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Multivariate regression analysis was performed to evaluate the impact of the establishment of the Japanese regulatory agency Pharmaceuticals and Medical Devices Agency (PMDA) in 2004 with respect to the contents of guidance for proper usage. Results: From 91 approved oncology pharmaceuticals, we obtained 59 guidance for proper usage for 50 approved oncology pharmaceuticals. The median total number of pages in the guidance for proper usage was 48 (range, 11−98 pages). The proportions of pages in the guidance that discussed toxicity, drug information, and the results of registration trials were 30%, 26%, and 11%, respectively. After the PMDA was established, the total number of pages and the proportion of pages discussing the results of registration trials significantly increased (p = 0.007 and p = 0.002, respectively). On analyzing guidance published for different types of drugs, we observed that the total number of pages and the proportion of pages discussing toxicity in the case of molecular-targeted drugs was significantly greater (p < 0.001 and p = 0.008, respectively) than that for the other types of drugs, whereas the proportion of pages discussing indications was significantly lower (p = 0.001) than that for the other types. Conclusion: The guidance for proper usage distributed to medical oncologists in Japan include drug information that is not provided in package inserts. The establishment of the PMDA and the type of drugs for which the guidance for proper usage were distributed may have influenced the contents of and trends with regard to the guidance for proper usage.

e12516 Background: GBM is an aggressive malignancy with a poor outcome. Retrospective studies have correlated clinicopathologic and molecular variables with prognosis and constructed nomograms pred...

e19689 Background: Surgery offers the only potential for cure in localized pancreatic cancer and most patients (pts) are >65 years (yrs) at diagnosis. Due to compromised physiological reserve, co-m...

e19621 Background: In an aging cancer population treatment decisions become more complex. Treatment options in GBM are increasing and there is a paucity of data in the elderly (>65 years). We sought to review our institution’s experience of treating this patient (pt) population. Methods: A prospectively maintained database was evaluated for pts with GBM reviewed at our institution between Aug 2004 and Dec 2009. Pts were divided into: age groups > and 65 yrs (24.3%) and 4 pts were >75 yrs (2.8%). 132 pts received treatment (92%), which was optimal in 82 pts (57%). In Gp A 34 pts were treated (97%); of these, treatment was optimal in 15 (43%) compared wi...

209 Background: Understanding of the role of host energetics in cancer outcomes has been increasing in recent years. In early stage prostate cancer trials obesity is associated with worse outcome. Its effect on treatment response and survival in advanced disease is largely unexplored. We sought to explore the relationship between BMI, the most validated measure of obesity, and biochemical response as well as overall survival in patients receiving first-line chemotherapy. Methods: We reviewed a prospectively-maintained institutional database identifying patients who received docetaxel (D) for CRPC. Demographics and PSA levels during treatment were extracted. Pts were divided into 2 BMI groups (> and < 30 kg/m2). We calculated biochemical responses as per historically validated surrogates: PSA decrease > 30% at 3months; overall decrease > 50%; time to PSA nadir and PSA half-life after 4 cycles, for each group. Results were compared with unpaired t-test and chi-square test. Results: 33 pts were identified between June ‘04 and Sept ‘10, 16 pts with BMI > 30 (hBMI) (range 30.1-34.2) and 17 with BMI < 30 (nBMI) (21.5-29.6). Median age for the entire cohort was 67.9 yrs (47.7-79.8), median Gleason score 8, median cycles of D received was 6 (3-20) with median duration of 3.7 months (1.4-8.7), p>0.05. Baseline PSA was 89.1 ng/ml (0.34-417) and 259.2 (16.1-1,589) for hBMI and nBMI respectively, p = 0.023. For hBMI group, only 56.3% (9/16) of patients demonstrated biochemical response, compared with 88.2% (15/17) in nBMI group(p = 0.039). Of the biochemical responders, 6/16 (38%) of hBMI and 9/7 (53%) of nBMI achieved >50% fall in PSA (p = 0.743) while 8/16 (50%) patients in hBMI group and 10/17 (59%) in nBMI group had a PSA drop >30% at 3 months (p = 0.61); Median time to PSA nadir was 3.4 months (0.7-4.9) and 2.7 (0.7-7.5), and median PSA half life was 56.4 days (16-138) and 46.1 days (16-302) for hBMI and nBMI groups, respectively, p > 0.05. Conclusions: Obese patients with CRPC have lower pre-D PSA levels. However, they also experience a lower rate of biochemical response to therapy. PSA kinetics in biochemical responders do not appear to be influenced by BMI. Survival data will be presented. No significant financial relationships to disclose.

467 Background: Clinical trials have shown that tumor KRAS status predicts response to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC). We sought to compare distribution of wild-type and mutated KRAS in an Irish population and identify clinicopathologic correlates. Methods: From our prospectively maintained database we retrospectively identified patients with mCRC and documented KRAS status between Jan 2007 to June 2010. Medical notes were examined for patient demographics and disease characteristics. Variables were extracted and compared using unpaired t test and chi2 test. Results: 52 patients were identified, 29 (55.8%) with mutated (mt) and 23 (44.2%) with wild type (wt) KRAS from tumor tissue. Males accounted for 61.5% (n=31). Median age at diagnosis of metastatic disease for the KRASmt group was 66.4 years (range 56.7-82.1) and for the KRAS wt group was 64.2 years (40.1-76.8), p= 0.08. 21 (72.4%) of the KRASmt group and 16 (69.6%) of the KRASwt group had metastatic disease at presentation (p=0.81). For patients who presented initially with localised disease, time to development of metastases was 22.5mo (range 14-37.6) for the KRASmt group and 16.7mo (3.2-123.7) for the KRASwt (p=0.30). 21 (72.4%) of KRASmt and 17 (74.1%) of KRASwt tumors had left-sided primary (p = 0.84) with equal numbers of primary tumor resection in both groups. There was no statistical difference in TN-stage or the presence of liver metastases. Numbers of patients with KRASmt tumors with one, two and three or more different sites of metastases was 22 (75.9%), 5 (17.2%), and 2 (6.9%), and in KRASwt tumors there was no significant difference: 18 (78.3%), 4 (17.4%), and 1 (4.3%), respectively (p = 0.93). Median CEA at diagnosis for both groups were 19.7 μg/l (range 1.2-5958) and 6.1 (1.3-696.9; p = 0.11). Conclusions: We found that the ratio of KRASmt to KRASwt tumours in an Irish population is comparable to that in large international trials. Our analysis revealed no association between KRAS status and clinicopathologic variables. The inclusion of BRAF status, not readily available in our institution, may help define poor prognosis tumors. At present there is no validated molecular biomarker that is superior to standard clinicopathologic variables. No significant financial relationships to disclose.

354 Background: Gallbladder cancer (GBC) is rare, is often diagnosed at an advanced stage, and survival >1 yr is uncommon. Recent randomized trials have demonstrated improved survival with well-tolerated chemotherapies. In this light, we retrospectively reviewed referral patterns to medical oncology services in our region. Methods: Prospectively maintained departmental databases from three hospitals serving 480,000 people were reviewed. Patient demographics, disease and treatment details, and outcomes were analyzed. Regional figures were obtained from National Cancer Registry data. Results: Between March 2003 and September 2010, 17 GBCs were referred to medical oncology, representing 25.5% of total GBC diagnosed in the region (Table). Median age at diagnosis was 63.6 years (range 47.0–72.5) and 65% (n=11) were female. The majority (n=13) initially presented with metastatic or locally advanced disease and 6 of these patients underwent cholecystectomy. Of those with early-stage disease, 2 patients were referred with relapsed disease and 2 were referred for adjuvant treatment. Sites of involvement were liver (10), lymph nodes (3), peritoneum (3), duodenum (2), gallbladder bed (1), and pancreas (1). No extra-abdominal metastases were noted. All patients were scheduled for chemotherapy, but 3 were not treated due to worsening performance score. Of the 14 patients who received chemotherapy, 7 received gemcitabine, 5 received 5FU and 2 received cisplatin/gemcitabine. Median duration of chemotherapy was 3.8 months (range 0.7–8.1) and 3 patients (21%) received second-line chemotherapy. 13 patients (76.5%) had died at the time of analysis. Median follow-up was 6.7 months (range 1.7-73.9) and median overall survival was 6 months. Conclusions: A minority of patients with GBC were referred to medical oncology. Given the emergence of level 1 evidence reporting a survival benefit with well-tolerated combination chemotherapy and the potential for adjuvant treatment, higher referral rates may lead to improved outcome. [Table: see text] No significant financial relationships to disclose.

10524 Background: The glucose-regulated protein GRP78, also referred to as BiP (immunglobulin heavy-chain binding protein) is an endoplasmatic reticulum chaperone in the heat shock protein 70 (HSP7...

4047 Background: CD44 is a transmembrane glycoprotein serving as receptor of hyaluronan and osteopontin, is associated with adhesion and metastasis in gastrointestinal carcinomas. Moreover, a gastric cancer stem cell population with CD44 as their defined surface marker has been identified showing increased resistance for chemotherapy- or radiation-induced cell death. High CD44 protein expression has been associated with poor prognosis in GA. We tested the hypothesis whether germline variations involved in the CD44 pathway will predict clinical outcome in patients with localized GA. Methods: Either blood or FFPE tissues specimens were obtained from 137 patients (54 females and 83 males; median age = 55 yrs; range = 21-85 yrs) with localized GA at University of Southern California (n = 105) and Memorial Sloan-Kettering Cancer Center medical facilities (n = 32). The median follow-up was 3.3 years. Sixty-one of 137 patients (45%) had tumor recurrence, with a probability of 3-year recurrence of 52%. Genomic DN...

3559 Background: Hepatic arterial infusion (HAI) with floxuridine + dexamethasone can be added safely and effectively to systemic (SYS) oxaliplatin + irinotecan in unresectable colorectal cancer li...

4054 Background: SPARC (Secreted Protein Acidic and Rich in Cysteine) is a glycoprotein involved in cellular adhesion acting as a key regulator of cell-matrix interactions. SPARC protein overexpression is frequently observed in gastric carcinoma and plays an important role in tumor progression, proliferation and metastasis. We tested whether two potentially functional germline variations (rs1059829 and rs3210714) within the SPARC gene are associated with clinical outcome in patients with surgically resected gastric cancer. Methods: Either blood or FFPE tissues specimens of 137 patients (54 females and 83 males; median age = 55 yrs; range = 21-85 yrs) were obtained at University of Southern California (n = 105) and Memorial Sloan-Kettering Cancer Center medical facilities (n = 32). The median follow-up was 3.3 years. Sixty-one of 137 patients (45%) had tumor recurrence, with a probability of 3-year recurrence of 52%. Genomic DNA was isolated from peripheral blood or FFPE tissues and two polymorphisms withi...

e15661 Background: Diabetes mellitus (DM) and impaired glucose tolerance (IGT) are frequent comorbidities in cancer patients. Their diagnosis is predictive of early recurrence following resection of colorectal cancer and of increased treatment related toxicity in localized breast cancer. Impaired glucose tolerance is a risk factor for the development of GE cancer. As nutrition and performance status are key determinants of outcome, we hypothesized that DM would influence treatment outcome in GE cancer. Our primary objective was to analyze the role of serum glucose, DM, serum albumin and BMI on treatment outcome and toxicity amongst a cohort of uniformly treated patients with GE cancer. Methods: 211 patients with GE cancer enrolled on 3 localized (2 esophagus, 1 gastric) and 4 metastatic consecutive prospective clinical trials (3 gastric, 1 esophagus) were examined. The studies involved treatment with chemotherapy combinations of taxanes, platinum, irinotecan, 5-fluorouracil, bevacizumab and cetuximab. Diagnosis of DM was based on clinical data, random glucose or fasting-glucose levels. Study parameters were tested for their association to time to treatment failure (TTF), overall survival (OS) and toxicity using the X2 test. Results: 132 metastatic pts were included: median age 57(range 32–76), M/F 96/36, median BMI 25.3 (16.2–40.1), 19 diabetic / 113 non-diabetic; overall survival was 10.8 months. 79 patients had localized disease: median age 61(32–80), M/F=53/26, median BMI 25.8 (range 16.1–38.5), 10 diabetic/69 non-diabetic; overall survival was 23.2 months. There was no statistically significant association of random glucose (p=0.06), DM (p=0.9), or BMI(p=0.2) with survival or with treatment related toxicity. Low serum albumin was associated with reduced survival, hazard ratio 2.12 (95% CI1.5–3.2), p No significant financial relationships to disclose.

e14534 Background: Recent evidence has suggested that baseline SUV and metabolic response measured on sequential PET scans early in the course of chemotherapy may predict for survival and response to chemotherapy. Methods: Patients with MPM suitable for platinum/pemetrexed chemotherapy were studied. Baseline pre-chemotherapy PET and CT scans were performed with a further PET scan before cycle 2. CT scans were repeated mid-treatment and at the end of 6 cycles. PET response was determined by measuring the change in the maximum and mean SUV, PET Vol (volume of tumor above SUV threshold of 3.5) and Total Lesion Glycolysis (TLG, calculated as PET Vol x SUV Max). Metabolic response (MR), as measured by a 25% drop in SUV Max, SUV Mean, PET Vol and TLG was compared to overall survival (OS) and to subsequent response to chemotherapy on CT. CT scans were read using Modified RECIST criteria and CT response was compared to OS. Results: 21 patients had baseline PET scans of whom 17 had a further PET before cycle 2. 19 patients had CT scans evaluable by Modified RECIST criteria. Baseline SUV Max and SUV Mean were found to predict for OS. Median survival was 17.2 months for patients with SUV Max less than 15 versus 6 months for those with SUV Max greater than 15 (p=0.0193). Median survival was 14.1 months for patients with SUV Mean less than 5 versus 6.5 months for those with SUV Mean greater than 5 (p=0.0681). MR defined by SUV Max, SUV Mean, PET Vol or TLG did not predict for OS. MR on PET correlated poorly with CT response with Kappa values of 0.01, 0.05, 0.15 and 0.31 for MR defined by SUV Max, PET Vol, SUV Mean and TLG respectively. CT response using Modified RECIST criteria correlated significantly with OS. Patients with partial response (PR), stable disease (SD) and progressive disease (PD) had median survivals of 25.6 months, 8.6 months and 4.6 months respectively (p=0.0072) Conclusions: MR measured by SUV Max, SUV Mean, PET Volume and TLG on early sequential PET scans did not correlate with CT assessed response to chemotherapy or OS. Baseline SUV Max >15 and SUV Mean >5 were indicative of poor prognosis. CT response as measured by Modified RECIST criteria correlated significantly with OS. No significant financial relationships to disclose.

19515 Background: Primary bone lymphoma (PBL) is a rare condition and accounts for less than 2% of all adult lymphomas and 3% of all primary bone malignancies. Presentation is usually in the fifth ...

13502 Background: Although DCF is a standard option for advanced gastric cancer, its toxicity limits widespread use. D is both a substrate and inhibitor of CYP3A4, the enzyme responsible for its cl...

10547 Background: Large-scale screening for germ-line mutations that lead to the onset of disease in adulthood is possible owing to recent technical advances. The care of those with inherited predisposition to breast and ovarian cancer is now becoming a mainstream component of medical care. It is more difficult to identify those with Lynch Syndrome (LS) as various criteria (Amsterdam and Bethesda) have not proved definitive. An important development is the examination of tumor tissue to detect mismatch repair (MMR) protein loss using immunohistochemical (IHC) techniques. When coupled with family history those at risk of harbouring a mutation for LS can be identified. Once a mutation is identified predictive testing can be offered to family members, risk-reduction measures applied and mortality from colorectal cancer reduced. Methods: Screening for MMR protein expression (MLH1, MSH2, MSH6, PMS2) was planned on all colorectal cancer (CRC) cases using IHC on formalin-fixed tumor tissue from January 1st 2002. Local ethics committee approval was obtained and then written informed-consent from patients. Family history data was gathered from the index case or an appropriate relative. An aliquot of blood was stored from index cases for subsequent genetic screening if indicated by IHC analysis and genetic counseling. Results: 108 cases with CRC (62 male, 46 female, median age 59 years) from a potential total of 612 have been screened for MMR protein expression by a gastrointestinal pathologist and independently validated. Turn-around time for IHC analysis was 9 weeks. 5 patients (4.6%) had loss of MMR proteins, MSH2/MSH6- 2 cases, MSH6 alone- 1 case and MLH1/PMS2- 2 cases. All 5 have opted for genetic counselling and sequencing of relevant genes. Conclusion: These early results in an Irish cohort with CRC showing MMR loss in 4–5% of cases is consistent with other population findings. Microsatellite instability analysis is difficult, expensive and relatively unavailable. IHC, however, is an established technique in pathology departments and can be the cheapest and most reproducible approach to identify LS cases. IHC results along with robust family data can guide the genetic counseling process towards preventing deaths from CRC and other LS-associated cancers. No significant financial relationships to disclose.

17113 Background: MPM is a rapidly progressive malignancy with a median survival of 6 to 9 months. Studies in non-small cell lung cancer, gastrointestinal stromal tumours, and breast cancer suggest that Positron Emission Tomography (PET) scanning may predict the clinical outcome of chemotherapy at an early stage of treatment. The role of PET in predicting and monitoring response to treatment in MPM is unclear. In this study we assessed if baseline and early interval PET scanning could be of benefit in MPM, correlating the results with standard Computerised Tomography (CT) assessment using the modified Response Evaluation Criteria In Solid Tumours (RECIST) of Byrne and Nowak. Methods: 10 patients with histologically proven MPM proceeded to baseline PET and CT scanning prior to chemotherapy. In 8 patients a second PET scan was performed within three weeks of commencing treatment. The following PET derived parameters were calculated: Standard Uptake Value (SUV)maximum, SUVaverage, PETvolume, and Total Lesion Glycolysis (TLG). Baseline SUVmaximum and early PET response was compared with CT response and survival. Results: Baseline SUVmaximum predicted subsequent CT response in the 10 patients studied. Four out of 5 patients with baseline SUVmaximum of th patient had resolution of a pleural effusion. All 5 patients with baseline SUVmaximum of >15 had stable or progressive disease on CT. In contrast change in early SUVmaximum from baseline to 3 weeks did not predict subsequent CT response (Kappa value 0.07) in the 8 patients evaluated. Change in PET volume and TLG correlated with subsequent CT response (Kappa value= 0.80 for both). Only 1 patient with a partial response on % PETvolume and %TLG has died 14 months after commencing treatment. The other 3 patients are alive at 17+, 19+ and 20+ months. The 4 patients with stable or progressive disease using these parameters were deceased at 5, 6, 10, and 12 months respectively. Conclusion: PET may be useful in predicting and evaluating response to treatment in MPM. Furthermore, the results suggest that PET response may be a useful prognostic tool in this disease. It is important to use the appropriate PET derived parameters. Further study with a larger patient population is warranted. No significant financial relationships to disclose.

Purpose The addition of nivolumab (anti–programmed death-1 antibody) to ipilimumab (anti–cytotoxic T-cell lymphocyte–associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. Methods This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome. Results Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four (< 1%) on-study deaths were attributed to therapy. Conclusion Frequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar.