rate of interleukin-10 (IL-10) /IL-6>1 was significantly lower than that at diagnosis (43.8% vs. 92.3%, p=0.008). However, the rate of IL-10≥50 pg/mL was high (81.3%) and not significantly different from that at diagnosis (92.3%, p=0.606). ConclusionsThis study did not identify an impact of intraocular recurrence on CNS manifestations or survival outcomes in patients with PVRL. Younger patients have a higher risk of intraocular recurrence, and combined systemic and intravitreal chemotherapy may reduce intraocular recurrence. Regular ophthalmic follow-up and IL-10 testing are recommended to detect intraocular recurrence.

Advancing Diagnostics and Therapy to Reach Universal Cure in Childhood ALL.

Systemic combination chemotherapy and intrathecal chemotherapy markedly increased the survival rate of children with ALL. In the past two decades, the use of minimal (measurable) residual disease (MRD) measurements early in therapy improved risk group stratification with subsequent treatment intensifications for patients at high risk of relapse, and enabled a reduction of treatment for low-risk patients. The recent development of more sensitive MRD technologies may further affect risk stratification. Molecular genetic profiling has led to the discovery of many new subtypes and their driver genetic alterations. This increased our understanding of the biological basis of ALL, improved risk classification, and enabled implementation of precision medicine. In the past decade, immunotherapies, including bispecific antibodies, antibody-drug conjugates, and cellular therapies directed against surface proteins, led to more effective and less toxic therapies, replacing intensive chemotherapy courses and allogeneic stem-cell transplantation in patients with relapsed and refractory ALL, and are now being tested in newly diagnosed patients. It has taken 50-60 years to increase the cure rate in childhood ALL from 0% to 90% by stepwise improvements in chemotherapy. This review provides an overview of how the developments over the past 10-15 years mentioned above have significantly changed the diagnostic and treatment approach in ALL, and discusses how the integrated use of molecular and immunotherapeutic insights will very likely direct efforts to cure those children with ALL who are not cured today, and improve the quality of life for survivors who should have decades of life ahead. Future efforts must focus on making effective, yet very expensive, new technologies and therapies available to children with ALL worldwide.

Personalized treatment in localized pancreatic cancer

SummaryThe treatment elements used for pancreatic ductal adenocarcinoma (PDAC) include surgical resection, systemic cytotoxic agents, and targeted drugs. For second- and third-line therapies in PDAC, approximately 15% of patients have actionable mutations although only 2.5% receive matched targeted treatment but with a significant improvement in survival of around 16 months. For the majority of PDAC patients the current most effective strategy is surgical resection of the primary tumor and systemic combination chemotherapy. The chemotherapy regimens and the order of delivery relative to the resection reference point have been based to a large extent on randomized trials using a newly developed empirical staging (Em) system. Although the reductionist TNM based AJCC and UICC systems work well for pathology staging, they are less accurate and less manageable for treatment decision-making. This Em system defines locally resectable (EmR), borderline resectable (EmBR), and unresectable (EmUR) stages, plus the emerging entity of oligometastatic disease (EmOm). For EmR patients, 6 months of adjuvant chemotherapy achieves 5‑year survival rates of 30–50%. In EmBR short-course (2 months) neoadjuvant plus 6‑month adjuvant chemotherapy increases 12-month survival rates to around 77%, compared to 40% for upfront surgery, despite resection rates of 64–85% and 75%, respectively. Longer-course (4 months) neoadjuvant chemotherapy has also been shown to achieve an 18-month overall survival of 67%. In EmUR, induction therapy (3–6 months) may result in resections rates of 20–60% with significantly improved survival rates compared to no resection. For all stages including the polymetastatic (EmPm) setting, patients with good performance status receive combination chemotherapies based on either oxaliplatin (FOLFIRINOX or NALIRIFOX) or gemcitabine (GEM-CAP, or Gem-NabP). Molecular subtypes (Moffitt, Collisson, Bailey, and Cheng-Sen-Yue) are shown to be associated with treatment responses. Transcriptomic signatures have also been developed as classifiers for determining either oxaliplatin- or gemcitabine-based therapies (PurIST, Tiriac, GemPred+, and ESPAC) and are being evaluated in various studies. Most notably the ESPAC transcriptomic signature is being used as the treatment classifier in the experimental arms of the randomized ESPAC6 adjuvant trial in EmR patients and the ESPAC7 induction therapy trial in EmUR patients. Genomic and transcriptomic profiling at baseline and over time is an integral part of ESPAC6/7 to deepen our understanding of tumor plasticity during the course of therapy, identifying the intrinsic (persister cell) and acquired (genetic) tumor plasticity evolving over time and in reaction to different therapies in order to enable a scientific approach to overcoming clonal-resistance clades.

Open-label, single arm phase II trial investigating the efficacy, safety and quality of life of neoadjuvant chemotherapy with liposomal irinotecan combined with oxaliplatin and 5-fluorouracil/folinic acid followed by curative surgical resection in patients with hepatic oligometastatic adenocarcinoma of the pancreas (HOLIPANC).

TPS4193 Background: As of today, the recommendation for patients with adenocarcinoma of the pancreas and hepatic metastases is systemic chemotherapy alone regardless of the number and location of metastases. In the past, case reports have repeatedly reported survival data of patients who received metastatic and primary tumor resection outside the guidelines. However, there are currently no controlled clinical data from prospective studies that have evaluated the effectiveness of systemic chemotherapy in combination with tumor and metastasis resection in the context of hepatic oligometastasis in pancreatic cancer. Methods: In this single arm, phase-2 trial, survival data from patients receiving neoadjuvant chemotherapy followed by R0/R1 resection will be compared to historic data from patients with oligometastatic adenocarcinoma of the pancreas. Inclusion criteria are patients with a maximum of 5 liver metastases and histology proven PDAC. The combination of liposomal irinotecan (nal-IRI), oxaliplatin (OX) and 5-fluouracil (5-FU)/folinic acid (FA) (Nal-IRIFOX) was chosen as neoadjuvant chemotherapy since recent data suggested superior efficacy and less toxicity compared to mFOLFIRINOX. The primary endpoint is overall survival (OS) after R0/R1 resection. Secondary efficacy endpoints are R0/R1 resection rate and progression-free survival (PFS). Secondary safety endpoints are type, frequency and severity of adverse events with severity according to NCI CTCAE version 5.0 and perioperative morbidity and mortality. Eligible patients with hepatic oligometastatic adenocarcinoma of the pancreas will receive neoadjuvant combination chemotherapy in cycles of 14 days for a duration of 16 weeks in total. In patients with progressive disease during or after the first 4 cycles, neoadjuvant chemotherapy will be permanently discontinued. Patients with tumor response or stable disease after the first 4 cycles according to RECIST v1.1 but a non-resectable primary tumor will receive 4 more cycles. Patients with tumor response or stable disease and a resectable primary tumor after the first 4 cycles will undergo explorative laparotomy and synchronous resection of the tumor and hepatic metastases, if feasible. In total 150 patients will be enrolled for this trial with an aim of 55 patients receiving a complete macroscopic synchronous tumor and metastatic resection. The study is currently ongoing on 11 high-volume centers for pancreatic surgery within Germany. This is the first clinical study to prospectively evaluate the value of multimodality therapy concepts in oligometastatic pancreatic cancer. Clinical trial information: NCT04617457 .

Innovative approaches to the treatment of local recurrent vulvar cancer in patients with lichen sclerosus

Background. In recent years, there has been an increase in the incidence of vulvar precancer (lichen sclerosus), as well as vulvar cancer. Since this disorder is rare, treatment planning and therapy itself are often suboptimal, which results in a high recurrence rate. Treatment of patients with local recurrence is even more difficult. Improper therapy often leads to fatal outcomes.Aim. To develop an innovative therapeutic approach to local recurrent vulvar cancer that includes combination (intraarterial and systemic) chemotherapy and surgery.Materials and methods. This pilot study included two patients with a second episode of local recurrent vulvar cancer. The first patient was denied special treatment, whereas the second one was offered abdominoperineal resection of the rectum. At the first stage, the patients received combination chemotherapy; at the second stage, they had combination reconstructive surgeries.Results. Combination chemotherapy was highly effective as demonstrated by the reduction of the recurrent tumor to a resectable size. Combination and reconstructive surgeries allowed us to preform radical treatment and preserve functions of the adjacent organs.Conclusion. Combination treatment was highly effective in patients with local recurrent vulvar cancer, when the tumor was located near the urethra, vagina, and anus or invaded them. Combination chemotherapy ensured good tumor regression, while surgery gave hopes for a favorable outcome.

Abstract 6749: Histiocytic sarcoma descriptors and clinicopathologic determinants of survival: Analysis of a pooled database

Abstract Background Histiocytic sarcoma (HS) is an aggressive, rare malignant neoplasm of cells with histiocytic differentiation. It can occur de novo or develop in the context of other malignant disorders. HS can present as disseminated or localized lesions in the skin, lymphatics, gastrointestinal tract, central nervous system, or other organs. Little is known about factors that impact HS clinical outcomes. We conducted this pooled database analysis to delineate key clinicopathological characteristics, prognostic indicators, and treatment modalities that affect survival in this rare histiocytic entity. Methods To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 146 cases of HS. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Results A total of 146 patients with confirmed HS were identified. The median age was 52, with bimodal peaks between 14-28 and 56-70 years. There was a male preponderance with M:F of 1.3. Primary sites of involvement were CNS (21%), GI(16%), soft tissues (12%), H&N and bones (9% each), skin (8%), liver (7%), spleen (5%), lung (4%), and breast (1%). Lymphadenopathy and bone marrow (BM) were involved in 21% and 42%, respectively. Constitutional symptoms were present in 6%. The median size of the HS tumor was 4.45cm. The median OS of the whole group was 16 months. Age younger than 55 had better median OS (NR vs. 6 months, p=0.038). The primary site of involvement also impacted the median OS, where soft tissues and visceral disease had longer OS than those with CNS and spleno-lymphatic disease (60 vs. 7 vs. 6 months, p=0.03). Stage 1 disease had better median OS than stages 2-4 (p=0.06). Furthermore, unifocal had better median OS than multifocal/multicentric disease (60 vs. 9 months, p=0.007). The presence of inflammatory background positively impacted OS (p=0.01). Compared to no treatment, localized therapies such as surgery (S) and radiation therapy (RT), and systemic combination chemotherapy (CT) were statistically superior, with a median OS of 1, 204, and 21 months, respectively (p=0.003). With HS not amenable to complete resection, CT and CT+S were superior to RT+S (15 vs. 60 vs. 7 months, p=0.008). While BM involvement and size >10 cm were associated with worse OS, the latter did not reach statistical significance. There was no difference in median OS with respect to sex. Conclusion This study presents updated clinicopathologic data from a pooled cohort of patients with HS. It identifies age, the primary site of the disease, stage and extent of the disease, the inflammatory background status, and treatment approach as key determinants of OS. Citation Format: Dinesh Keerty, Philip A. Haddad. Histiocytic sarcoma descriptors and clinicopathologic determinants of survival: Analysis of a pooled database. [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 6749.

Abstract 1565: Targeting of KIF11 and AURKA to improve outcomes in Ewing sarcoma

Abstract Ewing Sarcoma (EWS) is a rare and aggressive pediatric malignancy of the bone and soft tissues. Despite intensive systemic combination chemotherapy and surgery/radiotherapy for local control, patients with metastatic disease have dismal prognosis (<30% overall survival rate). To identify better therapies for patients with refractory, recurrent and metastatic disease, we previously conducted in silico and drug re-purposing screens (PMID: 27863422; 31025088) that identified proteins essential for mitotic spindle formation and cell cycle progression such as Aurora Kinase A (AURKA), Kinesin Family Member 11 (KIF11), Kinesin Family Member 15 (KIF15) and its binding partner; targeting protein for Xklp2 (TPX2) that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, indicating their potential as therapeutic targets. KIF11 and KIF15 are mitotic motor kinesins essential for bipolar spindle formation, whereas AURKA is a mitotic kinase essential for centrosome maturation and mitotic spindle assembly. Though KIF11 and AURKA inhibitors have been extensively used in clinical trials before but have not been tested together in combination for any type of cancer. We hypothesized that targeting these two key proteins essential for mitotic progression provides a therapeutic vulnerability for Ewing Sarcoma by inducing G2/M arrest and mitotic catastrophe. Specific KIF11 (SB-743921) and AURKA (VIC-1911, VITRAC Therapeutics) inhibitors were used for targeting these proteins. We evaluated the in vitro activity of VIC-1911 and SB-743921 and synergy was measured by percentage inhibition of growth via SynergyFinder, that employs reference models (Bliss) to score synergy (scores >10 is synergistic). EWS showed strong synergistic interaction at physiologically relevant doses compared to control cell lines (e.g., mesenchymal stem cells and non-EWS tumor cells). This drug combination was effective in refractory EWS cells established post-chemotherapy (synergy score >24) and at much lower doses in cells established from pre-treatment tumor tissue (synergy score >27) indicating effectiveness at various clinical stages of EWS disease. Importantly, this therapy appeared preferential to EWS cells with an EWS-ETS fusion as compared to non-EWS cells. We observed zero colony formation in vitro with the combination treatment and increased percentage accumulation of cells in G2/M phase upon cell-cycle analysis indicating mitotic arrest. In vivo studies in EWS xenograft mouse models showed sustained tumor regression (NED at 30 days after ending therapy). The combination arm showed significant survival versus control (p≤ 0.001, HR=0.42, 95% CI=0.14-1.25), VIC-1911 (p≤ 0.001, HR=0.48, 95% CI=0.16-1.42) or SB-743921 (p ≤ 0.01, p≤ HR=0.71, 95% CI=0.21-2.34) alone. Efforts are underway to translate these preclinical studies into an early phase clinical trial of patients with histologically proven EWS who have failed standard of care therapy. Citation Format: Soumya M. Turaga, Vikalp Vishwakarma, Stacey Hembruff, Rajni Puri, Priya Sabu, Glenson Samuel, Andrew K. Godwin. Targeting of KIF11 and AURKA to improve outcomes in Ewing sarcoma [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 1565.

Neoadjuvant Arterial Embolization Chemotherapy Combined PD-1 Inhibitor for Locally Advanced Rectal Cancer (NECI Study): a protocol for a phase II study

IntroductionThe NICHE trial showed remarkable results of neoadjuvant immunotherapy in colorectal cancer patients with mismatch repair (MMR) deficiency (dMMR). However, rectal cancer patients with dMMR accounted for only 10% of...

Combined intraperitoneal and systemic chemotherapy as adjuvant or perioperative chemotherapy for patients with type 4 scirrhous gastric cancer: PHOENIX-GC2 trial.

TPS477 Background: Despite recent progress in adjuvant and perioperative chemotherapy, the prognosis of patients with type 4 scirrhous gastric cancer remains poor due to a high risk of peritoneal metastasis. We have previously developed combination chemotherapy regimens of intraperitoneal (IP) paclitaxel (PTX) and systemic chemotherapy, and promising clinical efficacy was reported in gastric cancer with peritoneal metastasis. Herein, a multicenter, open-label, randomized, phase III study is proposed to verify the efficacy of IP PTX to prevent peritoneal recurrence. Methods: Gastric cancer patients with type 4 tumors and without apparent distant metastasis, including peritoneal metastasis, will be randomized for standard systemic chemotherapy or combined IP and systemic chemotherapy based on peritoneal lavage cytology findings. Those with negative peritoneal cytology will receive radical gastrectomy and adjuvant chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). Those with positive peritoneal cytology will receive three courses of S-1 plus oxaliplatin (control arm), or S-1 plus oxaliplatin and IP PTX (experimental arm). Subsequently, they undergo gastrectomy and receive postoperative chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). The primary endpoint is disease free survival after a 3-year follow-up period. Secondary endpoints are overall survival, survival without peritoneal metastasis, safety, completion rate, curative resection rate, and histological response of preoperative chemotherapy. A total of 300 patients are to be enrolled from 40 hospitals throughout Japan. Clinical trial information: jRCT2031200087 .