bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined chemotherapy and surgery for metastatic gallbladder cancer improve median survival
Authors: Gallardo J. O. , Rubio B. , Díaz J. C. , Maluenda F.
Published: March 2020

14136

Background: Metastatic gallbladder cancer (MGBC) is a rapidly progressive disease, orphan of treatment; its median survival is only 3 to 4 months. Since 1999 we had demonstrated that gemcitabine (Gem) and gemcitabine-cisplatin (Gem-plat) are active regimens against this disease, but median survival increases to only 8 months. We had seen some complete responses and cases with impressive partial responses, but all of them are transients, recurrence appears in all pts. The benefit of combining CHTx and surgery had not been tested in MGBC, but has demonstrated promising results in others GI cancers. Methods: A retrospective analysis was performed in data from 9 patients (pts) who had liver resection for MGBC. Gem o gem-plat was given to all patients. Between September 1999 and July 2005 we had included more than 70 pts in two trials and others 25 pts had been treated outside of clinical trials. Among then, 9 patients with metastases from MGBC who were treated with Gem ± plat, were sent for resection of residual tumors. All pts received radio-chemotherapy after resection The primary endpoint was overall survival. Safety was a secondary end point. Results: We report the results of the first 9 patients with at least 9 months follow-up post surgery. Median overall survival is 17 months (9+ - 24). Only one pt is free of recurrence, (at 9 months), all others died due to relapse. Liver was the most frequent site of recurrence (8/8), but also peritoneal cavity and duodenum. All pts presented recurrence distant to initial tumor site. Most possible explanation for recurrence in 3 cases was R1 resection. In the CHTx phase no one pts required a dose reduction. Grade ≥3 was rare, vomiting in 2.0%, febrile neutropenia in 1.3%. There was no toxic death. Surgical complications (within 30 days of surgery) were low, with no one requiring reoperation, and no deaths were observed. Conclusions: Chemotherapy with Gem ± cisplatin was safely administered. Surgical mortality and morbidity rates were low. Even though a high proportion of patients died due to relapse, and thus suggest that this approach in inconvenient, this combined therapy offer a double life expectancy compare to chemotherapy alone.

No significant financial relationships to disclose.
Efficacy of gemcitabine/irinotecan in female patients ≤ 56 yrs with metastatic pancreatic cancer
Authors: Posey J. A.
Published: March 2020

14139

Background: Pancreatic cancer remains extremely lethal due to marginally effective systemic therapies. Erlotinib, a tyrosine kinase inhibitor combined with gemzar has recently been approved for use in advanced disease for a modest improvement in survival. Other combinations with gemzar have demonstrated higher response rates in randomized trials, but without survival benefit. Gemzar and irinotecan was an early combination with promise from phase I/II findings; however, results from a randomized trial did not support wide use of the regimen. Methods: Five successive female patients, not on-study, with unresectable pancreatic cancer were treated with gemcitabine(Gem) and irinotecan (CPT-11) from 10/00 to 12/05 following a highly successful outcome in one patient who remains alive and without active disease. Two patients received Gem at 1 gm/m2/CPT-11 at 100 mg/m2 on days 1+8 every 21 days and three patients received fixed-dose rate (FDR) Gem 900 mg/m2 and CPT-11 at 100 mg/m2 on days 1 + 15 every 28 days. Ages at presentation were 47, 49, 50, 53, and 56. All patients had metastatic disease with primary tumors involving the head 2, body 2, and neck 1. One patient had recurrent metastatic disease following adjuvant xeloda/ XRT. One pt had a hx of diabetes. Number of courses ranged 4–12. One pt received in addition CI 5-FU/ XRT and 1 pt received 5 doses of FDR Gem prior to progressing and receiving combination treatment. Results: 39 courses of Gem/CPT-11 were administered on D1 + 8 or 15. Treatment delays occurred twice with both schedules due to grade 3 neutropenia. Grade ½ toxicities include nausea, fatigue, and diarrhea. 3 CR, {2 > 4 yrs}, 1SD, 1MR Conclusions: The quality and durability of the observed responses in this subset of pancreatic cancer patients’ has prompted an archival comparative tissue analysis of patients enrolled on PANCAN institutional trials during this period.

No significant financial relationships to disclose.
Phase II study of concurrent S-1/cisplatin and radiation therapy in locally advanced or metastatic esophageal cancer
Authors: Cho S. , Shim H. , Ahn J. , Yang D. , Kim Y. , Park C. , Lee J. , Chung I. , Kim H.
Published: March 2020

14154

Background: Although 5-FU and cisplatin had been widely used as radiosensitizer, the toxicities such as mucositis or bone marrow suppression were problematic. In this study, 5-FU was replaced with S-1. The primary end point of this study was to define the safety and the secondary end point was to evaluate the pathologic response and clinical efficacy as the first line therapy in locally advanced or metastatic esophageal cancer. Methods: Patients with locally advanced or metastatic esophageal cancer without history of previous chemotherapy or radiotherapy were eligible. Cisplatin was given intravenously with 75 mg/m2 on day 1 every 3 weeks. S-1 was administered at the dose of 80 mg/m2/day orally divided two times for 2 weeks followed by 1 week rest. Radiotherapy was started concomittently at day 1, total dose of 5040 cGY for 6 weeks. During radiotherapy, patients received 2 cycles of chemotherapy. Results: From May 2004 to Aug 2005, 33 patients were enrolled into this study. 6 patients were dropped out due to poor compliance (3), economic problem (2) and TEF (1) during treatment. 27 patients were evaluable for response and toxicity. The median age was 66 years (range, 54–82). Clinical response was 77.8% (21 pts) and pathologic response was shown in 29.6% (8 pts). The improvement of dysphagia was shown in 22 patients (81.5%). There were 7 (25.9%) pts with grade 3 neuropenia. Grade 3–4 odynophagia during concurrent chemoradiotherapy was observed only one patient. Conclusions: The concurrent chemoradiotherapy combined with S-1 and cisplatin was well tolerated and effective in advanced esophageal cancer to relieve obstructive symptoms and tumor regression.

No significant financial relationships to disclose.
A phase I/II study of S-1 and CPT-11 therapy for patients (pts) with metastatic gastric carcinoma (GC)
Authors: Uetake H. , Inokuchi M. , Sugihara K. , Danenberg K. D. , Danenberg P. V. , Danenberg P. V.
Published: March 2020

14156

Background: S-1 was recently developed as a first line chemotherapy for the treatment of metastatic GC. We performed a phase I study of S-1 plus CPT-11 therapy for metastatic GC and reported that the maximum tolerated dose and the recommended dose (RD) of CPT-11 were 90 and 80 mg/m2, respectively. Objectives of the present trial were to estimate the response rate (RR) of this regimen. Methods: Eligibility criteria were as follows; histologically proven CRC with measurable metastatic lesions, PS 0–2, age < 80, adequate organ functions, and written informed consent. No prior chemotherapy except adjuvant setting was allowed. S-1 was administered orally, 80 mg/m2/day on 14 consecutive days with 14 days’ rest for 4 weeks, and CPT-11 was infused at the RD in phase I trial on days 1 and 8. This schedule was repeated every 4 weeks. Results: Objective responses according to RECIST criteria were observed in 26 of the 42 pts (RR = 62%). Nineteen pts were with Grade 3 and 4 neutropenia and 10 with diarrhea Median survival time was 444 days. Intratumoral gene expression was analyzed using laser capture microdissection and RT-PCR method (Response Genetic Inc). Lower gene expression was observed in tumor cell of responder (P = 0.01). Conclusions: High RR and mild toxicity profile of S-1 plus biweekly CPT-11 therapy may be favorable for metastatic GC.

No significant financial relationships to disclose.
Prognostic risk factors for survival following adjuvant chemotherapy for locally advanced urothelial bladder cancer
Authors: Cordia I. , Ohlmann C. H. , Engelmann U. , Heidenreich A.
Published: March 2020

14510

Background: A recent meta-analysis has demonstrated a 25% relative risk reduction of death and an absolute survival benefit of 9% at 3 years for adjuvant chemotherapy following radical cystectomy (RCx) for lymph node positive bladder cancer. It was the aim of our analysis to identify predictors of survival following standard chemotherapy in lymph node positive bladder cancer. Methods: A retrospective analysis of 156 consecutive patients with lymph node positive urothelial bladder cancer was performed. All patients underwent systemic chemotherapy with 4 cycles gemictabine/cisplatin 4 to 6 weeks after RCx. The prognostic significance of the number of positive lymph nodes, lymph node diameter, extranodal extension, bilateral lymph node involvement, pT stage, grade, tumor diameter, presence of lymphatic (LI) or vascular invasion (VI) was analysed. Statistical analysis was performed by uni- and multivariate analysis. Results: Median follow-up is 6.5 (12 â€“ 3.5) years, minimum follow-up is 36 months. Median survival time is 56 months, 56% of the patients died due to tumor progression. pT stage (p = 0.002), tumor diameter (p = 0.005), LI (p = 0.0015) or VI (p = 0.0028), lymph node diameter (p = 0.026) and extranodal extension (p = 0.0002) were significant risk factors associated with survival by univariate analysis. Neither the number or bilaterality of positive lymph nodes nor tumor grade were associated with survival time. On multivariate analysis only extranodal extension (p = 0.001) and tumor diameter (p = 0.05) remained significant and independent prognostic predictors. Median survival was 64 and 21 months in patients with or w/o extranodal extension (p = 0.0001), resp.; median survival was 81 and 28 months in patients w/o and with LI/VI (p = 0.001). In patients with extranodal extension or LI/VI adjuvant chemotherapy had no impact on survival. Conclusions: Analysis of multiple pathohistological and clinical parameters reveal that extranodal extension, primary tumor diameter and presence of LI/VI represent risk factors predicting survival following adjuvant chemotherapy in lymph node positive bladder cancer. Patients exhibiting these adverse factors might be considered for a more aggressive systemic approach.

No significant financial relationships to disclose.
Perioperative immunomodulation with interferon-alpha in patients with renal cell carcinoma: Early results of a controlled phase II trial
Authors: Klatte T. , Ittenson A. , Röhl F. , Ecke M. , Allhoff E. P. , Böhm M.
Published: March 2020

14525

Background: Complex perioperative immunodysfunction occurs in patients with renal cell carcinoma undergoing surgery. Earlier, we presented evidence of a survival benefit in patients, who received perioperative immunomodulation with interleukin-2 (JCO 23 (16S):4601, 2005). Here, we report on the effect of interferon-alpha (IFN-α). Methods: Fifty-four consecutive patients, who underwent tumor nephrectomy, were enrolled into this prospective one stage phase II trial from June 2003 to May 2005. Patients were alternately assigned to the two study groups: 27 received immunomodulation with IFN-α (4 doses 9 million IU s.c a week before operation, followed by a daily dose of 3 million IU until a day before the operation), 27 did not. Parameters of immunity (differential blood count, CD3, CD4, CD8, CD16, CD19, CD28, CD56, HLA-DR, VEGF, IL-10) were measured in venous blood before and during IFN-α, one day before and immediately after the operation, and on the 1., 3., 5., and 10. postoperative day. The primary endpoint was tumor-specific survival. T-test, χ2-test and the log-rank test were used for statistical analysis. Results: The study groups did not differ with respect to age, sex, tumor stage and grade, histological type, operation time and technique. IFN-α related toxicity was WHO grade 0 (11%), 1 (59%), 2 (26%), and 3 (4%). During IFN-α administration leukocytes, CD19, HLA-DR and VEGF dropped significantly, while no difference was observed in T-cell and NK-cell markers, and IL-10. All patients showed postoperatively elevated leukocyte counts. T-cell and activation markers decreased, but CD3, CD4 and CD28 alterations were significantly less accentuated in patients who had been treated with IFN-α. Median follow-up was 14 months. The 1- and 2-year rates (±SE) of tumor-specific survival were 96% (±4%) and 83% (±12%) in the IFN-α group and 85% (±7%) and 85% (±7%) in the control group, respectively (p = 0.52). Also, no difference was seen in progression-free survival (p = 0.32). Conclusions: In this study with limited follow-up, perioperative IFN-α medication was not associated with a survival benefit, but was well tolerated. Interestingly, the decline in VEGF during administration suggests a role of IFN-α in the inhibition of angiogenesis.

No significant financial relationships to disclose.
Pre-treatment PSA doubling time (PSADT) predicts biochemical response to chemotherapy in patients with androgen sensitive PSA progression after local therapy
Authors: Mehta A. , Stein M. , Goodin S. , Yao S. , Shih J. , Todd M. , Dipaola R. S.
Published: March 2020

14528

Background: As phase III studies are developed in patients with androgen sensitive (AS) PSA progression after local therapy, efforts to stratify patients based on likelihood of benefit is critical. In an effort to define a pretreatment PSADT cutoff that predicts chemotherapy response in AS patients for use in hypothesis testing in phase III studies, we assessed patients with pretreatment PSA data in two of our prior published phase II studies of docetaxel (D) or mitoxantrone (M) chemotherapy in patients with AS PSA progression without metastasis. Methods: A retrospective analysis of PSADT was performed on 36 pts with AS PSA progression following local therapy without metastasis with available pretreatment PSA values (23 pts with D and 13 pts with M). PSADT was calculated as [LN(2)]/b, where b is the slope of the regression of LN(PSA) vs time. A t-test was used to compare the PSADT of responders vs non-responders; ANOVA was used for the combined data. A logistic regression analysis with ROC curves was used to evaluate the value of PSADT in discriminating response. Results: Mean PSADT of patients with ≥50% decrease in PSA with therapy was 204 vs. 99 days (P = 0.02). For D only, mean PSADT of pts with any PSA decrease (mean 52%) vs. increase was 211 vs. 115 days (P = 0.04). The mean PSADT of pts with ≥50% PSA decrease only on D was 203 vs. 174 days (P = 0.31). Overall, logistic regression analysis showed that PSADT is a good test to discriminate which pts will have some decrease in PSA while on treatment (P = 0.03). ROC curves (AUC = 0.807) for pts with a decline in PSA on treatment showed that the best balance of sensitivity and specificity was for a PSA DT cutoff of 70 days (sens = 70.0%, spec = 71.4%). Sensitivity was highest at a DT of 50 days (85%), and specificity at 180 days (93%). Conclusions: This study suggests that pretreatment PSADT may be a useful predictor of response to therapy in patients with AS PSA progression after local therapy, but will require larger confirmatory studies. A PSADT cutoff of 70 days can be considered to stratify patients in future trials in this patient population.

No significant financial relationships to disclose.
A phase II trial of docetaxel plus carboplatin in hormone refractory prostate cancer (HRPC) patients who have progressed after prior docetaxel chemotherapy: Preliminary results
Authors: Oh W. K. , Manola J. , Ross R. W. , Berkowitz A. , Ryan C. W. , Eilers K. M. , Beer T. M.
Published: March 2020

14533

Background: Treatment options for HRPC patients who progress after docetaxel chemotherapy are limited. Carboplatin may enhance the efficacy of docetaxel chemotherapy. Methods: We prospectively treated HRPC patients with documented PSA or radiographic progression during a minimum of 2 cycles of docetaxel-based chemotherapy or within 45 days of completing therapy. No prior platinum was allowed, though patients may have received other prior chemotherapy. Patients received docetaxel 60 mg/m2 and carboplatin AUC (4) every 21 days until progression or unacceptable toxicity. Measurable response was assessed by RECIST criteria. PSA declines were assessed per PSA Working Group; 2 patients were not evaluable as they received only 1 cycle of therapy but are included in the denominator. Results: Interim data is available on the 1st stage of patients (n = 16) enrolled in this ongoing phase II trial. Median age was 69 years (range 46–81), 94% white. Baseline performance status was 0 or 1 in 88%. Prior therapies included antiandrogens (80%) and ketoconazole (47%); docetaxel was used alone (33%), with estramustine (33%) or another agent (33%). Median PSA at baseline was 44 ng/ml (range 4.9–4801). Patients received a median of 3 cycles of docetaxel/carboplatin (range 1–12+). PSA declines of ≥50% were noted in 3 of 16 patients (19%, 90% C.I. 5–42%). In addition, 5 patients had SD, suggesting clinical benefit in 50% (90% C.I. 28–72%). Of 10 patients with measurable disease at baseline, 2 (20%; 90% C.I. 4–51%) had confirmed PR. Therapy was well-tolerated, with no treatment-related deaths and five grade 3 toxicities, including anemia (1), leukopenia (3) and hyperglycemia (1). Median time to progression was 2.7 months (range 0–13.4); median survival was 11.7 months (95% C.I. 6.7–14.0). Conclusions: In preliminary analyses, docetaxel plus carboplatin demonstrated encouraging activity in patients who progressed after docetaxel-based therapy. PSA declines ≥50% were seen in 19%; measurable responses in 20%. Accrual is ongoing. Final analyses will include correlation of response to serum markers of neuroendocrine differentiation. (Supported by BMS).

No significant financial relationships to disclose.
Variation in local treatment of prostate cancer by hospital within New Jersey
Authors: Blom T. R. , Somer R. A. , Shih W. , Sarno M. , McNally D. , Todd M. , Yao S. , Lu-Yao G. , Dipaola R. , Stein M. N.
Published: March 2020

14551

Background: Although prostate cancer diagnosis and treatment vary through the US, few studies have assessed variations in local therapy between multiple hospitals located within a very narrow geographic region. Methods: To determine the variation of diagnosis and treatment of prostate cancer between hospitals in a local region, data was derived and analyzed from 1,301 patients from fifteen Cancer Institute of New Jersey Oncology Group network hospitals. Tumor registry data from patients with a histological confirmed diagnosis of prostate cancer accessioned over a one-year period between January 1, 2003 and December 31, 2003 was analyzed by a multivariate logistic regression model. Results: Median age of the cohort was 66 and mean number of cases diagnosed at these hospitals for this period was 87 (26–161). When the cohort was assessed overall, 192 cases assessed were African American, 1049 Caucasian, 51 Hispanic, and 32 Asian. Median Gleason score was 6. A total of 463 patients underwent Prostatectomy, and 538 had radiation therapy. Multivariate analysis demonstrated that age and hospital were associated with use of surgery versus no surgery. Race and Gleason score were not associated with use of surgery in this group of hospitals. Multivariate analysis also demonstrated that age and hospital were associated with utilizing radiation therapy versus not utilizing radiation therapy. Again, race and Gleason score were not associated with utilization of radiation therapy in these NJ hospitals. Conclusions: Overall, the most important factors predicting for surgery, and radiation therapy, were age and hospital, which were independent of race and Gleason score. These data support our ongoing assessment of hospital and geographic characteristics that may be responsible for these associations.

No significant financial relationships to disclose.
DHAIS (Diagnosis-Helping-Accuracy-Imaging-Study) study: Combined endorectal MR and MR spectroscopic imaging in the diagnosis of prostate cancer
Authors: Pomara G. , Simone M. , Fontana L. , Giusti S. , Bartolozzi C. , Francesca F.
Published: March 2020

14562

Background: The DHAIS study is a prospective, three-step investigation, consisting in an initial two-step phase (Diagnosis-Accuracy) followed by an extension phase (Helping). The purpose was to compare endorectal MRI and MR spectroscopic imaging (MRSI) results with biopsy results (Diagnosis) and definitive histology after radical retropubic prostatectomy (RRP) (Accuracy). The helping extension will investigate the ability of combined MRI and MRSI to detect prostate cancer foci in men with prior negative prostate biopsy. Methods: MRI and MRSI were performed in 37 consecutive pts for increased PSA and/or abnormal rectal examination. A dedicated radiologist identified areas of interest as normal, equivocal or suspicious on MRI and MRSI separately. All pts underwent prostate biopsy (TRUS 10-core biopsy) by the urologist who was blind to imaging results. Patients with positive biopsies underwent RRP. MRI and MRSI results were compared to biopsy and step-section histology. Those pts with negative biopsies will underdo a second set of 10-core prostate biopsy with up to 4 additional biopsies targeted at the equivocal or suspected sites (Helping-phase). Results: Prostate cancer was detected in 8 of 37 subjects (21.6%). Six pts underwent RRP. The sensitivity, specificity, positive and negative predictive values (PPV, NPV) and the accuracy of MRI, MRSI and combined MRI/MRSI are shown in the Table. Conclusions: MRI and MRSI have the potential to identify cancer foci and potentially direct TRUS in patients undergoing TRUS biopsy. The third phase of this study could demonstrate the utility during repeated biopsies. Further larger studies are required to quantify the amount of benefit. [Table: see text]

No significant financial relationships to disclose.
Anaemia in patients with transitional cell carcinoma (TCC) of the bladder treated with radiotherapy
Authors: Joynson C. , Symonds P. , Sundar S.
Published: March 2020

14569

Background: Treatment of muscle invasive TCC of the bladder with radiotherapy allows organ preservation and is frequently used in the UK especially in patients not medically fit for cystectomy. Anaemia is known to be an indicator of poor response to radiotherapy in head and neck and cervical carcinomas. This study describes the prevalence and type of anaemia in patients with TCC of the bladder and looks at the impact anaemia has on treatment outcome. Methods: Retrospective review of notes was performed on patients treated radically between 1992 and1997. Potential patient, tumour and treatment prognostic indicators were reported. Patients were labelled as being anaemic if their pre treatment haemoglobin level was below the normal range (below 13.5g/dl for men and below 11.5g/dl for women). Time to local recurrence, metastases and overall survival was recorded. Recurrence free survival and overall survival actuarial estimations were done using the Kaplan Meier method and compared by log rank testing. Multivariate analysis was carried out using Cox Regression method, correcting for potential confounding factors. Results: Data on 100 patients were available for analysis. 52 patients were anaemic with 75% of these having a normochromic, normocytic anaemia. Univariate analysis showed no significant difference in time to local recurrence, a trend to shorter time to metastases, and a significant reduction in overall survival in anaemic patients (p = 0.04). Two year survival was 43% and 22% for non anaemic and anaemic patients respectively. Multivariate analysis using covariates tumour stage, grade, and serum creatinine found anaemia to be poor prognostic indicator for overall survival (p = 0.005) and time to metastases (p = 0.003). Conclusions: Anaemia is highly prevalent in patients with bladder cancer. This retrospective study shows anaemic patients to have a worse outcome with radiotherapy treatment than patients with a normal haemoglobin level. This is not accounted for by a difference in local control which may be expected from hypoxic radiobiological principles. Anaemia may be indicative of more aggressive malignancy or sub clinical metastases.

No significant financial relationships to disclose.
Adjuvant thalidomide improves disease specific survival for patients with renal cell carcinoma at high risk for relapse following surgery
Authors: Sanchez-Ortiz R. , Tamboli P. , Lozano M. L. , Matin S. , Wood C. G.
Published: March 2020

14586

Background: Observation is the standard of care for locally advanced renal cell carcinoma (RCC) after surgery. No adjuvant therapy for RCC exists. Thalidomide has shown activity in metastatic RCC. We studied thalidomide in the adjuvant setting for patients with locally advanced RCC. Methods: This phase III trial has enrolled 46 patients to date. All patients underwent resection of all disease. Eligible patients included T2N0M0 grade 3–4, T3a-cN0M0, T4N0M0, TanyN1–2M0, and TanyN0M0 bilateral disease completely resected. All RCC histologies were included. Patients were randomized to observation or thalidomide, 300 mg daily for 2 years. Dose reductions were allowed for toxicity. The primary endpoint was recurrence free survival. Secondary endpoints were disease specific survival and toxicity. Results: Twenty-three patients randomized to thalidomide and 23 were observed. In the thalidomide arm, one patient refused therapy and two stopped within one month due to toxicity. Only 1 patient tolerated therapy for 2 years without dose reduction. With a median follow-up of 18 months, there were 6 recurrences and 5 disease related deaths in the observation arm and 7 recurrences and 2 disease related deaths in the thalidomide arm. Using an intent to treat principle in our multivariate analysis, adjusting for grade, stage, and nodal status, we noted no significant difference in recurrence free survival between observation (mean 31 months; median not reached (NR)) and the thalidomide arm (mean 24.7 months; median NR) (Hazard ratio = 1.04, 95% CI 0.34 to 3.14, p = 0.945). Interestingly, disease specific survival was significantly better in the thalidomide arm (mean 40.1 months; median NR), as compared to the observation arm (mean 37.1 months; median NR) (Hazard ratio = 0.086, 95% CI 0.008 to 0.981, p = 0.048). Conclusions: In this limited experience with surgically resected RCC at high risk for relapse, thalidomide did not impact time to recurrence but significantly improved disease specific survival in the adjuvant setting. Despite this clinical benefit, significant toxicity limited tolerability of the drug. These data suggest that derivatives of thalidomide, with different toxicity profiles, might warrant testing in the adjuvant setting for RCC.

No significant financial relationships to disclose.
Hemochromatosis gene (HFE) mutations and chemotherapy-related cardiovascular risk profile in testicular cancer survivors (TCS)
Authors: De Haas E. C. , Meijer C. , Zwart N. , Van der Steege G. , Boezen H. M. , Sleijfer S. , Van Leeuwen F. E. , Smit A. J. , Sleijfer D. T. , Gietema J. A.
Published: March 2020

14589

Background: TCS show an increased incidence of treatment-related cardiovascular disease. Standard chemotherapy (CT) may cause tissue damage by inducing free oxygen radicals through release of redox-active iron from body iron stores. HFE mutations associated with altered body iron load may therefore contribute to an increase in CT-induced free oxygen radicals and tissue damage. We investigated whether two HFE mutations (C282Y and H63D) are associated with cardiovascular risk profile in TCS. Methods: From a group of 90 TCS with a known cardiovascular status (JCO 2005; 23: 3718–25), genomic DNA for genotyping was available for 63 TCS (median (range) age at follow-up 35 y (24–54) and median follow-up duration 7 y (3–13)). Two HFE genotype groups were composed: HFE mutation (mut) (n = 19; any mutation C282Y and/or H63D) and HFE wild type (wt) (n = 44). Both groups were compared for cardiovascular risk profile, using Mann-Whitney U Test or Fisher’s Exact Test. Results: Groups had received comparable CT regimens. Body iron stores as reflected by plasma ferritin and transferrin saturation were not different for the HFE mut vs HFE wt group, respectively 104 μg/l (21–413) vs. 90 μg/l (22–569); p = 0.53 and 31% (20–49) vs. 30% (11–59); p = 0.15. Signs of vascular damage estimated by urinary albumin excretion and Von Willebrand factor levels were not significantly different: respectively 8.3 mg/24 h (4–165) vs. 7.7 mg/24 h (3–647); p = 0.90 and 90% (52–296) vs. 102% (28–235); p = 0.25. The prevalence of cardiovascular risk factors obesity (BMI > 27.8 kg/m2), metabolic syndrome (NCEP ATP III-criteria) and hypertension (mean 24-h blood pressure >135/85 mmHg) are shown in the table. Conclusion: TCS with a mutation in the HFE gene do not show more signs of cardiovascular damage after CT compared to TCS with wt HFE. However, the data suggest that TCS with a HFE mutation may have more frequently cardiovascular risk factors. Further study in a larger group of TCS is needed to explore this observation. [Table: see text]

No significant financial relationships to disclose.
The influence of body mass index (BMI) on outcome in patients with advanced germ cell tumors (GCT)
Authors: Vaughn D. J. , Powell M. , Catalano P. J. , Loehrer P. , Nichols C. , Sweeney C. , Wilding G. , Dipaola R. S.
Published: March 2020

14594

Background: Obesity is associated with increased mortality in a variety of cancers. Using data from ECOG 3887, a phase III study comparing cisplatin, etoposide, and bleomycin or ifosfamide in advanced GCT, we explored the prognostic significance of BMI. Methods: From 10/87 to 4/92, 286 assessable patients (pts) were enrolled in the original study. 1 pt was ineligible, 3 pts were missing weight/height; 282 pts are included in this analysis. BMI was computed by dividing weight by square of height (kg/m2), and was categorized as underweight (< 18.5), normal (18.5–24.9), overweight (25–29.9) and obese (>30). A favorable response was defined as CR, NED post-surgery, or PR for ≥ 2 years. Fisher’s Exact Test was used to examine associations between BMI and favorable response. The Kaplan-Meier method was used to estimate overall survival by BMI. Proportional hazards models were used to examine the effect of BMI on survival after adjusting for International Stage (IS) and performance status (PS). As BMI was distributed similarly between the two treatment arms and no treatment differences were observed in the primary analysis, data from both arms were pooled to maximize power with regard to BMI. Results: Fifteen pts (5%) were underweight, 171 (61%) normal, 75 (27%) overweight, and 21 (7%) obese at study entry. The favorable response proportion was 53%, 67%, 51%, and 65%, respectively, for underweight, normal, overweight and obese pts. There was no association between BMI category and favorable response probability (chi square p = 0.08). 5-year survival for underweight, normal, overweight, and obese pts was 60%, 73%, 62%, and 67%, respectively. There was no difference in overall survival associated with BMI category (logrank p = 0.28), although statistical power is limited since there were few underweight/obese pts. After adjusting for IS and PS, there remained no association between overall survival and BMI category (hazard ratio per unit BMI 1.01, 95% CI 0.97–1.06). Conclusions: We observed no association between BMI and outcome, but statistical power is limited due to the small number of underweight and obese pts.

No significant financial relationships to disclose.
Summary of results in patients with metastatic renal cell cancer (RCC) from phase I studies of RAD001 (everolimus)
Authors: Porter L. L. , Burris H. A. , Jones S. F. , Calvert S. , Papadimitrakopoulou V. A. , Hazell K. , Shand N. , Lebwohl D. , Baselga J. , Judson I.
Published: March 2020

14599

Background: Activation of mammalian target of rapamycin (mTOR) is implicated in the pathogenesis of RCC. Hereditary RCC in tuberous sclerosis pts is associated with loss of function of TS complex genes and resultant activation of mTOR. In non-hereditary RCC, mutation of VHL reduces opposition to mTOR-dependant upregulation of HIF. HIF-1α stimulates growth-factor-mediated activities (VEGF, PDGF, TGFα) supporting tumor-growth and proliferation. RAD001, an orally bioavailable inhibitor of mTOR, could have a role in the treatment of pts with RCC. Methods: All pts with metastatic RCC treated in two phase 1 studies of RAD001 in advanced solid cancer were reviewed. Changes in tumor were assessed using RECIST. Results: There were 12 pts (8.2% of total study population) with histology of clear cell (10 pts), papillary (1 pt), sarcomatoid (1 pt). Dosing was either weekly (20 mg:1 pt, 50 mg:2 pts, 70 mg:4 pts) or daily (10 mg:5 pts). 8 pts were male, 4 female. Median age 60 yrs (range: 44–76). Baseline performance status (WHO) was 0 (2 pts) or 1 (10 pts). Metastatic sites included lung (9 pts), bone (7 pts), liver (2 pts). 10 pts had failed prior drug therapy including IL-2 (2 pts), bevacizumab & erlotinib (7 pts), others (5 pts). Most frequent suspected drug reactions (3 pts or more) were: fatigue, diarrhea, rash, anorexia, mucositis, nausea, abdominal distension, vomiting, headache. Gr.3 events in single pts comprised: hypertriglyceridemia, hyperglycemia, epistaxis with prolonged bleeding time. 6 pts were progression-free at 6 months, 4 pts beyond 12 months (max. 20 months ongoing). Partial response apparent in 1 pt (papillary) on D334 is ongoing at D502. Conclusions: Advanced RCC pts can benefit from RAD001 as indicated by prolonged stable disease in half the cohort. Tumor shrinkaqe may appear only after several months of treatment. Toxicity is mostly mild and similar to patients with other tumor types. Further studies of RAD001 in pts with RCC are planned.

[Table: see text]
A phase I study of LR-103 (1,24α(OH)2D2) in patients with refractory malignancies
Authors: Bailey H. , Kolesar J. , Fass T. , Weiss J. , Heideman J. , Alberti D. , Morgan-Meadow S.
Published: March 2020

14608

Background: Preclinical studies of calcitriol and vitamin D analogs demonstrate potent growth inhibition of tumor cell lines. The clinical development of calcitriol and other analogs have been hindered by hypercalcemia. 1α (OH)D2 is a Vitamin D analog which has produced objective responses in advanced androgen-independent prostate cancer patients and can be administered daily at 10mcg. LR103 is an active metabolite of 1α (OH)D2 with equivalent anti-tumor activity and significantly less calcemic effects in preclinical studies. This phase I study explores the maximal tolerated dose and toxicity of LR-103. Methods: LR-103 was administered daily beginning at a dose of 5 μg/day with a cycle length of 14 to 28 days. Dose escalation proceeded in two stages. In step A, intra-patient dose escalation (starting dose of 5mcg daily) was allowed based on degree of toxicity regardless of attribution. Step A escalation continued until 2 patients had ≥ grade 2 toxicity at a dose level. Step B is a standard, inter-patient only, dose-escalation trial (starting dose based on Step A) with cohorts of three. Dose limiting toxicity is defined as ≥ grade 3 toxicity. Results: Nineteen patients have enrolled between May and December 2005, eight to step A and eleven to step B. During step A escalation, two patients at 15 μg/day experienced severe toxicity (grade 4 hyperuricemia and grade 3 alkaline phosphatase) and two patients at 15 μg/day experienced grade 1 hypercalcemia. Hypercalciuria has been common. No hypercalcemia ≥ grade 2 has been observed. Step B enrollment continues at 30 μg/day without hypercalcemia. Conclusions: Daily administration of LR-103 has not resulted in significant hypercalcemia to date. Dose escalation continues.

No significant financial relationships to disclose.
Interferon-alpha (INF) and gefitinib or imatinib in patients (pts) with metastatic renal cell carcinoma (RCC)
Authors: Jac J. , Zhai Q. , Kareidy M. , Hernandez J. , Marsh L. , Amato R. J.
Published: March 2020

14616

Background: Overexpression of EGFR is associated with aggressive clinical behavior in several solid tumors and is frequent in RCC. We recently found that the majority of RCCs express c-kit and PDGFR-beta. EGFR tyrosine kinase (TK) is inhibited by GEF, while IM is an inhibitor of Bcr-Abl, c-kit and PDGFR TKs. IFN has activity in MRCC and is used in front-line therapy. This trial evaluates time to progression (TTP) determined from time of study entry and response rate of INF in combination with GEF or IM, as well as tumor expression of c-kit and EGFR-beta. Methods: Pts with MRCC were assigned to a treatment arm: IFN/GEF or IFN/IM. Eligibility included: MRCC, any previous therapy, PS ≤2, adequate organ/marrow function and no active CNS involvement. Pts received IFN 3MU subcutaneously TIW on week 1, then 6MU TIW thereafter. GEF dose is 500 mg and IM 600 mg daily. Tumor response is assessed using RECIST every 12 weeks. Results: 16 MRCC pts (12 M/4 F) with a median age of 58 (24–77) have been enrolled. Histology: 6 papillary, 7 clear cell, 1 chromophobe, 1 collecting duct and 1 unclassified. 14 pts received IFN/GEF and 4 pts IFN/IM. Two pts crossed over from IFN/IM to IFN/GEF. Of 14 pts on IFN/GEF, 3 demonstrated a partial response (PR) and 7 had stable disease at 12 weeks. Of 6 papillary, 3 had PR. 8 pts progressed on IFN/GEF at a median of 20 weeks (1–36). 4 pts are still on treatment. On IFN/IM, 3 pts had stable disease at 12 weeks, 2 at 24. 2 pts progressed at 4 and 14 weeks, two crossed over to GEF at 24 weeks. Adverse events of IFN/GEF included skin rash and diarrhea and of IFN/IM skin rash, thrombocytopenia and leukopenia. Both arms had flu-like symptoms and fatigue. Conclusions: IFN/GEF and IFN/IM combinations are well tolerated. Preliminary results show the potential of delaying TTP in pts with MRCC. The observed high tumor response rate of the papillary type to IFN/GEF requires validation in a larger number of pts. Enrollment is ongoing. Updated response data and tissue correlates will be presented.

[Table: see text]
Correlation of statin use and duration with increased survival in hormone refractory prostate cancer
Authors: Rich N. T. , Smith B. J. , Vaena D. A.
Published: March 2020

14617

Background: Prior studies associated statin use with prevention and reduced progression of prostate cancer. (Platz et al, 96th AACR abst. 4374). However, the effects of statins in hormone refractory prostate cancer (HRPC) are unknown. We evaluated the impact of statins on survival of HRPC patients by comparing actual survival data with predicted survival using the Halabi nomogram (JCO 21:(7);1232). Methods: Using the Iowa City VA (ICVA) prescription database since 2001 along with chart review, we identified 28 consecutive patients who were prescribed statins when they had HRPC. Survival information, duration of statin use while HRPC, and Halabi nomogram variables were collected (Hb, PS, Alk Phos, Gleason, PSA). An LDH value of 90 U/L (low-normal at ICVA) was used for all patients, since LDH values were not available. Log-rank and and Cox regression analyses were performed. The outcome of interest was overall survival. Patients alive at last follow-up were censored. Statin use was treated as a time-dependent covariate in the regression analysis, and subject-specific predicted survival from the Halabi nomogram as another covariate. Results: 17 patients were alive and 11 had died. Median duration of follow-up for patients alive was 23 months. The observed vs. nomogram-predicted estimated median survivals were 36 vs. 17 months, respectively. Study patients significantly outlived their nomogram-predicted survival (p = 0.0004). Four patients had negative bone scans. 12 patients outlived their nomogram, 8 died before, and 8 were indeterminate (censored prior to their Halabi-predicted survival). Risk of death decreased with greater length of statin use (p = 0.02). When covariates for Halabi nomogram and statin use were both included in a multivariate regression model, neither was statistically significant, although similar point estimates for the relative risks were obtained. Conclusions: Statin use, and longer duration of use, significantly improved survival of HRPC patients in univariate analysis. The sample size limits the multivariate analysis. Evaluation of a time-dependent statin effect in HRPC could be considered in larger studies.

No significant financial relationships to disclose.
The incidence of prostate cancer in patients under the age of 60 from an urban setting
Authors: Shum M. , Bodofsky E. , Skaff Z. , El-Khoury M. , Kankipati S. , Dalsania C. , Khemka V. , Parra R. , Dibiase S. , Somer R.
Published: March 2020

14622

Background: Although the risk for developing prostate cancer increases with age, few studies have reported the incidence of prostate cancer in men younger than 60 from an urban setting. Methods: All patients diagnosed and treated for prostate cancer at The Cancer Institute of New Jersey at Cooper University Hospital in Camden County, New Jersey from January 1, 2004 to December 31, 2004 were retrospectively identified from our tumor registry. Age comparison at diagnosis was made utilizing the Cooper registry and the National Cancer Database (NCDB), 2001. Results: A total of 141 men (88 Caucasians, 37 African Americans, 14 Hispanic, and 6 unknown) with a median age of 64 years (range, 44–88 years) were diagnosed with prostate cancer in 2004. Staging revealed Stage II (118), Stage III (3), Stage IV (4), Stage unknown (16) cases. Median Gleason score was 6. 74 patients underwent radical prostatectomy, 50 had radiation, 30 received hormone therapy and 2 received chemotherapy. At diagnosis, 19.95% of the men were under 50 and 41.84% were under 60 years of age. Our dataset from these two age groups compared to NJ and US figures are noted below. Conclusions: When comparing the respective data sets from CINJ at Cooper to NJ and US utilizing the NCDB, there are striking differences with a higher incidence of prostate cancer in younger men. These incidences parallel those seen in other urban university teaching hospitals from the Healthcare Utilization Project (2005), where more patients under the age of 60 are being diagnosed with prostate cancer when compared to community centers. Subset analysis shows that our institution had a disproportionately larger number of African American men with prostate cancer which may relate to our culturally directed screening program, accounting for the higher incidence. These data support that hospital characteristics may impact age at diagnosis of prostate cancer, and further investigation is warranted. [Table: see text]

No significant financial relationships to disclose.
The effect of androgen deprivation therapy (ADT) on cognition in men with prostate cancer
Authors: Allibhai Z. , Alibhai S. M.
Published: March 2020

14626

Background: ADT plays a central role in the management of prostate cancer. However, there is emerging evidence that ADT use may adversely affect cognition. Given the long natural history of prostate cancer and the elderly population it predominantly affects, this may be an important survivorship issue in this population. Methods: We performed a MEDLINE search of English-language literature from 1966 to December 2005 and identified eight prospective studies that evaluated the effect of ADT on cognition and one study that investigated the effect of therapy on the cognition of patients receiving ADT. Due to differences in study design and outcomes, studies could not be combined meta-analytically. Results: Studies were small, ranging from 19–82 patients. ADT was used in the neoadjuvant setting in 2 studies, a neoadjuvant or adjuvant setting in 1 study, and in a palliative setting for high-risk disease in 5 studies. Controls were featured in 4 studies. Follow-up ranged from 6 to 13 months. A variety of cognitive domains were assessed (using traditional and computer-based neuropsychological tasks). Whereas 4 studies found worsening in one or more domains in patients over time, 4 studies showed either no worsening or improvement in one or more cognitive domains after ADT was instituted. No cognitive domain was consistently affected by ADT. Three of the studies included follow-up 3 months after ADT was stopped and all 3 showed at least some improvement in cognitive function. Short-term supplementation with estradiol did not improve cognitive function in 1 study. There were fundamental differences across studies in terms of patient populations, cognitive domains tested and specific tests used, and type of ADT. Other important limitations included small sample sizes, limited follow-up, and practice effects. Conclusions: The impact of ADT on cognitive function and its potential reversibility are unclear, and further studies are needed. In the meantime, clinicians and patients should continue to carefully weigh the potential benefits and risks of ADT when making treatment decisions.

No significant financial relationships to disclose.
Weekly (QW) epoetin alfa (EPO) in prostate cancer (PC) patients (pts) with anemia not receiving chemotherapy (CT) or radiation therapy (RT)
Authors: Shasha D.
Published: March 2020

14634

Background: While EPO is widely used in the management of CT-related anemia, anemia in cancer pts may stem from causes other than CT. Tumor invasion of the bone marrow and cytokine-mediated inhibition of erythropoiesis are among the many disease-related causes of anemia in cancer. Data evaluating the use of EPO in pts not receiving CT or RT, particularly in specific tumor types, would be important information to healthcare providers. Methods: An open-label, prospective, non-randomized, multicenter pilot study was conducted to evaluate the efficacy and safety of EPO 40,000 U QW in anemic (hemoglobin [Hb] ≤ 11 g/dL) cancer pts not receiving CT or RT1. (Blood 2004;104:abstract 4223.) Treatment duration was up to 12 wks with a 4-wk post-treatment observation period. Primary efficacy endpoint was hematopoietic response during the treatment period (% of pts achieving a ≥ 1 or ≥ 2 g/dL Hb increase from baseline [BL]). Secondary endpoints included change from BL in quality of life as measured by the Linear Analog Scale Assessment (LASA). This is a retrospective subset analysis of PC pts (n = 24) enrolled in the prospective study. Results: For the safety population (all pts who received ≥ 1 EPO dose, n = 23), mean age was 71.4 ± 6.8 yrs; 21 (91.3%) had ECOG status of 0 or 1; and mean BL Hb was 10.4 ± 0.8 g/dL. Of 21 pts evaluated for efficacy, 17 (81.0%) achieved Hb increase from BL ≥ 2 g/dL, while 19 (90.5%) achieved ≥ 1 g/dL by wk 17/early withdrawal. EPO dose was increased in 5 (23.8%) pts (to 60,000 U for Hb increase < 1 g/dL after 4 wks) and held in 16 (76.2%) pts (due to Hb > 13 g/dL, with dosing resumed when Hb was ≤12 g/dL, at 30,000 U from 40,000 U or at 40,000 U from 60,000 U). Both Wk 9 and 17 LASA scores increased significantly from BL in all categories (Energy Level, Daily Activities, and Quality of Life; P < 0.001). 15 of 23 pts (65.2%) had at least one adverse event (AE); 4 (17.4%) pts had at least one serious AE. No clinically relevant thrombotic vascular events were noted. No pt received transfusion. 5 pts discontinued: 2 for AEs, 1 at pt request, and 2 at study sponsor request. Conclusions: This retrospective analysis suggests that EPO 40,000 U QW is safe and effective for treating anemia in PC pts not receiving CT or RT.

[Table: see text]