bluuebunny/crossref_metadata_2025 huggingface dataset:
First-line treatment with bevacizumab (B) and high dose (HD) bolus aldesleukin (IL-2) in metastatic renal cell carcinoma (mRCC) patients (Pts)
Authors: Ernstoff M. S. , Regan M. M. , McDermott D. F. , Sosman J. A. , Dutcher J. P. , Clark J. I. , Crocenzi T. S. , Ochoa A. , Atkins M. B.
Published: March 2020

15524

Background: The rationale for combining HD IL-2 with B includes potential synergistic immune interactions, non-overlapping toxicities, and potential for added clinical benefit. We have initiated a multi-center phase II study designed to estimate the efficacy of combination therapy of standard HD IL-2 and B therapy in mRCC pts. Methods: Pts with histologically confirmed mRCC, predominantly clear cell histology, measurable or evaluable disease, KPS of =80%, adequate end organ function for HD IL-2, and no underlying coagulopathy or thrombotic event are eligible for this study. One cycle consists of 84 days. B (10 mg/kg) IV is given every 2 wks beginning 2 wks prior to the first dose of IL-2. B is dosed 1 hr prior to initiating IL-2 on days IL-2 is given. HD IL-2 (600,000 IU/kg) IV Q8 hours (maximum 28 doses) is given during two 5-day courses separated by 9 days (starting on day 15 and 29). Results: We report the results of the first 15 of a planned 60 pts. The median age is 54 (range 40–73) with 9 men and 6 women. 14 pts have a MSKCC intermediate prognostic score, one pt has a poor prognostic score. In the first cycle, the median number of B doses was 7 of a planned 7 (range 2–7) and the median number of IL-2 doses was 17 of a planned 28 (range 6–26). There has been one treatment related death from unresponsive hypotension which occurred during the second cycle. Typical IL-2 toxicities have been noted thus far. Among a variety of correlative studies, we evaluated the serum L- ornithine (L-O) level, a byproduct of arginase-mediated arginine metabolism that has been shown to inversely correlate with TCR? chain expression. L-O level are significantly elevated in RCC pts possibly due to VEGF stimulation of arginase production. In 4 patients tested to date, peripheral blood L-O levels have dramatically decreased over the course of therapy. Conclusions: HD IL-2 and B can be given safely and may impact on immune regulatory pathways.

[Table: see text]
Adjuvant chemotherapy in lymph node positive bladder cancer
Authors: Gofrit O. N. , Stadler W. M. , Zorn K. C. , Silvestre J. , Shalhav A. L. , Zagaja G. P. , Steinberg G. D.
Published: March 2020

15526

Background: Lymph node-positive bladder cancer is a systemic disease in the majority of patients. Prescribing adjuvant chemotherapy shortly after surgery, when tumor burden is low seems reasonable, yet there is no proof that this treatment strategy improves survival. In this retrospective study, we compared the outcomes of patients with microscopic lymph node positive bladder cancer (pN1 or pN2) treated with radical cystectomy followed by adjuvant chemotherapy and those who declined chemotherapy. Methods: Sixty-seven patients with lymph node positive bladder cancer (pN1 in 26 patients and pN2 in 41) who underwent radical cystectomy between April 1995 and April 2005 were reviewed. Combined adjuvant chemotherapy (gemcitabine and cisplatin in most patients) was given to 35 patients (52%), but deferred by 32 (48%). The two groups were similar in performance status, postoperative complication rate and N stage but deferring patients were on average 4 years older and had a more advanced T stage. Results: Adjuvant chemotherapy was well tolerated with 28/35 patients (80%) completed all 4 cycles. Median overall survival of patients given adjuvant chemotherapy was 48 months compared to 8 months for deferring patients (hazard ratio 0.13, 95% CI 0.04–0.4, p<0.0001). Multivariate age adjusted analysis showed that adjuvant chemotherapy was an independent factor affecting overall survivals (hazard ratio 0.2, p<0.0001). Subgroup analysis demonstrated that chemotherapy provided survival benefit for patients with pN2 disease but not for patients with pN1 disease (p=0.0001 and p=0.235 respectively). Conclusions: This retrospective real-life study supports the use of adjuvant chemotherapy after radical cystectomy in patients with node positive bladder cancer, especially when more than one lymph node is involved.

No significant financial relationships to disclose.
Prediction of PSA spikes by isotope and patient age following permanent prostate brachytherapy
Authors: Bostancic C. , Merrick G. S. , Butler W. , Wallner K. , Allen Z. , Galbreath R. , Lief J. , Gutman S.
Published: March 2020

15535

Background: To evaluate prostate specific antigen (PSA) spikes (bounces) following permanent prostate brachytherapy in low-risk patients randomized to Pd-103 or I-125. Methods: The study population consisted of 164 prostate cancer patients who were part of a prospective randomized trial comparing Pd-103 with I-125 for low-risk disease. Sixty-one patients (37.2%) received short course cytoreductive androgen deprivation therapy (ADT). No patient received supplemental XRT. The median follow-up was 5.4 years. All patients were implanted at least 3 years prior to analysis. On average, 10.1 post-treatment PSA’s were obtained per patient. Biochemical disease-free survival was defined as a PSA = 0.40 ng/mL after nadir. A PSA spike was defined as a rise of = 0.2 ng/mL followed by a durable decline to pre- spike levels. Multiple clinical, treatment and dosimetric parameters were evaluated as predictors for a PSA spike. Results: Forty- four patients (26.9%) developed a PSA spike including 45.7% (21/46) of the hormone naïve I-125 patients and 14.0% (8/57) of the hormone naïve Pd-103 patients. In hormone naïve patients, the mean time between implant and spike was 22.6 months and 18.7 months for I-125 and Pd-103 patients, respectively. In patients receiving neoadjuvant ADT, the incidence of spikes was comparable between isotopes (28.1% for I- 125 and 20.7% for Pd-103). The incidence of spikes was substantially different in patients < 65 vs = 65 years of age (16.3% vs. 38.5%). In multivariate Cox regression analysis, patient age at implant (p < 0.001) and isotope (p = 0.002) were significant predictors for spike. Conclusions: In low-risk prostate cancer patients, PSA spikes are most common in patients implanted with I-125 and/or younger than 65 years of age. Differences in isotope-related spikes are most pronounced in hormone naïve patients.

No significant financial relationships to disclose.
Effects of zoledronate (Z) on bone mineral density (BMD) among African Americans (AA) with advanced prostate cancer, without skeletal metastases, recieving androgen ablation therapy
Authors: Kipping K. L. , Bennett C. , Evens A. , Munshi H. , Jovanovic B. , Gallot L.
Published: March 2020

15539

Background: Prostate cancer can be detrimental to bone health: it affects older men who have a higher risk of osteoporosis; common treatment is androgen ablation which can cause bone loss, and it frequently metastasizes to the bones. These issues are especially important in AA men, who present with higher rates of advanced disease and use of androgen ablation than whites. One study found beneficial effects of Z on the bone health of men with prostate cancer, it included only 106 men, and few were AA (Smith M, Journal of Urology).We wanted to evaluate the effects of Ca/Vitamin D ± Z on skeletal related events and BMD on AA and white men with prostate cancer who are receiving androgen ablation therapy. Methods: Prostate cancer patients receiving at least 3 months of androgen ablation were eligible. Exclusion criteria: use of bisphosphonates in last 12 months, abnormal liver/ kidney function, or prior bone disease. 41 patients have been randomized, 51% are AA. Patients on the Z arm receive 4 mg IV infusion of Z q 3 months over one year. Patients have bone densities at baseline and 13 months. Results: Interim analysis is available for patients who have completed study as of Jan 2007. 3 patients were taken off study (1 due to secondary cancer, 2 due to patient withdrawal).One patient withdrew due to jaw pain, follow up did not identify osteonecrosis. Two patients had lesions that may have been bone metastases, follow up testing was inconclusive. At treatment end, Z-treated patients had higher BMD scores than control group patients. AA patients treated with Z also showed increased BMD values at 13 months. Conclusions: Z appears to have a positive effect on BMD in AA men with prostate cancer- potentially more beneficial than among the effect previously reported for white men with prostate cancer. AA men with prostate cancer receiving androgen ablation should be considered for Z therapy to improve bone health.

[Table: see text]

No significant financial relationships to disclose.
Prognostic risk factors to predict final pathohistology in patients undergoing radical salvage prostatectomy for locally recurrent prostate cancer after radiation therapy
Authors: Pfister D. , Ohlmann C. , Sahi D. , Engelmann U. , Heidenreich A.
Published: March 2020

15544

Background: Radical salvage prostatectomy (sRPE) represents one local secondary treatment option with curative intent in patients failing radiation therapy for localized prostate cancer (PCA). Currently, there are very few studies correlating preoperative clinical and pathohistological variables with final pathohistology of sRPE specimens. It was the purpose of our study to identify prognosticators predicting organ confined and locally advanced PCA. Methods: 45 patients with biopsy-proven locally recurrent PCA underwent sRPE and extended pelvic lymphadenectomy (epLA) via a retropubic approach. Preoperative PSA, PSA doubling time, PSA prior to initial radiation therapy, biopsy Gleason score, number of positive biopsies, cT stage, 11choline PET/CT findings, type of radiation therapy, neoadjuvant androgen deprivation were correlated with the pathohistological stage by uni- and multivariate analysis. Results: A total of 45 patients underwent sRPE and epLA; 16 (35.5%), 12 (26.6%) and 17 (37.8%) patients had undergone external beam radiation (EBRT), HDR and LDR brachytherapy, resp. The mean preop. serum PSA was 7.8 (2–24) ng/ml; mean biopsy Gleason score was 5.6 (4–9). We did not encounter significant intraoperative compliations, the mean blood loss was 490 (200–950) ml. A mean of 19 (10 - 32) lymph nodes were removed. Pathohistology showed stage pT1–2pN0 in 27 (60%), stage pT3a/b and pTxpN1 PCA in 9 (20%) and 9 (20%) of patients, respectively. Positive surgical margins were identified in 5 (11%) patients. By multivariate analysis the parameters significantly associated with organ confined PCA sRPE are PSADT > 12 months, = 50% positive biopsy cores, biopsy Gleason score = 7 and previous LDR brachytherapy (pT1–2pN0R0 in all men); pre-radiation and preoperative PSA, PET/CT findings had no significant impact with final pTpN-stage. Conclusions: SRPE can be performed with a low morbidity in biopsy proven locally recurrent PCA after radiotherapy. The identified prognostic parameters will help to select patients most suitable for a local secondary surgical approach with curative intent. Especially in patients with local relapse following LDR brachytherapy sRPE represents a valuable treatment option.

No significant financial relationships to disclose.
A phase II trial of oxaliplatin and docetaxel in patients with androgen independent prostate cancer (AIPC) who have progressed to two prior regimens of chemotherapy
Authors: Feinstein T. , Appleman L. J. , Friedland D. M. , Jacobs S. A. , Ferri W. A. , Earle M. F. , Hyoung K. D. , Strausser H. , Corgnati S. , Chatta G. S.
Published: March 2020

15545

Background: Single agent docetaxel has demonstrated survival benefit in AIPC. In a phase I study of single agent oxaliplatin at our institution, two patients with AIPC experienced a substantial and durable reduction in PSA. Thus, we hypothesised that a combination of oxaliplatin and docetaxel maybe beneficial in AIPC. Methods: This single arm phase II trial in patients with previously treated (0–2 regimens) and progressive AIPC commenced in June 2005, with the objectives of evaluating PSA response rates, progression free survival, and the toxicity (tolerance/safety) of the regimen. In patients with soft tissue disease, measurable responses were assessed by RECIST criteria. Using Simon stage II design, a total of 37 patients with AIPC will be accrued. No prior treatment with platinum was allowed. Treatment consisted of oxaliplatin (110 mg/m2) and docetaxel (60 mg/m2), administered intravenously every 21 days for a maximum of 6 cycles. Results: 27 men have been enrolled to date: median age 66 yrs (56–84). 21 of 27 men have completed at least two cycles of the above regimen, and are evaluable. Prior therapies included antiandrogens (100%); ketaconazole (14%); docetaxel alone or in combination (27%); anthracyclines (27%); and vaccine (5%). Median PSA at baseline was 88 ng/ml (range 2.2–3559.4). 62% of patients received all six cycles. PSA declines of ≥50% were noted in 11 of 21 patients: 3 of 8 responders being chemo-naïve; and 8 of 13 with prior chemotherapy exposure. In addition, 4 of 11 patients with measurable disease at baseline, had a partial response. Treatment was well tolerated with no treatment-related deaths. The most significant grade 3/4 adverse event (AE) was neutropenia (43%). Grade 2 or less fatigue (66%), neuropathy (53%) diarrhea (47%), nausea (41%), anorexia (29%), thrombocytopenia (12%) and anemia (6%). Conclusions: The combination of oxaliplatin and docetaxel has promising activity in both chemo-naïve and previously treated AIPC. This 2-stage study will accrue a total of 37 patients. Final analysis will include time to progression, duration of response, and median survival.

[Table: see text]
Phase I study of picoplatin and docetaxel (D) with prednisone (P) in patients (pts) with chemotherapy-naive metastatic hormone refractory prostate cancer (HRPC)
Authors: Roman L. , Karlov P. , Kaprin A. , Gladkov O. , Breitz H.
Published: March 2020

15546

Background: Picoplatin is a sterically hindered platinum analogue specifically developed to overcome platinum resistance and to improve on the safety and efficacy of other platinum-based drugs. In >600 pts, picoplatin had single-agent activity in prostate, lung, ovarian and other malignancies with rare clinically significant nephro-, oto-, or neurotoxicity (∼2% grade 3 and 0% grade 4), even in platinum pretreated pts. An objective response rate of 20% and a PSA response rate of 25% were observed following 120 mg/m2 picoplatin q 3 wk in 20 chemotherapy-naïve pts with HRPC. D + P leads to superior survival, increased PSA response and improved quality of life in HRPC pts. Picoplatin has demonstrated synergy with taxanes in pre-clinical studies. Thus the current study is designed to investigate D + P + picoplatin in chemotherapy-naïve pts with metastatic HRPC. Methods: Pts with documented progression of metastatic disease during adequate hormonal therapy, ECOG performance status of 0 or 1 and preserved organ function received D, 60 mg/m2 q 3 wks + P, 5 mg, po bid + picoplatin. Picoplatin has been given to date to sequential cohorts of subjects at 60 mg/m2, 80 mg/m2 and 100 mg/m2. Results: 16 pts have been enrolled and have received up to 8 cycles of therapy. Therapy has been well tolerated. No dose limiting toxicity has been observed. Dose reduction for thrombocytopenia has been required in 1 pt, but there has been no cumulative myelotoxity. 7 pts in the first 3 dose cohorts have been evaluated for efficacy after 4 cycles (12 weeks): at doses below the maximum tolerated dose, there were 3 PSA responses and 1 objective partial response. Dose escalation continues. Conclusion: Picoplatin can be safely administered with D + P in chemo-naïve pts with HRPC. A phase 2 study of this combination will begin when an optimal, safe dose is defined.

No significant financial relationships to disclose.
Association of weekly gemcitabine to conformal radiotherapy as organ-sparing strategy in locally advanced or relapsed bladder cancer
Authors: Carillio G. , Alì M. , Mazzola A. , Bagnato S. , Todaro A. , D’Agostino A. , Girlando A. , Aiello R. , Fallica G. , Chiarenza M. , Caruso M.
Published: March 2020

15570

Background: Radical surgery is considered the only curative option for locally advanced or relapsed bladder cancer. However, the uncertain prognosis of disease and the poor quality of life due to lack of bladder reservoir require further investigation on possible therapeutic approaches. Methods: This trial has been designed for testing safety and activity of dose-escalating gemcitabine associated to concomitant conformal radiotherapy for locally advanced or relapsed bladder cancer. Patients received radiotherapy at 2 Gy per day to reach a total dose of 60 Gy over 6 weeks. Gemcitabine was administered once-a-week as one-hour IV infusion before starting the radiation treatment. The first explored dose of drug was 300 mg/m2 and the escalation was planned through a Fibonacci modified method by subsequent increases of 100 mg/m2 until definition of the dose-limiting toxicity (DLT). The recommended dose for future phase II study was one level inferior to the reached maximum tolerated dose (MTD). Results: Eighteen patients with median age of 72 years entered the study, half of whom affected by locally advanced tumours, the remainders by recurrence after conservative surgery. The majority of the latter initially had pT2 (UICC staging) muscle invasive transitional cell carcinoma. Twelve patients were treated with weekly gemcitabine at 300 mg/m2 without appearance of any DLT. Among the first 3 patients receiving the dose level of 400 mg/m2, one patient had grade 4 neutropenia. Further 3 patients were enrolled for testing the above dose level, but one of them experienced bowel perforation, therefore the established MTD was 400 mg/m2. The recommended dose of weekly gemcitabine was 300 mg/m2. Effectively, we could observe 11 (61%) pathological complete responses (pCR) confirmed by bladder mapping two months after treatment completion. Nine pCR (82%) occurred in the patients with locally advanced therapy-naïve bladder cancer. Patients with conserved bladders had excellent function, without hematuria, urgency or incontinence. Conclusions: The association of weekly gemcitabine to conformal radiotherapy provides a new alternative to radical surgery approach and strongly supports the organ-sparing strategy for locally advanced bladder cancer.

No significant financial relationships to disclose.
Validation of quantitative fluorescence imaging analysis (QFIA) of β-catenin in archived prostate tissues for cancer biomarker discovery
Authors: Hemstreet G. P. , Casale G. P. , Huang D. , Tian J. , Simpson M. A. , Kaleem Z. , Smith L. M. , Elkahwaji J. E. , Johansson S. L.
Published: March 2020

15575

Background: The objective of this study was to develop a sensitive tissue proteomic assay for quantifying proteins (e.g. β- catenin) in tissues and prostate core biopsies by QFIA. A second objective was to apply the validated methodology to quantify other biomarkers for prostate cancer risk assessment, and to study oxidative stress in BPH, prostate cancer, the cancer field, and in inflammatory prostatitis in animals and human prostatitis. Methods: Biopsies from controls and cancer patients were depariffinized, the antigen retrieved, and labeled with a robotic BioGenex Stainer with a primary mouse monoclonal antibody (1/100) to β-catenin. A secondary goat anti-mouse IgG antibody (2° Ab 1/100) coupled with Alexa Fluor 568 was used as the indicator system. The Leica Fluorescence Microscope was calibrated and standardized with fluorescence beads, LNCAP cells, and BPH tissue sections. QFIA of β-catenin was validated by RPPA methacarn fixed tissues. Adjacent 4-micron tissue sections were analyzed by QFIA for total β-catenin content by RPPA. Results: Reproducibility was 10% or less for the LNCAP cells and BPH tissue controls. Adjacent tissue sections assayed by QFIA and RPPA exhibited a strong linear correlation (r=.97) as did tissues fixed in methacarn vs.10% buffered-formalin and assayed by QFIA (r=0.84). For the core biopsy specimens the average MPI (AMPI) from 40 to 200 acini was quantified. The AMPI of cancerous acini (CA) compared to nomal acini (NA) was reduced in 37 of 42 cases p<.02. ROC plots revealed that β-catenin expression in NAA identified 42% (95%CI 25 - 52%) of cancer cases, with 88% (95% CI 80%-96%) specificity. The tissue QFIA method was used to quantify oxidative stress biomarkers (MnSOD, HNE, 8-OHdG) and other field disease biomarkers (Connexin42, and UDP-glucose dehydrogenase (UGDH) in BPH, prostate cancer, and in prostatitis. Conclusions: A tissue based QFIA method has been developed for the quantification of β-catenin in prostate core biopsy specimens, and the method has been validated by RPPA. Assay of β-catenin in prostate core biopsy specimens shows promise as a potential biomarker for a profile defining individuals at risk for prostate cancer and studying oxidative stress in relation to the pathogenesis of disease.

No significant financial relationships to disclose.
Androgen deprivation therapy does not impact cause-specific or overall survival in high-risk prostate cancer treated with brachytherapy and supplemental external beam
Authors: Allen Z. , Merrick G. S. , Butler W. , Wallner K. , Galbreath R. , Adamovich E. , Lief J.
Published: March 2020

15578

Background: To determine cause-specific (CSS), biochemical progression-free (bPFS) and overall survival (OS) in high risk prostate cancer patients undergoing brachytherapy with or without supplemental therapies. Methods: From April 1995 through July 2002, 204 patients with high risk prostate cancer (Gleason score = 8 and/or PSA > 20 ng/mL and/or clinical stage = T2c) underwent brachytherapy with or without supplemental therapies. Of the 204 patients, 193 (94.6%) received supplemental XRT and 119 (58.3%) received ADT (ADT = 6 months n=40 and ADT > 6 months n = 79). Median follow-up was 7.0 years. All patients were implanted at least 4 years prior to analysis. BPFS was defined by a PSA = 0.40 ng/mL after nadir. Multiple clinical, treatment and dosimetric parameters were evaluated for the impact on survival. Results: The ten-year CSS, bPFS and OS were 88.9%, 86.6% and 68.6%, respectively. A statistically significant difference in bPFS was discerned between hormone naïve, ADT = 6 months and ADT > 6 month cohorts (79.7% vs. 95.0% vs. 89.9%, p= 0.032). ADT did not impact CSS (94.0% vs. 87.1%, p=0.983 ) or OS (65.2% vs. 70.3%, p = 0.713). For bPFS patients, the median post-treatment PSA was < 0.04 ng/mL. A Cox linear regression analysis demonstrated that Gleason score was the best predictor of CSS while percent positive biopsies and duration of ADT best predicted for bPFS. OS was best predicted by Gleason score and diabetes. Thirty-eight patients have died with 26 of the deaths due to cardiovascular/pulmonary disease or second malignancy. Eleven patients have died of metastatic prostate cancer. Conclusions: Androgen deprivation therapy improved 10-year bPFS without statistical impact on CSS or OS. Death as a result of cardiovascular/pulmonary disease and second malignancies were more than twice as common as prostate cancer deaths. Strategies to improve cardiovascular health should positively impact overall survival.

No significant financial relationships to disclose.
Phase II screening study of an LHRH analog, dexamethasone and somatostatin analog versus LHRH analogue with dexamethasone in HRPC
Authors: Calais da Silva F. M. , Calais da Silva F. E. , Gonçalves F. , Oliver T.
Published: March 2020

15579

Background: As far as prostatic cancer is concerned, we know that somatuline (SMS) blocks GH, PRL, tissular growth factors (TGF) and that it has a direct antiproliferative cellular growth effect. The simultaneous administration of depot forms of SMS and LHRH analogues induced the greatest decrease in tumor growth. Methods: A randomised Phase II trial was carried out in M0 (PSA ≥ 20 ng/ml) and M1 patients with hormone refractory prostate cancer to simultaneously screen decapeptyl and dexamethasone, both with and without SMS (120 mg every 4 weeks), with respect to the PSA response rate, time to PSA progression, duration of survival and toxicity. Results: 72 patients with a median PSA of 77 ng/ml were randomised by 3 centers, 35 to decapeptyl, dexamethasone, both with and without SMS (DDS) and 37 to decapeptyl and dexamethasone (DD). 18 of 33 (54%) patients on DDS and 13 of 32 on DD (43%) had a PSA response (a decrease of at least 50% as compared to baseline). The median time to PSA was 5.5 months in the SMS group and 1.9 months in the group without SMS. At 6 months, 45.7% were PSA progression free in the SMS group versus 35.1% in the goup without SMS. The median time to PSA progression in PSA responders was 10.6 months in the SMS group and 13.9 months in the group without SMS. At 6 months, 73.7% of the PSA responders were progression free in the SMS group versus 81.3% in the group without SMS. 45 patients died (62.5%), 22 (62.9%) in the SMS group and 23 (62.2%) in the group without SMS. 15 and 19 of the deaths respectively were due to prostate cancer. The median duration of survival is 1.65 years in the SMS group and 1.48 years in the group without SMS. At 6 months, 85.7% were alive in the SMS group vs 78.1% in the group without SMS. At 12 months, 77.1% were alive in the SMS group vs 69.4% in the group without SMS. Conclusions: There is no evidence that SMS may have increased the incidence of side effects. The PSA response rate was slightly higher in the SMS group, 54% vs 43% and the median time to PSA progression in all patients appears to have been slightly longer in the SMS group. Fewer objective progressions were also observed in the SMS arm, 4 vs 12. These results suggest that SMS may add to the activity of decapeptyl and dexamethasone and thus have a role in the treatment of hormone refractory prostate cancer.

No significant financial relationships to disclose.
Spontaneous otoacoustic emissions (SOAE) changes in testicular cancer patients treated with cisplatin: A pilot study of whether the acute ototoxic effect of cisplatin treatment can be detected
Authors: Biro K. , Noszek L. , Prekopp P. , Vehovszky K. , Nemeth E. , Nagyivanyi K. , Geczi L. , Gaudi I. , Bodrogi I.
Published: March 2020

15581

Background: We studied the acute ototoxic effect of cisplatin in testicular cancer patients with two highly sensitive new methods for detecting high frequency hearing loss: distorsion product otoacoustic emissions (DPOAE), and spontaneous otoacoustic emissions (SOAE). Methods: Checking the acute effect, 32 (63 ears) testicular cancer patients (median age: 33 years, range: 16–59 years) were measured on the first day of their first cycle and after one week of their last cycle of cisplatin treatment. 20 mg/m2 cisplatin was administered for five days, in BEP chemotherapy regimen. The patients got on the average 2.19 cycles (2–3 cycles). We also measured the SOAE of ten healthy control persons (without chemotherapy) matching sex and age distribution of this group. A detailed medical history evaluated audiological risk factors and hearing problems. Tympanometry, DPOAE and SOAE were measured, to detect the acute changes in the inner ear after low cumulative dose of cisplatin treatment. Paired t-test, and sign test was used for statistical analysis. Results: The DPOAE did not show any changes close after cisplatin treatment (average: 2.19 cycles, 2–3 cycles), similarly to our earlier results with pure tone audiometry (PTA) and transiently evoked otoacoustic emission (TOAE). But the SOAE showed significant, early changes in incidence, shape and amplitude, in the treated group. 66% of the SOAE changed after treatment (p=0,006). In the control group (20 ears) the SOAE never changed in a three months period. (It behaves as a fingerprint) Conclusions: DPOAE did not change significantly after 2 or 3 cycles of cisplatin treatment, similarly to our earlier results with PTA, and TOAE, but the change of the SOAE-incidence, shape and amplitude close after cisplatin treatment shows acute changes in the inner ear function (first described in the literature) after administration of low cumulative dose of cisplatin. This case is the first indication of the possible clinical relevance of SOAE. Our observation has to be confirmed in further studies, with larger number of patients.

No significant financial relationships to disclose.
A phase I study of testosterone in patients (pts) with early castrate resistant prostate cancer (CRPC)
Authors: Knight D. A. , Mohile S. G. , Posadas E. M. , Manchen E. A. , Stadler W. M.
Published: March 2020

15584

Background: Transition to the castrate resistant state may be due, in part, to the development of a more sensitive and promiscuous androgen receptor (AR) pathway. Androgen therapy of CRPC leads to growth arrest and tumor shrinkage in preclinical models. Historical studies of exogenous testosterone in pts is limited. This study was designed to determine toxicity of a transdermal testosterone therapy (Androderm [A]) in early CRPC. Methods: Pts with progressive PSA increases following androgen ablation and antiandrogen therapy with minimal or no bone metastases (Bone Scan Index of < 1.4%) and no visceral metastases were eligible. Pts were randomized to treatment with 2.5, 5.0, or 7.5mg/day of A and LHRH agonist treatment was maintained. Toxicity was evaluated every 2 weeks and all subjects underwent laboratory, quality of life (UCLA Prostate Cancer Index), and hand grip strength testing at baseline and week 6. Treatment was discontinued for severe toxicity, radiologic progression, or a 3-fold increase in PSA. Results: To date fourteen men were enrolled. Median baseline PSA was 10.9ng/mL (Range:5.3–63.6). Eight pts had no radiologic evidence of disease. Median on therapy testosterone levels (ng/dL) were 216 (n=4), 308 (n=5), 325 (n=5) for 2.5, 5.0, 7.5mg/day dose levels, respectively. Toxicities included grade 2 rash (n=1, dose 7.5), grade 2 hypertension (n=1, dose 7.5), grade 2 hypoglycemia (n=1, dose 5), and grade 2 anorexia (n=1, dose 5). In 29% of pts (n=4), there was a decrease in PSA (max decrease = 43%) from baseline lasting from 4 - 36 weeks; two sustained an initial rise before PSA decline. All other subjects required discontinuation of therapy due to PSA increase and/or radiological progression within 2–13 weeks; none of these patients sustained symptomatic progression of disease and PSA decreased in 8/11 pts with available data after therapy discontinuation. In this small sample, there were no significant differences between baseline and 6-week QOL and hand-grip scores. Conclusion: Testosterone treatment in early CRPC is feasible and safe, although use of PSA to assess anti-tumor effects is difficult. Further evaluation would require a randomized trial to evaluate time to progression and QOL endpoints.

No significant financial relationships to disclose.
Adjuvant docetaxel chemotherapy with abbreviated hormonal therapy in patients with high-risk prostate cancer
Authors: Colocci N. , King C. R. , Brooks J. D. , Gill H. S. , Presti J. C. , Srinivas S.
Published: March 2020

15589

Background: We conducted a pilot adjuvant docetaxel and abbreviated androgen deprivation study (ADT) in patients with high-risk localized prostate cancer. Study objectives were to evaluate toxicity, feasibility of 6 months of ADT and 3 months of docetaxel treatment, and incidence of serum PSA relapse at 2 years compared to historical controls. Methods: Eligible patients had radical prostatectomy or radiation therapy for high-risk disease (pathologic node positive disease, capsule involvement, extra-capsular extension, seminal vesicle involvement, positive surgical margins, Gleason score = 8, clinical stage T2c or T3, serum PSA >20, or pre-op PSA > 15 plus any high-risk feature). Patients were treated with taxotere 35 mg/m2 weekly 3 out of every 4 weeks for 3 months, and an LHRH analog for 6 months concurrently. In this high-risk cohort, we estimated the risk of PSA recurrence to be as high as 65% in 2 years. To detect a reduction in recurrence rates after surgery or radiation by 40% at a power of 80% and a 2-sided alpha of 0.05, a total of 21 patients were needed in this pilot Phase II study. Results: Twentyone patients were enrolled between 9/04–9/05. The median age was 59.5 years (48–72). Ten patients had a radical prostatectomy and 11 had radiation therapy. All patients received 6 months of LHRH analog therapy. Median pre- treatment PSA was 9.5 ng/ml (4–120). Mean Gleason grade was 8 (7–9); 65% of the patients had >50% biopsies positive. Treatment was well tolerated. Acute toxicity included 1 grade IV hyperglycemia. There was 1 dose reduction and 1 treatment delay. One patient had grade III elevation in serum AST which was transient. Grade I/II toxicities were common and included fatigue, diarrhea, insomnia, and pedal edema. Median follow up is 20 months. Five patients have relapsed. One (of 11) patients treated with radiation has relapsed with metastatic bone disease at 9 months. Four (of 10) patients who underwent prostatectomy have had a serologic relapse at 14, 14, 17 and 21 months, respectively. Conclusions: These data suggest that adjuvant weekly taxotere with abbreviated course of ADT is feasible and well tolerated. In this pilot trial, at a median follow up of 20 months, 23% of patients have relapsed. Longer follow up is required and is ongoing.

No significant financial relationships to disclose.
Low molecular weight heparin (LMWH) increases the efficacy of immunotherapy in metastatic renal cell carcinoma patients with abnormal coagulation
Authors: Tsimafeyeu I. , Madzhuga A. , Demidov L. , Somonova O. , Kharkevich G. , Yelizarova A. , Petenko N.
Published: March 2020

15591

Background: Antitumor effects of LMWH are unclear. Heparin can bind with fibroblast-growth factor, other heparine-binding angiogenic factors, their receptors, and/or impact on coagulation system which induces angiogenesis. We previously revealed hypercoagulation is a frequent symptom in metastatic renal cell carcinoma (MRCC) patients (pts) and clinically correlates with progression of the disease. Methods: Pts with MRCC and high level of fibrinogen, D-dimer or fibrin, antithrombin III and prothrombin were stratified by MSKCC prognostic criteria and included to receive immunotherapy plus LMWH (IL-2, 1 MIU, i.v, 3 tiw + IFN alpha, 5 MU, s.c, 3 tiw ± 5-FU 500 mg/m2, i.v. once a week, and Dalteparin, LMWH, 5000 IU, s.c, every day, for 3 weeks) or immunotherapy alone. Demographic and treatment characteristics were similar between both arms. The primary endpoint was cancer-related overall survival (OS). Results: Flu-like syndrome, hypotension, anorexia were most common side effects (CTC grade 1). There were no bleedings in LMWH group. Conclusions: These results demonstrate that Dalteparin significantly improves cancer specific overall survival and decreases disease progression rate in combination with immunotherapy in MRCC pts with abnormal coagulation. Phase II randomized multicenter open-label discontinuation trial will be conducted.

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No significant financial relationships to disclose.
Phase II trial of oral imatinib in combination with every-three-week intravenous docetaxel in patients with metastatic, hormone- refractory prostate cancer
Authors: Appleman L. J. , Friedland D. , Chaussard C. , Gooding W. , Feinstein T. , Sulecki M. , Evans T. , Corgnati S. , Strausser H. , Chatta G.
Published: March 2020

15603

Background: Imatinib is a small molecule tyrosine kinase inhibitor specific for Bcr-Abl, platelet-derived growth factor receptor (PDGFR) and c-Kit. Inhibition of PDGFR abrogates pericyte migration and perturbs regulation of interstitial fluid pressure, suggesting potential anti-tumor effect in combination with chemotherapy. Docetaxel is a microtubule-stabilizing cytotoxic agent shown to prolong survival in men with androgen-refractory prostate cancer (AIPC) when administered at 75 mg/m2 every 21 days. We have previously established that imatinib 400 mg daily plus docetaxel 60 mg/m2 every 21 days is well tolerated and now hypothesize that this combination will prolong time to disease progression (TTP) in patients with AIPC. Methods: Subjects with progressive AIPC received docetaxel 60 mg/m2 intravenously every 21 days (day 1; up to 8 cycles) plus imatinib 400 mg by mouth daily starting on day -3. After the first 6 subjects, the study treatment was modified so that subjects receive oral imatinib 400 mg only on days -3 thru +7 of each 21-day cycle. The primary endpoint is TTP. The sample size is 43 patients, providing 90% power to detect an increase in TTP from 5 to 8 months. Results: Nineteen subjects have enrolled in the study between August 2005 and October 2006. Age range of subjects was 54 to 84 years (median 69 years). Serious adverse events (=Grade (G) 3) were principally hematologic: neutropenia (G4=5, G3=2); thrombocytopenia (G4=1, G3=1), hemoglobin (G4=1). There was one G4 myocardial infarction and one incident of G5 sepsis associated with methicillin-resistant S. aureus bacteremia and normal neutrophil count. One instance each of the following G3 toxicities were observed: fatigue, myalgia, dyspnea, nausea/vomiting, diarrhea, chest pain, dizziness, urinary retention. Five subjects had >50% decrease in serum PSA. Eight subjects received 4 or more cycles of docetaxel, and 4 subjects continued on imatinib maintenance after completing 6–8 cycles of docetaxel plus imatinib. Conclusions: Intravenous docetaxel on day 1 plus oral imatinib on days -3 thru +7 of a 21-day cycle is generally well- tolerated in men with AIPC. Prolonged stable disease and/or serum PSA response was observed in several subjects.

[Table: see text]
Delaying conformal radiation therapy in high-risk prostate cancer patients lowers the actuarial distant metastases free survival
Authors: Nakamura R. A. , Monti C. R. , Trevisan F. A. , Prestes J. C. , Cruz M. R. , Castilho L. N. , Reinato J. A. , Borges L. F.
Published: March 2020

15614

Background: It is not well documented on medical literature the value of time to treat prostate cancer. This study was performed to evaluate the value of treatment time with conformal radiotherapy (3DCRT) in high-risk prostate cancer patients. Methods: From October 1997 to January 2002, 116 patients with high-risk prostate cancer were submitted to 3DCRT and were analyzed retrospectively. The median age was 65 years-old. High risk patients were defined as patients with PSA > 20 ng/ml, and/or T3 clinical stage and/or Gleason score > 7, or two factors of intermediate risk (PSA >= 10 and < 20 ng/ml, T2b-T2c and Gleason score = 7). The median time from diagnosis to 3DCRT was 2.9 months (0.9–134.9). The median doses of radiation on prostate and on seminal vesicles were 81 Gy (72–82.8) and 61.2 Gy (45–77.4), respectively. The neoadjuvant and concomitant androgen suppression therapy were performed on 69 (59.5%) and 79 (68.1%) patients, respectively. Results: On median follow-up of 54.5 months (13.5–93.9), the 5-year actuarial overall survival, the 5-year actuarial biochemical progression-free survival and the 5-year actuarial distant metastases free survival were 84.3%, 64.7% and 88.6%, respectively. The 5-year actuarial distant metastases free survival for patients treated with 3DCRT less than or equal to 5 months was 92.5% versus 72.1% for patients treated with 3DCRT > 5 months (p=0.0076). The 5-year actuarial distant metastases free survival for patients with biochemichal progression was 68.8% versus 100% for patients with no biochemical progression (p 65 years-old (p=0.0160). Conclusions: The study suggests that delaying 3DCRT in high-risk prostate cancer patients lowers the actuarial distant metastases free survival. Biochemical progression may be a strong prognostic factor for distant metastases and, consequently, poor quality of life.

No significant financial relationships to disclose.
Perifosine (P), active as a single agent for renal cell carcinoma (RCC), now in phase I trials combined with tyrosine kinase inhibitors (TKI)
Authors: Stephenson J. , Schreeder M. , Waples J. , Hargis J. , Campos L. , Birch R. , Henderson I.
Published: March 2020

15622

Background: P is an oral alkylphosphocholine with effects on multiple pathways including Akt, MAPK and JNK. Akt/S6 is often activated in RCC and associated with resistance. In a phase I study of P, 3/6 RCC patients (pts) had stable disease (SD) lasting for 4, 6 and 14 months (m). RCC was further assessed in a broad phase 2 trial, and subsequently, two phase 1 trials combining P with TKIs have been initiated. This is an update of the phase II and first report of the phase I combination trials. Methods: From 3/05 to 5/06 241 pts, including 13 with RCC, were randomized to P, 50 mg daily or 1200 mg weekly. Subsequently the protocol was amended to P, 100 mg daily or 900 mg weekly, and enrollment continues. Pts with measurable disease who received at least 2 courses of P and at least one tumor measurement after initiation of P were considered evaluable for response using RECIST criteria. After demonstrating P activity in RCC, two phase 1 studies of P combined with either sorafenib (SOR) or sunitinib (SUT) were initiated. In each study, the dose of P is escalated from 50 mg qd to 50 mg tid. SOR is escalated from 400 mg qd to 400 mg bid and SUT from 25 to 50 mg qd for 4 weeks out of 6. Results: In the broad phase II study, 6 pts (66%) achieved clinical benefit. (See table ) including 3 pts (33%) with partial responses [duration 4, 6.5 and 9 m] and 3 pts (33%) with SD [9+, 9+ and 10 m]. Three pts progressed. The main toxicities were grade 1 nausea, vomiting, diarrhea, and fatigue. Daily P was significantly better tolerated than weekly and data are presented in detail in another abstract. Enrollment in cohorts 1 and 2 of the P/SOR study is complete. No grade 3 or 4 toxicities and increase in hand foot syndrome has been seen. Accrual to cohort 1 of the P/SUT study is also complete. Enrollment will be complete by May 2007. Conclusions: P is active in RCC. Phase 1 trials of P with TKIs have demonstrated no increased toxicity with less than maximal doses of P and TKI

[Table: see text]

No significant financial relationships to disclose.
VEGF, PDGF alpha, PDGF beta, and C-Kit expression are not independent survival predictors in stage D2 prostate cancer (PC)
Authors: Kasimis B. , Chang V. T. , Hoover D. , Sikder M. , Gounder S. , Finch Cruz C. , Gonzalez M. L. , Cogswell J. , Srinivas S. , Blumenfrucht M.
Published: March 2020

15623

Background: In PC, overexpression of VEGF, PDGF alpha, PDGF beta, and C-Kit has been reported in over 50% of biopsy samples and may be important predictors of survival. Methods: In an ongoing project, we reviewed the records of 26 patients (pts) with stage D2 PC and stained their archival tissue specimens for VEGF, PDGF alpha, PDGF beta, and C-Kit expression. Immunohistochemistry was performed at US LABS (Irvine CA). All immunostains were evaluated by two pathologists. Immunoreactivity was scored using a semiquantitative system for intensity of staining (0–3+) and % of tumor cells (0–3+). The total score was obtained by averaging the scores between the two readers. All pts had androgen deprivation and were followed at 3 months intervals with physical examination, CBC, chemistry profile and PSA levels. A stepwise Cox model was used with variables: Gleason score, Hemoglobin (Hgb), Alkaline Phosphatase (Alk Phos), PSA, LDH levels, and C-Kit positive or negative staining. Results: Median values were as follows: age 69 years (56–91), Alk Phos 139 U/L(60–1298), PSA 178 ng/ml (1.8–5677), LDH 169 IU/L (100–350), Hgb 12.8 gm/dl (6.8–16.3), Gleason score 8 (5–10), Survival 26 mos (8.3–144.1). The median value for C-Kit staining was 3 on a scale of 0–6. 18 pts were grouped into low staining group (0–4) and 8 pts in a high staining group (4.5–5). The Kappa Coefficient for C-Kit was 0.83, and ranged from 0.78–0.91 for the other 3 stains. In univariate survival analyses, C-Kit staining was a predictor for survival (p=0.037) but not PDGF alfa, PDGF beta, or VEGF. In the stepwise Cox model, independent survival predictors in order of significance were the Gleason score, Hgb, and PSA levels. Conclusions: In this sample, VEGF, PDGF alpha, PDGF beta, and C-Kit overexpression by immunohistochemistry in archival tissue are not independent predictors of survival. The C-Kit, however, has a small association with survival but may have collinearity with known predictors of survival.

No significant financial relationships to disclose.
Phase II trial of paclitaxel in front-line therapy of hormone refractory metastatic prostate cancer
Authors: Kolevska T. , Goldstein D. , Davis C. , Fehrenbacher L.
Published: March 2020

15628

Hormone refractory prostate cancer patients have poor prognosis with median survival of only 16 months. They are frequently elderly men with many co-morbid conditions unable to tolerate treatments with substantial toxicity. Docetaxel, the only drug shown to prolong survival causes significant toxicities, requires steroids administration, may cause poorly reversible neuropathy and requires long infusion times, all limiting its use in elderly men that are mostly affected by hormone refractory prostate cancer. Abraxane is a novel agent delivering paclitaxel without steroids, requires only 30 minutes infusion times and low toxicity potential that may be effective and more tolerable in patients with prostate cancer. The goal of our study is to evaluate the effectiveness and toxicity of Abraxane in first line chemotherapy of men with hormone refractory prostate cancer. Considering the favorable toxicity profile of Abraxane and in an effort to make our results applicable to the majority of prostate cancer patients we are including men with performance status of 2. Main eligibility criteria are: hormone refractory metastatic prostate cancer documented by PSA progression, no prior chemotherapy, PSA >5 and performance status 0–2. Primary endpoint is efficacy based on PSA response. Secondary endpoints are time to PSA progression, overall survival, and toxicities. The clinical trial has been opened at Kaiser Permanente Northern California since September 2005. There are 15 patients enrolled. All have been evaluable for toxicity and the drug is very well tolerated so far by this population of patients. Out of 15 patients 12 are evaluable for response. Two patients have recently started the protocol therapy and have not met the time point for disease assessment. One patient discontinued the treatment after one infusion due to toxicity (elevated LFTs). One patient completed 11 cycles of Abraxane, while maintaining stable disease on bone scan and achieved a PR by PSA. Ten patients have come off study due to progressive disease based on clinical presentation, rising PSA or signs of radiological progression. There are currently 4 patients actively receiving therapy. Updated results will be presented at the time of ASCO 2007 meeting.

No significant financial relationships to disclose.