Completion Of Protocol Treatment Research Articles

A phase II study of perioperative capecitabine plus oxaliplatin (CapeOx) therapy for advanced gastric cancer with multiple lymph node metastases (OGSG 1701).

304 Background: Gastric cancer with paraaortic lymph node metastasis or bulky lymph node metastasis is difficult to undergo curative resection without preoperative chemotherapy. Even if curative resection can be performed, the prognosis is extremely poor. The purpose of this study was to evaluate the efficacy and safety of perioperative capecitabine plus oxaliplatin combined chemotherapy (CapeOx) for such advanced gastric cancer with multiple lymph node metastases. Methods: In this phase II trial, eligibility criteria were as follows; histologically proven gastric carcinoma; HER2 negative or unknown; with paraaortic lymph node metastases (#16a2/16b1) > 10 mm and/or bulky lymph node metastases located at celiac axis, common hepatic artery, splenic artery and/or upper mesenteric vein which make a huge bulk > 3.0 cm and/or multiple large bulks > 1.5 cm; without any other metastatic lesions; not a large (≥ 8 cm) type 3 or type 4 gastric cancer; and age between 20 and 80 years old. Treatment included three cycles of preoperative CapeOx (capecitabine; 2,000 mg/m2 for 14 days, oxaliplatin; 130 mg/m2 day 1) every 3 weeks, followed by five cycles of postoperative CapeOx after radical gastrectomy. The primary endpoint was response rate according to the RECIST v1.0. The planned sample size was 30 patients calculated on the hypothesis that the expected response rate was 65% and the threshold was 50%, with one-sided alpha of 0.05 and the power of 90%. Results: Thirty patients from 14 institutions were enrolled from September 2017 to June 2022. The number of patients with compete response, partial response, stable disease, progressive disease, and inevaluable were, 0, 20, 8, 1, and 1, respectively. The response rate was 66.7%, with the 90% confidence interval of 50.1 - 80.7% ( p = 0.049). The curative resection rate was 93.3%. The protocol treatment completion rate was 53.3%. The preoperative chemotherapy completion rate was 93.3%. The operation completion rate was 90.0%. The postoperative chemotherapy completion rate was 70.0%. The relative dose intensities were 94.8% for capecitabine and 95.2% for oxaliplatin on preoperative CapeOx, and 80.8% for capecitabine and 64.2% for oxaliplatin on postoperative CapeOx. The histological response rate (Grade ≥ 1b) was 66.7%. The adverse events of Grade ≥ 3 included neutropenia in 3.3%, anemia in 6.7%, and anorexia in 10% on preoperative CapeOx, and neutropenia in 23.8% and diarrhea in 9.5% on postoperative CapeOx. The final results of the survival analysis are yet to come. Conclusions: Perioperative CapeOx therapy for advanced gastric cancer with multiple lymph node metastasis showed favorable response rate, curative resection rate and acceptable adverse events, and was considered a promising treatment regimen. Clinical trial information: UMIN000028749 .

Investigating documented reasons for withdrawal from clinical trials for patients with advanced prostate cancer (PCa).

105 Background: In clinical trials, treatment efficacy rates are based on participants who can tolerate treatment through study endpoints. Attrition from clinical trials can potentially lead to biased results (PMID: 30379822). Many oncology clinical trials censor the subject data of participants because of early trial intervention discontinuation due to adverse events (AEs), withdrawal of consent, or loss to follow-up. Despite high attrition rates reported across various oncology clinical trials (10-38%), there is inconsistency regarding investigating the reasons for withdrawal (PMID: 23132290). We aim to identify the causes of the withdrawal of participants with advanced PCa from clinical trials. Methods: In this IRB-approved single-center retrospective study (Sept 2014 to Sept 2022), the OnCore Research Database was used to capture data on the participants with advanced PCa enrolled in clinical trials. The included trials were specific to prostate cancer, and mixed solid tumor trials were excluded. Endpoint reports from all included trials were assessed. Participants who discontinued treatment for any reason were included. The primary objective was to obtain reasons for clinical trial withdrawal before primary endpoints, identify potential clinical intervention areas, and determine potential areas of adjustment to future study designs to improve retention rates. Eligibility criteria: diagnosis of metastatic prostate cancer, receipt of protocol treatment until discontinuation, and documentation of a reason for discontinuation of the protocol treatment. Results: 272 pts from the 18 clinical trials met eligibility criteria and were included in the study. The most common reasons documented for discontinuation were: the progression of disease (46.69%), other reasons (15.44%), adverse events (5.15%), personal preference (15.81%), and completion of protocol treatment (11.76%) of the total number of enrolled participants. We noted a statistically significant difference between participants who withdrew for other reasons in the castration-resistant versus castration-sensitive setting (6.08% vs. 32.38%, p value=0.03). Notably, declining performance status and symptom progression were listed under the “other reasons” category. The documentation of patient withdrawal due to clinical symptoms was reported across multiple withdrawal categories. Conclusions: In approximately one-third of participants, the reason for protocol treatment discontinuation was not apparent (documented as patient preference and other reasons with no further specifications). Further exploration of the exact reasons contributing to therapy discontinuation in these patients will be critical to improving patient retention in clinical trials.

Neoadjuvant docetaxel, oxaliplatin and S-1 therapy for the patients with large type 3 or type 4 gastric cancer (OGSG1902): protocol of a multi-center, phase II study

BackgroundLarge type 3 and type 4 gastric cancers have extremely poor prognoses. To address this, neoadjuvant chemotherapy may be a promising approach. The phase III JCOG0501 study, conducted to confirm the superiority of neoadjuvant S-1 plus cisplatin followed by D2 gastrectomy over upfront surgery, showed no survival benefit for neoadjuvant S-1 plus cisplatin. In Korea, the PRODIGY study, which was a phase III study of neoadjuvant docetaxel plus oxaliplatin plus S-1 (DOS) followed by surgery and adjuvant S-1 versus surgery and adjuvant S-1 for gastric cancer of T2-3N+ or T4Nany, showed that progression-free survival (PFS) was significantly superior in the neoadjuvant DOS arm. Therefore, DOS therapy may be a promising candidate for preoperative chemotherapy for large type 3 or type 4 gastric cancer.MethodsPreoperative docetaxel 40 mg/m2 and oxaliplatin 100 mg/m2 will be intravenously administered on day1 every three weeks. S-1 will be orally administered 80 mg/m2 on days 1–14 of a 21-day cycle. Patients will receive three courses of treatment and gastrectomy with ≥D2 lymph node dissection. Postoperative S-1 plus docetaxel therapy (DS) will be administered according to the JACCRO GC-07 (START-2) study. The primary endpoint is the 3-year PFS rate. Secondary endpoints include PFS time, overall survival time, pathological response rate, response rate according to RECIST version1.1, proportion of completion of neoadjuvant chemotherapy, R0 resection rate, proportion of completion of surgery, proportion of completion of protocol treatment, proportion of negative conversion of CY, adverse event occurrence rate, and nutritional evaluation. The null hypothesis for the 3-year PFS rate is 45% and the expected value is 60%. The total sample size is 46 considering that the registration period and follow-up period are two and three years, respectively.DiscussionThis is a prospective, multicenter, single-arm, open-label, phase II trial assessing the efficacy and safety of preoperative DOS and postoperative DS for large type 3 or type 4 gastric cancer. The results will inform future phase III trials and are expected to lead to new treatment strategies for large type 3 or type 4 gastric cancer.Trial registrationRegistered with Japan Registry of Clinical Trials on October 11, 2019 (jRCTs051190060).

Phase II study of neoadjuvant chemotherapy with S-1 plus oxaliplatin for gastric cancer clinical T4 or N2-3

In Japan, the standard treatment for stage II or III gastric cancer is D2 gastrectomy followed by administration of S-1 for one year. However, patients with stage III disease have unsatisfactory survival rates. The purpose of this study was to evaluate the efficacy and safety of neoadjuvant chemotherapy consisting of S-1 and oxaliplatin for advanced gastric cancer. Patients with cT4 or cN2-3 gastric cancer were scheduled to receive two courses of chemotherapy (130 mg/m2 oxaliplatin on Day 1, 80 mg/m2 S-1 per day twice daily for 14 days) followed by surgery. The primary endpoint was the R0 resection rate. The secondary endpoints were rates of completion of protocol treatment, pathological response, and adverse events; and 3-year overall survival, 5-year overall survival, and 5-year recurrence-free survival. Between May 2016 and March 2019, 30 patients were enrolled in the study, all of whom completed the protocol treatment. The R0 resection rate (primary endpoint) was 93.3% (95% confidence interval: 77.9-99.2). The pathological response rate was 63.3%. Grade 3-4 toxicities included anemia (3.3%), anorexia (6.7%), and fatigue (3.3%). Relative dose intensities were 91.2% and 94.2% for S-1 and oxaliplatin, respectively. Neoadjuvant S-1 and oxaliplatin is highly effective, achieving an acceptable R0 resection rate with relatively few severe toxicities and good compliance.Trial registration: Registry name: A prospective intervention study on the availability of preoperative SOX therapy for T4 or N2-3 gastric cancer. Trial ID: UMIN: UMIN000024656. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R00002836.

Pre- and Postoperative Capecitabine Without or With Oxaliplatin in Locally Advanced Rectal Cancer: PETACC 6 Trial by EORTC GITCG and ROG, AIO, AGITG, BGDO, and FFCD.

The PETACC 6 trial investigates whether the addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative capecitabine improves disease-free survival (DFS) in locally advanced rectal cancer. Between November 2008 and September 2011, patients with rectal adenocarcinoma within 12 cm from the anal verge, T3/4 and/or node positive, were randomly assigned to 5 weeks preoperative capecitabine-based chemoradiation (45-50.4 Gy) followed by six cycles of adjuvant capecitabine, both without (control arm, 1) or with (experimental arm, 2) oxaliplatin. The primary end point was improvement of 3-year DFS by oxaliplatin from 65% to 72% (hazard ratio [HR], 0.763). A total of 1,094 patients were randomly assigned (intention to treat), and 1,068 eligible patients started their allocated treatment (arm 1, 543; arm 2, 525), with completion of protocol treatment in 68% (arm 1) v 54% (arm 2). A higher rate of grade 3/4 adverse events was reported in the experimental arm (14.4% v 37.3% and 23.4% v 46.6% for neoadjuvant and adjuvant treatment, respectively). At a median follow-up of 68 months (interquartile range, 58-74 months), 157 and 156 DFS events were observed in arms 1 and 2, respectively (adjusted HR, 1.02; 95% CI, 0.82 to 1.28; P = .835). Three-year DFS rate was not different, with 76.5% (95% CI, 72.7% to 79.9%) in arm 1, which is higher than anticipated, and 75.8% (95% CI, 71.9% to 79.3%) in arm 2. The 7-year DFS and overall survival (OS) rates were not different as well, with DFS of 66.1% v 65.5% (HR, 1.02) and OS of 73.5% v 73.7% (HR, 1.19) in arms 1 and 2, respectively. Subgroup analyses revealed heterogeneity in treatment effect according to German versus non-German site location, without detectable confounding factors in multivariable analysis. The addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative adjuvant chemotherapy impairs tolerability and feasibility and does not improve efficacy.

Panobinostat and decitabine prior to donor lymphocyte infusion in allogeneic stem cell transplantation

AbstractOutcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is adversely affected by relapse to a considerable degree. To exploit the graft-versus-leukemia effect more effectively, we assessed the feasibility of early initiation of epigenetic therapy with panobinostat and decitabine after allo-HSCT and before donor lymphocyte infusion (DLI) in poor-risk patients with acute myeloid leukemia (AML) or refractory anemia with excess blasts with International Prognostic Scoring System score ≥1.5. A total of 140 poor-risk patients with AML aged 18 to 70 years were registered, and 110 proceeded to allo-HSCT. Three dose levels were evaluated for dose-limiting toxicities, including panobinostat monotherapy 20 mg at days 1, 4, 8, and 11 of a 4-week cycle (PNB mono group) and panobinostat combined with either decitabine 20 mg/m2 (PNB/DAC20 group) or decitabine 10 mg/m2 (PNB/DAC10 group) at days 1 to 3 of every 4-week cycle. After phase 1, the study continued as phase 2, focusing on completion of protocol treatment and treatment outcome. PNB mono and PNB/DAC10 were feasible, whereas PNB/DAC20 was not related to prolonged cytopenia. Sixty of 110 patients who underwent transplantation were eligible to receive their first DLI within 115 days after allo-HSCT. Grade 3 and 4 adverse events related to panobinostat and decitabine were observed in 23 (26%) of the 87 patients, and they received epigenetic therapy. Cumulative incidence of relapse was 35% (standard error [SE] 5), and overall survival and progression-free survival at 24 months were 50% (SE 5) and 49% (SE 5). Post–allo-HSCT epigenetic therapy with panobinostat alone or in combination with low-dose decitabine is feasible and is associated with a relatively low relapse rate. The trial was registered at the European Clinical Trial Registry, https://www.clinicaltrialsregister.eu, as ECT2012-003344-74.

Efficacy and feasibility of S-1 plus oxaliplatin (C-SOX) for treating patients with stage III colon cancer (KSCC1303): final analysis of 3-year disease-free survival

Adjuvant chemotherapy is an accepted treatment to improve survival rates in patients with stage III colon cancer, and regimens including oxaliplatin have been shown to be superior to those containing 5-FU alone. The purpose of this study was to examine the efficacy and feasibility of S-1 plus oxaliplatin (C-SOX) as adjuvant chemotherapy for patients with stage III colon cancer following curative resection. Patients with colon cancer who underwent curative resection were enrolled and received oral S-1 40-60mg twice daily on days 1-14 every 3weeks plus intravenous oxaliplatin 130mg/m2 on day 1 for eight courses. The primary endpoint was 3-year disease-free survival rate. Secondary endpoints were the rate of treatment completion, adverse events, relative dose intensity, and overall survival. Between February 2014 and December 2014, 89 patients were enrolled. One patient was excluded from the analysis because of ineligibility, and the remaining 88 patients were included. The rate of protocol treatment completion was 72.3%. The relative dose intensity of S-1 and oxaliplatin was 72% and 76.3%, respectively. Hematological severe adverse events (Grade 3/4) were neutropenia (21.3%) and thrombocytopenia (15.7%). The most frequent symptom was diarrhea (Grade 3/4: 5.6%). The incidence of grade 2 neuropathy has decreased from 8.1 to 2.7% after 3years of the therapy. Three-year disease-free survival rate was 73.9% (95% CI 63.8-81.9), and 3-year overall survival rate was 94.3% (95% CI 86.8-97.6) CONCLUSIONS: C-SOX is a safe and feasible adjuvant chemotherapy regimen in patients with stage III colon cancer undergoing curative resection.

Abstract PD10-09: Impact of insurance and socioeconomic status on clinical outcomes in therapeutic clinical trials for breast cancer

Abstract Background: Studies have shown an association between insurance status, socioeconomic status (SES) and disparities in clinical outcomes among breast cancer patients. The objective of this study was to evaluate insurance status and SES with respect to protocol treatment completion and survival among participants in two large randomized adjuvant breast cancer clinical trials. Methods: The data sources for this study were the ECOG-ACRIN (EA) clinical trials E1199 and E5103. An Agency for Healthcare Research Quality (AHRQ) SES index was calculated using zip codes from the trial patients’ residence and were linked to county level data on occupation, income, poverty, wealth, education and crowding. Insurance status at randomization was categorized into private, government (Medicaid, Medicare, and other government insurance), and self-pay. Logistic regression models and Cox proportional hazard models were used to estimate odds ratios [OR] and hazard ratios [HR] for the association between insurance type (government relative to private and self-pay relative to private) with protocol treatment completion (yes vs. no) and with overall survival respectively. The estimates reported here were adjusted for SES, race, age, tumor size, nodal status, hormone receptor status, and primary surgery at randomization. Preliminary analyses of individual government insurance types with outcome showed no difference in results versus using one combined ‘government’ insurance type category. Results: The study sample included 4954 patients from E1199 and 4836 patients from E5103. The majority of patients in E1199 and E5103 had private insurance 83.8% (4154/4954) and 82% (3987/4836) respectively. The median(range) SES index was 53.8 (41.8-66.8) for E1199 and 54.1(44.5-66.1) for E5013. Patients with government type insurance were less likely to complete treatment per protocol (OR (.95CI): E1199 0.73 (0.57-0.94), E5103 0.76 (0.64-0.91)) and had increased association with death (HR (.95CI):E1199 1.44 (1.22-1.70), E5103 1.29 (1.06-1.58)) compared to those patients with private insurance. Conversely, there was no association in completing treatment per protocol (E1199 1.03(1.01-1.06), E5103 1.14 (0.67-1.95)) or survival (E1199 1.00 (0.98-1.01), E5013 1.17(0.63-2.20)) between those patients who self-paid for care relative to those who were privately insured. There was no association between SES index and completing treatment per protocol (E1199 1.03(1.01-1.06), E5103 1.01 (0.99-1.03)) or survival (E1199 1.00(0.98-1.01), E5103 0.98(0.96-1.00)). Conclusions: In these two clinical trials, patients with government type insurance appeared to face barriers in trial treatment completion and had a lower survival compared to their privately insured counterparts. Future studies are encouraged to focus on patient and institution related variables that might be contributing to these insurance-based disparities in outcomes. Citation Format: Samilia Obeng-Gyasi, Anne O'Neil, Fengmin Zhao, Sheetal M Kircher, Timsina R Lava, Lynne I Wagner, Kathy D Miller, Joseph A Sparano, George W Sledge, Ruth C Carlos. Impact of insurance and socioeconomic status on clinical outcomes in therapeutic clinical trials for breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD10-09.

TRLS-09. RTOG1119: PHASE II RANDOMIZED STUDY OF WHOLE BRAIN RADIOTHERAPY / STEREOTACTIC RADIOSURGERY IN COMBINATION WITH CONCURRENT LAPATINIB IN PATIENTS WITH BRAIN METASTASIS FROM HER2-POSITIVE BREAST CANCER

The addition of trastuzumab to cytotoxic chemotherapy has improved outcomes for patients with HER2 positive breast cancer. Increased survival coupled with limited blood-brain barrier (BBB) penetration of trastuzumab may contribute to the increased incidence of brain metastasis in these patients. Half of these patients die of intracranial disease progression rather than extracranial disease. Therefore, strategies to improve survival must include increased CNS disease control in these patients. Lapatinib crosses the BBB and demonstrates modest activity against intracranial metastases. Based upon preclinical data and results of a phase I study, we hypothesized that lapatinib plus WBRT /SRS can improve the intracranial disease control compared to WBRT / SRS alone. A randomized phase II trial of WBRT (37.5 Gy/3 weeks) or SRS plus or minus concurrent lapatinib (daily 1000 mg for 6 weeks) was initiated. CNS penetrating HER2 targeted therapy is permitted throughout the study, but patients not on trastuzumab, pertuzumab or any other breast cancer therapy at study entry are not permitted to begin this therapy while on protocol treatment, but may begin it 24 hours after completion of protocol treatment. Eligibility includes HER2+ breast cancer with at least one measurable, unirradiated parenchymal brain metastasis. The two populations targeted for accrual include patients with 1) newly diagnosed, multiple brain metastases or 2) progressive brain metastases after stereotactic radiosurgery (SRS) or surgical resection of 1–3 metastases. Prior lapatinib is allowed. Patients are stratified by breast-specific graded prognostic assessment; use of non-CNS penetrating HER2 targeted therapy; and prior SRS or surgical resection. The primary endpoint is complete response rate in the brain 12 weeks after WBRT. Secondary endpoints include objective response rate, lesion-specific response rate, CNS progression-free survival, and overall survival. 140 of 143 target accrual have enrolled (4/22/2019).

Neoadjuvant hypofractionated chemoradiotherapy with S-1 for patients with resectable and borderline resectable pancreatic cancer

The ideal neoadjuvant treatment protocol for patients with pancreatic cancer (PDAC) remains unclear. We evaluated the efficacy and safety of neoadjuvant hypofractionated chemoradiotherapy with S-1 (NACRT) for patients with resectable (R) and borderline resectable (BR) PDAC. Methods: Eligibility criteria included patients with R and BR PDAC, performance status 0-1, and age 20-85 years. Hypofractionated external-beam radiotherapy (30 Gy in 10 fractions) with concurrent S-1 (60 mg/m2) was delivered 5 days/week for 2 weeks prior to pancreatectomy. Results: Fifty-seven patients were enrolled, including 33 R and 24 BR patients. The total rates of protocol treatment completion and resection were 91% (50/57) and 96% (55/57). No patient experienced grade 4 toxicity. CT showed 52 (91%) with a SD, 4 (7%) with a PR, and 1 patient (2%) with PD. Pathologically negative margins (R0) were achieved in 54 of 55 patients (98%) who underwent pancreatectomy. Pathological response was classified as Evans grade I in 8 patients (15%), IIa in 31 (56%), IIb in 14 (25%), III in 1 (2%), and IV in 1 (2%). The 1-, 3- and 5-year overall survival (OS) rates were 93%, 73% and 49% in R and 75%, 47% and ND in BR patients, respectively (p=0.025). Conclusion: Present study demonstrated that hypofractionated NACRT with S-1 is well tolerated and safe. Our protocol allowed a high rate of subsequent resection, with encouraging survival data. This is the first and largest study to evaluate the safety and efficacy of hypofractionated NACRT with S-1 in patients with R and BR PDAC.

A prospective phase II study of pre-operative chemotherapy then short-course radiotherapy for high risk rectal cancer: COPERNICUS

BackgroundNeoadjuvant chemotherapy (NAC) allows earlier treatment of rectal cancer micro-metastases but is not standard of care. There are currently no biomarkers predicting long-term progression-free survival (PFS) benefit from NAC.Patients and methodsIn this single arm phase II trial, patients with non-metastatic magnetic resonance imaging (MRI)-defined operable rectal adenocarcinoma at high risk of post-operative metastatic recurrence, received 8 weeks of oxaliplatin/fluorouracil NAC then short-course preoperative radiotherapy (SCPRT) before immediate surgery. Sixteen weeks of post-operative adjuvant chemotherapy (AC) was planned. A pelvic MRI was performed at week 9 immediately post-NAC, before SCPRT. The primary end point was feasibility assessed by completion of protocol treatment up to and including surgery. Secondary endpoints included compliance, toxicity, downstaging efficacy, and PFS.ResultsIn total 60 patients were recruited May 2012–June 2014. In total 57 patients completed protocol treatment, meeting the primary endpoint. Compliance with NAC was much better than AC: Comparing NAC vs. AC, the median percentage dose intensity for fluoropyrimidine was 100% vs. 63% and for oxaliplatin 100% vs. 45%. Treatment-related toxicity was acceptable with no treatment-related deaths. Post-NAC MRI showed 44 tumours (73%) were T-downstaged and 22 (37%) had excellent MRI tumour regression grade (mrTRG 1–2). Median follow-up was 27 months with 2-year PFS of 86.2% (10 events). On exploratory analysis, post-NAC mrTRG predicted PFS with no event among those with excellent regression.ConclusionThe regimen was well tolerated with effective downstaging and encouraging PFS. mrTRG response to NAC may be a new prognostic factor for long-term PFS, but needs validation in larger studies.

Multicenter Phase II Clinical Trial of Sorafenib Combined with Transarterial Chemoembolization for Advanced Stage Hepatocellular Carcinomas (Barcelona Clinic Liver Cancer Stage C): STAB Study

PurposeTo evaluate safety and efficacy of combining sorafenib with transarterial chemoembolization in patients with advanced stage hepatocellular carcinomas (HCCs). Materials and MethodsSystemic chemotherapy–naïve patients with a Child-Pugh class A liver profile and advanced stage HCCs were enrolled. Sorafenib therapy (daily dose 800 mg) was initiated within 4 weeks after initial conventional transarterial chemoembolization with an allowance of subsequent on-demand conventional chemoembolization. The primary endpoint was rate of protocol treatment completion, which was defined as sorafenib administration for at least 2 months. Secondary endpoints included objective response rate, disease control rate, overall survival, progression-free survival, and incidence of adverse events. Thirty-one patients (24 men, 7 women; median age, 75 years; vascular invasion, n = 19; extrahepatic metastases, n = 18; both, n = 6) who met the inclusion criteria were enrolled. ResultsProtocol treatment was completed in 28 patients (90.3%, 28/31) with median protocol treatment duration of 7.0 months (range, 0.5–30 months) and median of 2 (range, 1–4) transarterial chemoembolization sessions. Objective response rate was 77.4% with median overall and progression-free survival of 17.3 months (95% confidence interval, 11.9–22.6 months) and 5.4 months (95% confidence interval, 4.6–6.2 months), respectively. The most common grade 3 or 4 adverse events were self-limiting elevation of aspartate aminotransferase (54.8%, 17/31) and alanine aminotransferase (45.2%, 14/31). ConclusionsThis combination therapy is feasible and promising in patients with advanced stage HCCs.

BMET-20RTOG1119 PHASE II RANDOMIZED STUDY OF WHOLE BRAIN RADIOTHERAPY WITH CONCURRENT LAPATINIB IN PATIENTS WITH BRAIN METASTASIS FROM Her2-POSITIVE BREAST CANCER: A COLLABORATIVE STUDY OF NRG AND KROG (NCT01622868)

BACKGROUND: The addition of trastuzumab to cytotoxic chemotherapy has improved outcomes for patients with HER2 positive breast cancer. Increased survival coupled with limited blood-brain barrier (BBB) penetration of trastuzumab may contribute to the increased incidence of brain metastasis in these patients. Half of these patients die of intracranial disease progression rather than extracranial disease. Therefore, strategies to improve survival must include increased CNS disease control in these patients. Lapatinib crosses the BBB and demonstrates modest activity against intracranial metastases. Based upon preclinical data and results of a phase I study, it's hypothesized that lapatinib plus WBRT can improve the intracranial disease control compared to WBRT alone. METHODS: A randomized phase II trial of WBRT (37.5 Gy/3 weeks) plus or minus concurrent lapatinib (1000 mg qd x 21 during WBRT and for 21 days after) was initiated. Non-CNS penetrating HER2 targeted therapy is permitted throughout the study, but patients not on trastuzumab, pertuzumab or any other breast cancer therapy at study entry are not permitted to begin this therapy while on protocol treatment, but may begin it 24 hours after completion of protocol treatment. Eligibility includes HER2+ breast cancer with at least one measurable, unirradiated parenchymal brain metastasis. The two populations targeted for accrual include patients with 1) newly diagnosed, multiple brain metastases or 2) progressive brain metastases after stereotactic radiosurgery (SRS) or surgical resection of 1-3 metastases. Prior lapatinib is allowed. Patients are stratified by breast-specific graded prognostic assessment; use of non-CNS penetrating HER2 targeted therapy; and prior SRS or surgical resection. The primary endpoint is complete response rate in the brain 12 weeks after WBRT. Secondary endpoints include objective response rate, lesion-specific response rate, CNS progression-free survival, and overall survival. 52 of 143 target accrual have enrolled (6/1/2015). Supported by NCI grants U10CA21661, U10CA180868, U10CA180822, U10CA37422 and UG1CA189867.

Feasibility of oral administration of S-1 as adjuvant chemotherapy in gastric cancer: 4-week S-1 administration followed by 2-week rest vs. 2-week administration followed by 1-week rest.

In 2006, the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) demonstrated that S-1 is an effective adjuvant therapy for gastric cancer. Following that study, S-1 has been used as the standard adjuvant therapy for gastric cancer in Japan. However, the 1-year completion rate was only 65.8% in the ACTS-GC study and feasibility remains a critical issue. We conducted a study to evaluate the feasibility of 2 weekly administration regimens of S-1 as adjuvant chemotherapy in gastric cancer. The criteria for eligibility included histologically proven stage II (excluding T1), IIIA or IIIB gastric cancer with D2 lymph-node dissection. The patients were randomly assigned to either arm A (S-1 administration for 4 weeks followed by 2 weeks of rest) or arm B (S-1 administration for 2 weeks followed by 1 week of rest). In each arm, treatment was continued for 12 months unless recurrence or severe adverse events were observed. The primary endpoint was feasibility (protocol treatment completion rate). The secondary endpoints were safety, relapse-free survival and overall survival. A total of 47 patients were assigned to arms A or B between May, 2008 and February, 2010. During the first interim analysis, the protocol treatment completion rates in arms A and B were 83 and 100%, respectively at 6 months and 49 and 89%, respectively, at 12 months (P=0.0046). Therefore, S-1 administration for 2 weeks followed by 1 week rest was more feasible as adjuvant chemotherapy in gastric cancer. Grade 3 adverse events in arm A included fatigue (8.0%), anorexia (8.0%), nausea (4.0%), vomiting (4.0%) and hand-foot syndrome (4.0%), whereas none were observed in arm B. There were no reported grade 4 adverse events in either arm. In conclusion, the 2-week S-1 administration followed by 1-week rest regimen appears to be a more feasible oral administration regimen for S-1 as adjuvant chemotherapy in gastric cancer.

Phase I/II trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil (DCF) followed by concurrent chemoradiotherapy in locally advanced esophageal squamous cell carcinoma.

4074 Background: Standard of care for unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is concurrent chemoradiotherapy (CRT). However, its survival remains limited. Neoadjuvant chemotherapy with docetaxel, cisplatin and 5-FU (DCF) demonstrated promising activity with pathological complete response (CR) of 22% for resectable stage II/III ESCC (Hara H et.al, ASCO 2012). This study was performed to assess the efficacy and safety of induction chemotherapy with DCF followed by CRT in patients with unresectable locally advanced ESCC. Methods: Eligibility criteria included clinically T4 and/or M1 lymph node (LYM) ESCC, PS 0-1, and 20-70 years old. Treatment consisted of docetaxel 70 mg/m2, cisplatin 70 mg/m2 on day 1 and fluorouracil 750 mg/m2 on days 1 to 5, repeated every 3 weeks for three cycles, followed by cisplatin 70 mg/m2 on days 64 and 92, and fluorouracil 700 mg/m2on days 64 to 67 and 92 to 95 concurrently with radiotherapy (60Gy in 30 fractions, 5 days/week). Results: From August 2009 to November 2011, 33 patients were enrolled.There were 16 pts with T4M0 disease, 13 with nonT4M1 LYM, and 4 with T4M1 LYM.Most grade 3 or 4 toxicities were neutropenia (66%), leukopenia (39%), anorexia (18%), dysphasia (12%), nausea (9%), febrile neutropenia (6%), and hyponatremia (6%) during induction chemotherapy. Most grade 3 or 4 toxicities were leukopenia (27%), neutropenia (20%), dysphasia (17%), anorexia (13%), esophagitis (13%), nausea (10%), and febrile neutropenia (3%) during CRT. No treatment related death was observed. The completion rate of protocol treatment was 88% (29/33). The overall response rate after completion of induction chemotherapy was 61%. Eleven pts (38%) achieved CR after completion of protocol treatment. With a median follow-up period of 14 months, 1y-PFS and 1y-OS are 38.5 and 78.6 %, respectively. Of a total of 33 patients, eighteen patients (55%) received secondary treatment. Conclusions: Induction chemotherapy with DCF followed by CRT in unresectable locally advanced ESCC was well tolerated. Although these data are preliminay, this approach warrants further evaluation. Clinical trial information: UMIN000003370.

Phase II study of preoperative chemotherapy with S‐1 and cisplatin followed by gastrectomy for clinically resectable type 4 and large type 3 gastric cancers (JCOG0210)

We conducted a phase II study to evaluate the safety and efficacy of preoperative chemotherapy with S-1 + cisplatin followed by gastrectomy in patients with linitis plastica (type 4) or large ulcero-invasive-type (type 3) gastric cancer. Eligibility criteria included histologically proven adenocarcinoma of the stomach; clinically resectable gastric cancer of type 4 or type 3. Patients received two 28-day courses of preoperative chemotherapy of S-1 (80-120 mg/body, p.o., days 1-21) and cisplatin (CDDP; 60 mg/m(2), i.v., day 8). Primary endpoints were completion of protocol treatment and incidence of treatment-related death (TRD). Among the 49 eligible patients with the median age of 61 years, 36 completed the protocol treatment comprising two courses of preoperative chemotherapy and R0/1 resection (73.5% completion, 80% CI, 63.7-81.7%). One TRD was observed during the first course of chemotherapy. Median survival and 3-year overall survival were 17.3 months and 24.5%, respectively. Preoperative chemotherapy with S-1 + CDDP followed by gastrectomy is a safe and promising treatment for type 4 and large type 3 gastric cancers. Based on the results of this study, we are now conducting a phase III study (JCOG0501) to confirm the superiority of this treatment.

P2-19-01: Impact of Zoledronic Acid on Fractures, Bone Mineral Density and Bone Remodeling in the AZURE Trial (BIG 01–04).

Abstract Background: The AZURE trial was designed to determine whether the addition of zoledronic acid (ZOL) to standard adjuvant therapy improves disease free survival (DFS) in patients (pts) with stage II/III breast cancer. Although in a recent analysis after 752 events and a median follow-up of 59 months no difference in overall DFS was seen between ZOL and control pts, significant benefits were seen in women >5years post menopause. Here, we report the impact of ZOL on fractures in the main study, and on bone mineral density (BMD) and bone remodeling evaluated within a sub-study. Materials and methods: 3360 pts were randomized to receive (neo) adjuvant chemotherapy (CT) and/or endocrine therapy with (n=1681) or without (n=1678) up to 19 doses of ZOL 4mg over 5 years. Pts with osteoporosis and those using bisphosphonates, either at baseline or in the previous year, were excluded from study entry. BMD was assessed in 228 patients within a sub-study; 40 of these also underwent quantitative bone scanning (QBS), a novel imaging technique that yields values for 99mTc-MDP/HMDP whole skeleton plasma clearance (Kbone) as a surrogate for the rate of bone remodeling and enables assessment of specific regions of interest within the skeleton. Results: Fractures occurred in 152 (4.5%) pts; 60 (3.6%) ZOL pts compared with 92 (5.5%) control (CTRL) pts (difference −1.9%; 95%CI −3.3%, −0.5%). The difference in fracture incidence appeared early and persisted throughout the follow-up period. Fifty-six (86.2%) of the fractures in the ZOL group and 68 (61.8%) in the CTRL group occurred in the absence of, or prior to a DFS event. The fracture rates before disease recurrence were similar at 3.0% (51 pts) in the ZOL group and 3.4% (57 pts) in the CTRL group (difference −0.4%; 95%CI −1.6%, 0.8%). In contrast, 2.1% (8 ZOL pts) and 9.1% (34 CTRL pts) experienced a fracture after a DFS event (difference −6.9%; 95% CI −10.2%, −3.7%). For pts with a DFS event, the majority of fractures occurred after a skeletal recurrence; 87.5% (7 of 8) ZOL and 88.2% (30 of 34) CTRL pts. BMD Z-scores at completion of protocol treatment were higher in patients treated with ZOL. Kbone was lower in ZOL patients (26.5 vs 29.8 ml min−1 using 99mTc-MDP and 34.3 vs 39.3 ml min−1 with 99mTc-HMDP). Expressed as a percentage of whole skeleton clearance, regional values in the mandible were similar 1.15% (ZOL) vs. 1.22% (CTRL). Conclusions: Adjuvant ZOL given in the schedule studied in AZURE reduced the fracture rate in patients who developed recurrence of breast cancer. BMD was higher and the rate of bone remodeling less in patients treated with ZOL. Further follow-up will determine the duration and clinical relevance of these effects on bone health. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-19-01.

Phase II feasibility trial of a 3-week cycle of cisplatin plus radiation for post-operative high-risk head and neck cancer in a Japanese population.

e16007 Background: The current standard of care for post-operative high-risk head and neck squamous cell carcinoma (HNSCC) is a three-week cycle of cisplatin plus radiation (RT). In two pivotal trials (RTOG 9501 and EORTC 22931), however, the complete delivery rate of three cycles of cisplatin and RT was only about 60%. Here, we evaluated the feasibility and safety of adjuvant cisplatin plus RT in a Japanese population. Methods: Post-operative high-risk HNSCC patients were enrolled. Definitive surgery for locoregional recurrence was allowed. High-risk factors were a microscopically incomplete resection (ICR), extracapsular extension (ECE), and two or more lymph node metastases. Subjects received three cycles of cisplatin (100mg/m2) concomitant with RT (66Gy/33 Fr). Protocol treatment completion was defined as three cycles of cisplatin with a total dose of more than 240 mg/m2 with RT. Results: From August 2006 to May 2009, 25 eligible subjects were accrued, including 13 males, with a median age of 59 years, ECOG PS 0/1 (18/7), stage III/IVa/IVb/recurrent (1/18/1/5), oral cavity/oropharynx/hypopharynx/larynx (17/4/3/1), and ICR and/or ECE in 20. Protocol completion rate was 80%. Lower limit of the one-sided 90% CI was 66%, which met the predefined statistical criteria. Median relative DI of cisplatin was 0.83. Grade 3/4 acute toxicity included mucositis (44%), dysphagia (28%), dermatitis (24%), nausea/vomiting (16%), neutropenia (32%), and anemia (36%). Grade 3/4 late toxicity included dysphagia (10%), xerostomia (5%), and osteonecrosis (5%). 1-year feeding tube rate was 20%. No treatment-related deaths were observed. With a median follow-up of 25 months, 13 have had progression and 10 have died. Estimated 2-year OS and RFS were 58% and 47%. Univariate analysis revealed that oral cavity cancer and locoregional recurrence might be poor prognostic factors.Conclusions: This is the first phase II feasibility trial of a three-week cycle of cisplatin plus RT for post-operative high-risk HNSCC in an Asian population. Adjuvant three-week cycle of cisplatin plus RT was feasible and safety profile was identical to those in pivotal phase III trials.

A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin's lymphoma: A randomized trial

Lamivudine is effective to control hepatitis B virus (HBV) reactivation in HBV-carrying cancer patients who undergo chemotherapy, but the optimal treatment protocol remains undetermined. In this study, HBV carriers with newly diagnosed non-Hodgkin's lymphoma (NHL) who underwent chemotherapy were randomized to either prophylactic (P) or therapeutic (T) lamivudine treatment groups. Group P patients started lamivudine from day 1 of the first course of chemotherapy and continued treatment until 2 months after completion of chemotherapy. Group T patients received chemotherapy alone and started lamivudine treatment only if serum alanine aminotransferase (ALT) levels elevated to greater than 1.5-fold of the upper normal limit (ULN). The primary endpoint was incidence of HBV reactivation during the 12 months after starting chemotherapy. During chemotherapy, fewer group P patients had HBV reactivation (11.5% versus 56%, P = 0.001), HBV-related hepatitis (7.7% versus 48%, P = 0.001), or severe hepatitis (ALT more than 10-fold ULN) (0 versus 36%, P < 0.001). No hepatitis-related deaths occurred during protocol treatment. Prophylactic lamivudine use was the only independent predictor of HBV reactivation. After completion of chemotherapy, the incidence of HBV reactivation did not differ between the 2 groups. Two patients, both in group P, died of HBV reactivation-related hepatitis, 173 and 182 days, respectively, after completion of protocol treatment. When compared with an equivalent group of lamivudine-naïve lymphoma patients who underwent chemotherapy, therapeutic use of lamivudine neither reduced the severity of HBV-related hepatitis nor changed the patterns of HBV reactivation. Prophylactic lamivudine use, but not therapeutic use, reduces the incidence and severity of chemotherapy-related HBV reactivation in NHL patients.

Quality of Life With Docetaxel Plus Cisplatin and Fluorouracil Compared With Cisplatin and Fluorouracil From a Phase III Trial for Advanced Gastric or Gastroesophageal Adenocarcinoma: The V-325 Study Group

Therapy of patients with advanced gastric or gastroesophageal junction cancer should provide symptom relief and improve quality of life (QOL) because most patients are symptomatic at baseline. Using validated instruments, we prospectively assessed QOL (even after completion of protocol treatment) as one of the secondary end points of the V325 phase III trial. Four hundred forty-five patients randomly received either docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) each on day 1 plus fluorouracil 750 mg/m(2)/d continuous infusion on days 1 to 5 every 3 weeks (DCF) or cisplatin 100 mg/m(2) on day 1 plus fluorouracil 1,000 mg/m(2)/d continuous infusion on days 1 to 5 every 4 weeks (CF). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and, where available, the EuroQOL EQ-5D questionnaire were administered every 8 weeks from baseline until progression and then every 3 months. Time to definitive deterioration of QOL parameters was analyzed. The proportions of patients having assessable EORTC QLQ-C30 and EQ-5D questionnaires at baseline were 86.0% and 78.7% with DCF, respectively, and 89.7% and 92.8% with CF, respectively. Time to 5% deterioration of global health status (primary end point) significantly favored DCF over CF (log-rank test, P = .01). QOL was preserved longer for patients on DCF than those on CF for all time to deterioration analyses, demonstrating the statistical superiority of DCF compared with CF. V325 represents the largest trial with the longest prospectively controlled evaluations of QOL during protocol chemotherapy and follow-up in patients with advanced gastric or gastroesophageal junction cancer. In V325, advanced gastric or gastroesophageal junction cancer patients receiving DCF not only had statistically improved overall survival and time to tumor-progression, but they also had better preservation of QOL compared with patients receiving CF.