bluuebunny/crossref_metadata_2025 huggingface dataset:
Does panitumumab have a clinical benefit in cetuximab-refractory KRAS wild-type metastatic colorectal cancer?
Authors: Watanabe Toshiyasu , Shinozaki Eiji , Kijima Sho , Ohhara Yoshihito , Kuboki Yasutoshi , Takagi Koichi , Ozaka Masato , Ogura Mariko , Kikuchi Yoshinori , Suenaga Mitsukuni , Chin Keisho , Matsusaka Satoshi , Koike Junichi , Funahashi Kimihiko , Urita Yoshihisa , Mizunuma Nobuyuki , Hatake Kiyohiko , Kaneko Hironori , Sugimoto Motonobu
Published: February 2017

654

Background: Panitumumab and cetuximab can be used in metastatic colorectal cancer (mCRC) and these drugs are IgG2 fully human and IgG1 chimeric (mouse/human) monoclonal antibody against the epidermal growth hactor receptor (EGFR) respectively. The efficacy of panitumumab as a salvage chemotherapy after cetuximab-based chemotherapy failure is not clarified.

Methods: This study aimed to evaluate the panitumumab efficacy to KRAS wild-type mCRC patients who failed cetuximab-based chemotherapy. Response, progression-free survival (PFS) and serum tumor marker level (CEA and CA19-9), were assesed. We studied response by days from last cetuximab-based chemotherapy to panitumumab induction (C-P days).

Results: 22 patients (11 men, 11 women, median age 54 years m4 0-78 n) were enrolled. All of thease patients were cetuximab-based chemotherapy refractory KRAS wild-type mCRC. After progression, they received panitumumab monotherapy (6 mg/kg every 2 weeks).The best response was SD 10/22 (45.5%), PD 11/22 (50%) and NE 1/22 (4.5%). Overall median PFS was 90 days (13 to 182). The patients C-P days less than 30 days were 15 patients(5:SD, 10:PD). The patients more than 79 days were 7 patient(5:SD, 1:PD, 1:NE). Serum tumor marker level was decreased more than 50% patients.

Conclusions: This study suggested that it might be limited as possibility of clinical benefit with panitumumab administration after cetuximab failure.
Capecitabine monotherapy and the clinical significance of neutrophil-lymphocyte ratio versus platelet-lymphocyte ratio in patients with metastatic colorectal cancer.
Authors: Lee Suee , Kwon Hyuk-Chan , Kim Sung-Hyun , Oh Sung Yong , Lee Ji Hyun , Yoon Hyun-Hwa , Choi Hong Jo , Kim Hyo-Jin
Published: February 2017

660

Background: Oxaliplatin- and irinotecan-based combination chemotherapy with infusional 5-FU and leucovorin are currently the standard therapies for metastatic colorectal cancer. The objectives of this study were to evaluate the efficacy of capecitabine monotherapy as third line therapy for metastatic colorectal cancer after failure of chemotherapy containing oxaliplatin and irinotecan, and to determine whether the neutrophil-lymphocyte ratio (NLR), or the platelet-lymphocyte ratio (PLR) are significant prognostic marker in metastatic colorectal cancer.

Methods: We analyzed 60 patients with metastatic colorectal cancer who received capecitabine monotherapy after the failure of FOLFOX and FOLFIRI. Capecitabine was administered at 1250mg/m2 twice daily for 2 weeks, every 3 weeks. The NLR and PLR were calculated from complete blood counts in baseline laboratory test before the first cycle chemotherapy.

Results: The overall response rate was 6.7% and stable disease was 41.7%. The disease control rate was 48.3%. The median progression-free survival (PFS) was 2.8 months (95% CI, 1.5-4.1 months) and the median overall survival (OS) was 9.7 months (95% CI, 7.6-11.7 months). The most frequent adverse event was hand-foot syndrome (all-grade 26.6%; grade3 5%). The response of capecitabine, NLR, and PLR were observed as good prognostic markers of OS in univariate analysis (p<0.001, 0.004, and 0.002, respectively). The response of capecitabine and PLR were independent prognostic marker in multivariate analysis (Hazard ratio 2.757, 95% CI 1.357-5.599, p=0.005 and hazard ratio 2.091, 95% CI 1.231-3.552, p=0.006, respectively).

Conclusions: The capecitabine monotherapy showed a moderate disease control and a tolerable toxicity profile as third line treatment for metastatic colorectal cancer. The response of capecitabine and PLR may be simple and useful prognostic index for metastatic colorectal cancer.
Liver resectability following mFOLFOX6 with bevacizumab as the first-line treatment of unresectable liver limited metastases from colorectal cancer in Japanese patients (KSCC 0802).
Authors: Samura Hironori , Beppu Toru , Emi Yasunori , Kakeji Yoshihiro , Saeki Hiroshi , Oki Eiji , Fujita Fumihiko , Inomata Masahumi , Sawai Terumitsu , Akagi Yoshito , Baba Hideo , Natsugoe Shoji , Ogata Yutaka , Tokunaga Shoji , Maehara Yoshihiko ,   Kyushu Study Group of Clinical Cancer
Published: February 2017

666

Background: There is no data concerning liver resectability following mFOLFOX6 with bevacizumab as the first-line treatment of unresectable liver limited metastases from colorectal cancer by prospective, multi-center study in Japan. The Kyushu Study group of Clinical Cancer (KSCC) conducted a phase II trial in this setting.

Methods: Eligibility criteria included unresectable liver limited metastases from histologically confirmed advanced colorectal cancer, ECOG PS 0-1 and adequate general condition. Patients (pts) received 6 cycles of mFOLFOX6 (oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2 d1 followed by 400 mg/m2 bolus 5-FU and a 46-hr 2,400 mg/m2 5-FU infusion every 2 weeks) with bevacizumab (5mg/kg) followed by evaluating the liver resectability. (UMIN000001308)

Results: Of the 40 pts enrolled from Sept. 9 2008 to Aug. 10 2010; M/F, 29/11; Median age, 63 years (range 37-74); ECOG PS 0/1, 38/2. The median number of administration cycles was 6 (range, 1–7). Response for CR, PR, SD, PD and NE were 0 (0 %), 12 (30.0 %), 22 (55.0%), 3 (7.5%) and 3 (7.5%), respectively. An overall response rate was 30.0% (95% CI: 16.6 % – 46.5 %). The grade 3-4 adverse events were; leukopenia (10%), neutropenia (32.5%), febrile neutropenia (5%), fatigue (2.5%), appetite loss (2.5%), diarrhea (2.5%), mucositis (2.5%), high AST (2.5%) and ileus (2.5%). The number of cases to intent operation was 17 (42.5%), the liver resectability was 16/40 (40.0 %). The number of R0 cases was 10 pts (25.0%, 95% CI; 12.7 - 41.2 %).

Conclusions: mFOLFOX6 with bevacizumab regimen is safe and effective for unresectable liver limited metastases from colorectal cancer, and might be to lead the high liver resectability.
The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint.
Authors: Salazar Ramon , de Waard Jan Willem , Glimelius Bengt , Marshall John , Klaase Joost , Van Der Hoeven Jacobus , Capdevila Jaume , Bibeau Frédéric , Stork-Sloots Lisette , Rosenberg Robert
Published: February 2017

678

Background: An 18-gene expression profile, ColoPrint, has been developed for identifying CC patients more likely to develop recurrent disease and who would be candidates for adjuvant chemotherapy. The gene signature was validated in in-silico datasets and independent patient cohorts of stage II and III patients. Uni-and multivariate analysis was performed on the pooled stage II patient set (n=320) who had a median follow-up of 70 months. ColoPrint identified two-third of the stage II patients (209/320) as low risk. The 3-year relapse-free survival was 94% for Low Risk patients and 79% for High Risk patients with a HR of 2.74 (95% CI 1.54 - 4.88; p=0.006). Moreover, the profile stratified patients independent of ASCO clinical risk factors.

Methods: A prospective trial, PARSC (Prospective study for the Assessment of Recurrence risk in Stage II CC patients) using ColoPrint has been initiated. Objectives are: (1) to validate the performance of ColoPrint in estimating the 3-year relapse rate in patients with stage II colon cancer; (2) to compare the risk assessment in stage II patients using the ColoPrint profile vs. a clinical risk assessment based on Investigator’s assessment of risk and ASCO high-risk recommendations; (3) to investigate therapy as a potential confounding factor for ColoPrint results; and (4) to assess the performance of ColoPrint in estimating the 3-year relapse rate in patients with stage III colon cancer. Inclusion criteria: age ≥ 18 years, adenocarcinoma of the colon, stage II and III, no prior neo-adjuvant therapy, no synchronous tumors, fresh tumor sample, and written informed consent. The treatment of the patient is at the discretion of the physician adhering to National Comprehensive Cancer Network (NCCN)-approved regimens or a recognized alternative.

Results: The trial started in Sept. 2008 with currently 30 participating sites in 11 countries. Thus far, 288 eligible stage 2 and 251 stage 3 patients have been enrolled.

Conclusions: The aim is to enroll 575 stage II patients to differentiate between 3 year RFS predicted by ColoPrint and clinical factors.
Racial differences in the pattern of hematologic toxicity in the treatment of colorectal cancer.
Authors: Oluwole Olalekan O. , Wu William , Wolff Steven N. , Hande Kenneth R.
Published: February 2017

679

Background: 5-fluorouracil (5-FU), a synthetic fluoropyrimidine, is a critical component of chemotherapy in many cancers. Its metabolites inhibit Thymidylate Synthetase (TS) causing cessation of DNA synthesis and are misincorporated into DNA and RNA causing ineffective DNA repair and faulty mRNA splicing. The rate limiting step in the catabolism of 5-FU is by the Dihydropyrimidine Dehydrogenase enzyme (DPD) which catabolizes over 80% of 5-FU. Patients with near total DPD enzymatic deficiency develop life threatening toxicity after a single administration and those with less severe deficiency will have delayed elimination of 5-FU and slowly accumulate active metabolites leading to toxicities.

Methods: We conducted a pilot retrospective cohort study of African American (AA) and Caucasian patients treated for colorectal cancer over a 9 year period, 2000 – 2008, in this IRB approved study. The primary outcome of interest was the rate of development of grade 3 or 4 neutropenia (Absolute Neutrophil Count <1000/uL = grade 3 and <500/uL = grade 4). Descriptive and univariate analysis were done. To test for differences between AA and Caucasians, we computed independent t-test for continuous and Fisher’s exact test for categorical variables. Relative Risk (RR) and p-values were computed. All statistics were done with SPSS v19 software.

Results: There were 66 evaluable patients (40 men, 26 women), 40 AA, 24 Caucasians and 2 of other races. Thirty-eight patients (15 Caucasians and 23 AA) received 5-FU containing chemotherapy. The two groups were comparable in baseline characteristics. AA were more likely to develop grade 3-4 hematological toxicity. Nine of 23 AA (39.1%) and one of 15 Caucasians (6.7%) developed grade 3-4 hematological toxicity. RR 8.56, 95% confidence interval 0.95 – 421.06 (p-value of 0.0561)

Conclusions: These results suggest that AA were more likely than Caucasians to have severe hematologic toxicity with the use of 5-FU containing chemotherapy. This difference did not meet statistical significance due to small sample size and few numbers of events in the Caucasian arm. A larger prospective study is needed to further evaluate the observed difference.
Long-term survival outcome of E1201: An Eastern Cooperative Oncology Group (ECOG) randomized phase II trial of neoadjuvant preoperative paclitaxel/cisplatin/radiotherapy (RT) or irinotecan/cisplatin/RT in endoscopy with ultrasound (EUS) staged esophageal adenocarcinoma.
Authors: Kleinberg Lawrence , Catalano Paul J. , Forastiere Arlene A. , Keller Steven M. , Anne Pramila R. , Benson Al Bowen ,   Eastern Cooperative Oncology Group
Published: February 2017

69

Background: E1201 included operable esophageal adenocarcinoma, staged II-IVa by EUS and accrual ended Oct 2004. The primary endpoint was pathologic complete response (pCR), a surrogate endpoint generally associated with survival which did not meet criteria for further study of either arm. Long term survival results are now available. Stratification included clinical/EUS stage and ECOG performance status (PS).

Methods: 81 eligible patients (pts) began treatment. Arm A was cisplatin (C) 30mg/m2 and irinotecan (I) 50 mg/m2 on days (d) 1, 8, 22, 29 of 45 Gy RT/5 weeks. Post-op therapy was C 30 mg/m2 and I 65 mg/m2 d 1, 8 q21 days x 3. Arm B therapy was C 30 mg/m2 and paclitaxel (P) 50 mg/m2 1 hour infusion d 1, 8, 15, 22, 29 with RT. Postoperative therapy was C 75 mg/m2 and P 175 mg/m2 day 1 q21 days x 3.

Results: In Arm A, 26/39 have died. Median survival (S) is 35 m (months) and the 5, 6, and 7 year S was 46%, 39%, and 35%. In Arm B, 31/42 pts have died (one pt refused follow-up). Median S in arm B is 21 m. The 5, 6, and 7 year S was 27%, 27%, and 23%. Survival by EUS stage strata: For strata 1 (Stages T2N0M0 or T3N0M0), 14/20 have died. Median S is 37 m and 5 year S is 44%. In stage stratum 2 (Stages T1-3N1M0 or T1-3N0-1M1a), 43/61 have died. Median S is 24 m and 5 year S is 34%. For PS Strata: Patients with PS 0, had median S 35 m and 5 year S of 37% whereas for those with PS 1, the outcomes were 20m and 35%. Survival differences for the treatments and for these strata were not statistically significant.

Conclusions: Long term survival is similar for both treatment arms and does not appear superior to results achieved with 5FU based regimens. The prognostic importance of the pretreatment strata was not confirmed. These data, along with the reported pCR (15% arm A; 17% arm B) and toxicity data (> =grade 3 during chemo/RT 68% arm A; 65% arm B), may have importance in aiding in the design and interpretation of ongoing and planned phase II trials adding novel agents or treatment approaches to backbones built on variations of these two regimens.
FLOX regimen (5-FU, folinic acid, oxaliplatin) and FLIRI regimen (5-FU, folinic acid, irinotecan) as first-line treatment in metastatic and locally advanced gastric cancer: A randomized phase II study.
Authors: Glenjen Nils , Hammerling Katrin , Hatlevoll Ingunn , Småland Rune , Weber Hauge Petra , Eide Geir Egil , Sorbye Halfdan , Dahl Olav , Frykholm Gunilla
Published: February 2017

71

Background: The Norwegian Gastrointestinal Cancer Group (NGICG) conducted a phase II randomized study comparing the efficacy and safety of FLOX and FLIRI as first line treatment in metastatic or locally advanced gastric cancer. At progression or unacceptable drug related toxicity, a crossover to the other treatment arm should be done, if second line chemotherapy was indicated.

Methods: 66 patients from 6 treatment centers in Norway were randomized to FLOX (oxaliplatin 85 mg/m2 on day 1, bolus 5-FU 500 mg/m2 and FA 60 mg/m2 on day 1 and 2, or FLIRI (irinotecan 180 mg/m2 on day 1, bolus 5-FU 500 mg/m2 and FA 60 mg/m2 on day 1 and 2). Both treatments were repeated every second week. The primary endpoint was response rate (RR) and time to progression (TTP). Secondary endpoints were overall survival (OS) and safety data.

Results: At the present time data from 63 patients are available for analysis. First-line treatment: FLOX (n = 32) versus (v.) FLIRI (n = 31): Complete response (CR) n = 0 in both arms, partial response (PR) n = 16 v. 9, stable disease (SD) n = 12 v. 13, progressive disease (PD) n = 3 v. 6, not assessable for evaluation n = 1 v. 3 patients. RR was 50 % in the FLOX arm v. 29 % in the FLIRI arm, p = not significant (n.s), Pearson Chi-Square test. Median TTP was 5 months (95 % CI 2.2-7.8) v. 4 months (95 % CI 2.2-5.8), p = n.s, median OS was 11 months (95 % CI 9.2-12.8 ) v. 10 months (95 % CI 5.7-14.3), p = n.s, Log Rank test. Patient characteristics were well balanced. Febrile neutropenia was present among 10 % of the patients in the FLOX arm versus 7 % in the FLIRI arm. Second line treatment: 30 patients received second line treatment with FLOX or FLIRI. Data regarding RR, TTP, OS and safety will be updated in December 2011.

Conclusions: The FLOX and FLIRI regimens are well tolerated among patients with locally advanced and metastatic gastric cancer. As first line treatment the FLOX regime had a higher RR of 50% v. 29% for the FLIRI regime, longer TTP; 5 v. 4 months and longer OS 11 v. 10 months, but the difference did not reach statistical significance.
Adjuvant paclitaxel followed by oral fluoropyrimidines for gastric cancer: Safety data of the factorial phase III SAMIT trial.
Authors: Kobayashi Michiya , Tsuburaya Akira , Yoshida Kazuhiro , Yoshino Shigefumi , Miyashita Yumi , Morita Satoshi , Oba Koji , Buyse Marc E. , Macdonald John S. , Sakamoto Junichi
Published: February 2017

72

Background: Adjuvant chemotherapy with fluoropyrimidine (FP) with or without platinum for gastric cancer (GC) has become standard almost worldwide; however, there has been no comparison among concurrent, sequential, and monotherapy. Paclitaxel (PTX) is one of key drugs in GC widely used as 2nd-line chemotherapy in Japan.

Methods: SAMIT is a randomized, multicenter phase III study of FP (S1 or UFT) vs. PTX followed by FP in patients (pts) with gastric adenocarcinoma. Eligibility includes T3/T4, N0-2, M0 except for positive lavage cytology, chemotherapy- and radiotherapy- naive, being able to start chemotherapy 14 and 56 days after D2 gastrectomy. Pts received either UFT 267 mg/m2/day for 4w, q4w x 6 cycles (arm A); S1 80 mg/m2/day for 2w, q3w x 8 cycles (arm B); PTX 80 mg/m2 Day 1, 8 for the first 3w x 1 cycle, Day 1, 8, 15 q4w x 2 cycles, followed by UFT 267 mg/m2/day for 4w, q4w x 3 cycles (arm C); or PTX as in C, followed by S1 80 mg/m2/day for 2w, q3w x 4 cycles (arm D). The FP cycles was prolonged by 24w after ACTS-GC publication in 2007. Primary endpoint is disease-free survival and total number of patients was calculated to be1480 where 90% power for superiority of C+D group vs. A+B. The Independent Data Monitoring Committee undertook a review of the 1417 pts at the 2nd interim analysis in 2011.

Results: Arm A (n=353), arm B (n=359), arm C (n=352), arm D (n=353) were well balanced for baseline factors. The compliance with UFT in arm A and S1 in B was 74% and 76% in the first 12 weeks, and 89% and 90% between week 37 and 48; that in arm C and D was 83% and 80% in the second 12 weeks, and 94% and 84% between week 37 and 48. Numbers of grade 3/4 hematological and non-hematological adverse events (AEs) were 3 and 46, 0 and 64, 5 and 35, and 16 and 67 for arm A, B, C, and D, respectively. Anorexia was the most common AE observed in 5.8%, 6.8%, 1.7%, and 5.1% for arm A, B, C, and D, respectively. There were 363/1323 (27%) deaths and 762/1323 (58%) of pts survived disease free.

Conclusions: Adjuvant chemotherapy with sequential PTX and FP for GC was safe and the compliance of the FP part could be better than that of FP monotherapy. The final efficacy results will be formally assessed in 2012.
Seventh edition (2010) of gastric adenocarcinoma AJCC staging system: Is there room for improvement?
Authors: Patel Manali I. , Rhoads Kim F , Ma Yifei , Ford James M. , Norton Jeffrey A. , Poultsides George A.
Published: February 2017

77

Background: The gastric cancer AJCC staging system recently underwent significant modifications of the T and N categories as well as stage groupings. The new system has not been validated on a US population database, but studies on Asian patients have reported no difference in survival between stages IB and IIA, as well as IIB and IIIA.

Methods: California Cancer Registry data linked to Office of Statewide Health Planning and Development discharge abstracts were used to identify patients with gastric adenocarcinoma (gastroesophageal junction tumors excluded) who underwent curative-intent surgical resection from 2002 to 2006. AJCC stage was reclassified based on the 7th edition. Disease-specific survival (DSS) probabilities were calculated using the Kaplan-Meier method and compared using the log rank test.

Results: Of 4,985 patients identified, 2,262 had complete pathologic data and known cause of death. Median age was 70 years and 60% were males. Median number of examined lymph nodes was 12 and 39% of patients received adjuvant chemotherapy. The 7th edition AJCC system did not distinguish outcome adequately between stages IB and IIA (P = .25), or IIB and IIIA (P = .33, Table ). By merging stage II into one category and moving T2N1 to stage IB and T2N2, T1N3 to stage IIIA, we propose a new grouping system which showed improved discriminatory ability ( Table ).

Conclusions: In this first study validating the new 7th edition AJCC staging system for gastric cancer on a US population, we found stages IB and IIA, as well as IIB and IIIA to perform similarly. We propose a revised stage grouping for the AJCC system that better discriminates between outcomes.

[Table: see text]
Prognostic significance of isolated tumor cells in regional lymph nodes in patients with T2-T3 stage gastric cancer.
Authors: Jin Sung-Ho , Cho Soo-Youn , Lee Kyu-Jae , Park Sunhoo , Yu Hang-Jong , Bang Ho-Yoon , Lee Jong-Inn
Published: February 2017

8

Background: The prognostic impact of isolated tumor cells (ITCs) in regional lymph nodes is unclear. This study was aimed to evaluate the prognostic significance of ITCs in subpopulation with T2-T3 gastric cancer by adopting the standard definition for ITC (≤ 0.2 mm, detected by H&E or IHC) and micrometastsis (≤ 2 mm, detected by H&E or IHC) in 7th AJCC staging.

Methods: A total of three hundred eleven patients diagnosed as pT2-3/N0-2/M0 gastric carcinoma after curative surgery at Korea Cancer Center Hospital between January 1996 and December 2000 was retrospectively studied. All tumor and lymph node specimens by H&E received reexaminations, and 5,825 lymph nodes from 191 patients without macrometastasis (> 2.0 mm) were re-evaluated after IHC staining with anti-cytokeratin (AE1/AE3). And N stage was reclassified into pN0(i-), pN0(i+), pN1mi, pN1, and pN2. Survival analyses were performed using Kaplan-Meier method with Log-rank test and Cox regression model.

Results: According to original N stage, 5-year overall survival rates were estimated as 80.5% in N0, 79.3% in N1, 68.8% in N2 without statistical difference between N0 and N1 (p=0.790). Whereas according to reclassified pN stage, survival rates were estimated as 92.3% in pN0(i-), 75.5% in pN0(i+), 84.4% in pN1mi, 76.1% in pN1, and 69.0% in pN2, and significant difference was found between pN0(i-) and pN0(i+) (p=0.034). In the multivariate Cox model with backward conditional method, reclassified pN stage was remained as an independent prognostic factor along with age and tumor location while excluding original N stage, and the hazard ratio (95% CI) of pN0(i+) compared to pN0(i-) was 3.60 (1.08-12.00).

Conclusions: The result demonstrates that ITCs in regional lymph nodes is a bad prognostic factor, even after adjusting for other prognostic factors. So we suggest that ITCs should be classified separately from the N0 in gastric cancer staging.
A phase II study of preoperative docetaxel, cisplatin, and capecitabine in patients with gastric carcinoma.
Authors: Voon Pei-Jye , Soe Mu-Yar , Zee Ying Kiat , Chuah Benjamin , Lim Robert S. C. , Shabbir Asim , So Jimmy , Yong Wei-Peng
Published: February 2017

89

Background: Perioperative chemotherapy has been shown to improve outcomes among patients with locally advanced gastric adenocarcinoma. As docetaxel (D), cisplatin (C), and capecitabine (X) are active agents in gastric adenocarcinoma, we conducted a phase II trial to assess the efficacy and tolerability of preoperative DCX in patients with gastric adenocarcinoma.

Methods: We enrolled patients with locally advanced gastric adenocarcinoma (clinical T3/4 or N positive) to preoperative DCX repeated every 21 days for three cycles, followed by surgery. The first cohort of 10 patients received docetaxel 35 mg/m2, cisplatin 35mg/m2 on days 1 and 8, with capecitabine 750 mg/m2 twice daily from day 1 to day 14. A subsequent cohort of another 11 patients had dose modifications for docetaxel and cisplatin, both to 30mg/ m2 on days 1 and 8.

Results: Twenty-one patients were recruited. Median age was 61 years. Seventy-one percent of patients completed a total of 3 cycles of planned chemotherapy. Fourteen patients have successfully undergone surgery. R0 resection rate was 88%. Pathological complete response (pCR) and near complete response (pnCR) were both 17%. Preoperative radiological assessment showed a partial response rate of 65% after 2 cycles of treatment. Good pathological response (pCR and pnCR) was associated with better event-free survival (26 months vs 12 months, p=0.031). Common grade 3/4 toxicities were diarrhea (38%), neutropenia (30%), stomatitis (14%) and hypokalemia (14%). However, the diarrhea rate was reduced to 15% with dose modifications as mentioned above after 50% of the first cohort of 10 patients developed grade 3/4 diarrhea during the first cycle of chemotherapy. Febrile neutropenia rate was 14%. There was one treatment related death before surgery but no postoperative mortality.

Conclusions: Preoperative DCX is highly active with modest toxicity in locally advanced gastric adenocarcinoma. DCX represents an attractive alternative regimen without the need for protracted infusional drug in perioperative chemotherapy for patients with locally advanced gastric adenocarcinoma. Good pathological response is associated with better outcome.
Cetuximab plus chemotherapy in patients with liver-limited or non-liver-limited KRAS wild-type colorectal metastases: A pooled analysis of the CRYSTAL and OPUS studies.
Authors: Kohne Claus-Henning , Bokemeyer Carsten , Sartorius Ute , Schlichting Michael , Rougier Philippe , Van Cutsem Eric
Published: February 2017

96

Background: In the CRYSTAL and OPUS studies, adding cetuximab (cet) to first-line chemotherapy (CT) improved clinical benefit in patients (pts) with KRAS wild-type (wt) metastatic colorectal cancer. In a pooled analysis of these trials the benefit of treatment according to whether pts had liver-limited disease (LLD) or non-LLD was investigated.

Methods: Cox‘s proportional hazards model for overall survival (OS) and progression-free survival (PFS) or logistic regression model for objective response rates (ORR) and R0 resection were used on individual pt data, stratified by study. Likelihood ratio tests were used to statistically explore interactions.

Results: Adding cet to CT significantly improved PFS and ORR in LLD pts, and OS, PFS and ORR in non-LLD pts ( table ), and increased R0 resection rates: LLD 11.8% vs 5.3%, odds ratio=2.38, p=0.11 and non-LLD, 3.3% vs 1.7%, odds ratio=1.97, p=0.19. No treatment-by-study interactions were noted. Treatment effects did not vary significantly by LLD status (PFS, p=0.60, OS, p=0.68, ORR p=0.074). However LLD vs non-LLD pts had improved outcome in each treatment arm: PFS, CT HR=0.74, p=0.091; CT + cet HR=0.66, p=0.031; OS, CT HR=0.70, p=0.009; CT + cet HR=0.74, p=0.039; ORR, CT odds ratio=1.20, p=0.47, CT + cet odds ratio=2.32, p=0.002; R0 resection, CT odds ratio=3.15, p=0.050, CT + cet odds ratio=3.82, p=0.0018.

Conclusions: The OS benefit from adding cet to CT is mainly seen in pts with non-LLD, thus strengthening the value of cet in palliative treatment. LLD status appears to be predictive for response in pts receiving CT + cet, facilitating potential resection. A larger number of pts (with R0 resection and longer follow-up) may be needed to confirm an OS benefit from CT + cet in LLD pts.

[Table: see text]
Results of a comparison between European countries for esophagectomy and gastrectomy: Initiative for a European upper GI audit (EURECCA Upper GI).
Authors: Van De Velde Cornelis J. H. , Dikken Johan L. , Wouters Michel W. , Putter Hein , Lemmens Valery E. P. , Verheij Marcel , Cats Annemieke , Johansson Jan , Jensen Lone S. , Allum William H. , Coupland Victoria , van Sandick Johanna W.
Published: February 2017

98

Background: In Europe, several countries have implemented national audit programs to reduce variation in outcomes and improve care for esophageal and gastric cancer. These audits provide insight in national variations, but currently no international comparisons can be made. Purposes of the current study were to compare patterns of care and outcomes in several European countries, and to evaluate the effect of hospital volume on outcomes for esophagectomy and gastrectomy.

Methods: Data were obtained from national cancer registries or audits in the Netherlands, Sweden, Denmark, and the United Kingdom. Differences in postoperative 30-day mortality and 2-year survival were adjusted for available case-mix variables and separately analyzed for esophagectomy and gastrectomy, using generalized estimated equations and Cox regression. In the current study, high-volume hospitals were defined as hospitals with an annual volume of > 20.

Results: From 2004-2009, 10,854 esophagectomies and 9,010 gastrectomies were performed in the participating countries. Availability of case-mix variables varied between countries, and a limited number of variables could be used in the international comparison. On univariate analysis, 30-day mortality and 2 year survival differed significantly between participating countries, but on multivariate analysis, no significant differences were found. The percentage of resections performed in high-volume hospitals varied considerably between countries (esophagectomy: 20% to 94%, gastrectomy: 0% to 59%). Increasing annual hospital volume was associated with lower 30-day mortality after esophagectomy (P < 0.001) and gastrectomy (P = 0.025), and with improved 2-year survival after esophagectomy (P = 0.004), but not after gastrectomy.

Conclusions: This study provides an initial step towards a European Upper GI Cancer Audit. However, with the available data only limited case-mix adjustments could be made. Future steps would include synchronization of registered variables and the use of uniform variable definitions. Increasing annual hospital volume is associated with improved short-term outcomes of upper GI cancer surgery.
Value of multimodality MRI and MR-guided biopsy at inclusion in an active surveillance protocol for prostate cancer.
Authors: Somford Diederik Meindert , Hoeks Caroline M. , van den Bergh Roderick C. , Vergunst Henk , van Oort Inge M , Smits Geert A. , Oddens Jorg R. , Hulsbergen - van de Kaa Christina A , Bangma Chris H. , Witjes J. Alfred , Barentsz Jelle O.
Published: February 2017

105

Background: To prevent overtreatment of insignificant and/or low-risk prostate carcinoma in the PSA screening era, active surveillance is emerging as a treatment strategy for selected patients. In our series we aim to establish whether MRI could aid in correct risk assessment for these patients within the framework of the Prostate Cancer Research International Active Surveillance (PRIAS) study.

Methods: We included patients in our protocol based on contemporary criteria for active surveillance: - Diagnosis of prostate cancer by TRUS-guided biopsy. - PSA ≤10 ng/mL, PSA density <0.2 ng/mL/mL - Clinical stage ≤ T2 - Gleason score (GS) ≤3+3=6 - ≤ 2 biopsy cores with cancer All patients underwent multimodality MRI of the prostate, including T2-weighted, diffusion-weighted and dynamic contrast-enhanced MR sequences. When a tumor-suspicious region (TSR) could be identified a targeted MR-guided biopsy (MRGB) was performed to obtain pathology. Patients were referred for definitive treatment in case of GS > 3+3=6 upon MRGB or T3 stage at MRI.

Results: In 48 of 49 included patients at least one TSR was identified, with a median of 2 TSRs (range1-4) per patient. MRGB was obtained from every TSR, with a median of 4 MRGBs taken per patient. Five patients had a GS >3+3=6 upon MRGB and were excluded. Three patients were excluded due to suspicion of T3 stage on MRI. Five patient were excluded upon physician’s discretion due to multifocal prostate cancer upon MRGB. Combined multimodality MRI/MRGB in our active surveillance cohort thus excluded 27% (13/49) of patients who were incorrectly stratified as low-risk prostate carcinoma by contemporary criteria.

Conclusions: Application of multimodality MRI and MRGB in an active surveillance protocol improves risk stratification, adding onto contemporary PSA and TRUS-guided biopsy criteria for low-risk prostate cancer. This approach might increase safety and reliability of active surveillance for prostate cancer and deserves ongoing prospective evaluation.
Comparing long-term toxicity between external beam radiotherapy modalities: A SEER/Medicare database study.
Authors: Reddy Chandana A. , Ciezki Jay P. , Abdel-Wahab May , Angermeier Kenneth , Ulchaker James , Stephans Kevin L. , Tendulkar Rahul D. , Altman Andrew , Chehade Nabil , Klein Eric A.
Published: February 2017

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Background: The use of intensity modulated radiotherapy (IMRT) for the treatment of prostate cancer (CaP) has been widely promoted due to the hypothesized benefit of low late toxicity.

Methods: The SEER-Medicare database was queried for CaP patients treated with external beam radiotherapy (EBRT), 1991-2007. CPT billing codes were used to identify patients treated with IMRT or standard EBRT (sEBRT), which was comprised of conformal radiotherapy or a four-field technique. Patients without a treatment billing code were excluded from the analysis. Information on dose is unavailable. CPT codes were also used to identify procedures associated with gastrointestinal (GI) or genitourinary (GU) toxicity related treatments. Cumulative incidence rates for GI and GU toxicity were calculated with death treated as a competing event.

Results: A total of 137,427 patients who were 65 years or older at the time of CaP diagnosis and who had CaP as their only cancer diagnosis were retrieved from the SEER-Medicare database: 60,806 were treated with EBRT and a treatment billing code was identified for 35,388 patients. No patient received combined therapy. Seventeen percent of patients received IMRT. The median follow-up for patients receiving IMRT is 40 months (mo) (range 2-157) vs 77 mo (range 0-203) for patients receiving sEBRT. Overall, 3,699 (10%) patients experienced a toxicity requiring an intervention. The five year rate of GI The gastrointestinal (GI) and genitourinary (GU) toxicity comparisons are listed in the table. For both endpoints, rate of toxicity at five years was higher for the IMRT group. The most common GU toxicity for both groups was dilation of a urethral stricture (3.8% of all sEBRT patients vs 3.4 of all IMRT patients). Cauterization of rectal bleeding was the most common GI toxicity (2.4% of all sEBRT patients vs 1.6 of all IMRT patients).

Conclusions: While the rates of GI toxicity between IMRT and sEBRT are comparable, of concern is the higher rate of GU toxicity for the IMRT patients despite this group having a shorter follow up than the sEBRT group.

[Table: see text]
Role of homeobox pathway in prostate carcinogenesis.
Authors: Chen James Lin , Otto Kristen , Vander Griend Donald
Published: February 2017

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Background: Identifying aberrant activity of developmental pathways in prostate cancer provides therapeutic opportunities. To this end, despite a shared embryonic origin and similarities to prostate cancer in histology and androgen dependence, seminal vesicle cancer is exceptionally rare. Genomic pathway analyses of their critical developmental differences may reveal uncharacterized oncogenic pathways. Previous attempts to do so have used whole tissue preparations. We hypothesized that careful gene profiling of pure primary epithelial cultures from normal prostate and seminal vesicles would reduce confounding noise during analysis and provide more robust pathway prioritization.

Methods: Paired normal prostate and seminal vesicle epithelium cultures were created from three de-identified patients. Derived gene expression profiles were grouped into cancer biomodules using a protein-protein network algorithm to analyze their relationship to known oncogenes. Each resultant biomodule was assayed for its prognostic ability in independent Kaplan-Meier analyses of prostate cancer patients for time to recurrence and overall survival. Protein products from prioritized biomodule genes were then evaluated in vitro.

Results: Gene expression profiling and protein network prioritization resulted in three cancer biomodules. Survival analysis revealed that the embryonic developmental biomodule centered on homeobox genes Meis1, Meis2 and Pbx1 to have clinical import. This homeobox biomodule detected a survival difference in a set of active surveillance patients (n=172, p=0.05) and identified men who were more likely to recur biochemically post-prostatectomy (n=78, p=0.02). We analyzed in vitro protein expression of Meis1, Meis2, Pbx1 and confirmed decreased gene expression in independent datasets of prostate cancer versus normal tissue.

Conclusions: The Meis1/Meis2/Pbx1 biomodule may explain key differences in seminal vesicle and normal prostate epithelium development. In contrast to other cancers, Meis1, Meis2, and Pbx1 may play a tumor suppressor role in prostate cancer. Thus deregulation of this biomodule may be critical in prostate cancer oncogenesis.
Overcoming chemotherapy resistance in patients (pts) with chemotherapy-failure, castration-resistant prostate cancer (CRPC) with sorafenib.
Authors: Nabhan Chadi , Cygan Peter Hubert , Meyer Andrew , Tolzien Kathy , Galvez Angel G. , Lestingi Timothy M. , Bitran Jacob D.
Published: February 2017

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Background: SOR is an oral multi kinase inhibitor that promotes apoptosis through downstream pathways that can be deregulated in CRPC leading to chemotherapy resistance. We hypothesized that SOR Could overcome chemotherapy resistance in non-responders or in those who progress shortly after stopping chemotherapy.

Methods: Eligible pts were those who progressed while receiving chemotherapy [docetaxel (D) or mitoxantrone (M)] or within 12 weeks from stopping it. Pts were then continued or resumed on their last chemotherapy with the addition of SOR at 400 mg PO BID. Pts were allowed a maximum of 6 cycles of chemotherapy +SOR followed by SOR as monotherapy until progression. Primary end point: Safety of SOR+ chemotherapy. Secondary end points: Toxicity, time to progression (TTP). And responses (biochemical and radiographic)

Results: Twenty-two pts were enrolled; 21 evaluable (73% Gleason ≥ 7). Median age was 68 (59-83). Median PSA was 142 ng/dl (13.6-9,584). Median time from last chemotherapy to SOR was 4 weeks. Visceral and bone disease was present in 64%. D was given in 16 pts while M in 6. Ten pts (45%) showed biochemical response (18% with >50% PSA decline). Despite progression before being on study, 16 pts (76%) achieved SD after starting SOR for a median duration of 6 months (4-12). The combination of SOR with either chemotherapy agent proved safe. Main grade 3/4 non-hematologic toxicities: Fatigue 7 (32%), 4 (18%) hand/foot syndrome, hypocalcemia and hyperglycemia in 2 pts (9%) each. Grade 3/4 leukopenia was seen in 7 (31%), neutropenia in 6 (27%), and thrombocytopenia in 2 (9%). Dose reduction of SOR occurred at least once in 15 pts (68%). Major reasons are hand/foot syndrome (22%), fatigue (22%), rash (13%), and neutropenia (9%). With a median follow-up of 19 months (3-46), 5 pts (23%) remain alive for a median OS of 8 months. TTP by PSA was 3 months (2-6) and TTP by imaging and/or clinically was 6 months (2-12). Median number of treatment cycles given was 6 (1-10).

Conclusions: SOR can safely be combined with chemotherapy. SOR overcomes chemotherapy-resistance and shows biochemical and radiographic stability in this refractory pt population.
Effect of neoadjuvant docetaxel treatment for locally advanced prostate cancer on miRNA expression: A pilot study.
Authors: Falzarano Sara Moscovita , Zhou Ming , Carver Paula , Klein Eric A. , Dreicer Robert , Magi-Galluzzi Cristina
Published: February 2017

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Background: Taxanes are microtubule-stabilizing drugs used investigationally in adjuvant and neoadjuvant settings of prostate cancer (PCA) treatment in an attempt to improve systemic control of high risk disease. Understanding mechanism of response to taxanes is an essential step in developing novel combination therapies to improve PCA response rates. MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression by binding target messenger RNAs and inhibiting their stability and/or translation. In cancer miRNAs can act as oncogenes and/or tumor suppressor genes. The objective of our study was to identify miRNAs that are affected by neoadjuvant docetaxel in high-risk PCA.

Methods: Whole cell RNA was extracted from formalin-fixed paraffin-embedded (FFPE) radical prostatectomy specimens from 8 patients with high grade PCA treated with neoadjuvant docetaxel, 8 high grade untreated PCA and their corresponding untreated non-neoplastic tissue. Tumors were matched by Gleason score, patient age and year of surgery. The expression of 88 cancer-associated miRNAs was then quantified using a PCR-based miRNA microarray assay.

Results: Thirty-eight (43%) of the 88 analyzed miRNAs (including miR-205, miR-222, and miR-1) were sgnificantly downregulated in untreated PCA compared with untreated non-neoplastic tissue, and one (miR-183) was upregulated. Twenty (23%) miRNAs (including miR-218, miR-124, and let-7b) were significantly upregulated in treated compared to untreated PCA. The expression levels of 16 of these miRNAs (including miR-9, miR-133b, and miR-27b) were reverted to values similar to untreated non-neoplastic prostatic tissue, as a result of docetaxel treatment.

Conclusions: Our results indicate a potential role of miRNAs in PCA response to taxanes. A subset of miRNAs are downregulated in untreated tumors but upregulated in treated PCA to the levels compared to untreated non-neoplastic tissue, suggesting a miRNA modulation towards a non-neoplastic expression profile with neoadjuvant docetaxel treatment. Further studies are underway to evaluate the miRNA-mediated effects of taxanes in PCA.
Phase I study of imatinib mesylate (IM) and sorafenib (S) in patients (pts) with refractory castration-resistant prostate cancer (CRPC).
Authors: Nabhan Chadi , Villines Dana , Valdez Tina V. , Tolzien Kathy , Lestingi Timothy M. , Bitran Jacob D. , Susan Christner M. , Egorin Merrill J. , Beumer Jan H.
Published: February 2017

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Background: IM is an inhibitor of protein-tyrosine kinases including those that are over-expressed in bone metastases and primary prostatic adenocarcinoma. S is a potent inhibitor of wild-type and mutant BRAF, C-RAF, VEGFR2, VEGFR3, FLT3, and PDGFR-beta with modest activity in CRPC. We combined IM+S to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) in CRPC pts.

Methods: CRPC pts with measurable disease and adequate organ function who failed chemotherapy were eligible. Dose escalation followed a 3+3 study design. Toxicity was scored following CTCAEv3. Responses were defined by RECIST1.0. IM pharmacokinetics (PK) were determined on day 15, 4 h post-dose with a validated LC-MS assay.

Results: Seventeen pts were enrolled; 10 were evaluable. At dose level 0 (DL0), 6 pts received S at 400 mg S with 300 mg of IM both given daily. At DL1, 4 pts received 400 mg S twice/day with 300 mg IM daily; inevaluable pts received <1 cycle (5 withdrew consent, 1 rapid early progression, 1 non-compliant). Median age was 73 (57-89) and median PSA was 284 ng/ml (11.7–9027). Median number of prior non-hormonal therapies was 3 (1–12) and 12 pts had Gleason score ≥7 while 15 pts had bone as the major site of metastases. On DL0, 1/6 pts had DLT (gr 3 hand/foot). On DL1, 2/4 pts had DLT (1 gr 3 hand/foot, 1 gr 3 diarrhea). MTD was 300 mg IM and 400 mg S both qd. No biochemical responses were observed. Two pts on DL1 had stable disease radiographically by RECIST (overall clinical benefit for the entire cohort 20%). Median time to progression was 2 months (1-5) while median OS was 6 months (1-30+) with 3/17 patients (17%) remaining alive at a median follow-up of 21 months. Of patients enrolled, 10 had PK data, which suggested that S reduced IM clearance by 40%, resulting in 60% increased exposure (P = 0.009; two-tailed t-test on log-transformed values, compared to historic data).

Conclusions: To our knowledge, this is the first report to show that IM+S can be safely combined in CRPC. The phase II recommended dose for future trials is 300 mg IM and 400 mg S, both given daily. The PK interaction might be of questionable clinical relevance because IM concentrations are within the commonly observed range.
Differences in prostate cancer survival between Denmark, Iceland, and Sweden: A high-resolution study.
Authors: Ingimarsdottir Inga Jona
Published: February 2017

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Background: Register-based studies have demonstrated large differences in relative survival and excess mortality following the diagnosis of PC in the Nordic countries. These differences may reflect differences in patient characteristics, diagnostics (PSA-use) and treatment strategies. This high-resolution study explores the background for the differences in PC survival between Denmark, Iceland and Sweden.

Methods: Patients with newly diagnosed PC in 1997 were identified through population-based national cancer registers in Denmark and Iceland. Information on clinical findings was retrieved by reviewing hospital files. In Sweden information was gathered from two regional population-based prostate cancer registers providing both time of diagnosis and clinical information. Country specific excess mortality rates were compared adjusting for available information on known prognostic factors.

Results: The overall relative survival in the cohorts was comparable to population-based results previously published. Across countries significant differences in excess mortality rates were seen. These differences were largely explained by differences in patient characteristics at diagnosis, and when adjusting for differences in patient characteristics i.e. metastatic / non-metastatic disease, clinical T-stage, and PSA level at diagnosis, the differences in excess mortality diminished or disappeared. The difference in percentage of patients with metastatic disease at diagnosis was the one factor responsible for the major differences in mortality-rates across countries.

Conclusions: Register-based studies on relative survival and excess mortality following a PC diagnosis may be influenced by national differences in clinical presentation at diagnosis. Differences between countries in the proportion of patients with metastatic spread at diagnosis apparently explains most of the difference in relative survival previously reported. Further studies and cross country comparisons of survival and excess mortality for PC should adjust for differences in patient characteristics, mainly TNM.