bluuebunny/crossref_metadata_2025 huggingface dataset:
The final report of post-marketing surveillance for cetuximab in colorectal cancer in Japan.
Authors: Yamaguchi K. , Satoh T. , Watanabe T. , Ishiguro M. , Maruyama K. , Seriu T. , Miki T. , Ito H. , Sugihara K. , Sakata Y. ,   Advisory Board for Proper Use of Cetuximab
Published: February 2017

590

Background: Cetuximab (ERBITUX) was approved in Jul 2008 in Japan with indication for EGFR-positive and unresectable metastatic or refractory colorectal cancer. Post-marketing surveillance is required by Japanese Health Authority to collect, obtain, verify or validate information on the safety, efficacy and quality of medicines. We conducted this surveillance in all patients treated with cetuximab to access in practical use since clinical data on Japanese patients are limited.

Methods: The target number of patients was 1,800. Following adverse drug reactions were investigated: infusion reaction, skin disorders, interstitial lung diseases, electrolyte abnormalities (including hypomagnesemia), heart toxicities, gastrointestinal disorders, thrombosis/embolism, delayed wound healing, and eye disorders.

Results: Between Sep 2008 until Jan 2010, 2,126 pts registered, 2,006 pts were evaluable for safety (safety population), 1,687 pts for efficacy (efficacy population). Of the 2,006 pts, 1,975 pts (98.5%) were EGFR-positive. Patients characteristics: male/female; 1,234/772 (61.5%/38.5%), median age; 64 (range 18-87), site of primary tumor; colon/rectal/others (multiple selection); 1,235/775/3 (61.6%/38.6%/0.2%), PS0/PS1; 1,370/630 (68.3%/31.4%), combination chemotherapy; cetuximab monotherapy/CPT-11/FOLFIRI: 460/1,255/256 (22.9%/62.56%/12.8%). Of the 2,006 pts, 133 pts (6.6%) and 1,869 pts (93.2%) were treated in second-line and in third-line or later treatment, respectively. The adverse drug reactions incidence was 89.9%. Incidence of skin disorders, gastrointestinal disorders, electrolyte abnormality including hypomagnesaemia, and infusion reaction were 83.7%, 23.1%, 11.5%, and 5.7%, respectively. Efficacy result: Of the 1,687 pts, 658 pts (39.0%) were evaluated to be effective. Of the 658 pts, 614 pts (93.3%) experienced skin adverse reactions.

Conclusions: This post-marketing surveillance confirms the safety and efficacy of cetuximab in the Japanese population treated in clinical practice. The outcome of this surveillance with Japanese 2,006 pts would be useful for clinical use of cetuximab.

[Table: see text]
Increased incidence of adverse events after concomitant hepatic arterial infusion plus systemic chemotherapy and bevacizumab for colorectal cancer with liver metastasis.
Authors: Sadahiro S. , Suzuki T. , Maeda Y. , Tanaka A. , Okada K. , Ogoshi K. , Kamijo A.
Published: February 2017

591

Background: FOLFOX+bevacizumab (BEV) is the standard systemic chemotherapy for metastatic colorectal cancer (CRC). We investigated the combination of FOLFOX4 and hepatic arterial infusion (HAI) in patients who had isolated liver metastasis from CRC. We also compared efficacy and safety between this combination therapy and its concomitant use with BEV.

Methods: Twenty-five patients entered a phase I/II trial of HAI (5-FU 250 mg/d, leucovorin 25 mg/d; d1-7, q2w) combined with FOLFOX4. Fourteen other patients with a similar background received HAI + FOLFOX4 combined with BEV and the two regimens were compared.

Results: In the phase I/II study, the recommended doses for FOLFOX were as follows: L-OHP, 85 mg/m2; l-LV, 100 mg/m2; 5-FU (bolus), 400 mg/m2; and 5-FU (infusion), 600 mg/m2. Sixteen patients who received this regimen showed a response rate of 93.8% (2 CR and 13 PR), a median progression-free survival of 323 days, and a one-year survival rate of 93.7%. In the subsequent phase II trial of HAI + FOLFOX4 with BEV, 14 patients were enrolled and the response rate was 78.6% (2 CR and 9 PR). The outcome was inferior when BEV was used concomitantly. The median numbers of doses were 10 (range: 1-27) for FOLFOX4 and 9 (1-27) for HAI without BEV, whereas the corresponding numbers with BEV were 8 (1-12) and 2 (0-9), respectively. There was a marked decrease in the number of HAI procedures when BEV was used. Thrombosis occurred in 8 patients who received concomitant BEV, which was the most common reason for cessation of HAI. Other adverse events (≥Grade 3) were neutropenia (n=7; 43.8%) and thrombocytopenia (n=2; 12.5%) without BEV or neutropenia (n=7; 43.8%) and diarrhea (n=1; 7.1%) with BEV, and no marked difference was seen between the two regimens. Both regimens were well tolerated. Severe neuropathy was only observed in 1 patient (6.3%; Grade 3) who received concomitant BEV.

Conclusions: In the present study, HAI + FOLFOX combined with BEV caused thrombosis and disturbance of wound healing, thereby increasing the incidence of complications and making it difficult to continue treatment. These findings suggest that BEV should not be administered with HAI therapy.

No significant financial relationships to disclose.
A phase II trial of high-dose cetuximab (cmab) plus irinotecan in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (MCRC) who progressed on standard-dose cmab plus irinotecan.
Authors: Patta A. M. , McMahon J. A. , Samborski C. , Fakih M.
Published: February 2017

598

Background: Prior clinical data suggest a dose-related response to cmab when combined with irinotecan in pts with KRAS WT tumors who do not develop grade 2 and above rash with standard cmab dosing. However, the investigation of higher doses of cmab in the setting of acquired or innate resistance to standard dose cmab has not been previously investigated. We conducted a phase II clinical trial of high-dose cmab plus irinotecan in KRAS WT pts with standard-dose cmab plus irinotecan – refractory disease to address this question.

Methods: Pts with KRAS WT MCRC progressing on standard dose of cmab with irinotecan were eligible for study. Pts should have received a minimum of 6 weeks of prior standard dose cmab plus irinotecan and progressed within 4 weeks from the last dose. Cmab was administered at 500 mg/m2/week and irinotecan was administered at the same dose/schedule on which the patient previously progressed. 12-week PFS rate was the primary endpoint.

Results: 8 pts were treated on study: median age 68 yrs (45-85), 5 pts were males, ECOG performance status was 1 in all 8 pts. Grade ≥ 3 toxicities consisted of hypomagnesaemia (4 pts), anemia (1 pt), leucopenia (1 pt), fatigue (1 pt), and diarrhea (1 pt). 6 pts achieved stable disease (with regression in target lesions noted in 3 pts). 12 week PFS rate is 5/8 and 18 week PFS is 4/8. 3 pts remain on study at 4.5, 5, and 8 months from enrollment.

Conclusions: High-dose cmab/irinotecan is well tolerated except for hypomagnesemia. Encouraging prolonged disease stabilizations warrant further investigation of this approach in pts in KRAS WT population. Accrual is ongoing.

[Table: see text]
Prophylactic administration of epinephrine in oxaliplatin-related hypersensitivity reaction.
Authors: Iwasa S. , Hamaguchi T. , Tada K. , Yanai T. , Hashimoto H. , Nakajima T. E. , Kato K. , Yamada Y. , Shimada Y.
Published: February 2017

610

Background: Alongside disease progression or neurotoxicity, oxaliplatin-related hypersensitivity reaction is a common reason for treatment discontinuation and remains a critical issue. It is unclear whether prophylactic administration of epinephrine to patients with this severe hypersensitivity reaction is effective and safe.

Methods: We retrospectively reviewed 839 consecutive colorectal cancer patients treated with oxaliplatin-containing regimens at our hospital between April 2005 and March 2010. The medical records of those patients who had received prophylactic epinephrine (1:1000 solution) were examined. Hypersensitivity reaction was graded according to CTCAE version 3.0.

Results: Twelve patients (8 male and 4 female; median age, 66 years) had received prophylactic epinephrine. The hypersensitivity reaction, even though the patients were receiving prophylactic corticosteroid and antihistamine drugs, was grade 0/1/2/3 = 0/0/10/2. The median number of epinephrine doses administered was 6 (range, 1 to 21). The worst grade of hypersensitivity for rechallenge with oxaliplatin under prophylactic administration of epinephrine was grade 0/1/2/3 = 4/3/4/1. Reasons for treatment discontinuation were disease progression in 10 patients and neurotoxicity in one patient. The remaining one patient developed grade 3 hypersensitivity reaction during 4 cycles of treatment under prophylactic administration of epinephrine, but the reaction subsided after additional administration of epinephrine and corticosteroid. Common adverse events with administration of epinephrine were hypertension (4 patients), palpitation (3 patients) and headache, dizziness, fatigue, and bladder pain (1 patient each).

Conclusions: Prophylactic administration of epinephrine may be effective and tolerated in patients with moderate to severe oxaliplatin-related hypersensitivity reaction.

No significant financial relationships to disclose.
Clinical experience with neuroendocrine rectal tumors.
Authors: Derbel O. , Limem S. , Tassy L. , Desseigne F. , Rivoire M. , Meeus P. , Peyrat P. , Stella M. , Martel-Lafay I. , De La Fouchardiere C.
Published: February 2017

611

Background: Carcinoids are heterogeneous neuroendocrine tumors with malignant potential. The rectum is the third most common location for gastrointestinal carcinoids after small bowel and colon. Due to their rarity, the characteristics and behavior of this unusual malignancy remain unclear.

Methods: Retrospective review of the clinicopathologic features of patients treated for carcinoid tumors of the rectum.

Results: A single institute's tumor registry was retrospectively queried, identifying nine patients with rectal carcinoid tumors over a 10-year period. The mean age at diagnosis was 57.6 years. Four of the nine patients were female. Presenting symptoms included abdominal pain in five patients, rectal bleeding in two patients and a change in bowel habits in one patient. As previously reported, no patient had symptoms consistent with carcinoid syndrome. The rectal tumor size was > 2 cm in five patients. The rectal tumor was located in the lower third of the rectum in three cases (< 5 cm from anal verge) whereas three were in the middle third (6-11 cm) and two in the upper third (11-15 cm). Four of the tumors were well differentiated tumors (grade 1), 1 was atypical carcinoid or moderately differentiated tumors (grade 2), and 4 were poorly differentiated tumors (grade 3) according to the SEER. Initially, 5/9 patients had distant metastasis. As an initial site of metastasis, the liver was the most common site (4/5 patients, 80%). Five patients underwent surgical treatment of their rectal tumor, two with endoscopic transanal resection whereas 3 patients had a low anterior resection (LAR). Three patients received chemotherapy treatment only in the metastatic setting and one patient received chemotherapy and radiotherapy as palliative treatment. Of the nine patients, five had progressive disease after initial treatment. With a median follow-up of 14 months, the overall survival of the entire population was 13.4 months.

Conclusions: Neuroendocrine carcinomas of rectum are uncommon. Only small rectal carcinoids can be safely managed and surgery represents the treatment that can offer a greater chance of survival to these patients. Larger primary tumors have a high tendency to spread early. They are associated with aggressive behavior, resistance to chemotherapy and poor prognosis.

No significant financial relationships to disclose.
Characteristics of treatment-related dermatological toxicity in colorectal carcinoma.
Authors: O'Reilly A. M. , Bird B. R. , O' Keeffe J.
Published: February 2017

617

Background: The use of novel targeted therapies is becoming increasingly prevalent. This study aimed to determine how novel- targeted therapies have changed the profile of dermatological toxicity in patients being treated for colorectal carcinoma.

Methods: Retrospective analysis was performed in a single institution for all patients presenting over a period of 4 weeks. Participants were followed up for the remainder of the study period. Patient charts were reviewed for previou incidences of dermatological toxicity. Toxicity was graded using the Common Toxicity Criteria version 3. Statistical analysis was performed using SPSS version 19.

Results: A total of 45 patients receiving treatment for colorectal carcinoma were included in the final analyses. Twenty-nine of these received novel targeted therapy (NTT) including bevacizumab, cetuximab, capecitabine, and panitumumab. Sixteen participants received traditional chemotherapy. In total 79 toxicities were evaluated. Participants receiving NTT experienced a higher mean number of toxicities (2.2 [95%CI 1.9-3.7]) then those receiving traditional chemotherapy (0.9 [95%CI 0.6-1.2]), p < 0.01. Those receiving NTT experienced significantly more HFS (p < 0.01) and rash (p < 0.01) Participants receiving NTT experienced significantly more grade 2 or above dermatological toxicity (p < 0.01) Those receiving NTT underwent more alterations in chemotherapy then those receiving traditional chemotherapy (p < 0.05). HFS affected 14 (31%) participants, 4 of these were grade 2 or above. Twenty (44%) participants experienced rash, 4 of these were grade 2 or above. All patients (9) receiving cetuximab experienced acneiform rash, 3 were grade 2 or above, 5 patients required dose reduction/dose delay. Fifteen (33%) participants experienced stomatitis. Additional toxicities evaluated include alopecia (13%), nail dystrophy, and xerosis.

Conclusions: Those receiving novel targeted therapy for the treatment of colorectal carcinoma may be at increased risk of developing dermatological toxicity. Dermatological toxicity in this group may be of higher grade and greater complexity. Treatment of dermatological toxicity in this group may require more dose modifications.

No significant financial relationships to disclose.
A retrospective study of first-line combination chemotherapy in advanced colorectal cancer: A Korean single-center experience.
Authors: Lee S. , Park J. , Park S. , Kang W. , Lim H. , Park Y. , Park K. , Lee J.
Published: February 2017

623

Background: Fluoropyrimidine-based combination chemotherapy, in combination with either oxaliplatin or irinotecan, have demonstrated efficacy and tolerability against advanced colorectal cancer (ACC).

Methods: Between Jan 2006 and Dec 2007, 478 ACC patients were treated with combination chemotherapy in first-line setting: 5-fluorouracil, folinic acid plus oxaliplatin (FOLFOX, n=172), 5-fluorouracil, folinic acid plus irinotecan (FOLFIRI, n=95), capecitabine plus oxaliplatin (XELOX, n=155), and capecitabine plus irinotecan (XELIRI, n=56). FOLFOX and FOLFIRI were repeated every 2 weeks, whereas XELOX and XELIRI were repeated every 3 weeks until disease progression or unacceptable toxicity occurred or until a patient chose to discontinue treatment.

Results: The median age was 58 years (range, 19-84 years) and the median chemotherapy duration for FOLFOX, FOLFIRI, XELOX and XELIRI were 4.9, 4.5, 5.7 and 5.4 months, respectively. Combination chemotherapy regimens were generally well tolerated. The estimated median PFS for all patients was 6.8 months (95% confidence interval, 6.3-7.3 months). No statistically significant difference in PFS was found each regimen used as first-line chemotherapy. Sixty-percent (n=290) of patients received second or further lines of therapy after failure.

Conclusions: Fluoropyrimidine-based combination chemotherapy regimens appear to be equally active and tolerable as first-line therapy for ACC.

No significant financial relationships to disclose.
Analysis of pO2 in malignant ascites of patients with peritoneal dissemination of gastric cancer.
Authors: Emoto S. , Kitayama J. , Ishigami H. , Yamaguchi H. , Yamashita H. , Kaisaki S. , Nagawa H.
Published: February 2017

63

Background: Peritoneal metastasis is considered to develop from carcinoma cells detached from the serosal surface of the primary site and dispersed in the peritoneal cavity. And oxygen is one of the most important environmental factors for tumor development. To investigate the oxygenation condition in the abdominal cavity, that is largely unknown, we collected ascitic fluid from patients with peritoneal dissemination of gastric cancer and measured pO2 of it.

Methods: In 19 patients with peritoneal dissemination of gastric cancer, who had a considerable amount of ascites and was receiving systemic and/or intraperitoneal chemotherapy, ascitic fluid was collected at the bedside in room air, and its pH, pCO2 and pO2 were measured using a blood gas analyzer immediately.

Results: In 19 patients, pH of malignant ascites was significantly lower than that of arterial blood (7.39 ± 0.069 vs 7.44 ± 0.025 mmHg, p < 0.05). pCO2 tended to be higher in ascites than in arterial blood. Unexpectedly, pO2 in malignant ascites showed relatively high values (85.47 ± 23.31 mmHg), which were mostly the same as that of arterial blood (97.19 ± 10.40 mmHg, p = 0.149), and appeared to be higher than that in solid tumor tissue.

Conclusions: Malignant ascites in gastric cancer patients showed an unexpectedly high oxygen tension, which was almost the same as that of arterial blood. The hyperpermeability condition may enable efficient oxygen delivery to peritoneal fluid via the microvessels lining the peritoneal cavity. Since the oxygen level critically affects the sensitivity of tumor cells to chemotherapeutic agents through metabolic transformation, aerobic conditions may be beneficial for the progression of peritoneal metastasis and also clinically important in considering the efficacy of chemotherapy.

No significant financial relationships to disclose.
Reduction of nodal micrometastases in patients with histological node-negative esophageal cancer after neoadjuvant treatment.
Authors: Wang D. , Smit J. K. , Hollema H. , Plukker J. T.
Published: February 2017

73

Background: Neoadjuvant chemoradiation (CRT) is important in the treatment ofesophageal cancer. Rationales are tumor-downstaging and elimination of micrometastases improving resectability and curability rate. In this study we evaluated the effect of neo-adjuvant CRT on nodal micrometastases (NMM) in pN0 esophageal cancer patients.

Methods: From a prospective database, we selected a matched group of patients on cT-stage, histological type and treatment without (group 1) or with neo-adjuvant CRT (group 2). Patients were staged by EUS, PET-scan, CT-scan and EUS guided cytology. CRT was given in a randomized clinical trial and consisted of paclitaxel 50 mg/m2 and carboplatin AUC = 2 for 5 weeks and concurrent radiotherapy (41.4 Gy/23 frs). All patients (n = 19) underwent a curative intended transthoracic esophagectomy with extended 2-field nodal dissection. After reviewing routine pathological examination all tumors were confirmed as stage pN0. Four sections of every examined lymph node (n = 261) were made at different levels according to a sentinel node protocol and further analyzed immunohistochemically with anti-CK8/18 (CAM 5.2) to detect NMM.

Results: Patients characteristics were equally distributed. All patients had a microscopically radical (R0) resection. In group 2 (n = 9) the response rate was 55% which was complete (CR) in 33%. The median number of resected nodes was comparable: 15 ± 6.5 and 15 ± 5.6 in both groups. Thirtheen of the 261 (5%) pN0 nodes in these 19 pts contained NMM. In group 1 (n = 10); 12 of the 136 (9%) examined pN0 lymph nodes were positive and in group 2 only one of the 125 (0.8%) examined pN0 nodes was positive (p = 0.003). NMM were found in 7 pts (70%) in group 1 and in only one patient (11%) in group 2 (p = 0.02). Interestingly, this last patient had responded well to CRT.

Conclusions: Neo-adjuvant CRT seems to have a significant impact on the numbers of NMMs in esophageal cancer. Based on the presence of NMM even in patients with good responses, we still advocate a curatively intended nodal dissection.

No significant financial relationships to disclose.
Validation study of sentinel lymph node mapping using radio- and dye-guided methods in gastric cancer: 431 cases at a single institution.
Authors: Niihara M. , Takeuchi H. , Kamiya S. , Kaburagi T. , Oyama T. , Saikawa Y. , Wada N. , Takahashi T. , Nakamura R. , Kitagawa Y.
Published: February 2017

76

Background: Some papers have reported that sentinel lymph node (SLN) concept can be applied in patients with early gastric cancer, in particular clinically T1N0M0 or T2N0M0 with a tumor diameter of 4cm or less. Little is, however, available on the SLN study with the other criteria than listed above. The aim of the present work was to investigate the accuracy of the SLN biopsy of gastric cancer with various stages and evaluate the indication for SLN navigated gastrectomy.

Methods: A total of 431 consecutive patients were diagnosed with operable gastric cancer during the period April 1999 through December 2007. Reasons for inclusion were, in principle, T1N0M0 or T2N0M0 gastric cancer. However, several patients diagnosed preoperatively with T3N0M0, T2N1M0, remnant gastric cancer, multiple gastric cancers and additional treatment after endoscopic therapy were also enrolled in this study according to their request. All patients underwent a radical gastrectomy with SLN mapping with an informed consent. The SLNs were identified using both radio-guided and dye-guided method.

Results: Detection rate of hot and/or blue node was 95.8% (413/431). The accuracy of metastatic status based on SLN was 97.6% (403/413). In six of 10 false-negative cases, some clinical backgrounds and problems were present; scirrhous gastric cancer, the tumor penetration of serosa, multiple lesions, remnant gastric cancer after partial resection and the technical issue of tracer injection. Nine of these 10 false-negative cases had the metastatic lymph nodes within only the sentinel basins. Specifically, in the group of clinically T1N0M0 untreated gastric cancer with a tumor diameter of 4 cm or less, there were only 3 false- negative cases. In addition, all the metastatic lymph nodes of the 3 cases located within the sentinel basins.

Conclusions: Our study suggested that SLN concept for untreated early gastric cancer could be validated. The sentinel basin dissection might be used to advantage to improve curativity for gastric cancer.

No significant financial relationships to disclose.
The effect of preoperative chemotherapy on lymph node yield in gastric cancer.
Authors: Dikken J. L. , Krijnen P. , Van De Velde C. J. , Verheij M. , Gonen M. , van Grieken N. C. , Tang L. H. , Brennan M. F. , Coit D. G.
Published: February 2017

80

Background: While a minimum of 15 lymphnodes (LNs) should be evaluated for accurate staging of gastric cancer, LN yield in western countries is generally low. With the increasing use of preoperative chemotherapy, it is unknown what the effect of this treatment is on lymph node yield. The aim of the study is therefore to determine whether preoperative chemotherapy influences the number of LNs that can be obtained from specimens of patients who underwent curative surgery for gastric adenocarcinoma.

Methods: In1,205 patients from a high-volume U.S. center and 1,220 patients from the Netherlands Cancer Registry (NCR) who underwent a total or distal gastrectomy with curative intent for gastric adenocarcinoma, the LN yield was compared between patients who received preoperative chemotherapy and patients who received no neoadjuvant therapy. Multivariate Poisson regression was used to identify significant predictors of LN retrieval.

Results: Of the 2,425 patients who underwent a gastrectomy, 340 patients (14%) received preoperative chemotherapy. Median LN yields were 23 in the U.S. institution and 10 in the NCR. Separate multivariate analyses of the U.S. institution data and the NCR population showed in both groups that preoperative chemotherapy was not associated with a significant difference in LN yield (Table). Factors that were associated with higher LN yield were the same in both groups: female sex, younger age (6% more nodes with every 10 years decrease in age), total gastrectomy (vs. distal gastrectomy) and increasing tumor (T) stage.

Conclusions: In both a high-volume cancer center, and a population-based cancer registry, female sex, younger age, total gastrectomy and advanced tumor stage were associated with an increase in lymph node retrieval in surgical specimens. Preoperative chemotherapy did not influence lymph node yield after a resection for gastric cancer. The threshold for what should constitute an adequate assessment of regional lymph nodes after curative surgery for gastric cancer should not be changed after administration of preoperative chemotherapy.

[Table: see text]

No significant financial relationships to disclose.
Value of the primary tumor initial standardized uptake value (iSUV) of 18F-fluorodeoxyglucose positron emission tomography (PET) to predict overall survival (OS) in patients with esophageal or gastroesophageal junction carcinoma undergoing definitive chemoradiotherapy.
Authors: Suzuki A. , Xiao L. , Hayashi Y. , Welsh J. , Lin S. H. , Lee J. H. , Bhutani M. S. , Hofstetter W. L. , Mehran R. J. , Ajani J. A.
Published: February 2017

82

Background: The value of iSUV of PET for predicting OS is unclear in patients with advanced esophageal or gastroesophageal carcinoma treated with definitive chemoradiotherapy. We tested the hypothesis that iSUV would correlate with OS and recurrence free survival (RFS).

Methods: We performed retrospective analysis, selecting patients with esophageal or gastroesophageal carcinoma who had a pretreatment PET and endoscopic ultrasonography (EUS) and who received definitive chemoradiotherapy from 2002 to 2008. Correlations were performed with continuous and dichotomized iSUV, baseline EUS results, OS, and RFS.

Results: Two hundred and nine patients were analyzed. The median OS time was 20.7 months (95% CI: 18.8-26.3 months) and the median RFS time was 11.2 months (95% CI: 9.44, 14.34). OS rate and RFS rate at 3 years were 35.7% (95% CI: 29.0-43.9%) and 24.8% (95 % CI: 19.1–32.1 %). The median iSUV was 12.7 (range: 0–51). In univariate analysis, iSUV was associated with OS (Cox model, P = 0.012; log-rank test, P = 0.002) and RFS (Cox model, P = 0.0003; log-rank test, P < 0.0001). In multivariate analysis, dichotomized iSUV cut off by median was associated with OS (P = 0.024) but not RFS (P = 0.11).

Conclusions: Data from our study suggests that higher iSUV is associated with poor survival. Baseline PET may become a useful stratification factor in randomized trials and for individualized therapy.

No significant financial relationships to disclose.
Overall survival benefit with masitinib mesylate in imatinib-naive, locally advanced, or metastatic gastrointestinal stromal tumor (GIST): 4-years follow-up of the French Sarcoma Group phase II trial.
Authors: Blay J. , Le Cesne A. , Bin Bui N. , Bouche O. , Adenis A. , Julien D. , Cioffi A. , Moussy A. , Hermine O.
Published: February 2017

85

Background: Masitinib is a novel tyrosine kinase inhibitor which, in vitro, has greater activity and selectivity than imatinib (IM) against both wild-type KIT receptor and its mutated form in the juxtamembrane region (IC 50=100 nM versus 200 nM for IM, 3 nM versus 27nM and 40 nM versus 120nM, respectively, for exons 9,11, and 13). This multicenter phase II study evaluated efficacy and safety of masitinib as a first-line treatment of advanced GIST.

Methods: IM-naïve patients with inoperable, locally advanced or metastatic GIST received oral masitinib (7.5 mg/kg/day) until progression, refusal or toxicity. Efficacy variables included response rate, best response (RECIST), progression-free survival (PFS) and overall survival (OS). Initial results were previously reported in EJC 2010. We present here the same series with updated PFS and OS (median follow up of 48 months).

Results: 30 patients with a median age of 58 years (60% of males) were included from June 2005 to April 2007 in five French institutions. At the cut-off date (31 august 2010), 9 patients are still under treatment with a median treatment duration of 41 months (min=33, max=52). Two additional progressions have been reported for a total of 14 events (13 progressions and 1 death). Updated median PFS is 41 months (95% CI: [17.5; NR]) with PFS rates of 60% [39; 77], 56% [35; 73] and 45% [24; 64] respectively at 2, 3 and 4 years. With 8 patients dead, median OS is not yet reached with OS rates of 90% [72; 97], 87% [68; 95] and 74% [52; 87], respectively, at 2, 3, and 4 years. The main frequent relevant grade 3 toxicities were: rash (10%), neutropenia (7%) and abdominal pain (7%) with one patient presented a grade 4 skin exfoliation. No other relevant long-term toxicities were reported and no more patients discontinued treatment due to suspected toxicity.

Conclusions: The long term results observed with masitinib confirm a very interesting activity with prolonged PFS and OS. These results support the head to head comparison with imatinib in the currently ongoing phase III randomized clinical trial in first line locally advanced or metastatic GIST patients.

[Table: see text]
The Prostate Cancer Clinical Trials Consortium (PCCTC) bone scan data capture tool for clinical trials using Prostate Cancer Working Group 2 (PCWG2) criteria: Effect on data accuracy and workload.
Authors: Morris M. J. , Farrelly J. S. , Fox J. J. , Dennis E. R. , Schwartz L. H. , Schöder H.
Published: February 2017

121

Background: PCWG2 Concensus Criteria proposed time-to-event endpoints in early phase clinical trials. Chief among these was time to radiographic progression for bone scintigraphy (BS), based on a standardized definition with additional rulesets to account for early flare. The PCCTC created a tool to operationalize these definitions in clinical trials. We tested the impact of the tool on clinical trial workload and data adequacy.

Methods: The BS capture tool was vetted and amended through nine versions by a multidisciplinary group from PCCTC participating institutions. Accruals at Memorial Sloan-Kettering Cancer Center on two phase III trials using the same drug, contracting research organization (CRO), and electronic data capture system were analyzed. The first trial did not use the PCCTC tool. The second incorporated the tool in its data collection plan and case report form. Workload and data capture adequacy for each trial were determine by examining the total number of imaging queries from the database query reports obtained from the CRO as a function of the total number of scans and patients.

Results: Data from this analysis are found in the table . The relative number of queries per scan was reduced by 85.33% by use of the tool. The queries:scan ratios were 0.82 versus 0.12 before and after the use of the tool respectively; likewise, the ratios of queries: patient were 2.81 vs. 0.44.

Conclusions: Using the PCCTC BS tool to standardize data capture and operationalize PCWG2 radiographic progression criteria, imaging data are more completely reported and workload for study research staff decreased. The reproducibility and feasibility of the BS tool is further being tested in two ongoing phase III studies in which PCWG2 criteria are being clinically qualified. These efforts to quantitate, standardize, and qualify imaging data advance the goal of developing an imaging biomarker in metastatic prostate cancer.

[Table: see text]

No significant financial relationships to disclose.
Use of variation in sex steroid methyl transferases to predict efficacy of androgen-deprivation therapy (ADT) in advanced prostate cancer.
Authors: Kohli M. , Mahoney D. W. , Chai H. S. , Hillman D. W. , Rider D. R. , Costello B. A. , Cerhan J. R.
Published: February 2017

14

Background: We evaluated the association of germline variation in genes regulating hormonal pathways with duration of treatment response in prostate cancer patients receiving ADT, focusing on genes in the androgen biosynthesis (the C4 Δ; C5 Δ; C21 CYP pathways and the alternate “backdoor pathway”) and metabolism pathways.

Methods: We successfully genotyped 747 single nucleotide polymorphisms (SNPs) from 84 genes in a cohort of 304 patients with advanced prostate cancer who progressed on ADT. Tagging SNPs with a minor allele frequency (MAF) of >5% and r2 ≥0.8 were selected from HapMap, NIEHS and Seattle SNP databases. The primary endpoint was time to ADT failure, and we conducted a gene-level test (principal components), along with individual SNP level tests adjusted for patient age and Gleason score. To account for multiple testing, we calculated the false discovery rate (FDR), and FDRs of 0.10 were considered noteworthy.

Results: The median age of the cohort at ADT failure was 72 years (range 65-78 years), and the overall median time to ADT failure was 3.21 years (IQ [25-75]: 1.54-6.20 years). At the gene level, TRMT11 (tRNA methyltransferase 11 homologue) showed the strongest association with time to ADT failure (p<0.0008; adjusted p-value for FDR-0.068). Two of four TRMT11 tag SNPs were associated with time to ADT failure. The first was the intronic SNP rs1268121 (A>G) with a MAF of 15%, for which there was a positive association of median time to ADT failure with the number of variant alleles (p=0.023): 3.1 years for 0, 4.1 years for 1, and 5.9 years for 2 variant alleles. The second was the SNP rs6900796 (A>G) in the 3' untranscribed region with a MAF of 49%, for which the median time to ADT failure was 2.6 years for 0, 2.5 years for 1, and 3.8 years for 2 variant alleles (p=0.023). Four additional genes showed an association with ADT response at the p<0.10 level, including LOC390956, PRMT3, SLC7A6OS, and WBSCR22, although all FDRs were >0.95.

Conclusions: Variation in TRMT11 was associated with time to ADT failure. Confirmation of these findings in an independent cohort is needed.

No significant financial relationships to disclose.
Dose-finding and efficacy phase II study of inecalcitol, a new VDR agonist, in combination with docetaxel-prednisone regimen for castration-resistant prostate cancer (CRPC) patients (pts).
Authors: Medioni J. , Deplanque G. , Ferrero J. , Maurina T. , Rodier J. P. , Raymond E. , Allyon J. , Renaux S. , Dufour-Lamartinie J. , Oudard S.
Published: February 2017

142

Background: Inecalcitol is a novel vitamin D receptor (VDR) agonist which shows high antiproliferative effects in human cancer cell lines and a 100-fold lower hypercalcemic activity than calcitriol the natural ligand of VDR.

Methods: Escalating dosages of inecalcitol were combined to chemotherapy in naive metastatic CRPC patients. Safety and efficacy were evaluated in groups of 3-6 pts receiving inecalcitol every other day, daily or twice a day on a 21-day cycle in combination with docetaxel (75mg/m2 q3w) and oral prednisone (5mg bid). Pts received up to six cycles unless unacceptable toxicity or disease progression. Primary endpoint was dose limiting toxicity (DLT) defined as G3 hypercalcemia within the first cycle. Efficacy endpoint was PSA response defined as ≥30% decline within 3 months.

Results: Eight dose levels from 40 to 8,000 μg have been evaluated in 54 pts; 83 % had bone metastases, 13% had visceral disease only. Median age was 71 years (range, 49-87), median Gleason score (Gs) 7 and median PSA 28.5 ng/mL (range, 0.8-962.4). DLT occurred in 2/4 patients receiving 8,000 μg/day after 1 and 2 weeks of treatment. Calcemia normalized in few days after interruption of treatment. The 2 other experienced only G2 and were stepped down to 4,000 μg. After dose reduction, calcemia remained within normal ranges and G1.The maximum tolerated dose is defined at 4,000 μg qd. Most of adverse events reported were grade 2. G3-4 were mainly hematological toxicity. Frequency of AEs related to docetaxel did not seem to be modified.82% of the patients had ≥30% PSA decline within 3 months of treatment whereas in historical data around 65% are responder with docetaxel as a single agent. PSA response was observed after 1 cycle of treatment in 43% of the patients. Time to biochemical relapse defined as an increase of 25% over nadir was 169 days.

Conclusions: High antiproliferative daily dose of inecalcitol, a new VDR, agonist has been safely used in combination with docetaxel in CRPC patients. This combination treatment shows encouraging PSA response (> 30% PSA response: 82%). A multicenter randomized double blind phase III study is forecasted to confirm these results.

[Table: see text]
Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer (DRPC).
Authors: Reuter C. W. , Morgan M. A. , Gruenwald V. , Fenner M. , Ivanyi P. , Ganser A.
Published: February 2017

172

Background: Cabacitaxel has recently been approved by the FDA as second-line chemotherapy for patients progressing during or after first-line docetaxel chemotherapy. However, cabacitaxel treatment is hampered by high costs and toxicity. Carboplatin in combination with docetaxel may also be effective in DRPC. Platinum(II)-complexes have been shown to lower testosterone levels by inhibiting 3β-hydroxysteroid dehydrogenase and 17α hydroxylase (Schertl et al. J Cancer Res Clin Oncol. 2007;133:153-67).

Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Since February 2005, 55 consecutive DRPC pts were treated with at least two cycles of carboplatin AUC5 iv for 30 min on day 1 every 4 weeks (q4w), docetaxel at a dose of 35 mg/m2 iv for one hour on days 1, 8, (15) plus prednisone 2×5mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. Free testosterone levels were measured before and during carboplatin/docetaxel chemotherapy (n=25).

Results: Response of prostate-specific antigen (PSAR; ≥50% PSA) was observed in 28/55 (50.9%) patients. At the time of the current analysis the median follow-up time was 11.9 months and 32/55 patients had died. Median progression-free survival (PFS) for all patients was 7.5 months (CI 95% 5.7, 9.3) and median overall survival (OS) was 17.1 months (CI 95% 10.3, 23.9). In PSAR, PFS was 13.6 (CI 95% 7.8, 19.4) months versus 4.3 (CI 95% 2.9, 5.7) months in PSANR (p<0.001; hazard ratio HR 0.159) and OS was 24.4 months (CI 95% 18.1, 30.8) versus 8.1 (CI 95% 3.4, 12.8) months (p<0.001; HR 0.208). This regimen was reasonably well tolerated, with leukopenia/neutropenia as the most common reversible grade 3/4 toxicity (44.2/40.4%). Median free testosterone levels were 1.05 pg/ml before and 0.26 pg/ml during carboplatin/docetaxel treatment (p<0.01).

Conclusions: Our data suggest that carboplatin/docetaxel may be an important therapeutic second-line treatment option for DRPC patients by inferfering with the testosterone synthesis.

No significant financial relationships to disclose.
Can PSA testing stop 10 years after radical prostatectomy?
Authors: Loeb S. , Feng Z. , Ross A. , Trock B. J. , Humphreys E. B. , Walsh P. C.
Published: February 2017

179

Background: Biochemical recurrence (BCR) most frequently occurs within the first five years following radical prostatectomy. Prior studies have suggested an association between lower-risk disease features and BCR at 5 years postoperatively. The objective of our study was to determine predictors of BCR ≥10 years after radical prostatectomy, and to examine the relationship between timing of BCR with the subsequent risk of metastases and cancer-specific mortality.

Methods: Among 10,609 men from our institutional radical prostatectomy database, we identified 1684 men with BCR (PSA >0.2 ng/ml) without prior hormonal or radiation therapy. These men were classified into by the time of BCR: early (<5 years), intermediate (5-10 years), and late (>10 years). Univariable and multivariable models were used to examine the association of clinico-pathologic variables with the timing of BCR. We also examined metastasis-free and cancer-specific survival based upon the timing of BCR.

Results: Of BCR, 77.0%, 16.6%, 4.9%, and 1.5% occurred at <5, 5-10, 10-15, and >15 years postoperatively. Late recurrences were associated with more favorable pathologic features, and were unlikely to develop metastases or prostate cancer-specific mortality.

Conclusions: The majority of BCR occurs within 10 years of surgery. Although 6.4% of BCR occurred at ≥10 years, these patients were unlikely to subsequently develop metastases or die from prostate cancer. Patients who remain free from progression at 10 years postoperatively should be counseled that their risk of subsequent cancer-related morbidity and mortality is low.

No significant financial relationships to disclose.
Tumor response and adaptation to CYP17 inhibition in prostate cancer: Induction of steroidogenesis and androgen receptor splice variants.
Authors: Mostaghel E. A. , Marck B. , Matsumoto A. M. , Nelson P. , Vessella R. , Plymate S. R. , Montgomery R. B.
Published: February 2017

18

Background: Abiraterone is a novel inhibitor of the steroidogenic enzyme CYP17 and suppresses tumor growth in patients with castration-resistant prostate cancer (CRPC). The efficacy of abiraterone in suppressing tumor androgens or mechanisms of resistance to abiraterone are not known.

Methods: Human CRPC xenografts LuCaP 23 and LuCaP 35 grown in castrated male mice were treated with abiraterone to determine effects on tumor growth and tumor androgen levels. Tumor gene expression measurements were obtained to delineate mechanisms of abiraterone resistance.

Results: Abiraterone i.p. for 21 days improved survival (time to tumor size 750 mm3) vs vehicle control (VC) in LuCaP 35 (HR 3.8 [95% CI 3.1-53.7] median survival 39 vs 18 days) and LuCap 23 (HR 2.4 [1.43-10.24] median survival 24 vs. 14 days). Greater anti-tumor activity correlated with superior tumor androgen suppression. Tumor testosterone was strongly suppressed in both LuCaP35 (0.20 + 0.24 vs VC 0.69 + 0.36 pg/mg) and LuCaP 23 (0.07 + 0.11 vs VC 0.49 + 0.22 pg/mg). DHT levels were also markedly suppressed in LuCaP35 (1.17 + 1.46 vs VC 3.49 + 1.81pg/mg). In contrast, DHT levels in LuCap23 were unchanged early (day 7-21) and only partially suppressed at longer time points (VC 5.73 + 1.88; early 5.31 + 2.69; late 2.82 + 2.27 pg/mg). Expression of the abiraterone target CYP17 was upregulated in both xenografts (LuCaP23 2.5 fold, p<0.0001; LuCap35 2.9 fold, p=0.028). Overall, LuCap23 appeared resistant to suppression of tumor androgens due to induction of steroidogenic transcripts (including STAR, CYP11, HSD3B1 and AKR1C3) without statistically significant increases in androgen receptor (AR). In contrast, LuCap35 demonstrated strong induction of transcripts for AR and AR splice variants (AR 3.8 fold, p<0.0001, V7 AR splice variant 3.7 fold, p<0.0001), with induction of steroidogenic transcripts only at late time points.

Conclusions: Abiraterone treatment suppressed intratumoral androgen levels and reduced growth of CRPC xenografts. Abiraterone resistance may occur through upregulation of the abiraterone target CYP17, and/or the induction of AR and AR splice variants that confer ligand-independent AR trans-activation.

[Table: see text]
Diabetes mellitus, race, and the odds of high-grade prostate cancer in men diagnosed with prostate cancer in the United States.
Authors: Mitin T. , Chen M. , Moran B. J. , Dosoretz D. E. , Katin M. J. , Braccioforte M. H. , Salenius S. , D'Amico A. V.
Published: February 2017

180

Background: African American (AA) men present more frequently with high-grade prostate cancer (PCa) and are also more likely to have diabetes mellitus (DM). We evaluated whether there is an independent association between DM and the risk of high-grade PCa in men diagnosed with PCa, adjusting for the known predictors of high-grade PCa including AA race.

Methods: Between 1991 and 2009 15,377 men newly diagnosed with PCa and treated at 1 of 26 centers, were analyzed in 2 cohorts. Multivariable logistic regression was performed to evaluate whether a diagnosis of DM was associated with the odds of Gleason 7 or 8 to 10 PCa, adjusting for AA race, advancing age, PSA level, and DRE findings.

Results: AA men (AOR, 1.87; 95% CI, 1.04-3.37, P=0.04) and non-AA men (AOR, 1.61; 95% CI, 1.34-1.93; P<0.001) with diabetes were more likely to have GS 8 to 10 versus GS 6 or less PCa, compared to non-diabetic men. AA as compared to non-AA race was not significantly associated with the odds of having GS 8 to 10 as compared to 6 or less PCa, both in men with a diagnosis of DM (AOR, 1.47; 95% CI, 0.87-2.50; P=0.15) and without DM (AOR, 1.27; 95% CI, 0.92-1.74, P=0.14). AA race, however (AOR, 1.37; 95% CI, 1.17-1.60, P<0.001), but not DM (AOR 1.09; 95% CI, 0.97-1.22, P=0.16), was associated with GS 7 versus 6 or less PCa.

Conclusions: A diagnosis of DM is a risk factor for presenting with Gleason 8 to 10 PCa independent of race.

[Table: see text]

No significant financial relationships to disclose.
Diabetes and cancer risk in the REDUCE trial.
Authors: Wu C. , Moreira D. M. , Gerber L. , Rittmaster R. S. , Andriole G. L. , Freedland S. J.
Published: February 2017

194

Background: Men with diabetes mellitus (DM) are less likely to be diagnosed with prostate cancer (PC). As diabetic men have lower PSA values, it is unclear if this is due to reduced PC incidence or lower biopsy rates from the lower PSA. To account for differential biopsy rates, we explored the link between DM and risk of PC and high-grade PC in the REDUCE trial. We also explored if these associations differed by body mass index (BMI) as a prior study suggested BMI may modify the effect of DM on PC aggressiveness.

Methods: The 4-year REDUCE study tested the effect of dutasteride 0.5 mg daily on PC risk reduction in men with PSA of 2.5-10.0 ng/mL and a negative prostate biopsy. Men underwent study-mandated biopsies at 2 and 4 years regardless of PSA. DM was determined by self report at baseline. BMI (kg/m2) was calculated from height and weight measured at baseline. The risk of PC and high-grade PC (Gleason 7-10) was determined using multivariate logistic regression adjusting for age, race, BMI, PSA, and treatment arm. Effect modification by BMI (<25, 25-29.9, and >30 kg/m2) was tested via interactions.

Results: Of 8,122 men in the REDUCE trial, 499 (6.1%) had DM. Diabetic men were older (63.8 vs. 62.7 yrs, p=0.001) with a higher BMI (median BMI 27.8 vs. 26.8, p<0.0001). After adjusting for age and BMI, diabetic men had lower PSA values (p=0.04). On multivariate analysis, DM was not associated with PC risk (OR 0.96, 95% CI 0.75-1.22, p=0.74). When stratified by BMI, DM was not associated with PC risk in any group (all p>0.23) and the results did not vary by BMI category (p-interaction=0.13). DM was not associated with high-grade PC on multivariate analysis (OR 0.88, 95% CI 0.58-1.33, p=0.55). When stratified by BMI, though DM was not associated with high-grade PC risk in any single group (all p>0.14), there was a suggestion of effect modification by BMI (p-interaction=0.056) with a positive association between DM and high-grade PC in obese men (OR 1.32) and an inverse association in normal weight men (OR 0.35).

Conclusions: In the REDUCE trial, when all men undergo biopsy regardless of PSA, DM is not associated with lower PC risk, but rather equal PC risk and equal risk of high-grade PC. These results suggest the lower rate of PC among diabetic men in prior studies may be driven by lower biopsy rates from lower PSA.

[Table: see text]