bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II evaluation of imatinib mesylate (G) in stage M0 prostate cancer (PC) patients (pts) on hormonal therapy (HT) with evidence of biochemical relapse
Authors: Sinibaldi V. J. , Carducci M. A. , Elza-Brown K. , Rosenbaum E. , Denmeade S. , Pili R. , Walczak J. , Garrett-Mayer E. , Moore-Cooper S. , Eisenberger M. A.
Published: March 2020

14612

Background: Imatinib mesylate (Gleevec, G) is a potent inhibitor of the tyrosine kinases and other signaling mediated events. Preclinical models suggest that G inhibits platelet derived growth factor (PDGF) and stem cell factor (SCF) which are important for prostate cancer growth. This trial was designed to evaluate the safety and efficacy of G in PCA pts on HT with stage M0 disease. Methods: Eligible PCA pts included: stage M0 disease with rising PSA levels while on hormonal therapy, no prior chemotherapy. Planned treatment included G 400 mg PO BID given up to a maximum of 12 months. The statistical endpoint for this trial was the% of pts with a ↓ in prostate specific antigen (PSA) ≥ 50% lasting ≥ 4 wks. A 2 stage trial was designed where the study would terminate if the% of pts meeting the endpoint was not convincingly > 30% with 5% chance for error. Pts with a > 50% rise in PSA from baseline were removed from study. Follow-up included monthly toxicities and PSA (specimens frozen/stored until completion of each 3 months of therapy). Results: From 10/1/02–10/11/04, nine pts were enrolled. Pt characteristics included median: age of 67 years (range 52–80), ECOG performance status of 0 (range 0–1), baseline PSA of 29.6 ng/ml (range 2.69–39.52), # prior hormonal manipulations of 3 (1–5). Prior local therapies included: 1 status post (s/p) RP alone, 2 s/p RT alone, 2 s/p neoadjuvant HT plus RP, 2 s/p neoadjuvant HT plus RT. Two pts had no prior local therapy. Two pts had prior salvage RT, 1 had prior palliative RT. Eight of 9 pts evaluable for response and toxicity. One patient never received treatment. None of the pts had a decline 50% decline in PSA level lasting ≥ 4 weeks. Three of 8 pts (38%) had rapid increases in PSA and 4/8 pts (50%) developed metastatic disease after 3 months of therapy. Only one pt completed 12 months of planned therapy. Grade 3/4 toxicities included: fatigue (25%), rash (25%), arthralgias (12.5%), peripheral edema (25%), depression (12.5%), necessitating dose delays and/or discontinuation of G in 4/8 pts (50%). Conclusions: These data suggest significant toxicity and low clinical benefit. Further evaluation of Gleevec in this pt population is not warranted.

No significant financial relationships to disclose.
Robotic-assisted laparoscopic prostatectomy in obese patients: The Columbia University experience
Authors: Levinson A. W. , Samadi D. B. , Collins S. M. , Urdaneta A. E. , Goluboff E. T. , Benson M. C.
Published: March 2020

14619

Background: In addition to being more likely to be found with more aggressive prostate cancer (PCa), obese patients (OPs) face challenges with treatment options for localized PCa. Several studies have shown that open radical retropubic prostatectomy, pure laparoscopic, and robotic-assisted laparoscopic prostatectomy (RALP) may be associated with increased operative times, blood loss, and even a higher rate of capsular incision. We examined our own experience with the surgical and pathologic outcomes of OPs undergoing transperitoneal RALP at our institution. Methods: We queried the Columbia University IRB approved database for transperitoneal RALPs performed by a single fellowship trained laparoscopic oncologist (DS) for which body mass index (BMI) data was available. We identified patients who met the CDC definition of obese (BMI > or = 30 kg/m2) at the time of surgery. We compared surgical and pathologic outcomes between these OPs and NOPs. Of note, operative time was defined as the time from initial trocar placement to skin closure, and does not include robotic set-up time. Results: BMI data was available for 78% of RALP patients in the database. We identified 22 OPs (mean BMI 32.7 (30.1 to 46.7)) and 112 NOPs (mean BMI 25.6). One patient in each group was converted to open. There were no statistically significant differences in the surgical outcomes of mean blood loss, operative time or length of stay for the OPs vs. NOPs (179cc v. 191cc, 213min v. 221min, and 1.4d vs. 1.7d, respectively). There was no significant difference in preoperative PSA, pre-treatment MSKCC 5yr progression-free probability, pre or post-operative Gleason sum, margin status, or perioperative complications. There was a trend towards increased prostatic volume in OPs vs NOPs (51cc vs 44cc, p = 0.10). Conclusions: Unlike a prior robotic, pure laparoscopic and ORRP series, OPs who received transperitoneal RALP at our institution had no statistically significant increases in blood loss, operative time or perioperative complications when compared to their non-obese cohorts. We believe RALPs may be safely recommended to OPs as an option for treatment of localized prostate cancer.

No significant financial relationships to disclose.
Phase II study of xyotax (PPX) for androgen independent prostate cancer (AIPC)
Authors: Khan M. , Sharef S. , Amato R. J.
Published: March 2020

14624

Background: PPX is a polymer conjugate of paclitaxel. In preclinical studies, PPX has an improved therapeutic profile relative to paclitaxel, in addition demonstrated activity in paclitaxel-resistant tumor models. This study investigates whether single agent PPX can induce PSA responses and increase time to progression in AIPC. Methods: Eligibility included: progressive disease based on at least one of the following: a) 3 consecutive rising PSA levels or b) new or progressive measurable disease, or c) new or progressive metastatic lesions on bone scan. Castrate levels of serum testosterone (≤ 50 ug/l), anti-androgen withdrawal, no more than 1 prior chemotherapy regimen, Zubrod performance status of ≤ 2, neuropathy ≤ grade 1, and adequate organ/marrow function. PPX is administered intravenously over 10–20 minutes without routine premedications, at a dose of 150 mg/m2 every 28 days. Dose modifications are based on nature and grade of toxicity observed. Patients (pts) are restaged every 8 weeks until progression or a maximum of 12 months of therapy. Results: 12 patients (pts) (11 previously treated/1 untreated) have been enrolled to date. 7 of the previously treated pts received prior taxanes. 3 pts continue on treatment. 9 pts have completed a range of 6–28 weeks of therapy. Based on a reduction in PSA of at least 50% and maintained for at least 8 weeks, 2 previously treated pts (1 prior taxotere) responded to treatment. 3 pts demonstrated a delay in their PSA velocity. Adverse events were assessed and included: 1 pt who developed a hypersensitivity reaction, 5 pts with grade 2/3 neuropathy, 5 pts with grade 2/3 leukopenia, 2 pts with grade 3/4 neutropenia and 1 pt with grade 4 thrombocytopenia. Other common reversible grade 1/2 toxic effects have been: nausea, fatigue, elevated LFTs and anemia. 6 pts have required dose reduction. Conclusion: PPX is well tolerated and demonstrates promising activity in patients with AIPC. Efficacy assessments are measured by: absolute PSA response, PSA velocity changes, and toxicity data will be presented.

[Table: see text]
Application of the International Germ Cell Consensus Classification (IGCCC) to the Nova Scotia population of patients with germ cell tumors (GCT)
Authors: Maydanski Murphy E. , Douglas J. , Thompson K. , Wood L. A.
Published: March 2020

14625

Background: The IGCCC is the internationally accepted, clinically based, prognostic classification used to aid in the management of GCT. The goal of this study was to determine if the IGCCC is applicable to a population based cohort. Methods: A retrospective chart review of all patients diagnosed with GCT in NS between 1984–2004 was completed, and IGCCC classification (good, intermediate, poor) was assigned to each patient based on the site of the primary lesion, the presence or absence of non-pulmonary visceral metastases and pre-chemotherapy tumor marker values. Kaplan-Meier estimates of five year progression free survival (PFS) and overall survival (OS) were calculated for each IGCCC group, for both non-seminomatous GCT and seminomatous GCT. Results: The distribution, PFS and OS are shown below. Conclusions: The IGCCC seems applicable to a population-based cohort, with similar distribution of categories, as well as clear prognostic ability. This project was funded by a Norah Stephen Oncology Scholars Summer Studentship Grant from Cancer Care Nova Scotia. [Table: see text]

[Table: see text]
Phase I/II study of GM-CSF gene-transduced allogeneic prostate cancer cellular immunotherapy (GVAX IT) in advanced prostate cancer patients made lymphopenic by chemotherapy and infused with autologous peripheral blood mononuclear cells (MC)
Authors: Curti B. D. , Assman I. , Moudgil T. , Ratzow T. , Haley D. , Walker E. , Hege K. , Sacks N. , Urba W. J. , Fox B. A.
Published: March 2020

14635

Background: GVAX IT has been tested in phase I/ II and is currently being tested in phase III clinical trials of patients (pts) with androgen-independent prostate carcinoma (AIPC). Immunological and PSA responses have been described in men receiving GVAX IT. Preclinical studies have shown that antitumor immune responses induced by GVAX IT could be augmented further by making animals lymphopenic and reconstituting with lymphocytes prior to vaccination. A clinical trial was designed to study the effects of lymphopenic reconstitution in pts with AIPC. Methods: All pts had MC collection by leukapheresis pre-treatment. Study groups were as follows: Arm A - GVAX IT given every two weeks for 6 months; Arm B - Cyclophosphamide (350 mg/m2 IV on days 1–3), MC infusion on day 6, GVAX IT on day 7, then every 2 weeks for 6 months; Arm C - Cyclophosphamide (350 mg/m2 IV on days 1–3) and fludarabine (20 mg/m2 IV on days 1–3), MC infusion on day 6, GVAX IT on day 7, then every 2 weeks for 6 months. Results: Seven pts have been treated thus far and completed at least 2 GVAX IT treatments. Pts had ECOG performance status ≤ 1, castrate testosterone levels, ≤ 1 prior chemotherapy regimen and measurable or evaluable metastatic AIPC. Lymphopenia was induced in all pts enrolled in Arms B and C, with recovery of total granulocytes and lymphocytes within 4 weeks following treatment. Monitoring of humoral and cellular immunological responses is underway and shall be presented. Conclusions: GVAX IT and lymphopenic reconstitution is feasible in men with AIPC. Analysis of clinical and immune response is ongoing. Supported by DAMD grant PC020094 and generous support of Mr. Tom Denhart, the Chiles Foundation and the Murdock Trust.

[Table: see text]
A multicenter phase II study of thalidomide in combination with interleukin-2 (IL-2) in patients with previously untreated metastatic renal cell carcinoma (MRCC)
Authors: Farray D. , Clark J. I. , Kuzel T. , Dutcher J. P.
Published: March 2020

14636

Background: Thalidomide, a drug with immune modulating and anti-angiogenic properties has shown activity in relapsed/refractory MRCC; furthermore, early phase I data of oral thalidomide with subcutaneous low-dose IL-2 showed the combination to be safe. The potential anti-tumor activity of this combination formed the basis of this study. Methods: The aim of this multi-center, open label, phase II study was to determine the efficacy and safety of thalidomide and IL-2 given in combination. Patients (pts) with untreated clear cell MRCC with measurable disease and previous nephrectomy were eligible. Two 6-week cycles of thalidomide and IL-2 were planned. Each cycle consisted of thalidomide started at 200 mg orally daily and titrated to 400 mg daily on the 4th day for 6 weeks; IL-2 was started one week post initiation of thalidomide at a dose of 7mIU/m2 subcutaneously days 1–5 for 4 weeks, followed by 2 weeks off therapy. Therapy was to be continued until progression, if there was at least stable disease (SD). Planned accrual was 53 patients. Results: 11 pts were enrolled. The trial was terminated early due to lack of responses. Median age was 57 years (51–66). All pts had an Eastern Cooperative Oncology Group performance status of 2 or better. The only grade 3 toxicities were fatigue (3 pts), neuropathy (1 pt), anorexia (1 pt), dyspnea (1 pt), edema (1 pt); these required dose reductions as per protocol. There were no objective responses: 3 pts had SD, 8 pts had progressive disease (PD). The 3 pts with SD completed 4, 4, and 6 cycles of therapy respectively; of the 8 pts with PD, 3 completed two cycles, and 5 completed one cycle of therapy. Conclusions: The combination of thalidomide and low-dose IL-2 was well tolerated, but in this trial did not show anti-tumor activity in patients with clear cell MRCC. We thank Celgene for support of this trial.

No significant financial relationships to disclose.
Trial of chemotherapy (CHT) plus hormonal therapy an initial treatment for prostate cancer (PC)
Authors: Shu T. , Hernandez J. , Karediy M. , Khan M. , Amato R. J.
Published: March 2020

14637

Background: The delivery of CHT in a setting of androgen-independent (AI) PC has demonstrated: survival benefit associated with a PSA decline and tolerable toxicity, thus strongly suggesting that disease modifying potential exists. Preclinical data supports the benefit of simultaneous CHT and androgen deprivation (AD). The stage is set for CHT to be given earlier in men with PC. Data suggests a transformation from an androgen-dependent to an AI phenotype is mediated by the expansion of an AI clone already present at the time of AD. If this model is correct, it would be feasible to bring CHT up front when the corresponding tumor burden is minimal. Methods: A course of CHT is defined as 8 weeks (6 on/2 off). The therapy consists of weeks 1, 3, and 5 with adriamycin 20 mg/m2 as a 24 hour intravenous infusion on the first day of every week in combination with ketoconazole 400 mg orally 3 times a day, daily for 7 days. Weeks 2, 4, and 6 treatment consisted of docetaxel 35 mg/m2 intravenously over 1 hour on the first day of every week in combination with estramustine 280 mg orally 3 times a day, daily for 7 days. Hormone therapy, GnRH antagonist, is initiated within the first 6 months of starting CHT. Following the completion of 3 courses of CHT, the addition of casodex occurs. Hormone management then continues for a total of 24 months, and then is discontinued. Patients (pts) are followed every 12 weeks with a PSA, testosterone and routine laboratory evaluation. For those men who have had a PSA recurrence, hormone therapy will be reinitiated. Results: 34 men have been enrolled to date. 47% of the men had no prior local therapy, while the other 35% had surgery, 15% had radiation therapy or 3% had both. 3% had a gleason 6, 41%/7, 26%/8, 27%/9 and 3%/10. 64% of the men presented with bone and/or nodal metastasis. Baseline median PSA was 11.2 (1.0–1065.5). The median PSA reduction to date has been 96% with associated nodal and bone scan improvement. Conclusion: Information regarding PSA response, radiographic outcome, toxicity and results of men who are discontinuing hormones will be presented.

[Table: see text]
High intensity focused ultrasound in the treatment of small kidney tumours— The Oxford experience
Authors: Leslie T. A. , Illing R. O. , Kennedy J. E. , Wu M. F. , Ter Haar G. R. , Phillips R. R. , Protheroe A. S. , Cranston D. W.
Published: March 2020

14645

Background: High-intensity focused ultrasound (HIFU) provides a potential non-invasive alternative to conventional therapies. We have been using the extracorporeal ultrasound-guided Model-JC Tumor Therapy System (HAIFU Technology Company, China) in clinical trials to evaluate the safety and feasibility of treating small renal tumours. Methods: Patients with renal tumours less than 4cm diameter and unsuitable for surgery were treated with HIFU were enrolled into this phase II prospective trial. Treatment was delivered under general anaesthesia in a single session using the Model-JC Tumor Therapy System. Magnetic resonance imaging (MRI) 12 days after treatment provided an initial assessment of response (technical success). Patients are followed-up with further MR imaging at 6 months and one year to gauge technique effectiveness. A total of 14 patients will be included in the trial. Results: Eight patients with kidney tumours have been treated to date. All eight have had pre- and 12-day post-treatment MR imaging. One patient was not included in the analysis as treatment was suspended due bowel interposition in the treatment field during therapy. MRI changes suggestive of kidney tumour response have been seen in 4/7 (57%) cases. Complete ablation has been seen in two cases and partial ablation in two cases. One patient remains disease free 12 months after HIFU. Mild transient discomfort was reported by 4/8 patients (50%), and moderate discomfort in 3/8 (38%) but more severe pain needing opiate analgesia has not been encountered in this series. Minor skin toxicity (1mm blister at the treatment site) was seen in two patients. All patients were discharged the day after the procedure. There have been no adverse effects on renal, haematological or hepatic function. Conclusions: Extracorporeal HIFU has the ability to completely ablate small renal tumours. Our early clinical experience suggests that HIFU treatment of kidney tumours is safe and extremely well tolerated. The reasons for the variability in observed response remain obscure, and reliability of tumour ablation will need to improve before extracorporeal HIFU can be proposed for wider clinical use.

[Table: see text]
Docetaxel in combination with radiation in prostate cancer: A phase I dose-finding study
Authors: Berry W. R. , Fairbanks R. K. , Gersh R. H. , Mull S. M. , Ilegbodu D. , Asmar L.
Published: March 2020

14649

Background: Docetaxel (D), one of the more active agents against prostate cancer, also enhances the effects of radiation therapy (XRT). However, there is little information on the tolerability of the addition of D to pelvic XRT. This Phase I multicenter study was conducted to determine the maximum tolerated dose (MTD) and toxicities of D when given in combination with pelvic XRT. Methods: Patients (pts) with PSA levels >4.0 and <8.0 ng/mL after radical prostatectomy who were referred for salvage XRT were treated at 3 dose levels of D: 10 mg/m2, 16 mg/m2, and 22 mg/m2. One treatment course consisted of D given on Day 1 of each 1-week cycle for 7 cycles with daily XRT administered at 180 cGy Monday–Friday. The 3+3 standard Phase I escalation rule was used to establish the MTD. Results: A total of 9 pts were treated, 3 in each cohort at 3 dose levels. Median doses in the 3 cohorts were 22 mg, 35 mg, and 46 mg. Of the 9 pts, 89% were white, 89% had ECOG PS of 0, and 56% had Stage III disease. The median age was 56 years (range, 48–71). Eight patients completed all 7 weeks of D and XRT; 1 pt went off study after Week 4 due to a fall and fractured arm; 3 other pts subsequently went off study due to PD. In the 3rd cohort, 1 pt had Grade 3 diarrhea (a predefined dose-limiting toxicity [DLT]). The cohort was not expanded by 3 additional pts, and the study was closed to enrollment. The MTD of D with concurrent XRT was not determined. The most frequent adverse events (AEs) were fatigue and diarrhea (67% each), nausea and proctitis (44% each), and anorexia and insomnia (22% each). Except for fatigue, the incidences of these AEs were as expected for treatment with D. Four patients (44%) had a CR (1 CRu). There were 4 PR (1 PRu; 44%) and 1 SD (11%). The median time to response was 1.88 mo. (range, 1.8–7); the overall survival was 27.5 mo.; and the median progression-free survival was 17.7 mo. (range, 1.8–27.5). All patients are currently alive. Conclusions: This Phase I study did not allow definition of the MTD of weekly D with XRT before the trial was terminated. The maximum dose tested was 22 mg/m2/week for 7 weeks. D with pelvic XRT to the prostate was well-tolerated and showed promising responses. It thus deserves further study in Phase II trials. Supported in part by sanofi-aventis, Bridgewater, NJ.

[Table: see text]
Phase II study of topotecan and carboplatin in the treatment of platinum-sensitive recurrent ovarian and peritoneal cancer
Authors: Hanjani P. , Shahin M. S.
Published: March 2020

15001

Background: The aim of this trial was to investigate the efficacy and toxicity of the combination of Topotecan (T) and Carboplatinum (C) in the management of recurrent platinum sensitive ovarian and peritoneal cancer. Methods: T (1 mg/m2) was given as a 30-minute infusion daily × 3 days and C (AUC 5) was given as a 30-minute infusion following T on day 3 on a 21-day cycle. Results: Thirty patients (pts) were enrolled and all pts were evaluable for response and toxicity. Mean age was 63.2 (range = 44–84). One hundred eighty five cycles (mean/pt = 6, range 2–10) were evaluable for toxicity. Dose escalation (T = 1.25 mg/m2) was possible in 25 (83.3%) pts. Hematologic toxicity grade 3 and 4 neutropenia was seen in 60 (32.4%) and 10 (5.4%) cycles, respectively. Grade 3 thrombocytopenia was encountered in 24 (13%) cycles. Grade 3 Hgb was observed in 4 (2.2%) cycles. No grade 4 thrombocytopenia/Hgb or neutropenic fever was encountered. Blood transfusions were required in 9 (4.9%) cycles. Bone marrow support with erythropoiten (40% pts), and filgrastim (43.3% pts) were utilized. No neuropathy > grade 1 was encountered. Fourteen pts (46.6%) pts had a hypersensitivity reaction to C and successful desensitization was carried out in 8 (57.1%). Mean follow-up interval was 16.9 months (mos) (Range 1.7–43). To date, 6 (20%) pts are alive without disease, 16 (53.3%) are alive with disease, and 8 (26.7) have died of disease. The overall response rate was 83.3% (5 CR and 20 PR). Five (16.6%) pts had SD. Median progression-free interval was 8.2 mos. Overall mean survival for the cohort was 31.2 mos (95% CI: 24.47–37.71). Conclusions: Given the ICON-4 data, supporting combination therapy in recurrent platinum-sensitive patients, this regimen provides an effective and tolerable alternative to Taxane-platinum combination with no significant neuropathy. This regimen is especially attractive in patients who have significant residual neuropathy after initial treatment. Carboplatinum desensitization was feasible in previously pre-treated patients.

No significant financial relationships to disclose.
Novel method for predicting chemoresistance to paclitaxel in epithelial ovarian cancer patients
Authors: Silasi D. , Rutherford T. J. , Schwartz P. E. , Chen R. , Alvero A. , Visintin I. , Mor G.
Published: March 2020

15007

Background: No available test exists to guide the selection of effective chemotherapeutic regimen in recurrent ovarian cancer. Preliminary studies in our lab have identified a protein, MyD88, a major component in the inflammatory pathway, to be highly expressed in epithelial ovarian cancer cells that exhibit primary or acquired Paclitaxel chemoresistance. The objective of this study was to develop a sensitive approach that can detect expression of MyD88 in ovarian cancer tissue. We report the development of a test based on Laser capture microdissection that allows detection of MyD88 in a 6000 cell sample. Methods: Tumor tissue was obtained at surgery from epithelial ovarian cancer patients and snap-frozen in liquid nitrogen. Eight micron sections were prepared on polyethylene covered glass slides and tumor cells were dissected with a Laser capture microdissection system. Protein expression was detected by Western blot analysis. Results: Protein expression was detected by Western blot analysis in 1000 microdissected cells. An inverse correlation was observed between MyD88 expression in tumor cells and clinical response to Paclitaxel. Furthermore, this method allows the isolation of CD-45 positive cells from the tumor and analysis of their protein expression. Conclusions: We describe for the first time a method that will allow us to predict chemoresistance. Laser capture microdissection is a powerful technique that can be used to study the protein profile of each of the cellular components present in the tumor microenvironment. This technique will facilitate our understanding of the proteins necessary for tumor growth and may help to identify novel markers or potential protein targets.

No significant financial relationships to disclose.
Study design considerations for phase II trials of anaplastic gliomas and its impact on phase III survival studies
Authors: Levin V. A. , Hess K. R.
Published: March 2020

1501

Background: Phase 2 trials for anaplastic gliomas (AG; WHO 3) such as anaplastic astrocytoma, oligoastrocytoma, and oligodendroglioma remain the most productive path for the development of new therapeutic strategies for the treatment of patients with these tumors. To better understand methodology for their conduct and impact of phase 2 trials on survival-based phase 3 studies, we reviewed a large patient database of patients treated by faculty from the UTMDACC. Methods: Combined data from contemporary (1999–2004) clinical trials and a UT MDACC patient database of AG patients treated on phase 2 studies were analyzed to determine progression-free survival (PFS) at 6, 9, and 12 months. Variables of age, KPS, number of prior chemotherapies, and response to treatment were also evaluated in an effort to define PFS with respect to treatment activity (durability). Results: A total of 547 patients in 17 phase 2 studies were analyzed. The major effecter of PFS outcome at 6, 9, and 12 months was the specific chemotherapy used. The covariates of age, KPS, treatment response rate, and number of prior chemotherapies did not significantly affect PFS to the same extent. Cluster analyses demonstrated the existence of four major therapeutic efficacy groups ranging from A to D. A-group PFS6 was 13% and D-group 40%; for PFS12 A-group was 15% and D-group 32%. Conclusions: The relative differences in PFS among the 4 groups was similar implying that using PFS6 for AG studies is a valid endpoint and extending studies to PFS12 is not cost- or time-effective (27 patients vs. 57 patients). In addition, given that 8 of the 17 studies achieved PFS12 of >25%, it raises the question whether phase 3 survival studies can or should be conducted at this time. Since there are many effective secondary and tertiary treatments for patients who fail chemotherapy, the objective of overall survival for phase 3 AG studies is a flawed objective. For phase 3 studies, PFS is a much more valuable and reliable number to reflect the true antitumor benefit of a form of chemotherapy. Since the median survival of AG patients can range from 4 to 6 years, focusing on PFS in phase 3 studies will also allow more rapid studies and, therefore, the potential to evaluate and discover more and better treatment options for our patients.

No significant financial relationships to disclose.
Drug safety profiling for assessment of drug combinations in oncology
Authors: Voss S. N. , Czarnecki A.
Published: March 2020

15037

Background: It is important to understand the safety profile (SP)/toxicity of new drug regimens in oncology. We compared SPs of gemcitabine (Gem) + carboplatin (Carbo) in NSCLC with Gem alone and in different combinations and also tested the methodology of drug safety profiling (DSP). Methods: Spontaneous cases for the period of 1995–2005 were reviewed on the Lilly Safety Database (LSD). DSP was used to evaluate differences in the SPs of several combinations: Gem+Carbo in NSCLC, Gem+Carbo in ovarian cancer, Gem+ cisplatin (Cis) in NSCLC, Gem+Carbo in all indications, and Gem regardless of treatment regimen, for all indications. Frequencies of adverse events (AEs) for all MedDRA System Organ Classes (SOCs) were used for each regimen. In addition, the MedDRA Preferred Terms (PTs) were reviewed to detect potential safety signals. The numbers of AEs in different SOCs were assessed as proportions of the total reports for the Gem combinations in the LSD. Results: With the exception of the Investigations SOC, the proportions of AEs for patients treated for NSCLC with Gem+Carbo were consistent with those for patients treated for NSCLC with Gem+Cis and with Gem for all indications. However, the frequency in the Investigations SOC was consistent with that reported for Gem+Carbo in all indications (14.2% v. 12.0%). A greater frequency of AEs was seen in the Gastrointestinal Disorders SOC for patients treated with Gem+Carbo for ovarian cancer compared to patients treated with Gem+Carbo for NSCLC. The review of individual PTs for Gem+Carbo did not reveal any safety signals. Conclusions: The SP of Gem+Carbo in NSCLC using DSP showed similar patterns to all other Gem combinations with only some differences due to the indication. DSP is a useful tool in assessing the new drug combination treatments in existing or new indications.

[Table: see text]
Weekly topotecan for platinum resistant ovarian cancer
Authors: Abushahin F. , Grendys E. C. , Lurain J. R. , Singh D. K. , Rademaker A. W. , Schink J. C. , Schink J. C.
Published: March 2020

15040

Background: Topotecan is currently used to treat recurrent ovarian cancer after failure of platinum-based therapy. The FDA-recommended regimen (1.5 mg/m2 for 5 consecutive days of a 21-day cycle) is associated with a high incidence of grade 3/4 myelosuppression. Alternate dosing and scheduling may increase patient convenience and reduce toxicity. The objective of this study is to evaluate toxicity, response and progression free survival of weekly topotecan therapy in women with primary and secondary platinum resistant ovarian cancer after failure of 1 or more regimens. Methods: A retrospective analysis of 59 patients that received weekly topotecan with a median dose of 3.75 on days 1, 8, and 15 of a 28-day cycle treated between November 2002 and May 2005. All patients had recurrent epithelial ovarian cancer with primary or secondary resistance to platinum. Disease response was evaluated by CA-125 levels, physical exam, and when appropriate by imaging studies. Toxicity was evaluated using the NCI Common Toxicity Criteria. Results: Response to therapy was noted in (22%) 13 of 59 patients (complete 6.75%, partial 15.25%). Stable disease was noted in 19 patients (32.2%) and progression in 25 patients (42.4%). Two patients (3.4%) had significant side effects that warranted the discontinuation of therapy. There was no significant difference in response to therapy between patients with primary and secondary platinum resistance. A total of 204 cycles were given with a median of 3 (1–12) cycles per patient. Grade 3 and 4 myelosuppression were rare with 1 cycle (0.5%) with grade 3 leukopenia, 15 cycles (6.4%) with grade 3 or 4 neutropenia, 1 cycle (0.5%) with grade 3 anemia, and 1 cycle (0.5%) with grade 3 thrombocytopenia. No patients were admitted with neutropenic fever. The Median Progression-free-survival for responders was 195 days (56–471). Conclusions: Weekly topotecan is a well tolerated and effective regimen for platinum resistant ovarian cancer with considerable less hematological toxicity when compared with historical data for the 5-day regimen.

[Table: see text]
A phase II study of two induction schedules of high dose carboplatin (HDC) vs weekly paclitaxel/gemcitabine (WPG) followed by paclitaxel/carboplatin/gemcitabine (PCG) in advanced ovarian cancer (AOC)
Authors: Bolis G. , Polverino G. , Sciatta C. , Scarfone G. , Scambia G.
Published: March 2020

15062

Background: Patients (pts) with newly diagnosed AOC generally receive platinum plus taxane therapy. G represents a new active agent to improve the standard regimen. To investigate the safety of two schedules of induction treatments both followed by triplet PCG we have drafted a phase II study. Methods: 14 pts, suboptimally debulked (FIGO stage IIIc) entered the study. HDC ( AUC 7,5) was administered for 2 courses every 21 days ( arm A) and P ( 80 mg/sqm, d 1,8,15,22) + G ( 2500 mg/sqm, d 1,15) (arm B). Both regimens have been followed by standard triplet P ( 175 mg/sqm, d1) + C ( AUC 5, d1) + G ( 800 mg/sqm, d1,8) every 21 days for a total of 6 courses. Antiemetics, corticoids, antihistaminics and ranitidine have been added. Results: The median age was 57 y (39–68). Histology was serous in 64.3%, mixed 14.3% and other 21.4%. All pts had Grade 3 tumor but one. Seven pts received arm A schedule and 7 arm B both followed by PCG regimen. Worst haematological toxicities ( in term of nadir) observed in all courses for all pts were neutropenia G4 ( 42.8% arm A vs 71.4% arm B), anemia G2 (71.4% arm A vs 57.1% arm B), thrombocytopenia G2 ( 57.1% arm A vs 42.8% arm B). Most common non haematological toxicities were alopecia and mild nausea/vomiting. Mild paresthesias in both regimens were observed. No sepsis or neutropenic fever nor unespected toxicity or treatment-related deaths were observed. 71.4% of pts completed foreseen schedules of treatments. 78.5% of pts received erytropoietin and 28.5% G-CSF support. Conclusions: HDC and weekly PG followed by triplet PCG are feasible and safety regimens in AOC pts ( residual disease > 1 cm). Further phase II-III setting study using these schedules will be conducted.

No significant financial relationships to disclose.
Ovarian tumours associated with pregnancy
Authors: Bakhidze E. V.
Published: March 2020

15063

Background: Ovarian cancer occurs in 1.5–5.6% of all combination of malignant tumours and pregnancy. The purpose of this study was to review patients with ovarian tumours in pregnancy, the efficiency of the available methods of treatment and their prognosis. Methods: A retrospective research of the data about 52 patients with ovarian tumours associated with pregnancy who were operated in The N.N.Petrov Research Institute of Oncology from 1960 to 2002. Results: From 52 patients with ovarian tumours associated with pregnancy there were 40 patients (76.9%) with benign tumours and 12 patients (23.1%) with malignant tumours. Middle age of patients was 24.9 ± 5.2 years. Among malignant tumours there were 4 epithelial tumours, 7 herm cell tumours (6 were dysgerminoma and 1 choriocarcinoma) and 1 sex cord-stromal tumour. 9 patients had I stage, 2 had II stage and 1 patient had III stage by FIGO. 14 patients with benign and 7 patients with malignant tumours was operated during the pregnancy: 13 patients (9 with benign, 4 with malignant tumours) were operated during I trimester, 4 patients (3 with benign, 1 with malignant tumours) were operated during II trimester and 4 patients (2 with benign, 2 with malignant tumours) were operated during III trimester of pregnancy. 26 patients with benign tumours and 7 patients with malignant tumours were operated after delivery or abortion. All patients with benign tumours were treated by unilateral salpingoophorectomy. 6 patients with malignant tumours were treated by organ-preserving operations. The 5-year free reccurance survival rate was 83.3% in patients operated during I trimester both for radical and organ preserving operations. The 5-year free reccurance survival rate was 50% in patients operated during II, and 33.3% in patients operated during III trimester. In 6 patients with Ia stage dysgerminoma associated with pregnancy the 5-year free reccurance survival rate was 100%. Conclusions: Benign ovarian tumours associated with pregnancy occur in much more cases (76.9%). Among malignant ovarian tumours the non-surface epithelial tumours occur more often (66.6%). The majority of patients with malignant ovarian tumours who were operated during pregnancy had I stage by FIGO (75%). Prognosis depended not on but on stage and hystotype of tumour and trimester of pregnancy in which patients were operated.

No significant financial relationships to disclose.
Analysis of serum phospholipid-fatty acid and antioxidant system in patients with cervical intraepithelial neoplasia and cervical cancer
Authors: Kim H. Y. , Kim J. W. , Kim Y. T. , Kim E. S. , Kim S. Y. , Shim Y. J. , Ko Y. S. , Yoon B. S. , Lee Y. J.
Published: March 2020

15068

Background: The membrane compositions, especially phospholipid-fatty acid (PL-FA) and antioxidant system have been focused on carcinogenesis. Therefore, the objective was to examine the patterns of PL-FA and antioxidant status in patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. Methods: Blood samples were obtained from 23 patients diagnosed as invasive cervical cancer, 32 with CIN and 41 with other benign gynecologic diseases as the control group. Compositions of serum PL-FAs, total antioxidant performance (TAP), and lipid peroxidation were assessed and compared between these 3 groups. Serum levels of PL-FAs were analyzed by the GC system, after extracting phospholipids using Folch and TLC methods. Fluorometer were used to measure lipid-soluble radical for assessment of TAP and serum malondialdehyde (MDA) was quantified to evaluate the degree of lipid peroxidation. Results: With the highest proportion of saturated fatty acids (SFAs), polyunsaturated fatty acids (PUFAs)/SFAs ratio was lowest in the invasive cervical cancer group. While the EPA (eicosapentaenoic acid, C20:5ω3) + DHA (docosapentaenoic acid, C22:6ω3)/linolenic acid (C18:3ω3) ratio (ω3 product/ω3 precursor) was significantly lower in the CIN group (p < 0.0001), arachidonic acid (C20:4ω6)/linoleic acid (C18:2ω6) ratio (ω6 product/ω6 precursor) tended to be higher in patients with CIN and cervical cancer (p = 0.0682). In w6 series fatty acids, consistent trends of higher desaturation indices and lower enlongation indices were observed in CIN and invasive cervical cancer groups. The level of MDA was significantly higher in cervical cancer group than in CIN and control groups. The value of TAP was significantly lower in CIN. Conclusions: In patients with cervical neoplasia, the endogenous production of DHA and EPA, as well as ω3 derivatives seems to be decreased. Since cervical cancer patients displayed higher MDA levels and lower TAP, antioxidant status also tends to be lower in this group. These significant changes in patterns of PL-FAs and antioxidant status in cervical cancer patients suggest their possible involvements in carcinogenesis, but further studies are mandatory to define the exact causal relationship.

No significant financial relationships to disclose.
Phase I/II trial of twice-daily temozolomide and celecoxib for treatment of relapsed malignant glioma: Final data
Authors: Pannullo S. C. , Burton J. , Serventi J. , Stieg P. , Subramanian H. , Elsoueidi R. , El-Jassous I. , Balmaceda C.
Published: March 2020

1519

Background: Anaplastic astrocytoma (AA) and Glioblastoma multiforme (GBM) overexpress COX-2 enzyme. COX-2 inhibitors demonstrate preclinical efficacy in glioma models and have non-overlapping toxicity with chemotherapy, prompting a phase I/II trial for patients with recurrent/progressive AA or GBM utilizing a regimen of combined temozolomide (TMZ) and celecoxib (CEL). Final survival data is presented. Methods: For phase I, TMZ was given as a fixed loading dose of 200 mg/m2 followed by 9 doses of 90 mg/m2 BID for 5 days. CEL was given in 5 dose levels starting at 60 mg/m2 BID, escalating to 240 mg/m2 BID (maximum 400 mg BID) for 10 days. Cycles were repeated every 28 days until disease progression or toxicity occurred. Results: 46 patients (28 M, 18 F) received 247 cycles of therapy. 37 patients had GBM, 9 AA. Prior treatment was radiation (N=46) and chemotherapy (N=12). No patient received prior TMZ. Median age was 54 years (range 34–74). No dose-limiting toxicity was observed. Hematologic toxicity was mild with Grade 3/4 neutropenia occurring in 3/235 cycles and Grade 3 thrombocytopenia in 3/235 and did not recur following TMZ dose reduction. Grade 1/2 constipation was common, occurring in 28% of patients. No thrombotic events occurred. Overall response rate after 6 cycles was 72%, with 1/18 (5.6%) CR, 7/18 (38.9%) PR, 5/18 (27.8%) SD, and 5/18 (27.8%) PD. Average duration of response was 6 months (range 2–15). Median survival (MS) from time of trial entry for recurrent disease was 8 months (8 months for GBM, 10 months for AA). MS from initial tumor diagnosis was 15 months (15 months GBM, 23 months AA). Conclusion: A regimen of twice-daily TMZ and CEL is safe and potentially effective for the treatment of recurrent/progressive GBM and AA. This combination warrants further study, especially in patients newly diagnosed, given the current use of TMZ in newly diagnosed GBM and the possible value of COX-2 inhibitors in the upfront setting.

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Imatinib mesylate in the treatment of patients with recurrent high grade gliomas expressing PDGF-R
Authors: Marosi C. , Vedadinejad M. , Haberler C. , Hainfellner J. A. , Dieckmann K. , Rössler K. , Hassler M. R.
Published: March 2020

1526

Background: Despite noticeable progress in the treatment of high-grade gliomas (HGG), most patients experience tumor recurrence after standard treatment consisting of surgery, radiotherapy and concomitant chemotherapy. Imatinib mesylate, a tyrosine kinase inhibitor of PDGFR-α, -β, c-kit, abl and arg, has been shown to produce tumor response in patients with recurrent gliomas (Raymond ProcASCO 2004, Dresemann ProcASCO 2004&2005, Reardon Proc ASCO 2005). We treated 34 patients with recurrent HGGs showing immunohistochemical expression of “imatinib targets” in the tumor tissue with imatinib. Methods: 34 patients, 16 women, 18 men, aged from 27 to 72 years, in median 49 years with recurrent HGG (GBM n= 23, AA n=11) were treated with imatinib 400 mg/day as continuous daily oral dosing. MRI was performed every three months or at clinical suspicion of progression. The median interval from diagnosis to the start of imatinib was 12.6 months (range 4.3 to 143 months). Imatinib was the 2nd line therapy in 15 patients, 3rd line in 13 and 4th line in 6 patients. ECOG performance score at start of imatinib was 1 in 9, 2 in 21 and 3 in 4 patients, respectively.Immunohistochemical analysis was performed on formalin fixed and paraffin embedded tumor tissue with antibodies against PDGFR-α, and -β. Results: The median treatment period with imatinib was 4 months (3 weeks to 17 months). The best response achieved was major response in 2 patients, partial remission in 6, stable disease in 12 and progressive disease in 14 patients. Eleven patients were free from tumor progression after 6 months (PFS-6 32,4%). The two patients with major response improved clinically and showed no more evidence of increased metabolism as well in MRI spectroscopy as in C11-methionine PET for 13 and 17 months, respectively. One of them showed widespread PDGF-R-α expression in the tumor tissue. In all patients with objective response to imatinib, a clinical benefit was noted within the first month of treatment. Conclusions: Compared to the results of Raymond et al, we observed a higher percentage of patients with progression free survival at 6 months. Detailed analysis of imatinib targets in tumor tissue of patients treated with imatinib will be helpful to explore the potential of imatinib as treatment option for patients with HGG.

No significant financial relationships to disclose.
Detection of subclinical systemic disease in primary central nervous system lymphoma (PCNSL) by polymerase chain reaction (PCR) of the rearranged immunoglobulin heavy chain (IgH) genes
Authors: Jahnke K. , Hummel M. , Korfel A. , Burmeister T. , Mueller H. , Seide C. , Stein H. , Thiel E.
Published: March 2020

1533

Background: An unresolved question is why some PCNSL spread systemically while most others do not. It was postulated that extracerebral relapse of PCNSL may represent a sequel of initial occult systemic disease rather than true extracerebral spread. Methods: To elucidate this question, we examined bone marrow and peripheral blood specimens of 24 patients with newly diagnosed PCNSL using PCR for the presence of clonally rearranged IgH genes. The applied IgH PCR method was recently developed by a European Concerted Action (BioMed-2). To all samples (50 ng DNA), three different FR primer sets (FR1, FR2 and FR3) were applied in conjunction with a JH consensus primer (JH22). Baseline routine staging procedures showed no evidence of systemic lymphoma manifestations in all patients. Results: The same dominant PCR products were found in bone marrow aspirates, blood samples and tumor biopsy specimens from three patients, indicating the presence of the same tumor cell population in the CNS as well as in extracerebral sites. No concordant dominant amplificates were detectable in the remaining 21 patients. To date, nine patients have relapsed intracerebrally and none systemically after a median follow-up of 25 months. Median overall survival was 30.5 months. Of the three patients with monoclonality outside the CNS, two are still in complete remission 24 and 25 months after diagnosis, respectively. The third patient relapsed intracerebrally 12 months after diagnosis, achieved complete remission after whole-brain irradiation and died in complete remission 16 months after diagnosis due to pulmonary embolism. Conclusions: Extracerebral disease not detectable by routine staging may be present in PCNSL patients. This finding may have an impact on the understanding of PCNSL pathogenesis and the extent of staging and treatment.

No significant financial relationships to disclose.
The role of systemic and cranial 18Fluorodeoxyglucose positron emission tomography (FDG PET) in primary central nervous system lymphoma (PCNSL)
Authors: Mohile N. A. , Deangelis L. M. , Abrey L. E.
Published: March 2020

1535

Background: The utility of body and brain FDG PET in staging and management of PCNSL is unknown. Methods: We performed a retrospective study of 166 PCNSL pts at Memorial Sloan-Kettering Cancer Center between January 2000 and August 2005. Pts. who underwent PET imaging were identified using the electronic medical record. PET reports and clinical data were reviewed to determine the reason for the study and impact on management. Results: 61 (37%) pts had ≥1 PET scans. Of 93 studies, 58 were body scans and 35 were brain scans. 72% (42/58) of body PET were done for systemic staging at diagnosis and 28% (16/58) at relapse. 19% (8/42) of scans done for initial staging had suspicious systemic foci. Lymphoma was found in 3 (37.5%), adrenal adenoma in 1 (12.5%), duodenal adenocarcinoma in 1 (12.5%) and non-diagnostic tissue in 1 (12.5%); biopsy was not pursued in 2 (25%). 31% (5/16) of scans done at relapse were abnormal. In 3 (19%) of these, biopsy revealed lymphoma; in 2 (12.5%), biopsy was not pursued. In 8% (4/50) of pts (SUV 12.8, 14.3, 22, 30.5), PET was the only study to demonstrate systemic lymphoma. 2 other pts found to have systemic disease had suspicious findings on conventional imaging in addition to positive body PET (SUV 3.8, 4.1). 43% (15/35) of brain PET were done at diagnosis and 57% (20/35) were done to evaluate residual MRI abnormalities after treatment. 14 brain PET at diagnosis were positive; SUV reported in 7 of these pts ranged from 7.5 to 26.8. The pt with a negative PET was receiving steroids. 10 brain PET done after treatment showed residual tumor and affected interpretation of MRI response. SUV reported in 7 of these pts. ranged from 8.1 to 29. Conclusions: Body PET imaging appears to be a sensitive tool for the detection of occult systemic lymphoma that may be missed with other diagnostics. While Brain PET at initial diagnosis did not yield incremental information, it may be useful in the interpretation of persistent MRI abnormalities after treatment.

No significant financial relationships to disclose.