Real-world experience supporting the role of oncologic resection and adjuvant chemotherapy in biliary tract cancers.

Background: Complete resection followed by adjuvant chemotherapy is the gold standard for patients with localized cholangiocarcinoma (CC) or gallbladder cancer (GBC). However, this is not always feasible, and recurrence rates remain high. Objectives: To understand the real-world proportions and reason for treatment failure in resected biliary tract cancers. Design and methods: We performed a retrospective population-based review of patients with GBC or CC [intrahepatic (IHCC) or extrahepatic (EHCC)] resected between 2005 and 2019 using the BC Cancer provincial database. A chart review was conducted to characterize demographics, treatments received and outcomes. Results: In total, 594 patients were identified of whom 416 (70%) had disease recurrence. Most GBCs (96%) were diagnosed incidentally, and repeat oncologic resection was performed in 45%. Adjuvant chemotherapy was received in 51% of patients diagnosed after 2017 (mostly capecitabine). Patient co-morbidities, disease progression and patient preference were the commonest reasons for not proceeding with adjuvant chemotherapy. One-third of patients did not complete all planned cycles. Median overall survival was significantly higher in those with complete (R0) versus incomplete (R1) resection [31.6 versus 18 months, hazard ratio (HR): 0.43, 95% confidence interval (CI): 0.35-0.53] and in those with versus without re-resection for GBC [29.4 versus 19 months, HR: 0.55, 95% CI: 0.41-0.73]. There was a trend towards improved survival with versus without adjuvant therapy (HR: 0.79, 95% CI: 0.61-1.02). Only 25% in the more contemporary cohort (2017-2019) had an R0 resection and completed adjuvant chemotherapy. Conclusion: Complete resection, including reresection for incidentally diagnosed GBCs, and adjuvant chemotherapy were associated with improved outcomes in this retrospective cohort, yet many patients were not able to complete these treatments. Neoadjuvant strategies may improve treatment delivery and ultimately, outcomes.

Use, response and outcomes of second-line chemotherapy in patients with advanced biliary tract cancers.

INTRODUCTION: First-line chemotherapy for advanced biliary tract cancers has been established as gemcitabine and cisplatin; however, there is currently no recognized standard second-line chemotherapy. The purpose of this study is to review and evaluate the outcomes of second-line chemotherapy for advanced biliary tract cancers. METHODS: Patients who received chemotherapy for unresectable or metastatic biliary tract cancers at BC Cancer between August 2009 and December 2015 were retrospectively studied to identify second-line chemotherapy treatments used and to determine overall survival, time-to-treatment discontinuation and characteristics predicting for improved overall survival. RESULTS: Of 325 patients who received first-line chemotherapy for advanced biliary tract cancer, 90 (30%) received second-line chemotherapy. Median overall survival for patients who received only first-line chemotherapy was 9.5 months versus 17.3 months for patients who received second-line chemotherapy. Median time-to-treatment discontinuation for second-line chemotherapy was 2.0 months. Common drugs used in second-line chemotherapy treatments included capecitabine (30%), 5-fluorouracil and irinotecan (17%) and 5-fluorouracil monotherapy (15%). There was no difference in overall survival for patients who received single-agent second-line chemotherapy compared to doublet second-line chemotherapy. CONCLUSIONS: Patients who are fit enough to receive second-line chemotherapy may benefit in terms of overall survival and should be offered treatment with single-agent therapy. Capecitabine was the most common second-line chemotherapy treatment. The improved median overall survival for patients who received second-line chemotherapy may be impacted by independent patient-specific factors which are unknown at this time.

Treatment journey of patients with hepatocellular carcinoma using real-world data in British Columbia, Canada.

Aim: This study examined treatment patterns, survival outcomes and healthcare costs related to hepatocellular carcinoma (HCC) in British Columbia. Methods: The study utilized data from two physician databases (HCC and MOTION) and the provincial British Columbia transplant database. Results: The analysis revealed diverse treatment approaches and identified the varying treatment journeys of patients. Liver transplant and systemic therapies demonstrated improved survival rates. However, there was a scarcity of Canadian-specific cost data. Conclusion: The research emphasizes the complexities of managing HCC and underscores the need for personalized treatment strategies to enhance patient outcomes. These findings contribute valuable insights into HCC management and provide a foundation for future studies and interventions aimed at optimizing care and resource allocation.

This study looked at how people diagnosed with liver cancer in British Columbia were treated, how long they lived and how much treatment cost. Treatment records were reviewed, and depending on the extent of the disease, treatments could include surgery, treatments directed at the liver and/or anti-cancer therapy. The average survival time varied from 21­33 months, with an average cost per patient of $94,000. This helps us understand the patient journey and future studies would include current treatment options.

Characterizing the KRAS G12C mutation in metastatic colorectal cancer: a population-based cohort and assessment of expression differences in The Cancer Genome Atlas.

Introduction: In metastatic colorectal cancer (mCRC), RAS mutations impart inferior survival and resistance to anti-epidermal growth factor receptor (EGFR) antibodies. KRAS G12C inhibitors have been developed and we evaluated how KRAS G12C differs from other RAS mutations. Patients and Methods: This retrospective review evaluated patients in British Columbia, Canada with mCRC and RAS testing performed between 1 January 2016 and 31 December 2018. Sequencing information from The Cancer Genome Analysis (TCGA) was also obtained and analysed. Results: Age at diagnosis, sex, anatomic location and stage at diagnosis did not differ by RAS mutation type. Progression free survival on first chemotherapy for patients with metastatic KRAS G12C tumours was 11 months. Median overall survival did not differ by RAS mutation type but was worse for both KRAS G12C (27 months) and non-G12C alterations (29 months) than wildtype (43 months) (p = 0.01). Within the TCGA, there was no differential gene expression between KRAS G12C and other RAS mutations. However, eight genes with copy number differences between the G12C and non-G12C RAS mutant groups were identified after adjusting for multiple comparisons (FITM2, PDRG1, POFUT1, ERGIC3, EDEM2, PIGU, MANBAL and PXMP4). We also noted that other RAS mutant mCRCs had a higher tumour mutation burden than those with KRAS G12C mutations (median 3.05 vs 2.06 muts/Mb, p = 4.2e-3) and that KRAS G12C/other RAS had differing consensus molecular subtype distribution from wildtype colorectal cancer (CRC) (p < 0.0001) but not each other (p = 0.14). Conclusion: KRAS G12C tumours have similar clinical presentation to other RAS mutant tumours, however, are associated with differential copy number alterations.

To share or not to share: communication of caregiver-reported outcomes when a patient has colorectal cancer.

BACKGROUND: The importance of patient-centered measurement in cancer care has led to recognition of the potential for caregiver-reported outcomes to improve caregiver, patient and healthcare system outcomes. Yet, there is limited evidence to inform caregiver-reported outcome implementation. Our purpose was to generate evidence to inform the meaningful and constructive integration of caregiver-reported outcomes into cancer care to benefit caregivers, including exploration of the question of the extent to which these assessments should be shared with patients. We focused on caregivers of patients with colorectal cancer (CRC) because CRC is common, and associated caregiving can be complex. RESULTS: From our Interpretive Description analysis of qualitative interview data from 78 participants (25 caregivers, 37 patients, and 16 healthcare providers [HCPs]), we identified contrasting perspectives about the sharing of caregiver-reported outcome assessments with patients with CRC. Those who preferred open communication with both the patient and caregiver present considered this essential for supporting the caregiver. The participants who preferred private communication without the patient, cited concern about caregiver- and patient-burden and guilt. Recognizing these perspectives, HCPs described strategies used to navigate sensitivities inherent in preferences for open versus private communication. CONCLUSIONS: The integration of caregiver-reported outcomes into cancer care will require careful consideration of caregiver and patient preferences regarding the communication of caregiver assessments to prevent additional burden.

Impact of Tumor Location on Patient Outcomes in Small Bowel Cancers.

BACKGROUND: Small bowel cancers are rare gastrointestinal malignancies and tumor location impact on outcomes is unclear. MATERIAL AND METHODS: A retrospective review was performed on stage I to IV small bowel cancer cases from 2000 to 2017 in British Columbia, Canada. Baseline patient characteristics, disease-free survival (DFS) and overall survival (OS) were evaluated by tumor location and systemic therapy use patterns were summarized. RESULTS: Of 340 patients included, primary tumor distribution was: duodenum (51.2%), ileum (19.1%), jejunum (18.5%), and unspecified (11.2%). Median DFS for stage I to III disease was 37.7, 49.1, and 26.7 months for duodenal, jejunal, and ileal tumors (P = .018). Median OS was 9.6, 35.2, and 20.1 months for duodenal, jejunal, and ileal tumors (P < .0001). Compared to duodenal primaries, both jejunal and ileal tumors were associated with significantly improved OS (HR 0.43, P < .001 for jejunal; HR 0.71, P = .035 for ileal). Adjuvant therapy was given to 21.6% of stage II and 50.6% of stage III cancers. Among patients with metastatic disease, median OS was 4.2, 11.4, and 6.9 months for duodenal, jejunal, and ileal tumors (P = .0019). Jejunal tumors had the best prognosis (HR 0.48, P = .001 vs. duodenum). CONCLUSION: Survival differences exist when small bowel cancers were assessed by tumor location, and jejunal tumors portended better prognosis overall.

Evaluation of Clinical and Pathological Factors to Predict High Risk of Recurrence in Patients With Stage II Colon Cancer.

BACKGROUND: The ability to predict patients with stage II colon cancer at high risk of recurrence is currently limited to certain clinicopathologic factors. PATIENTS AND METHODS: This population-based study reviewed various prognostic factors to identify those associated with worse time to recurrence (TTR) and improved disease-specific survival (DSS), and to subsequently develop a prognostic index (PI) to identify high risk cancers. RESULTS: Multivariate analyses revealed factors significant for TTR and DSS. A PI derived from the TTR risk factors identified 3 risk groups using 5-year rate without relapse: 88% for low-risk, 81% for intermediate-risk, and 59% for high risk. CONCLUSION: This model was better at identifying high risk patients than using equally weighted standard risk factors.

Impact of surveillance among patients with resected pancreatic cancer following adjuvant chemotherapy.

BACKGROUND: Pancreatic adenocarcinoma carries a high risk of recurrence even after surgery and adjuvant chemotherapy. Current guidelines do not endorse routine surveillance imaging due to lack of evidence supporting a survival benefit. With current first-line palliative chemotherapy options, it is unclear whether surveillance allows for early detection of asymptomatic disease and therefore an improved opportunity to offer chemotherapy to fit patients. We sought to describe patterns of surveillance of resected pancreatic cancer at British Columbia (BC) Cancer and determine whether utilization of computerized tomography (CT) scans affected likelihood of receiving palliative chemotherapy at the time of recurrence. METHODS: A retrospective review was completed to identify patients treated at BC Cancer centres between 2010-2016 who had undergone curative intent resection and received at least one cycle of adjuvant chemotherapy. Information was collected on baseline characteristics, imaging scans done between adjuvant chemotherapy and recurrence, and receipt of palliative chemotherapy. Two cohorts were defined based on number of scans done between completion of adjuvant chemotherapy and recurrence: those with only 1 scan were defined as "symptomatic" recurrences and patients who had undergone more than 1 scan were considered "surveillance" recurrences. RESULTS: In total, 142 patients were included of which 115 (81%) patients developed recurrence. There were 22 patients (19%) in the "symptomatic" cohort and 93 patients (81%) in the "surveillance" cohort. Median time to recurrence 274 days (9.1 months) in the symptomatic cohort compared to 471 days (15.7 months) in the surveillance group. Patients who underwent surveillance scans were more likely to receive palliative chemotherapy at the time of recurrence, though statistical significance was not reached: 51% in surveillance group versus 27% in symptomatic group [odds ratio (OR) 2.11, 95% confidence interval (CI): 0.75-6.58, P=0.17]. CONCLUSIONS: Despite the absence of surveillance recommendations, the majority of patients underwent surveillance imaging. We demonstrated a non-significant increase in the likelihood of receiving palliative chemotherapy among patients who underwent surveillance scans. With more efficacious palliative chemotherapy options available, studies to determine whether receipt of chemotherapy in asymptomatic recurrences translates into improved survival and/or quality of life are warranted.

The Impact of Geography in Hepatocellular Carcinoma: A Retrospective Population Based Study.

BACKGROUND: The treatment of hepatocellular carcinoma (HCC) includes different therapeutic modalities and multidisciplinary tumor board reviews. The impact of geography and treatment center type (quaternary vs. non-quaternary) on access to care is unclear. METHODS: A retrospective chart review was performed on HCC patients who received sorafenib in British Columbia from 2008 to 2016. Patients were grouped by Statistics Canada population center (PC) size criteria: large PC (LPC), medium PC (MPC), and small PC (SPC). Access to specialists, receipt of liver-directed therapies, and survival outcomes were compared between the groups. RESULTS: Of 286 patients, the geographical distribution was: LPC: 75%; MPC: 16%; and SPC: 9%. A higher proportion of Asians (51% vs. 9% vs. 4%; p < 0.001), Child-Pugh A (94% vs. 83% vs. 80%; p = 0.022), and hepatitis B (37% vs. 15% vs. 4%; p < 0.001) was observed in LPC vs. MPC vs. SPC, respectively. LPC patients were more likely referred to a hepatologist (62% vs. 48% vs. 40%; p = 0.031) and undergo transarterial chemoembolization (TACE) (43% vs. 24% vs. 24%; p = 0.018). Sixty percent were treated at a quaternary center, and the median overall survival (OS) was higher for patients treated at a quaternary vs. non-quaternary center (28.0 vs. 14.6 months, respectively; p < 0.001) but similar when compared by PC size. Treatment at a quaternary center predicted an improved survival on multivariate analysis (hazard ratio (HR): 0.652; 95% confidence interval (CI): 0.503-0.844; p = 0.001). CONCLUSIONS: Geography did not appear to impact OS but patients from LPC were more likely to be referred to hepatology and undergo TACE. Treatment at a quaternary center was associated with an improved survival.

Efficacy and Prognostic Factors for Y-90 Radioembolization (Y-90) in Metastatic Neuroendocrine Tumors with Liver Metastases.

Background: Yttrium-90 (Y-90) can be an effective liver-directed therapy for patients with metastatic neuroendocrine tumors (NETs), but population-based data are limited. We characterized the use of Y-90 in NET patients and identified factors associated with response. Methods: We identified 49 patients with metastatic liver-dominant NETs across BC Cancer's six regional centres who received Y-90 between June 2011 and January 2017 in British Columbia, Canada. Baseline characteristics, radiographic responses, and outcomes were summarized. Results: Of the 49 patients who received Y-90, the median age was 56 years (range 21-78), 49% were male, and 94% had an ECOG performance status of 0-1. The primary location of the NET included pancreas (31%), small bowel (41%), large bowel (6%), unknown (14%), and others (12%). 69% of these patients had liver metastases alone, and tumors were graded as G1 (61%), G2 (25%), G3 (2%), and unknown (12%). Prior therapies included surgery (63%), local ablative therapy (25%), somatostatin analogue (69%), and systemic therapy (35%). The median Y-90 dose was 2.2 GBq (range 0.8-3.6), as SIR-spheres (69%) or TheraSpheres (29%). Median time to Y-90 from diagnosis of metastases measured 1.54 years. 88% received segmental Y-90, with 1 (69%), 2 (29%), and 3 (2%) treatments. Y-90 resulted in partial response (53%), stable disease (33%), and progressive disease (12%). Y-90 was well-tolerated, with infrequent grade 3-4 biochemical toxicities (2%) and grade 3 abdominal pain (6%). Longer overall survival (OS) was associated with resection of primary tumor, well-differentiated histology, and low Ki-67. Median OS was 27.2 months (95% CI 8.0-46.5). Conclusions: In our population-based cohort, Y-90 was well-tolerated in patients with metastatic liver-dominant NETs. Prior surgical resection was an important predictor of OS.

Real-world treatment attrition rates in advanced esophagogastric cancer.

BACKGROUND: Over the last decade, multiple agents have demonstrated efficacy for advanced esophagogastric cancer (EGC). Despite the availability of later lines of therapy, there remains limited real-world data about the treatment attrition rates between lines of therapy. AIM: To characterize the use and attrition rates between lines of therapy for patients with advanced EGC. METHODS: We identified patients who received at least one cycle of chemotherapy for advanced EGC between July 1, 2017 and July 31, 2018 across six regional centers in British Columbia (BC), Canada. Clinicopathologic, treatment, and outcomes data were extracted. RESULTS: Of 245 patients who received at least one line of therapy, median age was 66 years (IQR 58.2-72.3) and 186 (76%) were male, Eastern Cooperative Oncology Group (ECOG) performance status 0/1 (80%), gastric vs GEJ (36% vs 64%). Histologies included adenocarcinoma (78%), squamous cell carcinoma (8%), and signet ring (14%), with 31% HER2 positive. 72% presented with de novo disease, and 25% had received previous chemoradiation. There was a high level of treatment attrition, with patients receiving only one line of therapy n = 122, 50%), two lines n = 83, 34%), three lines n = 34, 14%), and four lines n = 6, 2%). Kaplan-Meier analysis demonstrated improved survival with increasing lines of therapy (median overall survival 7.7 vs 16.6 vs 22.8 vs 40.4 mo, P < 0.05). On multivariable Cox regression, improved survival was associated with better baseline ECOG and increased lines of therapy (P < 0.05). CONCLUSION: The steep attrition rates between therapies highlight the unmet need for more efficacious early-line treatment options for patients with advanced EGC.

Eligibility for Second-line Therapy in Patients With Advanced Hepatocellular Carcinoma: A Population-based Study.

INTRODUCTION: With an increasing number of systemic therapy options for hepatocellular carcinoma (HCC), optimal sequencing is an important consideration. There remains limited real-world data about the eligibility of patients for second-line therapies in advanced HCC. We characterized real-world eligibility and use of second-line therapies post sorafenib. MATERIALS AND METHODS: We identified all patients with advanced HCC who received ≥1 cycle of first-line sorafenib between January 1, 2014 and December 31, 2017 in British Columbia, Canada. All patients were Child-Pugh class A for initiation of sorafenib. Baseline characteristics and clinical outcomes were reviewed. Eligibility for second-line therapy was determined using the RESORCE and CELESTIAL study entry criteria. RESULTS: Of 144 patients with advanced HCC who received ≥1 cycle of first-line sorafenib, median age was 65.3 years (range, 32.2 to 83.4 y) and 85% were male. Median duration of sorafenib was 2.6 months. Twelve patients (8%) received second-line treatment but 37 patients (26%) were eligible for second-line therapies based on inclusion criteria from recent registration trials. Primary reasons for ineligibility included ECOG ≥2 (58%), and deterioration to Child-Pugh status B (28%). On Cox regression, improved survival was associated with better ECOG and recurrent disease after initial locoregional therapy. Eligibility for second-line treatment was associated with improved median overall survival from end of first-line treatment (8.5 vs. 5.1 mo; P<0.01). CONCLUSIONS: Only a minority of real-world patients with advanced HCC were eligible for second-line therapies based on trial criteria. Given the high rate of attrition, improved first-line treatment options are urgently needed.

Quality of Online Information Regarding Cervical Cancer.

Introduction The internet is an important source of health information, and yet the quality of the resources that patients' access can vary widely. Previous research has evaluated the quality of information for several types of cancer; however, this has not yet been done for cervical cancer beyond treatment information. The goal of this project was to systematically evaluate the quality of resources for cervical cancer information available against a range of metrics, including content breadth and accuracy, readability, and accountability.  Methods An internet search was performed using the term "cervical cancer" using Google and two meta-search engines, Dogpile and Yippy. The top-100 websites returned across all three engines were evaluated using a validated structured rating tool.  Results Only 32% of websites disclosed their author and only 38% used citations, while 64% of websites had been updated in the last two years. Readability was at university-level or higher for 19% of websites, and high-school level for 78%. Coverage was highest for etiology and risk factors (93% of websites) and prevention strategies such as pap smears and vaccines (92%); coverage was lowest for prognosis (49%), staging (52%), side effects (47%), and follow-up (25%). When a topic was covered the information was predominantly accurate, and few websites had inaccurate information. At least one social-media platform was linked to by 79% of websites.  Conclusions This project highlights the strengths and limitations in the quality of the top-100 informational cervical cancer websites. These findings can inform the dialogue between health care providers and patients around selecting and evaluating information resources. These findings can also inform specific improvements to make online resources for cervical cancer more accessible, comprehensive, and relevant to patients.

Prognosis of patients with hepatocellular carcinoma treated with sorafenib: a comparison of five models in a large Canadian database.

Several systems (tumor-node-metastasis [TNM], Barcelona Clinic Liver Cancer [BCLC], Okuda, Cancer of the Liver Italian Program [CLIP], and albumin-bilirubin grade [ALBI]) were developed to estimate the prognosis of patients with hepatocellular carcinoma (HCC) mostly prior to the prevalent use of sorafenib. We aimed to compare the prognostic and discriminatory power of these models in predicting survival for HCC patients treated with sorafenib and to identify independent prognostic factors for survival in this population. Patients who received sorafenib for the treatment of HCC between 1 January 2008 and 30 June 2015 in the provinces of British Columbia and Alberta, and two large cancer centers in Toronto, Ontario, were included. Survival was assessed using the Kaplan-Meier method. Multivariate Cox regression was used to identify predictors of survival. The models were compared with respect to homogeneity, discriminatory ability, monotonicity of gradients, time-dependent area under the curve, and Akaike information criterion. A total of 681 patients were included. 80% were males, 86% had Child-Pugh class A, and 37% of patients were East Asians. The most common etiology for liver disease was hepatitis B (34%) and C (31%). In all model comparisons, CLIP performed better while BCLC and TNM7 performed less favorably but the differences were small. The utility of each system in allocating patients into different prognostic groups varied, for example, TNM poorly differentiated patients in advanced stages (8.7 months (m) (95% CI 6.5-11.5) versus 8.4 m (95% CI 7.0-9.6) for stages III and IV, respectively) while ALBI had excellent discrimination of early grades (15.6 m [95% CI 13.0-18.4] versus 8.3 m [95% CI 7.0-9.2] for grades 1 and 2, respectively). On multivariate analysis, hepatitis C, alcoholism, and prior hepatic resection were independently prognostic of better survival (P < 0.01). In conclusion, none of the prognostic systems was optimal in predicting survival in sorafenib-treated patients with HCC. Etiology of liver disease should be considered in future models and clinical trial designs.

Molecular characterization of metastatic pancreatic neuroendocrine tumors (PNETs) using whole-genome and transcriptome sequencing.

Pancreatic neuroendocrine tumors (PNETs) are a genomically and clinically heterogeneous group of pancreatic neoplasms often diagnosed with distant metastases. Recurrent somatic mutations, chromosomal aberrations, and gene expression signatures in PNETs have been described, but the clinical significance of these molecular changes is still poorly understood, and the clinical outcomes of PNET patients remain highly variable. To help identify the molecular factors that contribute to PNET progression and metastasis, and as part of an ongoing clinical trial at the BC Cancer Agency (clinicaltrials.gov ID: NCT02155621), the genomic and transcriptomic profiles of liver metastases from five patients (four PNETs and one neuroendocrine carcinoma) were analyzed. In four of the five cases, we identified biallelic loss of MEN1 and DAXX as well as recurrent regions with loss of heterozygosity. Several novel findings were observed, including focal amplification of MYCN concomitant with loss of APC and TP53 in one sample with wild-type MEN1 and DAXX Transcriptome analyses revealed up-regulation of MYCN target genes in this sample, confirming a MYCN-driven gene expression signature. We also identified a germline NTHL1 fusion event in one sample that resulted in a striking C>T mutation signature profile not previously reported in PNETs. These varying molecular alterations suggest different cellular pathways may contribute to PNET progression, consistent with the heterogeneous clinical nature of this disease. Furthermore, genomic profiles appeared to correlate well with treatment response, lending support to the role of prospective genotyping efforts to guide therapy in PNETs.

A phase I trial of everolimus in combination with 5-FU/LV, mFOLFOX6 and mFOLFOX6 plus panitumumab in patients with refractory solid tumors.

PURPOSE: This phase I study investigated the safety, dose-limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered (1) in combination with 5-fluorouracil with leucovorin (5-FU/LV), (2) with mFOLFOX6 (5-FU/LV + oxaliplatin), and (3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors. METHODS: Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in Sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in Sub-trial B. RESULTS: Thirty-six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in level 6A. In Sub-trial B, 2/3 patients experienced DLT on level 1B and subsequent patients were enrolled on level 1B-1 without DLT. Three of six patients in cohort 2B-1 experienced grade 3 mucositis, and further study of the combination of everolimus, mFOLFOX6 and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45 % of patients remaining on treatment with stable disease for at least 3 months. CONCLUSIONS: While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies.

Implementing survivorship care plans for colon cancer survivors

PURPOSE/OBJECTIVES: To evaluate the feasibility, usability, and satisfaction of a survivorship care plan (SCP) and identify the optimum time for its delivery during the first 12 months after diagnosis. DESIGN: Prospective, descriptive, single-arm study. SETTING: A National Cancer Institute-designated cancer center in the southeastern United States. SAMPLE: 28 nonmetastatic colon cancer survivors within the first year of diagnosis and their primary care physicians (PCPs). METHODS: Regular screening identified potential participants who were followed until treatment ended. An oncology certified nurse developed the JourneyForward™ SCP, which then was delivered to the patient by the oncology nurse practitioner (NP) during a routine follow-up visit and mailed to the PCP. MAIN RESEARCH VARIABLES: Time to complete, time to deliver, usability, and satisfaction with the SCP. FINDINGS: During one year, 75 patients were screened for eligibility, 34 SCPs were delivered, and 28 survivors and 15 PCPs participated in the study. It took an average of 49 minutes to complete a surgery SCP and 90 minutes to complete a surgery plus chemotherapy SCP. Most survivors identified that before treatment ended or within the first three months was the preferred time to receive an SCP. CONCLUSIONS: The SCPs were well received by the survivors and their PCPs, but were too time and labor intensive to track and complete. IMPLICATIONS FOR NURSING: More work needs to be done to streamline processes that identify eligible patients and to develop and implement SCPs. Measuring outcomes will be needed to demonstrate whether SCPs are useful or not.

A two-cohort phase I study of weekly oxaliplatin and gemcitabine, then oxaliplatin, gemcitabine, and erlotinib during radiotherapy for unresectable pancreatic carcinoma.

OBJECTIVES: Gemcitabine is a potent radiosensitizer. When combined with standard radiotherapy (XRT) the gemcitabine dose must be reduced to about 10% of its conventional dose. Oxaliplatin and erlotinib also have radiosensitizing properties. Oxaliplatin and gemcitabine have demonstrated synergy in vitro. We aimed to determine the maximum tolerated dose of oxaliplatin and gemcitabine with concurrent XRT, then oxaliplatin, gemcitaibine, and erlotinib with XRT in the treatment of locally advanced and low-volume metastatic pancreatic or biliary cancer. METHODS: A modified 3+3 dose-escalation design was used for testing 4 dose levels of oxaliplatin and gemcitabine given once weekly for a maximum of 6 weeks with daily XRT in fractions of 1.8 Gy to a total dose of 50.4 Gy. Dose-limiting toxicity (DLT) was defined as any grade 4 toxicity or grade 3 toxicity resulting in a treatment delay of >1 week. In addition, dose reduction in 2 of the 3 patients in a given cohort was counted as a DLT in dose escalation-deescalation rule in the modified 3+3 design. RESULTS: Eighteen patients were enrolled, all with pancreatic cancer. Grade 4 transaminitis in a patient in cohort 3 resulted in cohort expansion. Cohort 4, the highest planned dose cohort, had no DLTs. The recommended phase II dose is oxaliplatin 50 mg/m(2)/wk with gemcitabine 200 mg/m(2)/wk and 50.4 Gy XRT. The most prevalent grade 3 toxicities were nausea (22%), elevated transaminases (17%), leucopenia (17%), and hyperglycemia (17%). Median progression-free survival was 7.1 months (95% confidence interval, 4.6-11.1 mo) and median overall survival was 10.8 months (95% confidence interval, 7.1-16.7 mo). The addition of erlotinib was poorly tolerated at the first planned dose level, but full study of the combination was hindered by early closure of the study. CONCLUSIONS: Weekly oxaliplatin 50 mg/m/wk combined with gemcitabine 200 mg/m/wk and XRT for pancreatic cancer has acceptable toxicity and interesting activity.

Phospho-ERK and AKT status, but not KRAS mutation status, are associated with outcomes in rectal cancer treated with chemoradiotherapy.

BACKGROUND: KRAS mutations may predict poor response to radiotherapy. Downstream events from KRAS, such as activation of BRAF, AKT and ERK, may also confer prognostic information but have not been tested in rectal cancer (RC). Our objective was to explore the relationships of KRAS and BRAF mutation status with p-AKT and p-ERK and outcomes in RC. METHODS: Pre-radiotherapy RC tumor biopsies were evaluated. KRAS and BRAF mutations were assessed by pyrosequencing; p-AKT and p-ERK expression by immunohistochemistry. RESULTS: Of 70 patients, mean age was 58; 36% stage II, 56% stage III, and 9% stage IV. Responses to neoadjuvant chemoradiotherapy: 64% limited, 19% major, and 17% pathologic complete response. 64% were KRAS WT, 95% were BRAF WT. High p-ERK levels were associated with improved OS but not for p-AKT. High levels of p-AKT and p-ERK expression were associated with better responses. KRAS WT correlated with lower p-AKT expression but not p-ERK expression. No differences in OS, residual disease, or tumor downstaging were detected by KRAS status. CONCLUSIONS: KRAS mutation was not associated with lesser response to chemoradiotherapy or worse OS. High p-ERK expression was associated with better OS and response. Higher p-AKT expression was correlated with better response but not OS.