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Before its regulatory approval in Canada, bevacizumab to treat patients with colorectal cancer (crc) was accessed through the Bevacizumab Expanded Access Trial and a special-access program at the Jewish General Hospital. We retrospectively evaluated patient outcomes in that large cohort. All patients (n = 196) had metastatic crc, were bevacizumab-na&iuml, ve, and received bevacizumab in combination with chemotherapy at the Jewish General Hospital between 2004 and 2009. We collected patient demographics and clinical characteristics, relevant medical history, disease stage and tumour pathology at diagnosis, type, duration, and line of therapy, grades 3 and 4 adverse events (aes), time to disease progression (ttp), and overall survival (os) from diagnosis. Median follow-up was 36.0 months. Median ttp was 8.0 months [95% confidence interval (ci): 7.0 to 9.0 months). Median os was 41.0 months (95% ci: 36.0 to 47.0 months). Of the 40 grades 3 and 4 bevacizumab-related aes experienced by 38 patients (19.4%), the most common were thrombocytopenia (n = 17), deep-vein thrombosis (n = 6), pulmonary embolism (n = 4), and hypertension (n = 3). In an expanded access setting, our data reflect the efficacy and safety of bevacizumab-based therapy in the controlled post-registration clinical trial setting.

In the last half of the century, advances in the systemic therapy of cancer, including chemotherapy, hormonal therapy, targeted therapy, and immunotherapy have been responsible for improvements in cancer related mortality in developed countries even as the population continues to age. Although such advancements have yet to benefit all cancer types, systemic therapies have led to an improvement in overall survival in both the adjuvant and metastatic setting for many cancers. With the pressure to make therapies available as soon as possible, the side-effects of systemic therapies, in particular long-term side-effects are not very well characterized and understood. Increasingly, a number of cancer types are requiring long-term and even lifelong systemic therapy. This is true for both younger and older patients with cancer and has important implications for each subset. Younger patients have an overall greater expected life-span, and as a result may suffer a greater variety of treatment related complications in the long-term, whereas older patients may develop earlier side-effects as a result of their frailty. Because the incidence of cancer in the world will increase over the next several decades and there will be more people living with cancer, it is important to have an understanding of the potential side-effects of new systemic therapies. As an introductory article, in this review series, we begin by describing some of the major advances made in systemic cancer therapy along with some of their known side-effects and we also make an attempt to describe the future of systemic cancer therapy.

Irinotecan is cytotoxic in patients with advanced colorectal cancer (CRC). SN-38 (10-hydroxy-7-ethyl-camptothecin) is the active metabolite of irinotecan. Attachment of polyethylene glycol (PEG) polymer chains (pegylation) to SN-38 (EZN-2208) increases the solubility, exposure, and half-life of SN-38. Preclinical studies demonstrated superior in vitro efficacy of EZN-2208 when it was tested in irinotecan-refractory human CRC cell lines.Patients with metastatic or locally recurrent CRC who had previously received 5-flurouracil (5-FU), oxaliplatin, and irinotecan were assigned to receive EZN-2208 monotherapy (9 mg/m(2) on days 1, 8, and 15 every 28 days for patients with KRAS-mutant tumors only [arm A]), and patients with KRAS wild-type tumors were randomized (2:1) to receive either EZN-2208 plus cetuximab (400 mg/m(2) loading dose on day 1 followed by 250 mg/m(2) weekly starting on day 8 [arm B]) or irinotecan 125 mg/m(2) on days 1 and 8 every 21 days plus cetuximab at the same doses indicated above (arm C).The overall response rate and progression-free survival were 0% and 1.8 months, respectively, in arm A; 10.7% and 4.9 months (95% confidence interval [CI], 3.2-5.8 months), respectively, in arm B; and 14.3% and 3.7 months (95% CI, 2.1-5.8 months), respectively, in arm C. EZN-2208 was well tolerated in combination with cetuximab. No statistically significant difference in survival was observed between arm B (9.8 months; 95% CI, 7.2-11.2 months) and arm C (9.1 months; 95% CI, 6.0-13.0 months).EZN-2208, either as monotherapy or in combination with cetuximab, was well tolerated in patients with refractory CRC. Overall survival and progression-free survival were similar in the cetuximab plus irinotecan arm and the EZN-2208 arm.

Background: Panitumumab is a fully human monoclonal antibody, directed against the epidermal growth factor receptor, that was shown to be effective in third-line metastatic colorectal cancer. We performed a retrospective analysis of patients with chemo-refractory non-KRAS-mutated metastatic colorectal cancer, who received panitumumab at the Jewish General Hospital in Montreal, Canada, between 2009 and 2012. Methods: This chart review included 44 patients (median age: 60 years; performance status: 0–3), of whom 50% had already received three lines of treatment. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival and safety. Tumour progression was determined by radiologic assessments performed once every 3 months per clinical guidelines or by clinical deterioration as determined by the clinician–investigator. Results: In our sample, median PFS was 21.86 ± 5.23 weeks (95% confidence interval: 12.9 to 36.9 weeks) and overall survival was 35.14 ± 7.75 weeks (95% confidence interval: 25.6 to 73.4 weeks) with a median of 5 cycles of panitumumab treatment. The most frequently reported toxicities with panitumumab were skin toxicity (16.2% grade 3) and hypomagnesemia (10.8% grade 3). No infusion reactions were reported. Conclusions: Despite a small sample size from a single institution, our survival and efficacy data are encouraging and comparable to results obtained from the registration panitumumab trial. Our findings suggest that panitumumab can be effective and tolerable in a real-world setting.

498 Background: Metastatic pancreatic adenocarcinoma (mPDAC) carries a dismal prognosis, with often a poor response to treatment (Tx). Although gemcitabine with nab-paclitaxel (GnP) is now a standard 1st-line (1L) Tx in mPDAC, provincial policies limit its use. To understand the implications of the restriction, this real-life study was conducted. Methods: A historical prospective data was compiled using the local electronic medical record (Endovault Oncology v3.0, NY) at the Jewish General Hospital-McGill. All patients (pts) diagnosed with mPDAC that received GnP from 2013-2016 were identified. Demographics and Tx data was obtained. Primary objective was to evaluate tolerability in all lines of Tx [grade >2 CTCAE v4.03, mean Tx delay (mTxd)]. Secondary objectives were Tx attrition and outcomes [RECIST 1.1, complete response (CR), stable disease (SD) and progression disease (PD)]. Results: Of the 40 pts (female 60%, median age 64.3), 25 (62.5%) had primary at the head of the pancreas and 30 (75%) liver metastasis. 1L Tx: GnP 24 (60%), FOLFIRINOX 10 (FFX, 25%), Gemcitabine 5 (Gc, 12.5%) and FOLFOX 1 (2.5%). 70% of both FFX and Gc pts had grade 2 peripheral neuropathy (PN), neutropenia (NEUT) and fatigue. Half GnP pts had grade 2 NEUT and fatigue. mTxd in GnP, FFX and Gc were 7, 14 and 7 days. All FFX and Gc pts had PD. GnP cohort had 1 CR and 7 SD. 2L Tx was in 22 (55%): GnP 13 (59.5%), FFX 3 (13.5%), Capecitabine 2 (9%), FOLFOX 2 (9%) and Gc (9%). FFX pts 66.6% had grade 3 fatigue. GnP pts had grade 2 NEUT, PN and fatigue in 53.8%, 15.3% and 46.2%. mTxd were GnP 14 days and FFX 14 days. Except 1 SD, all FFX pts had PD. GnP pts had 1 CR, 6 SD, and 6 PD. All pts on Capecitabine, FOLFOX and Gc had PD. 3L Tx was in 6 (15%): 3 GnP (50%) and 3 on clinical trials (50%). All pts had PD and < 3 cycles. In 1L FFX pts, 7/10 and 3/6 went on to receive GnP in 2L and 3L. All 1L Gc pts had 2L GnP. Only 3 pts and 1 pt from 1L GnP pts went on to receive 2L and 3L Tx. Conclusions: Due to access limitations to GnP, its use was likely reserved for poor performance status pts. Instead, 1L FFX was used when possible. 1L FFX pts received more Tx lines due to initial pt selection. Further studies are needed in broader populations to evaluate optimal 1L Tx selection accounting for expected attrition and overall survival.

BASELINE PLASMA MATRIX METALLOPROTEINASE 9 (MMP9) PREDICTS OVERALL SURVIVAL (OS) BENEFIT FROM BEVACIZUMAB INDEPENDENTLY OF MOLECULAR SUBTYPES IN NEWLY DIAGNOSED GLIOBLASTOMA : RETROSPECTIVE ANALYSIS OF AVAglio

e15154Background: Phase III trials CORRECT and CONCUR have shown that Regorafenib confers survival advantage in metastatic colorectal (mCRC) patients. Unfortunately, toxicity often limits its full ...

e15030Background: More than ever, patients with metastatic colorectal cancer (mCRC) are exposed to multiple sequential chemotherapeutic and biological treatment lines (CLs) / agents (CAs). Yet rece...

2020Background: BEV + radiotherapy/temozolomide (RT/TMZ) improves progression-free survival (PFS) (vs placebo [PBO] + RT/TMZ) in newly diagnosedGBM, but this does not translate into an OS benefit (...

ObjectivesThis study describes the management of patients with bilobar colorectal liver metastases (CRLM).MethodsA retrospective collection of data on all patients with CRLM who were considered for staged resection (n= 85) from January 2003 to January 2011 was performed. Patients who underwent one hepatic resection were considered to have had a failed staged resection (FSR), whereas those who underwent a second or third hepatic resection to produce a cure were considered to have had a successful staged resection (SSR). Survival was calculated from the date of diagnosis of liver metastases. Complete follow-up and dates of death were obtained from the Government of Quebec population database.ResultsMedian survival was 46months (range: 30–62months) in the SSR group and 22months (range: 19–29months) in the FSR group. Rates of 5-year survival were 42% and 4% in the SSR and FSR groups, respectively. Fifteen of the 19 patients who remained alive at the last follow-up date belonged to the SSR group.ConclusionsIn patients in whom staged resection for bilobar CRLM is feasible, surgery would appear to offer benefit.

This phase II trial was undertaken to evaluate the efficacy of TLN-4601 in patients with glioblastoma (GBM) at first progression. TLN-4601 inhibits the Ras-MAPK signaling pathway, and in animal models crosses the blood-brain barrier and accumulates in implanted gliomas, possibly by binding specifically to the peripheral benzodiazepine receptor. A maximum of 40 patients with recurrent GBM were to be enrolled in this study. TLN-4601 was administered at a dose of 480 mg/m(2)/day by continuous intravenous (CIV) administration. Each 21-day cycle consisted of a 14-day CIV administration and a 7-day recovery period. Samples were obtained from all patients for pharmacokinetic evaluations (PK) and for Raf-1 and pERK biomarker assessment using immunohistochemistry and flow cytometry. Following enrollment of 20 patients, this study was terminated due to a lack of efficacy. Of 17 evaluable patients, 14 had MR scans performed after two cycles of TLN-4601. Of these 14 patients, three had stable disease and 11 had disease progression. Only three patients had MR scans performed after four cycles and all had evidence of radiographic progression. Serum PKs confirmed that patients were exposed to TLN-4601 at targeted drug levels. TLN-4601 was generally well tolerated although two patients discontinued treatment due to adverse events. Biomarker analysis did not show consistent changes. TLN-4601 infused via CIV at 480 mg/m(2)/day for 14 of 21 days is well tolerated by patients with progressive GBM. However, this agent is ineffective in progressive GBM when administered as monotherapy in this schedule.

Aim:To review the impact of molecular biomarkers on response to therapy and survival in patients with primary glioblastoma (GBM).Materials & Methods:Tissue specimens were analyzed for p53 mutations, EGFR amplification, loss of PTEN and p16, and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Demographic and clinical data were gathered from medical records.Results:Clinical and pathological data of 125 patients were collected and analysed. MGMT promoter methylation was associated with improved median overall survival (OS) (61 vs. 42 weeks, p = 0.01) and was an important prognosticator independent of age at diagnosis, extent of resection and post-operative ECOG performance status (HR 2.04, 95% CI 1.11-3.75). Among patients with MGMT promoter methylation, survival was significantly improved with chemoradiotherapy (CRT) over radiotherapy (RT) alone (71 vs. 14 weeks, p < 0.01). Furthermore, amongst those treated with temozolomide (TMZ) based CRT, the presence of EGFR amplification, maintenance of PTEN and wild-type p53 and p16 were each associated with trends towards improved survival.Conclusion:MGMT promoter methylation is a strong, independent prognostic factor for OS in GBM. EGFR amplification, maintenance of PTEN, wild-type p53 and p16 all appear to be associated with improved survival in patients treated with CRT. However, the prognostic value of these biomarkers could not be ascertained and larger prospective studies are warranted.

Advanced hepatocellular carcinoma has a dismal prognosis, with a median overall survival of 7.9 months if untreated and of 10.7 months if treated with sorafenib. We present a case of advanced previously unresectable hepatocellular carcinoma in a 49-year-old man that achieved a pathologic complete response and was made amenable to surgery with sorafenib in combination with 90Y radioembolization. The patient&rsquo, s survival was more than double the median for patients treated with sorafenib alone.

Purpose Concomitant temozolomide (TMZ)/radiotherapy followed by adjuvant TMZ has increased survival in patients with glioblastoma multiforme (GBM). However, few options are effective for patients who experience treatment failure. We conducted a multicenter, phase II study to assess the efficacy and safety of continuous dose-intense TMZ for recurrent GBM. Patients and Methods Patients with malignant glioma at progression after standard TMZ 150 to 200 mg/m2 × 5 days in a 28-day cycle for three or more cycles were stratified by tumor type (anaplastic glioma group A, GBM, group B). Ninety-one patients with GBM were prospectively divided into three groups (early [B1], extended [B2], and rechallenge [B3]) according to the timing of progression during adjuvant therapy. All patients received continuous dose-intense TMZ 50 mg/m2/d for up to 1 year or until progression occurred. Response was assessed by using RECIST (Response Evaluation Criteria in Solid Tumors). Results A total of 116 of 120 patients were evaluable for efficacy. For patients with GBM, 6-month progression-free survival (PFS) was 23.9% (B1, 27.3%; B2, 7.4%; B3, 35.7%). One-year survival from time of study entry was 27.3%, 14.8%, and 28.6% for the B1, B2 and B3 groups, respectively. For patients with anaplastic glioma, 6-month PFS was 35.7%; 1-year survival was 60.7%. The most common grades 3 and 4 nonhematologic toxicities were nausea/vomiting (6.7%) and fatigue (5.8%). Grades 3 and 4 hematologic toxicities were uncommon. Conclusion Rechallenge with continuous dose-intense TMZ 50 mg/m2/d is a valuable therapeutic option for patients with recurrent GBM. Patients who experience progression during the first six cycles of conventional adjuvant TMZ therapy or after a treatment-free interval get the most benefit from therapy.

The objective of this study was to evaluate the antitumor activity and safety profile of 5 mg/m2 plitidepsin administered as a 3-h continuous intravenous infusion every 2 weeks to patients with advanced malignant melanoma who relapsed or progressed after one line of systemic therapy. Objective response rate (primary efficacy endpoint) was evaluated according to Response Evaluation Criteria In Solid Tumors and toxicity was assessed using National Cancer Institute -Common Toxicity Criteria Version 2.0. Of 39 enrolled patients (median age: 53 years), 37 patients were treated who received a total of 167 treatment cycles (median: 3 cycles per patient; range: 1-32). All patients had received prior systemic therapy with a median of one line per patient (range: 1-6 lines). Of the 35 evaluable patients, two dacarbazine-resistant patients (5.7%) with metastatic cutaneous melanoma achieved partial responses. Five other patients (14.3%) reported stable disease (median stable disease duration: 3.5 months; range: 2.2-15.8 months). Therefore, the rate of tumor growth control was 20.0%. With a median follow-up of 11.0 months, the median progression-free survival was 1.3 months and the median overall survival was 3.5 months. Six patients (16.2%) had the following treatment-related grade 3/4 adverse events: myalgia (n = 3), injection-site reaction (n = 2), hypersensitivity, hypotension, and fatigue (n = 1 each). One patient was withdrawn from the trial because of grade 4 hypersensitivity reaction and hypotension. No severe neutropenia was reported. Plitidepsin showed a minor degree of antitumor activity in patients with refractory advanced malignant melanoma. Further evaluation of plitidepsin in combination schedules may be warranted.

Background:Since temozolomide (TMZ) entry into routine practice in the first-line management of glial tumors, post-TMZ recurrences present a growing challenge. Without standard chemotherapy for TMZ failure, care in such palliative settings requires consideration not only of efficacy but of toxicity and convenience.Methods:At our institution, a combination regimen has been used: oral alkylating agents procarbazine (PCB) (100-150 mg/m2/day) and TMZ (150-200 mg/m2/day) administered on days 1-5 of a 28-day cycle. This treatment has been initiated upon radiological and/or clinical disease progression, and continued until evidence of further progression or toxicity. We retrospectively reviewed our experence with this regimen.Results:Since November 2004, 17 patients (median age 53) were treated for histologically confirmed glioma (glioblastoma multiforme (GBM), N=12; Grade 3 glioma, N=3; Grade 2 glioma, N=2) after a median of 2 recurrences. TMZ was previously given either as adjuvant therapy (post-chemoradiotherapy maintenance in 8 of 13 cases) or as salvage monotherapy (4 cases). Of 16 evaluable cases, 14 (13 high grade tumors) showed O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Two patients achieved partial response and one had complete response by RECIST criteria. Disease progressed after a median of 4 cycles (range 1 to 11+), with an actuarial progression-free survival of 42% after 6 cycles. Grade 3/4 toxicity was rare, and no dose reductions were needed. One patient discontinued treatment due to procarbazine hypersensitivity.Conclusion:Combination PCB-TMZ is well-tolerated, with modest activity in TMZ-exposed glioma.

665 Background: Selection and sequencing of treatment regimens for individual metastatic colorectal cancer (mCRC) patients is governed by the goals of maintaining reasonable quality of life while extending survival. The timing of KRAS testing and its effect on EGFRi therapy is poorly described. The goals of this analysis wereto describe rates and timing of KRAS testing relative to EGFRi therapy for Canadian patients diagnosed with mCRC. Methods: A retrospective chart review conducted at 6 Canadian centres included patients diagnosed with mCRC from Jan 1, 2009 onwards, who commenced 1st-line systemic treatment for mCRC between Jan 1–Dec 31, 2009. Information on the proportion of patients who received 2nd, 3rd, or subsequent lines of systemic therapy for mCRC was determined and the rates and timing of KRAS testing was ascertained. Results: 200 patients commenced 1st-line therapy and the median age was 62 yr; 78% had mCRC at the time of diagnosis. The proportions of patients who started 2nd, 3rd, and 4th lines of systemic therapy were 70%, 30%, and 15%, respectively. 103 (52%) patients had KRAS testing; 6%, 18%, 57%, 16%, 2%, and 1% of patients were tested at diagnosis or before the 2nd, 3rd, 4th, 5th and 6th lines of therapy, respectively. Median time from testing to EGFRi treatment was 105 (range, 7–1192) days, and varied by site. The frequency of KRAS testing for patients ranged from 30%–70% across study sites; across provinces, the frequency of testing ranged from 46%–60%. 38/68 (56%) of patients with wt KRAS tumors received EGFRi; 31 (46%) patients received EGFRi therapy as next therapy following KRAS testing. 19 (28%) died and 4 were lost to follow-up within 120 days of KRAS testing with no other therapy. 2 additional patients with unknown KRAS status received EGFRi (1 without KRAS testing; 1 undetermined). Conclusions: KRAS testing occurred after starting 2nd line in 76% of cases and varied by site and province. About half of patients underwent KRAS testing and 56% of those patients with wt KRAS tumors received an EGFRi. The short time interval between (K)RAS testing and EGFRi therapy may point to the need for earlier testing if EGFRi therapy is to be used in earlier lines of therapy.

192 Background: An exploratory analysis of a randomized phase II study in HCC comparing doxorubicin (D) alone to doxorubicin plus sorafenib (D+S) showed a significant improvement in overall survival favoring D+S (JAMA, 2011). The results appeared promising compared to the historic outcomes seen in the pivotal sorafenib (S) trials. CALGB 80802 was designed to determine if D+S improved survival compared to S alone. Methods: Patients with histologically proven advanced HCC, no prior systemic therapy and Child-Pugh A were randomized to receive D 60 mg/m2 every 21 days plus S 400 mg PO twice daily (D+S) or S alone. For bilirubin ≥ 1.3x normal, D and S doses were halved. D was maxed out at 360 mg/m2. The study was stratified by extent of disease (locally advanced; metastatic), the primary endpoint was overall survival (OS); and secondary endpoint progression-free survival (PFS). The final analysis was to occur when 364 events were observed among 480 total patients, with 90% power to detect a 37% increase in median OS (10.7 to 14.7 months; 1-sided α = 0.05). Results: The Alliance DSMB halted the study after accrual of 346 patients (173 on each of D+S and S) when a futility boundary was crossed at a planned interim analysis. With 107 events in each arm, median OS was 9.3 months (95%CI 7.1-12.9) for D+S, and 10.5 months (95% CI 7.4-14.3) for S with a hazard ratio (HR) 1.06 (95% CI 0.8-1.4) for D+S vs. S. Median PFS was 3.6 (95% CI 2.8-4.6) and 3.2 months (95% CI 2.3-4.1), respectively (HR = 0.90, 95% CI 0.72-1.2). There were 38 deaths on treatment: 18 on D+S and 20 on S. Among these 8 [sepsis (1), dysphagia (1), pneumonia (1), cardiac (2), hepatic failure (2), and not otherwise specified (1)] on D+S, and 3 [fatigue (1), hepatic failure (1), and a secondary malignancy (1)] on S, were at least possibly related to treatment. A maximum grade 3 or 4 only hematologic adverse events (AE) occurred in 37.8% of patients on D+S and 8.1% of patients on S. Non-hematologic AEs were comparable, in 63.6% and 61.5% of patients, respectively. Conclusions: The addition of D to S resulted in higher toxicity and did not improve OS or PFS. The S median OS of about 10 months is consistent with previous reports. NCI Grant U10CA180821 Clinical trial information: NCT01015833.

199 Background: Cancer treatment is associated with neurocognitive sequelae and changes in structural and functional brain imaging in older adults, even if they do not receive central nervous system directed therapy. Because the brain continues to develop into the 3rd decade of life, YA (age 18-39 yrs) may also be vulnerable to neurocognitive dysfunction. In YA, cancer disrupts acquisition of developmental milestones and is associated with psychological distress. This study aims to characterize neurocognitive functions and its relation to psychological distress in YA. Here we present baseline results of our longitudinal study. Methods: In this prospective, inception-cohort study, we recruited 3 groups of YA from ambulatory oncology clinics: YA with cancers (YAC; lymphoma, breast, gynecology, gastrointestinal, genitourinary, sarcoma) who required chemotherapy (YAC+, n = 55), YAC who do not require it (YAC-, n = 31), and healthy YA (HYA, n = 54). Participants completed a 2-hr battery of standardized neurocognitive tests and validated self-report questionnaires. YAC were assessed within 3 months of diagnosis, and YAC+prior to chemotherapy. Test scores were converted to age-corrected scaled scores and transformed to z-scores (mean 0, SD 1). A global neurocognitive function score and 6 domain scores were evaluated. Results: There were no group differences in neurocognitive domains (ANOVA, all p-values > .1), or in the number of impaired test scores (defined as z < -1). YAC+ reported greater symptoms of somatic distress (p = .001) and anxiety (p = .004) than both HYA and YAC-. Symptoms were unrelated to neurocognitive performance (ρ < .16 for all). However, each group had poorer memory compared to population norms (1-sample t-tests: YAC+ p = .007; YAC- p = .047; HYA p = .023). Conclusions: Prior to treatment, neurocognitive functions of YAC were not different from HYA, suggesting that cancer itself is not a neurocognitive risk factor in YA. It is important to use appropriate control groups, rather than relying on normative data for comparison. We continue to follow this cohort to document neurocognitive function and distress over time, and to identify risk factors that contribute to outcomes in YA.

BACKGROUND: RTOG 0825 and AVAGlio studies showed mixed survival results when bev was added to first line GBM treatment. In North America, use of bev is only approved for recurrent disease. Others have explored the reasons for bev failure; two hypotheses included 1) bev promoting distant and diffuse PP as a resistance mechanism 2) AEs related to the use of bev. This study was undertaken to describe and compare PPs and AEs associated with bev in newly diagnosed and recurrent GBM. METHODS: Sixty-four GBM patients treated with bev at McGill University Hospitals between 2008-2014 were identified. 30/64 (46.9%) patients received bev 1st line (B1L) and 34/64 (53.1%) received bev in 2nd line and beyond (B2L+). The median length of treatment was 24.4 weeks (range 0-232.7). Retrospective data collection through chart review for PPs was categorized: local, distant, diffuse and multifocal progression (LoP, DsP, DfP, MfP) or multi-pattern progression (MpP). AEs were documented as per CTCAE version 4.0. RESULTS: B1L vs B2L+ showed following PP: LR 46.7% vs 26.5%, DsP 3.3% vs 2.9%, DfP 20% vs 47%, MfR 10% vs 8.8%, MpP 3.3% vs 11.8%. No difference between B1L vs B2L+ were observed in DsP (p = 0.3) and DfP (p = 0.4) PP. Grade 3/4 AEs in B1L vs B2L + : fatigue 33.3% vs 17.6%, hypertension 26.7% vs 5.9%, thrombocytopenia 26.7% vs 11.8%, neutropenia 26.7% vs 11.8%, anemia 23.3% vs 11.8%, leucopenia 20% vs 8.8%, deep vein thrombosis, 23.3% vs 5.9%, seizures 16.7% vs 8.8%, brain hemorrhage 6.7% vs

Therapeutic resistance remains a major obstacle in metastatic colorectal cancer (mCRC) and biomarkers to guide treatment are essential to improving survival and quality of life in mCRC patients. A biopsy-driven prospective study was designed to identify biomarkers and mechanisms of resistance to a standard first-line therapy in patients with mCRC which could be useful in guiding treatment selection (QCROC-01; NCT00984048). We also hoped to recognize molecular changes over time, or resulting from the selection pressure of treatment, which could have implications for subsequent therapy. This study is ongoing and approved at thirteen sites with one-hundred patients enrolled so far. Patients with mCRC receiving FOLFOX (5-fluorouracil, leucovorin and oxaliplatin) with bevacizumab consented to three needle core tumour biopsies at pre-treatment and at the time of resistance. The rate of both patient and physician acceptance of biopsies has steadily risen with time and experience. Serial bloods were also collected for proteomic analysis and circulating tumor DNA. Twenty-five biopsy samples were profiled using exome sequencing (tumor and germ line), RNAseq, low pass genome sequencing and miRNA analysis. Differential gene expression analysis revealed signatures associated with clinical response and resistance when comparing tumours obtained pre- and post-treatment. We detect changes in variant allele fraction including both depletion and enrichment of individual somatic mutations over the course of treatment, the latter of which may indicate subclonal and acquired “driver” mutations that confer therapeutic resistance. A small number of genes show recurrent evidence for changes in clonal enrichment at the time of relapse across multiple patients. These could also represent therapeutic targets for subsequent therapy for these patients, and as such, represent new treatment opportunities. Our findings provide insights into tumor evolution during first-line chemotherapy of mCRC that may hold clues to optimize current first-line therapeutic decision making and identifies potential target pathways for second-line stratification of patients. This study is part of the Canadian Colorectal Cancer Consortium which is a multi-site collaboration funded by the Terry Fox Research Institute and le fonds de recherche du québec - santé. Citation Format: Suzan McNamara, Ryan Morin, Mathilde Couëtoux du Tertre, Rosemary McCloskey, Rebecca Johnston, Daniel Fornika, Benoit Samson, Bernard Lespérance, Thierry Alcindor, Yoo-Joung Ko, Richard Dalfen, Eve St-Hilaire, Lucas Sideris, Felix Couture, Hans Prenen, Sabine Tejpar, Ronald Burkes, André Constantin, Errol Camlioglu, Adriana Aguilar, Adrian Gologan, Benoit Têtu, Celia M. Greenwood, Cyrla Hoffert, Samia Qureshi, Zuanel Diaz, Maud Marques, Micheal Witcher, Thérèse Gagnon-Kugler, Petr Kavan, Gerald Batist. Molecular profiling of sequential biopsies in patients with metastatic colorectal cancer identifies genomic alterations that evolve during first-line therapy and could have therapeutic implications: A prospective study to identify molecular mechanisms of clinical resistance (QCROC-01: NCT00984048). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3888. doi:10.1158/1538-7445.AM2015-3888

e14692 Background: Contrary to the general population, incidence of CRC in AYA is on the rise. However, their clinical outcomes and treatment (tx) efficacy remains somewhat abstruse. A MIRR was per...

e14664 Background: Standard of care in the treatment of stage III colorectal cancer (CRC) involves 6 months of adjuvant combination chemotherapy with 5-FU and oxaliplatin. Despite lack of true comparative study, 2 regimens FOLFOX (MOSAIC trial) and CAPOX (XELOXA trial) are believed to be similar in their efficacy and tolerability. However, the latter has been disputed as real-life data presented from Canada has shown CAPOX to be more toxic, leading to more frequent rate of reduction in its dose intensity. Consequently, its impact on clinical outcomes has been brought to question. Methods: A retrospective data review was conducted by Segal Cancer Centre (SCC) Quebec, and Tom Baker Cancer Centre (TBCC) Alberta, on patients with stage III CRC between 2006-2013. Patients were treated with either CAPOX or mFOLFOX6 as per Canadian treatment guidelines. Primary endpoints were dose intensity and toxicity with secondary endpoints disease free survival (DFS) and overall survival (OS). Results: 180 patients (80 SCC,...

e15215 Background: Epidemiology and clinical outcomes for pancreatic adenocarcinoma (PDAC) are not well described in adolescent and young adult (AYA) population. Furthermore, treatments’ efficacy f...

TPS9636 Background: Chemotherapy is associated with long-lasting neurocognitive sequelae and structural and functional brain imaging changes in about 25% of older adults who do not receive central ...

Background Adrenocortical tumors (ACTs) are rare in the pediatric population. The pathogenesis, prognostic indicators, and management of these tumors are still unclear because of its infrequent occurrence. This case series presents the surgical experience of the authors' center over 29 years. Methods The medical records of children treated for ACTs between 1974 and 2003 were reviewed. Information on age, sex, presenting symptoms, hormonal levels, pathology, stage, treatment, and outcome was obtained. Results Nine children (5 girls, 4 boys) were treated for ACTs. The median age at presentation was 29 months (range, 5 months to 11 years). Endocrine dysfunction was found in 8 patients. Four presented with virilizing symptoms, 4 presented with both virilizing and Cushing's symptoms, and 1 patient with Beckwith-Wiedemann syndrome was identified during routine screening. One was an adenoma, and 8 were carcinomas. Of the carcinomas, 3 were stage I, and 5 were stage II. The mean tumor weight was 125 g (range, 42 g to 336 g) with a mean volume of 139 cm 3 (range, 30 cm 3 to 626 cm 3 ). All patients had complete excision of the tumor with spillage occurring in 2 cases. Lymph node biopsies were done in all but 2 patients. Two patients were treated with chemotherapy because of large tumor size and nodal involvement. All patients are doing well including those with tumor spillage. Conclusions This study shows that surgical excision continues to be the mainstay of treatment for ACTs. Extensive lymph node biopsy in small ACTs can probably be avoided given the generally good outcome with surgery alone. The role of adjuvant chemotherapy remains unclear because most of the children in our series were effectively treated with surgical resection only. Patients should be enrolled in multicenter trials to assess the added value of chemotherapy.

Aim: Use of bevacizumab in the management of glioblastoma multiforme (GMB) remains controversial. Currently in Canada, it is approved for recurrent GBM treatment. We describe the use of bevacizumab and analyses the efficacy across treatment lines in GBM. Methods: Patients (pts) diagnosed GBM (primary or secondary) from 2008-2014 and treated with bevacizumab were identified at McGill University Hospitals; demographics, diagnosis, and treatment pattern were collected via chart review. Primary endpoints were median progression-free survival (PFS) and overall survival (OS) estimated via Kaplan-Meier method. Secondary endpoint was toxicity. Grading of adverse events (AEs) were in accordance to CTCAE 4.0 criteria. Results: 64 pts were identified and their files were analyzed (40 males; median age at diagnosis 54 years, range 26-83). Majority had KPS score ≥70 (n = 56, 87.5%). 49 (76.6%) pts had primary and 15 (23.4%) had secondary GBM. Available MGMT testing was performed in 24 pts (methylated n = 10, 15.6%; unmethylated n = 14, 21.9%). 30 (46.9%) received bevacizumab in 1st line and 34 (53.1%) 2nd line and beyond (2L+). The median duration of bevacizumab in 1st line 36.6 weeks and 2L+ 14.21 weeks (overall 24.4 weeks; range Conclusions: Our results show bevacizumab treatment may be more efficient after a recurrence than when used in the beginning of treatment and are in line with reported registration trials data. Disclosure: All authors have declared no conflicts of interest.

3514 Background: In contrast to BRAFV600 mutated (BRAFm) advanced melanoma, BRAFm colorectal carcinoma (CRC) does not respond to BRAF inhibitors due to strong feedback activation of the epidermal g...

TPS3656 Background: Biopsy-driven trials offer unique opportunities for discovery and validation of molecular signatures. We began a Phase II investigator-initiated study (IIS) to identify biomarke...

e14627 Background: Pts with mCRC receiving a first-line (1L) OX-t exhibit a PFS that extends beyond their treatment duration. However, the perception is that neurotoxicity limits OX-t treatment dur...

e14584 Background: XELOX for colorectal cancer (CRC) reportedly causes more grade III/IV toxicity in clinical practice, leading to a greater reduction in dose intensity than mFOLFOX6. We reported t...

Treatment of Hodgkin's disease in children should be directed at maximizing cures and minimizing the long-term effects of alkylating agents, anthracyclines, and bleomycin. In this study methotrexate and etoposide were used in the VAMP/VEPA regimens to treat 60 clinically staged pediatric patients with Hodgkin's disease. Twenty-nine patients with stages I-IIA received four courses of VAMP plus low-dose radiotherapy. Thirty-one IIA bulky disease and IIB-IVB patients received four or six courses of VEPA plus low-dose radiotherapy. There were 6 partial remissions after the completion of chemotherapy and all of these patients relapsed, but 4 were successfully salvaged with ABMT. Two patients have died. The 3.1-year overall survival rate is 97% (100% VAMP, 94% VEPA) and the event-free survival rate is 88% (97% VAMP, 77% VEPA). These results suggest that VAMP is a reasonable treatment for low stages of Hodgkin's disease, but more advanced disease is not adequately treated by VEPA and low-dose radiotherapy.

2005^ Background: GBM has a high disease burden and poor prognosis, and impacts negatively on HRQoL. Symptomatic therapies for GBM, such as corticosteroids (CS), may impact patient status negatively Methods: AVAglio, a randomized, double-blind, placebo (P)-controlled trial in patients (pts) ≥18 yrs with newly diagnosed GBM, evaluated the addition of Bv or P (10mg/kg, q2w) to 6 wks of T (75mg/m2/d) + RT (2Gy, 5d/wk) followed by 28 treatment-free days, then 6 cycles of T (150–200 mg/m2/d, 5d q4w) with Bv or P (10 mg/kg, q2w), and then single-agent Bv or P (15 mg/kg, q3w) until disease progression (PD)/unacceptable toxicity. Co-primary endpoints were investigator-assessed PFS and overall survival. Secondary endpoints included HRQoL (EORTC QLQ-C30 and BN20, with 5 prespecified domains based on relevance in GBM). HRQoL time to definitive deterioration (TDD) was defined as time from randomization to ≥10 point deterioration from baseline with no subsequent improvement, PD, or death. Exploratory endpoints included KPS and CS use. Results: Baseline characteristics were well balanced. Bv significantly prolonged PFS (HR 0.64, 95% CI 0.55–0.74, p

e14556 Background: Xelox and Folfox regimens have been shown to be equivalent in clinical trials for colorectal cancers. However, concerns about toxicity induced by Xelox in clinical practice have been reported, resulting in reduced dose intensity. In this retrospective analysis, we compared the dose intensity of Xelox to Folfox in relation to toxicity. Methods: 208 patients were treated in adjuvant (Xelox: n=56, median age 65 years; Folfox: n=40, median age 66 years) or metastatic (Xelox: n=65, median age 66 years; Folfox: n=47 median age 62 years) settings. 90% of patients had ECOG 0-1. Results: In the adjuvant setting, 86% of patients treated with Xelox received a lower dose of the drug up front, compared to only 10% of Folfox-treated patients. Additional dose reductions occurred in subsequent cycles in 23% of Xelox-treated patients (mean relative dose intensity (RDI) Oxaliplatin: 72%; Capecitabine: 74%) but not Folfox-treated patients (mean RDI Oxaliplatin: 85%, 5-FU: 86%). A higher percentage of Folfox-treated patients had toxicities compared to Xelox-treated patients: nausea (30% vs 18%), diarrhea (47% vs 24%), and peripheral sensory neuropathy (32% vs 3%). Treatment delays were more frequent in Folfox (40%); mean cumulative delay, 9.4 (range 2.1-52.4) weeks, compared to Xelox (20%); mean cumulative delay, 10.2 (3.1-48.1) weeks. Mean treatment duration was equal (Xelox: 22.8 (3.0-78.1); Folfox: 22.6 (2.3-64.4) weeks). In the metastatic setting, results followed a similar pattern. 75% of Xelox-treated patients received a lower dose up front compared to 33% of Folfox-treated patients. Further dose reductions occurred in 31% of Xelox-treated patients (mean RDI Oxaliplatin: 70%; Capecitabine: 67%) compared to 20% of Folfox-treated patients (mean RDI oxaliplatin: 75%; 5-FU: 69%). Treatment delays occurred in 60% of Folfox-treated patients and 43% of Xelox-treated patients becauseof toxicities. Mean treatment duration was 24.9 (3.0-65.0) and 26.1 (4.0-60.1) weeks respectively. Conclusions: The higher dose reduction of Xelox compared to Folfox appeared to enable treatment completion with less toxicities. The impact on survival and cost of treatments will be presented.