Systemic Combination Chemotherapy Research Articles

Combination of HAI-FUDR and Systemic Gemcitabine and Cisplatin in Unresectable Cholangiocarcinoma: A Dose Finding Single Center Study

Background: Unresectable cholangiocarcinoma has a poor prognosis and treatment options are limited. Combined systemic and intrahepatic chemotherapy may improve local control and enable downsizing. The aim of this study was to determine the maximum tolerated dose (MTD) of intravenous gemcitabine combined with intravenous cisplatin and hepatic arterial infusion (HAI) with floxuridine (FUDR) in patients with unresectable intrahepatic or hilar cholangiocarcinoma. Methods: Twelve patients were treated within a 3 + 3 dose escalation algorithm with 600, 800, or 1,000 mg/m² gemcitabine and predefined doses of cisplatin 25 mg/m² on days 1 and 8, q21, for 4 cycles, and FUDR 0.2 mg/kg on days 1–14 as continuous HAI, q28, for 3 cycles. Safety and toxicity as well as resectability rates after 3 months and preliminary survival data are reported. Results: The determined MTD for gemcitabine was 800 mg/m². Dose limiting toxicities were neutropenic fever and biliary tract infections. In total, 27% of the patients showed partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, the 3-year overall survival rate was 33%, median overall survival 23.9 months (range 1–49), and median progression-free survival 10.1 months (range 2–40). Conclusions: Intravenous gemcitabine/cisplatin plus HAI-FUDR is feasible and appears effective for disease control. Larger prospective studies evaluating this triplet combination are warranted.

Conventional transarterial chemoembolization combined with systemic therapy versus systemic therapy alone as second-line treatment for unresectable colorectal liver metastases: randomized clinical trial.

The combination of conventional transarterial chemoembolization (cTACE) and systemic therapy has the potential to treat chemotherapy-refractory unresectable colorectal liver metastases (CRLMs). This study aimed to compare survival after this combined treatment versus systemic chemotherapy alone. This single-centre RCT included patients with unresectable CRLMs that progressed after first-line treatment. Patients were randomized on a 1:1 basis to either systemic chemotherapy with or without cTACE, without further stratification. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall response rate, disease control rate, conversion rate to liver resection, overall survival, and adverse events. Of 180 patients recruited, 168 were randomized. Eighty-five patients in arm A received systemic chemotherapy plus cTACE and 83 in arm B received systemic chemotherapy alone. Median PFS was longer in arm A than B (6.7 versus 3.8 months; hazard ratio (HR) 0.67, 95 per cent c.i. 0.49 to 0.91; P = 0.009), but did not translate into prolonged median overall survival (18.4 versus 14.8 months; HR = 0.92, 0.62 to 1.36; P = 0.669). Overall response rates (20 versus 22 per cent; P = 0.788) and conversion rate to liver resection (18 versus 16 per cent; P = 0.730) were no different between arms A and B. The disease control rate was higher in arm A than arm B (67 versus 51 per cent; P = 0.030). No adverse event higher than grade 3 according to the Common Terminology Criteria for Adverse Events was observed during treatment. Systemic chemotherapy plus cTACE is a safe option as second-line treatment for unresectable colorectal liver metastases, with a modest effect on PFS. Registration number: NCT03783559 (http://www.clinicaltrials.gov).

Successful Pre-Operative Local Control of Skin Invasion of Breast Cancer Using a Combination of Systemic Chemotherapy and Mohs Paste

Locally advanced breast cancer (tumor > 5 cm, widespread infiltration of the skin and muscle, or metastases to lymph nodes) is difficult to resect by surgery, and even when it is resectable, there is a high probability of local recurrence and distant metastasis. Therefore, systemic therapy should be administered first. However, as cutaneous infiltration progresses, the patient's quality of life is impaired by pain, bleeding, presence of exudates, and a foul-smelling odor. Treatment with Mohs paste with systemic therapy can control symptoms associated with skin infiltration and can also be expected to decrease tumor volume. Herein, we report a case in which a tumor was resected following Mohs paste and systemic chemotherapy administration, and the skin defect was reconstructed with a latissimus dorsi myocutaneous flap. We also review the literature for previously reported cases of breast cancer involving Mohs paste.

Improved Treatment Results in Childhood B-Cell Neoplasms With Tailored Intensification of Therapy: A Report of the Berlin-Frankfurt-Mu¨nster Group Trial NHL-BFM 90

In study NHL-BFM 90, we investigated whether the serum lactate dehydrogenase (LDH) concentration and early response are useful markers for stratification of therapy for childhood B-cell neoplasms in addition to stage, if the outcome of patients with abdominal stage III and LDH >/=500 U/L can be improved by high-dose (HD) methotrexate (MTX) at 5 g/m(2) instead of intermediate-dose (ID) MTX at 500 mg/m(2) in the preceding study 86; whether 2 therapy courses are enough for patients with complete resection; and whether combined systemic and intraventricular chemotherapy is efficacious for central nervous system-positive (CNS(+)) patients. After a cytoreductive prephase, treatment was stratified into 3 risk groups: patients in R1 (completely resected) received 2 5-day courses (ID-MTX, dexamethasone, oxazaphorins, etoposide, cytarabine, doxorubicin, and intrathecal therapy), patients in R2 (extra-abdominal primary only or abdominal tumor and LDH <500 U/L) received 4 courses containing HD-MTX, and patients in R3 (abdominal primary and LDH >/=500 U/L or bone marrow/CNS/multilocal bone disease) received 6 courses. Incomplete responders after 2 courses received an intensification containing HD-cytarabine/etoposide. Patients with no or necrotic tumor thereafter received 3 more courses; 6 patients with viable tumor received autologous bone marrow transplantation. From April 1990 through March 1995, 413 evaluable patients were enrolled (R1, 17%; R2, 40%; and R3, 43%). The 6-year event-free survival (pEFS) was 89% +/- 2% for all and 100%, 96% +/-2%, and 78% +/- 3% in R1, R2, and R3, respectively. The pEFS of patients with abdominal stage III and LDH >/=500 U/L was 81% +/- 4% as compared with 43% +/- 10% in study 86. Of 26 CNS(+) patients, 5 died early, but only 3 relapsed.

Distinct Genomic Profiles are Associated With Conversion to Resection and Survival in Patients With Initially Unresectable Colorectal Liver Metastases Treated With Systemic and Hepatic Artery Chemotherapy.

To examine genomic correlates of conversion to resection (CTR and overall survival (OS) in patients with initially unresectable colorectal liver metastasis (IU-CRLM) treated with combination systemic and hepatic artery infusion (HAI) chemotherapy. In patients presenting with IU-CRLM, combination systemic and HAI chemotherapy enables CTR with associated long-term OS in a subset of patients. Genomic correlates of CTR and OS in IU-CRLM have not been previously explored. Specimens from IU-CRLM patients receiving systemic/HAI chemotherapy (2003-2017) were submitted for next-generation sequencing. Fisher Exact test assessed associations with CTR, and Kaplan-Meier/Cox methods assessed associations with OS from HAI initiation. Of 128 IU-CRLM patients, 51 (40%) underwent CTR at median 6 months (range: 3-35) from HAI initiation. CTR and persistently unresectable cohorts differed significantly in preoperative systemic chemotherapy exposure, node-positive primary status, and size of largest liver metastasis. Median and 5-year OS was 66 months and 51%. CTR was associated with prolonged survival (time-dependent HR 0.23,95% CI: 0.12-0.46, P < 0.001). The most frequently altered genes were APC (81%), TP53 (77%), and KRAS (37%). Oncogenic mutations in SOX9 and BRAF were associated with CTR. BRAF mutations, any RAS pathway alterations, and co-altered RAS/RAF-TP53 mutations wereassociated with worse survival. Classification and regression tree analysis defined prognostically relevant clusters of genomic risk to reveal co-altered RAS/RAF-TP53 as the highest risk subgroup. Co-altered RAS/RAF-TP53 remained independently associated with worse survival (HR 2.52, 95% CI: 1.37-4.64, P = 0.003) after controlling for CTR, number of liver metastases, and preoperative extrahepatic disease. Distinct genomic profiles are associated with CTR and survival in patients with IU-CRLM treated with HAI/systemic chemotherapy. Presence of SOX9, BRAF , and co-altered RAS/RAF- TP53 mutations are promising biomarkers that, when validated in larger datasets, may impact treatment of IU-CRLM patients.

Constrictive bronchiolitis in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.

BackgroundDiffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is characterised by multifocal proliferation of neuroendocrine cells and belongs in the spectrum of pulmonary neuroendocrine tumours. Some patients with DIPNECH develop airflow obstruction but the relationship between the two entities remains unclear.MethodsWe performed a computer-assisted search of the Mayo Clinic's electronic medical records for biopsy-proven cases of DIPNECH. We extracted clinical, pulmonary function, imaging and histopathological data along with treatments and outcomes.ResultsAmong 44 patients with DIPNECH 91% were female and the median age was 65 years (interquartile range 56–69 years); 73% were never-smokers. Overall, 38 patients (86%) had respiratory symptoms including cough (68%) and dyspnoea (30%); 45% were previously diagnosed to have asthma or COPD. Pulmonary function testing showed an obstructive pattern in 52%, restrictive pattern in 11%, mixed pattern in 9%, nonspecific pattern in 23%, and was normal in 5%. On chest computed tomography scan, 95% manifested diffuse nodules and 77% manifested mosaic attenuation. For management, 25% of patients were observed without pharmacological therapy, 55% received an inhaled bronchodilator, 41% received an inhaled corticosteroid, 32% received octreotide; systemic steroids, azithromycin, or combination chemotherapy was employed in four patients (9%). Of 24 patients with available follow-up pulmonary function tests, 50% remained stable, 33% worsened and 17% improved over a median interval of 21.3 months (interquartile range 9.7–46.9 months).ConclusionDIPNECH occurs mostly in women and manifests diffuse pulmonary nodules and mosaic attenuation on imaging. It is commonly associated with airflow obstruction due to constrictive bronchiolitis, which manifests limited response to current pharmacological therapy.

Therapeutic response assessment in pancreatic ductal adenocarcinoma: society of abdominal radiology review paper on the role of morphological and functional imaging techniques.

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related death in the United States and is projected to be the second by 2030. Systemic combination chemotherapy is considered an essential first-line treatment for the majority of patients with PDA, in both the neoadjuvant and palliative settings. In addition, a number of novel therapies are being tested in clinical trials for patients with advanced PDA. In all cases, accurate and timely assessment of treatment response is critical to guide therapy, reduce drug toxicities and cost from a failing therapy, and aid adaptive clinical trials. Conventional morphological imaging has significant limitations, especially in the context of determining primary tumor response and resectability following neoadjuvant therapies. In this article, we provide an overview of current therapy options for PDA, highlight several morphological imaging findings that may be helpful to reduce over-staging following neoadjuvant therapy, and discuss a number of emerging imaging, and non-imaging, tools that have shown promise in providing a more precise quantification of disease burden and treatment response in PDA.

CML-245: Central Nervous System Restricted Lymphoid Blast Phase Transformation of CML

Objective We describe the clinical manifestations and management of a patient with lymphoid blast transformation of CML with sole compromise of central nervous system. Design case report Setting Hematology ward of Hospital San Juan de Dios, Caja Costarricense Seguro Social, Costa Rica Patients or other participants A 65-year-old male with chronic myelogenous leukemia with a history of non-adherence to TKI. Due to not reaching the European LeukemiaNet milestones, the patient was switched from imatinib to nilotinib. After three months on nilotinib, the patient complained of leg weakness and deafness. Due to persisting neurological symptoms, lumbar puncture was performed. Cerebrospinal fluid flow cytometry demonstrated 92% lymphoblasts. Interventions Full blood count was normal. Bone marrow aspiration showed no evidence of blast phase transformation, polymerase chain reaction showed 17% of BCR ABL transcripts. Head and spine CT and MRI showed no lesions. Tyrosine kinase inhibitor change to dasatinib was solicited. Systemic combination chemotherapy was started. The patient received induction with weekly vincristine and dexamethasone. Anthracycline was omitted due to cardiac disfunction. Triple intrathecal chemotherapy with was administered twice a week until the spinal tap analysis showed no blast presence by flow cytometry. The patient continued on a BFM-like protocol with high dose methotrexate of which he has received four courses. Results In his last follow-up visit the patient had a normal blood count. His last PCR for BCR ABL transcripts had failed to achieve molecular response. BCR ABL mutation study showed no evidence of mutations, medication non-adherence was suspected and addressed. His last spinal tap showed no evidence of blast presence by flow cytometry, his bone marrow aspiration showed no evidence of lymphoblasts. Conclusions The progression to blast phase is a rare event, most of the time related to the development of resistance to tyrosine kinase inhibitors. Less than 20 cases are described in the literature. Central nervous system is the most frequent location. Blast crisis usually presents with a lymphoid phenotype, the frequency of ABL mutations is usually low. The prognosis in these cases is usually dismal with overall survival less than six months.

1163P Lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours (NETs): An international double-blind, placebo-controlled randomized phase II trial

Patients (pts) with aggressive metastatic or locally advanced, non-resectable, grade 1-2 well-differentiated duodeno-pancreatic (WDDP) NETs should receive a combination of systemic chemotherapy until progression. Aggressive disease is defined as progressive and/or symptomatic metastases and/or with significant hepatic invasion (>30-50%), and/or bone metastases.

Abstract 947: Differential expressions of immune check point receptors on tumor infiltrating lymphocytes after neo-adjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC)

Abstract Background: Recent advances in tumor biology and immune system have identified check points modulating the anti-tumoral immune response. This study aimed to determine immune check point expressions patients with locally advanced breast cancer to explore any associations between clinical and prognostic factors to show effectiveness of targeted therapies for these molecules. Materials and Methods: This prospective study was carried out between September 2018 and November 2019 in the Department of General Surgery of Istanbul University Istanbul Faculty of Medicine Breast Unit. Twenty-four patients with LABC with a partial response to neoadjuvant chemotherapy (NAC) were included in the study. Tumor infiltrating lymphocytes (TILs) were isolated from the residual tumor burden separated from the surgical material with cell dissociation kit by using MACS tumor separation device. Expressions of immune checkpoints receptors including PD-1, LAG-3, TIM-3, TIGIT and CTLA-4 on CD8 T lymphocytes and Natural Killer (NK) cell subsets obtained from TIL were analyzed by using flow cytometry. Results: TILs of patients &amp;lt;50 years were more likely to express CTLA-4 on CD8−T lymphocytes in compared to patients ≥ 50 years (p= 0.004). In addition, patients with an initially advanced clinical tumor stage pT3-T4 were more likely to have increased LAG 3 expression on CD56+ NK cells and PD-1, CTLA-4 expression on CD8+ T cells in regards to pT1-T2 (p = 0.014, p = 0.018, p = 0.042; respectively). Contrarly, PD-1 expression on cytokine secreting CD56bright NK cells were found to be lower in patients with pN+ than those patients with pN- (p= 0.022). Interestingly, increased TIGIT, LAG-3, PD-1 and CTLA-4 expressions in CD16+ NK cells were demonstrated in patients with extensive intra-ductal component (p=0,024, p=0,003, p=0,032, p=0,013; respectively). However, HER2+ patients were more likely to have increased TIM-3 expressions on cytotoxic CD8- T cells compared to others (p = 0.043). Furthermore, TIGIT expressions in CD8+ T and CD56bright NK cells were significantly higher in patients with higher response to NAC (p = 0.014, p = 0.030; respectively). Finally, there was a significant correlation between pathological regression scores and CTLA-4 expressions of cytotoxic NK cells in Pearson analyses (p = 0.03). Conclusion: Our results suggest that patients with a younger age and advanced tumor burden are more likely to benefit from immunotherapeutical approaches using immune check point inhibitors. Furthermore, combination of systemic chemotherapy with immunotherapy may increase the pathologic response rate in breast cancer patients. Citation Format: Ayxan Abbasov, Esin Çetin, Neslihan Cabioglu, Baran Mollavelioglu, Semen Onder, Selman Emiroglu, Mustafa Tukenmez, Mahmut Muslumanoglu, Abdullah Igci, Gunnur Deniz, Vahit Ozmen. Differential expressions of immune check point receptors on tumor infiltrating lymphocytes after neo-adjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 947.

PARP Inhibitors in First-Line Therapy of Ovarian Cancer: Are There Any Doubts?

The standard of care for newly diagnosed advanced ovarian cancer (NADOC) is represented by surgical debulking followed by systemic platinum–taxanes combination chemotherapy. At the last European Society for Medical Oncology (ESMO) Congress, results from three trials testing three different poly-adenosine-diphosphate-ribose-polymerase (PARP) inhibitors (olaparib, niraparib, veliparib) in first-line therapy of OC have been presented. For the first time, these studies evaluated the efficacy of PARP inhibitors in this setting and the relative predictive biomarkers for patients' selection. The use of a PARP inhibitor is related with prolonged progression free survival (PFS) in the whole population of NADOC, although the magnitude of benefit varies widely among subgroups, highlighting the need to identify specific biological subtypes into clinical practice. In this minireview, we discuss the updated data available from clinical studies in this scenario.

Factors associated with the use of adjuvant neratinib in stage I-III HER2-positive breast cancer.

e12517 Background: HER2-positive breast cancers have a higher risk of recurrence, though systemic chemotherapy in combination with HER2-targeted agents significantly reduces this risk. Neratinib (N) is a small molecule inhibitor of HER2 that was shown in the ExteNET trial to improve invasive disease-free survival in patients with stage II-III breast cancer. The purpose of this study was to investigate factors associated with the use of adjuvant N in patients with HER2-positive breast cancer treated in the University of Colorado Health system (UCH). Methods: We performed a retrospective chart review of women diagnosed with stage I-III breast cancer who received adjuvant trastuzumab (T) between July 2016 and April 2019 at UCH to coincide with the approval of N in July 2017. We collected patient demographics, baseline characteristics, and cancer treatments. Results: A total of 350 patients were identified who received adjuvant T for treatment of stage I-III HER2-positive breast cancer within the inclusion timeframe. 234 patients (74.1%) were either ≥ T2 and/or node-positive at diagnosis as in the inclusion criteria of ExteNET. Of these, only 31 (13.3%) were prescribed adjuvant N within 2 months of completing adjuvant T. 81 (34.6%) received adjuvant pertuzumab (P) in addition to T. Of those who received N, 78.8% were ≥ T2 and 78.8% were node-positive. The average age of those receiving N was 49.3 versus 54.9 years in those not receiving N. Hormone receptor (HR)-positive disease was noted in 72.7% of those receiving N and 68.6% in those who did not (P = 0.624). The vast majority (97.0%) of patients were prescribed diarrheal prophylaxis with N. Patients receiving adjuvant N were less likely to have had a pathologic complete response (pCR) following neoadjuvant chemotherapy than those who did not receive N (23.1% versus 51.0%, P = 0.008). Of those who received N, 18 (54.5%) were treated at an academic hospital, where 34.2% of the total studied patient population was treated. Conclusions: The use of adjuvant N in patients with ≥ T2 or node-positive HER2-positive breast cancer in our patient population was low. Patients who did receive adjuvant N were more likely to have residual disease following adjuvant chemotherapy and be treated at an academic hospital. Despite the greater benefit of adjuvant N in HR-positive HER2-positive breast cancer in ExteNET, HR status did not correlate with the use of adjuvant N in our study. Trials assessing the additional benefit of adjuvant N in patients receiving adjuvant P or trastuzumab emtansine will likely be required prior to widespread use of adjuvant N.

Pathological complete response after intraperitoneal paclitaxel and systemic combined chemotherapy in a patient with peritoneal metastases from gastric cancer: a case report

BackgroundDespite recent progress in systemic chemotherapy, the prognosis of patients with peritoneal metastases from gastric cancer is still poor. Efficacious intraperitoneal and systemic combination chemotherapy regimens to treat patients with peritoneal metastases have recently been developed.Case presentationA 74-year-old man with gastric cancer T4b (transverse mesocolon) N3 M1 (peritoneum) received combination chemotherapy with intraperitoneal administration of paclitaxel, intravenous oxaliplatin, and oral S-1. Eight courses of combined chemotherapy had remarkable anti-tumor effects on the primary lesion, lymph node metastases, and peritoneal metastases. Total gastrectomy with regional lymph node dissection was performed. Pathological examination revealed no viable tumor cells in the resected specimens. After gastrectomy, the patient received 25 courses of the same chemotherapy without oxaliplatin and has no evidence of recurrence 24 months later.DiscussionTherapeutic approaches including systemic chemotherapy, extended resection, and heated intraperitoneal chemotherapy have been used to treat patients with peritoneal metastases. Repeat therapy with intraperitoneal paclitaxel has been used recently. Intraperitoneal administration of paclitaxel results in prolonged retention in the peritoneal cavity with effects against peritoneal metastases. Repeated administration of paclitaxel does not cause adhesions in the peritoneal cavity. When combination chemotherapy is effective, salvage gastrectomy is a promising option with minimal morbidity and mortality.ConclusionCombined chemotherapy with intraperitoneal paclitaxel and systemic chemotherapy followed by gastrectomy is a promising strategy for patients with advanced gastric cancer and peritoneal metastases.

Successful pre-operative local control of skin exposure by sarcoma using combination of systemic chemotherapy and Mohs\u2019 chemosurgery

BackgroundSarcomas sometimes invade the skin and become exposed, producing malignant wounds characterized by bleeding, exudate, odor, and infection. Malignant cutaneous sarcomas are generally incurable and ultimately impair patients’ quality of life. Mohs’ chemosurgery is a previously published technique for chemical fixation of a cutaneous tumor and subsequent excision.Case presentationWe present the case of a 44-year-old man with an undifferentiated pleomorphic sarcoma arising in the right chest wall and rupturing through the skin. The tumor manifested as a malignant wound with ulceration, bleeding, exudate, and a strong odor. Treatment with systemic chemotherapy and Mohs’ chemosurgery was initiated. After repeated courses, the tumor demonstrated significant shrinkage. We were then able to perform wide resection and reconstruction with a rectus abdominis musculocutaneous flap. Pathologic examination of the resected specimen confirmed negative margins.ConclusionsMohs’ chemosurgery with concurrent systemic chemotherapy is an effective and reliable treatment option for achieving pre-operative local control of sarcomas that rupture through the skin.

The application of point source electroporation and chemotherapy for the treatment of glioma: a randomized controlled rat study

The prognosis of Glioblastoma Multiforme patients is poor despite aggressive therapy. Reasons include poor chemotherapy penetration across the blood-brain barrier and tumor infiltration into surrounding tissues. Here we studied the effects of combined point-source electroporation (EP) and systemic chemotherapy in glioma-bearing rats. 128 rats were studied. Treatment groups were administered systemic Cisplatin/Methotrexate before EP (either 90 or 180 pulses). Control groups were treated by EP, chemotherapy, or no treatment. Tumor volumes were determined by MRI. Tumors growth rates of the EP + Methotrexate group (1.02 ± 0.77) were significantly lower (p < 0.01) than the control (5.2 ± 1.0) 1-week post treatment. No significant difference was found compared to Methotrexate (1.7 ± 0.5). Objective response rates (ORR) were 40% and 57% for the Methotrexate and EP + Methotrexate groups respectively. Tumor growth rates and ORR of the EP + Cisplatin groups (90 pulses 0.98 ± 0.2, 57%, 180 pulses 1.2 ± 0.1, 33%) were significantly smaller than the control (6.4 ± 1.0, p < 0.01, p < 0.02, 0%) and Cisplatin (3.9 ± 1.0, p < 0.04, p < 0.05, 13%) groups. No significant differences were found between the control groups. Increased survival was found in the EP + Cisplatin group, Χ2 = 7.54, p < 0.006 (Log Rank). Point-source EP with systemic chemotherapy is a rapid, minimal-invasive treatment that was found to induce significant antineoplastic effects in a rat glioma model.

Prognostic Factors for Eye Globe Salvage by External Beam Radiation Therapy for Resistant Intraocular Retinoblastoma.

PURPOSE:To analyse the prognostic factors for eye salvage for eyes with intra-ocular retinoblastoma (RB) that is resistant to systemic chemotherapy and focal therapy by external beam radiation therapy (EBRT).METHODS:A retrospective analysis of 28 eyes with intra-ocular RB that was resistant for systemic chemotherapy and focal consolidation therapy and received EBRT. Outcome measures included tumor stage at diagnosis, stage migration, type of tumor seeds, treatment modalities, eye globe salvage, metastasis, and survival.RESULTS:Most of the patients (83%) had bilateral RB, and 42% were females. All eyes were treated initially by combination of systemic chemotherapy and focal consolidation therapy. The dose of EBRT was 45 Gy. The mean follow-up was 6.5 years, and the overall eye globe salvage rate post EBRT was 46%: 67% (2/3) for group B, 71% (5/7) for group C, and 33% (6/18) for group D. Patient's gender, tumor site, laterality, and tumor stage at diagnosis were not significant prognostic factors (p> 0.05) for final outcome. The significant poor prognostic factors were tumor stage migration during systemic chemotherapy (p= 0.03) and presence of vitreous seeds at time of EBRT (p=0.001). Post EBRT complication rate was 68% (19/28) including; retinal detachment (3), vitreous hemorrhage (4), neovascular glaucoma (1), cataract (16), radiation retinopathy (2), and second malignancy (2).CONCLUSION:EBRT is an alternative for enucleation when RB is resistant to combined chemoreduction/focal consolidation therapy in absence in vitreous seeds. The known risks for EBRT are not justified for patients with unilateral RB and for those who have functional vision in the other eye.

Recent Advances in Intra-peritoneal Chemotherapy for Gastric Cancer.

Peritoneal metastasis (PM) frequently occurs in patients with gastric cancer (GC) and confers a dismal prognosis despite advances in systemic chemotherapy. While systemic chemotherapy has poor peritoneal penetration, intraperitoneal (IP) chemotherapy remains sequestered, resulting in high peritoneal drug concentrations with less systemic side-effects. The first application of IP treatment was hyperthermic intraperitoneal chemotherapy (HIPEC) with cytoreductive surgery (CRS) for gastric cancer peritoneal metastasis (GCPM); but was associated with an increased morbidity and mortality rate without significantly improving overall survival (OS). While CRS confers limited benefit, the potential role of prophylactic HIPEC and laparoscopic neoadjuvant HIPEC are currently being evaluated. Combination systemic and IP chemotherapy (SIPC) gained popularity in the 1990s, since it provided the benefits of IP treatment while reducing surgical morbidity, demonstrating promising early results in multiple Phase II trials. Unfortunately, these findings were not confirmed in the recent PHOENIX-GC randomized controlled trial; therefore, the appropriate treatment for GCPM remains controversial. Small observational studies from Japan and Singapore have reported successful downstaging of PM in GC patients receiving SIPC who subsequently underwent conversion gastrectomy with a median OS of 21.6–34.6 months. Recently, the most significant development in IP-directed therapy is pressurized IP aerosol chemotherapy (PIPAC). Given that aerosol chemotherapy achieves a wider distribution and deeper penetration, the outcomes of multiple ongoing trials assessing its efficacy are eagerly awaited. Indeed, IP-directed therapy has evolved rapidly in the last 3 decades, with an encouraging trend toward improved outcomes in GCPM, and may offer some hope for an otherwise fatal disease.

Clinical Application of Circulating Tumor DNA in Plasma of Patients with Primary Central Nervous System Lymphoma

Introduction Circulating tumor DNA (ctDNA) which is tumor‐specific DNA sequences found in blood, has been considered an important new strategy that will aid in the treatment of non‐Hodgkin's lymphoma (NHL) because ctDNA could be used in various aspects of NHL management such as diagnosis prior to therapy and early prediction of treatment failure as well as disease relapse. High‐throughput DNA sequencing of ctDNA encoding tumor‐specific mutations also could serve as a surrogate for the entire tumor genome and overcome the barrier of spatial and temporal tumor heterogeneity. However, the role of ctDNA in blood is still not determined in primary central nervous system lymphoma (PCNSL) because it is not clear how blood-brain barrier affects the level of ctDNA in blood of patients with PCNSL. Thus, we performed this pilot study to explore clinical relevance of ctDNA in patients who were consecutively diagnosed with PCNSL. Methods The study population was from our prospective cohort study for lymphoma patients (NCT03117036) that has been enrolling patients since January 2017. All patients were enrolled after obtaining written informed consents, and plasma samples for the isolation of ctDNA and targeted sequencing were collected at diagnosis and after the interim and final response evaluation. Additional samples were also collected at the time of relapse. Using DNA samples extracted from plasma, high-depth targeted sequencing consisting of 66 genes was performed. Out of 853 patients enrolled in this cohort, we selected 42 patients who were diagnosed with PCNSL after excluding secondary CNS lymphoma. Results Their median age was 52 years (range, 19-85 years) and, male (n=22) was a slightly more than female (n=20). All patients included in the study were administrated with combination systemic chemotherapy consist of rituximab, high dose methotrexate, vincristine and procarbazine as the first line. By confirming the somatic genetic mutation of tissue samples, we have proven that the detected ctDNA originated from the parent brain tumor. In plasma analysis, targeted sequencing was performed for 41 patients except a patient as a DNA quality control failure. Among 41 patients, the ctDNA amount at the diagnosis was 13.6ng/mL (Range 3.3-121.6). Fifteen patients (36.58%) only carried at least one mutation within the target regions of the panel. BCOR, BTG2 and IDH2 were highly ranked mutated genes in our study, followed by BTG1, DNMT3A, DUSP2, HIST1H1E, PIK3CA, PIK3CD, and PIM. Unlike previously reported studies, we could not observe MYD88 mutation, but more wide range profiles of ctDNA obtained. Compared to ctDNA amount and brain MRI imaging at baseline, we measured the long axis of the largest brain mass and analyzed the association with ctDNA amount. We could figure out the correlation between the amount of ctDNA and brain mass size. The median follow-up duration was 8.9 months (range 1.1-71.2) and median overall survival was 45.8 months (NR). The patients detected ctDNA at the diagnosis did not show any particularly inferior survival outcome than patients without ctDNA (NR vs.45.8months, p-value=0.92). Conclusion In the results of evaluating only the baseline samples, the detection rate in our study was 37% in PCNSL. In addition, the amount of plasma ctDNA showed the possibility of clinical application to predict disease burden at the time of diagnosis. In the future, we would analyze serial ctDNA amount, after then investigate the correlation with chemotherapy response and residual disease monitoring. In conclusion, although more research and time are required for the settlement of ctDNA in clinical practice, it will be possible to realize precision medicine with the advantage of non-invasive procedure. Disclosures Kim: F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding.

EXTH-14. PULSED ELECTRIC FIELDS FOR THE TREATMENT OF BRAIN TUMORS

Abstract When high pulsed electric fields (PEFs) are applied to the brain electroporation occurs. Depending on the electric fields strength, irreversible electroporation, inducing necrotic cell death or reversible electroporation, inducing BBB disruption may occur. We have developed a unique minimally-invasive setup for treating brain tumors employing a single insulated intracranial electrode with an exposed tip placed within the tumor and an external surface electrode. This unique setup, termed point-source electroporation, provides intratumoral irreversible-electroporation (inducing necrosis) with surrounding reversible BBB disruption, enabling efficient delivery of systemically administered drugs into the infiltrating zone. Treatment duration is 1–2 min. An efficacy study conducted with 120 glioma-bearing rats resulted in suppressed tumor growth rates in the electroporation+Cisplatin group (1.1±0.1) relative to growth rates in the control group (5.2±1.0), p&lt; 0.047, and in the Cisplatin-only group p&lt; 0.012 (3.92±1.0) (Welch’s F(2,12.73)=10.84; p&lt; 0.002; ω2=0.28). Kaplan-Meir analysis revealed that electroporation+Cisplatin prolonged survival significantly (χ2=7.54; p&lt; 0.006). Immunofluorescence analysis revealed significant infiltration of peripheral macrophages and CD8+ cells in the residual tumor. A finite elements simulation demonstrated the feasibility for obtaining clinically-relevant treatment volumes (~6cm diameter) using a single 3mm (diameter) intracranial catheter. Additionally, we discovered that low PEFs, an order of magnitude lower than electroporation threshold, can also transiently disrupt the BBB by a different mechanism, enabling penetration of both small (Gd/NaF) and large (Evans blue bound to serum albumin) molecules and immune cells, non-invasively. The extent of BBB disruption, measured in mice using delayed-contrast MRI, was found to be linearly dependent both on the electric field strength (r2=0.9,p&lt; 0.03) and on the number of applied pulses (r2=0.94,p&lt; 0.003). These results demonstrate the feasibly of applying combined systemic chemotherapy with point-source electroporation, a minimal-invasive/rapid treatment of PEFs, for obtaining significant antineoplastic effects. Furthermore, low PEFs may be applied non-invasively, rapidly and repeatedly for obtaining reversible BBB disruption.

Peritoneal Carcinomatosis from Ovarian Cancer - Current Clinical Impact of Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemotherapy.

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 locoregional spread of peritoneal carcinomatosis. A combination of systemic chemotherapy and cytoreductive surgery has been the standard treatment since the mid-1990s. However, conventional chemotherapy is poorly delivered to the peritoneum due to the plasma-peritoneal barrier. Intraperitoneal chemotherapy can improve survival by eliminating residual microscopic disease. A combination of hyperthermic intravenous and intraperitoneal chemotherapy may reduce plasma toxicity and increase therapeutic effectiveness. Several experts are investigating the effectiveness of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for both primary and recurrent ovarian cancer worldwide. Recent randomized studies indicate that this method prolongs overall patient survival and the disease-free interval. This approach is not yet part of standard guidelines and is the subject of several other clinical trials. However, indications should be considered in women with significant residual disease after neoadjuvant chemotherapy because these patients can benefit from comprehensive surgical resection in combination with hyperthermic intraperitoneal chemotherapy to prevent locoregional relapses.