Received Combination Chemotherapy Research Articles

Comprehensive Genomic Profiling (CGP) of Angioimmunoblastic T-Cell Lymphoma (AITL) to Prospectively Inform Diagnosis and Clinical Management

Background: AITL is a rare mature T-cell lymphoma with an aggressive clinical course. Accurate diagnosis is confounded by low tumor content limiting molecular characterization, histologic resemblance to peripheral T-cell lymphoma (PTCL), and a scarcity of sensitive diagnostic tools for routine sample analysis. Also, to date, no confirmed standard of care exists; most patients receive combination chemotherapy, but this approach is largely ineffective. Several research studies report RhoAG17V as a genomic hallmark of AITL that often co-occurs with somatic mutations in epigenetic regulators (TET2, IDH2, or DNMT3A); however these findings have yet to be translated in the clinic. The detection of clinically-relevant genomic alterations in AITL has the potential to improve outcome for this patient population by identifying targeted therapeutic agents. CGP provides an opportunity to address these collective unmet needs; herein, we report on our experience using this methodology in AITL.Methods: To assess RhoAG17V specificity as a diagnostic marker of AITL, RhoA mutation was explored in an unbiased fashion across the Foundation Medicine database. This led to inclusion in the study of 21 patient specimens with diagnoses of suspected AITL (4), confirmed AITL (12), PTCL (2), or other neoplasms (3). Prior autologous stem cell transplant was noted in 2 of 12 patients with confirmed AITL and in 1 with PTCL. Four patients with AITL were HHV-4 positive. Median age of the cohort was 64y (range 38-88y). Using the FoundationOne® Heme platform, DNA and RNA were extracted from samples submitted as either FFPE material (lymph nodes, skin, soft tissue) or blood. Adaptor ligated sequencing libraries were captured by solution hybridization using a custom bait set targeting 405 cancer-related genes, and 265 genes involved in cancer-related fusions. All captured libraries were sequenced in a CLIA-certified, CAP-accredited, NYS-approved laboratory (Foundation Medicine, Inc).Results: RhoAG17V was found in 69% (11/16) of AITL samples; none harbored RhoA mutation at sites other than G17. In cases of suspected AITL, RhoAG17V was found in 3/4 samples, and in 8/12 of those confirmed. TET2 mutations, predominantly prematurely truncating and inactivating, were identified in 100% (16/16) of AITL cases, exceeding reported frequencies. Mutation of IDH2, affecting exclusively R172, was observed at a frequency of 31% (5/16), while DNMT3A was observed at a frequency of 25% (4/16) and was most commonly inactivating. In all 5 AITL samples with IDH2 mutation, RhoA and TET2 mutation also co-occurred. In PTCL samples lacking an AITL diagnosis, mutation in RhoA, TET2, IDH2, and DNMT3A was detected in 1/2, 2/2, 0/2, and 1/2 cases, respectively. An unbiased query of the Foundation Medicine database identified RhoAG17V mutation in 1 sample each of pleomorphic myxofibrosarcoma (MFS), marginal zone lymphoma (MZL), and cutaneous T-cell lymphoma (CTCL); in contrast to cases of AITL, these samples were devoid of TET2 and IDH2 mutations.Conclusion: Using CGP, AITL samples harbored co-occurring RhoA/TET2 mutations at high frequency. Importantly, RhoAG17V has been proposed as a diagnostic marker for this aggressive PTCL subtype. Our findings are suggestive that assessing mutations in TET2 simultaneously with that of RhoA may have greater diagnostic utility than RhoA alone. All samples with concurrent RhoAG17V/TET2 mutation were from patients with suspected or confirmed AITL, with one exception. A single case was diagnosed as PTCL containing immunoblastic proliferations reminiscent of AITL morphology. In contrast, while RhoAG17V was detected in other malignancies (MFS, MZL, CTCL), these lacked TET2 and IDH2 mutation, suggesting the specificity of the co-occurring mutations for AITL. Co-occurrence of RhoAG17V/TET2 mutation, identified by CGP, may, therefore, enable genomic reclassification to AITL from other mature T-cell neoplasms when used in conjunction with other clinical criteria.CGP may furthermore inform therapeutic approaches for AITL. Detection of frequent and co-occurring alterations in epigenetic regulators suggests DNA hypermethylation is common in this lymphoma and implicates hypomethylating agents as relevant. Studies are currently under way to examine clinical responses of AITL patients with IDH2 or TET2 mutations to IDH2 inhibitors and hypomethylating agents, respectively. DisclosuresMorley:Foundation Medicine, Inc.: Employment, Equity Ownership. He:Foundation Medicine, Inc.: Employment, Equity Ownership. Bailey:Foundation Medicine, Inc.: Employment, Equity Ownership. Nahas:Foundation Medicine, Inc.: Employment, Equity Ownership. Lipson:Foundation Medicine, Inc.: Employment, Equity Ownership. Yelensky:Foundation Medicine, Inc.: Employment, Equity Ownership. Ross:Foundation Medicine, Inc.: Employment, Equity Ownership. Ali:Foundation Medicine, Inc.: Employment, Equity Ownership. Erlich:Foundation Medicine, Inc.: Employment, Equity Ownership. Stephens:Foundation Medicine, Inc.: Employment, Equity Ownership. Miller:Foundation Medicine, Inc.: Employment, Equity Ownership. Vergilio:Foundation Medicine, Inc.: Employment, Equity Ownership. Mughal:Foundation Medicine, Inc.: Employment, Equity Ownership.

E40 - Clinical Outcome of Patients With Stage IV Colorectal Cancer Receiving Combination Chemotherapy Without Surgery As Initial Treatment

Background: At the time of diagnosis, 25% of patients (pts) with colorectal cancer (CRC) present synchronous unresectable metastases. The best therapeutic option for this pts is not yet defined: primary tumor resection (PTR) followed by chemotherapy or upfront chemotherapy without PTR? Methods: We conducted a prospective observation trial. Main study's objective was to describe the incidence of primary tumor–related complications in pts with stage IV CRC who received up-front oxaliplatin- or irinotecan-based combination chemotherapy with or without target therapies. Secondary objectives were: overall response rate (ORR- according to RECIST criteria), toxicity (CTCAE v4), progression free survival (PFS) and clinical benefit (defined as: increase in body weight and appetite, improvement of existing symptoms such as pain, bleeding, anorexia, asthenia). Results: From July 2013 to January 2015, 38 pts with median age of 65.8 years (range 44-83), were enrolled. Primary tumors were: right colon (cecum, ascending or transverse colon) in 26.3% of pts, left colon (descending or sigmoid) in 52.6% and rectum in 21.1%. The most common sites of metastasis were: liver (65.8%), retroperitoneal nodes (48.1%), lung (52.7%), peritoneum (21.1%), bone (21.1%) and brain (13.2%). Metastases involved one site or organ in 52.6% of pts, two sites in 26.3%, three sites in 13.2% and four sites in 7.9%. Of 38 pts, 97,4% never required surgical palliation of their primary tumor. One patients (2,6%) required medical therapy for primary tumor subobstruction. No bleeding or intestinal perforation were observed in the site of primary tumor. After 6 months, 94.7% of pts was evaluable for response: ORR was 25%, no complete response (CR), was observed, disease control rate (CR + partial response + stable disease) was 75% and progression was 25%; median PFS was 9.3 months (range 3-15). Grade 3/4 toxicities were as follows: neutropenia 19.2%; diarrhea 11.3%; nausea-vomiting 1.6%. Pain improved in 80% of pts, constipation in 60% of pts with less need for medical treatment (laxatives and enemas toileting), appetite improved in 64.8% of pts and an increase in body weight was observed in 48.3% of pts. Conclusions: These data showed that upfront chemotherapy, without routine prophylactic resection, could be an appropriate therapeutic option for pts with neither obstructed nor hemorrhaging primary colorectal tumors in the setting of metastatic disease.

A clinical study on capecitabine maintenance treatment after combination chemotherapy to the patients with recurrent and metastatic breast cancer

Objective To investigate the therapeutic effect, safety and its prognostic factors of capeci-tabine as maintenance treatment agent for prolonging the PFS of patients with recurrent and metastatic breast cancer after they received combination chemotherapy. Methods From January 2011 to June 2013, 38 cases with recurrent and metastatic breast cancer were collected in the department of medical oncology of the First Hospital of Lanzhou University. All the 38 patients received NX scheme (vinorelbine combined capecitabine chemotherapy), and some patients among of them had stabile disease after chemotherapy and were administered X scheme (capecitabine, twice a day, 2 000 mg/m2 daily, withdrawal for 7 days after a consecutive intake of 14 days, 21 days as a cycle, at least 2 cycles) until disease progressed or toxicity could not be tolerated. Adverse reactions and PFS were observed and recorded. Single factor chi square test and multivariate COX proportion hazard model were used to evaluate the relationships between clinic features and RR, PFS. Results The overall response rate (CR+ PR) was 55.26% (21/38), clinical benefit patients rate (CR+ PR+ SD) was 84.2% (32/38), with 4 patients of CR (4/32), 17 patients of PR, 11 patients of SD, 6 patients of PD. Thirty-two no progressived patients were administered capecitabine until PD. The median PFS was 10.0 months. Stratification analysis showed that patients whose Karnofsky (KPS)≥80 had an average PFS of 14.1 months, while an average PFS of 6.8 months for patients whose KPS<80, with a statistical significance (χ2 =6.251, P=0.000). Cox proportion hazard model also showed that age (RR=3.561, 95%CI: 1.372-5.216, χ2=4.025, P=0.031), menopausal status (RR=1.895, 95%CI: 1.124-4.452, χ2=5.725, P=0.048), KPS score (RR=4.553, 95%CI: 1.131-7.703, χ2=11.205, P=0.005), the number of metastasis (RR=5.781, 95%CI: 2.321~11.243, χ2=3.925, P=0.011) were important prognostic factors for the patients with breast cancer. Major treatment-related adverse reaction was grade Ⅰ-Ⅱ hand-foot syndrome. One patient discontinued treatment because of grade Ⅲ hand-foot syndrome. Conclusion Capecitabine as maintenance treatment can significantly prolong the PFS of patients with recurrent and metastatic breast cancers at remission or stable stage after combination chemotherapy with a better tolerance. Age of patients, menopausal status, KPS score, the number of metastasis are the prognostic factors for the efficacy of NX-X regimen. Key words: Breast neoplasms; Drug therapy, combination; Prognosis; Capecitabine

Combination chemotherapy of gemcitabine and vinorelbine for pretreated non-small-cell lung cancer: a retrospective study.

BackgroundAdvanced non-small-cell lung cancer (NSCLC) eventually progresses after first-line chemotherapy, and usually requires salvage treatment. Although neither gemcitabine nor vinorelbine is approved as a candidate drug in the second- or further-line for NSCLC, they can be alternative drugs in terms of anti-tumor effects and toxicities. Actually, in our institution, we often use a combination of these two anti-tumor drugs in our daily practice.MethodsWe retrospectively reviewed 85 patients with advanced NSCLC who had received combination chemotherapy of gemcitabine and vinorelbine after a platinum-based regimen from June 2007 to June 2014 in Osaka Police Hospital, and performed Cox proportional hazard analyses in order to detect predictive factors for progression-free survival (PFS).ResultsPatient characteristics included a mean age of 65.5 years, 56 males, 54 adenocarcinoma, 53 European Clinical Oncology Group performance status 0–1. Thirteen and 35 patients received the study treatment as the second- and third-line treatment, respectively. The overall response rate, disease control rate, PFS, and overall survival were 4.7% (95% confidence interval 1.3%–11.6%), 30.6% (21.0%–41.5%), 2.1 months (1.7–2.8 months), and 6.9 months (5.0–11.0 months). Twenty-one and six patients experienced grade 4 neutropenia and febrile neutropenia, respectively. European Clinical Oncology Group performance status 0–1 was detected as a factor predicting longer PFS by univariate (hazard ratio, 1.63; 95% confidence interval, 1.28–2.08; P<0.001) and multivariate (1.65, 1.27–2.14, P<0.001) analyses.ConclusionThis combination was ineffective and harmful to pretreated patients with NSCLC. We do not recommend this regimen as a later-line treatment option.

1627 Febrile neutropenia in patients with esophageal cancer receiving combination chemotherapy of docetaxel, cisplatin, and 5-fluorouracil

1627 Febrile neutropenia in patients with esophageal cancer receiving combination chemotherapy of docetaxel, cisplatin, and 5-fluorouracil

Predictors of non-sentinel lymph node metastasis in patients with positive sentinel lymph node (SLN) in endometrial cancer

histology (Grade 3, Type I vs. Type II), depth of invasion, and lymphovascular space invasion. Group B cases were older (65.5 ± 9.2 vs. 63.0 ± 10.9 years, P= 0.02) and had more pelvic LNs harvested (26.4 ± 10.5 vs. 18.8 ± 8.5, P b 0.0001). Aortic LN yields were identical (9.0 ± 5.6 vs. 9.0 ± 6.0). More pelvic LN metastases were detected in Group B (30.3% vs. 13.6%, P b 0.0001). Group B had more Stage IIIC1 cases (19.3% vs. 6.0%, P b 0.0001), fewer Stage IIIA cases (0.8% vs. 6.6%, P b 0.01), more GOG high-risk cases (32.8% vs. 19.8%, P b 0.01), fewer low-risk cases (21.8% vs. 36.3%, P b 0.01), and more patients receiving combination chemotherapy + radiation (28.6% vs. 16.3%, P b 0.003). A total of 18/36 (50%) Group B cases with LNmetastases were isolated to the SLN, and 12/18 (66.7%) of these were micrometastases or isolated tumor cells that were missed on hematoxylin-and-eosin pathology. These 12 upstaged cases would have been considered GOG low-risk (n= 4), low-intermediate risk (n= 2), and high-intermediate risk (n= 6) without SLN mapping. Conclusions: This study suggests that compared to traditional pelvic lymphadenectomy, the addition of SLN mapping identifies more pelvic lymph node metastases and shifts GOG lowand intermediate-risk cases to high-risk cases, possibly resulting in administration of more postoperative chemotherapy and radiation therapy.

Prognostic Role of Conversion Surgery for Unresectable Gastric Cancer

The prognosis of unresectable gastric cancer is poor. Chemotherapy occasionally converts an initially unresectable gastric cancer to a resectable cancer. The responses of noncurative factors to initial chemotherapy and the outcomes of additional (conversion) surgery were retrospectively evaluated in 151 patients with unresectable gastric cancer receiving combination chemotherapy with S-1 plus cisplatin or paclitaxel from February 2003 to December 2013. Forty (26 %) of 151 patients underwent conversion surgery. After chemotherapy, R0 resection was accomplished in 32 patients (80 %). The 5-year overall survival (OS) rate among the 40 patients who underwent conversion surgery was 43 % (median survival time, 53 months). The 5-year OS rate in the 111 patients treated with chemotherapy alone was 1 % (median survival time, 14 months). Patients who underwent conversion surgery had significantly longer OS times than patients who underwent chemotherapy alone (P < 0.01). The 5-year OS rate among patients who underwent R0 resection was 49 % (median survival time, 62 months). Patients who underwent R0 resection had significantly longer OS times than those who underwent R1 and R2 resection (P = 0.03). Among patients who underwent conversion surgery, multivariate Cox regression analysis showed that one noncurative factor (odds ratio 0.49; 95 % confidence interval 0.28-0.88; P = 0.02) and R0 resection (odds ratio 0.52; 95 % confidence interval 0.28-0.95; P = 0.03) were significant independent predictors for favorable OS. Patients with unresectable gastric cancer initially exhibiting one noncurative factor may obtain a survival benefit from chemotherapy and subsequent curative surgery.

Analysis of tumor lysis syndrome in 380 cases of acute leukemia

This studay was aimed to explore the incidence and risk factors of tumor lysis syndrome (TLS) in patients with acute leukemia. A tatol of 380 patients who were newly diagnosed as acute leukemia and received combination chemotherapy were retrospectively analyzed. The TLS was diagnosed according to criteria of Cario and Bioshop, the risk factors were evaluated on basis of examination results. The tumor lysis syndrome occurred in 20.8% (79/380) of patients, out of them the clinical TLS was 0.5% (2/380), laboratorial TLS was 20.3% (77/380). The unvariate analysis showed that male, high WBC count, hepatomegaly, splenomegaly, lympha-denoctasis, elevated AST, high creatinine, high uric acid level, high serum lactate dehydrogenase (LDH) level, or renal insufficiency were independent risk factors for TLS. The TLS is a clinically common complication in patients with leukemia, especially during induction chemotherapy, therefore, for AL patients with high risk factors the TLS should be closely monitored, prevented and given better therapy.

A clinical observation of treatment of peripheral T-cell lymphoma with L-asparaginase-containing combination chemotherapy

To investigate the efficacy and adverse effects of L-asparaginase (L-ASP) containing regimens in patients with newly diagnosed peripheral T-cell lymphoma. A total of 102 newly diagnosed patients with peripheral T-cell lymphoma who received combination chemotherapy with or without L-ASP were enrolled in the study between January 2011 and December 2013 in our hospital. Therapeutic and adverse effects were retrospectively analyzed, including the short-term efficacy such as complete remission (CR) rate, partial remission (PR) rate, overall remission (OR) rate, and long-term efficacy such as overall survival (OS) rate, progressive free survival (PFS) rate. The OR rate in patients treated with L-ASP containing regimens (L-ASP group) was apparently higher than the patients treated without L-ASP (non L-ASP group) [83.3% (35/42) vs 61.7% (37/60), P = 0.016]. Furthermore, the difference was especially significant in patients with stage III/IV [82.4% (28/34) vs 54.0% (27/50), P = 0.007] or IPI score ≥ 2 [82.1% (23/28) vs 50.0% (21/42), P = 0.006]. The 3-year OS rate of L-ASP group and non L-ASP group were 48.9% and 65.0% respectively (P = 0.974). Three-year PFS rate of L-ASP group and non L-ASP group were 40.8% and 61.0% respectively (P = 0.479). Neither had statistical significance. Although the incidence of adverse effects was higher in L-ASP group, most of them were mild and controllable after supportive treatment. There was no significant difference in serious infections caused by III-IV degree neutropenia between the two groups (P = 0.777). Other severe side-effects in L-ASP group such as hematencephalon and acute pancreatitis were only seen in one case respectively. Combination chemotherapy with L-ASP showed better short-term efficacy in newly diagnosed peripheral T-cell lymphoma patients and the adverse effects were controllable. Large scale prospective clinical trial of using L-ASP in peripheral T-cell lymphoma is worthy of developing and further studying.

Results of combination chemotherapy and radiation therapy in non-metastatic gastric cancer in Yazd--Iran.

Gastric cancer is the first cause of cancer death in Iran. Most of the patients are diagnosed in advanced stages and survival rate is low. The aim of this study was to evaluate the survival rate of patients with gastric and gastroesophageal junction adenocarcinoma receiving combination chemotherapy and radiation therapy in Iran. This study was conducted on 53 patients with gastric or gastroesophageal junction adenocarcinoma referring to Shahid Ramezanzadeh Radiation Oncology Center between 2004 and 2010. All patients underwent surgical operation, chemotherapy, and radiotherapy. Data contained in patients' records were extracted and follow-up was conducted through telephone contacts. To analyze the data, Kaplan Meier curves, and SPSS software were employed. Seventeen (32.1%) patients were female and 36 (67.9%) were male. Mean age was 58.32 years. In 14 patients (26.9%) no lymph node was resected or reported by the pathologist. In 29 patients (54.7%) one to six lymph nodes were found, and in10 patients (18.9%) seven lymph nodes or more were detected. In two patients, (3.77%) more than 15 lymph nodes were resected. Surgical staging was impossible for 16 patients (30.2%). Mean survival was 50.9 months and median survival was 51 months. 3,5 and 7 year survival rates were 73%, 36%, and 18% respectively. None of the variables had a significant relation to survival. Despite inadequate surgery, the survival rate in our study is one of the best one reported in our country. We think this advantage may be due to poly drug chemotherapy and sequential radiation therapy.

Mesenchymal chondrosarcoma: Prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study

BackgroundMesenchymal chondrosarcoma (MCS) is a distinct, very rare sarcoma with little evidence supporting treatment recommendations. Patients and methodsSpecialist centres collaborated to report prognostic factors and outcome for 113 patients. ResultsMedian age was 30years (range: 11–80), male/female ratio 1.1. Primary sites were extremities (40%), trunk (47%) and head and neck (13%), 41 arising primarily in soft tissue. Seventeen patients had metastases at diagnosis. Mean follow-up was 14.9years (range: 1–34), median overall survival (OS) 17years (95% confidence interval (CI): 10.3–28.6). Ninety-five of 96 patients with localised disease underwent surgery, 54 additionally received combination chemotherapy. Sixty-five of 95 patients are alive and 45 progression-free (5 local recurrence, 34 distant metastases, 11 combined). Median progression-free survival (PFS) and OS were 7 (95% CI: 3.03–10.96) and 20 (95% CI: 12.63–27.36) years respectively. Chemotherapy administration in patients with localised disease was associated with reduced risk of recurrence (P=0.046; hazard ratio (HR)=0.482 95% CI: 0.213–0.996) and death (P=0.004; HR=0.445 95% CI: 0.256–0.774). Clear resection margins predicted less frequent local recurrence (2% versus 27%; P=0.002). Primary site and origin did not influence survival. The absence of metastases at diagnosis was associated with a significantly better outcome (P<0.0001). Data on radiotherapy indications, dose and fractionation were insufficiently complete, to allow comment of its impact on outcomes. Median OS for patients with metastases at presentation was 3years (95% CI: 0–4.25). ConclusionsPrognosis in MCS varies considerably. Metastatic disease at diagnosis has the strongest impact on survival. Complete resection and adjuvant chemotherapy should be considered as standard of care for localised disease.

Plasmablastic Lymphoma : A Case Series of the Changing Epidemiology of a Rare Extramedullary Plasmacytoid Neoplasm, Diagnostic Challenges, and Therapeutic Implications

Introduction:Plasmablastic lymphoma (PBL) is a rare and aggressive lymphoma, with an immunophenotype of a terminally differentiated B-lymphocyte. It is more likely to occur in HIV-positive individuals, commonly involves oral sites, and is associated with EBV infection. However, in recent years, there have been several case reports suggesting the changing epidemiology of PBL affecting HIV-negative patients and increasingly involving non-oral sites.In order to investigate the epidemiology of PBL we conducted a retrospective analysis of all consecutive patients diagnosed with PBL at Montefiore Medical Center between Jan 1997 and May 2014. Patient demographics, tumor location and pathological characteristics, laboratory data, treatment received, and survival data were recorded.Results:A total of 16 patients (8 males, 8 females) with PBL were identified. Median age of all patients was 55.5 years (IQR, 37.3- 62.0), 10/16 (62.5%) patients were HIV positive (median age, 39.5; median CD4, 151.5) and 6/16 (37.5%) were HIV negative, including one post renal transplant patient. Most of the patients had extra-oral involvement 11/16 (68.8%) with the commonest extra-oral site being the GI tract. Half of the patients were Ann Arbor Stage III or IV and the median LDH was only mildly increased at 256 (IQR, 200.5-431.5) despite these tumors having a high Ki67. All tumors were CD20 negative and positive for CD138. EBV encoded small RNA (EBER) was positive in 13/16 patients (81.3%) and was more sensitivie than the EBV latent membrane protein 1 which was positive in only 68.8% of patients suggesting EBV infection. HHV-8 was negative in 12/16 (75%) patients. Only half of the patients (62.6%) had evidence of free light chain restriction (Kappa-restricted, 43.8%, Lambda-restricted, 18.8%). Data on Ki67 was available in 12/16 patients, and 8/12 patients had a Ki67 of >=90%. 4/12 (33.3%) patients had a Ki67 =<50%.Most of the patients received chemotherapy (75%), of which, 7/12 (58.3%) patients received combination chemotherapy with EPOCH. 3/12 (25%) received consolidation with autologous stem cell transplantation. The median overall survival calculated as the number of months from diagnosis to last follow up or date of death was 17 months (0-54). It is of note that 3/16 patients were initially diagnosed with solitary extramedullary plasmacytoma (SEP)/plasmacytoid neoplasm, and the disease course led to revision of the diagnosis to PBL.Conclusion:This is an important study highlighting the epidemiological changes in PBL, an aggressive B cell neoplasm, which is not limited to the HIV-positive population, nor to oral sites. In fact, more than half of our patients with PBL presented with tumors involving extra-oral sites. These tumors were CD 20 negative, and CD 138 positive, and the majority were EBER positive and HHV8 negative. A low Ki67 does not rule out the diagnosis of PBL. Distinction of PBL from SEP may be challenging and the aggressive clinical course of the former may occasionally be the only pointer to the diagnosis. Overall prognosis remains poor and new approaches are warranted in the management of this disease. DisclosuresNo relevant conflicts of interest to declare.

Flow Cytometric Quantification of Intraperitoneal Free Tumor Cells is a Useful Biomarker in Gastric Cancer Patients with Peritoneal Metastasis.

The frequency of intraperitoneal free tumor cells (IPTC) is considered to reflect the severity of peritoneal metastasis (PM). We quantified the relative number of IPTC against leukocytes in peritoneal fluid and evaluated its clinical relevance in gastric cancer (GC) patients, particularly those with PM. Cells recovered from ascites or peritoneal lavage fluid were immunostained with monoclonal antibodies (mAb) to CD45 and CD326 (EpCAM). Using flow cytometry (FACS), CD326(+) and CD45(+) cells were classified as either tumor cells (T) or leukocytes (L) and the T/L ratio (TLR) was calculated in a total of 506 samples obtained from 300 patients with GC and 33 patients with liver cirrhosis (LC). Median (M) of the TLR of the initial samples obtained from 199 patients with PM(+) GC was 1.32 % (0-1,868.44 %), which was significantly higher than that in patients with PM(-) GC (M = 0 %, 0-0.35 %; n = 101) or LC (M = 0 %, 0-0.031 %; n = 33). In 104 PM(+) patients who received combination chemotherapy including intraperitoneal paclitaxel, the TLR was repeatedly measured in peritoneal fluid obtained from the port. In these patients, the TLR showed a strong correlation with clinical features as well as cytological findings and carcinoembryonic antigen messenger RNA status. Finally, the median survival time of the 11 patients with initial TLR > 10 % was significantly shorter than that of the 52 patients with TLR < 10 % (271 vs. 627 days; p = 0.0002). The TLR excellently reflected tumor burden in the peritoneal cavity, and could be a reliable biomarker to determine the outcome, as well as the effectiveness, of chemotherapy in patients with PM(+) GC.

O1-17-4 - Continuation of Trastuzumab Beyond Progression for Her2-Positive Advanced Gastric Cancer as Second-Line Treatment

Background: Accumulating evidence supports the benefits of continuing trastuzumab (Tmab) beyond progression (TBP) in HER2-positive (HER2+) breast cancer patients, while its significance in HER2+ advanced gastric cancer (AGC) patients remains unclear. We retrospectively investigated the association between TBP and survival outcomes in HER2+ AGC patients who had progressed after first-line Tmab-based chemotherapy.Methods: Between January 2006 and December 2013, we identified 32 HER2+ AGC patients at two Japanese institutions who had received fluoropyrimidine-, platinum-, and Tmab-containing regimens as first-line therapy and had received irinotecan or taxanes with or without Tmab as second-line therapy. IHC3+ or IHC2 + /FISH+ tumors were defined to be HER2+.Results: Of the 32 patients, 17 patients received combination chemotherapy with Tmab (CT + T) and 15 patients were treated with chemotherapy alone (CT). Most patient characteristics were well balanced between both cohorts [age (median, 62.0 vs. 64.0 years), sex (male, 76% vs. 60%, P = 0.45), ECOG PS (0/1-2; 35%/65% vs. 47%/53%, P = 0.51), number of metastatic sites (1-2/ > 2; 59%/41% vs. 67%/33%, P = 0.73), and HER2 immunostaining (IHC3 + , 76% vs. 67%, P = 0.70)]. The response rate (RECIST ver. 1.1) was 14% and 13% in the CT + T and CT cohorts, respectively. No significant difference in PFS (median, 3.6 vs. 2.8 months; HR, 0.92; 95% CI, 0.42-2.02; P = 0.84) and OS (median, 9.5 vs. 7.6 months; HR, 0.63; 95% CI, 0.24-1.66; P = 0.35) was observed between both cohorts, while marginal improvements in PFS (median, 4.4 vs. 2.1 months; HR, 0.54; 95% CI, 0.18-1.59; P = 0.26) and OS (median, 7.8 vs. 6.7 months; HR, 0.47; 95% CI, 0.14-1.57; P = 0.22) were observed when confined to the IHC3+ subgroup.Conclusions: No significant difference was observed between the CT + T and CT cohorts for PFS and OS. Further prospective studies are warranted to clarify the benefit of TBP for HER2+ AGC.

Equivalence of outcomes for rural and metropolitan patients with metastatic colorectal cancer in South Australia.

To compare the management and outcome of rural and metropolitan patients with metastatic colorectal cancer (mCRC) in South Australia. Retrospective cohort study of patients with mCRC submitted to the South Australian mCRC registry between 2 February 2006 and a cut-off date of 28 May 2012. Differences in oncological and surgical management and overall survival (calculated using the Kaplan-Meier method) between city and rural patients. Of 2289 patients, 624 (27.3%) were rural. There was a higher proportion of male patients in the rural cohort, but other patient characteristics did not significantly differ between the cohorts. Equivalent rates of chemotherapy administration between city and rural patients were observed across each line of treatment (first line: 56.0% v 58.3%, P = 0.32; second line: 23.3% v 22.5%, P = 0.78; and third line: 10.1% v 9.3%, P = 0.69). A higher proportion of city patients received combination chemotherapy in the first-line setting (67.4% v 59.9%; P = 0.01). When an oxaliplatin combination was prescribed, oral capecitabine was used more frequently in rural patients (22.9% v 8.4%; P < 0.001). No significant difference was seen in rates of hepatic resection or other non-chemotherapy treatments between cohorts. Median overall survival was equivalent between city and rural patients (14.6 v 14.9 months, P = 0.18). Patterns of chemotherapy and surgical management of rural patients with mCRC in SA are equivalent to their metropolitan counterparts and lead to comparable overall survival. The centralised model of oncological care in SA may ensure rural patients gain access to optimal care.

Abstract 634: Combination chemotherapy significantly reduces indoleamine 2,3-dioxygenase activity in NSCLC patients

Abstract Heterogeneity and immunosuppression in the tumor microenvironment (TME) has dampened the efficacy of current frontline combination chemotherapies for lung cancer which has provided limited improvement in patient survival. Modified amino acid metabolism in the TME contributes to lung cancer progression and suppression of anti-tumor immunity. Enhanced tryptophan metabolism in primary lung cancer patients is indicative of advanced disease stage. One of the key regulators of tryptophan metabolism is an intracellular, heme-containing enzyme indoleamine 2,3-dioxygenase (IDO). IDO catabolizes the breakdown of tryptophan into a toxic, immunosuppressive metabolite, L-Kynurenine (L-Kyn). Induction of IDO and accumulation of its metabolite correlates with poor prognosis and overall patient survival. We hypothesized that IDO enzymatic activity would be elevated in lung cancer patients compared to normal healthy controls. We predicted that combination chemotherapy strategies would modulate serum levels of L-Kyn and IDO activity in the immune compartment of lung cancer patients. Using an IDO enzymatic activity assay to measure the production of L-Kyn, we demonstrate that prior to receiving combination chemotherapies, Non-Small Cell Lung Cancer (NSCLC) patients (n=11) display significantly elevated levels of this immunosuppressive serum metabolite compared to healthy relatives (n=8) (Student's t-test p=0.000087; Paired Means p=0.0001). Following the second cycle of treatment, serum L-Kyn was reduced significantly (Student's t-test p=0.023; Paired Means p=0.043) in a subset of patients (n=3 of 5) suggesting response to chemotherapy, but these post-treatment levels remained elevated overall compared to healthy relatives. Additionally, greater levels of IDO enzymatic activity were observed in circulating immunosuppressive myeloid-derived suppressor cells from NSCLC patients and peripheral blood mononuclear cells prior to receiving combination chemotherapy compared to those from healthy relatives. These preliminary studies suggest that the IDO enzymatic pathway and tryptophan metabolism may serve as important therapeutic targets and diagnostic markers in predicting clinical outcomes of combination chemotherapies in the treatment of NSCLC in humans. Citation Format: Cara C. Schafer, Yong Wang, Anandi Sawant, Tong Huan Jin, Selvarangan Ponnazhagan, Stefan C. Grant, Jessy S. Deshane. Combination chemotherapy significantly reduces indoleamine 2,3-dioxygenase activity in NSCLC patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 634. doi:10.1158/1538-7445.AM2014-634

Clinical Significance of Cytological Status of Peritoneal Lavage Fluid During Intraperitoneal Chemotherapy for Gastric Cancer with Overt Peritoneal Dissemination

A positive cytology of peritoneal lavage fluid (CY1) is a poor prognostic factor in patients with gastric cancer (GC). We have recently reported that CY1 often changes to negative (CY0) following combination chemotherapy including intraperitoneal (IP) paclitaxel (PTX), which results in marked prolongation of survival in GC patients with peritoneal dissemination (P1). A total of 95 P1 GC patients who received combination chemotherapy with S-1 and intravenous and IP PTX were enrolled. Peritoneal lavage fluid was periodically examined cytologically at the start of every cycle of chemotherapy, and the impact of CY status on patient outcome was retrospectively evaluated. Seventy-three (76.8%) of 95 patients were diagnosed as CY1 before initial treatment. Median survival time (MST) of the CY1 group was significantly shorter than that of the CY0 group (19.1 vs. 32.5 months, P = 0.033). Cytological status changed from CY1 to CY0 in 68 (93.2%) of 73 CY1 patients during the whole treatment period and MST of patients who showed a negative change was significantly longer than that of the unchanged group (20.0 vs. 13.0 months, P = 0.0017). In 64 patients who achieved CY0 by IP PTX regimen, the median time to achieve CY0 was 1.4 months, and patients who achieved a negative change within 1 month showed a particularly good outcome (MST = 26.1 months). Periodic cytological examination of peritoneal lavage fluid is clinically useful to evaluate the efficacy of treatment as well as to predict the outcome of patients with P1 GC.

Radiation Therapy for Nasopharyngeal Carcinoma: Predictability of Treatment Outcomes at Interim Re-assessment

As most prognostic factors of nasopharyngeal carcinoma (NPC) are based on pretreatment characteristics, individual radiosensitivity differences are not considered. We perform interim target volume re-assessments with CT and/or MRI at the end of elective nodal irradiation (ENI). We retrospectively investigated whether interim lymph node (LN) re-assessment is predictive of the treatment outcome in NPC patients. Between February 1996 and June 2007 we performed radiation therapy in 43 NCP patients. At pretreatment assessment, 9 and 34 patients were recorded as N0 and N+, respectively. Thirty-four patients received combination chemotherapy. ENI was with a median dose of 39.6 Gy. Thereafter, boost irradiation was delivered based on the interim re-assessment results; the primary tumor was irradiated with a median dose of 24 Gy, the cervical LN of 27 N+ patients with a median dose of 24 Gy. Planned neck dissection (ND) was performed in 7 patients. The patients with regional failure or residual carcinoma in the LN specimen were categorized as uncontrolled, and the remaining patients were categorized as controlled. The short axis of the largest cervical LN was measured by CT or MRI at pretreatment assessment and interim re-assessment, thereafter, receiver operating characteristic (ROC) analysis was used to compare the predictability of regional control using the LN size at both assessments. Median follow-up was 61 months (range 6-176 months); 60% of all patients had an overall survival (OS) of 5 years. Residual carcinoma in the LN specimens was confirmed in 4 patients with ND. Among 15 patients with treatment failure it was local in 6, regional in 1, and distant in 8. Of the 43 NCP, 5 were categorized as uncontrolled and 38 as controlled. The area under the ROC curve (AUC) at pretreatment assessment and interim re-assessment was 0.825 and 1.000, respectively. The optimal cut-off was 16 mm (Youden index = 0.6071) and 15 mm (Youden index = 1.0000) for the two assessments, respectively. None of the 16 patients without boost irradiation to the LN manifested regional failure; their LN measured 5-10 mm at interim re-assessment. All LN in controlled NPC were ≤ 15 mm at interim re-assessment, in uncontrolled NPC they measured 17-26 mm. An LN size ≤ 15 mm at interim re-assessment was a significant factor for 5-year OS (65% vs 20%, p = 0.03) while a pretreatment size of ≤ 16 mm was not (p = 0.78). Interim re-assessment yields better predictability of treatment outcomes in NPC patients than pretreatment assessment. LN measuring ≤10 mm at interim re-assessment need not undergo boost irradiation. Patients whose LN is > 15 mm are at high risk for regional failure and their prognosis is poor.

Efficacy and tolerance of pegaspargase-based chemotherapy in patients with nasal-type extranodal NK/T-cell lymphoma: a pilot study.

Nasal-type extranodal natural killer (NK)/T-cell lymphoma (ENKL) is a highly invasive cancer with a poor prognosis. More effective and safer treatment regimens for ENKL are needed. Pegaspargase (PEG-Asp) has a similar mechanism of action to L-asparaginase (L-Asp), but presents lower antigenicity. The aim of the present research was to evaluate the safety profile and the latent efficacy of a PEG-Asp-based treatment regimen in patients with ENKL. Data collected from 20 patients with histologically confirmed ENKL, admitted to the Third Affiliated Hospital of Sun Yat-Sen University from January 2009 to August 2013, were included in the study. All patients received 2500 IU/m2/IM PEG-Asp on day 1 of every 21-day treatment cycle. Patients received combination chemotherapy with CHOP (n=5), EPOCH (n=7), GEMOX (n=7) or CHOP with bleomycin (n=1). After 2-5 treatment cycles (median, 4 cycles) of PEG-Asp-based chemotherapy, five patients (25%) showed a complete response (CR), and the overall response rate (ORR) was 60%. Grade 3/4 neutropenia occurred in fourteen patients (70%). Grade 3 alanine aminotransferase (ALT) elevation was observed in two. Grade 1-2 non-hematological toxicity consisted of activated partial thromboplastin time (APTT) elongation (n=9), hypofibrinogenemia (n=6), hypoproteinemia (n=17), hyperglycemia (n=3), and nausea (n=6). No allergic reactions were detected. No treatment related death was reported. Our results suggested that PEG-Asp-based chemotherapy presented an acceptable tolerance and a potential short-term outcome in patients with nasal-type ENKL.

Primary choriocarcinoma of the posterior mediastinum in a male: A case report and review of the literature.

Primary choriocarcinoma of the posterior mediastinum is considered to be extremely rare, and the majority of these tumors occur in the gonads and uterus. The current study presents the case of a 40-year-old male who presented to the Department of Thoracic Surgery (Medical College of Yangzhou University, Yangzhou, China) with left chest pain for two months. Computed tomography of the chest showed a 4.9×5.2-cm mass in the posterior mediastinum and enlargement of the mediastinal lymph nodes. Resection of the tumor and upper lobe of the left lung was performed and the patient received combination chemotherapy with six courses of etoposide plus cisplatin. The patient recovered and was discharged. One year post surgery and chemotherapy, the patient was followed up and evidence of a recurrent tumor in the cerebrum was observed.