Patients Received Maintenance Chemotherapy Research Articles

Efficacy of continuous arterial perfusion chemotherapy combined with transarterial chemoembolization regional arterial thermal perfusion in the treatment of pancreatic cancer with liver metastases

Abstract Background The aim of the study was to investigate the efficacy of continuous transcatheter arterial infusion chemotherapy combined with transarterial chemoembolization (TACE) for the treatment of advanced pancreatic cancer with liver metastasis. Methods Sixty patients with advanced pancreatic cancer and liver metastases were enrolled in this study. In the treatment group, 31 patients underwent continuous transcatheter arterial infusion chemotherapy combined with TACE regional arterial thermal perfusion, whereas 29 patients included in the control group received intravenous chemotherapy with gemcitabine and S-1. All patients received maintenance chemotherapy with S-1 after 4 cycles of the study regimen. Treatment efficacy, quality of life, survival, and toxicity were evaluated. Results Efficacy was better in the treatment group than in the control group, as reflected by the objective remission, partial remission, and disease progression rates (all P < 0.05). The Eastern Cooperative Oncology Group and Numerical Rating Scale pain scores were also higher in the treatment group (both P < 0.05). In survival analysis, the 1-year overall survival rates in the treatment and control groups were 64.516% and 10.345%, respectively, whereas the median overall survival times were 16 and 6 months, respectively (both P < 0.05). The 6-month progression-free survival rates in the treatment and control groups were 77.419% and 13.790%, respectively, and the median progression-free survival times were 12 and 3 months, respectively (both P < 0.05). The rates of hematological and nonhematological toxicological adverse effects were also lower in the treatment group (both P < 0.05). Although the rate of liver dysfunction was higher in the treatment group, this finding had no adverse effects on prognosis. Conclusions Continuous transcatheter arterial infusion chemotherapy combined with TACE regional arterial perfusion chemotherapy resulted in better efficacy and safety outcomes in patients with pancreatic cancer and liver metastasis, suggesting its utility as a reference method for the clinical treatment of advanced pancreatic cancer.

EPID-07. EPIDEMIOLOGICAL CHARACTERISTICS AND SURVIVAL OF PATIENTS WITH DIFFUSE GLIOMA IN BRAZIL: PRELIMINARY RESULTS OF A MULTICENTRIC RETROSPECTIVE STUDY - LACOG 0619

Abstract INTRODUCTION In Brazil, most of the 9,196 deaths due to brain cancers in 2017 were gliomas. There is a dearth of epidemiological data on diffuse glioma in Brazil. METHODS LACOG 0619 is a multicentric retrospective cohort study, which included patients from nine tertiary oncology centers. Patients aged ≥18 years with histologically proven astrocytoma, oligodendroglioma, oligoastrocytoma or glioblastoma diagnosed from June 2010 to June 2019 were included. The study protocol was approved by each Institutional Review Board. RESULTS 642 patients were included in the analysis. Median age was 51.0 (19-91) years. Most patients were male (n=364, 56.8%), 175 (27.3%) had ECOG 0-1, and 480 (74.8%) had private healthcare insurance. Neurological symptoms were present in 568 (88.5%) patients at diagnosis, and 263 (41.0%) had a history of seizure before surgery. Regarding histology, 361 (56.2%) had glioblastoma, 162 (25.2%) had astrocytoma, 90 (14.0%) had oligodendroglioma, and 23 (3.6%) had glioma NOS. Gross total resection was performed in 168 (26.2%), subtotal resection in 292 (45.5%), biopsy in 108 (16.8%), conventional radiotherapy in 380 (59.2%), and hypofractionation in 44 (6.9%) patients. Concomitant chemoradiotherapy was administered to 370 (57.6%) patients, mostly with temozolamide (n=362, 97.8%). Furthermore, 434 (67.7%) patients received maintenance chemotherapy, 398 with temozolamide (< 6 cycles in 112 [28.4%], 6 cycles in 75 [18.8%], and >6 cycles in 214 [3.8%]). Median follow-up was 29 months (26-33). Median OS according to histology was: 35 months (95%CI 26-46) for glioblastoma, 91 months (95%CI 35-NR) for glioma NOS, and not reached for astrocytoma and oligodendroglioma. Median OS by number of temozolamide maintenance cycles was 18 months (95%CI 15-24) for < 6 cycles and not reached for 6 cycles or more. CONCLUSIONS This is the first multicentric cohort evaluating Brazilian patients with diffuse glioma, providing important data on epidemiology, treatment patterns, and survival in the country.

A case series of pediatric survivors of anaplastic pleomorphic xanthoastrocytoma.

BackgroundAnaplastic pleomorphic xanthoastrocytoma (APXA) is a rare subtype of CNS astrocytoma. They are generally treated as high-grade gliomas; however, uncertainty exists regarding the optimal therapy. Here, we report on 3 pediatric cases of APXA.MethodsOur institutional database was queried for cases of APXA and 3 cases were identified. Surgical samples were processed for methylation profiling and chromosomal microarray analysis. Methylation data were uploaded to the online CNS tumor classifier to determine methylation-based diagnoses to determine copy number variations (CNVs).ResultsTwo patients were male, 1 female, and all were aged 12 years at diagnosis. All underwent a gross total resection (GTR) and were diagnosed with an APXA. Immunohistochemical analysis demonstrated that 2 cases were BRAF V600E positive. Methylation-based tumor classification supported the APXA diagnosis in all cases. CNV analyses revealed homozygous CKDN2A deletions in all and chromosome 9p loss in 2 cases. All patients received radiation therapy (54 Gy in 30 fractions) with concurrent temozolomide. Two patients received maintenance chemotherapy with temozolomide and lomustine for 6 cycles as per the Children’s Oncology Group ACNS0423. The third patient recurred and went on to receive a second GTR and 6 cycles of lomustine, vincristine, and procarbazine. All are alive with no evidence of disease >4 years post-treatment completion (overall survival = 100%, event free survival = 67%).ConclusionsThe natural history and optimal treatment of this rare pediatric tumor are not well understood. This case series supports the use of adjuvant chemoradiotherapy in the treatment of APXA. The genetic landscape may be informative for optimizing treatment and prognosis.

Maintenance Chemotherapy with S-1 Following SOX Regimen Chemotherapy Improves Prognosis of Stage 3 Gastric Cancer After D2 Gastrectomy: A 5-Year Analysis.

ObjectiveTo assess the effectiveness and safety of treatment consisting of maintenance chemotherapy (MCT) with S-1 following S-1 plus oxaliplatin (SOX) chemotherapy for stage 3 gastric cancer (GC) after D2 gastrectomy.MethodsIn this retrospective study, we enrolled 255 patients with stage 3 GC who underwent D2 gastrectomy between February 2011 and May 2014. The SOX regimen chemotherapy was administrated to all of the patients as adjuvant therapy. The SOX regimen consisted of S-1 (for patients with a body surface area [BSA] of less than 1.25 m2, 80 mg/d; 100 mg/d for BSA=1.25 m2- <1.5 m2, and 120 mg/d for BSA≥1.5 m2, in 2 divided doses for 14 d) and oxaliplatin (130 mg/m2 given on Day 1), repeated every 21 d for 8 cycles. Following SOX chemotherapy, 122 of these patients received maintenance chemotherapy (the MCT group) with S-1, whereas 133 patients (the control group) received no MCT. The MCT consisted of S-1 (80, 100, or 120 mg daily based on BSA, in 2 divided doses for 14 d), repeated every 21 d for 8 cycles at most. The chemotherapy was discontinued if unacceptable toxicity or disease progression occurred or upon the request of the patient. All cases were followed up, and overall survival (OS), recurrence-free survival (RFS), and toxicities were compared.ResultsThe MCT group exhibited a distinctly higher 5-year OS (P=0.0425) and RFS (P=0.0479) than those of the control group. The incidence of hand-foot syndrome was markedly greater in the MCT group (P=0.0026). No toxicity-related death occurred.ConclusionMaintenance chemotherapy with S-1 following the SOX regimen chemotherapy provides significant survival benefit for stage 3 GC after D2 gastrectomy.

Malignant pleural mesothelioma: Treatment patterns and outcomes from the Spanish Lung Cancer Group

BackgroundMalignant mesothelioma is a rare but aggressive tumor arising from the pleura, typically associated with exposure to asbestos. The purpose of this investigation was to describe mesothelioma patient characteristics, treatment patterns, and outcomes in Spain. Material and methodsPatients diagnosed with malignant mesothelioma of the pleura were recorded in an anonymous online database (BEMME, Epidemiologic Spanish Malignant Mesothelioma Database) from June 2008 through May 2013. Patient and tumor characteristics at time of diagnosis, as well as subsequent treatments (surgery, radiation, and chemotherapy), were collected. Among patients treated with chemotherapy, we explored type of chemotherapy regimen and outcomes by treatments. ResultsA total of 560 malignant pleural mesothelioma (MPM) patients were recorded. The median age at diagnosis was 68 years, mainly with epithelioid histology (62 %), and any asbestos exposure was noted in 45 % of patients. Nearly two-thirds of patients (71 %) received chemotherapy, mainly platinum-pemetrexed combination, as part of their treatment. Surgery and radiotherapy were given in 36 % and 17 % of patients, respectively. The median overall survival (OS) in the whole cohort was 13.0 months (95 % confidence interval (CI), 11.1–14.8 months) with 1-year OS of 53.2 % (95 % CI, 48.7–57.7 %). In patients receiving first-line chemotherapy (N = 315), the median OS was 13.4 months (95 % CI, 10.8–16.0 months), reaching 20.2 months (95 % CI, 17.2–23.2 months) for those 68 patients receiving maintenance chemotherapy. Results of multivariate analyses showed significant association of ECOG-performance status, histology and treatment response with improved OS in MPM patients treated with palliative chemotherapy. ConclusionsDespite multimodal therapeutic intervention, survival of patients with mesothelioma in Spain remains poor. Although it did not reach significance in the multivariate analysis, a meaningful additional survival benefit was observed among those patients receiving maintenance chemotherapy.

Minimal Residual Disease (MRD) Status after Induction Therapy Is a Strong Prognostic Factor in the Treatment of Adult Ph (-) Acute Lymphoblastic Leukemia (ALL): Results of a Prospective Study (ALL MRD2008 Study)

IntroductionA clinical indication for allogeneic hematopoietic stem cell transplantation (HSCT) in adult Philadelphia-chromosome negative [Ph (-)] acute lymphoblastic leukemia (ALL) patients in complete remission 1 (CR1) remains to be clarified. Minimal residual disease (MRD) status has been reported to be a strong prognostic factor in adult ALL patients (Blood. 2006 107:1116, 2009 113:4153)( J Hematol Oncol. 2013 6:14). We prospectively monitored MRD status during induction and consolidation therapy in adult Ph (-) ALL patients to determine a clinical indication for HSCT.Materials & MethodsFrom December 2008 to November 2013, 103 adult ALL patients were enrolled in this study. Eligibility criteria included non-L3 ALL, 16-65 years of age, and adequate organ function. Of these patients, 95 were eligible for this study and 59 were Ph (-). The treatment protocol used in this study was modified CALGB 19802. Treatment consisted of 6 courses given in the order of A-B-C-A-B-C, followed by a maintenance phase. Induction chemotherapy (course A) consisted of cyclophosphamide (1,200 mg/m2), daunorubicin (60 mg/m2 x 3), vincristine (VCR) (1.3 mg/m2 (max 2mg) x 4), L-asparaginase (3,000 U/m2 x 6) and prednisolone. Granulocyte colony-stimulating factor was started on day 4 and continued until neutrophil recovery. Consolidation B consisted of mitoxantrone (10 mg/m2 x 2), cytarabine (2,000 mg/m2/day x 4) and intrathecal (IT) administration of methotrexate (MTX). Consolidation C consisted of VCR (1.3 mg/m2 (max 2mg) x 3) and MTX (1,500 mg/m2 x 3) with leucovorin rescue and IT MTX. Patients received maintenance chemotherapy on a monthly basis: prednisolone 60 mg/m2 on days 1-5, VCR (1.3mg/m2 (max 2mg) x 3) on day 1, oral MTX 20 mg/m2 weekly, and oral 6-mercaptopurine 60 mg/m2 daily. MRD status was evaluated after induction therapy (first course A) and after second consolidation therapy (first course C). When MRD statuses after the consolidation were positive, patients were supposed to proceed to HSCT whenever possible.ResultsAmong the 59 Ph-negative ALL patients, 51 patients (86%) could be monitored for MRD status, and the remaining 8 patients were not because of no clonal TCR/Ig targets or chimeric mRNA. The MRD status was determined by PCR analysis of major gene rearrangements and/or chimeric mRNAs (18 were positive for TCRγ, 16 for TCRδ, 13 for IgH, 1 for TCRγ and MLL-AF4, 1 for TCRγ and ETV6-RUNX1, 1 for IgH and MLL-AF4, and 1 for IgH and MLL-ENL). MRD quantifications were performed using ASO-primers with a sensitivity of ≤1 × 10−4, and MRD positivity was defined as a lower limit of detection of ≥1 × 10−3. The median follow-up time was 1597 days (range, 16-2870 days). A total of 51 patients included 29 males and 22 females, and their median age was 29 years ranging from 16 to 65. The median white blood cell count at presentation was 8.5 × 103/L (range 1.2-650.4). CR was achieved in 45 patients (88%). One patient died during induction due to intestinal bleeding. There were 29 survivors after the median follow-up period. The probability of 3-year OS and DFS in these patients with Ph-negative ALL was 69% (95%CI 54-80) and 50% (95%CI 36-63, respectively. In terms of CR1 status, MRD-negative patients after induction chemotherapy A in the first course (n = 17) showed a better 3-year DFS (65%) compared with MRD-positive patients (n = 31; 43%), as shown in Figure 1. The difference was not statistically significant (p = 0.07). There was no patient who proceeded to allogeneic HSCT among 17 MRD-negative patients after induction therapy in CR. In contrast, patients who were MRD-positive after induction but became MRD-negative after consolidation chemotherapy C in the first course (n = 11) showed a worse 3-year DFS compared with patients who were MRD-negative after induction chemotherapy A in the first course (45% vs. 65%, p = 0.08). Fourteen patients were MRD-positive after consolidation chemotherapy C in the first course. Among them, 5 patients proceeded to allogeneic HSCT in 1CR, and 9 did not. Three-year DFS with or without allogeneic HSCT were 60% (95%CI 13-88) vs 44% (95%CI 14-72, p=0.52), respectively.DiscussionThe present study indicates that MRD status after induction and consolidation therapies is a strong prognostic factor. Post-induction MRD-negative patients have been identified to have good-prognosis with chemotherapies, not suitable for up-front allogeneic HSCT. [Display omitted] DisclosuresTakamatsu:Taisho Toyama Pharmaceutical: Research Funding; TAIHO Pharmaceutical: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Kyowa Hakko Kirin: Research Funding; Chugai Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Celgene: Honoraria. Akashi:Celgene: Research Funding, Speakers Bureau; Novartis pharma: Research Funding; Ono Pharmaceutical: Research Funding; Eisai: Research Funding; sanofi: Research Funding; Pfizer: Research Funding; Chugai Pharma: Research Funding; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Asahi-kasei: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical: Research Funding; Taiho Pharmaceutical: Research Funding; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Astellas Pharma: Research Funding; Eli Lilly Japan: Research Funding.

Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial

Young children with medulloblastoma have a poor overall survival compared with older children, due to use of radiation-sparing therapy in young children. Radiotherapy is omitted or reduced in these young patients to spare them from debilitating long-term side-effects. We aimed to estimate event-free survival and define the molecular characteristics associated with progression-free survival in young patients with medulloblastoma using a risk-stratified treatment strategy designed to defer, reduce, or delay radiation exposure. In this multicentre, phase 2 trial, we enrolled children younger than 3 years with newly diagnosed medulloblastoma at six centres in the USA and Australia. Children aged 3-5 years with newly diagnosed, non-metastatic medulloblastoma without any high-risk features were also eligible. Eligible patients were required to start therapy within 31 days from definitive surgery, had a Lansky performance score of at least 30, and did not receive previous radiotherapy or chemotherapy. Patients were stratified postoperatively by clinical and histological criteria into low-risk, intermediate-risk, and high-risk treatment groups. All patients received identical induction chemotherapy (methotrexate, vincristine, cisplatin, and cyclophosphamide), with high-risk patients also receiving an additional five doses of vinblastine. Induction was followed by risk-adapted consolidation therapy: low-risk patients received cyclophosphamide (1500 mg/m2 on day 1), etoposide (100 mg/m2 on days 1 and 2), and carboplatin (area under the curve 5 mg/mL per min on day 2) for two 4-week cycles; intermediate-risk patients received focal radiation therapy (54 Gy with a clinical target volume of 5 mm over 6 weeks) to the tumour bed; and high-risk patients received chemotherapy with targeted intravenous topotecan (area under the curve 120-160 ng-h/mL intravenously on days 1-5) and cyclophosphamide (600 mg/m2 intravenously on days 1-5). After consolidation, all patients received maintenance chemotherapy with cyclophosphamide, topotecan, and erlotinib. The coprimary endpoints were event-free survival and patterns of methylation profiling associated with progression-free survival. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy); biological analyses included all patients with tissue available for methylation profiling. This trial is registered with ClinicalTrials.gov, number NCT00602667, and was closed to accrual on April 19, 2017. Between Nov 27, 2007, and April 19, 2017, we enrolled 81 patients with histologically confirmed medulloblastoma. Accrual to the low-risk group was suspended after an interim analysis on Dec 2, 2015, when the 1-year event-free survival was estimated to be below the stopping rule boundary. After a median follow-up of 5·5 years (IQR 2·7-7·3), 5-year event-free survival was 31·3% (95% CI 19·3-43·3) for the whole cohort, 55·3% (95% CI 33·3-77·3) in the low-risk cohort (n=23) versus 24·6% (3·6-45·6) in the intermediate-risk cohort (n=32; hazard ratio 2·50, 95% CI 1·19-5·27; p=0·016) and 16·7% (3·4-30·0) in the high-risk cohort (n=26; 3·55, 1·66-7·59; p=0·0011; overall p=0·0021). 5-year progression-free survival by methylation subgroup was 51·1% (95% CI 34·6-67·6) in the sonic hedgehog (SHH) subgroup (n=42), 8·3% (95% CI 0·0-24·0%) in the group 3 subgroup (n=24), and 13·3% (95% CI 0·0-37·6%) in the group 4 subgroup (n=10). Within the SHH subgroup, two distinct methylation subtypes were identified and named iSHH-I and iSHH-II. 5-year progression-free survival was 27·8% (95% CI 9·0-46·6; n=21) for iSHH-I and 75·4% (55·0-95·8; n=21) for iSHH-II. The most common adverse events were grade 3-4 febrile neutropenia (48 patients [59%]), neutropenia (21 [26%]), infection with neutropenia (20 [25%]), leucopenia (15 [19%]), vomiting (15 [19%]), and anorexia (13 [16%]). No treatment-related deaths occurred. The risk-adapted approach did not improve event-free survival in young children with medulloblastoma. However, the methylation subgroup analyses showed that the SHH subgroup had improved progression-free survival compared with the group 3 subgroup. Moreover, within the SHH subgroup, the iSHH-II subtype had improved progression-free survival in the absence of radiation, intraventricular chemotherapy, or high-dose chemotherapy compared with the iSHH-I subtype. These findings support the development of a molecularly driven, risk-adapted, treatment approach in future trials in young children with medulloblastoma. American Lebanese Syrian Associated Charities, St Jude Children's Research Hospital, NCI Cancer Center, Alexander and Margaret Stewart Trust, Sontag Foundation, and American Association for Cancer Research.

Intention to treat analysis of neoadjuvant chemoradiation and liver transplantation for perihilar cholangiocarcinoma.

394 Background: Neoadjuvant chemoradiation and liver transplantation is an option for selected unresectable patients with early stage perihilar cholangiocarcinoma (pCCA). This study aimed to determine the dropout rate, morbidity and survival of patients who entered a modified tri-modality protocol at Princess Margaret Cancer Centre. Methods: All patients enrolled into the protocol (Jan 2009 – Aug 2015) were included in the analysis. Enrollment criteria: ≤ 65 years old with brush biopsy-proven, unresectable pCCA proximal to the cystic duct, &lt; 3.5 cm in diameter. Neoadjuvant protocol consisted of conformal radiation therapy (54-75 Gy, 1.5 Gy BID) concurrent with Capecitabine 800 mg/m2 BID until radiation completion. Following surgical staging patients received maintenance chemotherapy (Cisplatin 25 mg/m2 and Gemcitabine 1000 mg/m2, day 1 and 8 of 21 day cycle), until transplant or progression. Intention to treat analyses were performed on prospectively collected data to determine time to progression (TTP), dropout rate, overall survival (OS), and number of biliary procedures. Results: Seventeen patients were enrolled, with a median age of 53.9 (26.7-62.8) years, and tumour diameter of 2.7 (2.0-3.4) cm. Five patients had primary sclerosing cholangitis. Median follow up was 14 (6-41) months. The cohort required a median of 3 (0-8) biliary stents, and percutaneous transhepatic biliary drainage in 11/17. Median TTP was 6 (2-16) months. Protocol dropout occurred in 10/17 due to metastatic disease identified during chemoradiation (2), surgical staging (6), or maintenance chemotherapy (2). No dropouts were due to neoadjuvant toxicity. Four patients underwent transplantation (two living donor, two deceased donor), and three are on the transplant waiting list. Median survival from first consultation and start of chemoradiation was 18.2 and 17 months, respectively. Conclusions: Neoadjuvant chemoradiation and liver transplantation for unresectable early stage pCCA is feasible, although dropout during the protocol is high. Less than half of patients who began the treatment protocol remained eligible for transplantation due to cancer progression or upstaging after surgical staging.

Clinical Outcomes of Adult Medulloblastoma: A Retrospective Analysis at a Single Institute

Objectives Adult medulloblastoma is a rare tumor, and few retrospective studies on medulloblastoma have been published to date. A standard treatment regimen has not yet been established. Accordingly, this study was designed to determine the treatment outcomes and prognostic factors for patients with adult medulloblastoma. Methods We retrospectively reviewed all cases of adult medulloblastoma at the Beijing Tiantan Hospital between 2004 and 2007. There were 33 patients in total. Tumor removal followed by radiotherapy was performed in all patients. Five patients received maintenance chemotherapy after radiotherapy. Statistical analysis was performed using the log-rank test, Kaplan–Meier method, and Cox regression analysis. Results The median follow-up period was 73 months. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 45.5% ± 8.7% and 51.5% ± 8.7%, respectively. Recurrence or progression was observed in 21 patients, and 14 patients were still alive. Tumor location at the midline with infiltration to the floor of the fourth ventricle was associated with the worst PFS and OS (P = 0.032). Hemispheric desmoplastic/nodular medulloblastomas (DNMBs) were associated with a better outcome than midline DNMB. The average-risk group tended to have a better 5-year PFS rate than the high-risk group (P = 0.065). Conclusions Tumor location is an important prognostic marker for adulthood MB. We propose a molecular and clinical staging system should be established for adulthood MB. Further prospective clinical trials should be performed to draw a conclusion.

Clinical outcomes of adult medulloblastoma: A retrospective analysis at a single institute

ObjectivesAdult medulloblastoma is a rare tumor, and few retrospective studies on medulloblastoma have been published to date. A standard treatment regimen has not yet been established. Accordingly, this study was designed to determine the treatment outcomes and prognostic factors for patients with adult medulloblastoma.MethodsWe retrospectively reviewed all cases of adult medulloblastoma at the Beijing Tiantan Hospital between 2004 and 2007. There were 33 patients in total. Tumor removal followed by radiotherapy was performed in all patients. Five patients received maintenance chemotherapy after radiotherapy. Statistical analysis was performed using the log-rank test, Kaplan–Meier method, and Cox regression analysis.ResultsThe median follow-up period was 73 months. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 45.5% ± 8.7% and 51.5% ± 8.7%, respectively. Recurrence or progression was observed in 21 patients, and 14 patients were still alive. Tumor location at the midline...

P1-17-3 - Chemotherapy with Cisplatin and Pemetrexed for Non-Small Cell Lung Cancer Patients: a Retrospective Single Center Study

Background: Cisplatin and pemetrexed combination regimen (CP) is one of the promising therapies for non-squamous NSCLC patients. The PARAMOUT trial demonstarated the survival benefits of continuation maintenance chemotherapy with pemetrexed (PEM) after four cycles of CP. In Japan, only one phase II study showed feasibility and effectiveness of CP therapy.Methods: Japanese advanced NSCLC patients who were administered CP in National Kyushu Cancer Center from 2009 to 2014 were enrolled in this retrospective study. The drugs were administered day1 every three weeks as a cycle. Treatment was repeated four to six cycles until disease progression or unacceptable toxicities. Non-PD patients received maintenance chemotherapy with pemetrexed until disease progression. The response rate of CP was evaluated retrospectively.Results: One hundred and six patients received CP treatment. Sixty six patients were male and 40 were female. Median age was 63 years (range 34-77). Pathological diagnosis was adenocarcinoma in 104, large cell carcinoma in 1 and NSCLC in 2. The clinical stage of patients was IIIA in 1, IIIB in 3, IV in 86 and postoperative recurrence was 16. ECOG performance status was 0 in 58 patients, 1 in 46 patients and 2 in 2 patients. EGFR mutation is positive in 31, negative in 68, and unknown in 7, respectively. The median cycles of induction chemotherapy were 4. Thirty nine patients (36.8%) had partial response, 44 patients (41.5%) had stable disease. The median progression-free survival from the initiation of induction chemotherapy was 163 days.Conclusions: CP combination therapy for Japanese non-squamous NSCLC patients is feasible. Effectiveness of this regimen in current study is equivalent to previous clinical trials. Further prospective studies are warranted.

Pretreatment Neutrophil to Lymphocyte Ratio (NLR) Is Prognostic in Resectable Pancreatic Cancer

Purpose/Objective(s): To assess resectability and overall survival (OS) among locally advanced pancreatic cancer (LAPC) patients treated with induction chemotherapy (CT) followed by dose-escalated chemoradiation using intensity-modulated radiation therapy (IMRT). Materials/Methods: We reviewed records of 135 LAPC patients were treated with induction CT (median duration 3.2 months) followed by IMRT (median dose 56Gy) between 11/2006 and 11/2012. Patients were deemed to have locally advanced disease based on T4 disease or unreconstructable involvement of portal vein/hepatic artery on imaging (n Z 112) or were found to be unresectable after an attempted resection (n Z 23). Induction CTwas gemcitabine-based (nZ 99) or FOLFIRINOX (nZ 32); concurrent CT was biweekly gemcitabine (40mg/m) in 89 pts, continuous 5-fluorouracil (225mg/m) in 27 pts or Xeloda (825mg/m2 BID)in 10 pts. After chemoradiation, 80 patients received maintenance CT. Results: With 20.1 month’s median follow-up, median OS was 19.7 months. Twenty-six (19%) patients underwent resection 4.1 months (mean) after chemoradiation; 22 (16%) had negative margins, one of whom had a pathologic complete response and 4 had a microscopically positive margin. The median treatment response on pathology was 70% [5-100] and 23 patients had negative nodes. One-year and 2-year OS for all the patients were 86% and 47%, respectively and for those who underwent surgical resection, the 1and 2-year OS were 96% and 88%, respectively. Partial response to chemoradiation and duration of maintenance CT were associated with undergoing surgery (p Z 0.022 and p Z 0.03 respectively) on univariate analysis. On multivariate analysis, clinical nodal staging and duration of maintenance CTwere associated with undergoing surgery (pZ 0.027 and p Z 0.0091 respectively). On univariate analysis, duration of maintenance CT were associated with improved OS (p Z 0.0167). On multivariate analysis, response to IMRT and duration of maintenance CT were associated with better OS (pZ 0.0125 and pZ 0.0123 respectively). Conclusions: Induction CT followed by chemoradiation for LAPC is associated with R0 resections in 16% of patients and an improved OS. Identifying both clinical and genomic predictors of response to chemoradiation may help in selecting a subgroup of patients with LAPC who should receive radiation therapy with the goal of allowing for surgical resection. Author Disclosure: C. Hajj: None. F. Huguet: None. A. Wu: None. W. Shi: None. Z. Zhang: None. E. O’Reilly: None. C. Winston: None. D. Reidy: None. A. Ho: None. P. Allen: None. K.A. Goodman: None.

Clinical Prognostic Factors for Locally Advanced Esophageal Squamous Carcinoma Treated after Definitive Chemoradiotherapy

PurposeLocally advanced esophageal cancers are generally treated with neoadjuvant chemoradiotherapy, followed by surgery in operable candidates. However, even if the patients were diagnosed as operable disease, surgery could not be performed on patients with poor condition or other comorbidity. In this case, definitive chemoradiotherapy (dCRT) is the other option for localized esophageal cancer. Therefore, the purpose of this study was to evaluate the efficacy and clinical prognostic factors for dCRT in locally advanced esophageal cancer.Materials and MethodsWe conducted a review of patients who received dCRT for locally advanced squamous esophageal cancer from 2004 to 2010, focusing on stages III and IVa. All patients received at least two cycles of platinum-based chemotherapy during radiation, and all tumor burdens were included in the radiation field. The treatment results were analyzed for patterns of failure and prognostic factors associated with survival.ResultsIn total, 63 patients were enrolled in this study. The overall response rate was 84.1%. Relief from dysphagia after dCRT was achieved in 48 patients. The most frequent failure was local recurrence. The median overall survival (OS) was 23.0 months, and the 2-year survival rate was 45.4%. Similar results were observed for elderly study patients. Significant prognostic factors for OS were duration of smoking, high grade of dysphagia (score of 3 or 4), and shorter duration of progression-free and dysphagia-free survival. Maintenance chemotherapy after dCRT did not influence OS. However, "good risk" patients receiving maintenance chemotherapy showed better OS than those who did not receive maintenance chemotherapy (30.4 months vs. 12.0 months, p=0.002).ConclusiondCRT has a major role in improving survival and palliation of dysphagia in inoperable advanced esophageal cancer, even in elderly patients. Maintenance chemotherapy after dCRT may be effective in prolonging survival in "good risk" patients.

Minimal Residual Disease Negative Status At the End of Induction Therapy Is a Potent Prognostic Marker in Adult Non-Ph Acute Lymphoblastic Leukemia: Results of the ALL MRD2002 Study

Abstract 2581 IntroductionA clinical indication for allogeneic hematopoietic stem cell transplantation (HSCT) in adult Philadelphia-chromosome negative [Ph (−)] acute lymphoblastic leukemia (ALL) patients in complete remission 1 (CR1) remains to be clarified. An international study showed that matched related donors HSCT for ALL in CR1 provides survival benefits for standard-risk ALL patients compared to chemotherapy (Blood. 2008 111:1827). Minimal residual disease (MRD) status has been reported to be a strong prognostic factor in adult ALL patients (Blood. 2006 107:1116, 2009 113:4153). We prospectively monitored MRD status during induction and consolidation therapy in adult Ph (−) ALL patients to determine a clinical indication for HSCT. Materials & MethodsFrom July 2002 to August 2008, 110 adult ALL patients were enrolled in this study. Eligibility criteria included non-L3 ALL, 16–65 years of age, and adequate organ function. Of these patients, 101 were eligible for this study and 59 were Ph (−). The treatment protocol used in this study was modified CALGB 19802. Treatment consisted of 6 courses given in the order of A-B-C-A-B-C, followed by a maintenance phase. Induction chemotherapy (course A) consisted of cyclophosphamide (1,200 mg/m2), daunorubicin (60 mg/m2 × 3), vincristine (VCR) (1.3 mg/m2 (max 2mg) × 4), L-asparaginase (3,000 U/m2 × 6) and prednisolone. Granulocyte colony-stimulating factor was started on day 4 and continued until neutrophil recovery. Consolidation B consisted of mitoxantrone (10 mg/m2 × 2), cytarabine (2,000 mg/m2/day × 4) and intrathecal (IT) administration of methotrexate (MTX). Consolidation C consisted of VCR (1.3 mg/m2 (max 2mg) × 3) and MTX (1,500 mg/m2 × 3) with leucovorin rescue and IT MTX. Patients received maintenance chemotherapy on a monthly basis: prednisolone 60 mg/m2 on days 1–5, VCR (1.3mg/m2 (max 2mg) × 3) on day 1, oral MTX 20 mg/m2 weekly, and oral 6-mercaptopurine 60 mg/m2 daily. MRD status was evaluated after induction therapy (first course A) and after second consolidation therapy (first course C). When MRD statuses after the consolidation were positive, patients were supposed to proceed to HSCT whenever possible. ResultsA total of 59 patients were Ph (−). MRD status of 41 of these patients (69.5%) could be monitored by the major rearrangement patterns of TCRƒÁ, TCRƒÁ, and IgƒÈ chain genes, and secondarily for IgH gene rearrangements (Blood. 1991 77:331), and chimeric RNA analysis (TCRƒÁ n=14, TCRƒÁ n=9, IgƒÈ n=6, IgH n=1, other n=1, E2A-PBX1 n=3, MLL-AF4 n=1). There were 21 male and 20 female patients. The median age was 31.0 (range 17–63 years). The median white blood cell count at presentation was 10,900/ml (range 1,000–408,700). A total of 36 patients (85.7%) achieved CR. The probability of 3-year overall survival and progression-free survival (PFS) were 59.3 % and 48.9 %, respectively. In terms of CR1 status, patients who were MRD (−) after induction therapy (first course A)(n = 22) had a significantly better 3-year PFS compared with those who were MRD (+)(n = 13)(72.2 % vs. 33.6 %, p = 0.011). Those MRD (−) patients also had a significantly lower 3-year probability of relapse compared with MRD (+) patients (27.8 % vs. 58.0 %, p = 0.031). Patients who were MRD (+) after consolidation therapy (n=3) had an ominous prognosis without HSCT (3-year PFS 0%), while the MRD (+) patients with HSCT (n=3) had 66.7 % 3-year PFS. On multivariate analysis, age (≥35 vs. <35 years, HR 4.535, p = 0.007) and MRD status after induction therapy (+ vs. -, HR 5.250, p = 0.009) were significant prognostic factors, whereas WBC count (≥30,000 vs. <30,000, HR 1.502, p = 0.498) was not. DiscussionHSCT for CR1 ALL has the greatest anti-ALL activity. However, HSCT has higher morbidity and mortality rates than chemotherapy. Thus, HSCT should be avoided in patients who have good prognosis with chemotherapy alone. Our results show that patients with molecular remission after induction therapy have an excellent PFS without HSCT, and patients who are MRD (+) after several consolidation therapies have very poor PFS without HSCT. The present study indicates that MRD status after induction and consolidation therapies is a significant prognostic factor. MRD monitoring is useful to determine a clinical indication of HSCT for patients who achieve CR1. For CR1 patients with MRD (+) status after several consolidation therapies, further intensification of chemotherapy may be possible when HSCT is not a suitable option. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Improved Overall Survival with 12 Cycles of Single-Agent Paclitaxel Maintenance Therapy following a Complete Response to Induction Chemotherapy in Advanced Ovarian Carcinoma

Objectives: Previously reported studies have suggested that maintenance therapy in the treatment of ovarian cancer may provide progression-free survival (PFS) benefits, although they have not discerned a similar impact on patient overall survival (OS). Methods: We examined the long-term PFS and OS of a previous study population consecutively treated with either 3 cycles (group A; n = 13 patients) or 12 cycles (group B; n = 13) of paclitaxel (135 mg/m²; Q21 days) maintenance therapy. Eligible patients received maintenance chemotherapy following a complete response to 6 cycles of primary induction chemotherapy, comprising 6 cycles of carboplatin (AUC = 5), paclitaxel (175 mg/m²), and gemcitabine (800 mg/m²) per protocol. Results: There were statistically significant PFS differences between group A (12 months) and group B (24 months) (p = 0.016). Moreover, the OS in group A was 38 months and 80 months for group B (p = 0.012). Current follow-up for this patient population exceeds 58 months. Conclusions: In the present investigation, 12 cycles of single agent paclitaxel maintenance therapy were associated with improved patient PFS and OS benefits. Despite contradictory reports, paclitaxel-based maintenance therapy may favorably impact both PFS and OS in advanced ovarian cancer patients who obtain a complete response to primary induction chemotherapy.

Postoperative Gemcitabine Alone and Concurrent with Radiation Therapy in Locally Advanced Pancreatic Carcinoma

To evaluate the treatment results of gemcitabine alone and concurrent with radiotherapy after R0/R1 resection of locally advanced pancreatic cancer. From 1999 to 2005, 55 patients with stage II resected pancreatic cancer treated with gemcitabine-based radiochemotherapy were retrospectively evaluated. Initially, one cycle of induction gemcitabine was administered and followed by weekly gemcitabine concurrent with radiotherapy. After the completion of radiochemotherapy, patients received 3 additional courses of gemcitabine. Thirteen patients were stage IIA and 42 were stage IIB. Forty-six patients (83.6%) had R0 and 9 patients (16.4%) had R1 resection. All of the patients received induction chemotherapy and radiotherapy, all but 3 received concurrent radiochemotherapy, and 46 (84%) patients received maintenance chemotherapy. During induction, concurrent and maintenance phases of the protocol, 11%, 13.5% and 19.5% of the patients had at least one > or = grade 3 toxicity, respectively. Within a median 47 months (range, 34-105) of follow-up, 4 (7.3%) patients had isolated local recurrence, 5 (9%) patients had local recurrence and distant metastases, and 27 (49%) had only distant metastases. Median disease-free survival and overall survival were 13 (range, 4-105) and 19 months (range, 6-105), respectively. In multivariate analysis, nodal stage, AJCC stage and number of lymph nodes dissected were the significant factors affecting disease-free survival whereas Karnofsky performance status was the only significant factor for overall survival. The prognosis for pancreatic cancer remains poor despite adjuvant radiochemotherapy. More aggressive treatments should be considered in patients with unfavorable prognostic factors.

The prognostic significance of optimal debulking in the setting of a complete clinical response for advanced ovarian carcinoma patients receiving maintenance chemotherapy

We investigated if optimal surgical debulking increases tumor responsiveness to maintenance chemotherapy and improves survival in advanced ovarian cancer patients who previously attained a clinical complete response (CCR) to primary chemotherapy. We retrospectively reviewed 75 advanced ovarian cancer patients, of whom 43 and 32 underwent optimal versus suboptimal cytoreduction, respectively. All patients exhibited a CCR following 6 cycles of paclitaxel and carboplatin and subsequently received maintenance chemotherapy (paclitaxel 135 mg/m(2); q21 days). The median progression free survival (PFS) for the optimally debulked patients was 35 months, compared to 20 months for the suboptimal population (P = 0.003). Moreover, a Cox model analysis revealed that an increased number of maintenance chemotherapy cycles and optimal surgical reduction significantly correlated with favorable patient PFS (P < 0.001). In regard to overall survival (OS), the patients who had optimal cytoreductive surgery exhibited improved OS results compared to the sub-optimal surgery group (42 vs. 27 months; P < 0.001). However, a Cox model analysis indicated that a greater number of maintenance chemotherapy cycles was a surrogate marker for improved OS (P < 0.001), but surgery type was not (P > 0.05). Duration of overall patient follow-up exceeds 41 months. In advanced ovarian cancer patients who achieve a CCR following induction chemotherapy, optimal cytoreduction may confer a greater clinical benefit from a maintenance approach compared to suboptimal cytoreduction.

Survival Outcomes of Patients Receiving Thalidomide-Dexamethasone for Previously Untreated Multiple Myeloma.

Background: In three recent Phase 2 and 3 studies, the combination of thalidomide-dexamethasone (TD) induced responses in 64–72% of patients, including complete responses in 4–16% of patients. However, long term outcomes of patients receiving induction therapy with TD have not been well described.Patients and Methods: In a retrospective fashion, we updated our experience (median f/u of 50 mos.) of 58 patients treated between 7/2000 and 5/2002, with thalidomide at 100mg nightly, increasing by 100mg every 7 days as tolerated to a maximum dose of 400mg (median 200mg), and dexamethasone (20mg/m2) on days 1–4, 9–12, and 17–20 (decreased to days 1–4 only, beginning with cycle 3). Cycles were repeated on day 28 and patients were treated on protocol for a maximum of 4 courses. To prevent thrombosis, 34 patients received therapeutic doses of either warfarin (INR 2–3) or low molecular weight heparin.Results: Of 58 patients, 31 proceeded to myeloablative therapy followed by autologous stem cell support. Another 16 patients received maintenance chemotherapy until disease progression. The median age at enrollment was 60.5 (37–78), and 60% were male. By International Staging System criteria, 41% of patients were stage 1, 33% stage 2 and 26% stage 3. The overall response rate was 72%, including 12% with CR. Median overall survival (OS) of those who received autologous stem cell transplant (ASCT) exceeds 59.6 months. Median OS of those who did not receive ASCT was 31.8 months. The observed difference in OS may be partially explained by differences in performance status between the 2 groups.Conclusion: Our survival data with TD induction does not differ significantly from either historical data with alkylating agent based therapy, or from previously noted prolongation of OS after intensive therapy with stem cell support (IFM-90). Further study of the impact of thalidomide and other novel agents as induction therapy in both the ASCT and non-ASCT settings is warranted.

Role of Radiotherapy in Supratentorial Primitive Neuroectodermal Tumor in Young Children: Results of the German HIT-SKK87 and HIT-SKK92 Trials

To assess the outcome of young children with supratentorial primitive neuroectodermal tumor (stPNET) treated by intensive postoperative chemotherapy alone compared with treatment with chemotherapy and delayed radiotherapy (RT). From 1987 to 1992, children younger than 3 years of age with stPNET were enrolled in the HIT-SKK87 trial in Germany and Austria. After surgery, low-risk patients received maintenance chemotherapy before RT. In high-risk patients, intensive induction chemotherapy was followed by maintenance chemotherapy until delayed RT was initiated. In the following trial, HIT-SKK92 methotrexate-based chemotherapy was applied. In children with complete remission after three cycles, therapy was finished without irradiation. Otherwise, radiotherapy or salvage chemotherapy was administered. Twenty-nine children were eligible (age, 3.0 to 37.0 months). All children received chemotherapy. In 15 children, no RT was administered. Four children had tumor progression during chemotherapy and underwent irradiation. In 10 patients, RT was given after chemotherapy. Overall survival (OS) and progression-free survival (PFS) rates after 3 years were 17.2% and 14.9%, respectively. Twenty-four children relapsed (13 at the tumor site only, three at distant site, and eight at both local and distant sites). Positive impact on survival was observed in children with complete resection but without statistical significance. Administration of RT was the only significant predictive factor for OS and PFS. Only one child not having RT survived. Outcome of infants and babies with stPNET is unsatisfactory. Omission of RT jeopardizes survival, even if intensive chemotherapy is applied. We suggest to limit any delay of RT to a maximum of 6 months even in young children.

A phase I trial of erlotinib, gemcitabine and radiation for patients with locally advanced, unresectable pancreatic cancer

4107 Background: Pre-clinical data indicates that inhibition of EGFR potentiates the effect of gemcitabine (gem) and radiation (RT) in pancreatic cancer cell lines. Based on this data, we are conducting a phase I trial to determine the maximal tolerated dose (MTD) of erlotinib (Tarceva), an oral EGFR TKI, in combination with gemcitabine and RT in patients with histologically-proven, locally-advanced unresectable pancreatic adenocarcinoma. Methods: Cohorts of 3–6 patients received escalating doses of erlotinib (100mg, 125mg) with gem (40mg/m2, biw) and RT (50.4 Gy in 28 fractions to the primary and regional nodes.) Four weeks following completion of chemoradiation (CRT), patients received maintenance chemotherapy with gem 1000 mg/m2 (d1, 8 every 21 days) and erlotinib 100 mg daily for 4 cycles. Eligibility criteria included laparoscopically-staged, locally-advanced disease; no prior therapy; normal organ and bone marrow function; ECOG PS ≤ 2. Toxicity was assessed during and for 2 weeks following CRT Results: Nine patients have been enrolled: M:F 3:6, median age 58 (range 45–79), median PS 1. Three patients received erlotinib at 100mg and 6 patients at 125mg. Common non-heme toxicities included fatigue, abdominal pain, nausea/vomiting, weight loss and rash. Grade 3/4 leukopenia (n=4) and thrombocytopenia (n=2) was observed only at erlotinib 125 mg. One patient at 100 mg (fever) and 2 patients at 125 mg (fever, N/V) were hospitalized while receiving CRT. DLT at the 125 mg dose level was observed in 2 patients: persistent myelosuppression which delayed completion of treatment beyond 7.5 weeks (n=1) and grade 3 transaminitis (n=1). Following CRT, 8 patients were evaluated for response radiographically: (7 SD, 1 POD). Of 6 patients with an elevated CA19–9 at baseline, 4 experienced a decrease by > 50%. One patient was referred for exploratory laparotomy and underwent an R1 resection. We are treating 10 additional patients at the MTD to better define toxicity and efficacy. Conclusions: The MTD of erlotinib in combination with gem 40mg/m2 biw and standard RT is 100mg daily. Correlative tissue stained by IHC for EGFR, pEGFR, HER2/neu, pAKT and PTEN will be presented. (Supported by ACS MRSG 04–239-01-CCE) No significant financial relationships to disclose.