bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine tumors
Authors: Kulke M. H. , Stuart K. , Earle C. C. , Bhargava P. , Clark J. W. , Enzinger P. C. , Meyerhardt J. , Attawia M. , Lawrence C. , Fuchs C. S.
Published: March 2020

4044

Background: Inhibitors of the VEGF pathway have been shown to have activity in neuroendocrine tumors (NETs). Temozolomide (TMZ), an oral analog of dacarbazine is also active in this setting. We performed a prospective, phase II study to assess the safety and efficacy of TMZ, administered in combination with bevacizuamb, in patients (pts) with advanced NETs. Methods: Pts received TMZ, 150 mg/m2/day po for 7 days every other week, and bevacizumab, 5 mg/kg IV every other week. Due to anticipated lymphopenia, pts received prophylaxis with trimethoprim/sulfamethoxazole (1 DS tablet q MWF) and acyclovir (400 mg po TID). Pts were followed for toxicity, response, and survival. Results: Enrolled patients (n=34) had the following characteristics: M:F = 19:15; median age 61 (range 37–75); ECOG PS 0/1/2 = 12/20/2; carcinoid/pancreatic NET = 16/18. Prior treatments included chemoembolization (n=7) chemotherapy (n=12); and octreotide (n=17); pts on octreotide remained on octreotide at stable doses for the duration of the study. Pts had either well-differentiated tumors (n=27) or moderately/poorly-differentiated NETs (n=7); pts with small cell carcinoma were not eligible for the study. Pts have received treatment for a median of 22 weeks. Grade 3–4 toxicities included: lymphopenia (n=21, 62%), leukopenia (n=2, 6%), thrombocytopenia (n=7, 21%), neutropenia (n=2, 6%), hyponatremia (n=1, 3%), vomiting (n=3, 9%), nausea (n=2, 6%), dehydration (n=1, 3%), fatigue (n=2, 6%), constipation (n=1, 3%), and hypertension (n=1, 3%). 20 pts had elevated CGA levels (>36.4 ng/ml) at baseline; 0/9 (0%) carcinoid and 4/11 (36%) pancreatic NET experienced CGA decreases of >50% from baseline on two consecutive assessments. 29 pts are currently evaluable for radiologic response ( Table ). Conclusions: The combination of TMZ and bevacizumab can be safely administered and shows promising activity in pts with advanced pancreatic NETs. Additional studies with this combination are warranted.

[Table: see text]

[Table: see text]
Impact of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) on outcomes of postoperative patients with gastric cancer
Authors: Matsubara J. , Yamada Y. , Shimoda T. , Eguchi T. , Hamaguchi T. , Shimada Y. , Okayama Y. , Sugimoto Y. , Oka T. , Shirao K.
Published: March 2020

4053

Background: The clinical significance of biomarkers in resected gastric cancer (GC) remains unclear. Detailed exploratory evaluations are required to better understand the clinical implications of biomarkers. Methods: The study group comprised 87 patients who received chemotherapy for recurrent or residual GC after resection of their primary tumors at National Cancer Center Hospital. The patients received 1 to 5 regimens of chemotherapy (median: 2). Total RNA was isolated from laser-captured tumor cells of the resected cancer specimens, and the gene expressions of TS, DPD, DHFR, ERCC1, MRP1, and 22 other biomarkers related to anticancer drug sensitivity were quantitatively evaluated by a real-time RT-PCR assay. Results: The gene expressions of TS, DHFR, MTHFD, RRM1, and ERCC1 were significantly related to survival ( Table ). Multivariate analysis revealed that high DHFR (p < 0.001, RR = 1.70 [95% CI, 1.28–2.29]) and high TS (p = 0.004, RR = 1.53 [1.15–2.06]) gene expressions were independently related to poor survival. As compared with intestinal type tumors, diffuse type tumors had higher DPD (p < 0.001) and lower Her2 (p < 0.001) gene expressions. As for first line chemotherapy, an analysis of 29 patients treated with S-1, an oral DPD inhibitory fluoropyrimidine, showed that patients with diffuse type tumors tended to respond better (p = 0.13) than those with intestinal type tumors. An analysis of 29 patients treated with cisplatin plus irinotecan as first line therapy showed that low ERCC1 gene expression was slightly but not significantly related to a better response (p = 0.087). Analyses of patients treated with other first line regimens revealed no significant correlation of any biomarker with response. Conclusions: Increased gene expressions of DHFR and TS in surgical specimens are significantly predictors of poor outcomes in postoperative patients with GC.

[Table: see text]

[Table: see text]
Neoadjuvant combined modality therapy with weekly docetaxel (D) and cisplatin (P), 5-fluorouracil (5FU) continuous infusion (c.i.) and concurrent radiotherapy (RT) provides high pathological response rate in esophageal cancers (EC): A phase II study
Authors: Pasini F. , De Manzoni G. , Grandinetti A. , Pedrazzani C. , Griso C. , Sava T. , Minicozzi A. , Durante E. , Bonetti A. , Maluta S. , Cetto G.
Published: March 2020

4057

Background: The achievement of pathological complete response (pCR) is deemed essential to improve survival in EC. In a phase I study (Pasini et al, Ann Oncol 16; 1123, 2005) we demonstrated the feasibility of a novel protocol of neoadjuvant chemoradiation based on weekly D and P, c.i. of 5-FU and concurrent RT. Based on the promising results of the study, we then performed a phase II study aimed at evaluating pathological response rate and toxicity. Methods: 50 pts with stage II-III EC (26 adenocarcinomas) were enrolled (Simon test: P0=0.2, P1=0.6, alpha 0.05 beta 0.1; 54 pts); median age was 59 yrs (42–73). Treatment consisted of D 35 mg/m2 and P 25 mg/m2 d 1,8,15,29,36,43,50,57 plus 5-FU 180 mg/m2 c.i. d 1–21 and 150 mg/m2 c.i. d 29–64; concurrent RT (50 Gy) started on d 29. Surgery was performed 6 to 8 weeks after completion of RT. Results: 49/50 pts (98%) completed the planned chemo-radiation. Median follow-up is 22 mo (7–39). During chemo-radiation, grade 3–4 hematological toxicity occurred in 9 pts (18%)(4 pts grade 4) requiring GCSF support and postponement of CT of one week in 4. One HCV+ pt discontinued CT and continued with RT alone. In the last 2 weeks 12 pts (24%) experienced grade 3 non-hematological toxicities (asthenia, esophagitis, nausea) without need of treatment discontinuation. There was a fatal pulmonary embolism in a non neutropenic pt after completion of the therapy. 45 pts underwent surgery, while 5 did not (2 refusal). Pathological findings: pT0 pN0 (pCR): 25 (50%); pTrm pN0: 6 (12%)[residual microfoci]; pT2 pN0: 1 (2%); pT0–4 pN+: 9 (18% ); R+:4 ( 8%). Response rate was similar between adeno and squamous cell carcinoma. With a median follow-up of 24 mo, only 2 of 25 pCRs (8%) died (1 relapse, 1 postoperative death). Conclusions: i) a substantial pCR rate (50%) was achieved; ii) the weekly schedule allowed concomitant chemo-radiation at cumulative doses otherwise impossible with standard three weeks protocols; iii) because of the acceptable, but not negligible toxicity, this protocol requires to be managed in dedicated institutions.

No significant financial relationships to disclose.
Inter-criteria reproducibility of RECIST, WHO, Japanese response criteria for gastric cancer or esophageal cancer: From the response dataset of Japan Clinical Oncology Group (JCOG) phase III trials
Authors: Kurokawa Y. , Yoshimura K. , Yamamoto S. , Sato A. , Saito I. , Fukuda H.
Published: March 2020

4065

Background: For assessments of tumor response in upper gastrointestinal cancers, Japanese criteria (JPN), which needs X-ray or endoscopic findings for primary lesion, has been generally used in Japan instead of international RECIST or WHO criteria. To compare the inter-criteria reproducibility of these radiological assessments, we analyzed the datasets of tumor responses from two phase III trials. Methods: A total of 115 gastric cancer patients in two treatment arms of JCOG9205, 5-FU and 5-FU plus cisplatin, and 103 esophageal cancer patients in a neoadjuvant 5-FU plus cisplatin arm of JCOG9907 were eligible for this analysis. Overall response rates (ORR) were calculated according to each of three criteria. The tumor responses, furthermore, were divided into four categories (CR, PR, SD, PD), following estimation of kappa statistics between two criteria as agreement measure. Results: As shown in the Table , ORR according to RECIST and WHO were very similar in both cancers. JPN tended to estimate higher ORR comparing to RECIST or WHO, particularly in esophageal cancer. In gastric cancer, kappa for concordance to RECIST were 0.92 for WHO and 0.86 for JPN. While in esophageal cancer, kappa were 0.72 for WHO and 0.40 for JPN. Conclusions: In these trials for gastric cancer and esophageal cancer, there was fairly consistent reproducibility between unidimensional RECIST and bidimensional WHO criteria. JPN criteria, depending on assessment of primary lesion, may give higher ORR particularly in esophageal cancer, and cautious interpretation may be necessary when evaluating ORR from Japanese trials using JPN criteria (Table). Overall response rates of respective treatment arms calculated according to RECIST, WHO and JPN criteria.

[Table: see text]

No significant financial relationships to disclose.
Preliminary results of a randomized phase III trial comparing streptozotocin plus fluorouracil versus interferon for metastatic carcinoid tumors (FNCLCC - FFCD 9710)
Authors: Seitz J. F. , Dahan L. , Rougier P. , Raoul J. L. , Gamelin E. , Etienne P. L. , Cadiot G. , Smith D. , Ricard F. , Bonnetain F.
Published: March 2020

4090

Background: Streptozotocin and 5 FU in combination is widely used for the treatment of advanced carcinoids tumors. Interferon is an effective treatment of the malignant carcinoids tumors. This randomized multicenter phase III trial compared those treatments in patients with metastatic carcinoïd tumors. Methods: Patients with metastatic carcinoid tumors, clinical or biological progression, WHO status 0–2 (PS) and age ≤ 75 years were randomized 1:1 between interferon alpha 2a recombinant (3MU × 3 per weeks) and 5FU (400 mg/m2/day day1 to day5) plus streptozotocin (500 mg/m2/day day1 to day5) every 6 weeks. Stratification was done according to center, PS and anterior treatment. Primary endpoint was progression free-survival (PFS). It was required to include 120 pts and to observe 38 progressions to detect an expected improvement in 1year PFS from 55% to 80% (bilateral α = 5 % and β = 20 %). Secondary endpoints included 1-year and 2-year overall survival (OS). Intent to treat analyses were performed. Results: From February 1998 to june 2004, in 23 centers, 63 patients has been included, 32 in 5FU-STZ arm and 32 in interferon arm: median age (59 years [37–77] vs 63 [39–75]), male/female ratio (1.2 vs 1), PS 0–1 (91% vs 97%), anterior chemotherapy (13% vs 16%), surgery (69% vs 59%), radiotherapy (6% vs 0%) are well balanced between arms. The median number of 5FU-STZ and Interferon cycles was respectively 5 and 4. After a median follow-up of 26 months, the median OS for interferon was 44.3 months versus 37.7 months for chemotherapy: HR = 0.90 [0.43–1.90]; 1- year and 2-year survival rates were 89% and 72% for interferon versus 84% and 73% for chemotherapy. Conclusions: Interferon alpha 2a does not prolong OS in advanced metastatic carcinoid tumors as compared to the combination of 5FU-streptozotocin. After checking clinical and biological progression, PFS analyses will be presented at the meeting.

No significant financial relationships to disclose.
Neuroendocrine tumors (NET) of the gastrointestinal tract: A decade of experience at the Princess Margaret Hospital
Authors: Rothenstein J. , Cleary S. , Pond G. R. , Dale D. , Gallinger S. , Siu L. L.
Published: March 2020

4093

Background: NET are uncommon malignancies with variable natural history and often indolent biological behavior. Over the past decade novel treatment approaches have been developed. There have been few recent descriptions of large institutional experiences with multi-modality therapy for this disease. Methods: The Princess Margaret Hospital cancer registry identified 207 patients (pts) with NET of the gastrointestinal tract or unknown primary who had their initial visits between 1992 and 2002. A retrospective chart review was performed. Results: The median follow-up duration was 25 months for pts who have died and 54 months for those alive at last follow-up. Demographics of the entire cohort of 207 pts were as follows: M:F = 53%:47%; mean age = 55 years; age-adjusted Charlson score 0 = 71%. Anatomical distribution of the primary location revealed that 33% were from the foregut, 37% from midgut, 13% from hindgut and 17% from unknown origin. Pathological distribution demonstrated that 73% were NET/carcinoids, 21% were islet cell tumors and 6% were small cell carcinomas. One-third of the cohort had biochemically and/or clinically functional tumors, 24% were non-functional, and 43% were not biochemically tested and were clinically non-functional. At presentation, 61% of pts had distant metastases and 39% had locoregional disease. Curative surgery was performed in 38% of the cohort, whereas radiotherapy and chemotherapy of any intent were delivered to 15% and 34% respectively. Octreotide LAR was part of the therapeutic regime in 13% of pts. Two-year survival analysis was evaluated among 114 pts, with the remaining cohort being excluded due to either insufficient follow-up or because pts were seen for second-opinion only. Factors that were significantly related to decreased survival in univariate analyses were the presence of distant metastases and small cell histology. All pts who underwent curative surgery in this subgroup were alive at 2 years, and 88% were alive at 5 years. Conclusions: Pts with NET who are offered curative surgery have a good outcome. Distant metastases are commonly found at presentation and portend a worse prognosis. These patients should be evaluated by a multidisciplinary team regarding new approaches to surgery and other therapies.

No significant financial relationships to disclose.
Evaluation of a novel MUC1 biomarker/target antigen for pancreatic cancer
Authors: Gold D. V. , Modrak D. E. , Newsome G. , Karacay H. , Sharkey R. M. , Goldenberg D. M.
Published: March 2020

4096

Background: Pancreatic cancer provides a major challenge in terms of diagnosis and treatment. We have developed an anti-MUC1 MAb, PAM4, which identifies an epitope that is more restricted to MUC1-expressed by pancreatic cancer than MUC1 from other forms of cancer. PAM4 has been studied for in vitro and in vivo detection and therapy of pancreatic cancer. Methods: The in vitro immunoassay consists of PAM4 as the capture reagent and an IgG fraction derived from a polyclonal, anti-MUC1 antiserum as the probe. For in vivo detection and therapy, PAM4 is either directly radiolabeled or used in a 2-step pretargeting protocol. Results: The PAM4-based immunoassay provided high sensitivity (77%) and specificity (95%), with a value ≥ 10.2 units/ml indicating a high likelihood of pancreatic cancer, as compared to normal and benign disease groups and non-pancreatic cancers. A direct pairwise comparison of the PAM4 and CA19–9 immunoassays for discrimination of pancreatic cancer and pancreatitis demonstrated a superior performance of the PAM4-immunoassay (P<0.003). Initial clinical studies with directly labeled 131I-PAM4 provided positive imaging in 8/10 patients, with one negative patient having only pancreatitis, and the other negative patient having a tumor that was MUC1-negative. A Phase I, dose-escalation study of 90Y-humanized PAM4 administered as a single dose to patients with advanced pancreatic cancer is in progress (Immunomedics, Inc), and has already achieved doses of 20 mCi/m2. Finally, pretargeting involving a bispecific MAb with one arm being PAM4 targeting MUC1 and the other arm capturing a hapten peptide carrying a radionuclide is under preclinical evaluation. This second generation targeting system has shown higher tumor/nontumor ratios and improved imaging (111In) as compared to directly radiolabeled PAM4. Conclusions: These results suggest that the PAM4-reactive MUC1 epitope may prove useful as a selective biomarker/target antigen for diagnosis, detection, imaging, and therapy of pancreatic cancer. (Supported in part by grants CA96924and CA98488 from the NIH).

[Table: see text]
Long-term results of concurrent gemcitabine (G) and radiotherapy (GRT) for locally advanced (LA) or high-risk resected (R) pancreatic cancer
Authors: Townsley C. , Brade A. M. , Brezden-Masley C. , Hedley D. , Gallinger S. , Pond G. R. , Oza A. M. , Brierley J. , Moore M. J.
Published: March 2020

4101

Background: G is active against pancreatic carcinoma and is a potent radiosensitizer. We present extended follow up data from a phase I/II study of patients treated with combination GRT. Methods: Eligible patients had either LA or high-risk resected [R] pancreatic cancer [positive nodes or positive margin]. 28 were enrolled in a Phase I study of increasing doses of radiotherapy (35 Gy [n = 7]/43.75 Gy [n = 11]/52.5 Gy [n = 10] given over 4, 5 or 6 weeks, respectively in 1.75 Gy fractions) concurrently with 40 mg/m2 gemcitabine biweekly. Subsequently 35 were treated with induction gemcitabine (G) 1000 mg/m2 7/8 weeks followed by concurrent bi-weekly gemcitabine (40 mg/m2) with 52.5 Gy (30 fractions of 1.75 Gy over 6 weeks). In total there were 63 patients (31 LA and 32 R) treated between March 1999–July 2001. Results: In the LA population the best response observed was CR - 1, PR - 2, SD - 10, PD - 10. GRT was not delivered to 8 patients due to progression on G alone (n = 5) or patient request (n = 3). By intent to treat analysis, the median survival in LA disease was 15.1 months and the 2 year survival was 19%. In the resected population the median time to progression was 14.3 months, the median survival was 17.9 months and the 5 year survival was 19%. The treatment was generally well tolerated during both the induction G and the GRT ( Table ). Conclusion: Survival for both LA and HR patients with this concurrent gemcitabine radiotherapy regimen is promising and warrants further investigation.

[Table: see text]

No significant financial relationships to disclose.
Impact of surgery and chemotherapy on survival in patients with advanced cholangiocarcinoma: A multivariate analysis in a cohort of 242 consecutive patients
Authors: Dreyer C. , Le Tourneau C. , Faivre S. , Paradis V. , Zhan Q. , Degos F. , Farges O. , Hammel P. , Ruszniewski P. , Belghiti J. , Raymond E.
Published: March 2020

4133

Background: Cholangiocarcinoma remains an orphan disease for which prospective studies are missing to evaluate the impact of systemic chemotherapy on survival. Methods: Univariate and multivariate analysis of parameters that might impact survival were analyzed in a cohort of 242 consecutive patients with cholangiocarcinoma treated in a single institution between 2000 and 2004. Variables were WHO performance status (PS), age, symptoms, tumor size, extent of the disease, lymph node involvement, site of metastasis, tumor markers, pathology, and type of treatment including surgery, chemotherapy and radiotherapy. Results: Statistically significant prognostic factors of survival in univariate analysis are displayed in the table : In multivariate analysis, PS, tumor size and surgery were independent prognostic factors. Subgroup analysis demonstrated that in patients with advanced diseases (lymph node involvement, peritoneal carcinomatosis and/or distant metastasis), patients who had no surgery benefited of chemotherapy (median survival 13.1 versus 7.4 months in patients with/without chemotherapy, p = 0.006). Moreover, survival was further improved when patients could benefit of chemotherapy following total and/or partial resection (median survival 22.9 versus 13.0 months in patients with/without chemotherapy, p = 0.03). Conclusions: This study strongly suggests the positive impact on survival of multimodality approaches including surgery and chemotherapy in patients with advanced cholangiocarcinoma.

[Table: see text]

No significant financial relationships to disclose.
Feasibility of a multi-institutional liver cancer registry
Authors: Sun W. , Schwartz J. , Zhu A. , Philip P. A. , Metz J. , Thomas M. B.
Published: March 2020

4146

Background: Hepatocellular carcinoma (HCC) is one of major causes of cancer-related death globally, with increasing incidence in the United States. There is still a lack of effective therapy for the disease. Many small phase II studies of systemic therapies for advanced HCC have been performed in the US. Most studies are too small to make definitive conclusions. This registry was developed to pool phase II studies from member institutions of the Liver Cancer Research Group (LCRG) to evaluate the characteristics and outcomes of patients receiving systemic treatments in an attempt to validate known and to identify potentially new prognostic factors in HCC. Methods: An Internet based registry was initiated on the OncoLink website ( https://www.oncolink.org ) and directed by the LCRG. This registry has undergone IRB approval. All data is password protected and maintained on physical and electronically secure servers. The registry contains 37 fields for each patient, which details demographics, tumor parameters, underlying liver disease, and detailed treatment information of chemotherapy and/or biological therapies. Results: As of 1/10/2006, 101 patients have been entered in the database from 5 institutions. The median age of patients in these studies is 59 years old (range 26–82) with 22 female (22%) patients. The racial distribution was: 67% of Caucasian, 15% African American, 11% Asian, and 6% Hispanic. The median performance status of patients included in these phase II studies was ECOG 1 (PS 0/1/2: 41/56/4). A variety of cytotoxic and biological agents (either as a single agent or as combination) were included in the analysis including doxorubicin, epirubicin, gemcitabine, oxaliplatin, capecitabine, thalidomide, erlotinib, and bevacizumab. All patients had extensive disease, most of them with multiple lesions (51% ≥ 5 lesions) and bilobar involvement (69%). The mean size of lesions was 8.3 cm (range 1–20 cm). Within the population, 25% patents have hepatitis B and 44% have hepatitis C as their background diseases. Conclusions: This multi-institutional database for HCC treated on phase II clinical trials in the US is feasible. This database continues to expand through the support of the LCRG. As the data matures, future studies on outcomes related to biological and chemotherapeutic regimens will be presented.

No significant financial relationships to disclose.
Two novel histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 are active against biliary tract cancer and potentiate the efficacy of gemcitabine
Authors: Wiedmann M. , Bluethner T. , Niederhagen M. , Schoppmeyer K. , Moessner J. , Caca K.
Published: March 2020

4149

Background: Chromatin remodelling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. NVP-LAQ824 and NVP-LBH589 are two novel chemical entities belonging to a cinnamic hydroxamic acid class of compounds. Little is known about their efficacy for the treatment of biliary tract cancer. Methods: Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for p21WAF-1, acH3Lys9 and acH4, cell cycle analysis, PARP assay, TUNEL assay, and immunhistochemistry for MIB-1. Results: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines (mean IC50 (3d) 0.08 and 0.04 μM, respectively) and was associated with hyperacetylation of nucleosomal histones H3 and H4, increased expression of p21WAF-1, cell cycle arrest at G2/M-checkpoint, and induction of apoptosis (PARP cleavage). After 28 d, NVP-LBH589 reduced tumor mass by 66% (bile duct cancer) and 87% (gallbladder cancer) in vivo in comparison to placebo and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis (TUNEL) and reduced cell proliferation (MIB-1). Conclusions: Our findings suggest that NVP-LBH589 > NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.

No significant financial relationships to disclose.
Reduced thromboembolic events with DN-101 (high-dose calcitriol) treatment of androgen-independent prostate cancer: Hypothesis for a new class of anticoagulants
Authors: Venner P. M. , Ryan C. , Petrylak D. P. , Chatta G. S. , Ruether J. , Chi K. N. , Curd J. , Beer T. M.
Published: March 2020

4505

Background: Thromboembolic events (TEs) occur at an increased rate in patients with advanced malignancies including androgen-independent prostate cancer (AIPC). DN-101, a new high-dose oral formulation of calcitriol (1,25-dihydroxycholecalciferol), is the active form of Vitamin D and the natural ligand for the nuclear receptor VDR. Calcitriol upregulates thrombomodulin, a natural anticoagulant, and downregulates tissue factor, a procoagulant both in vitro and in vivo. Further, VDR knockout mice demonstrate increased susceptibility to thrombosis. ASCENT is a double-blind, placebo-controlled study in 250 men with metastatic AIPC. Efficacy results have been previously reported (ASCO, 2005). Methods: 250 patients were randomized 1:1 to docetaxel 36 mg/m2 plus 45 μg DN-101 weekly or to the same docetaxel regimen plus placebo. In this exploratory analysis the incidence of TE (defined as deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), cerebrovascular accident (CVA) and arterial thrombosis (AT)) in the two study groups was compared using the Fisher’s exact test. Results: There were fewer patients with serious adverse events (SAEs) in the DN-101 group than in the placebo group (27 % vs. 41%). As shown in the table , DN-101 treated patients experienced fewer TEs including fewer TE SAEs, Grade 3 or 4 TEs and all grade TEs. No imbalance in baseline use of anticoagulants was observed. Conclusions: The well-described effects of calcitriol on protein components of the coagulation cascade provide a biologic basis for the observed reduction in thromboembolic events in the DN-101 treated patients. This hypothesis should be tested prospectively in future studies of DN-101.

[Table: see text]

[Table: see text]
Increased late toxicity in 12–20 year survivors of germ cell tumors (GCT)
Authors: Raghavan D. , Davis M. S. , Tsao-Wei D. , Ross R. , Groshen S.
Published: March 2020

4509

Background: There is extensive literature on occurrence of late effects of cisplatin-based chemotherapy, but it comes from centers of excellence and may reflect case selection or ascertainment biases. Funded by the NIH SEER Program and the Lance Armstrong Foundation, we studied community-based late outcomes via identification of cases from the Los Angeles SEER Tumor Registry and comparison with a control group. Methods: We identified 951 patients treated in Los Angeles County through the records of the L.A. SEER Cancer Registry/Cancer Surveillance Program (CSP) for 1983–1987, giving a minimum follow-up of 12 years. Consent was obtained from physician of record and forms sent to the patients, requesting information about a broad range of demographic, treatment-related and psycho-social issues. In addition, patients were asked to provide a “control”, a friend of approximately the same age at time of diagnosis, known to the patient before diagnosis and known not to have a history of testis cancer. Questionnaires were also sent to controls, to allow data comparison with patients. Anticipated initial difficulties included mobility of young males and invalid addresses. This occurred in > 50% of cases, and we used a planned strategy for acquisition through State agencies, Department of Motor Vehicles, etc. Results: Surveys were returned by 298 cases and 67 control subjects, and 35 patients refused. In 1983–87, success rates were lower, and 142 patients had died. An unexpected problem was reluctance or inability of subjects to identify friends of comparable age to provide a control population. Differences in groups are summarized in the Table. Conclusions: Long term survivors with GCT have an excess of late toxicity, including cardiovascular, neurological, hematologic, musculoskeletal and neoplastic problems, which increase with time. These data should assist in design of surveillance protocols.

[Table: see text]

No significant financial relationships to disclose.
A prospective study of 18FDG PET in the prediction of relapse in patients with high risk clinical stage I (CS1) non-seminomatous germ cell cancer (NSGCT): MRC study TE22
Authors: Huddart R. , O’Doherty M. , Padhani A. , Rustin G. , Mead G. , Joffe J. K. , Vasey P. , Hain S. , Kirk S. J. , Stenning S. P.
Published: March 2020

4520

Background: High risk stage I NSGCT is characterised by vascular or lymphatic invasion within the primary tumour. This group comprises ∼50% of stage I pts with, (untreated) a relapse rate of 35–40%. Options for the management of such pts include adjuvant chemotherapy, retroperitoneal lymph node dissection (± adjuvant chemotherapy) and surveillance, each achieving similarly high cure rates. An FDG PET scan may be able to aid discrimination between pts without occult metastatic disease, for whom surveillance is an attractive option, and those requiring immediate therapy. Methods: High risk (vascular invasion +ve) CS1 NSGCT pts underwent FDG PET scanning within ∼8 weeks of orchidectomy. PET+ve pts went off study, PET -ve pts were followed on surveillance. The primary outcome measure was the -ve predictive value of PET, defined as the 2-year relapse-free rate (RFR) in pts with a negative PET scan. Assuming a RFR of ∼90%, to exclude a RFR < 80% with 80% power (5% significance), ∼100 PET negative pts were required from ∼135 scanned pts. All baseline CT scans were subject to central review blinded to PET result and relapse status and, in relapsed pts, a retrospective comparison of the CT and PET scan results. Results: Pts were registered between 5/02 and 1/05, when the trial was stopped early by the independent Data Monitoring Committee due to an unacceptably high relapse rate in the PET-ve pts. 116 pts were registered of whom 111 underwent PET scans. 88 pts (79%) were PET-ve; 87 proceeded to surveillance and one requested adjuvant chemotherapy. With median follow-up of 11 months, 33 of the 87 pts on surveillance relapsed for a one-year relapse-free rate of 63% 90% CI (54%, 72%). The PET +ve/relapse rate was 69% in patients with normal markers pre-orchidectomy (n = 36) and 41% in those with raised markers (n = 66). There has been one death (suicide) amongst the PET -ve pts. The radiology and PET scan review will be completed by May 2006. Conclusions: Though PET identified a proportion of pts with disease not detected by CT scan the relapse rate amongst PET -ve pts remains high. The study results therefore suggest that 18FDG PET scanning is not able to identify pts at sufficiently low risk of relapse to replace other treatment options in this setting.

No significant financial relationships to disclose.
A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC)
Authors: Amato R. J. , Misellati A. , Khan M. , Chiang S.
Published: March 2020

4530

Background: RAD001 an oral serine-threonine kinase inhibitor of mTOR, blocks progression from the GI to the S phase of the cell cycle by a mechanism of action that is unique for an anticancer drug. Mechanistically, it is thought that RAD001 may play a role in VEGF inhibition. Main endpoints were to evaluate: time to progression (TTP), response rate, toxicity and to assess changes in metabolic imaging utilizing CT-PET. Methods: Eligibility included: progressive measurable MRCC, adequate organ/marrow function, zubrod performance status (ZPS) ≤ 2, no more than 1 prior therapy, and no active CNS involvement. RAD001 is given orally at a dose of 10mg daily without an interruption (28-day cycle), with dose modifications for toxicity. Re-evaluation was assessed every 3 cycles (12 weeks). RECIST criteria is utilized to determine response rate. TTP is determined from entry into the study. Results: 25 pts have been enrolled as of this review. 19 male/6 female, range 43–80 (median 60) years. All pts had predominant clear cell elements with progressive MRCC. 17 pts received prior immunotherapy, targeted agents, or chemotherapy. 22 pts had a ZPS of 0, 2/1 and 1/2. Sites of disease included: lung, nodal, bone, adrenal, kidney and liver. 7 pts had 1 metastatic site, 10 pts/2 metastatic sites and 8 pts/3 or more metastatic sites. 22 pts continue to receive RAD001 therapy. 7 pts had partial responses, 11 pts were stable for 3+ months, (5 pts/6+ months). 4 pts too early. Median duration of therapy is 7+ months (range 1+ to 9+). Treatment related adverse events to date include: mucositis, skin rash, pneumonitis, hypophosphatemia, hyperglycemia, thrombocytopenia, anemia and elevated LFTs. Conclusion: RAD001 has promising anti-tumor activity in pts with MRCC as demonstrated by a 33% partial response rate. Anti-tumor activity was further suggested by prolonged TTP ≥ 3 months for 86% of pts. The tumor effect was also demonstrated as a second line therapy. Independent radiology review is planned. Anti-tumor activity, toxicity and metabolic imaging correlation will be presented.

[Table: see text]
Pharmacokinetics (PK) and efficacy of sunitinib in patients with metastatic renal cell carcinoma (mRCC)
Authors: Houk B. E. , Amantea M. , Motzer R. J. , Michaelson M. D. , Rini B. I. , George D. J. , Redman B. G. , Hudes G. R. , Poland B. , Bello C. L.
Published: March 2020

4531

Background: Sunitinib malate (SU11248) is an oral, multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, KIT, FLT3, and RET. Clinical studies have demonstrated efficacy of sunitinib in patients with multiple tumor types including two phase II studies in mRCC, where second-line monotherapy with sunitinib showed a response rate of greater than 40% by RECIST, with an additional ≥25% of pts exhibiting prolonged stable disease. A population PK analysis was performed to assess the exposure-response relationship between PK and tumor volume changes, clinical response, and time to tumor progression (TTP) in these two mRCC studies. Methods: In these two studies, 169 patients with mRCC were treated with sunitinib 50 mg/day for 4 weeks, followed by a 2-week off period (Schedule 4/2). Response to treatment was assessed by measuring tumor volume. Clinical response was assessed using RECIST and TTP using logistic regression and Kaplan-Meier survival analysis. A previously described population PK model of sunitinib and its primary active metabolite SU12662 was updated using additional data from three trials, including the two RCC trials. Using the model and trough plasma concentrations, steady-state AUCs of sunitinib plus SU12662 were estimated for each mRCC patient and tested as a predictor of response. Results: PK profiles were evaluable for 149 patients in the two mRCC trials. Plasma clearance (CL) decreased by an average of 28% in mRCC patients relative to healthy volunteers. Covariates, such as gender, age, and ECOG score also affected CL, however all of these changes were less than the estimated inter-individual variability in CL of 43%. Improved clinical response and longer TTPs were associated with greater AUCs. Within 12 weeks of treatment, mean tumor volume decreased by 24–32% in each trial. Conclusions: Individual patient exposures to sunitinib and SU12662 can be predicted with sparse concentration measurements using population PK analysis, and an exposure-response relationship is evident in mRCC. Dose adjustment is not warranted based upon any evaluated covariate. Over the first 12 weeks of treatment at 50 mg daily on Schedule 4/2, increased exposure was associated with improved clinical response and decreased tumor volumes.

[Table: see text]
A phase I study of sunitinib malate (SU11248) in combination with gefitinib in patients with metastatic renal cell carcinoma (mRCC)
Authors: Ronnen E. A. , Kondagunta G. V. , Lau C. , Fischer P. , Ginsberg M. S. , Baum M. , Kim S. T. , Chen I. , Baum C. M. , Motzer R. J.
Published: March 2020

4537

Background: Sunitinib malate (SU11248) is an oral multitargeted tyrosine kinase inhibitor of VEGF and PDGF receptors. Two phase II trials with sunitinib given as second line therapy in patients with mRCC showed a ≥40% response rate (JCO 2006;24:16–24; Proc ASCO 23,380s). Combining sunitinib and gefitinib (an EGFR inhibitor) may enhance antitumor activity by providing a broader spectrum of tyrosine kinase inhibition. The maximum tolerated dose (MTD) of sunitinib in combination with gefitinib was assessed in this Phase I trial. Methods: Patients with mRCC previously treated with cytokine therapy were enrolled in the study. Cohorts of 4–6 patients received escalating doses of sunitinib and a fixed dose of gefitinib. Dose levels of sunitinib were 37.5 mg and 50 mg. Dose limiting toxicity (DLT) was defined as Grade 4 hematologic toxicity, Grade 3 nonhematologic toxicity of ≥7 days or a Grade 2 cardiac toxicity. Six-week treatment cycles comprised of sunitinib daily for 4 weeks followed by 2 weeks off and continuous gefitinib at 250 mg daily except in Cycle 1 where gefitinib was begun on Day 10. Results: In the first dose level (n=4, 37.5 mg of sunitinib and 250 mg of gefitinib), no DLTs were observed. In the second dose level (50 mg of sunitinib and 250 mg of gefitinib), there were 7 patients enrolled, but 1 patient had dose reduction for hypertension during the sunitinib monotherapy part of the study and was not included in the cohort defining MTD. 2 of 6 patients experienced a DLT (Grade 2 decline in ejection fraction, persistent Grade 3 fatigue) and the MTD was determined as 37.5 mg of sunitinib with 250 mg of gefitinib. Grade 3 adverse events included: diarrhea (n = 2) and hand/foot syndrome (n = 2). Laboratory abnormalities included grade 4 neutropenia (n = 1), grade 3 neutropenia (n = 2), and grade 3 thrombocytopenia (n = 2). Overall, 5 of 11 patients demonstrated a partial response and patient accrual to the phase 2 portion of the study is underway. Conclusions: The combination of sunitinib and gefitinib in mRCC patients was well tolerated and MTD was determined. The efficacy and toxicity of this combination is being assessed in a phase II component of this trial.

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Self-reported paresthesias, Raynaud’s phenomena, tinnitus, and hearing impairment in a large cohort of long-term testicular cancer (TC) survivors
Authors: Brydoy M. , Oldenburg J. , Klepp O. , Bremnes R. M. , Wist E. , Dahl O. , Fossa S. D.
Published: March 2020

4547

Background: Persisting side-effects of treatment may impair the well-being of TC survivors. The aim of this study was to assess long-term Raynaud’s phenomena, oto-, and neurotoxicity related to prior therapy. Methods: A follow-up survey was conducted in men treated for TC 1980–1994 in Norway. The 1319 eligible responders had a median follow-up time of 11 years (range 4–21) and were allocated to four separate treatment groups: Surgery (Surg), Radiotherapy (Rt), and chemotherapy (Cisplatin [Cis] ≤ 850 mg and Cis > 850 mg). The questionnaire included six items assessing the relevant toxicities. The responders’ scores were dichotomized [minor (“not at all” or “a little”) vs. major (“quite a bit” or “very much”)] and analyzed by logistic regression with Surg as reference. Results: The proportion of cases (%) reporting major symptoms and the corresponding Odds ratios (OR) varied significantly between treatment groups ( table ). Rt was not statistically significantly different from Surg for any symptom, but showed a trend for higher scores of paresthesias in the feet. Cis > 850 mg differed significantly for all symptoms with major symptoms reported by 25–49% with the highest OR (8.1) for Raynaud’s phenomena in hands. Apart from Raynaud’s phenomena, paresthesias in feet were the only symptom significantly different in Cis < 850 mg compared to Surg. Conclusions: Toxicities induced by cisplatin-based chemotherapy persist in many TC survivors. A cold climate may contribute to the high perception of Raynaud’s phenomena in Norwegian TC survivors.

[Table: see text]

No significant financial relationships to disclose.
Chemo-hormonal therapy for biochemical progression of prostate cancer
Authors: Taplin M. , Xie W. , Morganstern D. , Bubley G. , Ernstoff M. , Regan M.
Published: March 2020

4559

Background: Androgen deprivation therapy (ADT) is effective for relapsed prostate cancer, but is rarely curative. The purpose of this trial was to determine the feasibility, toxicity and PSA response of chemotherapy and ADT for men with PSA relapse. Methods: Eligible men had a rising PSA and no metastases after prostatectomy and/or radiation for localized disease. Treatment consisted of four cycles of docetaxel (70 mg/M2) every 21 days and estramustine 280 mg three times daily on days 1–5. After chemotherapy, goserelin acetate and bicalutamide 50 mg daily were prescribed for 15 months. Results: Sixty-two patients were enrolled at four institutions: median age 65 (range 49–78), median PSA 3.01 ng/mL (range 0.08–47.04), 24% Gleason 8–10. A complete PSA response (CR) was defined as PSA at or below assay-specific lower limit (0.01–0.2 ng/mL). The proportion of patients with CR after chemotherapy, after ADT and at one year off ADT was 53%, 63% and 36%. Testosterone was > 100 ng/dL (median 250 ng/dL) one year off ADT in 97%. Patients with a PSA < 3.0 ng/mL had a significantly longer time to progression (p-value 0.0002). At the time of last follow-up 24/56 (43%) who are at least one year off ADT have not progressed. Median TTP is 34 months from treatment initiation (maximum 74 months free from progression). Toxicity was manageable with no toxic deaths: there were 4 thromboses on chemotherapy and 38% of cycles were associated with grade III/IV neutropenia with 5 cases of documented infections. Conclusion: Chemotherapy prior to hormone therapy was feasible for early prostate cancer relapse. Forty-three percent of men who are at least one year off ADT with recovered testosterone have not progressed. This approach is being tested in a randomized trial with investigation of predictors of response.

No significant financial relationships to disclose.
Preliminary results of a randomized placebo-controlled double-blind trial of weekly docetaxel combined with imatinib in men with metastatic androgen-independent prostate cancer (AIPC) and bone metastases (BM)
Authors: Mathew P. , Thall P. F. , Johnson M. M. , Oh W. K. , Meluch A. A. , Morris M. J. , Troncoso P. , Bucana C. D. , Fidler I. J. , Logothetis C. J.
Published: March 2020

4562

Background: To further examine preclinical (Uehara, JNCI 2003) and clinical (Mathew, JCO 2004) evidence that the platelet-derived growth factor receptor (PDGFR) inhibitor, Imatinib, may modulate taxane activity in AIPC with BM, a randomized trial was conducted. Methods: 144 men with progressive AIPC with BM, no prior taxane, ECOG Performance Score (PS) ≤ 2, stratified by PS, hemoglobin, alkaline phosphatase and number of prior regimens, were planned for equal randomization to i.v. Docetaxel 30mg/m2 D 1, 8, 15, 22 q42 + Imatinib 600 mg daily (DI) or placebo (DP) for an improvement in time-to-progression (TTP) from 4.5 to 7.0 months (two-sided α = 0.05,β = 0.20). Secondary endpoints included toxicity, tumor response and phospho-PDGFR expression. An IRB review of gastrointestinal adverse events led to a recommendation to halt accrual early. Results: 104 evaluable men (52/arm) accrued between April 2003 and July 2005 were followed for a median of 7 months (range 0.5–23.4). The median TTP was 4.4 months (95% CI: 3.2–8.7) for DI and 5.3 months (95% CI: 3.4–11.3) for DP (p = 0.49, log-rank test). Median overall survival was 21.3 months for DI and not attained for DP (p = 0.56). Partial response was observed in 11 (3 DI, 8 DP), stable disease in 23 (14 DI, 9 DP), progressive disease in 56 (27 DI, 29 DP). Excess Grade 3 AEs with DI were principally fatigue (16 vs 6), gastrointestinal (11 vs 6), and arrhythmia (5 vs 1). Five cases of perforated sigmoid diverticulitis (4 DI, 1 DP; one death) were associated with high-dose steroid use (Fisher’s exact test p < 0.0001). Expression of phospho-PDGFR on tumor cells (≥2+ intensity) was established by immunohistochemistry in 12/14 (86%) of informative bone marrow biopsies. After cross-over to DI from DP, 5/23 (22%) patients were progression-free at 12 weeks without partial response. Conclusion: Notwithstanding the likely high prevalence of activated PDGFR in AIPC BM, Imatinib does not detectably modulate Docetaxel activity and excess toxicity was noted in this population. In-vivo monitoring of p-PDGFR and bone markers will qualify these findings.

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A blinded, randomized controlled trial of neo-adjuvant celecoxib in patients with early prostate cancer
Authors: Sooriakumaran P. , Macanas-Pirard P. , Fox S. , Coley H. , Bucca G. , Lovell D. , Henderson A. , Smith C. , Langley S. , Laing R.
Published: March 2020

4563

Background: Celecoxib inhibits tumorigenesis in many in vitro and in vivo models by anti-angiogenesis, induction of apoptosis, and inhibition of tumour cell proliferation and hypoxia. Methods: 45 cT1–2 prostate cancer patients were block randomized 2:1 to four weeks celecoxib 400mg b.d. or no drug prior to radical prostatectomy (RP). Tumour immunohistochemistry was performed for cell proliferation (Ki-67), angiogenesis (CD-31, VEGF, VEGF-R2), hypoxia (HIF-1), apoptosis (TUNEL), and COX-2. All scoring was performed blind by PS and a random 20% were validated blindly by an immunopathologist (SBF). In 19 patients (12 celecoxib-treated, 7 control), peri-operative peripheral zone biopsies were subjected to cDNA microarray analysis to identify differences in gene expression profiling (GEP) between the groups. Results: There was ‘substantial’ (kappa >0.6) or ‘almost perfect’ (kappa >0.8) inter-observer agreement in immunoscoring for all stains. Baseline scores were not significantly different between the celecoxib and control groups. In the celecoxib group, RP scores were significantly lower for Ki-67 (p = 0.036), and non-significantly lower for hypoxia (p = 0.15), KDR (p = 0.16), COX-2 (p = 0.19), microvessel density (p = 0.53), and VEGF (p = 0.83); tumour apoptosis was non-significantly higher (p = 0.26). MANOVA of the full model of stains showed that the difference between the two groups approached statistical significance (p = 0.058), and this was visualized with principal component analysis. GEP revealed that 76 genes were significantly differentially expressed between the celecoxib and control groups using uncorrected t-tests. In the celecoxib group, the tumour suppressor gene p73 and genes associated with protection against oxidative stress were significantly up-regulated; genes associated with cell adhesion were significantly down-regulated, consistent with a reduction in metastatic potential. Conclusions: Celecoxib appears to have marked anti-cancer effects on prostate tumours, most notably affecting cell cycle regulation, oxidative stress, and cell signalling. It may therefore be a promising agent in the management of prostate cancer and warrants further investigation.

No significant financial relationships to disclose.