bluuebunny/crossref_metadata_2025 huggingface dataset:
New criteria for complete response (CR) after definitive chemoradiotherapy for recectable squamous cell carcinoma of esophagus
Authors: Takeda A. , Koyama I. , Otani Y. , Sasaki Y. , Dikiya T.
Published: March 2020

14032

Background: According to a series of clinical trials, definitive chemoradiotherapy for esophageal cancer has become one of the accepted treatment methods even for respectable-stage disease. But preciously outlined CR criteria after definitive chemoradiotherapy has not been established. The purpose of this study is to assess the validity of new criteria for CR of esophageal cancer treated with definitive chemoradiotherapy. Methods: We reviewed 40 patients with T1b-T4, N0–1, M0 (clinical TNM stageI-III) resectable esophageal cancer treated with definitive chemoradiotherapy from April 2000. The patients received 5-Fluorouracil combined with cisplatin plus 50.4–60gy of radiation. We have here designated the CR criteria after definitive chemoradiotherapy 1)able to observe the entire esophagus by endoscopy with disappearance of the tumor lesion and ulceration 2)absence of cancer cells in pathological evaluation 3) no appearance of distant metastasis by CT scan during a series of treatment, in addition 4) no new recurrent lesions at least 6 months using the multimodality observation from determination of primary-CR. Results: Primary CR was achieved in 26 in 40 patients (65%) at the end of a series of treatment. Primary-CR rate in patients with stageI,II,III was 100% (3 out of 3), 85.7% (18 out of 21), 31.2% (5 out of 16) with a remarkable difference between TNM StageI,IIand III patients. There were 6 patients (33.3%) who were confirmed to have local recurrence in stageII esophageal cancer after determination of primary-CR. Likewise, one patient (20%) of recurrent disease in stageIII. Time at first relapse from the initial date of treatment to determine CR was 50–152 days in all recurrent patients. There were no patients with recurrence in the patients who could maintain CR for 6 months over after the determination of CR with a median follow-up of 13 months. Patients maintaining CR after the determination of CR have a significant good survival rate compared with recurrent patients after determination of CR (P<0.001) Conclusions: Our new criteria considered the time from determination of CR appear to be useful for clinical application, predict favorable survival for respectable esophageal cancer patients treated with definitive chemoradiotherapy.

No significant financial relationships to disclose.
Efficacy of adjuvant immunochemotherapy with polysaccharide k (PSK) for patients with curatively resected gastric cancer
Authors: Oba K. , Teramukai S. , Kobayashi M. , Matsui T. , Nakazato H. , Ito K. , Sakamoto J.
Published: March 2020

14038

Background: An anti-tumor effect of non-specific immunomodulators, mainly PSK and OK-432, via an immunological response has been reported and combination immunochemotherapy has been examined. However, the survival benefit of immunochemotherapy for patients with curatively resected gastric cancer was unclear in the world. We performed a meta-analysis in order to evaluate the survival effect of immunochemotherapy employing a biological response modifier Polysaccharide K (PSK) in Japan. Methods: We reassessed by means of meta-analysis of data with central randomization from 5164 patients enrolled in Japanese eight clinical trials. In all eight trials patients were followed up for at least 5 years after surgery and enrollment of the last patient and outcomes for standard chemotherapy were compared with those for chemotherapy plus PSK. The endpoint was 5-year survival odds ratio. Data were analyzed by using a weighted average of the log odds ratios (using Peto’s method). Results: The 5-year odds ratio for all eligible patients was 0.88 (95% confidence interval: 0.78–0.98; p=0.021). There was a significant heterogeneity between the trials (p=0.016). Conclusions: The results of this meta-analysis suggest that adjuvant immunochemotherapy with PSK can improve survival of patients with curatively resected gastric cancer.

No significant financial relationships to disclose.
PET/CT can direct diagnostic and therapeutic decisions in pancreatic lesions
Authors: Casneuf V. , Delrue L. , Kelles M. , Berrevoet F. , Duyck P. , De Hemptinne B. , Van Damme N. , Monsaert E. , Peeters M.
Published: March 2020

14048

Background: This study aimed to determine the role of PET/CT in differentiating pancreatic lesions and changing therapeutic approach. Methods: A retrospective analysis of prospectively collected data of 33 PET/CT scans (Philips, Cleveland, USA) was performed. Scans were made between October 2004 and July 2005 for differentiating primary or recurrent pancreatic disease found on CT, MRI or/and EUS. All PET/CT scans were assessed by a radiologist in co-operation with a nuclearist. Pancreatic lesions were interpreted based on visual assessment and by use of a semi-quantitative evaluation (SUV). These results were correlated with pathological diagnoses or clinical follow-up, dividing patients into 2 groups: ‘positive’ (malignant) versus ‘negative’ (benign disease/no lesion). In each patient therapeutic change after PET/CT was assessed. Results: The patient group consisted of 33 consecutive patients, of whom 14 were female. Median age was 61 years (range 33–76 years). SUV values in malignant lesions were significantly higher than those found in benign lesions [5.77 (95%CI 4.08–7.46) versus 1.76 (95%CI 0.79–2.7), P<0.01]. Eleven patients with benign disease or no lesion, had a negative PET/CT. Twenty-two patients had malignant disease of the pancreas. Twenty of 22 patients had a positive PET/CT. Sensitivity and specificity of PET/CT for diagnosing benign or malignant disease visually was 90.9% and 100% respectively. In the benign/no lesion group, a change in therapeutic approach was noted for 9/11 patients (81,8%): no surgery (n=6), no chemotherapy (recurrence excluded, n=3). No change was noted in 2/11 patients (18,2%): no differentiation pancreatitis/tumor. In the malignant group, a change in therapeutic approach was noted for 14/22 patients (63,6%): recurrence confirmed (n=8), up-staged (n=5), down-staged (n=1). No change was seen in 8/22 patients (36,4%): incorrectly sent to surgery (n=4), no differentiation pancreatitis/tumor (n=2), recurrence missed (n=1), false positive diagnosis of liver metastasis (n=1). Conclusions: PET/CT has 90.9% sensitivity and 100% specificity for diagnosing benign or malignant disease visually. PET/CT is a useful tool for directing therapeutic strategy. Overall, therapeutic approach was changed in 23/33 (69,7%) of patients.

No significant financial relationships to disclose.
Oxaliplatin plus 5-fluorouracil/folinic acid as palliative treatment for progressive malignant gastrointestinal neuroendocrine carcinomas
Authors: Pape U. , Tiling N. , Bartel C. , Plöckinger U. , Wiedenmann B.
Published: March 2020

14074

Background: Oxaliplatin in combination with 5-fluorouracil and folinic acid is an antitumoral agent with relatively low toxicity and satisfactory efficacy in several gastrointestinal neoplasms. However, it has not been studied in malignant gastrointestinal neuroendocrine carcinomas (NEC) for which platinum-based chemotherapy is a standard treatment with considerable toxicity. Methods: 16 patients (6 female, 10 male; mean age 57) with documented progress of histologically proven, irresectable, malignant NEC were retrospectively analyzed for safety and efficacy of cytotoxic treatment (from october 2001 to december 2005) according to the FOLFOX-4 regimen. Primary tumors were in the foregut in 9 (2 bronchial, 5 pancreas, 2 stomach), in the midgut in 3 (1 ileum, 2 coecum), and in the hindgut in 2 (1 colon, 1 rectum) patients. The primary tumor was unknown in 2 patients. No patient had clinical signs of hormone hypersecretion. NEC were low-grade malignant in 8 and high grade malignant in the remaining 8 cases. The ki67-index was ≥ 10% in 13 cases (81.3%). Results: A mean of 7.25 cycles (range 1–19) of FOLFOX-4 were administered. Stable disease for a minimum of 9 weeks was observed in 62.5% (10/16) for a mean duration of 19.4 weeks; overall mean time to progression (TTP) as measured by imaging studies was 17.8 weeks (range 2–70 weeks). Reasons for discontinuation of treatment included documented tumor progression in 8 cases (50%) and adverse events in 4 cases (25%) (grade II neurotoxicitiy in 3 cases and grade III neutropenia in 2 cases). 2 patients died during treatment due to tumor progression. 4 patients currently still receive FOLFOX-4 after a mean treatment period of 16 weeks. Side effects according to CTC-NCI-criteria include mild anemia (grade I: n=15), thrombocytopenia (I: n=4, II: n=1), neutropenia (I: n=1, III: n=2), increased serum creatinine (I: n=2), nausea (I: n=4, II: n=4, III: n=1), vomiting (I: n=2, II: n=2), and neurotoxicity (I: n=1, II: n=4). Conclusions: The FOLFOX-4 regimen was well tolerated and effective in progressive malignant NEC with increased proliferative potential. Response may be comparable to current standard regimens. FOLFOX-4 should be evaluated in a prospective controlled clinical trial.

No significant financial relationships to disclose.
Levels of circulating endothelial cells (CECs) as early pharmacodynamic markers of activity of anti-angiogenic (AA) therapy in advanced pancreatic cancer (PC)
Authors: Iyer R. V. , Javle M. M. , Pande A. U. , Yu J. , Wilkinson D. , Rustum Y. , Wallace P.
Published: March 2020

14080

Background: Clinical evaluation of targeted AA therapy may be enhanced by non-invasive biomarkers assessing relevant drug action. In this study we tested the hypothesis that AA therapy with bevacizumab (BV), may result in early release of mature CECs from the tumor vasculature into the peripheral circulation and that this change may serve as a surrogate pharmacodynamic marker of response. Methods: In an ongoing phase II study, patients with advanced PC received BV (15 mg/kg IV, d1), capecitabine (650 mg/m2 twice daily × 14 days) and gemcitabine (1000 mg/m2 IV d1 & 8) given q21 days as first line therapy. CECs (CD34+, CD31+, and CD45− cells) were assessed pre treatment on d1 and on d3 of cycle 1 by 4-color flow cytometry. Quality of life (QOL) was assessed prior to each cycle using the PAN26 questionnaire. Radiographic response by RECIST criteria and CA 19–9 were assessed every 8 weeks. Kendall’s tau, the Wilcoxon signed rank test and Mann-Whitney U-test were used to investigate an association between biomarkers (CEC and CA 19–9), paired data and independent data, respectively. Results: Twenty six of planned 34 pts have been accrued; 13 pts are assessable for change in CECs, 10 are evaluable for response, 3 are too early. Patient demographics: M/F: 4/9; median age 63 years (range 38–79). Best response in 10 pts: 2 PR, 7 SD and 1 PD. On day 3, CECs increased in 8 and decreased in 5 pts compared to baseline. During treatment CA19–9 decreased in 7 and increased in 6 pts. No significant association between CEC and CA 19–9 was detected (Kendall’s tau=-0.2, p=0.367). No significant differences of CEC levels or CA 19–9 were found pre and post-treatment, QOL improved and unimproved, and response and no-response groups. Conclusion: Preliminary analysis in 10 patients reveals no correlation between change in CECs and QOL or radiographic or tumor marker response. This may be due to delayed change (beyond day 3) or release of non-viable CECs that are not currently measured. The limited sample at this early analysis may also account for this finding. These results will be updated as accrual continues with refined CEC measurements which include a viability probe. This study was supported by a grant from NCCN and Genentec pharmaceuticals

No significant financial relationships to disclose.
The prognosis of the patients with gastric cancer intraoperatively detected microscopical free abdominal cancer cells at Douglas cavity
Authors: Kishimoto T. , Imamura H. , Furukawa H. , Tatsuta M. , Yamamoto K. , Ohshiro R. , Yonekawa M. , Yamauchi M.
Published: March 2020

14090

Background: The free abdominal cancer cells in the patients with gastric cancer probably result in peritoneal dissemination. In Japan, the detection of free abdominal cancer cells at Douglas cavity is usually examined immediately after lapalotomy for advanced gastric cancer, because this procedure is recommended in Japanese Classification of Gastric Carcinoma 1999 provided by Japanese Gastric Cancer Association. The patients detected free abdominal cancer cells are diagnosed as stage IV, even if they undergo the surgical curative operation. However some of them have relatively long survival. We investigated that the amount of free abdominal cancer cells or histological type might affect their prognosis. Methods: Surgeon collected 50ml of saline with which Douglas cavity was irrigated. Pathologist stained cells by Papanicolaou follwed by differential centrifugation (2000G for 5 minutes) of saline. Among all 492 patients who underwent surgery for gastric cancer in our institute between 2000 and 2004, 46 patients underwent the curative surgery except free abdominal cancer cells. We investigated the amount of free abdominal cancer cells and histological type as the factors to affect prognosis of these 46 patients. The log-rank test was used to evaluate the survival curves calculated by Kaplan-Maier method. Results: 5 or less and more than 5 cancer cells per 1 cm2 were microscopically detected in 22 (Group A) and 24 patients (Group B), respectively. The median survival time (MST) of Group A and B were 877 and 384 days, respectively (P=0.16). The two-year survival rates of Group A and B are 63.7% and 27.2%, respectively. The cancer cells diagnosed histologically as differentiated and undifferentiated type were detected in 13 (Group X) and 33 patients (Group Y), respectively. The MSTs of Group X and Y were 877 and 383 days, respectively (P=0.13). The two-year survival rates of Group X and Y are 82.1% and 28.9%, respectively. Conclusions: In patients who have advanced gastric cancer with free abdominal cancer cells, a larger number or undifferentiated type of cancer cells may reduce the survival periods of patients with curative resection.

No significant financial relationships to disclose.
A phase I study of sequential administration of S-1 and cisplatin (CDDP) for patients with metastatic gastric cancer (MGC)
Authors: Baba E. , Fujishima H. , Kusaba H. , Esaki T. , Ariyama H. , Kato K. , Tanaka R. , Nakano S. , Harada M.
Published: March 2020

14101

Background: The combination of 5-FU and CDDP has been reported to be active against metastatic gastric cancer (MGC), and great synergy has been shown in vivo and in vitro when 5-FU precedes CDDP. We investigated a sequential combination of S-1 (Tegafur, oxonic acid, CDHP) followed by CDDP for MGC. Methods: In order to determine a maximum tolerated dose (MTD) and recommended phase II dose (RD), we conducted a phase I trial applying increasing doses of oral administration of S-1 (65–80mg/m2) for 21 days and increasing doses of CDDP (60–80mg/m2) on day 22 every 35 days. Pts with metastatic or recurrent gastric cancer, no prior chemotherapy, measurable disease, performance status ECOG less than 3, and adequate organ functions were eligible for the study. Three pts were treated at each dose level with escalation based on toxicity. Fifteen pts were included and evaluated for DLT and MTD. Results: DLT was NCICTC grade 3 anorexia and fatigue in patients treated at the dose level 5 of S-1 80mg/m2 and CDDP 80mg/m2. Other toxicity more than grade 3 was neutropenia (grade 3) and nausea/vomiting (grade 3). Non-hematological toxicities were grade 1/2 and included diarrhea, nausea and stomatitis. There was no treatment-related mortality. The recommended dose was a combination of S-1 80mg/m2 and CDDP 70mg/m2. A tentative median survival was 19.5 months. Conclusions: This sequential S-1 and CDDP administered every 35 days is tolerable and beneficial for patients with MGC, and thus the consequent phase II trial is recommended. A multicenter phase II study is currently under way.

No significant financial relationships to disclose.
Escalating doses of hepatic arterial oxaliplatin in combination with docetaxel and capecitabine in patients with liver metastases from non-colorectal gastrointestinal malignancies
Authors: De La Cruz S. , Rodriguez J. , De La Cámara J. , Nagore G. , Viteri S. , Reyna C. , Chopitea A. , Viúdez A. , Gúrpide A. , García-Foncillas J.
Published: March 2020

14110

Background: Docetaxel (T), oxaliplatin (O) and capecitabine (C) are active agents in gastrointestinal (g.i.) tumors. Synergism has been reported in several preclinical studies. The purpose of this study was to assess the maximum tolerated dose of hepatic arterial oxaliplatin in combination with docetaxel and capecitabine in patients (pts) with hepatic metastases from non-colorectal g.i. tumors. Preliminary evidence of activity was also evaluated. Methods: Patients with liver metastases from gastric (n=3), pancreas (n=6), esophageal (n=2) and cholangiocarcinoma (n=1) were treated with fixed doses of docetaxel (60 mg/m2), capecitabine (650 mg/m2 bid on days 1–14) and escalating doses of hepatic intraarterial oxaliplatin. Oxaliplatin dose was escalated according to the following schedule: level 1, 100 mg/m2; level 2, 110 mg/m2; level 3, 120 mg/m2. The cycle was repeated every 3 weeks. A CT scan or MRI was performed to evaluate response. Liver function tests were performed the day after and before the hepatic arterial infusion. Results: The median number of cycles was 5. At first dose level, 1 pt showed grade 3 mucositis and capecitabine intolerance that required treatment discontinuation. Three pts were later included in the same level with no further toxicity. At dose level 3, grade 3 vomiting was recorded in 1 pt and subsequently this level is now being expanded. Liver function tests on day 2 were elevated over baseline in 10 pts (83%). Seven pts (58%) required morphine due to pain associated with intraarterial infusion. Among 11 evaluable pts, 10 (83%) PRs have been confirmed. Conclusions: Accrual is ongoing at dose level 3. Preliminary data on efficacy seems promising.

No significant financial relationships to disclose.
A combination phase I study of biweekly docetaxel and 5’-DFUR in patients with unresectable or recurrent gastric cancer
Authors: Yoshino S. , Oka M. , Hazama S. , Shimizu R. , Yamamoto T.
Published: March 2020

14115

Background: Docetaxel (DOC) and 5’-DFUR (an intermetamolite of capecitabine) have single-agent activity in gastric cancer and have distinct mechanisms of action and no overlap of key toxicities. Synergistic interaction between DOC and 5’-DFUR is mediated by taxane-induced up-regulation of thymidine phosphorylase. The objectives of this study were to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT) and the recommended dose (RD) of the combination therapy of biweekly DOC and 5’-DFUR. The DLT was set in low grade to treat the patients in the outpatient clinic. Methods: Eligibility criteria included patients with histologically proven unresectable or recurrent gastric cancer, no requirement of prior chemotherapy, a performance status of 0–2, adequate organ function and written informed consent. DOC was administered by 1-hour intravenous infusion (level 1, 2, 3, 4: 30, 35, 40, 45 mg/m2) biweekly for 4 weeks. 5’-DFUR was administered orally at a fixed dose of 600mg/body everyday. Toxicity and efficacy were evaluated during the 2 cycles for 8 weeks. Three or 6 patients were enrolled at each dose level. Administration of DOC was skipped in the event of grade 2 hematologic toxicity. DLT was defined as grade 3 hematologic toxicity, grade 2 non-hematologic toxicity. The MTD was defined as the dose level at which at least two of three patients or three of six patients presented with DLT. Results: Twelve patients with a median age of 58 years (range, 29 to 75) were enrolled in this study. Five patients have received prior chemotherapy. Eight patients were unresectable and 4 had recurrent tumors. At level 1 (n=3), 2 (n=3), 3 (n=3), no patients developed DLT. Two patients developed DLT at level 4 (n=3). All DLT was neutropenia. Only 1 developed grade 4 neutropenia at level 4. Non-hematological toxicity was uncommon. Level 4 was determined as the MTD. Of 8 evaluable patients, responses included 4 PR, 3 SD and 1 PD for an overall response rate of 50%. Conclusions: The MTD of DOC in this combination is 45 mg/m2 and the RD is 40 mg/m2. This regimen is well-tolerated with high response rate in outpatient setting. A phase II study is necessary to evaluate the response of this regimen.

No significant financial relationships to disclose.
Evaluation of nitinol stent placement complications for palliation of malignant dysphagia
Authors: Alach E. , Troncoso E. , Barbero A. , Mainella A. , Lavezzaro M. , Zapata G. , Bonicatto S.
Published: March 2020

14120

Background: Over 50% of patients (pts) with obstructive carcinoma are inoperable at the time of the diagnosis and only 18% of them survive beyond a year. Palliative treatment must be quickly effective, safe, well tolerated and focused to relieve symptoms, improving the nutritional state and quality of life. The objective of the study was to investigate the clinical effectiveness and complications of palliative treatment with esophageal stent placement. Methods: Descriptive and prospective study about functionality of nitinol autoexpandible stent was carried out. Evaluable pts included those with confirmed histological diagnosis of inoperable or unresectable esophageal cancer, with some clinical contraindication due to risk or personal rejection. An immediate post placement follow-up was performed after 24hours, 7 and 30 days, to evaluate the stent proper location, its permeability as well as its degree of expansion, presence of epigastric or precordial pain, reflux and degree of dysphagia. Results: From August/02 to September/05 stent was placed in 20 people, 9 women and 11 men, mean age 67.8 (range: 42–85). The autoexpandible stent placement was achieved in 100% of pts (3 = gastric carcinoma and 17 = esophagus carcinoma). Histological diagnosis was epidermoid (11 pts) and adenocarcinoma (9 pts). Inoperable malignant stricture was as follows: lower third: 11 pts (55%), middle third: 9 pts (45%). A second stent was required in 2 pts. Median time of hospitalization was 48 hours.Immediate complications appeared in 12 pts: pain 3 (15%), vomiting 3 (15%), pneumonia 2 (10%), cough 1 (5%), pyrosis 1 (5%). After 24 hour control: pain 2(10%), respiratory complications 2 (10%). The delayed ones were as follows: level 4 dysphagia 2 (10%), pain 8 (40%), reflux 5 (25%). No mortality related to stent placement was observed. Dysphagia was perceptibly reduced, from 3.0 to 1, (p < 0,005). Conclusion: The nitinol stent is easy to place, it provides effective palliation of malignant esophageal obstruction with short hospitalization time and low risk of serious complications.

No significant financial relationships to disclose.
Lymphadenectomy in carcinoma stomach: Experience from a regional cancer centre
Authors: Mahajan V.
Published: March 2020

14121

Background: Carcinoma stomach is the most common cancer in males in chennai city. Lot of controversy exists regarding the need for extended lymphadenectomy because of the morbidity and mortality associated. Methods: A retrospective analysis was done to assess the benefit of extended lymphadenectomy. The records of all the patients operated at Cancer Institute from 1991 to 2004 were analysed. Out of 5050 cases of carcinoma stomach seen, only 570 cases were taken up for some form of treatment. 400 cases underwent resection, of which 366 patients records were retreived from the tumor registry for analysis. Followup ranged from 1 year to 10 years. Results: Male to female ratio was 3:1, most patients were in 40 - 60 year age group (60%). 60% patients had antral tumors and the rest were evenly distributed. 79 patients (21%) underwent conventional gastrectomy (D1), 243 patients (66%) underwent extended lymphadenectomy and 44 patients (12%)underwent palliative gastrectomy. 280 patients underwent subtotal gastrectomy, 54 patients total gastrectomy, 28 esophago gastrectomy and 5 had transhiatal esophagectomies. Stage wise distribution was IA 4.9%, IB 9.8%, II 21%, IIIA 29.4%, IIIB 12.8%, IV 22.1%. The total number of nodes dissected in the Extended nodal dissection group was less than or equal to 15 in 12% patients, 15 to 30 nodes in 48% patients and >30 nodes in 40% patients. 72% patients had node positive disease. Overall Survival at 5years was 38.9% for all the cases. 5year ovarall survival for conventional gastrectomy group was 37% and was 48% for the extended lymphadenectomy group which was statistically significant(p =0.06) .On substratification for T status and stage, the difference in survival between conventional and extended lymphadenectomy arms was not found to be significant.However,there was a trend towards improved survival in the lymphadenectomy arm.There were 7 post operative deaths in the lymphadenectomy arm,5 of which were in the first year of starting extended lymphadenectomies, which points to the learning curve for these procedures. Conclusions: Larger trials may be required to prove the advantage of extended lymphadenectomies in Gastric cancer. In addition neoadjuvant chemotherapy and Intraoperative radiotherapy may need to be studied to improve survival in gastric cancer.

No significant financial relationships to disclose.
Analysis of preclinical and clinical data on the role of hyperthermia with gemcitabine and carboplatin on pancreatic adenocarcinoma
Authors: Peters S. O. , Stoltz A. S. , Bakshandeh A. , Vollmert M. , Wagner T.
Published: March 2020

14123

Background: Preclinical data show synergism of whole body hyperthermia (HT) of 41.8°C with gemcitabine (G) and carboplatin (CP) in lung head and neck tumor cell lines. Advanced pancreatic adenocarcinoma is an aggressive disease and is associated with high morbidity and a median survival of 8 to 12 months. The role of whole body HT with G and CP in the treatment of pancreatic cancer is unknown. Methods: We first show preclinical data to study the effects of combining HT of 37°, 39°, 41.8 and 43°C for 1 h with G and CP on the human pancreas carcinoma cell line DAN-G. We assessed proliferation ratios using crystal-violett assays and cell cycles by flow cytometry. We secondly analyzed the clinical outcome of 13 pts that received whole body HT of 41.8°C with G and CP for advanced pancreatic cancer on a compassionate-use basis at our institution between 2000 to 2004 was assessed for toxicity, response and overall survival. Results: Preclinical studies showed no effects of HT of 37, 39 and 41.8°C on DAN-G cell proliferation and cell cycle behaviour when used alone without cytostatic drugs. At 43°C cells decompose (in all experiments). Additional G and/or CP at concentrations of IC50 to HT of 37, 39, 41, 8°C did not alter the effects of the drugs alone. Cell cycle anaylsis showed that an increment of temperatures did not effect cycle phases. Analysis of the clinical data of patients whole body HT with G and CP showed partial remissions in 3 pts (23%) and no change situations in 5 pts (38%). Of 13 pts received only 2 cycles because of disease progression (n = 5) or because they refused to further treatment due to minor toxicities. 4 pts received all 4 therapy cycles initially planned. Overall survival was 11.4 months, one year survival for all patients was 38%. Generally the treatment was well tolerated. Grade 3–4 toxicities were thrombocytopenia in one patient and therapy induced anemia and neutropenia in another patient occurring after the forth cycle of treatment. Conclusions: Preclinical and clinical data show that HT plus G and CP is of no benefit in the treatment of pancreatic cancer.

No significant financial relationships to disclose.
An open-label phase II study evaluating the safety and efficacy of PTK787 in patients with progressive metastatic neuroendocrine cancer
Authors: Anthony L. B. , Cronin M. , O’Dorisio T. , O’Dorisio S.
Published: March 2020

14124

Background: PTK787, an aminophthalazine, is an orally active angiogenesis inhibitor blocking all known vascular endothelial growth factor receptors (VEGFR)- and platelet-derived growth factor receptor (PDGFR)-tyrosine kinases . The majority of metastatic neuroendocrine malignancies express VEGF and PDGF receptors. Since both growth factors have been implicated in tumor-induced angiogenesis, PTK787 offers a novel approach for inhibiting tumor growth. Methods: In a phase II trial, we investigated the safety and antitumor activity of PTK787 in patients who had biopsy-proven metastatic neuroendocrine cancer, such as carcinoid, and had shown evidence of progression on somatosatin analog therapy. Eligible patients had measurable lesions other than bone, a Karnofsky performance status >60 and normal hematologic, renal and hepatic functions. Patients on octreotide therapy were required to be on a stable dose not exceeding 30 mg monthly of the LAR formulation. Initial dosing of PTK787 was 1,250 mg daily. Results: Six patients (4 males) were enrolled between 5/20/05 to 8/09/05. Median age was 61 years (range, 48 to 65). There was 1 withdrawal of consent. The remaining 5 patients continue on treatment as of January 2006. One patient required a 10 day discontinuation for rising SGOT/SGPT and alkaline phosphatase. Resumption of PTK787 at 1,000 mg daily was well tolerated in this patient. Radiographically and scintigraphically, all 5 patients have demonstrated stable disease by CT and OctreoScan, respectively. Recruitment to this trial continues. Conclusions: PTK787 is generally well tolerated in patients with metastatic neuroendocrine cancer and may be effective in controlling somatostatin analog resistant disease though partial radiographic responses have not been observed.

No significant financial relationships to disclose.
Laboratory based low dose combination chemotherapy + bevacizumab for recurrent refractory and unresectable gastric cancer
Authors: Bruckner H. W. , Hrehorovich V. R. , Degregorio P.
Published: March 2020

14133

Twenty consecutive prospectively registered patients with refractory or Stage IV gastric cancer were treated with GFLIP (Bruckner el al ASCO 2002;2005). The last 10 upon relapse were treated with GFL[OX]T and Bevacizumab, substituting oxaliplatin (OX) 30→40 mg/M2, taxotere (T) 30→40 mg/M2 for cisplatin in the q2wk schedule. One or both regimens produced; objective responses for 15 patients including 5 complete (radiologic, tumor markers, PET responses) and 2 surgical downstaging resulting in resection or successful completion surgery; 3 patients had stable disease greater than 4 months with subjective benefit, gemcitabine was given at 400→500 mg/M2 as tolerated (→), 2 failed both regimens. One-year actuarial survival was 75%, two-year survival was 25%. All 20 lived more than six months. The level of activity, multiple crossover responses, responses with both regimens, a number of long remissions (long survival after 5FU cisplatin and GFLIP failed) and clinical downstaging allowing further surgery identify both regimens either individually or in sequence as deserving systematic investigation. The utility of low doses (responses), unusual clinical benefits, quality of life and safety offer possible advantages compared to standard dose regimens.This strategy appears to reduce and delay the limiting toxicity of the irinotecan (I) 80 mg/M2, cisplatin (P) 40 mg/M2 OX/T which are conventionally treatment limiting drugs. The regimens were designed based on laboratory evidence of low dose drug interaction including reversal of resistance to conventional drugs (applicable to both pancreatic and gastric cancer (Janat et al, Amer Asso Cancer Res 1999). After clinical demonstrations of high response rates and reversal of resistance against refractory pancreatic cancer (Bruckner et al, AntiCancer Res and ASCO 2005). The regimens were offered to patients with recurrent previously treated and refractory gastric cancer and then based on initial exceptional responses to high risk patients with poor prognosis due to clinical complications of their gastric cancer.

No significant financial relationships to disclose.
Efficacy of oxaliplatin and 5-fluorouracil in advanced hepatocarcinoma
Authors: Tahri A. , Quang T. , Dien V. , Nam L. , Biset J. , Guillon J. , Tahiri F.
Published: March 2020

14143

Background: Hepatocarcinoma (HCC) is one of the commonest malignancies worldwide. Advanced HCC represents one of the most frustrating issue, when further loco-regional therapy is not available for tumor extension, major blood vessel thrombosis or poor liver function. Systemic and palliative treatments are still discouraging. Oxaliplatin (OXA) and 5-Fluorouracil (5-FU) combination has shown in vitro and in vivo activity, moreover prolonged infusion of 5-FU could be useful in preventing DNA repair from OXA. This combination can be an interesting treatment for patients affected by advanced HCC as previously reported (Bearz A. et al, Proc ASCO # 2343, 2001. Frustaci S. et al, Proc ASCO # 1346, 2003). The goal of this work is to evaluate the feasibility, toxicity and response rate of this protocol. Methods: Inclusion criteria were inoperable or metastatic HCC, measurable parameters, PS < 2, creatinine < 1,5 mg/dL, total bilirubin < 4 mg/dL, any previous treatment. Chemotherapy consisted of: OXA 100 mg/m2 in 2 hrs perfusion; 5-FU 200 mg/m2/day as a continuous infusion for 14 days. Cycles were repeated every 2 weeks until progression or grade 3–4 toxicities. Results: From October 2002 to November 2004, 8 patients (pts) (6M, 2F) were treated. Median age was 53 years, 2 pts were affected by hepatitis C (HCV), 3 by hepatitis B (HBV), 2 by both HCV and HBV and 1 by alcoholic cirrhosis. Stage: IVA in 4 pts, IVB in 4. 5 pts were totally untreated and 3 had chemoembolization. Median number of administered cycles for patient was 6 (3–11). We observed haematological toxicity grade 2 in 2 cases, diarrhoea, peripheral neuropathy and nausea grade 2 in 1 case respectively. Partial response was obtained in 4 pts, stable disease in 2, progression in 1, 1 patient is lost to follow-up. Up to now, median duration of response is 6 months. Conclusions: The regimen showed to be feasible tolerable and with interesting response rate for HCC patients not suitable for other therapeutical options. The results are encouraging and warrant a further phase III study.

No significant financial relationships to disclose.
Our experience of low-dose consecutive CDDP and intermittent S-1 (LP/IS) therapy for advanced gastric cancer
Authors: Kobayashi K. , Enjoji A. , Nagata Y. , Tajima Y. , Kanematsu T.
Published: March 2020

14145

Background: 5-FU and CDDP combination chemotherapy (FP) has been widely used as standard therapy for advanced gastric cancer (AGC), and in Japan FP therapy was modified into [5-FU (CVI) and low-dose consecutive CDDP (LC-P)](LFP) Therapy from 1990. LFP therapy has been widely used for the treatment of AGC, because of low toxicity and high response rate. We observed that CDDP inhibited metionine transport into tumor cells, both in vitro and in vivo, with synergistic interaction by CDDP functioning as a modulator of 5-FU. However LFP Therapy needs 24-hour continuous infusion of 5-FU, the applicants for LFP must be hospitalized. Therefore we used S-1, novel oral fluoropyrimidine as effector of 5-FU, and combined LC-P aiming the same synergy as LFP therapy. In addition, utilizing the difference in cell cycle between normal cells and tumor cells, we applied intermittent administration of S-1, which leads lower toxicity than conventional LFP therapy. We tried this LC-P and intermittent S-1 (LP/IS) Therapy for AGC, examining whether LP/IS was possible as outpatient-basis. Methods: Patients with AGC received LP/IS therapy. S-1 (80 mg/m2/day) was administered per orally and CDDP (10 mg/body/day) was infused for half an hour. The administration schedule consisted of S-1 for 1,3,5 days intermittently and CDDP for 2,5 days twice a week for each four weeks. RESIST criteria and NCI-CTC (ver.3) were used to assess LP/IS. Results: Between July and November 2005, four patients (A/B/C/D) were entered into this trial. Information is available for all patients. Characteristics were: age (A/B/C/D=75/59/65/54): sex (A/B/C=M, D=F): disease status (A/B= locally advanced, C/D= postoperative recurrence). S-1 and CDDP were administered to 97.9% and 84.4% of planned dose, respectively. As for toxicity, only grade 2 taste disturbance and anorexia occurred in two patients. All the patients had one course LP/IS and are evaluable for anti-tumor effects; primary (A/B=NC/NC), metastatic (A/B/C/D=NC/NC/NC/PD), respectively. A and B could undergo total gastrectomy. TTF was (A/B/C/D=42/35/55/29 days), and survival time was (A/B/C/D=164/94/104/71 days, C: dead). Conclusions: Because of low toxicity and high feasibility, LP/IS therapy is appropriate for out-patient basis chemotherapy for AGC.

No significant financial relationships to disclose.
Capecitabine therapy in advanced gall bladder cancer: A phase II study
Authors: Chowdhury Q. , Reza S. , Hai M. , Shahid S.
Published: March 2020

14153

Background: Thymidine phosphorylase (TP) activity is found at higher levels in gall bladder cancer (GBC) tissues than in adjacent healthy tissues. GBC is relatively sensitive to 5-FU. TP activated capecitabine (CAP) mimics the continuous infusion of 5-FU. In view of drug potentiality this present study was initiated. Our aim was to evaluate the therapeutic efficacy and safety of CAP in previously untreated GBC patients (Pts). Methods: It was an open-labelled, single-centred, non-randomised and prospective study. Outcome measures were response rate and type of response for efficacy measurement and safety was measured by adverse events & laboratory blood values (LBV). All LBV were within reference range at baseline. The patients had no prior chemo/ radio therapy or a family history of malignancy; adenocarcinoma (stage III–IV); age 40–70 yrs; male/female: 16/ 30; KPS ≥ 70%. 46 pts were treated with 306 cycles (min 3–max 12) of CAP at a dose of 2500 mg/day in two divided doses from day 1–14 followed by 1-week rest. Results: Median age was 50 yrs. Hand foot syndrome occurred in 17.39% pts, diarrhoea (grade 3 & 4) 21.75% and both 15.21%, all toxicities were manageable. Mean LBV before and after CAP therapy were hemoglobin: 11.38–0.35 g/dl (95% CI, 10.66–2.10); total count of WBC: 9,260–580/mm3 (95% CI, 8,680–9,840); platelet count: 251,000–2,000/mm3 (95% CI, 227,000–275,000) and serum bilirubin: 1.17–0.33 mg/dl (95% CI, 0.5–1.84). The LBV between baseline and after CAP therapy were not statistically significant. Partial response was found in 12 pts (26.08%), stable disease in 26 pts (56.21%), and progressive disease in 8 pts (17.39%). Mean KPS value after therapy was 76% (95% CI, 69–84). Conclusion: This clinical experience indicates that CAP is a convenient choice in phase II chemo naïve GBC pts not adversely affecting haematological values.

No significant financial relationships to disclose.
Expression of caveolin-1 in renal neoplasms
Authors: Zhou M. , Tamaskar I. , Sercia L. , Rini B. I. , Bukowski R. M.
Published: March 2020

14509

Background: Caveolin-1 is the major structural and functional component of caveolae, which are specialized lipid raft microdomains on cell membrane important for signaling pathways related to cell adhesion, growth and survival. Studies have shown that clear cell renal cell carcinoma (CCRCC) expressed caveolin-1 and that the over-expression correlated with adverse pathological findings and poor outcomes. The expression of caveolin-1 in other types of renal tumors has not been studied. Methods: A tissue microarray (TMA) was constructed from 60 normal kidneys, 22 CCRCC, 20 papillary renal cell carcinomas (PRCC), 16 chromophobe renal cell carcinomas (ChRCC), and 19 oncocytomas (ONC). The TMA was immunostained for caveolin-1 protein. Membranous caveolin-1 expression was scored using the internal vascular endothelial cells as positive control. Results: Membranous caveolin-1 expression was detected in 19/22 (86.4%) CCRCC, in 1/20 (5%) PRCC, 0/16 (0%) ChRCC, and 1/19 (5.3%) ONC. Cytoplasmic caveolin-1 was detected in 16/22 (72.7%) CCRCC, 13/20 (65%) PRCC, 8/16 (50%) ChRCC and 13/19 (68.4%) ONC. Membranous caveolin-1 expression correlated with tumor size (Pearson correlation = 0.266, p = 0.043). There was no correlation between membranous or cytoplasmic caveolin-1 expression and other pathological parameters, including Fuhrman nuclear grade, or TNM stage. Conclusion: Caveolin-1 exhibits distinct subcellular localization in different renal tumors. Membranous caveolin-1 is most commonly detected in CCRCC, rarely found in PRCC and ONC, and is absent in ChRCC. This finding suggests that caveolin-1 may play an important role in the pathogenesis of CCRCC.

[Table: see text]
The effect of warfarin on the risk of prostate cancer
Authors: Tagalakis V. , Tamim H. , Collet J. , Kahn S. R. , Blostein M. , Hanley J. A.
Published: March 2020

14524

Background: The anticancer activity of oral anticoagulants has been a matter of debate for several years. Recent evidence suggests that prolonged treatment with warfarin may be associated with a reduced incidence of newly diagnosed urogenital cancer during long-term follow-up of patients with venous thromboembolism. The aim of this study was to assess whether exposure to warfarin was associated with reduced risk of prostate cancer in a large population-based cohort. Methods: We conducted a matched case-control study nested within the population of beneficiaries of the Saskatchewan Prescription Drug Plan aged 50 years and older from 1981–2002 with no history of cancer since 1967. New cases of prostate cancer diagnosed between 1981 and 2002 were identified using the linked Saskatchewan Cancer Agency registry. Six controls per case matched on age, gender, and sampling time were randomly selected. The cumulative exposure to warfarin in the five years preceding the cancer diagnosis was assessed. Prescription counts were used to define warfarin exposure. Exposure in the year immediately preceding the cancer diagnosis was excluded to control for detection bias. Conditional logistic regression analysis was used to assess confounding by other drugs such as nonsteroidal anti-inflammatory medications. Results: Among 11502 cases and 69012 controls, 7.4% of cases and 7.1% of controls had a history of any warfarin use. Compared to men who had never used warfarin, adjusted odds ratio (OR) for prostate cancer among ever-users in the 5 year period was 0.94 (95% confidence interval (CI), 0.86–1.03). In those who accumulated 1, 2, 3 and 4 years of warfarin use, the adjusted ORs were 1.01 (95% CI, 0.89–1.16), 1.00 (95% CI, 0.82–1.23), 0.81 (95% CI, 0.60–1.09), and 0.80 (95% CI, 0.65–0.99), respectively (p-trend=0.03). Conclusion: Our results suggest that cumulative use of warfarin of at least 4 years may be associated with a reduced risk of prostate cancer. However, confounding by other determinants of prostate cancer associated with warfarin use is possible. Nonetheless, confirmation of these findings by prospective studies may provide the evidence necessary to consider the use of warfarin in prostate cancer prevention.

No significant financial relationships to disclose.
A phase II study of biweekly docetaxel and vinorelbine for hormone-refractory prostate cancer (HRPC)
Authors: Vázquez Estévez S. , Mel Lorenzo J. , Álvarez Gómez E. , Quintero Aldana G.
Published: March 2020

14529

Background: Docetaxel is active in HRPC alone, with prednisone, and with estramustine. We evaluated the efficacy and toxicity of its combination with vinorelbine, another active drug in HPRC. Methods: Patients with metastatic HRPC, no praevious chemotherapy, ECOG PS=0–2 and adequate organ function were included. Docetaxel was administered at 40 mg/m2 and vinorelbine at 20 mg/m2 days 1 and 14. Cycles were repeated every 28 days until disease progression, occurrence of unacceptable toxicity or voluntary withdrawal. A maximum of 6 cycles was allowed. Results: A total of 25 patients were included, with median age73 years (61–81) and ECOG PS 0–1 in 96% of patients. Median number of metastatic lesion was 1 (84% of patients), located in bone (96%), lymph nodes (12%), pleural effusion (4%) and liver (4%). A total of 128 cycles (median 5, range 2–9) and 243 infusions (median 10, range 4–17) were administered. Median relative dose intensity for both drugs was 91.68%. Toxicity: Grade III/IV hematologic toxicity per patient was neutropenia (48%) and anemia (4%). Febrile neutropenia was observed in 2 patients. Grade III/IV non-hematologic toxicity per patient was asthenia (8%), diarrhea (4%) and constipation (4%). There were no toxic deaths. Efficacy: Of 22 evaluable patients (3 have just begun chemotherapy), 1 achieved CR, 12 PR, 5 SD and 4 progressed (PSA response), resulting in an ORR of 59% (95% CI: 38.5–79.6%). Median TTP were 340 days (95% CI: 274.47–405.53). Median OS has not been achieved. Mean OS was 765.8 days (95% CI: 590.84–940.76). Conclusions: Biweekly docetaxel and vinorelbine is an active and feasible regimen in HRPC.

No significant financial relationships to disclose.
MDX-070, a human anti-plasma antibody, administered as either a single dose or as multiple doses to patients with hormone-refractory prostate cancer
Authors: Mays T. A. , Sarantopoulos J. , Tolcher A. , Lowy I. , Preston G. , Levy E. , Oslund M. D. , Manchen E. , Kelly A. , Stadler W. M.
Published: March 2020

14549

Background: Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is specifically expressed in prostatic epithelial cells and up-regulated in hormone refractory prostate cancer (HRPC). MDX-070 is a HuMAb that recognizes conformational epitopes on PSMA, mediates anti-body-dependent cellular cytotoxicity (ADCC), and is internalized. The primary objective of these studies was to establish the safety and tolerability and maximum tolerated dose (MTD) of MDX070 in patients (pts) with HRPC. Secondary objectives included characterization of the pharmacokinetic (PK) profile and a preliminary assessment of clinical antitumor activity measured by PSA levels and scans. Methods: MDX070 was administered intravenously over 90 minutes to pts with HRPC as either a single dose (Protocol MDX070–01) at dose levels of 0.1 (3 pts), 0.5 (3 pts), 1 (3 pts), 5 (3 pts), or 10 (6 pts) mg/kg/dose or every two weeks for up to 4 doses (Protocol MDX070–02) at dose levels of 1 (9 pts), 5 (6 pts), and 10 (15 pts) mg/kg/dose. Pts with stable disease or better at the end of the treatment period could receive additional treatment cycles until progression in a companion protocol (MDX070–03). Results: There were no Grade 4 toxicities judged to be related to MDX070 administration. One patient experienced Grade 3 anorexia that was possibly drug-related (5 mg/kg). Grade 1 or 2 toxicities (reported in 35 pts in the clinical database- 18 in 01, and 17 in 02) deemed to be related to MDX070 included anorexia (2), fatigue (3), fever (4), nausea (3) and vomiting (2). No significant differences in toxicity were seen between dose groups. No >50% decline in PSA or response according to RECIST criteria occurred in any of the dosing cohorts, but 6 patients had stable disease and received 1 or more additional cycles of treatment at the same dose. Conclusions: MDX-070 as monotherapy, at the dose levels administered, was safe and well tolerated. No objective antitumor activity was observed at the dose levels tested, however, 20% (6/30) had stable disease. Enrollment is continuing at the 10 mg/kg multi-dose cohort. PK analysis is ongoing.

[Table: see text]