bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and thyroidal effects of sunitinib in Japanese patients with metastatic renal cell carcinoma: Hypothyroidism and thyroid atrophy as potential biomarkers for sunitinib?
Authors: Shinohara N. , Takahashi M. , Kamishima T. , Ikushima H. , Sazawa A. , Kanayama H. , Nonomura K.
Published: August 2020

e16097

Background: Although hypothyroidism is a well-known adverse effect of sunitinib in western patients (pts) with metastatic renal cell carcinoma (MRCC), the effects on thyroid gland of sunitinib in Japanese pts still remain unclear. We therefore evaluated thyroid dysfunction and thyroid atrophy in Japanese RCC pts who received sunitinib. Methods: Fourteen (8 males, 6 females) of 51 pts who were treated in a phase II trial of sunitinib in Japanese pts with MRCC were included in this retrospective study. All 14 pts were euthyroid at baseline. The measurement of serum thyroid function test (fT3, fT4, TSH) was performed at the beginning of each sunitinib treatment cycle. A TSH concentration greater than 10 mU/L was considered as hypothyroidism regardless of subclinical or clinical. CT volumetry of the thyroid gland was performed utilizing the data obtained for tumor assessment in a phase II trial. Tumor response was evaluated based on the RECIST criteria. Results: 9 (64%) of 14 pts achieved RECIST-defined objective response (1 CR, 8 PRs). With regard to thyroid function, hypothyroidism was experienced by 11 (79%) pts. Three of 11 pts had Sunitinib-induced thyrotoxicosis before experiencing hypothyroidism. The mean time to development of hypothyroidism was 55 days (range 13–668). Six pts received typical doses of L-thyroxine. The response rate was 73% (8/11) in pts with hypothyroidism and 33% (1/3) in pts without. With regard to the volume of thyroid gland in 13 pts, 8 pts had more than 50% reduction comparing the volume at the baseline. Median reduction rate in volume of 13 pts was 57% (range 0–95%). Hypothyroidism was experienced by all 8 pts with more than 50% reduction in volume and 2 of 5 (40%) without. Furthermore, the response rate was 88% (7/8) in former pts and 40% (2/5) in latter pts. Conclusions: In addition to high anti-tumor efficacy, hypothyroidism and thyroid atrophy were commonly observed in Japanese MRCC pts who received sunitinib. Although further study should be required, these abnormal findings in thyroid gland following treatment with sunitinib may be potential biomarkers for tumor response to sunitinib.

[Table: see text]
Phase I trial of sorafenib in combination with interferon-alpha in Japanese patients with unresectable or metastatic renal cell carcinoma
Authors: Sumiyoshi Y. , Hashine K. , Niwakawa M. , Yamaguchi R. , Fujii H. , Hamamoto Y. , Fukino K.
Published: August 2020

e16107

Background: Sorafenib (SOR) is a multi-kinase inhibitor, targeting Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-β. Interferon-α (IFN) is most commonly used for metastatic renal cell carcinoma (RCC) in Japan. In this phase I study, we investigated the safety profile, pharmacokinetics (PK), and tumor response of SOR/(recombinant)IFN combination in Japanese patients (pts) with RCC. Methods: After 2 weeks of IFN-alone treatment, a total of 18 pts (6 in each cohort) with unresectable/metastatic RCC received 28-day cycles of continuous SOR 200 (Cohort 1 [C1]) or (Cohorts 2 and 3 [C2 and C3]) 400 mg bid combined with intramuscular IFN 6 (C1 and C2) or 9 (C3) MIU three times a week (tiw). Objectives were safety/tolerability and recommended dose of SOR/IFN as primary, and tumor response and PK as secondary. Results: Pt characteristics were: median 64.5 y.o.; ECOG-PS 0:1, 14:4; prior anticancer therapy in 13 pts. All pts completed Cycle 1 and entered Cycle 2 or later cycles. At data cut-off (September 30, 2008), dose-limiting toxicities were reported in all cohorts, including G3 fatigue, G3 anorexia, and G3 skin disorders. Common drug-related grade 3/4 adverse events (AEs) included fatigue (50%), lipase increased (44%) and neutropenia (39%), all of which were reversible and manageable. AEs resulting in treatment discontinuation in Cycle 2 or later cycles were seen in 5 pts in Cohort 3. One death was reported in C1 at Cycle 18 due to gastrointestinal and intraabdominal hemorrhage. It seemed attributable to DIC accompanied by RCC. Five PR (1 in C1 and 4 in C3) and 11 SD (4 in C1, 5 in C2, and 2 in C3) were achieved as the best response. IFN had no relevant impact on PK of SOR. Conclusions: SOR/IFN combination has promise for clinical benefit in RCC, and its recommended dose was continuous SOR 400 mg bid and IFN 6 MIU tiw.

[Table: see text]
Synergistic growth inhibition of RCC and NSCLC cell lines by sorafenib plus vorinostat and induction of angiogenic genes by ER stress
Authors: Drabkin H. A. , Sharma G. , Costa L. J. , Korch C. , Gemmill R. M.
Published: August 2020

e16114

Sorafenib, vorinostat and the combination were examined in 34 RCC and NSCLC cell lines. In growth assays, sorafenib at 8 μM resulted in synergy with multiple vorinostat doses, whereas no synergy was seen with lower doses. Changes in phospho-ERK and AKT were not predictive of growth inhibition, whereas frequent inhibition of cyclin D1 and upregulation of p21Waf1 was observed. To anticipate resistance mechanisms to the anti-angiogenic effects of sorafenib, we studied the expression of 13 angiogenic factors in 10 selected lines. At baseline, bFGF, VEGF and IL-8 were highly expressed in RCCs, whereas Gro-α, VEGF, and IL-8 predominated in NSCLCs. Multiple angiogenic factors were upregulated by sorafenib and vorinostat, especially VEGF, IL-6, CTGF, EDN1, PDGFβ, and IL-8. Importantly, sorafenib at 8 μM, but not lower doses, induced ER stress in these cell lines and thapsigargin or tunicamycin treatment recapitulated many, but not all, of the observed angiogenic gene responses to sorafenib. In fact, CHOP induction by sorafenib plus vorinostat was the only parameter, other than growth inhibition, that changed in a synergistic manner. In summary, sorafenib plus vorinostat potently inhibits the in vitro growth of RCC and NSCLC cell lines. Upregulation of multiple angiogenic genes, in part by an ER-stress mechanism, may contribute to acquired resistance in vivo.

No significant financial relationships to disclose.
A phase II trial of gefitinib and pegylated interferon alfa 2b (PEG-IFN) in previously-treated renal cell carcinoma (RCC)
Authors: Shek D. W. , Longmate J. , Quinn D. , Margolin K. , Twardowski P. , Gandara D. , Pan C. , Lara P.
Published: August 2020

e16115

Background: Modulation of the epidermal growth factor receptor (EGFR) pathway is relevant to IFN activity in RCC. Cell lines sensitive to IFN's antiproliferative effects downregulate EGFR, while IFN treatment of resistant cells precludes such an effect. (Eisenkraft et al, Cancer Res. 1991) Lack of EGFR down-regulation may thus be responsible in part for IFN resistance. To explore this hypothesis, we conducted a trial of the EGFR tyrosine kinase inhibitor gefitinib plus PEG-IFN in RCC patients (pts). Methods: Unresectable or metastatic RCC pts (no limit on prior therapies; performance status 0–2, and adequate end-organ function) were eligible. Prior IFN was allowed. Dose schedule: PEG-IFN SQ weekly (6μg/kg/week or 4 μg/kg/week) × 12 weeks and gefitinib 250 mg po daily until progression. A 6-month progression free survival (PFS) rate of 50% was considered promising (vs. 30%) in a two-stage design incorporating the Green-Dahlberg rule. We accrued 21 patients in the first-stage of accrual. Results: Pt characteristics: Males -16; median age - 56 years; Prior nephrectomy - 12. All had > 1 prior systemic therapy . Accrual slowed with increased use of small molecule kinase inhibitors, bevacizumab, and temsirolimus for RCC. At 6 months, PFS was 26% (95% CI: 9%, 49%); 20% (4 pts) had died. Best responses by RECIST: complete (1), partial (4), stable (8); progression (4). Response duration: CR (35+ months) and PR (3, 5, 5, 38+ months). Median time to treatment failure was 18.4 weeks (95%CI: 7.4, 24.9). Median PFS and overall survival were 23 and 53 weeks, respectively. Most common treatment-related toxicities were leucopenia, thrombocytopenia, rash, nausea, diarrhea, and hyperglycemia. Conclusions: Although gefitinib plus PEG-IFN did not meet the pre-specified 6-month PFS of 50%, it appears to have activity similar to other first-line therapies even in this previously-treated setting. (Supported by Astra Zeneca)

[Table: see text]
A dose-escalating phase I study of biweekly docetaxel in older men with hormone refractory prostate cancer (HRPC)
Authors: McDevitt J. , Hauser R. , Simon J. , Balducci L.
Published: August 2020

e16117

Background: Docetaxel has been shown to be effective and is used in the treatment of HRPC. This phase I study is designed to investigate the maximum tolerated dose, tolerability and activity of docetaxel administered on a biweekly schedule in older patients with HRPC. This study will also explore the feasibility of a self-report geriatric assessment tool in this population. Methods: HRPC patients with progression of metastatic disease during hormonal therapy received docetaxel q 2 wks at dose levels of 40 (level 0), 45 (level 1), 50 (level 2), or 55 mg/m2 (level 3). The trial is a conventional phase I 3+3 dose-escalation design. Treatment was continued until progression, refused further treatment, or unacceptable toxicity. Patients were given the Vulnerable Elders Survey (VES-13) for completion every 4 weeks. Results: 16 patients were enrolled in the study. All are evaluable for toxicity, 10 for response. Pts had a median (range) age 76 (72–87). Median doses administered was 6 (range 3–19). The maximum tolerated dose (MTD) was not reached in the study. No dose limiting side effects were reported for any of the dosing levels in the 8 week assessment period. Five patients had a ≥50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. Of the 10 patients with measureable disease, 2 patients (one at dose level 0 and one at dose level 3) achieved a complete response, 2 patients (one at dose level 1 and one at dose 2) achieved a partial response, and 3 patients had stable disease (one each at dose levels 1, 2, and 3). At the time of entry onto the study, 4 patients required narcotic analgesics for bone pain; after treatment, 1 (25%) discontinued their pain medications. The completion rate of the Vulnerable Elders Survey (VES-13) was 94.6%. Conclusions: Biweekly docetaxel can be safely administered in older metastatic HRPC patients and showed activity. For phase II evaluation, a bi-weekly dose of 55 mg/m2 appears to be suitable. The administration of the VES-13 was feasible in this population.

[Table: see text]
Malignant transformation of teratoma to primitive neuroectodermal tumor (PNET): Outcome analysis with PNET based chemotherapy
Authors: Brames M. , Ehrlich Y. , Einhorn L.
Published: August 2020

e16121

Background: Metastatic testis cancer is uniquely chemosensitive and highly curable. Residual teratoma can be surgically resected. However, testicular teratoma can differentiate along endodermal, ectodermal, or mesodermal elements (malignant transformation of teratoma), with capacity to metastasize and not be amenable to surgical resection. We report results of malignant transformation of teratoma to metastatic PNET treated with PNET based chemotherapy. Methods: Retrospective review of 42 patients with PNET in testis or at metastatic sites seen at Indiana University from 1999–2007. Of these 42 patients, 10 had inoperable or unresectable PNET treated with cyclophosphamide 1200 mg/M2, doxorubicin 75 mg/M2, and vincristine 2 mg IV alternating with ifosfamide 1.8 grams/M2 × 5 days plus etoposide 100 mg/M2 × 5 days. Courses were given every 3 weeks for 6 courses or until progression or undue toxicity. Results: 9 of 10 patients had at least 1 prior platinum based combination chemotherapy regimen for their germ cell tumor. Tumor markers (human chorionic gonadotropin and alphafetoprotein) were normal at start of chemotherapy for biopsy proven PNET. Eight of 10 achieved objective response. Two of 10 are currently disease-free for 16 and 33 months from initiation of PNET specific chemotherapy and 3 other patients are alive with disease at 73, 34, and 30 months. These 5 patients all had subsequent surgery. Conclusions: PNET specific chemotherapy has a high objective response rate for malignant transformation of teratoma to PNET, with some patients capable of long-term survival with chemotherapy followed by surgical resection.

[Table: see text]
Impact of nail toxicity on survival of patients with hormone-refractory prostate cancer (HRPC) treated with docetaxel
Authors: Scotte F. , Banu E. , Medioni J. , Boudraoui M. , Tourani J. M. , Banu A. , Oudard S.
Published: August 2020

e16122

Background: Docetaxel is the standard first-line treatment for patients (pts) with metastatic HRPC. Taxanes are a well known cause of nail toxicity but docetaxel-related nail toxicity is rarely explored. Methods: Eligible HRPC pts included in the current analysis were from a phase II, multicentre, case-control study (Scotte F et al, J Clin Oncol 2005). Pts were treated with docetaxel 75 mg/m2 every 3 weeks and oral prednisone 10 mg daily. Nail toxicity was graded according to NCI CTC version 2 (0: absence of toxicity; 1: minor changes; 2: onycholisis). The endpoint of interest was the impact of nail toxicity on overall survival (OS) using Cox regression analysis as the main statistical method. OS was the time from the start of chemotherapy to death or last follow-up. Results: Data from 23 HRPC pts treated in two French centres were analyzed. The median age was 68 years, 91% of pts had bone metastases, 84% had a single metastatic site, 49% had a Gleason score of ≥ 8 and 91% had an ECOG performance status (PS) of 0 or 1. Median OS was 16.7 months [95% confidence interval (CI), 5.7–27.6 months], all pts died. There were differences in OS between nail toxicity categories (see Table). Median OS was 10.6 months (95% CI, 9.5–11.7) and 22.7 months (95% CI, 15.1–30.3) for pts without and with nail changes, respectively. Nail changes severity was significantly related to OS: hazard ratio (HR)=0.50 (95% CI, 0.28–0.92), P=0.027 (univariate analysis). The multivariate analysis adjusted by ECOG PS (the second covariate associated with prognosis) showed a 63% reduction in the risk of death for pts with nail toxicities: HR=0.29 (95% CI, 0.09–0.82), P=0.049. Conclusions: Our results suggest that pts with docetaxel-related nail toxicity have a better OS than those with no nail toxicity. This demonstrates that nail changes in HRPC pts treated with docetaxel are predictive of OS; these findings should be validated in a large cohort of pts. [Table: see text]

No significant financial relationships to disclose.
Alterations of natural killer cells in metastatic prostate cancer
Authors: Veuillen C. , Gravis G. , Marcy M. , Walz J. , Bladou F. , Salem N. , Brunelle S. , Olive D.
Published: August 2020

e16131

Background: Recently, prostate cancer (PCa) has been considered as a potential target for antitumoral immunotherapy and cells such as Natural Killer (NK) cells, with antitumoral activity are a promising candidate. NK cells activity is regulated by opposite signals delivered by inhibitory (NKRi) and activating receptors (NKRa). Primary human PCa express ligands for NKRa but the HLA class I (ligands for NKRi) expression is downregulated. Recently, our group have reported that patients with acute myeloid leukaemia have defective interactions receptor -ligand in NK cells due to a decreasing expression of Natural Cytotoxicity Receptors and it could be used as a evasion mechanism by leukaemia cells. The aim of this work was to evaluate the activating receptors expression to know if it could be used as evasion mechanism of the immune response in PCa. Methods: Activating and inhibitory receptors were analysed by flow cytometry in peripheral NK cells from 8 patients with metastatic androgen dependent prostate cancer (ADPC), 10 with metastatic androgen independent prostate cancer (AIPC), 7 patients with localized prostate cancer (LPC ) and 15 healthy donors. Results: The expression of NKp30, NKp46, and NKG2D (as determined by MFI) was significantly lower on NK cells from patients with ADPC and AIPC than in healthy donors. In ADPC patients, the ratio MFI (MFI receptor/MFI control isotype) of NKP30 (4.73 ± 1.07, p = 0.0003), of NKp46 (16.62 ± 3.42, p = 0.036) and of NKG2D (19.61 ± 6.44, p = 0.026) significantly differed from healthy donors (NKp30 26.65 ± 6.12; NKp46 39.73 ± 9.66 and NKG2D 37.97 ± 6.77). It was similar for AIPC NK cells(NKp30 6.28 ± 1.27, p = 0.0002; NKp46 16.24 ± 2.34, p = 0.014; NKG2D 13.61 ± 2.29, p = 0.0003). In ADPC and AIPC NK cells, the expression of NKRi and other NKRa did not differ from healthy donors. In LPC NK cells, the expression of NKRi and NKRa did not differ from healthy donors. Conclusions: We observed a decreased expression of principal activating receptors only in metastatic form of PCa. This could affect the interactions receptor-ligand in NK cells. Is it hormonal therapy or extension of the disease that is responsible of NK cells alterations? Moreover, this could constitute a potential mechanism for cancer cells immune escape and a possible target for therapies improving NK functions.

No significant financial relationships to disclose.
Hypercoagulability as a prognostic factor for survival in patients with metastatic renal cell carcinoma
Authors: Tsimafeyeu V. I. , Madzhuga A. , Demidov L.
Published: August 2020

e16134

Background: In experimental systems, interference with coagulation can affect tumor biology. We suggested that abnormal coagulation could be a negative predictor for response to immunotherapy and survival among patients with metastatic renal cell carcinoma (MRCC). Methods: To address this issue, retrospective analysis of 289 previously untreated MRCC patients entering on institutional review board-approved clinical trials was conducted between 2003 and 2006. In addition, two groups of MRCC patients with (n = 28) or without (n = 28) hypercoagulability were compared in a case-control study. Baseline and treatment characteristics were well balanced. Results: Hypercoagulability was present at treatment start in 40% of patients. Median baseline fibrinogen was 6.2 mg/dl. Serious disorders were found in 68% of patients. Abnormal coagulation was strongly associated with a number of metastatic sites (2 and more metastatic sites vs. 0–1 (p = 0.001). Patients with high extent of hypercoagulability had significantly higher number of metastatic sites (p = 0.02). On univariate analysis, patients with hypercoagulability had significantly shorter overall survival than patients with normal coagulation; median survivals of 8.9 and 16.3, respectively (p = 0.001). Short survival and low response rate also were significantly associated with hypercoagulability in a case-control study. Median cancer-specific survival was 8.2 months and 14.6 months, respectively (p = 0.0011). Disease control rate (overall response + stable disease) was significantly higher in patients with normal coagulation: 71.4 versus 42.9% (p = 0.003). We did not reveal VTE-related deaths. Conclusions: Hypercoagulability disorders were found to be prognostic factor for response rate to systemic therapy and survival in patients with MRCC.

No significant financial relationships to disclose.
MR-based biomarkers in the diagnosis and the evaluation of the therapeutic response to radiotherapy (ETRR) in prostatic carcinoma (PCa): Implementation of clinical and experimental approaches
Authors: Crehange G. , Walker P. M. , Parfait S. , Maingon P. , Cochet A. , Brunotte F. , Tizon X. , Provent P. , Duchamp O.
Published: August 2020

e16136

Background: ETRR in PCa remains a challenging task. New biomarkers in the form of metabolites, detected with Proton Magnetic Resonance Spectroscopy (1H-MRS), and quantitative Apparent Diffusion Coefficient (ADC), determined with Diffusion-Weighted Magnetic Resonance Imaging, could be of value in the ETRR for PCa. Methods: Twenty-one men with biopsy proven localized PCa were examined before external radiotherapy. 3D-1H-MRS was performed at 3.0T without endorectal coils. The delivered radiotherapy dose was 78 Gy in 39 fractions with 6 MV photons. MR follow-up examinations up to 36 months post-radiotherapy were performed. For the pre-clinical study, healthy rat prostate was studied in 3 nude rats. PC3-MM2 and PAC-120 tumors were subcutaneously (SC) and orthotopically (OT) xenografted in 5 nude rats, respectively. Radiotherapy anti-tumor efficacy administered as HDR-brachytherapy (SC) or X6 external beam irradiation (OT) delivering 10 Gy/5 fractions was evaluated. 1H-MRS was performed at 4.7 T using SVS. Results: Twelve men received the 3-month examination, 8 patients are at 6-months, 4 are at 9 months and 1 has been followed for 1 year. At baseline, healthy prostate shows a low Choline (Cho)/Citrate ratio, whereas the presence of cancer considerably increases this ratio. At 3 months, we observed metabolic atrophy except for Cho. Although, higher ADC values are normally found in peripheral zone than in central gland, these differences disappear after radiotherapy. In healthy rat prostate high levels of Cho without citrate were noted. Cho and free lipids were detected in PC3-MM2 and PAC120 SC-grafted tumors, with a higher Cho content in PC3-MM2. Radiotherapy induced significant antitumor activity in PC3-MM2 (SC) (T/C% = 38%) and OT (ILS% = 58%) tumors, but was not efficient in PAC120 SC-grafted tumors (T/C% = 90%). Radiotherapy slightly modified Cho content 4 days after the end of treatment but no modification on overall metabolic profile was observed before, during and after radiotherapy. Conclusions: Combined ADC and Cho are powerful biomarkers for the detection of PCa in men and could be useful for ETRR.The use of Cho in ETRR for PCa in rats appears to be promising.

No significant financial relationships to disclose.
Elective open nephron-sparing surgery for renal masses: Single-center experience with 223 consecutive patients
Authors: Francesca F. , Pomara G. , Campo G. , Casale P.
Published: August 2020

e16139

Background: To present our experience with elective, open, nephron-sparing surgery for renal masses in a contemporary, consecutive series. Methods: In this retrospective study, records of all patients who underwent elective nephron-sparing surgery (E-NSS) between March 1997 and December 2007 at our institution were reviewed. The preoperative workup included laboratory analysis, renal ultrasonography and abdominal computed tomography. The histological findings, complications, and oncologic outcome were studied. Results: A total of 231 E-NSS were performed in 223 patients (82 females,141males; mean age 64 years). 62 “hot ischemia” procedures and 169 “cold ischemia”. The mean tumor size was 4.6 cm (1.1–12cm). 52 patients presented renal masses > 4cm. Renal cell carcinoma was present in 177 patients (76.6%), benign renal masses were diagnosed in in 54 pazienti (23.3%): angiomyolipoma (35%), oncocytoma (40%), complicated cyst (25%). Worthy of note among these 54 patients, pre-operative diagnosis was present in 12 patients. Moreover, 17 benign lesions (31%) were > 4 cm. Complication rate was 5.3% (12 pts): splenectomy (2.2%), nephrectomy because of postoperative bleeding (0.8%), urinary fistulas (0.8%). After a median follow-up of 84 months (range 5 to 120), no patient had developed local recurrence, 19 (8.9%) died for other causes, 2 (0.9%) died for other tumor. Conclusions: The results of this contemporary, monocenter experience underline the role of open, elective, nephron-sparing surgery for patients with renal masses, confirming good results even for renal masses > 4cm. These conclusions are particularly important considering that benign histologic findings were present in almost one forth of patients.

No significant financial relationships to disclose.
Detection of prostate cancer recurrence using an ultrasensitive nanoparticle-based PSA assay
Authors: Storhoff J. , Lubben T. , Lefebvre P. , Holzman T.
Published: August 2020

e16146

Approximately 400,000 men are diagnosed each year with prostate cancer worldwide, and many of those patients undergo radical prostatectomy in an attempt to cure the disease. Although prostatectomy is effective for a majority of patients, approximately 15 to 40 % will experience prostate cancer recurrence within 5 years, and a majority of those patients will die from the disease (JAMA. 2008;299:2760-2769). Currently, prostate cancer recurrence is determined by monitoring prostate specific antigen (PSA) levels in patients following treatment, and those patients whose PSA levels rise above the clinical cutoff of 200 pg/mL PSA are defined as having recurrent prostate cancer. For those that do recur and have high PSA doubling times, early salvage radiotherapy confers a significant increase in prostate cancer specific survival (1). We have developed an ultrasensitive assay that measures PSA levels with a limit of detection of 0.5 pg/mL PSA with a CV of less than 20 % at 2 pg/mL. This assay utilizes functionalized gold nanoparticles to label PSA targets captured onto antibody coated glass substrates. The amount of PSA is quantified through silver enhancement of the functionalized gold. In this presentation, we describe the application of this technology in monitoring PSA levels in patients that are approximately 400 fold below the current clinical cutoff as a means of diagnosing prostate cancer recurrence at a much earlier timepoint than current assays.

[Table: see text]
Cytokine changes in castrate metastatic prostate cancer (CPMC) patients (pts) treated with ipilimumab (Ipi)
Authors: Yuan J. , Orlandi F. , Jefferson M. , Li H. , Gallardo H. , Ku G. , Wolchok J. , Scher H. , Allison J. , Slovin S. F.
Published: August 2020

e16149

Background: Ipilimumab (Ipi) is a human IgG1 monoclonal antibody that blocks the inhibitory action of the checkpoint molecule CTLA-4. Recent data [Proc Amer Soc Clin Onc, Abstr#5004, 2008] from castrate metastatic PC pts suggested that Ipi was active but was associated with grade 3 autoimmune adverse events (AEs), such as colitis, hepatitis, hypophysitis or rash, which required high dose steroids. We studied pts who were treated on a clinical trial with Ipi 10 mg/kg alone or with radiation to a single site in bone to determine whether there was any correlation between serum cytokine levels and autoimmune AEs. Methods: Thirteen pts were treated, of whom 10 had sufficient specimens for analysis. Of the 10 pts, 8 had ≥1 AE during treatment. Pts were stratified by ascertainment of clinical benefit (CB) vs. no clinical benefit (NCB) based on time-to-PSA-baseline relapse (TTBR) and also by toxicity (tox) using standard NCI tox criteria. TTBR was defined as time from study entry until the time when a PSA measurement reached or exceeded the baseline value. Pts with a TTBR greater than the median value were judged to have CB; those with a TTBR less than the median value had NCB. Pts with grade (gd) 0/1/2 tox were termed “low tox” while those with gd 3/4 tox were “high tox”. Sera at serial time points were analyzed for interferon-gamma (IFN-γ), tumor necrosis factor α and interleukins (IL)-1b, 2, 4, 8, 10, 12, 13 with the Meso Scale Discovery Multiplex Assay (MSD, Gaithersburg, MD). Results: IFN-γ was the predominant cytokine produced in 4 of 5 pts with CB and AEs; it increased at week 4 or 7 after two doses of Ipi, then declined. Four of 5 pts with NCB had minimal IFN-γ production. There was no difference in IL-10 production between those with CB vs. NCB or high vs. low tox. However, there was a suggestion that the IFN-γ /IL-10 ratio may be increased in pts who had high tox and/or CB vs. pts with low tox and NCB. This awaits confirmation. Conclusions: While this experience with Ipi in PC is small, there may be differences between pts with CB vs. NCB and pts with low vs. high tox. Investigation of the immunophenotype of pts who remain in follow- up and continue to be enrolled is ongoing as well as the impact of prior chemotherapy on development of toxicities.

[Table: see text]
Cost-effectiveness analysis of first-line treatment for metastatic renal cell carcinoma (mRCC) in Colombia (ONCOLGroup study)
Authors: Godoy J. , Cardona A. F. , Cáceres H. , Otero J. M. , Lujan M. , Lopera D. , Pacheco J. O. , Spath A. , Gis P.
Published: August 2020

e16150

Background: Renal cell carcinoma has increased its incidence by 126% since 1950. A local study developed a complete economic evaluation of sunitinib versus IFN in first-line treatment of mRCC in Colombia, finding that sunitinib was more cost-useful and cost-effective. Methods: A Markov model was developed using 6-week cycles for evaluating the cost-effectiveness of four interventions (IFN, sunitinib, bevacizumab+IFN, sorafenib) approved as first-line treatment for mRCC in Colombia. The model used the third-party payer perspective and a 5-year time-line; it also presumed that all the patients (pts) continued with active treatment until progression when it became acceptable to continue with a second-line treatment or BSC. Overall survival (OS) and progression-free survival (PFS) curves of IFN were used as reference framework; they were obtained form a published clinical trial. The hazard ratios (HR) for PFS and OS were estimated for comparing new generation medicaments with IFN. The information about frequency of use and health service cost units consumed in Colombia was taken from a series of 24 pts treated in Manizales, Pereira, Medellín and Bogotá. Service costs were requested from an external consultant and corresponded to the average value billed by the EPSs, calculated from 33 sources of information which were representative of the country's market. The cost of the medicaments was obtained from LCLC. The costs and benefits were discounted annually at 3%. (all cost are presented in Colombian pesos Col$ 2008 with an exchange rate 1 USD = 1836.20 Col$). Results: Incremental analysis indicated a difference of 41.1 million Col$ in the average total cost of treatment when Sunitinib was compared to IFN; in contrast, comparing sorafenib and Bevacizumab+INF to sunitinib demonstrated that the average total cost was less for the sunitinib by 8.3 and 104.2 million Col$, respectively. Additionally, the ratios of incremental cost-effectiveness by life years (LY) gained demonstrated sunitinib's simple dominance over sorafenib and the combination of bevacizumab+IFN, and an average by LY gained of 100.5 million Col$ compared to IFN. Conclusions: Sunitinib is the most cost-effective option as first-line treatment for mRCC pts in Colombia.

[Table: see text]
Maintenance GM-CSF in patients with castration-resistant prostate cancer (CRPC) who maximized their response to chemotherapy
Authors: Bitran J. D. , Tolzien K. , Lestingi T. M. , Nabhan C.
Published: August 2020

e16155

Background: There is no standard treatment for CRPC patients (pts) who completed chemotherapy. Time to progression (TTP) ranges from 3–6 months after stopping chemotherapy. GM-CSF (GM) is an immune-based growth factor with reported activity in CRPC. We hypothesized that GM maintenance in pts who have maximized their response to chemotherapy could delay TTP or time to next treatment (TNT). Methods: Eligible pts were those with CRPC who completed 10–12 cycles of docetaxel (D) or mitoxantrone (M) chemotherapy without progression; or those who maximized their response to chemotherapy before completing 10–12 cycles. Maximum response was defined as a <10% change in PSA repeated on two occasions with stable disease (SD) radiographically. Enrolled pts received GM at 250 ug/m2 subcutaneously for 14 days followed by 14-days of rest. GM was continued until disease progression. Primary end point was the clinical benefit defined as the sum of partial response (PR), complete response (CR) and SD. Secondary end points included toxicity, TTP, and TNT. Results: To date, 12 pts out of planned 20 have been enrolled (9 were on D and 3 on M). Median age was 78 (66–96). Median PSA at enrollment was 56.5 (0.1–566). Only 1 pt had a Gleason score < 7. Median time from initial diagnosis to GM was 70 months. Median number of chemotherapy cycles prior to GM was 9 (6–12). Eight pts (66%) had visceral and bone disease. GM was well-tolerated with no drug-related grade 3 and/or 4 toxicities. Ten pts are evaluable (1 pt withdrew consent and another did not comply). Median GM cycles received so far was 3 (2–11). With a median follow up of 11 months (2–17), 3 pts demonstrated SD and 2 had PR for an overall clinical benefit of 50%. One pt remains on study at 7 months while the median response duration for the other 4 responding pts was 7 months. Four pts never received another treatment but the median TNT in other evaluable pts was 3 months. Conclusions: GM is safe, well tolerated, and has activity in CRPC after stopping chemotherapy. Combining chemotherapy with GM should be investigated in future studies.

[Table: see text]
Postoperative radiotherapy for prostate cancer: Sooner or later?
Authors: Igdem S. , Abacioglu M. U. , Alço G. , Ibrahimov R. , Kefeli A. , Çetin I. , Turkan S. , Okkan S.
Published: August 2020

e16157

Background: To report our experience with adjuvant or salvage radiotherapy for prostate cancer and to assess the tolerance of the patients. Methods: The charts of 139 men who received postoperative radiotherapy (RT) after radical prostatectomy (RP) between 1997–2007 in two institutions were retrospectively analyzed. Thirty-seven percent received adjuvant RT and 63% salvage RT. The median age was 65 years (range: 43–80). Pathologic Gleason score was 2–6 in 24%, 7 in 56%, and 8–10 in 20%. Seminal vesicle involvement was reported in 34%, positive surgical margins in 72%, lymph node involvement in 7%, capsular perforation in 61%, and perineural invasion in 73% of the patients. The median PSA level before RT was 0.29ng/ml (range: 0–19ng/mL). Median time from RP to RT was 3 months (range, 1–12 months) in the adjuvant setting, and 27 months (range, 2–96 months) in the salvage setting. Nineteen percent received radiation to the pelvis, 81% to the prostate bed only. The median dose to the prostatic bed was 66.6Gy (range: 60–76Gy). Before, during or after RT 49% received androgen deprivation for a median of 6 months (range, 3–48 months). Biochemical failure is defined as a post-RT PSA level >0.2ng/mL. Results: The median follow up time was 41 months (range, 12–133 months). At 4 years, for the entire cohort biochemical control, metastasis free survival, and overall survival was 68%, 92%, and 94%, respectively. Although there was a significant difference in favor of the adjuvantly treated group for biochemical control (81% vs 60%, p = 0.03) in univariate analysis, multivariate analysis demonstrated that higher preoperative PSA level (p = 0.02), and lymph node involvement (p = 0.02) predicted for a worse PSA outcome. No grade 3 acute gastrointestinal (GI) or genitourinary (GU) toxicity was reported during the treatment. At 4 years, 4% of patients had Grade 2 late GI toxicity, 0.7% had grade 3 late GI, and 0.7% brade 4 late GI toxicity, while 16% of patients reported late grade 2 GU, and 4% had late grade 3 GU toxicity. Conclusions: Our results suggest that adjuvant RT may offer a better biochemical outcome in patients who underwent radical prostatectomy for prostate cancer. Overall, the number of high grade toxicities for postoperative RT was low. Therefore it can safely be used in appropriate setting.

No significant financial relationships to disclose.
Significance of the expression of thymidylate synthase in prostate cancer
Authors: Mizutani Y. , Li Y. , Shiraishi T. , Nakamura T. , Mikami K. , Okihara K. , Takaha N. , Ukimura O. , Kawauchi A. , Miki T.
Published: August 2020

e16163

Background: Thymidylate synthase ( TS ) is an important enzyme in de novo DNA synthesis pathway. 5-Fluorouracil ( 5-FU ), an anticancer chemotherapeutic agent used clinically against a variety of cancers including prostate cancer, inhibits DNA synthesis by binding TS. In the present study, we examined TS expression in prostate cancer and investigated its prognostic significance. Methods: Fifty-two prostate cancer tissue specimens were obtained from patients who underwent radical prostatectomy for prostate cancer without neoadjuvant hormonal therapy. Forty-eight prostate cancer tissue specimens were also obtained from patients who underwent radical prostatectomy for prostate cancer with neoadjuvant hormonal therapy. We examined prostate cancer tissue and normal prostate tissue for TS expression by immunohistochemistry. Results: TS was expressed at higher levels in prostate cancer without neoadjuvant hormonal therapy, compared with normal prostate.TS expression in stage T3 prostate cancer was higher than that in stage T2 prostate cancer. In addition, the level of TS expression in Gleason score 7 or greater prostate cancer was higher than that in Gleason score less than 7 prostate cancer. Patients with prostate cancer with negative TS expression without neoadjuvant hormonal therapy had a longer postoperative recurrence-free rate than those with positive expression in the 5 year follow-up. In addition, patients with Gleason score less than 7 prostate cancer with negative TS expression had a much longer postoperative recurrence-free rate than those with positive expression in the 5-year follow-up. TS expression was significantly decreased in prostate cancer patients who received neoadjuvant hormonal therapy, especially stage T2 prostate cancer patients. Conclusions: The current study has demonstrated for the first time that TS expression may be a prognostic parameterr for prostate cancer patients undergoing radical prostatectomy.

No significant financial relationships to disclose.
Stage I nonseminomatous germ cell tumors of the testis: Clinical outcome of 45 patients on a surveillance protocol after orchiectomy alone at a single institution in Japan
Authors: Kakimoto K. , Ono Y. , Meguro N. , Takezawa K. , Yoshida T. , Arai Y. , Usami M.
Published: August 2020

e16165

Background: In Japan, risk-adapted treatment for patients with clinical stage I nonseminomatous germ cell tumor of the testis (NSGCTT) has been performed in very few institutions. This retrospective study was performed to evaluate histopathologic prognostic factors with stage I NSGCTT for whom careful follow-up with a surveillance protocol was possible at a single institution. Methods: We included 45 patients with a median age of 31 years (range 16 - 58) who were managed with a surveillance strategy after orchiectomy in our department between 1972 and 2006. Mean duration of follow-up was 8.1 years (range 1.4 –30). The patients were monitored at follow-up evaluation for tumor marker (AFP, beta-hCG) levels and by abdominal CT scan, chest x-ray, and physical examination. Primary testis tumor samples were assessed for prognostic factors including lymphatic and/or vascular (LV) invasion and pathological components such as the presence of embryonal carcinoma. Log-rank analyses were performed to identify prognostic factors. Results: All patients were alive and disease-free. Relapses occurred in 16 (35.6%) patients after a median follow-up of 5.7 months (range 3–45). In 11 patients (68.8 %), relapse was detected in the retroperitoneal lymph nodes. Two patients (12.5%) had metastases in the retroperitoneal lymph nodes and lungs, two patients (12.5%) had metastases in the lungs alone, and one patient (6.2%) had metastases in the retroperitoneal lymph nodes, lungs, and brain. LV invasion was identified in 17 patients, 53% of whom had relapsed, and relapse was found in 25% of 28 patients without LV invasion (p<0.01). Of 31 patients with an embryonal carcinoma component, 13 patients (42%) developed metastases, whereas 21% of those without an embryonal carcinoma component developed metastases (p=0.04). After chemotherapy and/or surgical treatment for relapse, the 5-year overall survival rate was 100%. Conclusions: As in previous reports, the presence of an embryonal carcinoma component and LV invasion appeared to be factors suggesting a high likelihood of relapse. The surveillance protocol described here is a reliable strategy for stage I NSGCTT patients if careful long-term follow-up is possible.

No significant financial relationships to disclose.
A Gynecologic Oncology Group study of frequent copy number aberrations in African American versus Caucasian women with stage I versus stage IIIC/IV endometrioid endometrial cancer
Authors: Morrison C. , Gaile D. , Darcy K. , Liu S. , Shepherd L. , Cohn D. , McMeekin S. , Nowak N. , Maxwell L.
Published: August 2020

e16501

Background: An array-based comparative genomic hybridization (aCGH) analysis was performed to determine if frequent (>40%) copy number aberrations (CNAs) exist in African American (AA) versus Caucasian (C) women with stage I versus stage IIIC/IV endometrioid endometrial cancers (EEC). Methods: Tumor DNA was isolated from 80 frozen primary tumors from the GOG-210 protocol. RPCI 19K BAC arrays were hybridized (GeneTAC HybStation) and scanned (Gene Pix 4200AL Laser Scanner). Spot fluorescence values were quantified using ImaGene, vetted for quality and loess corrected with adjustments for chip-specific spatial effects. The genome was segmented to identify regions with common copy number means (DNAcopy software). Posterior aberration probabilities for the regions were obtained using CGHcall and data was visualized and annotated using iGenomicViewer in R. Validation will be performed by fluorescence in situ hybridization using select BAC probes and endometrial cancer tissue microarrays (TMAs) with either 400 cases linked with clinical, treatment and outcome data or 180 AA versus 120 C women from GOG-136. Results: Recurrent CNAs were identified in all stage and race groups. Distinct genomic losses and gains were observed that appear to segregate Caucasian women with stage I disease from African American women with stage I disease and African American or Caucasian women with stage IIIC/IV disease. Conclusions: The GOG-210 bank yielded high quality DNA for detecting and mapping CNAs in frozen primary tumors with high resolution. Our results would imply that racial disparity for AA EEC has a genetic basis regardless of stage. Validation studies are currently underway in two endometrial cancer TMAs. [Table: see text]

No significant financial relationships to disclose.
Can primary recurrences in surgical stage I-II uterine papillary serous carcinoma (UPSC) patients be salvaged?
Authors: Fader A. Nickles , Rose P. G. , Frasure H. , Gehrig P. A. , Moore K. N. , Havrilesky L. J. , Huh W. K. , Axtell A. E. , O'Malley D. M. , Zanotti K. M.
Published: August 2020

e16503

Background: There is an absence of data in the literature on salvage rates for vaginal, pelvic, and extra-pelvic recurrences for early-stage UPSC patients (pts). The purpose of this study is to determine whether primary recurrences can be salvaged with chemotherapy or radiotherapy. Methods: A retrospective, multi-institution study of pts with stage I-II UPSC diagnosed from 1993–2006. All pts underwent comprehensive surgical staging. Postoperative treatment included either observation (OBS), radiotherapy (RT: brachytherapy, pelvic, abdominal or combo) or ≥ 3 cycles carboplatin/paclitaxel (CT) alone or with RT (CT+RT). Results: We identified 197 stage I-II pts; 44/197 (22.3%) experienced a primary recurrence during a median follow-up of 35 months. Patterns of recurrence analysis revealed that 17 (38.6%) were vaginal/pelvic (V/P) and 27 (61.4%) were extra-pelvic (EP). Multi-site relapses occurred in 13/44 (30%). Pts initially treated with adjuvant CT±RT (n = 108) had a significantly decreased risk of primary recurrence (9.9%) when compared to those patients treated with RT alone (n = 45; 37%) or OBS (n = 43; 35%; p < 0.001). There were no distinguishing risk factors for development of V/P versus EP recurrence. Median time to recurrence after diagnosis was 16 months. The majority of pts (86%) were not salvaged by second line therapy, with a median time from recurrence to death of 8.9 months. However, more pts with isolated vaginal recurrences (5/12 or 42%) were salvaged when compared to those with pelvic or EP recurrences (1/32 or 3.1%; p = 0.004). The 5 pts who are NED after vaginal relapse were treated with CT±RT (n = 3) or RT (n = 2); 80% had not received prior treatment and 20% had received prior CT. To date, more pts with EP recurrence are dead of disease (23/27) than with V/P recurrences (7/17; p = 0.003). Conclusions: Stage I-II USPC pts are more likely to experience an extra-pelvic than vaginal/pelvic primary recurrence, are unlikely to be salvaged and will have a short interval from recurrence to death. The exception is in those with isolated vaginal recurrence, who may be salvaged in select cases. The current best strategy to avoid primary recurrences in this setting is an initial staging surgery followed by adjuvant carboplatin/paclitaxel.

No significant financial relationships to disclose.
Tailored surgical staging and radiation therapy in clinical stage I endometrioid endometrial adenocarcinoma (EEA)
Authors: Bermudez Wagner K. M. , Thomas M. B. , Miyamoto C. , Micaily B. , Hernandez E.
Published: August 2020

e16511

Background: Pelvic lymph node dissection (LND) requirement to adequately stage endometrial cancer has been subject of debate. We conducted an outcome analysis of clinical stage I endometrioid endometrial adenocarcinoma (EEA) patients who underwent surgery with tailored LND and adjuvant therapy (radiation (RT) or chemotherapy) between 1997 and 2008. Methods: Retrospective chart review was performed at our institution. All patients underwent exploratory laparotomy, cytology, total abdominal hysterectomy and bilateral salpingoophorectomy. Pelvic and para-aortic LND was perforned in high-risk patients when technically possible. Cox proportional hazards and the Kaplan Meier method were used for data analysis. Results: 119 patients (stage I 92, II 11, III 15, and IV 1) were identified. Median BMI was 34 and 81% had significant co-morbidities. 50% underwent para-aortic LND (median 4 nodes) and 25% underwent pelvic LND (median 15 nodes), of whom 8% and 10% were positive, respectively. Postoperative complications occurred in 22%. 26% received RT. With a mean follow-up of 20 months, 5-year progression-free survival (PFS) and overall survival (OS) was 71% and 84%. The OS for stage I and IIIC was 88% and 83%, respectively. OS for patients with or without LND was not statistically different ( 73% vs.82%). 12 (10%) recurrences were noted, 8 of which were hematological (HF) with a 5-year HF probability of 21%. On multivariate analysis only myometrial invasion > 50% was independent risk factor for HF. Patients receiving RT showed a trend toward decreased in local recurrences ( 0% vs.30% p = 0.1) but no improvement in OS. Conclusions: In patients with EEA, a tailored approach to LND and adjuvant therapy results in good outcome, but many still have therapy-associated adverse events. Although no difference was found in OS between patients who underwent LND and those who did not, similar survival for patients with stages I and IIIC suggests that therapy directed by the knowledge of nodal status may have an impact on survival.

No significant financial relationships to disclose.