bluuebunny/crossref_metadata_2025 huggingface dataset:
Cinematic MRI imaging for hepatic malignancies: Implications for improving accuracy of radiation therapy.
Authors: Apisarnthanarax Smith , Fernandes Annemarie Therese , Lin Yingshu , Rosen Mark Alan , Plastaras John Peter , Metz James M. , Ben-Josef Edgar , Teo Kevin
Published: February 2017

300

Background: Accurate radiation therapy (RT) targeting of hepatic tumors is critically dependent on organ and tumor motion assessment, most commonly performed with 4DCT. Since 4DCT captures only a snapshot of tumor motion in time and is prone to artifacts and irregular breathing, it is unclear how reliable 4DCT is in determining intra-fraction tumor motion. CineMRI allows for prolonged real-time organ and tumor motion assessment with no radiation exposure. We compared the extent of tumor motion between 4DCT and cineMRI in patients with hepatic tumors treated with RT. Methods: Sixteen patients with hepatocellular carcinoma (n=11), cholangiocarcinoma (n=3), and liver metastasis (n=2) underwent 4DCT and 2D biplanar cineMRI scans during simulation to determine the extent of target motion in the superior/inferior (S/I), anterior/posterior (A/P) and lateral directions. Biplanar cineMRI was performed over 5 minutes. Tumor motion from MRI was determined by tracking the centroid position of the gross tumor volume (GTV) using deformable image registration. Margins were determined by using histograms of 90% confidence interval of GTV motion in each direction. Motion estimates from 4DCT were performed by evaluation of the marker positions in each phase of the CT. We compared the extent of GTV motion and resulting margin size between cineMRI and 4DCT. Results: 4DCT underestimated the S/I margin in 50% of patients by a mean of 3.4 mm (range: 1.5-7 mm), the A/P margin in 44% of patients by a mean of 2.8 mm (range: 1-5.5 mm), and the lateral margin in 63% of patients by a mean of 1.6 mm (range: 0.2-4.5 mm). The average inferior motion (median to 10th percentile) was of greater magnitude (5.0 mm vs. 3.5 mm) compared to the average superior motion (median to 90th percentile). Superior, inferior, lateral, anterior, and posterior margins of 6, 8, 5, 6, and 4 mm respectively would be needed to cover 90% of the intra-fraction GTV motion as defined by cineMRI. Conclusions: CineMRI frequently detects larger differences in hepatic intra-fraction tumor motion when compared to 4DCT, most notably in the S/I direction, and may be useful when treating without respiratory management, particularly in patients with unreliable 4DCT imaging.
Morbidity in long-term survivors after pancreatoduodenectomy for pancreatic adenocarcinoma.
Authors: Chen Kathryn Tzung-Kai , Hoffman John Parker
Published: February 2017

307

Background: Because the focus of pancreatoduodenectomy for pancreatic adenocarcinoma is placed on disease-free and overall survival, morbidity in long-term survivors is not well described. We sought to evaluate outcomes of long-term survivors of pancreatic cancer after pancreatoduodenectomy. Methods: We identified 30 patients from our prospectively collected database of patients with pancreatic adenocarcinoma who had undergone pancreatoduodenectomy, and who were without evidence of disease with at least 40 months of follow-up. Demographics, treatment and pathologic characteristics were collected for review. Data with regards to long-term sequelae were also collected, particularly those complications requiring additional procedures and the development of metachronous cancers. Results: The median length of follow up was 83 months, with 60% of patients still alive. Half the patients were male, and the median age at diagnosis was 70 years. With regard to treatment, 80% of patients received chemoradiation, with half of these patients receiving it in the neoadjuvant setting. All patients received an R0 resection, although two patients required at least partial resection of the superior mesenteric or portal veins. Thirty-three percent of patients had N1 disease. Forty-four percent of patients did not have any significant subsequent sequelae. In the remainder, four patients (13%) developed ascites requiring repeated paracentesis or Denver shunt, with median time to development (MTD) of 63 months. Six patients (20%) developed a biliary stricture requiring stent placement (MTD 56 months), one patient developed portal venous thrombosis requiring a venous stent (MTD 52 months), and 3 patients (10%) experienced clinically significant gastric anastomotic ulcers (MTD 47 months). With regards to metachronous cancers, 2 patients developed subsequent lymphomas (MTD 92 months). Conclusions: Long-term survivors of patients who undergo pancreatoduodenectomy for pancreatic adenocarcinoma can develop significant late sequelae, which often can manifest more than three to five years after surgery. Continued follow-up and counseling is warranted.
Long-term survival of patients receiving multimodality neoadjuvant therapy for resectable or borderline resectable pancreatic ductal adenocarcinoma.
Authors: McCormick Kinsey , Whiting Samuel H. , Gyurkey Grace , Koh Wui-Jin , Sinanan Mika , Coveler Andrew L.
Published: February 2017

309

Background: While surgery offers the only chance for cure in localized PDA, outcomes remain poor for those who have undergone surgical resection (SR). Neoadjuvant therapy (NATx) has several advantages, including early treatment of micrometastatic disease, the potential for tumor downstaging, and improved selection of patients (pts) for surgery by excluding those with chemotherapy-refractory disease. Methods: We report long-term follow-up on consecutive pts with resectable or borderline resectable (R/BR) PDA treated at our institution with an off-protocol, but defined regimen of multi-modality NATx. Demographic, clinical and outcomes data were extracted from medical records. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan-Meier analysis. Results: 16 pts with R/BR PDA were treated with NATx; median follow-up is now 41 months (mo) (7.9-91.5). The median age was 57, 50% were female, and all had an ECOG PS <2. Fourteen (88%) had BR disease, and 9 (56%) had radiographic evidence of nodal involvement. All pts received NA gemcitabine, docetaxel and capecitabine and 13 (81%) also received NA chemoradiotherapy with capecitabine +/- oxaliplatin. 14 pts (88%) underwent SR; of those, 11 (79%) received adjuvant chemotherapy. The median decline in CA19-9 over the course of NATx was 80%. An R0 resection was achieved in 11 pts (79%), and there were 2 pCR. To date, 12 pts have died, 4 are alive (including 2 with CA19-9 >1000 at dx), and 3 are without recurrence. The mPFS and mOS were 27.4 and 41 mo, respectively. 1- and 3-year survival rates were 94% and 56%, respectively. When analyses were restricted to pts who underwent SR, the mPFS and mOS were 29 mo and 47.8 mo, respectively. There were no surgery-related deaths. 3 pts had postoperative wound complications. Conclusions: In this series of mostly BR pancreatic cancer pts, treatment with multi-modality NATx resulted in an almost doubling of mOS when compared to historical controls. NATx was also safe, and did not increase surgical morbidity or mortality. Based on these encouraging results, a phase II protocol of multi-modality NATx for R/BR PDA was initiated and has now completed accrual.
Assessing pretest probability in phase II trials: One step back before two steps forward.
Authors: Halperin Daniel M. , Dagohoy Cecile Dagohoy , Lee J. Jack , Yao James C.
Published: February 2017

312

Background: With frequent phase III failures, only 5% of new oncology drugs entering clinical development gain FDA approval. We hypothesize that pivotal trial failures are directly related to the poor predictive value of “positive” phase II studies, with odds of success varying by multiple factors, including disease site. We assessed success rates from phase II to allow calculation of pretest probability of eventual approval. Methods: As the median time from trial start to FDA approval is 6.3 years, we systematically searched clinicaltrials.gov for phase II trials of GI cancer therapy from 1999-2004. We reviewed drug labels for FDA approval. Drugs without FDA approval within 12 months of clinical trial start were classified New Drug Application (NDA) eligible. Drugs with prior approval were considered supplemental NDA (sNDA) eligible. Success rates were calculated as proportion of trials with drugs eventually approved. Results: We identified 280 trials; some included multiple disease sites. Approvals are shown in the table. Trials in different diseases had distinct rates of drug approval. sNDAsuccess in colorectal tumors was driven by multiple trials of drugs later gaining approval. Conclusions: Variable rates of phase II trials resulting in eventual approval for different GI cancers reflect the landscape of distinct diseases in which we test new therapies. Posterior probability of approval after a positive phase II trial varies by prior probability. For a positive phase II study with type I and II error rates of 0.1, given pretest probability of 1%, 3%, or 10%, the odds of eventual approval are 8%, 22%, and 50% respectively. With a quantitative understanding, we can tailor phase II trial design to improve phase III success rates. [Table: see text]
Patterns of care and treatment outcomes in older patients with biliary tract cancer.
Authors: Horgan Anne M. , McNamara Mairead G , Aneja Priya , Le Lisa W , McKeever Elizabeth , Knox Jennifer J.
Published: February 2017

315

Background: Although cancers of the biliary tree (BTC) are more common in older age-groups, treatment approaches and outcomes are understudied in this population. Methods: Data from 913 patients diagnosed with BTC from January 1987 to July 2013 and treated at Princess Margaret Cancer Center, Toronto were analyzed. The impact of age, patient and disease characteristics on survival outcomes were assessed. Results: Five hundred and ninety four patients ≤70 years and 319 patients >70 years were identified. Older patients were less likely to receive active therapy - 154 (26%) patients ≤70 yrs received best supportive care alone compared to 130 (41%) of those >70 yrs; p<0.0001. The characteristics of those receiving active therapy (surgery +/- chemotherapy) are shown (table). For patients receiving active treatment, ECOG PS (p=0.002) and disease stage (p<0.0001) independently predicted overall survival. Adjusting for these variables, median survival did not differ between older and younger patients, median survival 20.1 (95% CI [17.8, 23.3]) and 20.5 (95% CI [18.7, 23]) months respectively; HR 1.064 (95% CI [0.86, 1.32]). Conclusions: In this large retrospective analysis, older patients with BTC are less likely to undergo surgery or chemotherapy. Active therapy results in similar survival benefits, irrespective of age. [Table: see text]
Src inhibition through a phase II study of 5-fluorouracil, oxaliplatin, plus dasatinib (FOLFOX-D) in first-line metastatic pancreatic adenocarcinoma.
Authors: George Thomas J. , Ivey Alison Marguerite , Daily Karen Colleen , Dang Long H. , Watson Scott , Granicz Renee , Tormes Kevin , Lu Xiaomin , Liu Chen , Allegra Carmen Joseph , Behrns Kevin , Hughes Steven J. , Ogunwobi Olorunseun Olatunji , Trevino Jose Gilberto
Published: February 2017

319

Background: Triplet drug therapy is now a standard for metastatic pancreatic cancer (mPCa) but limited in use due to toxicity. Src is constitutively active in mPCa and associated with increased chemoresistance. Src inhibition increases oxaliplatin (ox) activity. Inhibition of Src reduces tumor expression of thymidylate synthase with subsequent 5FU chemoresistance reversal. Dasatinib (D) is an oral multi-tyrosine kinase inhibitor (TKI) capable of inhibiting Src. Demonstrating activity of this triplet combination therapy in mPCa represents a scientifically rational approach to a clinical unmet need. Methods: Eligible pts have biopsy proven, RECIST measurable disease with no prior therapy for met disease and at least 6 months since completing adjuvant therapy, ECOG PS 0-2 and adequate organ function. Pts received standard doses of mFOLFOX6 chemotherapy (5-FU/LV 400mg/m2 bolus and Ox 85 mg/m2 D1; 5-FU 2,400 mg/m2CIVI x 46h D1-2) with continuous D (150 mg PO daily) repeated q14d with tumor assessments q8w. The primary endpoint is progression-free survival (PFS) with secondary endpoints of objective and biochemical response rates, freedom from mets, overall survival (OS), toxicity, and quality of life. Sample size was based on a 50% improved median PFS from 4 (historical) to 6 months (m). Results: 14 of 42 planned pts have received therapy and are included in this report. Baseline pt demographics are in the table. 10 pts (71%) had a grade 3 AE and 1 (7%; sepsis) had a grade 4 AE. There were no grade 5 toxicities. Most common grade 3 AEs included anemia (29%), hyponatremia (29%), neutropenia (21%) and fatigue (21%). Conclusions: Enrollment continues with ongoing toxicity and efficacy monitoring of this targeted combination. Exploratory tissue and serum correlative analyses to identify predictors of response are planned. Clinical trial information: NCT01652976. [Table: see text]
Effectiveness study of gemcitabine, oxaliplatin, and capecitabine as first-line treatment for nonresectable biliary tract cancer.
Authors: Jensen Lars Henrik , Mellergaard Anne Haahr , Hoegdall Dan , Larsen Ole
Published: February 2017

334

Background: Since 2010, the doublet gemcitabine and cisplatin has been standard first-line systemic treatment for non-resectable biliary tract cancer. In a phase I-II trial of the well-tolerated triplet of gemcitabine, oxaliplatin, and capecitabine, the median progression free survival (PFS) and overall survival (OS) were 6.9 and 12.5 months, respectively. Overall response rate was 34%. Since 2005 the regimen has been used in Denmark. We wanted to investigate the effectiveness of the triplet regimen given in daily clinic. Methods: We included 192 patients from two institutions. Patients had to have non-resectable biliary tract cancer and to be suitable for combination chemotherapy on doctor’s discretion. Gemcitabine 1000 mg/m2 and oxaliplatin 60 mg/m2 were given every two weeks followed by capecitabine 1000 mg/m2 b.i.d. for one week. At one institution the oxaliplatin dose was 50 mg/m2 and capecitabine dose 650 mg/m2 b.i.d. continuously. One cycle included two treatments and was typically administered for up to six cycles/months, but was allowed for longer time until progression. Results: At institution A, 117 patients were included and 73 (62%) were women. Median age was 66 years (range 25-80). Median treatment duration was six cycles/months (range 1-12). Thirty-five, 69, 12, and one patient(s) were in performance status 0, 1, 2, and 3, respectively. Ninety patients were evaluable for response and 6 (7%) had complete response, 18 (20%) partial response, 53 (59%) stable disease, and 13 (14%) progression as best response. Median PFS was 9.7 months (95% CI 8.5-11.7) and median OS 11.7 months (9.8-14.0). The results were comparable to institution B, where the response rate in 56 patients with measurable disease was 30%. In 75 patients evaluable for survival analysis, PFS was 8.1 months and OS 12.0 months for performance status 0-1 (n=55). Patients in performance status 2 (n=25) had a PFS and OS of only 1.7 and 2.8 months, respectively. Conclusions: A triplet of gemcitabine, oxaliplatin, and capecitabine given in daily clinic was well tolerated and has effectiveness comparable to results from a phase II trial and the pivotal phase III trial of gemcitabine and cisplatin.
Effects of the sequential administration of GEMOX followed by FOLFIRI in cholangiocarcinoma.
Authors: Sebbagh Sihem , Dreyer Chantal , De Gramont Armand , Hentic Olivia , Hammel Pascal , Raymond Eric , Faivre Sandrine J.
Published: February 2017

348

Background: Advanced cholangiocarcinoma are benefiting from platinum-based therapy (Valle et al, NEJM) but no validated option is available as second line systemic therapy. Methods: Objective : Explore the effect of 2 consecutive lines of chemotherapy in patients with cholangiocarcinoma fitted to receive sequential administration of received gemcitabine and oxaliplatin (GEMOX) followed by FOLFIRI. A retrospective study was conducted among patients who received GEMOX in first line followed by FOLFIRI in second line from January 2005 and September 2013 at Beaujon hospital (France). Overall survival, progression free survival and prognostic factors were determined by the Kaplan-Meier method and univariate analysis. Results: Thirty-four patients were included in the cohort. Eighteen patients (53%) presented intrahepatic cholangiocarcinoma (ICC) and 16 (47%) presented extrahepatic cholangiocarcinoma (ECC). At diagnosis, tumors were localized in 4 patients (12%), locally advanced in 13 patients (38%) and metastatic in 17 patients (50%). Among 10 patients with prior surgery, 7 received GEMOX adjuvant chemotherapy. The median overall survival time was 20.6 months in all patients and 17.1 months in patients who received GEMOX followed by FOLFIRI in the advanced setting. The median first line progression-free survival (PFS) was 5.7 months with a median number of 8 cycles of GEMOX. The median second line PFS was 2.9 months with a median number of 5 cycles of FOLFIRI. Patients who received >8 cycles of GEMOX in first line survived longer than those who received ≤ 8 cycles (23.1 vs 15.1 months; hazard ratio (HR) 5.22, P=0.009). The PFS of second line FOLFIRI was not different in patients who received more than 8 cycles of GEMOX (HR=1.72 P=0.26). Univariate analysis showed no correlation between age, sex, localization of primary, stage, and surgery with overall survival. No severe toxicity was reported related to GEMOX-FOLFIRI sequential combination in this study. Conclusions: Sequential administration of GEMOX followed by FOLFIRI is feasible for fitted patients with cholangiocarcinomas, yielding overall survival over 1 year.
Prognostic factors in advanced biliary tract cancer treated with first-line chemotherapy with cisplatin and gemcitabine.
Authors: Peixoto Renata D'Alpino , Renouf Daniel John , Lim Howard John
Published: February 2017

350

Background: Data regarding prognostic factors in advanced biliary tract cancer (ABTC) remains scarce. The aim of this study was to review our experience in ABTC as well as to evaluate potential prognostic factors for overall survival (OS) as defined in the ABC-02 trial. Methods: 106 consecutive patients with ABTC who initiated palliative chemotherapy with Cisplatin and Gemcitabine from 2009 to 2012 at the BC Cancer Agency were identified using our pharmacy database. Clinicopathologic variables and treatment outcome were retrospectively collected. Potential prognostic factors were assessed by univariate (Kaplan-Meier curves and log-rank test) and multivariate analyses (Cox proportional hazards model). Results: 106 patients (46 males) with a median age of 64 years (range 43 – 88) were included. Median progression free-survival (PFS) was 6.2 months (95%CI: 5.4-7.0). Median OS from diagnosis of advanced disease to death was 12.9 months (95%CI: 10.0-15.7), while median OS from initiation of chemotherapy to death was 10.0 months (95%CI: 7.3-12.6). 34.9% of the patients received 2nd line chemotherapy, with single-agent 5-fluorouracil being the most used drug. On univariate analysis, ECOG performance status (PS) at diagnosis, primary tumor location (gallbladder, intra-hepatic cholangiocarcinoma, extra-hepatic cholangiocarcinoma, ampulla of Vater, unkown), and sites of advanced disease (unresectable locally advanced, regional lymph nodes, liver-limited metastases, extra-hepatic metastases) were significantly associated with worse OS (p < 0.001, 0.003 and 0.009, respectively). Age, gender, CA19-9, CEA, hemoglobin, neutrophil count, prior stent and prior surgery were not significantly associated with OS. On multivariate analysis, predictors of poorer OS were ECOG PS (p<0.001), primary location (p=0.009), site of advanced disease (p=0.006) and CEA (p=0.002). Conclusions: In this population based analysis, outcomes for patients with ABTC were comparable to those noted in the ABC-02 trial. ECOG PS, primary tumor location, site of advanced disease and CEA were all found to be significantly prognostic.
Correlation between overall survival and other efficacy endpoints in advanced biliary tract cancer: Literature-based analysis from 13 randomized trials of first-line chemotherapy.
Authors: Moriwaki Toshikazu , Endo Shinji , Yamamoto Yoshiyuki , Yamada Takeshi , Sugaya Akinori , Kobayashi Mariko , Hyodo Ichinosuke
Published: February 2017

352

Background: Chemotherapy for advanced biliary tract cancer (ABC) has progressed. Now gemcitabine plus cisplatin combination is considered the standard 1st-line treatment based on the results of many randomized studies. However, the impact of various efficacy parameters on overall survival (OS) remains unclear. Methods: We searched PubMed database with the key words of (“biliary tract neoplasms” or “bile duct neoplasms” or “gallbladder neoplasms” or “cholangiocarcinoma” [All fields]) AND (“chemotherapy”[All fields]) AND Clinical trial [ptyp] between Apr 1984 to Jun 2013 and abstracts presented at the meetings of ASCO/Gastrointestinal Cancers Symposium (2004–2013) and ESMO/WCGC (2002–2013). Then we identified randomized trials of 1st-line chemotherapy for ABC, and analyzed the relations between the results of OS and those of progression-free survival (PFS) or time to progression (TTP), response rate (RR), disease control rate (DCR), post-progression survival (PPS = median OS − median PFS/TTP), and the proportion of patients who received 2nd-line chemotherapy (%2nd). Results: Among 329 papers/abstracts retrieved, 13 randomized trials, 26 treatment arms of first-line chemotherapy for ABC were identified. Number of trials with information on median OS, median PFS/TTP, hazard ratio (HR) for OS and PFS/TTP, RR, DCR, and %2nd were 13, 13, 6, 13, 12, and 7, respectively. The analysis of all these trials demonstrated the median values (range) of OS, PFS/TTP, HR of OS, HR of PFS/TTP, RR, DCR, PPS, and %2nd were 9.4 (4.6–13) months, 5.3 (2.7–8.5) months, 0.71 (0.39–0.93), 0.65 (0.44–0.85), 20 (7.1–36) %, 67 (21–87) %, 4.0 (1.0–7.6) months, and 41 (15–79) %, respectively. Spearman rank correlation coefficient of differences (Δ) OS with ΔPFS/TTP, ΔRR, ΔDCR, and ΔPPS were 0.66, − 0.07, 0.66, and 0.34, respectively. The correlation coefficient between HRs for PFS/TTP and OS was 0.60. The correlation coefficient between ΔPPS and Δ%2nd was − 0.15. Conclusions: OS was moderately associated with PFS/TTP and DCR.
Oxaliplatin, irinotecan, and PK-adjusted 5-fluorouracil within a multidisciplinary approach in patients with locally advanced pancreatic cancer (LAPC): Preliminary results.
Authors: Martin Romano Patricia , Aldaz Azucena , Chopitea Ana , Pardo Fernando , Arbea Leire , Subtil Jose Carlos , Rotellar Fernando , Garzon Carlos , Zufia Laura , Sola Iosu , Solorzano Jose Luis , Castanon Eduardo , Rodriguez Javier
Published: February 2017

356

Background: Neoadjuvant therapy is an increasingly used approach in LAPC patients (pts) but the optimal sequence remains to be defined. We evaluated the feasibility and efficacy of induction chemotherapy (ICT) with pharmacokinetic (PK) monitoring, chemo-radiotherapy (CRT) and surgery. Methods: Borderline resectable and unresectable LAPC pts with EUS stages T3-4/N+ were included. Pts were planned to receive 4 cycles of biweekly ICT with Oxalipatin (85mg/m²), Leucovorin (400mg/m²), Irinotecan (150mg/m²) and 5-FU (initial dose of 3200mg/m² in 46h and then tailored according to PK monitoring to reach an area under the curve (AUC) between 25-30 mg·h·L-1.) After ICT, pts with no progressive disease received CRT (50.4 Gy, daily concurrent Capecitabine and weekly Oxaliplatin). Surgery was planned 4 to 6 weeks after the completion of CRT. Pathological response was graded according to the CAP classification. Toxicity was recorded according to the NCI-CTCAE 4.0. Results: From November 2011 to February 2013, 13 LAPC treatment-naïve (M/F: 11/2) pts were enrolled (T4; 30.8%, N+; 61.5%, 8 borderline resectable, 5 unresectable due to celiac abutment (2 pts), SMA and celiac encasement (1 pt), unreconstructible SMV and portal occlusion (2 pts). Median age was 63. During ICT, 5- FU dose had to be increased from baseline in 30.7% pts. Grade 3-4 ICT-related toxicities were neutropenia (6 pts) and diarrhea (1 pt). During CRT, grade 3 toxicity included neutropenia (2 pts), thrombocytopenia (1 pt), diarrhea (1 pt), asthenia (1 pt) and mucositis (1 pt); three pts required hospital admission in hospital. Twelve pts completed the whole neoadjuvant program. Ten pts proceeded to surgery with an R0 resection rate of 76.9%. Pathological response was CAP 0 (no viable cells) and CAP 1 (small groups of cancer cells) in 20% and 50% of pts, respectively; ypT0 and ypN0 rates were 20 and 60%. After a median follow-up of 12 months, the 12-month actuarial median PFS and OS were 80% and 75%, respectively. Conclusions: This neoadjuvant strategy seems feasible and promising although a longer follow-up is required. 5-FU PK modulation may contribute to a better therapeutic index.
Pancreaticoduodenectomy (PD) for periampullary tumors: Results from Tata Memorial Centre (TMC) over two decades.
Authors: Shrikhande Shailesh V. , Mitra Abhishek , Sirohi Bhawna , Bal Munita , Goel Mahesh
Published: February 2017

366

Background: There is scarcity of short and long term data regarding results of pancreaticoduodenectomy done for periampullary tumours. Contrary to the western data, ampulla of Vater is the commonest site of involvement in Indian patients. Methods: A retrospective analysis PD was done for periampullary tumors from 1991 to July 2013 at TMC. The time period was divided into 4 spans A (1991 to 2001), B (2003 to July 2009), C (Aug 2009 to Dec 2012) and D (Jan 2013 to July 2013) based on the increasing surgical volumes and changing practice trends. Survival outcomes were analysed. Data was prospectively maintained from 2006 onwards. Results: 626 pts underwent PD for periampullary tumors over this time period. 144, 206, 150 and 126 pts were operated during span A, B, C and D respectively. Sites involved were ampulla (67.5%), head of pancreas (16.6%), duodenum (9.9%) and bile duct (6.9%). Adenocarcinoma was the most common histology (81.5%). The morbidity and mortality was 31.7% and 4.3%. Postoperative pancreatic fistula, delayed gastric emptying (DGE), post-pancreatectomy haemorrhage (PPH) and bile leaks were 12.4%, 2.8%, 4.8% and 2.7% respectively for the whole group. Morbidity, mortality, DGE, PPH and bile leak rates have declined over subsequent time periods. Majority of pts in span C and D received adjuvant chemotherapy with gemcitabine 1000mg/m2 on day 1,8 and 15 of a 28 day cycle. 2 year disease free survival (DFS) for periampullary adenocarcinoma-ampulla, bile duct & pancreas from April 2006 for 294 pts was 79.3%, 68.6% and 41.8% respectively. Overall 2 year DFS was 74%. Conclusions: These data represent the largest single centre experience with PD from Indian subcontinent. The improvement of results over the 2 decades can be due to increasing volume of pts, standardisation of surgical technique and gradually increasing experience of the operating team. The impressive 2 year DFS can be attributed to a large number of good prognosis ampullary tumors.
Chemoradiation for locally advanced perihilar cholangiocarcinoma.
Authors: Lim Seungtaek , Choi Hye Jin , Seong Jinsil
Published: February 2017

372

Background: Locally advanced perihilar cholangio-carcinoma (LA-PHC) is a rare malignancy with dismal prognosis, and chemoradiation (CRT) is used to palliate symptoms and extend survival. However, its role has not been established due to the rarity of these tumors. We intended to investigate the efficacy of chemo-concurrent radiotherapy (CRT) for patients with LA-PHC. Methods: This study included 52 patients who received CRT for LAPHC in a single institue. Patients received external beam radiotherapy with a median dose of 50.4Gy (range, 720-5400) with gemcitabine or 5-FU (or its analogues). The objective response rate (ORR), disease control rate (DCR), and overall survival (OS) were evaluated. All statistical analysis were performed by SPSS program version 18.0. Results: The median OS was 14.2 months (95% CI, 8.9~19.5). The ORR and DCR was 12% and 85%, respectively. Thirteen patients (19%) whose disease were converted to resectable after CRT had a significant survival advantage compared to patients who underwent CRT alone (29.2 vs. 10.8 months, P=0.005). CA 19-9 response (defined as more than 30% decrease in the CA 19-9 level compared to baseline) at 1month after CRT predicted prolonged survival (Table). CRT was generally well tolerated. Although gemcitabine-based CRT had a higher ORR, DCR, and CA 19-9 response at 1 month than 5FU-based CRT, the difference was not statistically different, and there was no difference in OS between two regimens. Moreover, patients treated with gemcitabine based CRT suffered more severe hematologic toxicity (grade 3 or 4 neutropenia, 20% vs. 4%). Conclusions: This study suggested that CRT is a good therapeutic option in the treatment of LA-PHC. Also, CA 19-9 response 1 month after completion of CRT was identified as a predictive marker of survival in patients who underwent CRT. Further research is warranted regarding optimal chemotherapy regimen, and schedule of radiation. [Table: see text]
Neoadjuvant therapy in Indian patients with locally advanced gall bladder cancer: Tata Memorial Centre (TMC) experience.
Authors: Sirohi Bhawna , Sheth Vipul , Singh Ashish , Engineer Reena , Ramadvar Mukta , Goel Mahesh , Shrikhande Shailesh V.
Published: February 2017

379

Background: Gemcitabine/platinum (Gem-P) is currently the standard of care for patients with advanced biliary tract cancers based on the ABC02 study. Pts usually present in locally advanced (LA) stage in India and as surgery remains the only curative option- neoadjuvant (NA) strategy needs to be explored. Methods: This is retrospective analysis of the prospectively maintained database of 38 patients with LA GB cancer treated at TMC between Feb 2009 to May 2013. Aim of the study was to assess resectability rate in patients with LA GB cancer (defined as GB mass invading liver > 2cm without porta hepatis / vascular invasion, GB mass adherent to duodenum and hepatic flexure, coeliac/gastrohepatic adenopathy/portocaval and peripancreatic nodes). Pts received cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on D1 and D8 of 21d cycle, for gem-oxaliplatin, pts received gemcitabine 1000mg/m2 D1 and oxaliplatin 100mg/m2 D2 every 14 days. Response was assessed after 3-4 cycles. Results: Of the 38 pts (median age 54 y,30-71; 11M, 29F, median CA19.9 19 (<2-74605), 33patients were treated with Gem-P (25 oxaliplatin, 8 cisplatin; 1cetuximab-Gem-P) based therapy and 5 pts received chemoradiotherapy (CTRT) with wkly gemcitabine 300mg/m2. Site of disease was liver in 22 pts, nodal in 12, adjacent organ in 9 & other in 3 pts. Median number of chemotherapy cycles given were 4 (1-12). Response rate to NA therapy was 5 (13%) complete response (CR), 17(45%) partial response (PR), 9 stable disease (SD), 5 (13%) progressive disease and not assessed in 2 patients (1 pt died post CTRT and 1 was inoperable at surgery). Overall clinical benefit rate (CR+PR+SD) was 82%. Of the 24 pts who underwent surgery, 21 (87%) had curative resection and 3 were inoperable. Of 9 pts with SD, 6 received 2nd –line NA therapy as they were not downstaged enough to undergo surgery– 4 CTRT, 1 gemcitabine-cape, 1 cape-Ox. Perioperative morbidity (biliary leak) was higher post CTRT. Overall, 7 pts have relapsed. Conclusions: This is the first report of the use of neoadjuvant chemotherapy in patients with LA GB cancer. We conclude that preoperative chemotherapy is feasible with acceptable toxicity and perioperative morbidity.
Primary small cell of esophageal carcinoma (SCEC): Experience of Beatson West of Scotland Cancer Center.
Authors: Alfayez Mohammad , McDonald Alexander , MacLaren Vivienne
Published: February 2017

38

Background: Primary Small Cell of Esophageal Carcinoma (SCEC) is an aggressive tumor with no established treatment guidelines. A treatment strategy was adopted based on small cell carcinoma of the lung, as many clinicopathological features are shared. Methods: We retrospectively collected data from fourteen patients who were treated for small cell of esophageal carcinoma at Beatson West of Scotland Cancer Center between 2005 and 2012. All patients were required to have a histological diagnosis of small cell carcinoma. Data were collected retrospectively by case note review and electronic record on demographic details, performance status (PS), comorbidity, treatment, and response to treatment. Results: The data suggest the median age for SCEC diagnosis is 71 years old. Diagnoses in males predominate (64%). The tumors were mainly located in the lower third of the esophagus (71%). The majority of patients with SCEC were in the limited Disease (LD) at the time of diagnosis (71%). About 50% of the patients received chemotherapy alone and 28% received consolidation radiotherapy. Three patients (21%) only received concomitant chemoradiation. None of the patients have Primary Cranial Irradiation (PCI). The overall survival of patients with limited Disease (LD) vs. Extensive Disease (ES) was 22.2 vs. 4.6 months (P=0.013). None of the patients reviewed developed brain metastasis. Conclusions: There is trend in the data that the combination of radiotherapy and chemotherapy improves local control. Radiotherapy alone is probably inadequate if used alone. It should be combined with adjuvant or neoadjuvant platinum-based chemotherapy. Palliative chemotherapy for patients presenting with extensive disease prolonged survival. PCI should not be a standard treatment for these patients. The data presented are the second largest series from the western world. These data will help establish further guidelines for treatment of the small cell of esophageal carcinoma.
Prospective evaluation of a 12-gene assay on patient treatment decisions and physician confidence in mismatch repair-proficient (MMR-P) stage IIa colon cancer patients.
Authors: Alberts Steven R. , Renfro Lindsay A. , Lopatin Margarita , Tezcan Haluk , Sloan Jeff , Chao Calvin Y. , Lee Mark
Published: February 2017

396

Background: The 12-gene Oncotype DXColon Cancer Assay is clinically validated as a predictor of recurrence risk in stage II colon cancer patients following surgery. We previously reported that the 12-gene assay led to 45% change in physician treatment (Tx) recommendations in a prospective study in MMR-P stage IIA colon cancer patients. Here, from the same prospective study, we report the influence of the 12-gene assay on patient Tx decisions, physician confidence, concordance in Tx choice between physicians and patients, and patient decisional conflict. Methods: Consecutive patients with resected stage IIA colon cancer who were candidates for adjuvant chemotherapy were enrolled by 105 physicians from 17 sites. Patient's tumor specimens were assessed by the 12-gene assay (RT-PCR) and MMR (IHC). Prior to and after receiving these results, patients completed surveys including (1) their Tx decisions (observation (Obs) vs. 5FU-monotherapy (5FU) vs. 5FU + oxaliplatin (Oxal)) and (2) indicators of decisional conflict. Results: 190 of 221 patients enrolled were evaluable including 139 who were MMR-P. Pre-assay: 46% of patients chose Obs, 3% 5FU, 7% Oxal, 2% other and 41% were undecided. Post-assay: 75% chose Obs, 12% 5FU, 11% Oxal, 3% other (undecided was not a possible response). Post-assay 129 (96%) of 135 definitive Tx decisions (Obs, 5FU, or Oxal) were concordant between patients and physicians compared to 49 (66%) of 74 definitive decisions pre-assay. In the majority of cases, patients (85%) and physicians (69%) reported that the assay influenced their Tx decisions. Assay results increased physician confidence in Tx recommendations in 126 (84%) and provided additional clinically relevant information to physicians in 129 (86%) of cases. Patient decisional conflict was significantly lower after assay results (p<0.001). Conclusions: In this prospective study, quantitative recurrence risk information provided by the 12-gene assay influenced Tx decisions for a majority of patients and physicians, increased physician confidence, improved concordance in Tx choice between patients and physicians and decreased patient decisional conflict.
Impact of preoperative sarcopenia on morbidity in gastric cancer surgery.
Authors: Sato Tsutomu , Aoyama Toru , Hayashi Tsutomu , Cho Haruhiko , Kawabe Taiichi , Fujikawa Hirohito , Ogata Takashi , Yamada Takanobu , Hasegawa Shinichi , Oshima Takashi , Rino Yasushi , Masuda Munetaka , Yoshikawa Takaki
Published: February 2017

40

Background: Skeletal muscle depletion, known as sarcopenia, is characterized by decrease in muscle mass and function. Recent reports demonstrated that sarcopenia was a significant risk factor for complications in colorectal cancer surgery. This study aimed to evaluate impact of preoperative sarcopenia on morbidity in gastric cancer surgery. Methods: Between May 2011 and June 2013, 293 consecutive primary gastric cancer patients who underwent curative surgery were retrospectively examined. All patients received the same perioperative care of enhanced recovery after surgery program. Preoperative skeletal muscle mass was evaluated by bioelectrical impedance analysis and was expressed as skeletal muscle index or SMI (muscle mass/height2) by adjusting absolute muscle mass with height. Preoperative muscle function was measured by hand grip strength (HGS). Each cutoff value was determined as the gender-specific lowest 20% of the distribution of each measurement. Grade 2 or higher morbidity, evaluated by Clavien-Dindo classification, was picked-up from the patient record. Risk factor for morbidity was examined by uni- and multi-variate analyses. Results: Median age (range) was 68 years (37-85 years). Male to female ratio was 192:101. Operative procedure was 122 total, 169 distal, and 2 proximal gastrectomy. Lymphadenectomy was 162 D1+ and 131 D2 including 53 splenectomy. Pathological stage was I in 149, II in 39, III in 91, and IV in 14 patients. Morbidity included 7 pancreatic leakage, 12 anastomotic leakage, 4 intra-abdominal abscess, and others. In total, morbidity was observed in 39 patients (13.3%); 21 in grade 2, 16 in grade 3a, 1 in grade 3b, and 1 in grade 4. No mortality was observed. Univariate analysis showed that male, total gastrectomy, splenectomy, and low HGS were significant risk factor for morbidity. Low SMI was not a risk factor. By multi-variate analysis, low HGS(HR 2.457, p=0.029), male(HR 2.610, p=0.038)and total gastrectomy(HR 2.747, p=0.027)remained significant. Conclusions: Low hand grip strength was one of significant risk factor for morbidity in gastric cancer surgery. Hand grip strength as a surgical risk has a value to be examined in the future prospective studies.
Impact of colonoscopically missed cancers on patient outcomes.
Authors: Govindarajan Anand , Rabeneck Linda , Tinmouth Jill , Paszat Lawrence Frank , Baxter Nancy
Published: February 2017

404

Background: There is increasing recognition of the potential for cancers to be missed on colonoscopy, but little is known about their outcomes. The objective of this study was to evaluate the outcomes of missed cancers relative to those detected by colonoscopy. Methods: We conducted a retrospective population-based cohort study, including all patients diagnosed with colorectal cancer (CRC) in Ontario, Canada from 2003-2009, who had undergone a colonoscopy within 36 months prior to diagnosis. Using previously defined time windows, we defined detected cancers as those diagnosed within 6 months of index colonoscopy and missed cancers as those diagnosed between 6 and 36 months after index colonoscopy. Patient and tumor factors were recorded as covariates. The primary outcome was overall survival, with secondary outcomes of resection rate, emergency presentation, and surgical complication rate. Logistic regression was used to analyze binary outcomes and Kaplan-Meier and Cox regression analyses were used for survival outcomes. Results: Overall, 30,475 patients were included in the study, with 2,804 being classified as having a missed cancer. Factors associated with missed cancers included colonic location (vs. rectum), older age, female sex, rural residence, and Charlson comorbidity score. Absolute 5-year overall survival was significantly lower in missed compared to detected cancers (60.8% vs. 68.3%, difference: 7.5%, p < 0.0001). In multivariable analysis, patients with missed cancers had a 22% higher hazard of death (HR: 1.22, 95% CI: 1.15 to 1.30, p < 0.0001). Patients with missed cancers were significantly more likely to present emergently with obstruction, bleeding or perforation (OR: 2.86, 95% CI: 2.56 to 3.13, p < 0.001) and were significantly less likely to have their tumors surgically resected (OR: 0.61, 95% CI: 0.55 to 0.67, p < 0.001). Conclusions: CRCs that are missed on initial colonoscopy are associated with markedly inferior patient outcomes, with a higher risk of emergent presentation, a lower likelihood of surgical resection, and most notably a significantly worse overall survival. These findings reinforce the critical importance of studying and improving quality measures of CRC screening to improve patient outcomes.
Predicting toxicities from adjuvant treatment in a population-based cohort of early colon cancer (CC) patients (pts): A strategy to improve use of curative chemotherapy.
Authors: Gresham Gillian , Sidhu Jasleen , Malhi Navraj , Cheung Winson Y.
Published: February 2017

412

Background: CC pts treated with chemotherapy are at risk of experiencing a number of toxicities. The identification of pts who may be at a higher risk of developing toxicities allows clinicians to be more vigilant in preventing and managing side effects early, thus enabling more optimal delivery of chemotherapy. Our aim was to determine clinical factors associated with toxicities from adjuvant FOLFOX in early CC. Methods: Pts diagnosed with stage III CC from 2005 to 2008, seen at any 1 of 5 regional cancer centers of the British Columbia Cancer Agency, and treated with adjuvant FOLFOX chemotherapy were reviewed. We evaluated various toxicities, including gastrointestinal, hematologic, cardiovascular, and neurological side effects. Baseline and clinical factors were assessed in univariate and multivariate models to determine potential predictors for each of the different chemotherapy toxicities. Results: In total, 475 pts were included: median age was 62 years (range 26-89), 16.2% were aged >70 years, and 54.5% were men. In terms of function, the majority (90.1%) was ECOG 0/1. Time to adjuvant chemotherapy (TTAC) >8 weeks (OR 1.91, 95% CI 1.8-3.1, p=0.006) and renal dysfunction with a GFR <50 (OR 1.69, 95% CI 1.1-2.6, p=0.0038) were significantly associated with higher odds of any GI toxicity. Likewise, TTAC >8weeks (OR 2.8, 95% CI 1.5-5.2, p=0.002), ECOG PS >1 (OR 2.86, 95% CI 1.2-6.7, p=0.016), and low white blood cell count <6.4 (OR 2.32, 95% CI 1.3-4.0, p=0.0043) were correlated with a greater risk of significant neutropenia. Multiple toxicities were more prevalent among those who waited >8 weeks to initiate adjuvant FOLFOX (OR 1.69, 95%CI 1.1-2.7, p=0.03). Further, advanced age >70 years was an indepenent risk factor for worse nausea and diarrhea. Conclusions: Consideration of important baseline characteristics such as TTAC, advanced age, renal function, and specific laboratory parameters when recommending adjuvant FOLFOX can be useful in identifying patients with increased likelihood of toxicities. This group of patients may benefit from increased monitoring in order to enable optimal doses of curative chemotherapy to be delivered.
Hollow spheroids beyond the invasive front and malignant potential of colorectal cancer.
Authors: Yokoyama Shozo , Ieda Junji , Yamamoto Naoyuki , Mitani Yasuyuki , Mizumoto Yuki , Takifuji Katsunari , Hotta Tsukasa , Matsuda Kenji , Watanabe Takashi , Tani Masaji , Yamaue Hiroki
Published: February 2017

418

Background: Hollow spheroid (HS) is a morophogenesis after budding at invasion front of colorectal cancer (CRC) tissue. HS formation of CRC cells has been shown to be induced by Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1) long cytoplasmic isoform dominance condition in three-dimensional (3D) in vitro culture. The aim of the current study is to address the existence and the clinical implication of HS in colorectal cancer. Methods: Immunohistochemical analyses were conducted with CEACAM1, CEACAM1-L, to address the existence of CEACAM1 expressing HS beyond the invasion front of CRC. The risk factors for metastases and survival were calculated using univariate and multivariate analyses on clinical samples from 164 patients with CRC. To investigate the role of HS for chemoresistance to 5-fluorouracil (5-FU), the risk factors for recurrence after adjuvant chemotherapy were calculated using univariate and multivariate analyses on clinical samples from 82 patients with Stage III CRC. Results: Immunohistochemical analyses showed that CEACAM1 expressing HS existed at the invasion front of colorectal cancer tissues. A multivariate analysis showed that the HS is an independent risk factor for lymph node metastasis (p = 0.004) and distant metastasis (p = 0.002). HS was also identified to be an independent prognostic factor by a Cox proportional hazards model (p = 0.020). The Kaplan-Meier evaluation for the overall survival analysis showed that HS was significantly associated with a shorter survival (p < 0.0001). Moreover, a multivariate analysis for recurrence after adjuvant chemotherapy showed that the HS is an independent risk factor (p = 0.0079). These results suggested that HS indicates malignant and chemoresistant phenotype. Conclusions: HS was significantly correlated with CRC metastasis, poor survival and chemoresistance to 5-FU. HS beyond the invasion front of CRC can be useful for diagnosis of malignant potential, and may be novel therapeutic target.
Nodal involvement and impact of adequate staging in older patients with resectable colon cancer: A population-based analysis.
Authors: Khan Hadi , Somasundar Ponnandai Sadasivan , Olszewski Adam J.
Published: February 2017

424

Background: The variation in nodal involvement between age groups has not been thoroughly studied in colon cancer, but it may affect strategies for extent of resection in geriatric patients (pts). The objective of our study was to compare nodal involvement in resectable colon cancer pts, with a focus on surgical staging practices in the elderly. Methods: We extracted data from the Surveillance, Epidemiology, and End Results registry on 183,055 pts diagnosed with stage I-III colon adenocarcinoma between 2000 and 2010. Proportions of pts undergoing colon resection, pts with adequate staging with ≥12 lymph nodes examined (LNE, n=99,308), and with node-positive (N+) cancers were compared in age groups using chi-squared test. Relative risk (RR) of N+ cancer was compared in a multivariable log-linear model, and relative survival in a flexible parametric model, reporting excess hazard ratios (HR) with 95% confidence intervals (CI). Results: While the rates of colon resection were similar in all age groups, older pts were significantly less likely to have ≥12 LNE (P<0.0001; Table). When adequately staged, older pts had a significantly lower proportion of N+ cancers (P<0.0001), even after adjusting for multiple other variables. Survival was better in pts with ≥12 LNE, with no significant difference in the benefit between the age groups (P=0.25 for interaction). Conclusions: When adequately staged, older pts are less likely to have N+ colon cancer, which may help them avoid the recommendation for adjuvant chemotherapy. Since the survival benefit of ≥12 LNE is similar in every age group, the guidelines for extent of resection and pathological examination should be diligently adhered to in all pts undergoing curative surgery, regardless of age. [Table: see text]