bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of survival for left-sided KRASwt mCRC patients treated with anti-EGFR based therapy as compared to right-sided mCRC.
Authors: Petruzelka Lubos B. , Obermannova Radka , Hejduk Karel , Ostrizkova Lenka , Zdrazilova-Dubska Lenka , Brancikova Dagmar , Bencsikova Beatrix , Vyzula Rostislav , Vocka Michal
Published: March 2017

763

Background: Anti-EGFR-antibody-based treatment is a standard of care in patients with RASwt metastatic colorectal cancer (mCRC). Right-sided mCRC is associated with frequent presence of KRAS mutation and with worse prognosis. Here we show the clinical outcome of 1st, 2nd, and 3rd-line anti-EGFR therapy in KRASwt mCRC patients in the context of primary tumor location. Methods: Data from 3 national comprehensive cancer centers in the Czech Republic were collected prospectively from 01/2009 to 03/2016. A retrospective analysis of outcomes of 567 pts with KRASwt mCRC treated with anti-EGFR was performed. Right-sided colon was defined as coecum, ascending colon and transverse; while left-sided contains the splenic flexure, descending and sigmoid colon. The group of metastatic rectal cancer was analyzed separately. The primary objective was assessment of OS and PFS in 1st, 2nd, and 3rd-line treatment of mCRC. OS and PFS were calculated using the Kaplan-Meier method and statistical significance was assessed using the log-rank test. Results: Right-sided tumor location was in 125 pts (22.0%), left-sided in 231 (40.7%) and rectal in 211 (37.2%). Median OS and PFS in months with 95% CI and log-rank test p-value are shown in a table. Conclusions: KRASwt mCRC patients with primary tumor in left-sided colon and rectum have comparable clinical outcome when treated with anti-EGFR-based therapy. In metastatic disease, primary right-sided KRASwt carcinoma is associated with short PFS and OS across all anti-EGFR-based treatment lines. The work was partially supported by Czech Ministry of Helth project no. 16-31966A and Technology Agency of the Czech Republic no. TA04010838. [Table: see text]
Immunotherapy using activated T cells with chemotherapy for metastatic colorectal cancer.
Authors: Yoshida Yoichiro , Aisu Naoya , Nagano Hideki , Komono Akira , Kojima Daibo , Mera Toshiyuki , Tanaka Toshihiro , Naitoh Keiko , Yasumoto Kosei , Kamigaki Takashi , Goto Shigenori , Hasegawa Suguru
Published: March 2017

767

Background: The programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, is demonstrated to induce an immune-mediated response and play a critical role in tumor initiation and development. T cell activation induces effective antitumor immune response in cancer patients. Adoptive immunotherapy of cancer is evolving with the development of novel technologies that generate proliferation of large number of T cells. We evaluated the safety and efficacy of the combination of adoptive immunotherapy using αβ T cells with chemotherapy for metastatic colorectal cancer (mCRC). Methods: Seventeen patients with mCRC received XELOX + bevacizumab + ex vivo expanded αβ T lymphocytes as a first-line chemoimmunotherapy. Results: Median age of the 17 patients (6 men, 11 women) was 64 years (range:38–80). The T cell number was more than 5.0×109 for each infusion. Median progression-free survival was 15.2 months. Response rate was 80% (complete response (CR) = 23.5%, partial response (PR) = 47.1%, stable disease (SD) = 29.4% and progressive disease (PD) = 0%). Most adverse events were mild to moderate in intensity and immunotherapy-associated toxicity was minimal. Conclusions: Combination of adoptive αβ T cell immunotherapy with chemotherapy for mCRC is safe and effective.
A phase I/II study for panitumumab combined with TAS-102 in patients with RAS wild-type metastatic colorectal cancer (APOLLON study): Phase I results.
Authors: Kato Takeshi , Kagawa Yoshinori , Komatsu Yoshito , Oki Eiji , Yoshino Takayuki , Yamazaki Kentaro , Yasui Hirofumi , Satake Hironaga , Shibuya Kazunori , Oba Koji , Yamaguchi Kensei
Published: March 2017

770

Background: Both panitumumab (Pmab), the anti-EGFR antibody and TAS-102, the combination drug of trifluridine and tipiracil are approved agents for the treatment of metastatic colorectal cancer (mCRC). In preclinical models, the combination of Pmab with TAS-102 demonstrated enhanced activities compared with either drug alone. This phase I/II study is designed to investigate the safety and efficacy of Pmab combined with TAS-102 in patients (pts) with RAS ( KRAS/NRAS) wild-type mCRC refractory to standard chemotherapies. Here we reported the results of phase I part. Methods: Eligible pts are aged 20-74 y, ECOG performance status (PS) 0-1 with confirmed RAS wild-type mCRC, and refractory or intolerant to fluoropyrimidines, irinotecan, oxaliplatin and anti-angiogenesis therapy, and had no prior treatment with anti-EGFR antibody, TAS-102 or regorafenib. Phase I part is designed to evaluate the incidence of dose limiting toxicities (DLTs) during the first course and to determine recommended phase II dose (RP2D) in the dose de-escalation design (3 + 3 manner) of Pmab (6 mg/kg on days 1 and 15, every 4 weeks per course) combined with TAS-102 (35 mg/m2 BID on days 1-5 and 8-12, every 4 weeks). DLTs were defined as drug-related adverse events (AEs) as follows; febrile neutropenia, G4 neutropenia > 7days, G4 thrombocytopenia, inability to start the 2nd course more than 14 days delay, and G3/4 non-hematological toxicities. Results: Seven pts (3 male, 4 female) with a median age of 68 (range 57-71) were enrolled. Pts were ECOG PS 0 (3/7) or 1 (4/7) with primary tumor located in the colon (3/7) or rectum (4/7). One pt was excluded for the DLT evaluation due to protocol deviation. No DLT was observed in the 6 DLT-evaluable pts. Most frequent drug-related AEs during the DLT evaluation period were G2/3 neutropenia, G1/2 stomatitis, G1 nausea, G1 anorexia and G1/2 rash. Three pts achieved a partial response, and 3 pts had a stable disease. Conclusions: The RP2D for Pmab combined with TAS-102 was determined as the standard dose of Pmab and TAS-102. The enrollment of phase II part is ongoing to evaluate the PFS rate at 6 months by investigator assessment as a primary endpoint with the target number of 46 pts. Clinical trial information: 02613221.
Does primary site of colorectal cancer become a prognostic factor of patients undergoing curative resection of liver metastases?
Authors: Kizawa Rika , Ichikawa Yasushi , Kumamoto Fumitaka , Sawada Yu , Matsuyama Ryusei , Kobayashi Noritoshi , Goto Ayumu , Tokuhisa Motohiko , Ishibe Atsushi , Momiyama Masashi , Suwa Yusuke , Hiroshima Yukihiko , Matsuo Kenichi , Ota Mitsuyoshi , Akiyama Hirotoshi , Yamanaka Takeharu , Tanaka Kuniya , Endo Itaru
Published: March 2017

772

Background: The comparison of prognosis between right and left-sided colon cancer (RC, LC) has recently attracted a lot of attention. We examined whether primary location of colo-rectal cancer represents a prognostic factor of patients received curative resection of liver metastasis. Methods: We reviewed all patients undergoing resection of liver metastasis of colo-rectal cancer from1992 to 2013 in the 2 YCU hospitals, and selected eligible 377 patients (59 [15.6 %] with RC, 318 [84.4 %] with LC) undergoing R0 or 1 resection of primary and metastatic lesions. Patients with transverse colon cancer were excluded. We stratified patients according to previously-reported prognostic factors of hepatic metastasis resection, and conducted univariate analysis by Log Rank test to compared overall survival (OS) in each stratum. Using those results, independent factors affecting OS were determined by multivariable Cox regression. Results: The median OS of 377 patients was 66 months, and disease free survival (DFS) was 11.6 months. Univariate analysis revealed that the number and maximum diameter of liver metastasis, existence of other metastasis apart from liver, CEA, and having pre- or post- operative chemotherapy showed significant difference of OS. Primary site did not show significant difference of OS (p = 0.547), but median OS of LC (67 months) was 24 months longer than of RC. As for DFS, there was no significant difference between RC and LC (10.75 vs. 11.6 months, p = 0.873). Multivariate Cox regression analysis was conducted using former factors showing significant difference and primary site. Then primary site was an independent prognostic factor (p = 0.047). LC showed a lower risk than RC (HR: 0.675). Conclusions: The primary site did not affect DFS, but could become a prognostic factor of OS with patients undergoing curative resection of liver metastases. It suggested that curative resection of liver metastases could contribute to prolong survival, regardless of RC or LC. And there is some possibility that the primary site affects prognosis after post-operative recurrence of colo-rectal cancer liver metastases.
Treatment strategy for colorectal liver metastases: Clinical impact of FOLFOXIRI regimen for unresectable cases.
Authors: Morine Yuji , Shimada Mitsuo , Imura Satoru , Ikemoto Tetsuya , Iwahashi Shuichi , Saito Yu , Ishikawa Daichi , Teraoku Hiroki , Yoshikawa Masato , Higashijima Jun
Published: March 2017

780

Background: Recent advances in systemic chemotherapy, including molecular target agents, can introduce “Conversion surgery” and achieve R0 resection even for initially unresectable colorectal liver metastasis (CRLM). We investigated the optimal indication for initial surgical induction and treatment strategy for unresectable CRLM. Methods: Our current surgical indication for CRLM as follows: i) curative resection is achievable, ii) no limitation of tumor size and number, and iii) future remnant liver volume over 35%. Additionally, same indication is applied even after chemotherapy.Two hundreds forty-one cases from 1994 to 2015, consisted of 134 initially resectable case and 107 unresectable cases, were included. Among 107 unresectable cases, 55 cases received current chemotherapy such as FOLFOX, FOLFILI, XEROX and FOLFOXIRI. Results: 1) Optimal indication for initially resectable case:Multivariate analysis revealed MDN (Maximum Diameter × Number) index more than 30 of metastatic liver tumor (HR3.06), non-curative resection of metastatic liver tumor (HR4.082) and poor differentiation of primary tumor (HR11.14).2) Treatment strategy of unresectable case for “Conversion surgery” (FOLFOXIRI vs. other regimen): Forty-two unresectable cases with MDN > 30 were included. Of those 14 cases, FOLFOXIRI regimen was applied. Regarding clinicopathological factors, the use of molecular targeted drug was introduced in all patients of FOLFOXIRI group, but 67.9% patients of other regimen group. The “Conversion” rate in FOLFIXIRI group and other regimen group were 64.3% and 39.3% (p = 0.126), and median period until “Conversion” were 6.2 courses and 11.8 courses (p = 0.038). Regarding tumor necrotic rate, FOLFOXIRI regimen induced higher necrotic rate than other regimen group (77.9% vs. 50.4%, p = 0.073). Overall survival in FOLFOXIRI group has been better than that in other regimen group and 3-years survival rates were 83.3% and 48.0% (p = 0.044). Also, relapse free survival in FOLFOXIRI group was significantly better than that in other regimen group (p = 0.002). Conclusions: MDN can predict surgical outcome for CRLM. FOLFOXIRI plus molecular target drug may be a promising option for CRLM with MDN > 30.
Phase II trial of capecitabine +/- erlotinib in advanced colorectal cancer, with retrospective KRAS and primary tumor site analysis.
Authors: Breadner Daniel Adam , Welch Stephen , Soulieres Denis , Sanatani Michael Susmoy , Klimo Paul , MacKenzie Mary J. , Whiston Frances , Stitt Larry , O'Connell Anne , Vincent Mark David
Published: March 2017

781

Background: Palliative capecitabine (X) monotherapy for advanced colorectal colorectal cancer (aCRC) is generally well tolerated by elderly or frail pts. Epidermal growth factor receptor (EGFR) monoclonal antibodies improve efficacy when added to combination chemotherapy for mCRC. Erlotinib (E), an oral EGFR tyrosine kinase inhibitor (TKI) may add benefit when added to X. We conducted a randomized phase II trial to investigate the novel “all-oral” combination of X and E in aCRC. Methods: Pts with untreated aCRC who were either deemed unfit for, or chose against, combination chemotherapy were randomized to X (1000 mg/m2 PO BID x 14 days) alone or in combination with E (150 mg PO OD) on a 3-week schedule. Primary endpoint was time to disease progression (TTP); secondary endpoints included: objective response rate (ORR), overall survival (OS), and safety. Tumours were designated as left-sided if there were distal to the transverse colon. KRAS status was retrospectively analyzed for 72 of 82 pts. Results: From 2004 to 2008, 82 pts were randomized to X alone (40 pts) or XE (42 pts). TTP was not different between X and XE (7.9 m vs. 9.2 m; p = 0.890), however, KRAS subgroup analysis revealed pts with KRAS mutations did significantly worse when treated with XE compared to X alone (1.9m vs 7.4m; HR = 2.63; P = 0.038). Pts with KRAS wild-type (WT) treated with XE had an improved TTP compared to those treated with X (11.7m vs. 8.4m, HR = 0.73; Wilcoxon P = 0.061). KRAS-WT pts treated with XE with left-sided disease had an improved OS compared to pts with right-sided disease (16m vs. 12.1m, not significant). KRAS-WT pts with left-sided primaries treated with XE had a non-significant improvement in TTP compared to pts treated with X alone (11.7m vs 8.4m). XE was well tolerated but had significantly higher rates of diarrhea and acneform skin rash. Conclusions: The addition of E to X is generally well tolerated but associated with additional toxicities. E may benefit pts with KRAS-wild-type CRC, specifically those with left-sided primary tumours, and likely harms those with KRAS-mutated CRC. Further study of oral EGFR-TKIs in left-sided KRAS-wild-type aCRC is warranted.
Impact of clinical and molecular features on risk of recurrence following curative intent resection of metastases in metastatic colorectal cancer.
Authors: Burge Matthew E. , Lee Belinda , Lee Margaret , Wong Rachel , Parente Phillip , Desai Jayesh , Tran Ben , Nott Louise M. , Shapiro Jeremy David , Richardson Gary Edward , Zimet Allan Solomon , Gibbs Peter
Published: March 2017

785

Background: Resection of metastases with curative intent is an integral component of mCRC management. However, relapse rates are high and identifying patients most likely to benefit from this approach is of considerable importance. Among patients with mCRC, mutations (mt) in RAS and BRAF genes portent a worse prognosis. Our hypothesis, therefore, is that patients harbouring these mutations may have a higher relapse rate after resection of metastases. We also wished to analyse clinical predictors of relapse, including site of metastases. Methods: We interrogated the TRACC database of patients undergoing resection with curative intent who had mutation status available. The frequency of RAS and BRAF mt was established and their association with clinical parameters determined. Relapse free (RFS) and overall survival (OS), from the date of resection, was estimated for the mt and wild type (wt) groups using the Kaplan Meier method. Multivariate analysis is planned to investigate factors associated with RFS, including stage of the primary tumour, synchronous metastases, site and number of metastases, CEA, peri-operative chemotherapy use, site of the primary (left v right) and RAS and BRAF mutation status. Results: 188 patients were identified. 89 were KRAS/BRAF wt, 92 KRAS mt and 7 BRAF mt. 40% had presented with metastatic disease and 27% had a right sided primary. 76%, 22% and 2% underwent resection of liver, lung or both metastases. Microscopic resection margin was involved in 6%. Resection was performed prior to any chemotherapy in 48%. No difference was seen in relapse free or overall survival between the mt and wt groups. Conclusions: We found no difference in relapse free or overall survival by mutation subgroup suggesting this should not influence suitability for curative intent resection, but analyses is planned on a much larger cohort once data is available. A multivariate analysis, adjusting for important prognostic variables, is planned.
Sex steroids, sex-binding globulin, and prolactin in tissues of adenocarcinoma and esophageal squamous cell carcinoma.
Authors: Kit Oleg Ivanovich , Frantsiyants Elena Mikhaylovna , Bandovkina Valeria , Kolesnikov Evgeniy N. , Myagkov Roman E. , Trifanov Vladimir , Tkalya Lyudmila Dmitriyevna , Chugunova Natalya , Tavaryan Irina Stasio
Published: March 2017

79

Background: Some researchers suggest that squamous cell carcinoma (SCC) and adenocarcinoma of the esophagus (ACE) are characterized by different pathogenesis, epidemiology and tumor biology, and therefore require different therapeutic strategies. The purpose of the study was to analyze local hormonal status in malignant esophageal tumors and surrounding tissues depending on the histogenesis. Methods: Levels of sex steroids – free testosterone (fT), estrone (E1), estriol (E3), prolactin (PRL) and sex steroid-binding globulin (SSBG) were studied by the standard ELISA methods in tumor tissue, perifocal zone and resection line of 39 patients aged 58-74 years: 27 SCC, 12 ACE, stage II, G2, pT1-2N1M0. Results: Differences were found in local hormonal content in all studied samples dependint on the tumor histotype. Levels of SSBG, PRL and E1 in ACE were higher than in SCC by 1.3, 3.3 and 1.4 times, respectively, while fT concentration was 2.4 times lower. Levels of PRL, E1 and E3 in perifocal zone of ACE compared to SCC were higher by 2.8, 3.3 and 3.1 times, and fT was 1.3 times lower. Resection line of ACE differed from that of SCC by higher tissue concentrations of SSBG – by 1.3 times, PRL – by 1.5 times, E1 – by 1.3 times, E3 – by 1.7 times and a lower level of fT – by 1.5 times. As a result, fT/E1 ratios in ACE and surrounding tissues were on average 3 times lower than in corresponding SCC samples. Conclusions: Levels of hormones in esophageal tumors and surrounding tissues depend on the histogenesis. ACE was characterized by hyperestrogenism in esophageal tissues along with a high prolactin concentration, while SCC – by hyperandrogenism with a low PRL level. Different pathogenesis of SCC and ACE was demonstrated by the fact that hormonal profile in both tumor and resection line depended on the tumor histology.
Rectal adenocarcinoma: Outcomes of adjuvant chemotherapy after neoajuvant chemoradiotherapy in a retrospective cohort.
Authors: Pachón Olmos Vanessa , Reguera Puertas Pablo , Ferreiro Monteagudo Reyes , LONGO FEDERICO , Rodríguez Garrote Mercedes , Vaz Salgado María Ángeles , Guillen Carmen , Gion Cortés Maria , Molina CerrilloMD Javier , Martinez Saez Olga , Villamayor Delgado Maria , Die Trill Javier , Tobaruela de Blas Estela , Moreno Montes Irene , García Pérez Juan Carlos , Pina Juan Diego , Caminoa-Lizarralde Aiza María Alejandra , Sempere Ortega Cayetano , López-Campos Fernando , Carrato Alfredo
Published: March 2017

790

Background: The role of adjuvant chemotherapy (AC) after chemoradiotherapy and surgery in stage II and III of rectal cancer is not well defined. Neither the regimen nor the duration is clear. Besides, guidelines from different expert groups are conflicting. Methods: 224 patients diagnosed from January 2003 to December 2013 with rectal adenocarcinoma T3/T4 and/or positive node staged by ultrasound or magnetic resonance imaging was collected retrospectively from the Pathology Department data base. Results: Of the 224 patients 61.6% were male, median of age at diagnosis 68.6 years (range 31.3-85.4). All of them received 50.4 Gy with different concomitant regimens (capecitabine, continuous infusion of fluoracil or bolus of fluoracil-leucovorin). 13.4% of patients achieved a pathological complete response. 76.8% of the cohort received adjuvant chemotherapy. The main reasons for not receiving chemotherapy were ECOG ≥ 2, surgery complications and a decision of the patient. 51.2% of patients received an oxaliplatin based regimen and the median time of chemotherapy duration was 4 months (range 1-6 months). Local relapse was diagnosed in 6.3% of patients while a systemic relapse was found in 22.3%. Patients without AC had a mean overall survival (OS) of 85.5 months (CI 95% 70.7-100.4) versus 119.8 monts (CI 95% 110.8-128.8) in the AC cohort (p 0.002) without reaching the median after 58 months (range 8-153.9) median follow-up. Disease free survival (DFS) was also better in the AC cohort with a mean DFS of 104 months (CI 95% 94.3-113.6) versus 71.4 months (CI 95% 55.4-87.4), p = 0.01. Conclusions: AC after chemoradiotherapy and surgery in stage II and III rectal cancer as a standard does not exist. In our cohort, AC showed a significant improve in OS and DFS, but the limitations of a retrospective study should be considered, as well as the impact of surgery on metastasis and salvage chemotherapies. Randomized studies are clearly needed.
Vitamin D levels among patients with colorectal cancer (CRC) from the San Francisco Bay area.
Authors: Savoie Marissa Barbara , Paciorek Alan T , Zhang Li , Sommovilla Nili , Atreya Chloe Evelyn , Chern Hueylan , Kelley Robin Kate , Ko Andrew H. , Sarin Ankit , Varma Madhulika G. , Abrams Donald I. , Venook Alan P. , Van Loon Katherine
Published: March 2017

793

Background: A growing body of literature suggests that 25-hydroxyvitamin D [25(OH)D] levels are inversely related to the risk of developing CRC and that deficiency is associated with CRC-specific mortality. Due to the unique racial-ethnic diversity and UV exposure patterns of the San Francisco Bay Area, we aimed to evaluate vitamin D levels among our CRC patients at time of diagnosis and during treatment. Methods: Permanent residents of the SF Bay Area with a new diagnosis of CRC of any stage were recruited between 2011 and 2015 prior to initiation of therapy. Self-reported data on sun exposure, diet, and exercise patterns were collected. Clinical data including disease stage and primary tumor location were abstracted from charts. Serum 25(OH)D levels at time of diagnosis and at 6-month follow-up were batched and measured using the Liaison XL assay (Heartland Assays). Supplement use was not restricted. Kruskal-Wallis and Pearson correlation tests were used for categorical or continuous variables, respectively, to evaluate the associations of patient characteristics with 25(OH)D levels. Results: Among 94 patients with a new diagnosis of CRC, median 25(OH)D level at baseline was 27.0 ng/mL (range 7.2-59.0); 26% had deficient levels (<20 ng/mL), 39% had insufficient levels (<20 and <30 ng/mL), and 35% had sufficient levels (<30 ng/mL). Race, multivitamin use, vitamin D supplementation, and disease stage were associated with baseline serum 25(OH)D levels (p<0.05). The median change in 25(OH)D from baseline to six months was -0.6 ng/mL (range -19.4-51.7) for patients treated with chemotherapy (n=60) and 1.6 ng/mL (range -6.4-33.2) for patients who did not receive chemotherapy (n=19) (p=0.51). Conclusions: Among patients with a new diagnosis of CRC in the San Francisco Bay area, vitamin D insufficiency was seen in more than half of patients, consistent with reports from other geographic areas. Allowing for vitamin D supplementation, serum 25(OH)D levels did not decrease significantly after 6 months of chemotherapy. We are routinely screening CRC patients for 25(OH)D insufficiency at time of diagnosis and during treatment.
A retrospective analysis on the impact of preoperative neutrophil to lymphocyte ratio in stage II colon cancer.
Authors: Jaiswal Deepna , Mantha Suparna , Wong Lucas , Seija Luis , Munoz Yolanda
Published: March 2017

794

Background: Inflammation has a critical role in tumor genesis and progression of cancer. The neutrophil to lymphocyte ratio (NLR) is an indication of balance between the immune systems pro and defense mechanism against cancer. Elevated NLR is of interest in many cancers, including colon cancer. Although surgery is the mainstay of treatment for early stage colon cancer, adjuvant chemotherapy for stage II colon cancer has remained debatable. We proposed to study the impact of the NLR in patients with stage II colon cancer and to identify high risk patients who would benefit from adjuvant chemotherapy. Methods: Three hundred and eighty patients diagnosed with Stage II colon cancer at our institution were included in this retrospective study. Kaplan-Meir curves and multivariate Cox-regression analyses were calculated for overall survival. Results: Univariate analysis showed NLR was not statistically significant as predictor of mortality (p-value=0.0857). However, after adjusting for recurrence, chemotherapy, age, white blood cell count, the NLR was predictive for survival, with a hazard ratio of 1.05 and 95% confidence interval of (1.006 - 1.1). Recurrence and age were also significant predictors of survival (p-values of <0.0001 for both), and HR of 3.1 (2.0 – 4.6) and 1.4 (1.2 – 1.5), respectively. Conclusions: The neutrophil to lymphocyte ratio might be an independent prognostic marker for overall survival in stage II colon cancer patients. Given the retrospective nature of our study, further studies are indicated to confirm our findings.
Exploratory evaluation of pharmacodynamic biomarkers and pharmacokinetics (PK) of ziv-aflibercept (Z) + FOLFIRI in a phase II study of Japanese patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Yoshino Takayuki , Sugimoto Naotoshi , Yamazaki Kentaro , Kajiwara Takeshi , Komatsu Yoshito , Sasaki Toru , Chiron Marielle , Ziti-Ljajic Samira , Brillac Claire , Hamaguchi Tetsuya
Published: March 2017

799

Background: Z + 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a 2nd-line treatment for mCRC. There are no established biomarkers that predict response to this treatment. This study aimed to identify such biomarkers. Methods: 62 pts with mCRC received Z (4 mg/kg) + FOLFIRI every 2 weeks. 78 potential protein biomarkers (e.g., cytokines) were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and pre-dose 3 (Day 1 of Cycle 3) were measured in all pts by enzyme-linked immunosorbent assays. Relationships between these levels and efficacy endpoints were assessed. PK data were calculated. Results: 10 potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001); the greatest changes were in placental growth factor (median: 4,716%) and vascular endothelial growth factor receptor 1 (2,171%). Baseline levels of 8 potential biomarkers correlated with overall survival (OS; see table) in a univariate Cox regression analysis; none correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Conclusions: Preliminary data show that these 8 biomarkers could be associated with OS. No significant drug interactions were found. Clinical trial information: NCT01882868. [Table: see text]
Efficacy of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with wild-type KRAS exon2 metastatic colorectal cancer previously treated with bevacizumab within 6 months.
Authors: Hayashi Kaori , Mitani Seiichiro , Taniguchi Hiroya , Hamauchi Satoshi , Sugiyama Keiji , Tsushima Takahiro , Honda Kazunori , Todaka Akiko , Masuishi Toshiki , Yokota Tomoya , Narita Yukiya , Machida Nozomu , Kadowaki Shigenori , Fukutomi Akira , Ura Takashi , Onozawa Yusuke , Ando Masashi , Yasui Hirofumi , Muro Kei , Yamazaki Kentaro
Published: March 2017

800

Background: The ASPECCT study showed panitumumab (Pmab) is non-inferior to cetuximab (Cmab) for chemotherapy-refractory and intolerant wild-type (WT) KRAS exon2 metastatic colorectal cancer (mCRC). In the subgroup analysis, Pmab provided more favorable outcomes than Cmab for patients (pts) previously treated with bevacizumab (Bmab). However, some reports suggested that anti-EGFR antibody (anti-EGFR) efficacy was reduced when received within 6 months of last administration of Bmab. In this study, we aim to evaluate the difference in efficacy between Pmab and Cmab in pts who received prior Bmab and were treated with anti-EGFR after a short interval. Methods: We retrospectively evaluated pts treated with anti-EGFR and irinotecan (IRI) after failure of Bmab, fluoropyrimidine, oxaliplatin, and IRI at two institutions. The main inclusion criteria were WT KRAS exon2 mCRC, ECOG PS 0-2, and no prior administration of anti-EGFR within 6 months after Bmab. Results: From Sep. 2008 to Mar. 2016, 124 consecutive pts met the inclusion criteria (Pmab/Cmab, 30/94). Pts’ characteristics were as follows (Pmab/Cmab): median age (range): 63/62 (38-76/27-82); male, 63%/72%; ECOG PS 0, 43%/27%; PS1, 57%/66%; PS2 0%/7%; tumor in left colon, 87%/76%; histology (por, muc), 10%/16%; ≥2 metastases, 67%/66%; ≥1 subsequent therapy, 73%/63%. Overall response and disease control rates in Pmab/Cmab were 31%/26% and 69%/67%, respectively. In Pmab/Cmab, the median overall survival was 15.8/12.2 months (HR, 0.62; 95% CI, 0.4-0.97; P=0.04) and the median progression-free survival was 6.5/5.5 months (HR, 0.75; 95% CI, 0.49-1.16, P=0.20). The adjusted HR with 10 covariates such as age, gender, PS, tumor location, histology, primary tumor resection, number of metastatic sites, liver limited disease, time from diagnosis of metastasis and initiation date of anti-EGFR plus IRI was 0.61 for PFS (p=0.1) and 0.61 for OS (p=0.04). Conclusions: Pmab plus irinotecan showed favorable outcomes compared with Cmab plus irinotecan in pts with WT KRAS exon2 mCRC within 6 months between the last administration of Bmab and initial anti-EGFR.
Gender differences in hormonal statuses of patients with esophageal squamous cell carcinoma.
Authors: Kolesnikov Evgeniy N. , Kit Oleg Ivanovich , Frantsiyants Elena Mikhaylovna , Bandovkina Valeria , Kozlova Margarita , Cheryarina Natalia D. , Mezentsev Stanislav Stanislavovich , Snezhko Alexander V.
Published: March 2017

85

Background: Esophageal squamous cell carcinoma (ESCC) is 4-8 times more frequent in men than in women, with poorer prognosis. The purpose of the study was to analyze systemic and local hormonal statuses in patients with ESCC in dependence on their gender. Methods: The study included 34 ESCC (G2, рT1-2N0-1M0) patients: 21 men and 13 women. 11 men (52.4%) had lymph node metastases. Levels of sex steroids – total (T) and free (fT) testosterone, progesterone (P4), estradiol (E2), estrone (E1), prolactin (PRL), LH, FSH and sex steroid-binding globulin (SSBG) – were studied in the peripheral blood, tumor and resection line by the standard RIA and ELISA methods. Results: Men showed a decrease in the blood T concentration by 1.4 times, P4 by 2 times, and E2 increase by 2.5 times, while women showed 1.3 times increase in T and 2 times decrease in P4. Metastases in men were accompanied by an increase in blood levels of anterior pituitary hormones: PRL by 2.5 times, LH by 2.3 times and FSH by 2.2 times compared to patients without metastases. Analysis of the local saturation with sex hormones in visually unchanged esophageal tissues of ESCC patients did not reveal any significant gender difference. However, women were characterized by a higher content of anterior pituitary hormones, PRL, LH and FSH, in esophageal tissues compared to men. Men with metastases showed local hyper-androgenization of tumor and surrounding tissues, as the fT to E1 ratio was increased. Conclusions: The results confirmed the data on T-stimulation of malignant growth in the esophagus and the possible protective effect of estrogens. The free testosterone to estrogens ratio in esophageal tissues can probably serve as one of prognostic factors for the disease course.
Thrombospondin-1 expressions in non-cancer tissue correlated with gastric carcinogenesis.
Authors: Kashihara Hideya , Shimada Mitsuo , Yoshikawa Kozo , Higashijima Jun , Nishi Masaaki , Takasu Chie
Published: March 2017

88

Background: Thrombospondin-1 (TSP1) correlated with the carcinogenesis in the intestinal inflammation. TSP1 binding CD36 evoked inflammation via the activation of TGFβ and STAT3. The aim of this study is to clarify the role of TSP1 in gastric carcinogenesis. Methods: Thirty-nine patients with gastric cancer who underwent gastrectomy were enrolled. The expression of TSP1 mRNA in non-cancer tissue was determined in clinicopathological factors (including mucosal inflammation and atrophy based on Sydney system). The expressions of CD36, STAT3 and TGFβR2 mRNA in the TSP1 high and low expression group in non-cancer tissue were examined. Results: TSP1 expression was high in mucosal atrophy group and tended to be high in Helicobacter pylori (H.pylori) (+) and multiple cancer group. In TSP1 high group, CD36, STAT3 and TGFβR2 mRNA showed significantly high. The expressions of TSP1 signaling pathway in multiple cancer or atrophy (+) or H.pylori (+) showed high compared with that in single cancer and atrophy (-) and H.pylori (-). The expressions associated TSP1 signaling pathway in non-cancer tissue with multiple gastric cancer showed higher than that with single gastric cancer. Conclusions: Our results indicated TSP1 expressions in non-cancer tissue correlated with gastric carcinogenesis.
Phase II, prospective, single-arm, single-institutional, open-label clinical trial on laparoscopic sentinel node navigation surgery in early gastric cancer.
Authors: Park Do Joong , Park Young Suk , Lee Hye Seung , Park Young Soo , Lee Kyoung Ho , Kim Young Hoon , Park Kyoung Un , Ahn Sang-Hoon , Kim Hyung-Ho
Published: March 2017

90

Background: The aim of this study was to evaluate the feasibility and safety of laparoscopic limited gastrectomy with sentinel basin (SB) dissection for gastric cancer using simultaneous indocyanine green and 99mTc-antimony sulfur colloid injections. Methods: The primary end point was the 3-year relapse-free survival rate of the patients who underwent laparoscopic sentinel node navigation surgery (SNNS). Secondary end points included sentinel node (SN) detection rate, false negative rate of intraoperative pathologic examinations for metastatic SN detection, postoperative morbidity and mortality, quality of life (QOL), and overall survival. Results: From July 2010 to April 2013, 100 patients were enrolled to this study. The SBs were identified in all patients (100%) by dual method. The mean number of SN and non-SN was 6.07 ± 3.84 [range 0-17] and 4.60 ± 4.76 [range 0-25]. Eleven patients had SN metastasis and they were converted to conventional laparoscopic gastrectomy with radical lymphadenectomy. Among 89 patients with negative SNs, 3 patients were considered as false negative of intraoperative pathological examination (3.37%). There was no significant difference between SN negative (n = 89) and positive (n = 11) groups in estimated blood loss, postoperative hospital stays and complication rate. Overall, QOL scores are more likely to be better in SNNS group than in conventional laparoscopic distal gastrectomy group. After median follow-up periods of 47.5 months in all patients, 4 patients who underwent SNNS died, and 2 patients who underwent SNNS had recurrences of cancer. The 3-year relapse-free survival rate for all patients (n = 100) was 97.0 %. In the subgroup analysis, the 3-year relapse-free for the SN negative group was 96.6%, and 100% for the SN positive group (P = 0.374). The 3-year overall survival rate was 98.0% for all patients; 97.7% for the SN negative group and 100% for the SN positive group (P = 0.418). Conclusions: Laparoscopic SNNS was feasible and safe in early gastric cancer. Phase III randomized controlled trial on comparing laparoscopic SNNS and conventional laparoscopic gastrectomy will be needed based on the present study. Clinical trial information: NCT01441310.
Trastuzumab beyond first progression in cases of HER2-positive advanced gastric or gastro-esophageal junction cancer: Initial results from KSCC1105, a trastuzumab observational cohort study.
Authors: Makiyama Akitaka , Shimokawa Mototsugu , Kashiwada Tomomi , Takahashi Ikuo , Emi Yasunori , Kusumoto Tetsuya , Yamamoto Kazuharu , Ishikawa Hiroshi , Negoro Yuji , Oki Eiji , Saeki Hiroshi , Kakeji Yoshihiro , Baba Hideo , Maehara Yoshihiko
Published: March 2017

93

Background: The concept of using trastuzumab (Tmab) beyond progression (TBP) is currently accepted in HER2-positive metastatic breast cancer. However, TBP has never been investigated in cases of HER2-positive advanced gastric or gastro-esophageal junction (G/GEJ) cancer. KSCC1105 is an observational cohort study designed to investigate the clinical outcomes associated with Tmab combined with chemotherapy including TBP strategy in part, as used in clinical practice, for the treatment of advanced G/GEJ cancer. Methods: Patients (pts) with advanced HER2-positive G/GEJ cancer receiving Tmab between March 2011 and January 2014 were enrolled. Data regarding the baseline characteristics before Tmab plus chemotherapy, pre-specified Tmab-related adverse events, and effectiveness were collected retrospectively. Treatment outcomes were estimated using Kaplan-Meier method and compared using log-rank test. Results: Of 181 enrolled pts, 179 were eligible for analysis and 123 received Tmab as first-line chemotherapy. Among the 123 pts, 85 were able to undergo second-line therapy with or without Tmab. We divided these 85 pts into those treated with Tmab (TBP group, n = 59; 69%) and those treated without Tmab (non-TBP group, n = 26; 31%) in the second-line chemotherapy. The baseline characteristics were similar between the two groups. The median OS was significantly longer in the TBP group (12.8 months; 95% CI 9.0–16.5 months) than in the non-TBP group (7.9 months; 95% CI 5.1–10.7 months) (hazard ratio = 0.50; 95% CI 0.29–0.84; p = 0.010). Infusion-related events were more frequent in the TBP group (20.3%) than in the non-TBP group (11.5%); however, no significant difference was observed. No cardiac event-related death was observed in either group. Conclusions: TBP may be associated with a better prognosis, without severe toxicity. A randomized controlled trial to assess TBP (T-ACT trial; WJOG7112G) is currently being undertaken by the West Japan Oncology Group.
Trastuzumab beyond progression in patients with HER2-positive advanced gastric adenocarcinoma: A multicenter AGEO study.
Authors: Palle Juliette , Tougeron David , Pozet Astrid , Soularue Emilie , Artru Pascal , Le Roy Florence , Dubreuil Olivier , Sarabi Matthieu , Williet Nicolas , Manfredi Sylvain , Martin-Babau Jerome , Rebischung Christine , Ben Abdelghani Meher , Evesque Ludovic , Dreanic Johann , Hautefeuille Vincent , Louvet Christophe , Lecomte Thierry , Taïeb Julien , Zaanan Aziz
Published: March 2017

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Background: Trastuzumab in combination with platinum-based chemotherapy is the standard first line regimen in HER2 positive advanced gastric cancer. However, there is no data concerning continuation of trastuzumab beyond first line progression. Methods: This retrospective multicenter study include all consecutive patients with HER2 + advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma who received after progression of trastuzumab plus platinum-based chemotherapy, a second line chemotherapy with irinotecan, taxane or platinum salt, with or without trastuzumab. The prognostic variables with P values ≤0.10 in univariate analysis were eligible for the Cox multivariable regression model. Results: From August 2007 to March 2015, 104 patients were included (median age, 60.8 years; male, 78.8%; PS 0-1, 71.2%) with advanced (metastatic : 99%) gastric (45.2%) or GEJ (54.8%) cancer. All patients had received first line treatment based on trastuzumab plus fluoropyrimidine and cisplatin (n=54; 51.9%) or oxaliplatin (n=50; 48.1%). As second line chemotherapy, 67 patients (64.4%) received FOLFIRI regimen, including 19 who have continued trastuzumab; 23 patients (22.1%) received a taxane regimen (paclitaxel or docetaxel), including 12 with trastuzumab; and 14 patients (13.5%) received a platinum-based chemotherapy (different from that used in first-line), including 8 with trastuzumab. When considering all regimens of second-line chemotherapy, continuation (n=39) versus discontinuation (n=65) of trastuzumab was significantly associated with an increase on PFS (4.4 vs 2.3 months; p=0.002) and OS (12.6 vs 6.1 months; p=0.001). In multivariate Cox model (including ECOG PS, tumor grade, number of metastatic site, and second-line treatment), continuation of trastuzumab was significantly associated with longer PFS (HR=0.56; 95%CI [0.35-0.89]; p=0.01) and OS (HR=0.47; 95%CI [0.28-0.79]; p=0.004). Conclusions: This study suggests that maintenance of trastuzumab plus second line chemotherapy beyond disease progression has clinical benefit in patients with HER2 positive advanced gastric cancer. These results deserve a prospective randomized validation.
Phase II study of intraperitoneal paclitaxel plus S-1/paclitaxel for gastric cancer with positive peritoneal cytology: CY-PHOENIX trial.
Authors: Aizawa Masaki , Ishigami Hironori , Yabusaki Hiroshi , Nashimoto Atsushi , Imamoto Haruhiko , Imano Motohiro , Yamashita Hiroharu , Kishi Kentaro , Kodera Yasuhiro , Uenosono Yoshikazu , Fujiwara Yoshiyuki , Hidemura Akio , Tamura Shigeyuki , Fukushima Ryoji , Yamaguchi Hironori , Kitayama Joji ,   Japan Intraperitoneal Chemotherapy Study Group (JIPG)
Published: March 2017

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Background: The presence of free cancer cells in the peritoneal cavity has been known as a poor prognostic factor in gastric cancer patients. Intraperitoneal (IP) paclitaxel (PTX) provides powerful local effects in the peritoneal cavity, and we previously reported the efficacy and safety of a regimen combining IP PTX with S-1/PTX in gastric cancer patients with peritoneal metastasis. This multicenter phase II study was conducted to evaluate the efficacy of IP PTX plus S-1/PTX for gastric cancer with positive peritoneal cytology. Methods: Eligibility criteria included pathologically confirmed gastric adenocarcinoma, intraperitoneal free cancer cells confirmed by peritoneal washing cytology, and no evidence of overt distant metastasis including macroscopic peritoneal metastasis. Patients were administered IP PTX 20 mg/m2, intravenous PTX 50 mg/m2 on days 1 and 8, and S-1 80 mg/m2/day on days 1-14, q3 weeks. The primary endpoint was the 1-year overall survival (OS) rate. Secondary endpoints were response rate, negative conversion rate on peritoneal cytology and safety. Results: Thirty eight patients were enrolled and fully evaluated for OS and toxicity. The median number of courses was 12.5 (range 2-35). The 1-year OS rate was 84.2% (95 % confidence interval, 68.2-92.6%). Of 3 patients with target lesions, partial response and stable disease were obtained in 2 and 1 patient(s), respectively. The peritoneal cytology findings converted from positive to negative in 36 (94.7 %) patients. The incidences of grade 3/4 hematological and non-hematological toxicities were 45 % and 26 %, respectively. The frequent grade 3/4 toxicities included neutropenia (23%), leukopenia (7%) and anemia (8%). Regarding adverse events related to IP port, 2 patients developed swelling around the port site. Conclusions: IP PTX with S-1/PTX was suggested to be a promising option for gastric cancer with positive peritoneal cytology through the clearance of cancer cells in the peritoneal cavity. Clinical trial information: UMIN000002850.
Adjuvant chemotherapy and overall survival in patients with node positive esophageal adenocarcinoma treated with neoadjuvant therapy and esophagectomy: A retrospective analysis using the National Cancer Database.
Authors: Ajmani Gaurav , Hensing Thomas A. , Kim Ki-Wan , Krantz Seth B. , Prinz Richard A , Talamonti Mark S. , Baker Marshall , Bentrem David J. , Roggin Kevin K. , Marsh Robert de Wilton
Published: March 2017

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Background: Node positive disease (N+) is frequent (~40%) following neoadjuvant therapy (NAT) and esophagectomy, yet limited data exist regarding the efficacy of adjuvant chemotherapy (AC) in this setting. There are no randomized studies addressing this question and single-institution, retrospective studies have reported mixed findings. Methods: A retrospective analysis was conducted using the National Cancer Database. 2,258 N+ patients were identified who had received NAT (83.3% chemoradiation and 17.7% chemotherapy alone) followed by esophagectomy. Patients with either incomplete staging or treatment data were excluded, as were those who died within 90 days following esophagectomy. Multivariate logistic regression was used to test for differences in patient characteristics between those who did (AC+) or did not (AC-) receive AC. Overall survival (OS) after surgery, by AC status, was analyzed using Cox regression in a sample propensity matched on relevant demographic and clinical factors. Results: 433/2258 patients received AC (19.2%). Patients who received AC tended to be younger (OR 0.98 per 1-year increase, P = .03) and had a higher socioeconomic status (SES) (OR 1.47 for high vs. low SES, P = .01). Although there were no significant differences in comorbidity (P = .32), AC+ patients had significantly shorter hospital stays after surgery (OR 0.98 per 1-day increase, P = .03). Pathologic T classification was unrelated to the likelihood of receiving AC (P = .39), however patients with a higher pathologic N stage were more likely receive AC (OR 2.12 for pN3 vs. pN1, P < .001). Those receiving AC had demonstrably longer OS from the time of surgery than those who did not (HR 0.78, P = .004). Median OS for the entire cohort was 22.6 months, whereas the administration of AC was associated with an improvement in median OS of 6.2 months (26.3 vs. 20.1 months). Conclusions: This retrospective analysis indicates that AC is associated with a significant improvement in OS (median 6.2 months) in N+ patients following NAT and esophagectomy. Further studies are needed to clarify the optimal role of AC in this setting.
A phase II study to examine the effectiveness of nutritional support with elemental diet for stage II/III gastric cancer patients receiving adjuvant chemotherapy with S-1 (OGSG 1108).
Authors: Kawada Junji , Imamura Hiroshi , Matsuyama Jin , Fukui Junichi , Nishikawa Kazuhiro , Kawase Tomono , Shimokawa Toshio , Kurokawa Yukinori , Satoh Taroh , Furukawa Hiroshi
Published: March 2017

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Background: Postoperative weight loss after gastrectomy causes deterioration in patient’s quality of life and tolerance for adjuvant chemotherapy in gastric cancer patients. Nutritional support may prevent postoperative weight loss and chemotherapy related adverse effects to improve compliance of adjuvant chemotherapy. Methods: Clinical stage II/III gastric cancer patients received R0 resection were registered in the first stage of the present study. Those patients were qualified and enrolled in the second stage who could intake more than 60% of elemental diet (Elental, 300 kcal/day for 14 days) in the postoperative period and were proven pathological stage II/III. Enrolled patients were planned to receive a total of 300 kcal/day of Elental for 24 weeks and additional courses was permitted up to 365 days. The primary endpoint was compliance of S-1: percent of patients who accomplish S-1 adjuvant for one year with more than 70% relative performance (RP). The secondary endpoints were nutritional parameters (body weight, BMI, s-albumin, s-protein, s-cholesterol), RP of 8 courses of S-1, adverse effects of S-1, RP of Elental and ratio of patients who were enrolled to the second stage. Results: From January 2012 to September 2014, 149 patients were registered in the first stage and 82 patients were enrolled in the second stage: including 50 men; 32 women; median age of 70 years (range, 42-85 years); and performance status were zero in 45 and one in 37 patients. Compliances of S-1 were 60.5% (95%CI: 49.0, 71.2) in 81 eligible patients and 69% (95%CI: 56.9, 79.5) in eligible patients without recurrence. In 81 eligible patients, RP of 8 courses of S-1 was 87.3 % (95%CI: 88.3, 85.9), and the body weight loss was 1.80kg (95%CI: -0.38, 4.48). Grade 3-4 toxicities were neutropenia 12%, anemia 4%, anorexia 4% and diarrhea 4%. Conclusions: Nutritional support for gastric cancer patients receiving adjuvant chemotherapy contributes to increase compliance of S-1 and potential effect on survival may be expected. Clinical trial information: UMIN000006872.