bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of PS-341 (bortezomib) with or without irinotecan in patients (pts) with advanced gastric adenocarcinomas (AGA)
Authors: Ocean A. J. , Schnoll-Sussman F. , Keresztes R. , Chen X. , Holloway S. , Matthews N. , Christos P. , Mazumdar M. , Wright J. , Wadler S.
Published: March 2020

14040

Background: We are conducting a phase II trial of the proteasome inhibitor, PS-341, with or without irinotecan in pts with AGA. The combination of PS-341 and irinotecan has been studied in preclinical tumor models including a murine xenograft model of colon cancer, where the combination achieved significantly more tumor shrinkage than either agent alone. The primary objective of this study is to determine response rates, toxicities, progression-free survival, and overall survival in pts with AGA receiving PS-341 alone or in combination with irinotecan. Methods: All pts had gastric adenocarcinoma beyond the scope of surgical resection, measurable disease, and normal bone marrow, hepatic and renal function. All gave informed consent. In previously untreated patients, PS-341 was administered at 1.3 mg/m2 on days 1, 4, 8, and 11 as IV bolus every 21 days. Irinotecan was administered IV at 125 mg/m2 over 90 mins on days 1 and 8 every 21 days (Arm A). For previously treated patients, PS-341 was administered as a single agent at 1.3mg/m2 on days 1, 4, 8, 11 as an IV bolus every 21 days (Arm B). Radiologic evaluation and tumor measurements were performed every 8 weeks. Results: Thirty-seven pts have been enrolled; 29 are evaluable (4 never treated, 4 TETE). Twenty-two pts were treated in Arm A, and 11 in Arm B. All pts were eligible and the 29 treated pts were fully evaluable. Median age 58 (33–87); 26 males/7 females; median number of cycles received was 2.0. Most common toxicities: Grade 4 cardiac arrest (1), stomach perforation (1), leukopenia (2), diarrhea (1), edema (1); Grade 3 nausea (6), vomiting (7), diarrhea (4), febrile neutropenia (3), thrombocytopenia (6), anemia (6); Grade 5 death (3). Severe toxicities likely attributed to disease progression. Response rate was 33% for Arm A, 9% for Arm B. Progression-free survival was 1.8 mo. in Arm A, 1.4 mo. in Arm B. Median overall survival was 4.8 mo. in Arm A, 5.4 mo. in Arm B. Conclusions: The combination of PS-341 and irinotecan, a non-cisplatin containing therapy, is active in AGA and should be considered a key regimen. Monotherapy with PS-341 has a 9% response rate in this population of pre-treated patients with advanced disease. Accrual to this study is continuing.

[Table: see text]
Low rate of progressive disease in metastatic gastric cancer using tandem chemotherapy with four active compounds
Authors: Wormann B. J. , Pies A. , Petersen P.
Published: March 2020

14069

Background: Taxanes and irinotecan have significantly increased the therapeutic options in the treatment of metastatic gastric cancer. However, the potential of all active substances is highest in first - line treatment. The rate of second remissions is low and survival after relapse is short. We performed a phase II study incorporating 5FU, irinotecan, cisplatin and docetaxel in a tandem protocol for first line treatment of patients with metastastic adenocarcinoma of stomach or cardia. Methods: Chemonaive patients received a 30-minute infusion of irinotecan 80 mg/m2 followed by IV bolus leucovorin 20 mg/m2 and infusional 5FU 2000 mg/m2 over 24 hours on days 1, 8 and 15. The second block included docetaxel 25 mg/m2 over 60 minutes followed by a 30-minute infusion of cisplatin 40 mg/m2 on days 29, 36 and 43. Patients were scheduled to receive two complete cycles. Primary objective was evaluation of remission rate. Further objectives were toxicity and overall survival. Results: 32 patients were included, 25 patients are currently evaluable. The median age was 56 years (36 - 72), 10 female and 15 male patients. 10/25 (40%) patients achieved a partial remission, 3 of these 10 patients had a very good partial remission. 13 (52%) patients had stable disease, and 2 (8%) patients progressed early. Main toxicities grade ≥ 3 were diarrhea (8/50 cycles), nausea and vomiting (3/50), neutropenia (2/50), anemia (1/50) and renal insufficiency (1/50). The median survival time was 11.7 months. Conclusions: This treatment schedule includes the four most active substances in the treatment of metastastic gastric cancer in a tandem protocol. Only 2/25 patients had progressive disease under therapy. Toxicity was moderate. Dose intensication may further increase the remission rate.

No significant financial relationships to disclose.
A phase II trial of oblimersen sodium (G3139) in combination with doxorubicin (DOX) in advanced hepatocellular carcinoma (HCC). NCI protocol # 5798
Authors: Knox J. J. , Chen E. , Feld R. , Nematollahi M. , Pond G. R. , Cheiken R. , Gill S. , Zwiebel J. , Moore M.
Published: March 2020

14072

Background: Advanced HCC is refractory to most standard forms of chemotherapy, however responses to DOX are seen. The bcl-2 protein confers resistance to apoptosis in cancer cells and is important in tumor progression and resistance to chemotherapy. The bcl-2 antisense oligonucleotide, G3139 (G), has been shown to enhance the activity of DOX in tumor models by blocking bcl-2 synthesis. This argues for evaluating G + DOX in combination in HCC. By decreasing tumor bcl-2 protein levels, HCC may be sensitized to the apoptotic effects of DOX. Methods: We completed a phase II trial evaluating treatment with G at 7 mg/ kg for 7 days cont. i.v. infusion (d1–8) plus DOX at 45 mg/m2 i.v. bolus d5, every 28 d (as determined from our phase I HCC study). Eligible patients (pts) had path-confirmed, measurable, advanced HCC. Minimal eligibility included Childs-Pugh A cirrhosis, adequate hematological (hem) parameters and ECOG PS <2. Tumor biopsies for correlative studies were obtained at baseline and cycle 1 d 4 in consenting pts. Results: 19 patients were accrued, 1 was ineligible, 18 evaluable for toxicity, 17 evaluable for response; receiving a median (med) of 2 cycles (range 1,10). Risk for HCC was 39% HBV, 22% HCV, 17% alcohol, 22% other. Most common toxicities were hem and could be attributed to both G+DOX and to G alone. Overall grade 3–4 toxicities seen were: ANC- 67% (med nadir d 24–25), lymphopenia - 44%, thrombocytopenia - 6%, transaminitis - 33% and grade 1–2 G-fever - 67%. No responses were seen and the trial was stopped at stage 1. Six patients (35%) had stable disease, with one pt completing 10 cycles as per protocol (pt # 22). Med TTP is 1.8 months (1.7-NA) and 6-month PFS is 17.2% (5.3–56.4). 18 of 19 pts have died with med OS of only 5.4 months (2.7–11.6). Correlative studies on 3 available pts’ paired tumor biopsies showed absent baseline bcl-2 expression but moderate expression of both bcl-xl and BAX protein and with no change after exposure to G (includes pt #22). Conclusions: G + DOX is inactive in HCC at this dose and schedule. The overlap of hem toxicity may have resulted in suboptimal DOX dosing in HCC. Low baseline bcl-2 tumor expression relative to bcl-xl seen may suggest a relative insensitivity to the effects of bcl-2 inhibition in these HCC tumors.

[Table: see text]
Second-line chemotherapy with mitomycin C and S-1 in patients with advanced gastric cancer
Authors: Shin D. , Lee S. , Park S. , Bang S. , Cho E. , Lee J.
Published: March 2020

14083

Background: S-1, a fourth generation oral fluoropyrimidine that mimics infusional 5-fluorouracil, has demonstrated activity against advanced gastric cancer. Based on a single agent activity and in vitro synergy between mitomycin C (MMC) and 5-fluorouracil, we conducted a phase II study to assess the efficacy and tolerability of the combination of S-1 and MMC as second-line chemotherapy for previously treated, advanced gastric cancer. Methods: Patients with measurable gastric cancer, progressive after at least one prior chemotherapy for metastatic disease, were treated with MMC 7 mg/m2 on day 1 and S-1 40 mg/m2 twice daily as an intermittent regimen of 4 weeks of treatment followed by a 2-week rest. Treatment was repeated every 6 weeks, for up to 4 cycles. Objective response rate was the primary endpoint and was evaluated every 2 cycles of chemotherapy. With a single-stage phase II design, at least 25 patients were required. Results: Of the 26 patients registered, 24 patients were evaluable for response and 26 for safety. Eighteen patients (69%) were previously treated with 5-fluorouracil-based chemotherapy, and 10 (39%) were treated with taxanes. The patients’ median age was 55 years (range, 38–73) and 7 (27%) had an ECOG performance status of 2. A total of 64 chemotherapy cycles were delivered (median, 2; range, 1–4). In an intent-to-treat analysis, 6 patients (23%) achieved a partial response, which maintained for 3.5 months. The median progression-free and overall survivals were 4.4 months (95% CI, 1.7–7.2) and 5.4 months (95% CI, 3.4–7.4), respectively. Major toxic effects included stomatitis, diarrhea and fatigue, but were generally mild and manageable. No patient developed hemolytic reaction. Conclusions: Second-line chemotherapy with MMC and S-1 is an effective regimen for advanced gastric cancer with an acceptable toxicity profile and a convenient administration schedule.

No significant financial relationships to disclose.
Circulating chromogranin-a (CgA) as a useful marker in the diagnosis and follow up of neuroendocrine tumors (nets): An Italian multicenter observational study (cromAnet)
Authors: Dogliotti L. , De Braud F. , Delle Fave G. , Degli Uberti E. , Tomassetti P. , Gion M. , Leon A. , Torta M. , Borgna L.
Published: March 2020

14091

The primary objective of this study was to validate the clinical significance of blood evaluation of CgA in NET patients at the diagnosis (PHASE I) and during 2 years of follow-up (PHASE II). From May 2003 to October 2004, 276 patients entered the study from 40 Italian centers: 270 were evaluable. All basal and every 3 months collected CgA blood samples were centrally measured in two reference laboratories (Orbassano-Turin and Venice) where ELISA (DAKO,Denmark) or IRMA (CIS-Schering, France) were performed to look at the correlation between the two methods and their sensitivity and specificity. Lab results at the baseline have been recently published (Leon et al., Intern. J. Biol. Markers, 2005). We are now collecting all the correlations between CgA and type and place of NETs; tumor bulk; metastatization; presence or not of specific syndrome;proliferation activity (Ki67); octreoscan; tumor specific markers. 223 patients (83%) had gastroenteropancreatic tumors, whereas 24 (9%) had medullary tyroid cancer, 16 (6%) Merkel cell carcinoma and 6 parathyroid NETs, pheochromocytoma, paraganglioma. Only 26% of GEP tumors presented with specific symptoms. At the entry in the study 58% of patients had a new diagnosis, 23% were in stable disease, whereas 18% had metastatic disease. According to the recent W.H.O. histologic classification (Solcia et al, 2000), 36% specific symptomatic patients had NE tumor, 57% well differentiated cancer and only 3% poor differentiated cancer, whereas 31% not symptomatic patients had NE tumor, 48% well differentiated and 16% poor differentiated cancer. This is the largest study worldwide performed on this topic and all the data about the correlation among all patient variables and CgA blood values will be ready in April 2006. Follow-up data will be evaluable next year.

[Table: see text]
Phase II study of oxaliplatin-based chemotherapy in patients with advanced gastric cancer
Authors: Vattemi E. , Pedersini R. , Kildani B. , Stocker J. , Baier S. , Cretella E. , Petric M. , Lusso M. , Graiff C.
Published: March 2020

14119

Background: The aim of the study was to assess the toxicity and the clinical activity of oxaliplatin in combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) administered every 2 weeks in patients with advanced gastric cancer. Methods: 26 patients with recurrent and/or metastatic gastric cancer were enrolled. They received oxaliplatin 85 mg/mq on day 1, FA 200 mg/mq as a 2 h infusion followed by bolus 5-FU 400 mg/mq repeated for 2 consecutive days (FOLFOX-4). Treatment was repeated every two weeks until disease progression or limiting toxicity. Results: Patients had a median age of 62 years (range, 74–40); 19 patients had a PS of 0–1. Twenty patients had a newly diagnosed metastatic disease and 6 patients had recurrent disease. The median number of sites involved was 2. Four patients had prior adjuvant chemotherapy with cisplatin, 5-FU and epirubicin. So far, 22 of 26 patients are evaluable. The mean number of cycles was 8.6 (range, 2–15). One complete response (4.5%) and 9 partial responses (41%) were observed for an overall response rate of 45%. Stable disease was seen in 8 patients (36%) and disease progression occurred in 4 patients (18%) Median progression free survival was 4.7 months and median overall survival was 9.8 months. No WHO grade IV toxicity occurred and the only grade III toxicity was peripheral neuropaty (10%). The most commonly reported hematologic event was grade II neutropenia (20%) and trombocytopenia (15%). Conclusions: FOLFOX-4 regimen shows good efficacy and accetable safety profile in advanced gastric patients.

No significant financial relationships to disclose.
Improved survival in patients with locally advanced esophageal cancer utilizing a multidisciplinary approach
Authors: Skaff Z. , Hannigan K. , Hughes S. , Atabek U. , Shum M. , Kankipati S. , Elkhoury M. , Hageboutros A.
Published: March 2020

14130

Background: Locally advanced esophageal cancer studies have reported a three year overall survival rate of 32% with a median survival of 16 months. These patients were treated with combined chemotherapy and radiation with surgery, when applicable. We conducted this study to determine whether using an individualized, multidisciplinary approach affected survival outcomes in patients treated for locally advanced esophageal cancer. Methods: All patients treated for locally advanced esophageal cancer were retrospectively identified from our database at The Cancer Institute of New Jersey at Cooper University Hospital. All patients were presented and discussed in a multidisciplinary gastrointestinal tumor board conference. After a consensus was obtained, a treatment plan was established for each patient based on his or her respective clinical characteristics: stage, performance status, medical suitability for surgery and resectabilty. Results: A total of 23 patients (median age: 66 years [range, 55–88 years]) were identified, the histopathologic diagnosis was adenocarcinoma in 13 and squamous cell carcinoma in 10 cases. TNM staging was as follows: 18 (78.3%) stage II or III and 5 (21.7%) stage IV. Initial management included esophagectomy for 9 (39.1%), 6 of which received preoperative chemotherapy (5-FU) and three received postoperative adjuvant chemotherapy, 14 (60.9%) received only combined chemotherapy (average four cycles of 5FU 1000 mg per square meter of body surface + Cisplatin 75 mg per square meter of body surface) and radiation at doses 50–64 Gy. Overall median survival was not reached since only five patients (21.7%) have died. The 1- year and 2-year survival rates were 87% and 74% respectively. Median follow-up for patients who received combination chemotherapy and radiation vs. surgery with preoperative therapy was 29 and 41 months, respectively. Conclusion: This retrospective analysis shows promising outcomes compared to published data supporting the role of an individualized, multidisciplinary approach in the management of each patient with esophageal cancer.

No significant financial relationships to disclose.
Phase 1 study of paclitaxel, cisplatin, and 5-fluorouracil (TCF) in patients with advanced gastric cancer
Authors: Yokoi K. , Omura K. , Hirano M. , Hara T. , Munemoto Y. , Asada Y. , Sakamoto J.
Published: March 2020

14134

Background: Paclitaxel is effective against gastric cancer with serosal involvement and/or peritoneal dissemination. Combination of cisplatin and 5-fluorouracil is also active against advanced gastric cancer. Therefore, we designed a phase I trial of a combination of paclitaxel, cisplatin and 5-fluorouracil (TCF) to explore potential synergistic effect. Methods: Eligible patients had metastatic or unresectable gastric cancer with up to 1 prior chemotherapy regimen. The fixed dose of cisplatin 25 mg/m2 and paclitaxel 80 mg/m2 with escalation dose of 5-fluorouracil from 300 mg/m2 to a maximum of 600 mg/m2 on days 1, 8 and 15 of a 28 day schedule were administered. MTD and anti-tumor activity were evaluated. Results: No grade 3 or 4 toxicities at least possibly related to the treatments resulting in DLT were observed on every dose level. The clinical effects were determined in 3 patients with measurable lesions out of 7 cases. There were 2 partial responses, and disease stabilization was seen in one patient. Conclusions: Combination of paclitaxel, cisplatin and 5-fluorouracil (TCF) is considered to be feasible, well tolerated and active in patients with advanced gastric cancer and warrants further examination in a phase II trial.

No significant financial relationships to disclose.
A SEER database analysis of conditional survival for prostate cancer patients
Authors: Luh J. Y. , Wang S. J. , Fuller C. D. , Thomas C. R.
Published: March 2020

14506

Background: Survival probability changes for patients who have already survived one or more years following diagnosis, and is more accurately represented by conditional survival. The specific aims of this study were to determine the 5-year conditional survival rates for prostate cancer patients. Methods: Using the Surveillance, Epidemiology, and End Results (SEER 11) database from the NCI, we analyzed 66,822 prostate cancer patients diagnosed between 1988 and 1994 that were staged using the SEER-modified AJCC staging system (3rd edition). Using the life table method, we computed observed 5-year conditional survival, stratified by stage, age, and race, for patients who had already survived 0 to 5 years after diagnosis. Results: For each category, we compared baseline 5-year observed survival at diagnosis with 5-year observed conditional survival after having already survived 5 years. Survival decreased from 79% to 67% for Stage I, decreased from 80% to 71% for Stage II, decreased from 83% to 75% for Stage III, but increased from 38% to 49% for Stage IV patients. Survival rates did not change for patients <70 years (79–80%), but decreased from 61% to 55% for patients >70 years old. Although blacks (60–62%) had lower survival than whites (69–71%), no race had any appreciable change in their conditional survival for those who had survived 5 years from diagnosis. Conclusions: For prostate cancer patients who have already survived some time after diagnosis, the expected 5-year conditional survival increases for Stage IV patients, but decreases for other stages and for older patients. Conditional survival can provide more accurate longer term prognostic information for prostate cancer patients who have already survived a number of years after diagnosis.

No significant financial relationships to disclose.
PSA flare-up in patients with hormone-refractory prostate cancer (HRPCA) receiving docetaxel-based chemotherapy: Incidence and differentiation from progressive disease
Authors: Sahi D. , Ohlmann C. H. , Cordia I. , Engelmann U. , Heidenreich A.
Published: March 2020

14523

Background: Docetaxel-based chemotherapy displays the standard therapy for patients with hormone-refractory prostate cancer. A subset of patients will experience an initial PSA increase after initiation of therapy followed by a subsequent PSA decrease. The aim of our study was to investigate the incidence of this phenomenon and to identify factors that differentiate the flare-up from progressive disease. Methods: We retrospectively analyzed the patient records of 46 patients who received docetaxel as monotherapy or in combination with either mitoxantron or estramustine for hormone-refractory prostate cancer. PSA flare-up was defined as an initial PSA increase of more than 25% after initiation of therapy over baseline followed by a PSA decrease of at least 75% compared to the maximum increase over baseline. Progressive disease was defined as a PSA increase of at least 25% over baseline in patients with no PSA response which had to be confirmed four weeks later. Results: Of 46 patients who received docetaxel-based chemotherapy 16 (34.8%) showed a PSA decrease of at least 50%, 6 (13.0%) between 30–50%, 17 (37.0%) had stable disease and 7 (15.2%) patients experienced progressive disease. An initial PSA increase followed by a subsequent PSA decrease was seen in 6 (13.0%) of the patients. Median PSA increase compared to baseline was 81.0% (25–239). The median following PSA decrease was 110.5% (77–160) compared to the initial increase. Median PSA doubling times of patients with PSA flare up or progressive disease were 113.3 and 100.7 days (p = 0.7941), respectively. Conclusions: PSA flare-up seems to be a common phenomenon in patients being treated with docetaxel-based chemotherapy for hormone-refractory prostate cancer. In order not to prevent those patients from a subsequent PSA decrease by early cessation of therapy it would be useful to discriminate them from patients with progressive disease. According to the results of our study PSADT does not differ between patients with flare-up or progressive disease and can therefore not be used to distinguish between the two.

No significant financial relationships to disclose.
SPC2968—A novel Hif-1α antagonist for treatment of clear cell renal cell carcinoma
Authors: Westergaard M. , Hansen H. F. , Thrue C. A. , Hansen J. B. , Kjaerulff L. S. , Straarup E. M. , Olsen O. , Dalby L. W. , Hildebrandt-Eriksen L. , Kearney P.
Published: March 2020

14581

Background: SPC2968 is a short (16-mer), oligonucleotide antagonist of Hif-1α mRNA in which potency has been enhanced through incorporation of Locked Nucleic Acid. Over-expression of Hif-1α has been correlated with increased vascularisation, metastatic potential and poor clinical outcome in a variety of malignancies, including Renal Cell Carcinoma (RCC) of clear cell aetiology, where Hif-1α dysregulation, brought about by mutations in the von Hippel Lindau gene, appears to play a major pathogenic role. Methods: In vitro, human cancer and endothelial cells grown under hypoxic conditions were used to evaluate the effect of SPC2968 on mRNA and protein to Hif-1α as well as phenotypic effects, measured by quantitative polymerase chain reaction (QPCR), Western blotting and biochemical/cellular assays. QPCR was also used to measure mRNA levels in SPC2968-treated mice, while the effects of the drug on tumour growth and vascularisation were evaluated in xenografts. To assess biodistribution in vivo, tritium-labelled SPC2968 was injected intravenously. Results: In vitro, SPC2968 at 1nM reduced both mRNA and protein levels of Hif-1α in cancer cell lines and downregulated two downstream targets of Hif-1, VEGF and MMP-2.Treatment also induced apoptosis in tumour cells and prevented tube formation by endothelial cells in vitro. Parenteral administration of SPC2968 in mice yielded potent inhibition of Hif-1α and VEGF mRNA in several tissues, including kidney, liver, and colon. Radioactively labelled SPC2968 distributed to kidney, liver, colon, bone marrow, lymph nodes and skin. Preclinical studies investigating acute and sub-acute toxicity and safety pharmacology of SPC2968 are completed, and SPC2968 was well tolerated. Conclusions: SPC2968 is an effective suppressor of Hif-1α mRNA and Hif-1α-regulated genes in vitro and in vivo and has shown good tissue biostability and biodistribution in rodents. Preclinical safety studies have been completed, and SPC2968 is ready for clinical testing. A phase I/II, dose-escalating study of SPC2968 in clear cell RCC in the US and the EU is planned to be submitted by mid 2006.

[Table: see text]
Safety and efficacy of the combination of high-dose calcitriol, docetaxel and aoledronic acid in hormone-refractory prostate cancer (HRPC): Interim report of a phase II trial
Authors: Shamseddine A. , Makarem J. , Abdel Khalik Z. , Bulbul M. , Taher A. , Khawli R. , Hemadeh K. , El-Saghir N.
Published: March 2020

14600

Background: The purpose of this study is to assess the efficacy and safety of Calcitriol, Docetaxel and Zoledronic acid in patients with metastatic HRPC. The primary endpoint of the study is the toxicity profile. Secondary endpoints include prostate specific antigen PSA response and time to disease progression. Methods: 16 patients with HRPC were enrolled. All patients had confirmed diagnosis of prostate cancer and no previous cytotoxic therapy. All patients signed an informed consent. Patients received oral Calcitriol 0.5μg/kg on day 1 on weekly basis six out of eight-week cycles, Docetaxel 36mg/m2 on day 2 on weekly basis six out of eight-week cycles, and Zoledronic acid 4mg intravenously on weeks 1 and 5 of every 8-week cycle. Results: A total of 52 cycles were administered and toxicity was acceptable. No treatment-related mortality was encountered. No grade IV anemia, neutropenia, thrombocytopenia or diarrhea was reported. No grade IV gastrointestinal toxicities or thromboembolic events were reported. Grade IV infection was seen in 2 (3.8%) cycles (herpetic esophagitis and listeria meningitis). Grade III neutropenia was seen in 2 cycles (3.8%). Grade III diarrhea was seen in 1 cycle (1.9%) and grade II diarrhea in 4 cycles (7.7%). Grade II to III nausea and vomiting was reported in 8 cycles (15.4%). Grade II to III sensory neuropathy was noted after 17 cycles (32.7%). Grade III fatigue was reported in 5 cycles (9.6%). 14 patients were eligible for response analysis. Overall PSA response rate of our patients was 57.2%. Median time to disease progression was 6.5 months (range 2–15). One year survival was 57.1% (8 out of 14 patients). Conclusions: This interim analysis showed that the addition of Calcitriol to Docetaxel showed an acceptable safety profile as compared to Docetaxel regimens alone with less incidence of neutropenia and diarrhea. Previous studies using Docetaxel alone has reported higher incidence of neutropenia reaching 43–56% and grade III to IV diarrhea (10–34%). Our study suggests that Calcitriol might have a protective effect against the Docetaxel toxicities.

No significant financial relationships to disclose.
Analysis of hormonal receptor status in tissue from prostate cancer that developed 26 years after bilateral orchiectomy and following 41 years of estrogen therapy
Authors: Miksad R. A. , Bubley G. , Church P. , Cooper A. , Rofsky N. , Kaplan I. , Sanda M.
Published: March 2020

14610

Background: The development of prostate cancer in the absence of normal male testosterone levels and in the presence of elevated estrogen levels is rare and poorly understood. Methods: The androgen, estrogen and progesterone receptors were evaluated in prostate cancer tissue from a 60-year-old, long-term transgender woman. Her serum hormone levels were assessed and the prostate specific antigen (PSA) level was followed during hormonal and radiation treatment. This patient began estrogen therapy at age 19 and underwent bilateral orchiectomy at age 34 during gender re-assignment surgery. Work-up for gross hematuria revealed a Gleason 8, locally advanced prostate cancer. Results: The tumor showed abundant staining for androgen receptors (AR), with a nuclear pattern consistent with hormone refractory prostate cancer. The tumor did not stain for estrogen receptors (ER) or progesterone receptors (PR). Compared to reference values for men, this transgender woman had low serum testosterone (44 ng/dl) and free testosterone (0.9 pg/mL) levels and elevated estradiol (53 pg/mL) and estrone (377 pg/mL) levels. Prior to the initiation of radiation, treatment with bicalutamide and dutasteride reduced her PSA from 240 ng/ml to 77 ng/ml at week 6 (see Table). After treatment with external beam radiation her PSA fell to 4.6 ng/mL. At week 24, her PSA was 0.8 ng/mL. Conclusions: This high-grade, locally advanced prostate cancer in a transgender woman represents the longest reported duration of a castrate state preceding the development of prostate cancer, exceeding prior reports by several decades. The AR positive and ER/PR negative status of this tumor in the setting of low testosterone and elevated estrogen levels challenge long-standing paradigms regarding the testosterone requirement for prostatic carcinogenesis. In addition, these findings raise questions about the role of estrogens in prostate cancer. [Table: see text]

[Table: see text]
Satraplatin, an oral platinum analog, is active and synergistic with paclitaxel and docetaxel in prostate carcinoma models
Authors: Lamphere L. , Obermayr F. , Caligiuri M. , Unteregger G. , Rudoltz M. S. , Wosikowksi K. , Casazza A. M.
Published: March 2020

14620

Background: Satraplatin is a novel oral platinum analog with potent cytotoxic and antitumor activity in preclinical models. Satraplatin showed activity in hormone refractory prostate cancer (HRPC) and other tumor types in Phase II trials. A pivotal Phase III trial evaluating satraplatin as 2nd-line therapy for HRPC completed accrual of > 900 patients in 2005. Satraplatin’s activity, safety profile and ease of administration make it attractive for combination regimens. Methods: Satraplatin and its active metabolite JM-118 were tested in vitro as single agents in the androgen-sensitive LNCaP and the androgen-insensitive PC-3 and DU-145 human prostate carcinoma (ca.) cell lines. For in vitro combination studies, PC-3 cells were treated with satraplatin or JM-118 either prior to, after, or concomitantly with paclitaxel or docetaxel. The PC-3 cell line was used for in vivo xenograft experiments in nude mice. Paclitaxel was given intravenously on Day 1, satraplatin orally on Days 2 to 6, and paclitaxel again on Day 8. Results: Satraplatin and JM-118 as single agents inhibited the growth of all three prostate ca. cell lines in vitro in a dose dependent fashion. IC50 values for JM-118 were < 1μM. Strong synergism was noted when PC-3 tumor cells were treated in vitro with paclitaxel or docetaxel followed by satraplatin or JM-118. Satraplatin administered orally inhibited the growth of PC-3 xenografts in nude mice. Treatment of advanced PC-3 tumors with paclitaxel (40 mg/kg) and satraplatin (35 mg/kg) was well tolerated and resulted in a Tumor Growth Delay equivalent to 3 Log Cell Kill, an effect superior to that of the single agents. Conclusions: In vitro, satraplatin and its metabolite JM-118 are active as single agents against human prostate ca. cells, and are synergistic with taxanes. In vivo, treatment with paclitaxel followed by satraplatin showed synergism without increased toxicity. These preclinical data support ongoing Phase I and II clinical trials that are evaluating combinations of satraplatin with paclitaxel or docetaxel.

[Table: see text]
Increasing overall survival with neoadjuvant and concomitant hormonal therapy plus conformal radiotherapy for high risk prostate cancer patients
Authors: Cruz M. R. , Nakamura R. A. , Monti C. R. , Prestes J. C. , Trevisan F. A. , Ferrigno R.
Published: March 2020

14641

Objective: To evaluate the value of neoadjuvant (NHT) and concomitant hormonal therapy (CHT) for high risk prostate cancer patients treated with conformal radiotherapy (3DCRT). Methods: From October 1997 to January 2002, 116 patients with high risk prostate cancer were submitted to 3DCRT and were analyzed retrospectively. High risk patients were defined as patients with PSA >20 ng/ml, and/or T3 clinical stage and/or Gleason score >7, or two factors of intermediate risk (PSA ≥10 and <20 ng/ml, T2b-T2c and Gleason score >7). The NHT and CHT were performed on 69 (59.5%) and 79 (68.1%) patients, respectively. The prostate and seminal vesicles median doses were 81 Gy (72–82.8) and 61.2 Gy (45–77.4) respectively. The median time from diagnosis to 3DCRT was 2,9 months (0.9–134.9). Results: On median follow-up of 54.5 months (13.5–93.9), the 5-year actuarial overall (OS) and 5-year biochemical progression-free survival (BPFS) were 84.3% and 64.7% respectively. The OS for patients submitted to NHT was 89.8% versus 76.4% for patients that were not submitted to (p = 0.0139). Patients that received CHT had an OS of 89.6% versus 73.4% for patients that did not receive CHT (p = 0.0201). Gleason score, clinical stage and seminal vesicles irradiation were significant to BPFS (p = 0.0372, p = 0.0412 and p = 0.0321 respectively). Conclusions: NHT and CHT increased OS of high risk prostate cancer of patients. Gleason score and clinical stage were important prognostic factors to BPFS. Seminal vesicles irradiation is recommended for high risk patients.

No significant financial relationships to disclose.
Outcomes associated with retinoblastoma and c-myc gene expression in patients with testicular cancer: A ten-year experience
Authors: Astudillo-De La Vega H. , Ruiz-Garcia E. , Salcedo M. , Torres A. , De La Cruz J. A. , Benitez A. , Gariglio P. , Gutierrez-Delgado F.
Published: March 2020

14656

Purpose: To determine and correlate the protein and mRNA expression of c-myc and Rb genes in normal testicular tissue and testicular cancer as possible markers of pharmacological response. Methods: Eleven fresh testicular cancer surgical specimens were obtained from untreated patients with histological diagnosis of seminoma (9/11) and non seminoma (2/11) during the period of 1992 to 1995. Age patient average was 35 (16–74). Two normal human testicular tissues also were evaluated as control. Single and double immunohistochemical assay was performed with peroxidase anti-peroxidase system using polyclonal antibody anti-pRb C-15 and monoclonal antibody anti- c-myc 1. Non radioactive in situ hybridization with cRNA probes was performed with cDNA from Rb (exons 2–27) and c-myc (exons 2,3). All seminomas were stage I and were treated with radiotherapy. Non-seminomas were stage III and were treated with chemotherapy. Results: Histological findings: Rb protein was expressed in mature cells toward the lumen of normal testicular tissue while c-myc was located in basal cells but decreasing the expression toward the lumen. High correlation between mRNA and protein levels for both genes was observed in normal testicular tissue. Rb protein and mRNA was absent in 6/11 (55%) tumors while the remaining showed a low level expression (45%). A high c-myc expression was observed in 6/11 (55%) seminomas specimens correlating in a few cases with absent Rb expression. Percentage of positive cells to c-myc gene expression (mRNA and protein) was highly increased in tumoral samples. Clinical findings: All patients with seminoma (9/11) and one of non seminoma (1/11) are alive and without tumoral activity a ten years of the diagnosis. A non-seminoma patient (1/11) have 11-year survival, a high expression of c-myc gene and absent retinoblastoma expression was observed in this case. Conclusion: The semiquantitative differences observed on c-myc and Rb gene expression in seminoma and non-seminoma tumors might correlate with the biological behavior including their high proliferation rate and the chemosensitivity.

No significant financial relationships to disclose.
Survival of patients with testicular germ-cell tumors with poor prognosis secondary to liver metastases
Authors: Martinez-Cedillo J. , Aguilar J. L. , Morán-Mendoza A. , Arrieta O. , Cruz-Lòpez J. , Calderillo G. , Rivera-Lamas A. , Torreblanca-Montaño M. , Lara-Medina F. , De La Garza J. G.
Published: March 2020

14657

Background: Most patients with disseminated germ-cell tumor have an excellent prognosis with cisplatin-based combination chemotherapy, although there have been described certain subgroups with a worse prognosis. The presence of liver metastases (LM) represents an independent cause of poor prognosis. This study reviews the clinical course and treatment results of patients treated at Instituto Nacional de Cancerología de México (INCan-Mex). Methods: The records of all patients with germ-cell cancer and LM between 1992 and 2002 were reviewed. Age, primary site, metastases site, number of metastasis sites, histopathology type, serum tumor markers (STM) levels, liver functional assay, number of LM and used chemotherapy were examinated. The overall survival (OS) and disease free survival (DFS) were analized with Kaplan-Meier method and Log Rank test. Results: Of 32 reviewed patients, median age was 24 (range 18–42 y). The primary site was testis in 27 patients and retroperitoneal in 5 patients. The number of metastasis sites was > 3 en all cases. All patients had nonseminomatous component, predominating choriocarcinoma (82%) and seminoma (78%). The 60% of patients had STM of poor prognosis. 50% of the patients had abnormal liver functional assay. 25 cases (78%) had multiple LM. First line chemotherapy had complete response (CR) in 2 patients, partial response with STM negative (PRM-) in 12 cases, partial response with STM positive (PRM+) 8, and progression in 9 patients. All patients were treated with cisplatin-based chemotherapy. No prognostic factors of chemotherapy response were determined. Only 11 cases underwent to resection surgery of retroperitoneal or pulmonary residual. No patients underwent to liver surgery. Five year OS of 32 cases were 50%, 34% with DFS, between the patients with superior response to chemotherapy (RC + PRM-) the OS and DFS was better in relation with minor response or progression (p < 0.05). The cases with RC in liver (11) were 5-year OS 100% and DFS 66% (p < 0.05). Conclusions: The clinical course and results of treatment in the 32 cases of the INCan-Mex were similar to the literature. This study represents the greatest individual serie reported. These patients with poor prognosis are candidates to innovative treatment modalities.

No significant financial relationships to disclose.
A randomized multicenter phase II study on neoadjuvant chemotherapy with carboplatin and docetaxel in advanced ovarian carcinomas (PRIMOVAR)
Authors: Park-Simon T. , Jänicke F. , Ortmann O. , Hilfrich J. , Breitbach G. , Höss C. , Möbus V. , Thomssen C. , Diedrich K. , Kuhn W.
Published: March 2020

15025

Background: In the past years the concept of neoadjuvant chemotherapy and interval laparotomy has emerged for patients with advanced ovarian cancer and unfavorable prognosis (e.g. diffuse peritoneal carcinosis). In a recent study on neoadjuvant chemotherapy higher tumor resection rates and longer median survival were demonstrated in patients with advanced ovarian carcinoma and ascites >500ml. Most studies use three cycles of preoperative chemotherapy. However, chemoresistant tumorclones may be induced by increasing number of preoperative chemotherapy cycles. The purpose of this study is to evaluate the optimal number of cycles prior to interval laparotomy. Methods: 67/73 patients with advanced serous ovarian carcinoma (FIGO IIIc n = 48, FIGO IV n = 19) and ascites >500ml were randomized into two arms, receiving either 2 (n = 33) or 3 (n = 34) cycles of Carboplatin (AUC5) and Docetaxel (75mg/m2) before interval laparotomy. Postoperatively, they received either 4 or 3 additional cycles. Response rate and postoperative residual tumor were evaluated. Results: Surgical response was assessed during interval laparotomy. At present 32 patients underwent tumordebulking. Partial remission was observed in 28/32 patients irrespective of the number of preoperative chemotherapy cycles. Two patients in each arm showed stable disease. Optimal cytoreduction was achieved in 25/32 patients. No severe adverse events were reported. Six of 73 patients were not eligible. Two patients were excluded due to therapy-unrelated events. In 4 patients ovarian cancer was excluded by laparoscopy prior to neoadjuvant chemotherapy. Conclusions: Neoadjuvant chemotherapy followed by interval laparotomy was safe and well tolerated. Diagnostic laparoscopy prior to neoadjuvant chemotherapy allowed differentiation of primary ovarian cancers from tumors of other origin. In these cases laparotomy could be circumvented. Optimal tumor reduction was achieved in a significant number of patients. Response rate and postoperative residual tumor were essentially the same in both arms. Our data indicate that two cycles of preoperative chemotherapy may be the preferential choice of therapy for future studies.

No significant financial relationships to disclose.
Pegylated liposomal doxorubicin and platinum in patients with advanced ovarian cancer in late relapse (>6 months)
Authors: Wei L. , Chen C. , Huang C. , Chien S. , Huang Y. , Cheng W. , Hsieh C.
Published: March 2020

15035

Background: Platinum and doxorubicin have different mechanisms of action, show no cross-resistance, and their toxicities do not overlap. Because pegylated liposomaI doxorubicin (Lipo-Dox was manufactured by TTY Biopharm Company Ltd. in Taiwan) appears to be a promising form of delivering doxorubicin with decrease of some of the most problematic toxicities, a combination with platinum should be assessed. Methods: An open-label, non-comparative, single center phase II clinical trial. Eligible patients must have histologically proven advance ovarian cancer with two-dimensioned measurable disease or evaluable disease (defined as CA-125 ≥ 40 U/ml), who have been treated with one or two previous platinum- and taxane-based regimen. All patients will hospitalize for 24 hours for treatment. The dose of platinum is fixed (cisplatin at 75 mg/m2 or carboplatin at AUC=5) on D1 and the initial dose of pegylated liposomaI doxorubicin (Lipo-Dox) is 35 mg/m2 on D2 at a 4-week interval. Results: Twenty patients were enrolled from July 2002 to January 2004 and follow up until June 2004. All eligible patients are assessable for response and toxicity. The overall response rate was 80%. Of the 20 patients eligible for response evaluation, 10 (50%) patients had a complete response, 6 (30%) had partial response, 3 (15%) were with stable disease, and 1 (5%) showed progressive disease. An overall response (OR) was achieved in 80% of patients. In patients achieving an OR based on WHO criteria, median CA125 levels declined from 142 U/ml (range, 13–3670 U/ml) during the baseline to 26.5 U/ml (range, 5–375 U/ml) during the last cycle. Median time to response was 65 days (range, 12–188 days). Median duration of response was 471 days (range 146–1085 days). Furthermore, the median time to progression was 481 days (range, 138–1136 days). The main toxicity was myelosuppression, with grade 3 and 4 neutropenia in 3 patients, anemia in 4 patients, and leukopenia in 2 patients. Conclusions: Based on effectiveness and toxicity advantages, the combination of pegylated liposomaI doxorubicin (Lipo-Dox) and platinum should be considered in patients with advanced ovarian cancer in late relapse.

No significant financial relationships to disclose.
Clinical experience of using docetaxel-cisplatin in the treatment of advanced ovarian cancer: A Bangladesh perspective
Authors: Mokhlesuddin M. , Akhter P. S. , Ahmed D. U. , Khan M. A. , Rahman M. A. , Islam T.
Published: March 2020

15070

Background: Docetaxel is an active agent in the treatment of recurrent advanced ovarian cancer. We conducted a multi-center phase II study to evaluate the response rate, toxicity and survival of docetaxel-cisplatin regimen as first-line treatment of advanced ovarian cancer in Bangladeshi population. Methods: Forty chemotherapy-naïve patients of advanced epithelial ovarian cancer were recruited between October 1999 to March 2002. Eligibility criteria included stage Ic-IV patients, age 18–75 years, an ECOG performance status of 0–3 with adequate hepatic, renal and bone marrow function. Docetaxel 60 mg/m2 as 1 hour IV infusion and cisplatin 75 mg/m2 were given on day 1 every 3 weeks for a maximum of 6 cycles (average 5 cycles). Tumor responses and toxicities were evaluated by relevant investigations and survival was documented. Results: A total of 40 patients were enrolled. Median age was 44 years (age range 18–75 years). All the patients were evaluable for response. Overall response was observed in 32 patients (80%) with complete response rate 38% (12 patients), partial response rate 62% (20 patients). Stable disease was seen in 5 patients (12.5%) and progressive disease was in 3 patients (7.5%).Two years survival was documented in 62% patients. Toxicities were limited with grade 3 neutropenia in 10 patients (25%) and some non-hematological toxicities (including nausea, vomiting and fluid retention) in twenty-six patients (65%). No severe febrile neutropenia and no events of death were observed. Conclusions: The combination of docetaxel and cisplatin appears to be effective with manageable toxicities in patients with advanced epithelial ovarian cancer in Bangladeshi population.

No significant financial relationships to disclose.
MGMT methylation status correlates with temozolomide-mediated radiosensitization in a panel of GBM orthotopic xenografts
Authors: Sarkaria J. N. , Carlson B. L. , Decker P. A. , Schroeder M. J. , Kitange G. J. , Ballman K. V. , James C.
Published: March 2020

1509

Background: Lack of MGMT methylation in GBM tumors is associated with a worse outcome with combined radiation (RT) and temozolomide (TMZ) therapy, and it is unclear whether non-methylated tumors benefit from TMZ treatment. Methods: The potential benefits of concomitant or adjuvant TMZ relative to methylation status were evaluated in 10 GBM tumors established from patient samples and maintained by serial passage in mice. For each tumor line, 32 mice with established orthotopic xenografts were randomized to A) placebo, B) TMZ PO daily × 5 (120 mg/kg or 66 mg/kg, as indicated) C) RT, 2 Gy bid × 10 fx., D) combined TMZ and RT, and mice were followed until moribund. Efficacy was evaluated by regression modeling and Kaplan-Meier statistical analyses. Results: Six lines with non-methylated MGMT (GBM10, 14, 26, 28, 36, 43) and 4 with methylated MGMT (GBM8, 12, 16, 34) were evaluated, and complete results are available in 6 lines. In all tumor lines and at both dose levels, there was a significant benefit for TMZ relative to placebo (p<0.003). Both methylated tumors (GBM8 and 12) and one non-methylated tumor (GBM14) were markedly sensitive to TMZ with greater than a 50 day extension in survival with monotherapy. Individually and in a pooled analysis, there was no evidence for a synergistic interaction between TMZ and RT in the non-methylated tumors (p=0.91 for pooled analysis). In contrast, there was a striking degree of synergy in GBM12 (p<0.001) and at least additive effects of combined treatment in GBM8 (5 of 8 mice still surviving in the RT/TMZ arm). In a pooled analysis of these 2 MGMT methylated tumors, there was a trend towards synergy (p=0.11). Conclusions: TMZ treatment did not sensitize MGMT non-methylated tumors to radiation, and with one exception, these non-methylated tumors were only modestly sensitive to TMZ alone. In contrast, treatment with TMZ appears to sensitize MGMT-methylated tumors to radiation and monotherapy is associated with marked and significant benefit.

[Table: see text]

No significant financial relationships to disclose.