bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoadjuvant bevacizumab treatment for colorectal liver metastasis: A retrospective study.
Authors: García P. , Alvarez S. , Muñoz A. , Lopez P. , Riesco M. , Adeva Alfonso J. , Martin M.
Published: February 2017

613

Background: Patients with colorectal cancer (CRC) and liver metastases have a poor prognosis and may benefit from perioperative chemotherapy and disease resection. Bevacizumab is proven to improve outcomes in patients with metastatic CRC.

Methods: This is a retrospective chart review performed in colorectal patients with liver metastases. All the patients were > 18 years old and have undergone bevacizumab therapy as neoadjuvant treatment.

Results: 20 patients were analyzed. Baseline characteristics: median age 54.8 (49.2-65.8) years; male 45%; ECOG 0/1 40%/60%, 13 patients had metastatic disease at the time of their initial diagnosis. Median time from diagnosis of metastasis to surgery was 7.1 (5.4-9.6) months. Primary tumour locations were rectum (21.4%), colon (64.3%) and colon and rectum (14.3%). 80% and 20% of the patients received one and two lines of treatment before surgery, respectively. Mean cycles were 7.3±3.4 and 3.5±1.8 in first and second line, respectively. In 95% of the patients resection was curative. Mean number of resected metastasis was 3.4±2.8. 90%·of the patients achieved complete resection (R0) and 10% incomplete resection (R1). All the synchronous primary tumours (15) were resected. Among 16 valuable patients for pathological response, 1 (6.3%) experienced a pCR, 11 (68.8%) major response and 4 (25%) minor response. The median DFS was 12.2 months. The median OS was 48.9 months. Only one patient experienced grade 3-4 toxicity (rectal haemorraghe). Most frequent surgical complications were anastomotic filtration (8.7%) and wound infection (8.7%). Most frequent hepatic toxicities after surgery were steatohepatitis (25%) and sinusoidal dilatation (20%).

Conclusions: These data provide evidence that neoadjuvant chemotherapy including bevacizumab can be safely administered in patients with mCRC.

No significant financial relationships to disclose.
Optimal use of antihypertensive agents in management of bevacizumab-associated hypertension.
Authors: Suenaga M. , Imada H. , Nakamoto E. , Matsusaka S. , Watanabe T. , Kawazoe Y. , Shinozaki E. , Chin K. , Mizunuma N. , Hatake K.
Published: February 2017

614

Background: Hypertension (HT) is the most common toxicity associated with bevacizumab (BV). Angiotensin converting enzyme inhibitors, calcium channel blockers (CCB), beta-blockers or diuretics are frequently chosen to control BV-associated HT. However, optimal use of these antihypertensive (AHT) agents for each grade of HT remains to be determined. Furthermore, the AHT agent to be used must be carefully chosen to avoid increasing risk for BV-associated cardiovascular adverse events.

Methods: Seventy-five consecutive patients with metastatic colorectal cancer who received first-line FOLFOX4 plus BV 5 mg/kg were included in the study. Treatment continued until progression of disease or unmanageable toxicity occurred. Blood pressure was measured prior to treatment in each cycle and graded using the NCI–CTC, version 3.0. The management protocol was as follows: 8-12 mg candesartan cilexetil (an angiotensin II receptor antagonist) as the first choice for grade 2 HT; 2.5 mg ≤ additional amlodipine besylate (a CCB) when grade 3 HT occurred; BV was discontinued if HT remained uncontrolled with use of both these agents. Stable blood pressure < 150/100mmHg during treatment was defined as manageable.

Results: Twenty patients (26.7%) had a history of HT. Grades 2-3 HT developed in 53 patients (70.7%) and grade 3 in 24 (32%). Median number of treatment cycles until onset of grades 2 and 3 HT was 3 and 4.5, respectively. Comparing patients with a history of HT to those without, the incidence of grade 3 was greater in the former (85 vs. 12.7%, respectively), and the median number of treatment cycles until onset of grade 3 was shorter (4 vs. 12 cycles, respectively); blood pressure was considered manageable in both groups (90 vs. 91%, respectively), and no difference in total duration of chemotherapy was observed. No AHT approach-related severe adverse events were observed.

Conclusions: Grade 3 HT was manageable during BV treatment, regardless of prior hypertensive history. However, to ensure improved survival, especially in patients with a history of HT, appropriate management is needed in BV-associated grade 3 HT. These data suggest that use of AHT agents is an effective and safe strategy in the management of BV-associated HT.

No significant financial relationships to disclose.
Predictors of oxaliplatin-induced peripheral neuropathy in patients with advanced colorectal cancer (CRC).
Authors: Lin A. Y. , Kouzminova N. B.
Published: February 2017

619

Background: Chemotherapy-induced neuropathy (CINP) is one of the major dose-limiting toxicities of oxaliplatin. The purpose of this study was to identify early predictors of CIPN and investigate the feasibility of using nerve conduction studies (NCS) to monitor CINP.

Methods: Under IRB-approved protocol, we systematically examined patient-reported symptoms, neurological tests and bilateral NCS of the peroneal, superficial peroneal and sural nerves every 3 weeks before each dose of oxaliplatin (75-130 mg/m2) in 12 CRC patients receiving 8 to 13 cycles of XELOX. The severity of neuropathy was graded by the NCI Common Toxicity Criteria (CTC v.4.0) and the Oxaliplatin-Specific Neurotoxicity Scale (OSNS).

Results: At the end of chemotherapy three of 12 patients developed peripheral sensory neuropathy CTC grade 3, five had grade 2, and four had grade 1 (3 of them had no self-reported symptoms with loss of Achilles tendon reflexes). At the eighth cycle test only 4 patients experienced CTC grade 2 criteria, but 7 of 12 patients had paresthesias persisting between the cycles of chemotherapy (OSNS grade 2 or higher). Development of grade 2 CINP by CTC or OSNS criteria by the eights cycle of chemotherapy was not associated with the total dose of oxaliplatin received (ANOVA p = 0.86 and 0.78 accordingly), but was significantly associated with administration of concomitant medication (Spearman correlation = 0.62, p = 0.03 for OSNS and 0.6, p = 0.04 for CTC grade 2 CINP). Presence of grade 2 or higher sensory neuropathy before the 8th cycle of oxaliplatin was significantly associated with development of grade 3 CINP by the time of chemotherapy completion (Spearman correlation = 0.8, p = 0.001). The maximal CINP grade that patients have reached during chemotherapy was also significantly associated with concomitant medication use (Spearman correlation = 0.76, p = 0.004).

Conclusions: Concomitant administration of medications was the only factor significantly associated with severity of CINP in our study cohort. Further study is needed to verify if it is associated with altered bioavailability of oxaliplatin.

No significant financial relationships to disclose.
O-glicosylation alterations of proteins in gastric carcinoma.
Authors: Santos Sousa H. , Bouca-Machado T. , Lima-da-Costa E. , Pinto-de-Sousa J. , Gomes C. , Reis C. A. , David L. , Costa-Maia J.
Published: February 2017

62

Background: The expression of immature forms of carbohydrates could help to better understand the biological behavior of gastric cancer.

Methods: From a universe of 50 patients with gastric or gastroesophageal junction carcinoma submitted to surgical treatment between January and October 2009, in our department, 36 out of 38 carcinomas ressected during this period, were selected for a tumor tissue immunohistochemical study of the simple mucin-type carbohydrate antigens (Tn, STn, T and ST) and the Lewis carbohydrate antigens (SLea and SLex). Several clinico-pathological parameters were evaluated according to the expression pattern of the antigens studied.

Results: The ressected gastric carcinomas presented a high incidence of tissue expression of the simple mucin-type and the Lewis carbohydrate antigens, with all cases presenting expression of at least 2 of the antigens and two thirds the expression of 4 or 5. The correlation between the simple mucin-type carbohydrate antigens was high, just as the same as with the Lewis carbohydrate antigens. The analysis of the clinico-pathological profile of gastric carcinomas according to the expression of these antigens revealed the following associations: Tn with venous invasion and perineural invasion; STn with tumor location and macroscopic form; T with age, gender, tumor dimensions and location; ST with macroscopic form and WHO classification; SLea and SLex with the tumor dimensions. Staging of the tumors also revealed associations with the expressions of these antigens: Tn with serosal invasion, lymph node metastases and stage; STn with lymph node ratio; SLea with serosal invasion and lymph node metastases; SLex with depth wall invasion, lymph node metastases and stage. The antigens T e ST did not reveal differences in the expression pattern according to staging.

Conclusions: O-glicosylation alterations of proteins are related with gastric carcinoma, not only their incidence is high but they can also be linked with various clinico-pathological characteristics. The knowledge obtained from this study might serve as a starting point for future investigations taking into account the identification of new biomarkers based on glicosylation alterations of proteins.

No significant financial relationships to disclose.
Gemcitabine and capecitabine as third-line treatment in patients with metastatic colorectal cancer after failure of irinotecan and oxaliplatin.
Authors: Qiu M. , Bi F. , Liu J. , Li Q. , Yi C.
Published: February 2017

620

Background: There is no standard chemotherapeutic regimen for patients with advanced colorectal cancer (CRC) progressing after combination regimens including irinotecan and oxaliplatin and having good performance status. 5-FU and gemcitabine are synergistic in preclinical studies of colon cancer cells. And gemcitabine also increases intracellular release of 5-FU from capecitabine. The aim of this study is to evaluate the efficacy and tolerance of the gemcitabine/capecitabine combination as third-line treatment for patients with advanced colorectal cancer.

Methods: Between May 2007 and September 2009, the data on 12 patients with metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens reviewed retrospectively. The median patient age was 54.0 years (range 37-77). The ECOG performance status was 0, 1 or 2. All patients has 2 or more previous chemotherapy. Patients received GemCap regimen (oral capecitabine 1,000 mg/m2 twice daily on days 1 to 14 plus Gem 1,000 mg/m2 on days 1 and 8 every 3 weeks). Eleven patients were evaluable for the response and all patients were evaluable for toxicity.

Results: No partial response was achieved and disease stabilization in 4 (36.4.3%) cases. Median progression-free survival and median overall survival were 9.1 weeks (range 3.0-18.0) and 22.3 weeks (range 10.5- 53.0). Four patients with disease stabilization had longer median progression-free survival than those with disease progression (13 weeks vs. 6.2 weeks). No toxic deaths occurred. Grade 3 toxicities were thrombocytopenia (in 2 patients), neutropenia (in 2 patients) and mucositis (in 1 patient), hand-foot syndrome (in 1 patient) and GI toxicity (in 2 patients).

Conclusions: The combination of gemcitabine and capecitabine was found to be a safe palliative regimen for heavily pretreated patients with metastatic CRC. Despite no patients had radiologic response, patients with disease stabilization achieved better progression-free survival. This regimen seems to be potentially effective regimen in the treatment of CRC.

No significant financial relationships to disclose.
Impact of FOLFOXIRI plus bevacizumab on resectability and survival in patients with initially unresectable liver metastases from colorectal cancer.
Authors: Shimada M. , Nishioka M. , Hanaoka J. , Mori H. , Ikemoto T. , Imura S. , Morine Y. , Utsunomiya T.
Published: February 2017

621

Background: Prognosis in patients with unresectable liver metastases from colorectal cancer is known to be very poor. However, thanks to progress of chemotherapy including molecular-target agents, “conversion” (from unresectable to resectable) has been sometimes seen. The aim of this preliminary study is to clarify the impact of FOLFOXIRI plus bevacizumab (Bev) on conversion and prognosis in patients with initially unresectable liver metastases from colorectal cancer.

Methods: Seven patients with initially unresectable liver metastases from colorectal cancer, who received FOLFOXIRI (LOHP 85mg/m2 D1, CPT-11 150mg/m2 D1, LV 200mg/m2 D1, and 5FU 2,400mg/m2 infusion over 46 hours, D1) plus Bev 5mg/kg bolus every 2 weeks, were included in this study. Resectability, disease-free survival (DFS), and overall survival (OS) after hepatic resection were investigated in detail. In addition, completeness and adverse effects were examined in this regimen.

Results: All 7 patients tolerated the regimen well, and no adverse effect of grade 3-4 was observed. Five out of 7 patients (71%) became resectable (conversion), except for 2 with multiple lung metastases and bone metastasis prior to chemotherapy. Our historical conversion rates were, 0% (0/7) in 5FU/LV regimen from 1994 to 2003, 25% (7/27) other regimens such as FOLFIRI and FOLFOX except for FOLFOXIRI plus Bev from 2004. In 5 patients who became resectable, CR was not observed, however, all had PR after 6 cycles of chemotherapy (RR 100%). All 5 patients could undergo curative (R0) hepatic resection, furthermore, all had pathological major response (grade 2). Follow-up period ranged from 8 to 18 months, with a median period of 14 months, and 2 patients relapsed (lung recurrence and peritoneal dissemination), and one died of lung metastases (1.5-year OS and DFS are 80 % and 60%).

Conclusions: Our preliminary data suggested the feasibility of this new therapeutic combination in patients with initially unresectable liver metastases from colorectal cancer, and a high conversion rate and better prognosis.

[Table: see text]
Maintenance treatment with cetuximab in a series of patients treated with standard chemotherapy and cetuximab in metastatic colorectal cancer.
Authors: Quintero-Aldana G. , Varela S. , Campos B. , Vazquez-Estevez S. , Maseda O. , Santos E. , Iglesias C. , Torres I. , Lancho A. , Mel J.
Published: February 2017

624

Background: New strategies are needed to improve outcomes and reduced toxicities of currently treatments for patients with advanced colorectal cancer. Nowadays maintaining treatment until disease progression is the standard option for these patients. Cetuximab is a recombinant humanized monoclonal antibody that neutralizes epidermal growth factor receptor and it has shown benefit not only in combination with standard chemotherapy in first- and second-line treatment or as a single agent in progression to standard chemotherapy in KRAS wild-type metastatic colorectal cancer (mCRC).

Methods: This data describes patients who received standard chemotherapy with cetuximab every two weeks. For patients with response or stable disease, cetuximab was continued until disease progression or unacceptable toxicity.

Results: Twelve patients are reported, nine were male (75%). The median age was 62 years (range, 46 to 78 years). All patients had stage IV, and liver was the most common location (75%). The majority of patients (75%) received FOLFOX VI as a first-line treatment in combination with cetuximab; only two patients were treated with FOLFIRI. Cetuximab was maintained after the first line of treatment in the 75% of patients. The median of cycles of chemotherapy and cetuximab was 12. Best response achieved in this setting was complete response (58.3%, 7/12). Median of monotherapy with cetuximab treatment was 7.5 cycles (range 3 to 12). At the moment of this analysis seven of twelve patients continued with the maintenance. In the rest of patients the treatment was followed until progression (33%, 3/12). No grade 3-4 toxicities were seen during maintenance cetuximab. The most common adverse effect during maintenance was cutaneous toxicity but the majority of patients had minor toxicity (50% grade 1).

Conclusions: Cetuximab has significant antitumor activity not only as a single agent or in combination with standard chemotherapy but may also when it is used as maintenance therapy after a complete or partial response to first or second line based chemotherapy in mCRC. Maintenance cetuximab is feasible, safe, and worthy of future study in advanced colorectal cancer.

No significant financial relationships to disclose.
Randomized controlled trial comparing Billroth-I and Roux-en-Y reconstruction in distal gastrectomy for gastric cancer.
Authors: Fujita J. , Imamura H. , Takiguchi S. , Fujitani K. , Miyashiro I. , Kobayashi K. , Kimura Y. , Ebisui C. , Matsuyama J. , Doki Y.
Published: February 2017

65

Background: In distal subtotal gastrectomy for gastric cancer, Billroth-I (B-I) reconstruction has been performed predominantly in Japan, while increasing number of surgeons chose Roux-en-Y (R-Y) reconstruction recently. To evaluate the safety and superiority of R-Y we conducted a multi-institutional prospective randomized controlled trial.

Methods: Gastric cancer patients who underwent distal gastrectomy were randomized to B-I or R-Y intraoperatively. The primary endpoint was the ratio of body weight loss 1 year after surgery, the secondary endpoints were the incidence of delayed gastric emptying (DGE) and postoperative morbidity.

Results: Between Aug 2005 and Dec 2008, a total of 332 patients were enrolled and 163 patients were assigned to B-I and 169 patients to R- Y. The patient's characteristics were well balanced between the two groups. The operation time was significantly longer in R-Y than B-I (median 180 min in B-I vs 214 min in R-Y, p < 0.0001). The postoperative morbidity was 14 patients (8.6%) in B-I and 23 (13.6%) in R-Y (p = 0.14), the incidence of DGE was 7 (4.3%) in B-I vs 16 (9.5%) in R-Y (p = 0.06), and the hospital stay after surgery was 14.1days in B-I vs 16.4 days in R-Y (p = 0.02). There was no hospital death in the two groups. The body weight loss at 1 year after surgery compared to preoperation was -5.4kg (-9.1%) in B-I vs -6.2kg (-9.8%) in R-Y (p = 0.11).

Conclusions: The advantage of R- Y reconstruction compared to B-I was not proved in terms of postoperative morbidity either the body weight loss 1 year after surgery.

No significant financial relationships to disclose.
Comparison of definitive chemoradiotherapy and esophagectomy for stage I esophageal squamous cell carcinoma.
Authors: Yamamoto S. , Ishihara R. , Motoori M. , Kawaguchi Y. , Takeuchi Y. , Higashino K. , Uedou N. , Yano M. , Nakamura S. , Iishi H.
Published: February 2017

67

Background: Chemoradiotherapy (CRT) of esophageal cancer has been proposed as an alternative to esophagectomy given the favourable survival rate and mild toxicity. However, no comparative study is reported between esophagectomy and CRT in stage I esophageal squamous cell carcinoma.

Methods: A total of 54 patients treated by definitive CRT and 116 patients treated by esophagectomy at out institution between February 1995 and August 2008 were included in the analysis. Overall survival and recurrence rates were evaluated.

Results: Of 170 patients who had clinical stage I esophageal squamous cell carcinoma and treated by definitive CRT or esophagectomy, 169 patients (99%) were completely followed up. CRT mainly consisted of two cycles of cisplatin and fluorouracil with concurrent radiotherapy of 60 Gy in 30 fractions. Median (range) observation period was 67 (10–171) months in SURG group and 30 (4–77) months in CRT group. In CRT group grade 3 or grade 4 hematological or non-hematological adverse effects were seen in 24 (44.4%) patients. 1-year and 3-year overall survival rates were 97.4% and 85.5% in the SURG group and 98.1% and 88.7% in the CRT group (P = 0.78). By using Cox proportional hazards modelling, overall survival was comparable between the 2 groups after adjusting for age, sex, and size of cancer. Hazard ratio of CRT for overall survival was 0.95 (95% CI: 0.37-2.47). The incidence or local recurrence including metachronous esophageal cancer was significantly higher in the CRT group than the SURG group (P < 0.0001). All recurrences were intramucosal carcinomas and all of them were cured after the salvage treatment mainly using endoscopy.

Conclusions: Overall survival rate of CRT was comparable with esophagectomy despite high local recurrence rate. Local recurrent carcinoma is endoscopically treatable in all patients without influence on overall survival. CRT appears to be a reasonable alternative to esophagectomy in patients with stage I esophageal cancer.

No significant financial relationships to disclose.
Clinicopathologic features and treatment outcomes of patients (pts) with HER2-positive (pos) adenocarcinomas (ACA) of the esophagus (E) and gastroesophageal junction (GEJ).
Authors: Phillips B. E. , Tubbs R. R. , Rice T. W. , Rybicki L. A. , Plesec T. , Rodriguez C. P. , Videtic G. M. , Saxton J. P. , Ives D. I. , Adelstein D. J.
Published: February 2017

71

Background: HER2 is overexpressed in 21% of gastric and 33% of GEJ ACA, and pts with advanced HER2pos disease survive longer after chemotherapy and trastuzumab than after chemotherapy alone. This retrospective analysis was undertaken to better define the clinicopathologic features and treatment outcomes in pts with HER2pos ACA of the E and GEJ.

Methods: Between 11/99 and 7/06, 156 pts with T3 or N1 or M1a ACA of the E or GEJ were entered on one of two Cleveland Clinic trials. Induction chemoradiation, with 96 hour infusions of cisplatin (20 mg/m2/d) and fluorouracil (1,000 mg/m2/d) beginning on day 1 of radiation (30 Gy at 1.5 Gy bid), was followed by surgery and identical post-operative chemoradiation. 76 pts also received 2 years of oral gefitinib. Pathology was tested for HER2 by immunohistochemistry using PATHWAY anti-HER-2/neu 4B5 rabbit monoclonal primary antibody (Ventana, Tucson AZ) and in situ hybridization with the inform HER2 dual ISH DNA probe cocktail assay (Ventana, Tucson AZ). Baseline characteristics and outcomes after treatment of the HER2pos and negative (neg) pts were compared.

Results: Of the 156 pts, 136 pts had either initial biopsy or resection specimen available. HER2 was deemed pos if either was pos. Discordance between biopsy and resection was found in only 6/65 pts (9%). 32 pts (24%) were HER2pos; 27% of 82 pts with GEJ, and 19% of 54 pts with E tumors (p=0.31). There was no statistical difference between HER2pos and neg pts in age, gender, race, stage, or pathological response. The only difference was that HER2neg tumors were more likely poorly differentiated (p<0.001). Locoregional control, distant metastatic control, freedom from recurrence and overall survival were statistically the same in both the entire cohort, and in the gefitinib-treated subset.

Conclusions: Except for tumor differentiation, HER2pos and neg pts with ACA of the E and GEJ do not differ in clinicopathologic characteristics and treatment outcomes. Given the demonstrated benefit of trastuzumab in HER2pos gastric cancer and the similar incidence of HER2 overexpression in the E and GEJ, further evaluation of HER2 directed therapy in this disease seems indicated.

No significant financial relationships to disclose.
Outcomes after complete pathologic response (pCR) to neoadjuvant treatment for gastric and gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Fields R. C. , Strong V. E. , Gonen M. , Brennan M. F. , Coit D. G. , Shah M. A.
Published: February 2017

75

Background: pCR is rare following neoadjuvant chemotherapy (NAChemo) ± radiation therapy (RT) for locally advanced gastric/GEJ adenocarcinoma. Recurrence and survival after pCR are not well characterized.

Methods: A retrospective review of a prospective database identified patients with pCR after NAChemo ± RT for gastric/GEJ adenocarcinoma. Recurrence, overall survival (OS), recurrence free survival (RFS), and disease specific survival (DSS) were analyzed.

Results: From 1985 – 2010, 2,676 patients underwent resection for gastric/GEJ adenocarcinoma, and 714 (27%) received NAChemo ± RT. There were 102 (14%) patients with a pCR. 60 patients (8%) had adequate pre-operative staging and follow-up and comprised the study group: 47 (78%) GEJ and 13 (22%) gastric tumors. 51 (85%) received neoadjuvant RT. With 46 month median follow-up, 14 patients (23%; 12 GEJ, 2 gastric) developed a recurrence (Table); 13 of 14 (93%) occurred within 2 years of follow-up with a median time to recurrence of 13.5 months. 5 (42%) recurred in the CNS. Median time to death after recurrence was 11.5 months. 5-year OS, RFS, and DSS were 56%, 70%, and 65%, respectively.

Conclusions: pCR occurs in less than 15% of cases after neoadjuvant therapy for gastric and GEJ adenocarcinoma. Despite a pCR, there is a significant risk of recurrence and cancer-specific death during follow-up. As CNS recurrence is more prevalent in this group of patients, whole brain imaging should be considered.

[Table: see text]

No significant financial relationships to disclose.
Room for improvement? The adoption of multimodal esophageal cancer care in the United States.
Authors: Merkow R. P. , Bilimoria K. Y. , McCarter M. , Stewart A. , Chow W. B. , Williams R. , Ko C. Y. , Bentrem D. J.
Published: February 2017

78

Background: Consensus guidelines recommend neoadjuvant chemo- or chemoradiation therapy as the preferred treatment for locally advanced esophageal adenocarcinoma; however, it is unknown if this recommendation has been widely adopted in the U.S. Our objective was to examine esophageal cancer multimodal therapy and identify factors associated with the use of neoadjuvant therapy.

Methods: From the National Cancer Data Base, patients with middle third, lower third and GE junction (GEJ) adenocarcinomas were identified. Patients who were clinical stage I-III and underwent surgical resection were included. Separate logistic regression models were developed to identify predictors of neoadjuvant therapy utilization and outcomes.

Results: From 1998 to 2007, 8,051 patients underwent surgical resection for esophageal cancer: 16.3% stage I, 45.0% stage II and 38.7% stage III. For stage II/III tumors, neoadjuvant use increased (49.0% to 77.8%, p<0.001). After adjustment, factors associated with underuse of neoadjuvant therapy in stage II/III patients were older age, Black or Hispanic ethnicity, more severe comorbidities, tumor location (GEJ and middle vs. lower third), tumor size ≥ 2cm, stage II (vs. III) and geographic region. Stage II/III patients not receiving neoadjuvant had an over two fold increased risk of positive lymph nodes (OR 2.14. 95% CI 1.79 – 2.55, p<0.001). In addition, the positive surgical margin rate increased almost three fold (OR 2.80 95% CI 2.17-3.62, p<0.001) but 30-day postoperative mortality risk was not significantly affected (OR 1.50 95% CI 0.94-2.39; p=0.090). For stage I patients, neoadjuvant therapy decreased over time (38.0% to 11.4%, p<0.001). The overuse of neoadjuvant therapy was associated with higher tumor grade, larger tumor size, and low surgical case volume (all p<0.05).

Conclusions: The adoption of neoadjuvant therapy has increased in the past decade; however, opportunity exists to improve guideline treatment for locally advanced esophageal cancer. Registry-based feedback to individual hospitals, such as benchmark comparison tools, could help institutions provide care in concordance with national guidelines.

No significant financial relationships to disclose.
Randomized phase II study of nimotuzumab, an anti-EGFR antibody, plus irinotecan in patients with 5-fluorouracil–based regimen-refractory advanced or recurrent gastric cancer in Korea and Japan: Preliminary results.
Authors: Kim Y. H. , Sasaki Y. , Lee K. H. , Rha S. Y. , Park S. , Boku N. , Komatsu Y. , Kim T. , Kim S. , Sakata Y.
Published: February 2017

87

Background: Nimotuzumab is a humanized IgG1 anti-EGFR monoclonal antibody. In previous studies, nimotuzumab has demonstrated efficacy associated with an absence of severe skin toxicity, commonly caused by other EGFR-targeting therapies.

Methods: This is a Korea and Japan collaborative, multi-center, randomized, open-label study of nimotuzumab (400 mg, IV q1 week) plus irinotecan (150 mg/m2 IV q2 weeks) (N+I) versus irinotecan (I) in patients with advanced or metastatic gastric cancer refractory to 5-fluorouracil-based regimen. The primary endpoint was PFS with an external review and the secondary endpoints included safety, ORR, OS, PK, and a biomarker.

Results: Eighty-two eligible patients (ECOG PS 0-1, one prior regimen) were treated with N+I (n = 40) or I (n = 42). Baseline characteristics were balanced between both arms. Archival tumor tissues collected from 48 patients (N+I arm: 26, I arm: 22) were analyzed for EGFR and K-ras. EGFR status, 0/1+/2+/3+, examined by immunohistochemistry was 44%/25%/13%/17%, respectively. Two patients in N+I arm had a K-ras mutation in codon 12 or 13. The efficacy analysis was conducted 6 months after completion of randomization with median follow-up period of 197 days. Median PFS was 73.0 days in N+I arm compared with 85.0 days in I arm (HR 0.860; 95% CI, 0.516, 1.435). MST was 293.0 days in N+I arm compared with 227.0 days in I arm (HR 0.717; 95% CI, 0.420, 1.224). In the sub-analysis, the hazard ratio in PFS for patients with EGFR +1/2+/3+ was 0.463 (95%CI, 0.177, 1.212) and that of EGFR 2+/3+ was 0.341 (95% CI, 0.080, 1.457) and the hazard ratio in OS was 0.584 (95% CI, 0.242, 1.409) and 0.295 (95% CI, 0.077, 1.129), respectively. The incidence of adverse events was similar between both arms. No adverse events of grade 3 skin rash or grade 3 infusion-related reaction were reported.

Conclusions: These results didn't demonstrate clear benefit at this sample size. However, EGFR-positive patients treated nimotuzumab showed a potential improvement of PFS and OS. This study supports the selection of gastric cancer patients by molecular status for future study of nimotuzumab.

[Table: see text]
Incidence and distribution of HER2-positive gastric and gastroesophageal junction (GEJ) adenocarinomas in British Columbia (BC).
Authors: Lim H. J. , Aubin F. , Kollmannsberger C. K. , Huntsman D. , Carter B. , Zhou C. , Woods R. , Gill S.
Published: February 2017

91

Background: HER2-positive rates have been reported as 20% of GC and 34% in GEJ adenocarcinoma in a recent global phase III trial with trastuzumab and chemotherapy. This study examines the incidence and distribution HER2-positive GC and GEJ adenocarcinomas in the province of BC.

Methods: Formalin fixed embedded tissue from patients (pts) with resected gastric or GEJ adenocarcinoma from 2004-2007 were identified retrospectively through the BC Cancer Agency registry and prospectively for pts with a new diagnosis of advanced disease. Biopsies and resection samples were analyzed via previously validated methods IHC (Ventana 4B5 antibody), FISH (Eurovision probes) and SISH (Ventana probes). IHC scores of 3 were considered positive, 2 were cequivocal and 0 or 1 were negative. A 10% cut-off was used to determine positive samples. Equivocal staining was considered positive via FISH or SISH. A ratio of > 2.0 was considered amplified for FISH and SISH. P values were calculated using a logistic regression model with HER2 positive as the endpoint.

Results: Of the 87 samples, 64 (74%) were gastric and 23 (26%) GEJ. Overall, HER2 was positive 20% (IHC), 18% (FISH) and 18% (SISH). 13% of cases tested IHC 3+ while 24% tested IHC 2+. In equivocal IHC 2+ cases, 7% were considered positive by FISH. Positivity rates were higher for GEJ (26%, 22% and 17%) vs. gastric (8%, 11% and 9%) via IHC (p = 0.02), but did not significantly differ by FISH (p = 0.19), or SISH (p = 0.30) respectively. The majority of positive cases were intestinal type vs. other (diffuse type or mixed) 25% vs. 0% IHC p = 0.0002, 25% vs. 3% FISH p = 0.001, 20% vs. 3% SISH p = 0.006. The positivity rates were similar with biopsy vs resection specimens (12% vs. 16% IHC p = 0.64, 12% vs. 21% FISH p = 0.30, 12% vs. 10%, SISH p = 0.88).

Conclusions: The rates of HER2-positive disease in a Western population based study were similar to the ToGA study. HER 2 positivity was associated with cancers arising in the GEJ and of intestinal type. The frequency of positivity was similar for testing by biopsy versus resection specimens. This study is ongoing and updated results will be reported.

No significant financial relationships to disclose.
Under- and upgrading of prostate cancer after radical prostatectomy in a screening setting.
Authors: Zhu X. , Bul M. , van Leeuwen P. J. , Roobol M. J. , Schröder F. H.
Published: February 2017

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Background: It has been well established that there is an upward drift in assigned Gleason score (GS) to prostate cancer (PC) biopsies. However, few studies have examined the concordance between biopsy GS and pathological GS after radical prostatectomy (RP) in a screening setting over time. We assessed the proportion of under and upgrading of PC after RP by comparing the prevalence screen with the incidence screens from the European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam.

Methods: From 1993 to 1999, a total of 42.376 men identified from population registries in the Rotterdam region (55-74 yrs) were randomized into a screening or control arm. Men with PSA ≥3.0 ng/ml were recommended for sextant prostate biopsy, which were lateralized since 1996. The screening interval was 4 yrs. Men with screen-detected PC, who underwent RP within 1 yr, were eligible for this study.

Results: In all, biopsy and pathological GS were known for 639 men who underwent RP. Of these RPs, 405 were performed between 1994 and 2000 (prevalence screen) whereas 235 cases were performed between 1998 and 2008 (incidence screens). In the prevalence screen, 49.8% of the biopsy GS matched the pathological GS ( Table ). This percentage improved to 58.3% in the incidence screens (p=0.045). The proportion of undergrading after RP was 23.0% in the prevalence screen, which declined to 16.2% in the incidence screens (p=0.049). Upgrading occurred in 27.2% of the cases in the prevalence and 25.5% in the incidence screens (p=0.71).

Conclusions: We have demonstrated an improved concordance between biopsy and pathological GS over time by comparing cancers detected in the prevalence screen with those detected in the incidence screens, which is in line with the upward shift of GS classification over time. In addition, significant less undergrading occurred in the incidence screens. However, one should keep in mind that within this screening program still a quarter of the biopsy GS were upgraded after RP in the incidence screens.

[Table: see text]

[Table: see text]
Use of a surgically derived nomogram to predict high likelihood of Gleason score upgrading for favorable-risk prostate cancer treated with permanent seed brachytherapy.
Authors: Bowes D. , Crook J. M. , Wallace K. , Evans A. , Toi A. , Finelli A. , Jewett M. A.
Published: February 2017

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Background: Crook et al have reported a 7-year disease-free survival (DFS) of 95.2% in 1,111 men with prostate cancer treated with Iodine-125 permanent seed brachytherapy (BT) at Princess Margaret Hospital. Two nomograms have been developed that estimate the likelihood of Gleason score (GS) upgrading for patients with favorable risk prostate cancer undergoing radical prostatectomy (RP). The purpose of this project was to apply these nomograms to a cohort treated with BT.

Methods: Records were examined for all men receiving prostate BT in 2006-7. 217 had favorable risk disease. The likelihood of GS upgrading was predicted using RP-derived nomograms created by Kulkarni et al (PMH, 2007) and Budaus et al (2010). Clinical and pathologic information were available on 208 patients to allow completion of the Kulkarni nomogram, and on 193 patients for the Budaus nomogram.

Results: The median age of the BT cohort was 62 years (range 44–77), and the median PSA level 4.68 ng/ml. Clinical stage was T1 in 65%, and 47.6% had positive findings on transrectal ultrasound. Median prostate volume was 33.3 cc (15.0–72.3). Uro-pathology review was available for 93%. 84.1% had extended biopsies, with 40.9% showing prostatic intraepithelial neoplasia and 10.1% inflammation. The median % of positive cores was 25%, with a median maximum % involvement per core of 20%. Two men received androgen deprivation therapy for prostate downsizing. The median predicted likelihood of GS upgrading was 51.6% using the Kulkarni nomogram, and 43.6% using the Budaus nomogram. The median PSA after 3.2 years median follow-up is 0.18 ng/mL.

Conclusions: In a population of men with favorable risk prostate cancer treated with BT, the estimated likelihood of GS upgrading using two surgical nomograms was substantial. The study cohort was taken from a larger population of patients treated over 10 years for whom 7-year DFS is 95.2%. This suggests that permanent seed brachytherapy is a highly effective treatment option for patients with favorable risk disease despite unfavorable clinical and pathologic factors. Patients should not be discouraged from brachytherapy on the basis of a high likelihood of GS upgrading.

No significant financial relationships to disclose.
11c-choline-PET/CT versus transrectal ultrasound-guided prostate biopsy to diagnose locally recurrent prostate cancer following radiation therapy.
Authors: Heidenreich A. , Pfister D. A. , Epplen R. , Brehmer B.
Published: February 2017

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Background: Radical salvage prostatectomy (SRP) represents one local secondary treatment option with curative intent in patients failing radiation therapy (RT) for localized prostate cancer (PCA). 11C-PET/CT represents an innovative imaging study to detect systemic spread of prostate cancer. However, there is only limited experience with regard to the sensitivity of C-PET/CT to detect locally recurrent PCA following radiation therapy. The purpose of our study was to analyse the sensitivity of C-PET/CT to diagnose PCA and extra- and intraprostatic extension.

Methods: 45 patients with the suspicion of locally recurrent PCA underwent 12-core transrectal ultrasound- guided biopsy of the prostate, C-PET/CT, bonne scan and radical salvage prostatectomy. Findings of the imaging studies were correlated with the pathohistological findings of the prostate biopsy and the radical prostatectomy specimen. All prostatectomy specimens were proceeded according to the Stanford protocol and the number and location of intraprostatic cancer foci > 5mm were correlated with the PE/CT findings.

Results: The mean preoperative serum PSA was 7.8 (2–24) ng/ml; the mean biopsy Gleason Score was 5.6 (4–9). Prostate biopsy was positive in 37/45 (82.2%) patients whereas 8/45 (17.8%) had a negative biopsy despite positive PET/CT findings. PET/CT was positive in 45/45 patients. Radical prostatectomy specimens identified locally recurrent PCA in 44/45 (97.8%). One patient turned out to have pT0pN0 disease despite increasing PSA. PET/CT identified 1, 2, and > 2 intraprostatic cancer foci of significant volume in 23 (51.1%), 13 (28.9%) and 9 (20%) patients, respectively. Sensitivity to detect intraprostatic, histologically proven PCA foci is 95.6% which is significantly superior to the biopsy results. There was a high correlation between the PET/CT results and the final histology of the radical prostatectomy specimens.

Conclusions: Choline PET/CT is an innovative imaging to identify patients with locally recurrent PCA following radiation therapy. PET/CT is superior to prostate biopsy and we recommend a PET/CT in patients who are candidates for radical salvage prostatectomy.

No significant financial relationships to disclose.
Inappropriate utilization of radiographic imaging in men with newly diagnosed prostate cancer.
Authors: Prasad S. M. , Gu X. , Lipsitz S. R. , Nguyen P. L. , Hu J. C.
Published: February 2017

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Background: The use of radiographic imaging (bone scan, computerized tomography and magnetic resonance imaging) following diagnosis of prostate cancer is recommended only in the setting of high-risk pathologic features. This study sought to characterize utilization patterns of imaging in men with newly diagnosed prostate cancer.

Methods: We identified 30,183 men diagnosed with prostate cancer from 2004-2005 using Surveillance, Epidemiology and End Results-Medicare linked data to characterize the determinants of radiographic staging following prostate cancer diagnosis.

Results: 36% of men with low risk and 49% of those with intermediate risk prostate cancer underwent unnecessary imaging for staging, while only 61% of men at high risk received any imaging test prior to treatment. Use of imaging was more common in men who were older than 75 (OR 1.25, CI 1.17–1.33) black (OR 1.11, CI 1.01–1.21), wealthier (OR 1.19, CI 1.08–1.32 for median income >$60,000 vs <$35,000), living in rural regions (OR 1.22, CI 1.11–1.34) and who underwent radiation therapies ( Table ). It was less common in men who were educated (OR 0.84, CI 0.76–0.92 between highest and lowest education levels) and chose active surveillance. There was no association between use of imaging and either marital status or Charlson score.

Conclusions: There is widespread overutilization of staging in low and intermediate risk patients, while a worrisome number of men at high risk undergo treatment without appropriate diagnostic imaging. Physicians may be prescribing costly and unnecessary tests with associated harmful radiation in over a third of patients while forgoing the recommended metastatic workup in almost 40% of high-risk patients prior to treatment.

[Table: see text]

No significant financial relationships to disclose.
Preclinical evaluation of 99mtechnetium-HYNIC(tricine/TPPTS)-aca-bombesin(7–14) as a targeted imaging agent in prostate cancer.
Authors: Ananias H. J. , Yu Z. , Elsinga P. H. , de Jong I. J.
Published: February 2017

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Background: The peptide bombesin (BN) and derivates thereof show high binding affinity for the gastrin-releasing peptide receptor (GRPR), which is highly expressed in primary and metastasized prostate cancer. We have synthesized a new BN-based radiopharmaceutical 99mTechnetium-HYNIC(tricine/TPPTS)-Aca-BN(7–14) (99mTc-HABN) and evaluated its GRPR targeting properties in vitro and in a xenograft tumor model for human prostate cancer in athymic mice.

Methods: 99mTc- HABN was synthesized and its lipophilicity and stability were investigated. The IC50, internalization and efflux properties were determined in vitro using the GRPR expressing human prostate cancer cell line PC-3. 99mTc-HABN biodistribution and microSPECT imaging were performed in PC-3 tumor-bearing athymic mice.

Results: 99mTc-HABN was prepared with high labeling yield (>90%), high radiochemical purity (>95%) and a specific activity of ∼19.8 MBq/nmol. The partition coefficient log P value was −1.60±0.06. 99mTc-HABN proved to be stable in human serum for 6 hours. The IC50 of HABN was 12.81±0.14 nM. Incubation of PC-3 cells with 99mTc-HABN demonstrated rapid cellular internalization and a long intracellular retention time. When mice were injected with 99mTc-HABN the activity was predominantly cleared via the kidneys. Uptake in the tumor was 2.24±0.64 %ID/g after 30 minutes, with a steady decrease during the 4 hours study period. In vivo experiments with a blocking agent showed GRPR mediated uptake. 99mTc-HABN microSPECT imaging resulted in clear delineation of the tumor.

Conclusions: 99mTc-HABN is a novel BN-based radiopharmaceutical that appears to be suitable for targeted imaging of prostate cancer.

No significant financial relationships to disclose.
A randomized, double-blind phase II trial of docetaxel plus prednisone (DP) combined with either AT101 or placebo for the first-line therapy of metastatic castration-resistant prostate cancer (CRPC).
Authors: Sonpavde G. , Matveev V. B. , Burke J. M. , Caton J. R. , Fleming M. T. , Karlov P. A. , Holmlund J. , Wood B. A. , Brookes M. , Leopold L. H.
Published: February 2017

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Background: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 protein family has broad preclinical activity including synergy with docetaxel (D). AT-101 has demonstrated activity alone and in combination with D in D-refractory patients with metastatic CRPC.

Methods: A randomized, double-blind, placebo-controlled phase II trial was conducted to compare the combination of DP with either A or placebo in chemo-naive men with progressive metastatic CRPC. A key requirement was progression (bone scan, RECIST or rising PSA ≥ 2 ng/mL) despite androgen deprivation. Stratification factors were pain and performance status. Patients received DP (75mg/m2 day 1; 5mg PO b.i.d.) Q 21 days (1 cycle) with either A (40 mg b.i.d.) or placebo PO on days 1–3. Radiological assessments were performed every 3 cycles. Primary endpoint was overall survival (OS) and 221 patients were planned for 110 events (80% power, HR 0.67, 1-sided alpha 0.1).

Results: 221 patients were randomized to ADP or placebo-DP and baseline factors were balanced. Efficacy outcomes (OS, PFS, PSA declines, disease control) were not significantly different ( Table ). In a subgroup of patients with poor-risk CRPC (n=34), efficacy endpoints appeared to favor ADP with a median OS of 19 months vs.14 months for placebo-DP. Grade 3/4 AEs that occurred with higher incidence in the ADP arm compared to placebo-DP included cardiac AEs (5% vs. 2%), lymphopenia (23% vs. 16%), neutropenia (47% vs. 40%), ileus (2% vs. 0%) and pulmonary embolism (6% vs. 2%).

Conclusions: The combination of AT-101 with DP in men with chemonaive metastatic CRPC was well tolerated but did not extend OS compared to placebo-DP. There was a potential benefit in a subset of high-risk patients.

[Table: see text]

[Table: see text]
Intermittent androgen-deprivation therapy in the management of castrate-resistant prostate cancer (CRPCa): Results of a multi-institutional randomized prospective clinical trial.
Authors: Organ M. , Wood L. , Wilke D. , Skedgel C. , Thompson K. , North S. , Cheng T. , Winch S. , Rendon R.
Published: February 2017

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Background: Patients who develop CRPCa typically continue on androgen deprivation therapy (ADT). Whether these patients need to remain on ADT has not been well studied. We conducted a multicenter randomized trial to compare intermittent versus continuous approach to ADT in CRPCa patients. Overall survival, health related quality of life (QOL) and cost were the main endpoints. We hypothesized that the intermittent approach would be cost-saving while maintaining similar oncologic and QOL outcomes.

Methods: CRPCa patients were randomized 1:2 to continuous or intermittent luteinizing hormone releasing hormone agonists (LHRHa). Patients were followed with clinical assessments, laboratory investigations, and QOL questionnaires (EORTC QLQ-C30 or PROSQOLI) every 2 months. If the serum testosterone rose above castrate levels (1.75nmol/L), LHRHa were re-initiated. The study was designed to close if >50% of patients needed to restart ADT in the intermittent arm.

Results: 31 patients were followed with a median follow-up of 26.8 months; 18 in the intermittent arm and 13 in the continuous. 12/18 patients on the intermittent arm were re-initiated on LHRHa at a median time of 17.9 months. There was no difference in overall or cancer-specific survival between the two arms. There was no statistically significant difference in QOL between the two arms at 0 and 12 months. The total mean costs at 24 months were significantly lower in the intermittent arm (3135 $CAD vs 8253 $CAD, p=0.0167) compared to the continuous arm largely due to the reduced costs of the LHRHa.

Conclusions: We have observed that intermittent ADT in patients with CRPCa, using a testosterone of >1.75 ngmol/L as a trigger to re-initiate LHRHa, results in a substantial cost savings with no negative impact on oncologic and QOL outcomes. These findings need to be corroborated in a study with a larger sample size.

[Table: see text]