bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of immune cell subpopulations in renal cell carcinoma patients by sunitinib.
Authors: Seliger B. , Giersberg C. , Staehler M. D.
Published: February 2017

395

Background: Increased numbers of immune suppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) as well as alterations in the frequency and function of activated and memory T cells in peripheral blood mononuclear cells (PBMNC) represent immune escape mechanisms of renal cell carcinoma (RCC). The tyrosine kinase inhibitor sunitinib, which is currently successfully implemented in the treatment of RCC has been shown to modulate immune suppressive cells as well as T lymphocytes thereby shifting the immune balance in these patients to a more stimulating setting.

Methods: Using flow cytometry and a large panel of antibodies directed against different immunomodulatory molecules, we here analysed the effects of (i) adjuvant sunitinib treatment (50 mg for 4 weeks, on 2 weeks off) on the composition of various immune cell populations, their function and activity in RCC patients and (ii) sunitinib treatment of PBMNC from healthy donors over time

Results: A time-dependent decrease in the frequency of Treg and MDSC was found in PBMNCs during in vitro and in vivo sunitinib treatment. In addition, the number of NK cells, activated and/or memory T cells was increased in PBMNC of TKI-treated patients over time.

Conclusions: This observation may have important implications for (i) the monitoring of the sunitinib activity on immune cells, (ii) the treatment schedule including duration of TKI therapy, and (iii) the implementation of sunitinib in combination with immunotherapies in RCC patients. Long-term monitoring of a larger patients' group will show whether the activation of T cells and NK cells as well as the decrease of immune suppressive cells due to sunitinib treatment is associated with enhanced antitumor responses.

[Table: see text]
Comorbidity and sorafenib (SOR) therapy in elderly patients with metastatic renal cell carcinoma (mRCC).
Authors: Gernone A. , Pagliarulo A. , Pagliarulo V.
Published: February 2017

398

Background: SOR is a multikinase inhibitor with activity in mRCC. Older patients (pts) benefit from SOR as reported in the subgroup analysis of the TARGET study populations. We evaluated the efficacy and safety in elderly pts (≥ 70) with comorbidities.

Methods: A comprehensive geriatric assessment (CGA) was used in older mRCC pts. From 2007 to 2010, 30 pts (23 males and 7 females) received SOR 400 mg BID continuous dosing. Comorbidities were evaluated using the cumulative illness rating scale for geriatrics (CIRS-G). The total score was 0–4. 10 pts with CIRS-G 1, 12 pts with CIRS-G 2, 8 pts with CIRS-G 3/4. Median age was 76 (70–84), ECOG PS 0–2, 24/30 had undergone prior nephrectomy. The most frequent comorbidities were arrhythmias, hypertension, chronic bronchitis, diabetes mellitus, neurological disease. The endpoints were response rate (RR) evaluated by RECIST criteria and correlations between comorbidities and toxicity.

Results: Dose reduction (400–600 mg/die) were required for pts with CIRS-G 3–4. No correlations were found between comorbidities (CIRS-G) and response to SOR. 18 pts (14 pts CIRS-G 1/2, 4 pts CIRSG 3/4) had partial response (PR)with a duration of 24 months (9-30) and 12 pts (8 pts CIRS-G 1-2, 4 pts CIRS-G 3/4) stable disease (SD) for 24 months (7–32). 17/30 pts (12 pts CIRS-G 1/2, 5 pts CIRS-G 5) remain on therapy. Drug related adverse events were mainly grade 1 and 2 and were medically manageable. 4 pts required dose interruption (3 pts CIRS-G 1/2, 1 pt CIRS-G 3/4). Pts with CIRS-G score 3–4 had poorer quality of life but the clinical benefit achieved with SOR therapy was high.

Conclusions: Comorbidities in pts with mRCC ≥ 70 years did not result in increased incidence of toxicity on SOR treatment. These data suggest that SOR is effective and safe in elderly pts with an overall clinical benefit rate (PR + DS) particularly high.

No significant financial relationships to disclose.
Activity of retreatment with sorafenib for metastatic renal cell carcinoma.
Authors: Nozawa M. , Matsumura N. , Yasuda M. , Okuda Y. , Uemura H.
Published: February 2017

404

Background: Treatment options for metastatic renal cell carcinoma (mRCC) have increased. Complete remission is, however, rarely seen and patients are treated with multiple sequential therapies. We assessed clinical activity of sorafenib rechallenge after progressing on other therapies.

Methods: Patients with mRCC who received a second course of sorafenib therapy after failure of prior sorafenib and other agents were retrospectively identified. RECIST-defined objective response rate and progression-free survival (PFS) and toxicity were analyzed.

Results: Fourteen patients with mRCC who were retreated with sorafenib were identified and twelve patients were assessable for this study. 92% were male. Median age at first systemic therapy was 63 years. Prior nephrectomy was performed in 92% of patients. 42% of patients had favorable or intermediate risk, 17% poor, and the rest not available per MSKCC criteria. Eighty-three percent of patients were treated with other agents before initial sorafenib therapy, including 75% interferon-alpha (IFN-alpha), 50% interleukin-2 (IL-2), and 17% sunitinib. First sorafenib therapy began a median of 9.0 months after the diagnosis of mRCC and produced a clinical benefit (PR + SD) rate of 75% and a median PFS of 5.0 months. 67% of patients discontinued initial sorafenib for disease progression and 33% for adverse events. Interval between discontinuation of initial sorafenib and rechallenge was a median of 7.6 months. During the intervening period, 50% of patients were treated with sunitinib, 33% with everolimus, 25% with VEGFR1 vaccine, and others. Clinical benefit rate of 67% and a median PFS of 4.3 months were obtained on sorafenib rechallenge. There was no significant difference in outcome to sorafenib rechallenge based on duration between sorafenib treatments or number or type of intervening treatments. No new severe toxicity was observed during rechallenge.

Conclusions: Sorafenib rechallenge has potential to achieve clinical benefits, is well-tolerated, and may be considered after multiple sequential therapies in select mRCC patients.

No significant financial relationships to disclose.
Multiphoton microscopy of human prostatic and periprostatic tissue architecture for improving identification of tissue structures: Implication in nerve-sparing radical prostatectomy.
Authors: Grover S. , Mukherjee S. , Sooriakumaran P. , Srivastava A. , Sterling J. , Shevchuk M. , Tewari A.
Published: February 2017

61

Background: Introperative differentiation of various tissue types would aid the surgeon during dissection in radical prostatectomy. Specifically, it will enhance decision-making with regards wide excision or nerve-sparing. We investigated the value of a novel imaging technology (multiphoton microscopy-MPM) for providing “virtual” histology.

Methods: We imaged intraoperative surgical margins and biopsies, as well as radical prostatectomy sections. The imaging was carried out using intrinsic fluorescence and scattering properties of the tissues without any exogenous dye or contrast agent. The corresponding tissues were subjected to hematoxylin and eosin staining for histological confirmation of the structures.

Results: High-resolution images of the periprostatic tissue, nerves, prostate capsule, underlying acini, and individual acinar cells were obtained at varying magnifications. There was good correlation between MPM and histology in identification of all anatomic structures.

Conclusions: MPM provides microscopy level resolution in fresh human prostatic tissue, without the need for any extrinsic labeling agents or phototoxicity. It shows promise as a real-time intraoperative aid during radical prostatectomy.

No significant financial relationships to disclose.
Impact of primary Gleason grade 4 on biochemical recurrence after permanent interstitial brachytherapy in Japanese patients with low- or intermediate-risk prostate cancer.
Authors: Saika T. , Uesugi T. , Edamura K. , Kobuke M. , Nose H. , Ebara S. , Nasu Y. , Katayama N. , Yanai H. , Kumon H.
Published: February 2017

77

Background: To reveal a predictive factor for biochemical recurrence (BCR) after permanent prostate brachytherapy (PPB) using iodine-125 (125I) seed implantation in patients with localized prostate cancer classified as low or intermediate risk based on the National Comprehensive Cancer Network (NCCN) guidelines.

Methods: From January 2004 to December 2009, consecutive 418 Japanese patients with clinically localized prostate cancer classified as low or intermediate risk based on the National Comprehensive Cancer Network (NCCN) guidelines were treated by PPB. The clinical factors including pathological data reviewed by central pathologist and follow-up data were prospectively collected. Kaplan-Meier and Cox regression analyses were used to assess the factors associated with BCR.

Results: Median follow-up was 36.0 months. The 2, 3, 4 and 5-year BCR free rates using Phoenix definition were 98.3%, 96.0%, 91.6% and 87.0% respectively. On univariate analysis, primary Gleason grade 4 in biopsy specimen was strong predicting factor (p<0.0001), while Gleason sum, age, initial PSA, initial PSA density, T stage and D90 were insignificant factors. Multivariate analysis indicated that primary Gleason grade 4 was most powerful prognostic factor associated with BCR (hazard ratio=10.101, 95% IC 3.080-33.126, p=0.0001).

Conclusions: The primary Gleason grade 4 carried a worse BCR than the primary grade 3 in Gleason score 7 prostate cancer. Therefore, the indication for PPB in patients with Gleason sum 4+3 should deserve careful and thoughtful consideration.

No significant financial relationships to disclose.
Update of the HIPRO study: Late toxicity and outcome at seven years.
Authors: Thomson D. , Merrick S. , Swindell R. , Coote J. , Elliott P. A. , Cowan R. , Wylie J. , Logue J. , Livsey J. E. , Choudhury A.
Published: February 2017

81

Background: Dose-escalated radiotherapy for localised prostate cancer improves disease control but at the expense of increased overall treatment time and late toxicity. Given the low alpha-beta ratio for prostate cancer, treatment with hypofractionation should be biologically advantageous. Intensity-modulated radiotherapy (IMRT) allows dose escalation with hypofractionation, while achieving acceptable levels of toxicity. We report our 7 year late toxicity data in patients treated with two such regimens within the Hypofractionated Dose Escalation utilising Intensity-modulated Radiotherapy in Carcinoma of the Prostate (HIPRO) study.

Methods: Sixty men, median age 75 years (50-87), with localised adenocarcinoma of prostate (T1-3NOMO) and either Gleason score ≥7 or PSA 20-50ng/L received 57Gy in 19 fractions (n=30) or 60Gy in 20 fractions (n=30) using 5-field inverse-planned IMRT. All patients received neoadjuvant hormone therapy, continuing for up to 6 months after treatment. Late toxicity was assessed at 7 years follow-up using RTOG criteria and LENT/SOMA questionnaire.

Results: Forty-four (73%) patients were alive at 7 years. Nine patients (21%) reported RTOG grade 1 bowel or bladder toxicity; there was no grade 2 toxicity or above and no difference between the fractionation schedules. LENT/SOMA questionnaires were returned by 31/44 patients. Mean and median scores were less than one for bowel and urinary symptoms. When compared with pre-treatment, the proportion of patients with significant (maximum LENT/SOMA ≥2) urinary symptoms remained similar (75% vs. 76%), problems with sexual function had decreased (84% vs. 98%) but bowel symptoms increased (62% vs. 25%). At 5 years, overall survival was 83% and 74% and cause-specific survival was 83% and 84% in the 57Gy and 60Gy groups respectively.

Conclusions: Dose-escalated hypofractionated IMRT for prostate cancer appears well tolerated with acceptable levels of late toxicity. Studies to assess long term disease control with these regimens are on-going.

No significant financial relationships to disclose.
Lower urinary tract morbidity after prostate brachytherapy with cesium-131.
Authors: Smith R. , Beriwal S. , Vargo J. , Benoit R. M.
Published: February 2017

97

Background: Cesium-131 is a relatively new radioisotope for prostate brachytherapy (PB), with limited long-term data for toxicity profiles. Here we report our 1-year follow up for severity and time to resolution of lower urinary tract toxicity using American Urological Association (AUA) and Expanded Prostatic Cancer Index Composite (EPIC) scoring.

Methods: 186 patients with prostate cancer [NCCN risk category: Low (n=79), Intermediate (n=83), and High (n=24)] treated with cesium-131 PB alone (n=128) or combined with external beam radiation therapy (EBRT) + PB (n=58) were followed as part of a longitudinal prospective study. Patients completed AUA and EPIC surveys pre-operatively and at 2 weeks, 4 weeks, 3, 6, 9, and 12 months post-operatively. The mean prostatic volume was 41.3 cm3 (range 14.9 – 89.1) and the mean prostate D90 and V100 were 105.7% and 92.4%, respectively. Outcomes were analyzed using descriptive statistics and student t-tests, with an AUA score increase > 4 and EPIC score decrease > 10 points considered clinically significant.

Results: Results are shown in the table below. As expected, there was acute urinary toxicity associated with PB. This is seen in the urinary summary score as well as in every one of the subset scales. These were most significant at the 2 and 4 week marks. The urinary summary score and every subscale improved to within 10 points of baseline by 3 months and stayed there through the 12 months of follow-up. Similar findings were reflected in the AUA scores.

Conclusions: For men undergoing PB with cesium-131, results for AUA and EPIC scoring are concordant with no clinically significant differences in lower urinary tract symptoms are observed after 3 months relative to pre-operative values. The largest decreases in symptomatology scoring were witnessed in the irritative/obstructive subset, while the smallest changes relative to pre-operative values were noted in the incontinence subset.

[Table: see text]

No significant financial relationships to disclose.
Phase III randomized trial of definitive chemoradiotherapy (CRT) with FOLFOX or cisplatin and fluorouracil in esophageal cancer (EC): Final results of the PRODIGE 5/ACCORD 17 trial.
Authors: Conroy Thierry , Galais Marie-Pierre , Raoul Jean Luc , Bouche Olivier , Gourgou-Bourgade Sophie , Douillard Jean-Yves , Etienne Pierre-Luc , Boige Valérie , Martel-Lafay Isabelle , Michel Pierre , Llacer-Moscardo Carmen , Berille Jocelyne , Bedenne Laurent , Adenis Antoine ,   UNICANCER-GI/FFCD PRODIGE Intergroup
Published: February 2017

LBA4003

Background: CRT is one of the best treatment options for localized EC. As new combinations are required to improve safety and survival, we launched a randomized phase II study to assess the complete response (CR) rate of CRT with FOLFOX versus 5FU/cisplatin in 97 pts with localized EC (Conroy 2010). The trial having met its objectives, it has been pursued as a phase III trial. Stratified randomization was performed centrally in a 1:1 ratio according to histological type, pretreatment weight loss in the prior 6 months (<10% vs ≥10%), ECOG PS (0 vs 1 vs 2), and center. Methods: Pts with technically unresectable cancer or those with surgical contraindications or who refused to undergo surgery were eligible. Eligibility criteria also included age >18 years (y), PS ≤ 2, previously untreated adenocarcinoma or squamous cell EC (any T, N0 or N1, M0 or M1a). The radiation dose was 50 Gy (2Gy/fr) 5 d/wk for 5 wks in both arms. In Arm A, pts received 6 bimonthly cycles (cy): oxaliplatin 85 mg/m2 d1 and leucovorin 200 mg/m2 followed by 5-FU 400 mg/m2 bolus d1 then 1,600 mg/m2 46h continuous infusion (ci) ; the first 3 cy were delivered during RT, the 3 other after. In Arm B, pts received 4 cy: cisplatin 75 mg/m2 d1 followed by 5FU 1,000 mg/m2/d ci d1-4, the first 2 cy during RT and 2 other after. The primary endpoint was PFS. Main secondary endpoints were OS, grade 3-4 toxicities, and quality of life. A total of 266 pts would provide 90% power to detect a 20% 3y-PFS difference (α=0.05). Results: 267 pts were enrolled between 10/2004 and 08/2011. Treatment cohorts were well balanced: male 81%; median age 61 y; PS 0 53%, squamous cell 85.8%, stage III 52%, IVA 6.0% and IVB 3.0%. Full treatment was delivered to 67.9% and 72.2% of pts in arms A/B, respectively. 7 toxic deaths occurred in each arm. Grade 3/4 toxicities per pt (%) in arms A/B were neutropenia 30.6/31.3, febrile neutropenia 5.3/7.0, anemia 5.4/11.0, asthenia 17.6/10.2, respectively. The median FU time was 25.3 mos. 3y-PFS was 18.2/17.4 % (HR=1.07; 95%CI =0.80-1.43) and median OS was 20.2 /17.5 m (HR=1.06; 95%CI =0.77-1.46). Conclusions: CRT with FOLFOX does not improve PFS compared to cisplatin and 5-FU and has similar toxicities.
Efficacy of RAD001/carboplatin in triple-negative metastatic breast cancer: A phase II study.
Authors: Singh Jasmeet Chadha , Volm Matthew , Novik Yelena , Speyer James L. , Adams Sylvia , Omene Coral Oghenerukevwe , Meyers Marleen Iva , Smith Julia Anne , Schneider Robert , Formenti Silvia , Goldberg Judith D. , Li Xiaochun , Davis Samantha , Beardslee Brian , Tiersten Amy
Published: February 2017

108

Background: Triple-negative breast cancer cells are unable to repair double stranded DNA breaks and have sensitivity to platinum agents. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. RAD001 (oral mTOR inhibitor) and Carboplatin combination may have activity in triple-negative breast cancer. Methods: The primary objective is to estimate clinical benefit (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting >6 months) and toxicity of the combination in triple negative metastatic breast cancer patients who have had 0-3 prior chemotherapy regimens. This design has > 80% power to test the null hypothesis i.e. clinical benefit rate is ≤ 10% vs. alternative hypothesis that clinical benefit rate is ≥ 30%. Prior carboplatin is allowed. Women with treated brain metastasis are eligible. Originally, carboplatin AUC 6 was to be administered every 3 weeks along with daily 5mg of RAD001 with a 3 patient run-in and then 10 mg daily. Due to a surprising amount of thrombocytopenia, the dose of carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001 (no escalation to 10 mg). Results: 23 out of 25 patients have been recruited. Median age is 59. Thus far, there have been 1 CR, 5 PR’s, 8 SD's and 6 PD’s. One SD was achieved in a patient progressing on single agent carboplatin at study entry. Median duration of response is 13 weeks (range: 6-74 weeks). 5 patients had grade 3/4 thrombocytopenia and 4 patients had grade 3 neutropenia (no febrile neutropenia). 13 patients had treatment held and/or dose reductions secondary to hematological toxicity. Since dosing amendment for carboplatin to AUC 4 the regimen has been well tolerated (only 1 patient with grade 3 neutropenia and thrombocytopenia). 1 patient had grade 3 dehydration. The estimated clinical benefit rate is 45% (95% C.I.: 23%, 67%). Median time to progression or death is 85 days from start of treatment. Conclusions: Our study has met the primary end point of demonstrating clinical benefit in triple-negative metastatic breast cancer. Dose-limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. Patient accrual continues at the amended dosing.
Cetuximab in combination with irinotecan as second-line treatment in patients with platinum-resistant gastroesophageal cancer (GEC).
Authors: Schoennemann Katrine Rahbek , Yilmaz Mette K. N. , Bjerregaard Jon Kroll , Jensen Helle Anita , Nielsen Kirsten Marie , Vestermark Lene Weber , Pfeiffer Per
Published: February 2017

101

Background: Inspired by the promising results seen in patients (pts) with chemo-resistant metastatic colorectal cancer we evaluated a biweekly schedule of cetuximab (cet) and irinotecan (iri) (Cetiri) (Pfeiffer et al. Ann Oncol 2008) in platinum resistant GEC.

Methods: We treated and evaluated 111 consecutive pts with histological verified GEC adenocarcinoma and documented failure to first-line platinum-based treatment. Pts received cet 500 mg/m2 and iri 180 mg/m2 day 1 every 2nd week until progression or unacceptable toxicity. Toxicity was evaluated according to NCI-CTCAE v. 3.0. Response rate (RR) was evaluated according to RECIST v. 1.0 every 8th week. Clinical parameters and blood samples at baseline were analyzed in order to find prognostic and predictive values for prolonged overall survival (OS).

Results: Pts were included from December 2007 to August 2010. Median age was 61 years (range 33-80). Performance status (PS) was 0-1 in 95 % of the pts. Thirty-six (46%) pts had more than two organs involved. Median number of courses was 8 (1-46). RR was 14% (2 CR, 13 PR) and 63% had stable disease for at least 2 months. Median PFS and OS were 3.2 months (CI 2-4) and 5.6 months (CI: 5-7) respectively. Seventy six (68%) pts had treatment induced skin toxicity, rash. In a univariate analysis PS 0-1, normal baseline haematology and skin rash was associated with significantly increased survival. These parameters retained significance in a multivariate analysis. One patient had a curative resection after end of treatment and four pts are still alive.

Conclusions: Biweekly Cetiri is a convenient and well-tolerated second-line (SL) regimen in pts with GEC adenocarcinoma. Good performance status, normal baseline and development of skin rash indicate increased survival. Based on our findings biweekly Cetiri can be recommended as SL treatment to GEC pts in a good PS. Further studies into the role of rash are warranted.
Survival analysis of adjuvant chemotherapy with S-1 plus cisplatin for stage III gastric cancer.
Authors: Takahari Daisuke , Hamaguchi Tetsuya , Yoshimura Kenichi , Katai Hitoshi , Ito Seiji , Fuse Nozomu , Kinoshita Taira , Yasui Hirofumi , Terashima Masanori , Gotoh Masahiro
Published: February 2017

107

Background: The efficacy of S-1 for stage II-III gastric cancer has been shown. However, the survival of stage III remains unsatisfactory (the 3-year recurrence free survival rates in stage IIIA and IIIB receiving S-1 were 68.0% and 49.8%, respectively). We already reported the feasibility of S-1 plus cisplatin as adjuvant chemotherapy for Stage III gastric cancer after curative resection (ASCO-GI 2009, Cancer Chemother Pharmacol 2011). Here we evaluate the recurrence and survival as secondary endpoints.

Methods: Japanese patients with stage III gastric cancer who underwent D2 gastrectomy were enrolled. Treatment consisted of 3 cycles of S-1 (40 mg/m2 po) twice daily on days 1-21 and CDDP (60 mg/m2 iv) on day 8 and S-1 monotherapy was given on days 1-28 every 6 weeks until 1 year post surgery.

Results: From August 2007 to September 2009, 63 patients were accrued. 35 patients were stage IIIA, the rest 28 patients were IIIB. After a median follow-up 2.9 years, 15 patients experienced recurrence, and 12 patients died. The 3-year recurrence free survival rate was 76.4% (95%CI:63.0-85.4%, IIIA 88.8%, IIIB 60.1%). The 3-year overall survival rate was 78.5% (95%CI:63.4-87.9%, IIIA 85.0%, IIIB 71.9%). The site of recurrence was mainly peritoneum (n=10), liver (n=3), and lymph node (n=3).

Conclusions: Our results indicated that adjuvant therapy with S-1 plus 3 cycles of cisplatin may reduce recurrence and improve survival of stage III gastric cancer. This treatment should be considered as an experimental arm comparing with S-1 monotherapy for the next postoperative adjuvant phase III trial.
Phase II feasibility study of adjuvant S-1 plus docetaxel for stage III gastric cancer patients after curative D2 gastrectomy (OGSG 0604).
Authors: Matsuyama Jin , Tamura Shigeyuki , Fujitani Kazumasa , Kimura Yutaka , Tsuji Takeshi , Iijima Shohei , Imamura Hiroshi , Inoue Kentaro , Kobayashi Kenji , Kurokawa Yukinori , Furukawa Hiroshi ,   Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG)
Published: February 2017

108

Background: An adjuvant chemotherapy with S-1 has become the standard treatment for patients (pts) with stage II/III gastric cancer (GC) who have undergone gastrectomy with D2 dissection in Japan, but it is assumed that the survival benefit for stage III pts who received S-1 is modest. S-1 plus docetaxel has shown that the response rate and median overall survival (OS) were 56% and 14.3 months in pts with advanced GC. The aims of this phase II study were to evaluate the feasibility and safety of adjuvant S-1 plus docetaxel in pts with stage III GC with D2 surgery.

Methods: Pts with pathological stage III GC who underwent gastrectomy with D2 dissection received oral S-1 (80 mg/m2/day) administration for 2 consecutive weeks and intravenous docetaxel (40 mg/m2) on day 1, repeated every 3 weeks (1 cycle). The treatment was started within 45 days after surgery, and repeated for 4 cycles, followed by S-1 administration until 1 year after surgery. The primary endpoint was feasibility of the 4 cycles administration of S-1 plus docetaxel; secondary endpoints were safety, progression-free survival (PFS), OS, and feasibility of S-1 administration until 1 year after surgery.

Results: We enrolled 53 pts, 42 males and 11 females with a median age of 65 years (range, 43-78), between May 2007 and August 2008. Pathological stages included IIIA in 36 pts and IIIB in 17 pts. The feasibility of planned 4 cycles of treatment was 77.4% (95% CI 63.8-87.7%, p < 0.001) with 41 pts out of 53 pts. Grade 4 neutropenia was observed in 28% of pts with grade 3 febrile neutropenia in 9%. Non-hematological toxicities of grade 3 or more involved fatigue in 6%, anorexia in 9%, and nausea in 6%. No treatment-related deaths occurred. Reasons for discontinuation were recurrent cancer in 1 pt, adverse events in 10, and miscellaneous in 1, respectively. 3 year overall survival was 78.8% (95% CI 68.4-90.7) and 3 year disease free survival was 50.3% (95% CI 34.4-73.3).

Conclusions: Adjuvant S-1 plus docetaxel therapy is feasible and has only moderate toxicity in stage III gastric cancer pts. We believe that this regimen will be a candidate for future phase III trials seeking the optimal adjuvant chemotherapy for stage III gastric cancer patients.
Nonsurgical treatments for stage 0-IA squamous esophageal cancer.
Authors: Ito Hitoshi , Itasaka Satoshi , Miyamoto Shinichi , Ezoe Yasumasa , Muto Manabu , Tanaka Eiji , Sakai Yoshiharu , Chiba Tsutomu , Hiraoka Masahiro
Published: February 2017

113

Background: Surgery has been the standard treatment for operable squamous esophageal cancer. However, radiation therapy/chemoradiotherapy (RT/CRT) or endoscopic resection (ER) could be an alternative treatment option for stage 0-IA (TNM 7th edition) squamous esophageal cancer, because these treatments are less invasive and can preserve the organ. To evaluate the efficacy of surgery, RT/CRT and EC for stage 0-1A squamous esophageal cancer in clinical practice, we reviewed our experience.

Methods: From March 2007 to December 2010, 92 patients with stage 0-IA squamous esophageal cancer were treated in our institute. Overall survival, relapse-free survival, and relapse pattern were evaluated according to the initial treatment modality.

Results: Of 92 patients (pts), 76 were male and 16 were women. Median age was 65.5 years old. Tis/T1a/T1b:4/36/52. Median follow up time was 29.1(4.7-55.5) months. As an initial treatment, 9 pts received surgery, 27 pts received RT/CRT and 56 pts received ER. Among the pts underwent ER, one patient underwent esophagectomy and 13 pts were received CRT based on the pathological evaluation for the risk of the lymph node metastasis. Two-year relapse free survival and overall survival of surgery, RT/CRT and ER was 77.8%/100%, 68.6%/100% and 89.8%/95.7%, respectively. After completion of initial therapy, local failures (residual or recurrent disease), regional lymph node relapse and distant metastasis and 1 undetermined relapse were observed in 6, 3 and 5 pts, respectively. Eight out of the 15 pts with recurrence could be disease free after salvage therapy. While 4 pts died during the follow up period, all pts died from other diseases and no pts died from esophageal cancer. Overall esophageal preservation rate was 89.1% (82/92).

Conclusions: Although longer follow-up was needed, this study showed that non-surgical treatments (RT/CRT or ER) for stage 0-1A squamous esophageal cancer could be an alternative treatment option and could provide a chance of organ preservation.

[Table: see text]
Phase I study of imatinib, cisplatin, and fluoruracil in patients with advanced gastric cancer.
Authors: Mayr Martina , Alberter Barbara , Becker Karin , Schmid Roland M. , Ebert Matthias Philip
Published: February 2017

115

Background: Combination chemotherapies are established as standard treatment in gastric cancer, but prognosis remains poor. Integration of targeted therapies may provide an additional benefit. Imatinib may inhibit platelet derived growth factor (PDGF) mediated tumor growth and amplify effects of chemotherapy. This Phase I study evaluated dose limiting toxicity (DLT) of imatinib in combination with cisplatin and fluoruracil/ capecitabine therapy in gastric cancer.

Methods: The study was designed as a 3-patient cohort dose-escalating trial. Patients (pts) received cisplatin (60 mg/m2 d1 q 21) and capecitabine (1250 mg/m2 bid d1-14 q 21) or cisplatin (50 mg/m2 d1, 15, 29 q 50) and leucovorin (500 mg/m2), followed by a 24-hour 5-fluoruracil infusion (2000 mg/m2 d1,8,15,22,29,36 q 50). Imatinib was started d - 4 and continuously administered with the dose being escalated from 300 to 700 mg QD in 100 mg steps.

Results: Characteristics of the 35 enrolled pts: Median age= 61 years (range 39-76). Male: female= 27:8. ECOG 0: 21 pts (60%), ECOG 1: 13 pts (37%), ECOG 2: 1 pt (3%). Localization: carcinoma of the gastroesophageal junction 17 pts (48%), gastric body 18 pts (52%). Histology: intestinal 8 (23%), diffuse 10 (28%), not specified 17 (49%). Metastatic disease: 21 pts (60%). At imatinib dose level 1 (300mg) one DLT was observed and three more pts were enrolled without further DLT. No DLT was encountered up to dose level 4. At dose level 5 (700 mg) two gastric perforations occurred, so 600 mg imatinib emerged as the maximum tolerated dose. Immediate surgery was performed on both with good clinical outcome. Therapy was delivered 14 weeks (range 1- 59) on average. Major grade 3/4 toxicities were nausea (6%), anemia (4%), fatigue (6%) and upper GI hemorrhage (3%). Response evaluation at 6 weeks revealed partial response (PR) in 27%, stable disease (SD) in 43% and progressive disease in 13% of the assessable pts.

Conclusions: Combination of imatinib and chemotherapy is a well tolerated therapeutic approach with promising activity. A relationship between study medication and the occurred gastric perforations remains disputable. Further investigations are required to confirm the assumed amplification of chemotherapy effects by imatinib.
Potential factors to explain decreased survival for ethnic subgroups with gastroesophageal adenocarcinoma.
Authors: Ostapoff Katherine , Schwarz Roderich , Mansour John C.
Published: February 2017

12

Background: Few studies focus on the reasons behind the inferior outcomes in Black and Hispanic patients compared to White and Asian patients. We investigated the association between racial survival differences and social, economic, and health systems factors not often included in large national databases.

Methods: Tumor registry data were reviewed at a single cancer program from 1999−2009. Patients with gastric or esophageal adenocarcinoma were included. ANOVA and X2 test were used for continuous and categorical variables. Median survival was estimated using the Kaplan−Meier method with log−rank comparison and Cox regression.

Results: Of 515 patients with gastric or esophageal adenocarcinoma, 254 (50%) were Black or Hispanic. Overall survival for Black and Hispanic patients was decreased compared to the rest of study population (8.4 vs 11 months,p=0.002). Black and Hispanic patients are more likely to present with metastatic disease (56% vs 38%,p<0.0001) and signet ring cell histology (p<0.001). On univariate analysis, survival was decreased for patients without insurance (p=0.0003) and lower incomes (p=0.02). Black and Hispanic patients were more likely to have the high risk characteristics of lower income (p<0.001) and lack of insurance (p<0.001). On multivariate analysis, only racial background was associated with differences in survival (HR, 1.4; 95% CI, 1.16 to 1.76; p=0.001). For nonmetastatic gastric cancer patients, rates of curative intent surgery were similar between ethnic groups (80% vs 79%). Blacks and Hispanics with Stage 2−4 disease were less likely to receive or be recommended chemotherapy (53% vs 67%,p=0.009).

Conclusions: Differences in survival for patients with gastric and esophageal adenocarcinoma are associated with biologic (signet ring histology and metastatic presentation) and social factors (insurance status and income). Black and Hispanic patients are more likely to belong to these poorer outcome groups. In addition, they may be less likely to receive complete multidisciplinary care. Despite controlling for these imbalances, ethnic status remains associated with inferior survival, indicating that additional factors may partake in this phenomenon.
Preliminary result of a multicenter phase II study of chemoradiotherapy with docetaxel for elderly patients with stage II/III esophageal carcinoma.
Authors: Hashimoto Jun , Kotani Namiko , Hokamura Nobukazu , Ito Yoshinori , Katada Chikatoshi , Ishiyama Hiromichi , Tamaki Yoshio , Nakamura Takayuki , Kato Ken
Published: February 2017

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Background: Definitive chemoradiotherapy (CRT) with 5-fluorouracil plus cisplatin (CDDP) is one of the most common treatment modalities for esophageal carcinoma (EC). However, there are limited data on CRT in elderly patients, and it is difficult for elderly patients to receive chemotherapy with CDDP due to poor organ function. The aim of this prospective study was to clarify the efficacy and safety of definitive CRT with docetaxel in elderly patients.

Methods: Eligibility criteria included clinical stage II/III (UICC 6th, non-T4) EC, PS 0-1, age over 70 years, and no desire for surgical treatment. A total of 40 patients were planned for enrollment. Chemotherapy consisted of 6 cycles of a 1-h infusion of docetaxel (10 mg/m2) repeated weekly. Radiation was concurrently administered to a dose of 60 Gy in 30 fractions. At this time, we evaluate the preliminary data of efficacy and safety of definitive CRT with docetaxel in elderly patients.

Results: A total of 16 patients were enrolled between July 2008 and January 2011, at which point, the trial was closed due to poor accrual. The median age was 77 years (range, 73-81); male/female: 14/2; PS 0/1: 4/12; cStage IIA/IIB/III/IV: 3/4/8/1. Fourteen patients (88%) completed the treatment protocol, 1 patient (6%) could not complete the treatment because of severe toxicities, and 1 (6%) refused to continue the treatment. The complete response (CR) rate was 19% (3/16). In this preliminary analysis, the median follow-up time was 17 months. The 1-year survival rate was 87.5%. The most common grade 3 or 4 toxicities were esophagitis (31%), anorexia (13%), leukopenia (6%), neutropenia (6%), thrombocytopenia (6%), mucositis (6%), and infection (6%). No treatment-related deaths were observed. Grade 3 or 4 esophagitis, pleural effusion, pericardial effusion, and pneumonitis developed as late adverse events in 13%, 13%, 6%, and 6% of patients, respectively.

Conclusions: This regimen is considered as feasible on hematological toxicities, however slightly toxic on non-hematological toxicities with modest activity. Lower rate of CR seemed to be due to severe esophagitis. Further follow-up is needed to estimate the efficacy of this treatment.
Retrospective analysis of neoadjuvant chemoradiotherapy for esophageal cancer: The Knight Cancer Institute experience.
Authors: Siddiqui Faisal A , Dolan James P. , Hunter John G. , Douthit Miriam A. , Bloker Lisa M. , Holland John M , Thomas Charles R.
Published: February 2017

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Background: Neoadjuvant chemoradiotherapy (NAT) followed by esophagectomy has been established as standard of care for early stage (II – III), resectable esophageal cancer (EC). Patients (pts) treated with NAT are more likely to be downstaged and have a complete (R0) resection. Additionally, pts with aggressive disease are more likely to progress during NAT and, consequently, avoid unnecessary surgery. The aim of the current report was to analyze the outcomes of trimodality therapy at the Knight Cancer Institute.

Methods: A retrospective study of 124 pts who underwent NAT followed by esophagectomy for EC from 1999-2010 at our institution was performed. All pts were initially staged by imaging (EUS, CT and/or PET imaging) prior to commencing treatment. After esophagectomy, pathological staging was compared to initial staging to determine the effect of NAT.

Results: There were 25 women and 99 men. Initial staging is shown in the table below. Patients received cisplatin, oxaliplatin or carboplatin with 5-FU plus concurrent radiotherapy (RT). RT total dose of 45 Gy to the tumor and regional nodes was given in 1.8 Gy daily fractions, followed by a boost to the tumor for final dose 50.4-54 Gy. 27 (21.8%) of the pts had a pathologic complete response. Additionally, 54 (43.6%) pts were downstaged by chemoradiation. Of the pts that had complete remission or were downstaged, pre-treatment clinical stage was Stage II (22 pts), Stage III (55 pts), and Stage IVa (4 pts).

Conclusions: NAT was effective in complete remission or downstaging of two-thirds (81) pts, including 4 pts that were initially unresectable (Stage IVa) and successfully underwent subsequent esophagectomy. As has been shown previously, NAT is effective for downstaging prior to esophagectomy making it more likely that pts will undergo R0 resection. This study also demonstrated that some pts with clinically unresectable tumors could undergo successful esophagectomy after NAT.

[Table: see text]
Survival of patients with HER2-positive gastric cancer with introduction of trastuzumab.
Authors: Shitara Kohei , Yatabe Yasushi , Sugano Masato , Matsuo Keitaro , Kondo Chihiro , Takahari Daisuke , Ura Takashi , Tajika Masahiro , Muro Kei
Published: February 2017

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Background: ToGA study showed that trastuzumab given in combination with first-line chemotherapy (fluoropyrimidine plus cisplatin) improved the overall survival of HER2-positive patients with advanced gastric cancer (AGC). Meanwhile, the prognostic value of HER2 or the efficacy of trastuzumab in second- or further-line chemotherapy remains controversial.

Methods: We retrospectively analyzed 567 patients with AGC who initiated systemic chemotherapy before March 2011. Among them, 287 were evaluated for their HER2 status. HER2 positivity was defined as IHC 3+ or IHC 2+ with amplification by FISH. Treatment outcomes were compared between patients with HER2-positive and HER2-negative AGC. To evaluate the impact of exposure to trastuzumab in any line of chemotherapy, we applied time-varying covariates (TVC) analysis to avoid possible lead-time bias.

Results: The median survival time (MST) of HER2-evaluated patients (n=287) tended to be better than that of HER2-non-evaluated patients (n=280, 14.5 vs. 13.2 months; P=0.03). Among the HER2-evaluated patients, 47 (16.3%) were HER2-positive and had longer survival than HER2-negative patients (24.1 vs. 13.4 months; P=0.05). Among the HER2-positive patients, 35 received trastuzumab; 15 patients received it as first-line therapy and 20 received it as second- or further-line therapy. The MST of HER2-positive patients with trastuzumab treatment was significantly longer than that of HER2-positive patients without trastuzumab (26.6 vs. 13.5 months; P=0.015). HER2-negative patients and HER2-positive patients without trastuzumab had similar survival durations. According to multivariate analysis with TVCs, exposure to trastuzumab was independently associated with better prognosis (HR 0.54, P=0.04).

Conclusions: Although the retrospective nature and small sample size are major limitations of this study, recent HER2-positive AGC patients showed a better prognosis than HER2-negative patients, especially with the introduction of trastuzumab.
Comparison of the clinical benefit of an adjuvant therapy in gastrointestinal stromal tumors (GIST) with other adjuvant cancer therapies.
Authors: Deflin Morgan , Parthan Anju , Taylor Douglas , Coombs John , Sasane Medha , Paolantonio Marc
Published: February 2017

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Background: Imatinib in the adjuvant setting for GIST has shown significant improvements in recurrence- free survival (RFS) vs placebo. Number needed to treat (NNT) is a useful measure to compare effectiveness across treatments (txts) from a health policy or population perspective. The objective of this study is to compare the NNT for adjuvant imatinib in GIST with other adjuvant cancer txts at both 1 and 3 yrs of follow-up using RFS.

Methods: In the absence of a placebo controlled trial for 3 yr imatinib, data from ACOSOG Z9001 and SSGXVIII/AIO trials were used to indirectly estimate NNT for adjuvant imatinib in GIST. Adjuvant txts in other cancer types were identified from published literature. Studies meeting the following criteria were included in the analysis: (1) study population consisted of cancer patients (pts) who underwent surgical resection of the primary tumor and considered cancer-free, (2) a randomized clinical trial conducted in pts in the US or Europe, (3) comparators were either placebo or no txt (4) RFS was reported and showed benefit with the experimental txt. NNT is defined as the number needed to treat to prevent 1 recurrence or death. NNT was calculated as the inverse of the absolute risk reduction (difference in event rate) between the study groups in each trial.

Results: 24 adjuvant txts in 8 different cancer types were identified. With longer follow-up (3 yrs vs 1 yr), 62.5% of txts showed a decreased NNT, including imatinib which decreased from 7 (1 yr) to 4 (3 yrs). The largest relative decrease in NNT over time was 91% for trastuzumab & cyclophosphamide (both used for breast cancer). About 25.0% of the txts had an increase in NNT over time. NNT for imatinib was lower than all other txts at 3 yrs of follow-up and lower than all but 2 txts at 1 yr of follow-up (mitomycin + tegafur [gastric cancer, NNT = 5] and gemcitabine [pancreatic cancer, NNT = 4]). About 28.0% and 41.7% of txts had an NNT less than 10 at 1 and 3 yrs of follow up, respectively.

Conclusions: Imatinib has one of the lowest NNTs among other adjuvant txts, at 1 and 3 yrs of follow-up. With longer follow-up duration, most adjuvant cancer txts show a decreased NNT.
Effects of chemotherapy for superficial meso and hypopharyngeal cancers with concomitant esophageal cancer.
Authors: Iizuka Toshiro , Kikuchi Daisuke , Hoteya Shu , Kaise Mitsuru , Udagawa Harushi
Published: February 2017

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Background: Recently, the frequency of superficial meso and hypopharyngeal cancer (Ph ca) has increased and elucidation of its biological behaviors is needed. There are no reports to analyze if superficial Ph ca responds to chemotherapy. Therefore, the aim of this study was to clarify the effects of chemotherapy for esophageal cancer on superficial Ph ca.

Methods: A total of 48 patients and 57 lesions with superficial Ph ca with concurrent esophageal cancer were enrolled from November 2007 to December 2010. Among these, 29 patients and 31 lesions for which no chemotherapy had been administered for the esophageal cancer, and two patients for whom details of the treatment regimen or evaluation after chemotherapy were not available were excluded. So 17 patients with 24 lesions were included. The maximum diameter of the Ph ca was measured before and after the treatment by endoscopy, the lesion was graded as CR, PR, NC and PD, and the response rate (CR + PR) was analyzed retrospectively.

Results: All patients were male with a mean age of 61.1 years. The Ph ca was located in the left piriform sinus in 9 lesions, right piriform sinus in 10 lesions, posterior wall of the hypopharynx in one lesion, and mesopharynx in 4 lesions. The mean diameter of the tumor was 16.3 mm. Among the concurrent esophageal cancers, 6 were classified into the superficial type and 11 into the advanced type. For treatment, DCF was administered for 4 patients and 5 lesions, FP for 8 patients and 11 lesions, FAN (doxorubicin + 5FU + nedaplatin) for one patient and two lesions, CPT11 + CDDP for one patient and one lesion, VP-16 + CDDP for one patient and two lesions, and weekly docetaxel for one patient and one lesion. Radiation therapy for concurrent esophageal cancer was administered in 8 cases. As a treatment response, 7 lesions showed CR, 7 showed PR, 9 showed SD, and one showed PD, so a total response rate was 58.3%. Especially for the 15 lesions whose tumor diameter was less than 20 mm, the response rate was 67%.

Conclusions: The response rate was 58.3%, which is relatively good. We believe that the results of this study would serve as important indicators for determining the treatment strategy for superficial Ph ca with concurrent esophageal cancer.
Cost-effectiveness of three years of adjuvant imatinib in gastrointestinal stromal tumors (GIST).
Authors: Sanon Myrlene , Parthan Anju , Taylor Douglas , Coombs John , Paolantonio Marc , Sasane Medha
Published: February 2017

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Background: Recent clinical trial data have demonstrated that 3 years (yr) of adjuvant imatinib therapy for patients with surgically resected GIST leads to a significant improvement in recurrence free survival and overall survival vs. 1 yr of therapy. The objective of this study is to assess cost-effectiveness of treating with 3 yrs vs. 1 yr of adjuvant imatinib in the US from a payer’s perspective.

Methods: A Markov model was developed to predict GIST recurrence, treatment (txt) costs, and quality-adjusted survival over a lifetime horizon. Patients transitioned between 3 health states: recurrence free GIST, GIST recurrence, and death. Monthly recurrence and mortality rates for 3 yr and 1 yr imatinib were derived from SSGXVIII/AIO clinical trial. The 5-yr recurrence rate observed in the trial was extrapolated for the remaining duration of the model horizon. First recurrence after active txt was treated with imatinib 400mg daily (800mg daily if recurrence during active txt). For subsequent disease progression, patients were treated with imatinib 800mg, sunitinib or best supportive care. After 5 years, txt specific mortality rate was applied for patients with recurrence. Costs and utilities were derived from published literature. Expected costs and quality-adjusted life years (QALYs) were estimated for each txt strategy. Costs and QALYs were discounted at 3% per yr. Extensive sensitivity analyses were conducted.

Results: Total lifetime cost per patient was $302,100 with 3 yrs vs. $217,800 for 1 yr of imatinib therapy. Patients on 3 yrs of imatinib had higher QALYs (8.53 vs 7.18) vs. 1yr of imatinib. Incremental cost effectiveness ratio of 3 yrs of imatinib vs 1 yr of imatinib was $62,600/QALY. Model results were sensitive to rate of GIST recurrence beyond 5 yrs and monthly cost of adjuvant imatinib. At a threshold of $100,000/QALY, 3 yr imatinib therapy was cost-effective in 100% of simulations vs. 1 yr of imatinib.

Conclusions: Model results suggest that treating patients with 3 yrs of imatinib is cost-effective vs. 1 yr of imatinib below the widely used $100,000/QALY threshold. Both clinical and economic results suggest treating surgically resected GIST patients with 3 yrs of imatinib would result in improved quality-adjusted and overall survival.