bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biochemical and immunologic correlates of clinical response in a combination trial of the GM-CSF-gene transduced allogeneic prostate cancer immunotherapy and ipilimumab in patients with metastatic hormone-refractory prostate cancer (mHRPC)
Authors: Gerritsen W. R. , van den Eertwegh A. J. , de Gruijl T. D. , Giaccone G. , Scheper R. J. , Sacks N. , Harding T. , Lowy I. , Stankevich E. , Hege K. 
Published: March 2020

5120 Background: A Phase 1 trial is underway to study the GM-CSF-secreting immunotherapy for prostate cancer (GVAX immunotherapy [GVAX IT]) and ipilimumab (ipi) in mHRPC patients (pts). Methods: Twelve pts were treated for 24 weeks (wks) with bi-weekly intradermal injections of GVAX IT and monthly Ipi. Pts were enrolled in cohorts of 3; each cohort received an escalating dose of ipi: 0.3, 1, 3 or 5 mg/kg. Results: Median follow-up is 15.0 months. All pts had GVAX IT injection site reactions. Five of six pts at the higher ipi doses (3 and 5 mg/kg) developed Grade 2 or 3 immune-related endocrinopathy, consistent with hypophysitis manifested by adrenal insufficiency and/or hypothyroidism, all successfully treated with standard hormone replacement. Two pts were tapered off Synthroid within 6 months (m). There was no induction of the alpha-21-hydroxylase auto-antibody that is seen in 90% of cases of auto-immune adrenal insufficiency. One pt in the 5 mg group developed a Grade 3 dose-limiting alveolitis. PSA responses (declines > 50%) were seen in 5/6 treated at the two higher ipi doses with median response duration of 4.9 m (2 on-going at 7.2 m and 12.8 m). These PSA responses were associated with immune-related endocrinopathy but were not consistently correlated with declines in adrenal androgens. One pt had resolution of measurable disease on abdominal CT scan. Immunomonitoring studies showed T cell and dendritic cell activation, more pronounced at higher doses. Biopsies of injection sites showed T cell infiltration. Multiple tumor-reactive antibodies (abs) induced by tx were identified by serologic analysis (SEREX), including abs to filamin B. Screening against 20 defined prostate cancer antigens demonstrated induction of abs to PSMA and NY-ESO-1. Conclusions: The GVAX IT and ipilimumab combination is active in mHRPC. There was an association between PSA response and immune-related adverse events. The PSA responses cannot be accounted for by adrenal insufficiency. The relationship between clinical activity and serologic response to identified antigens is under investigation. Tx of 16 additional pts is planned. No significant financial relationships to disclose.
Phase III study of intermitent monotherapy versus continuous combined androgen deprivation
Authors: Calais da silva F. E. , Calais da Silva F. M. , Gonçalves F. , Santos A. , Kliment J. , Antoniou N. , Pastidis S. ,   South European Uroncological Group
Published: March 2020

5125 Background: The intermittent monotherapy vs continuous combined androgen deprivation using an LHRH analogue and ciproterone acetate and associated components of quality of life. Methods: 854 patients (aged 44–81, mean 72) have been randomised (419 to Continuous and 435 to Intermittent). 350 patients have been randomised in the last years and the study is close to the target sample size 900 patients. The median PSA at randomisation is 1.0 ng/ml ranging from 0.1 to 4. 48 % of patients have a PSA less than 1 ng/ml at randomisation. Results: 1,000 men with a median PSA of 15.9ng/ml were registered between October 1999 and October 2006. 24% of registered patients have a PSA less than 10ng/ml; 39.3% of registered patients have a PSA greater than 20 ng/ml. 90.1% have a T3 tumour and only 13.5% have metastatic prostate cancer. After randomisation, sexual activity increases in the intermittent group to 32% (6 months), 32% (12 months), 24% (24 months) while in the Continuous arm the corresponding percentages are 19%, 20%, 6%, respectively. Among the 435 Intermittent patients only 18% returned to therapy within one year of randomisation because of symptoms or an increase in PSA and 40% have yet to return to therapy within 4 years of randomisation. An estimated 82% (95% Confidence Interval 79%, 87%) of patients have remained free of therapy for at least one year and 60% (95% CI 53%, 68%) for at least 2 years. Patients whose PSA reduces to less than 1 ng/ml at randomisation are off therapy longer than those whose PSA is between 1 and 4 ng/ml (p<0.05). 80% of patients with PSA < 1 ng are off therapy for at least 1.5 years whereas 80% with PSA between 1 and 4 ng/ml are off therapy for at least 9 months. 60% of patients with PSA < 1 ng/ml are off therapy for 2.5 years while 60 % of patients with PSA 1–4 ng/ml are off therapy for 1.5 years. Among the 142 Intermittent patients who returned to therapy because of an increase in PSA or symptoms the median time on therapy was 16.7 weeks (95% CI 15.0, 22.1). The time on therapy did not depend upon PSA at randomisation, p=0.17. The median follow up period is 2.8 years. Conclusions: The early results from this trial are promising and are in line with previous studies of intermittent therapy. It is too early for any progression data. No significant financial relationships to disclose.
A comparison of overall and cause-specific survival among patients with low- and intermediate-risk prostate cancer treated with brachytherapy, external beam radiotherapy, or radical prostatectomy
Authors: Ciezki J. P. , Reddy C. A. , Kupelian P. A. , Klein E. A. , Robinson C. , Chehade N. , Angermeier K. , Altman A. , Ulchaker J. 
Published: March 2020

5126 Background: The factors thought to influence overall survival (OS) and cause-specific survival (CSS) in patients treated for low and intermediate-risk prostate cancer (CaP) with brachytherapy (PI), external beam radiotherapy (RT), or radical prostatectomy (RP) were evaluated. Methods: From 1996 to 2003, 2285 patients with low or intermediate-risk CaP were treated at the Cleveland Clinic with either PI (n=662), RT (n=570), or RP (n=1053). Factors thought to influence OS and CSS were recorded. These factors included: Charlson score, age, socioeconomic status, race, body mass index (BMI), presence of coronary artery disease (CAD), presence of hypertension (HTN), presence of dyslipidemia (DL), initial prostate-specific antigen (iPSA), biopsy Gleason score (bGS), clinical stage, use of androgen deprivation (AD), AD duration, smoking history including pack-years, alcohol use, and cancer treatment modality (TX). Univariate and multivariate analyses were done using Cox proportional hazards regression. Results: The median follow-up is 59 months (range: 24–119 months). The 5- year OS rate is 96.0%, and the 8-year rate is 89.9%. Multivariate analysis revealed that Charlson score, age, smoking history, and TX were significantly associated with OS. Treatment with RT was independently associated with worse OS relative to PI and RP. CSS was grouped into 4 major categories: CAD, CaP, other cancer, and other. The only significant difference between these CSS categories and the treatment modalities was CaP. The percent of deaths due to CaP in the TX groups were: PI - 3.2%, RP - 9.7%, and RT - 24.5%. Conclusions: Charlson score, age, smoking history, and TX independently affect OS in patients treated for low and intermediate-risk CaP. The cause of the lower OS rate with RT may be related to an increased risk of death due to CaP. [Table: see text] No significant financial relationships to disclose.
Body mass index and mortality in men treated for locally advanced prostate cancer: An analysis of RTOG 85–31
Authors: Efstathiou J. A. , Bae K. , Shipley W. U. , Hanks G. E. , Pilepich M. V. , Sandler H. M. , Smith M. R. 
Published: March 2020

5128 Background: Greater body mass index (BMI) is associated with shorter time to prostate-specific antigen (PSA) failure following radical prostatectomy. We investigated whether BMI is associated with prostate cancer-specific mortality (PCSM) in a large randomized trial of men treated with radiation therapy (RT) and androgen deprivation therapy (ADT) for locally advanced prostate cancer. Methods: Between 1987 and 1992, 945 eligible men with locally advanced prostate cancer were enrolled on a phase III trial (RTOG 85- 31) and randomized to RT and immediate goserelin (Arm I) or RT alone followed by goserelin at relapse (Arm II). Height and weight data were available at baseline for 788 (83%) subjects. Cox regression analyses were performed to evaluate the relationships between BMI and all-cause mortality, PCSM, and non-prostate cancer mortality. Covariates included age, race, treatment arm, history of prostatectomy, nodal involvement, Gleason score, clinical stage, and BMI. Results: The 5-year PCSM rate for men with BMI<25kg/m2 was 6.5%, compared to 13.1% and 12.2% in men with BMI=25-<30 and BMI=30, respectively (Gray’s p=0.005). In multivariable analyses, as shown in the Table , greater BMI was significantly associated with higher PCSM [for BMI=25-<30, hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.02–2.27, p=0.04; for BMI=30, HR 1.65, 95% CI 1.02–2.66, p=0.04]. BMI was not associated with non-prostate cancer or all-cause mortality. Conclusions: Greater baseline BMI is independently associated with higher PCSM in men with locally advanced prostate cancer. Further studies are warranted to evaluate the mechanism(s) for increased mortality and to assess whether weight loss after prostate cancer diagnosis alters disease course. [Table: see text] No significant financial relationships to disclose.
Determining issues of importance for patients with prostate cancer: Results of a web-based study in 2,128 patients with prostate cancer for the development of a quality of life (QL) instrument, the prostate cancer symptom scale (PCSS)
Authors: Gralla R. J. , Hollen P. J. , Davis B. J. , Petersen J. A. , Thompson R. , Saad F. 
Published: March 2020

5138 Background: Identifying key issues for patients with malignancy is central to assessing QL and patient reported outcomes. This aids in evaluating the effectiveness of treatment programs for those with the disease. The immediate aim of this study was to determine content validity using a large patient panel for the PCSS, a QL measure for patients with prostate cancer. The PCSS also uses an inexpensive hand-held pocket PC to enhance feasibility. The PCSS concept is based on the LCSS (a validated lung cancer instrument). Methods: We used the established patient base of the web-based NexCura patient information resource to survey registered patients with prostate cancer. Demographic stratifications included stage of disease, prior radical prostatectomy, and current treatment (none, hormonal, non-hormonal). 2,128 patients completed the anonymous web-conducted survey, performed over a 3-day period. Patients were asked to rank 18 issues on a 5-point scale assessing the importance of each item. Issues included general, prostate-specific, psychosocial and summative items. Results: The 10 highest (and 2 lowest) ranked items are seen in the table ; results are described by the percent of patients choosing the top category (very important) and the top 2 rating categories of importance. Ratings by disease subsets (such as NED or metastatic disease; hormonal or non-hormonal treatment) were quite similar to results found for the whole group, as listed in the table . Conclusions: These results represent the largest survey of patient concerns in prostate cancer and support using computer-assisted survey technology to assess such information in all malignancies to obtain patient input rapidly from large patient samples. Strong support for content validity for the PCSS was obtained. [Table: see text] No significant financial relationships to disclose.
Chemosensitivity and stratification by a five monoclonal antibody IHC test in the NSABP B20 trial
Authors: Ross D. T. , Kim C. , Tang G. , Mejia O. M. , Beck R. A. , Ring B. Z. , Seitz R. S. , Paik S. , Constantino J. P. , Wolmark N. 
Published: March 2020

529 Background: We previously reported the association between a five monoclonal antibody test staining p53, NDRG1, SLC7A5, CEACAM5 and HTF9C and recurrence-free interval (RFI) in 711 ER+ N- breast cancer patients from Tamoxifen (Tam) arm of the NSABP trials B14 and B20 (SABCS 2006). In this study, we examined interaction between the test and chemotherapy in the B20 trial. Subjects and Methods: Tissue array sections from B20 paraffin blocks were stained using standard IHC protocols (N=457). Pre-defined scoring rules and cut- points were applied. RFI was defined as time from entry to any local, regional or distant recurrence. Log-rank test was applied to assess the effect of chemotherapy for each risk stratum pre-defined by this IHC test. Interaction between risk strata and treatment was assessed by the likelihood ratio test in a Cox model with age and clinical tumor size adjusted. Results: The IHC test identified high and low risk groups that both showed significant improvement upon treatment with cytotoxic chemotherapy. The moderate risk group was poorly populated and showed no significant difference between chemo-treated and Tam-only patients. Conclusion: It appears that five monoclonal antibodies may be able to identify groups of ER+, node negative patients who have greater absolute benefit from adjuvant Chemo compared to un-stratified patient populations. However, the formal test for interaction between Chemo and the risk group was not significant (p- value=0.127). This may be due to small sample size and a lack of statistical power. The results suggest that this test deserves further evaluation as a method for identifying subsets of patients who may receive more benefit from Chemo. [Table: see text] No significant financial relationships to disclose.
Neoadjuvant trastuzumab in locally advanced breast cancer (NOAH): Antitumour and safety analysis
Authors: Gianni L. , Semiglazov V. , Manikhas G. M. , Eiermann W. , Lluch A. , Tjulandin S. , Feyereislova A. , Vanhauwere B. , Valagussa P. , Baselga J. 
Published: March 2020

532 Background: NOAH (NeOAdjuvant Herceptin) is a Phase III trial of neoadjuvant trastuzumab; H) in combination with chemotherapy in patients (pts) with HER2-positive locally advanced breast cancer (LABC). Methods: 228 pts with centrally confirmed HER2-positive (IHC 3+ or FISH+) LABC received 3 cycles of doxorubicin-paclitaxel (AT: A 60 mg/m2, T 150 mg/m2 q3w), 4 cycles of T (175 mg/m2 q3w) and 3 cycles of cyclophosphamide/methotrexate/5-fluorouracil (CMF: C 600 mg/m2, M 40 mg/m2, F 600 mg/m2 q4w) on days 1 and 8, with (n=115) or without (n=113) concomitant H (8 mg/kg loading dose then 6 mg/kg q3w for 1 year) before surgery. Pts with HER2- negative disease (IHC 0/1+; n=99) were treated in parallel with AT/T/CMF. The primary end point was event-free survival (EFS); secondary end points included overall response rate (ORR), pathological complete response (pCR) rate and safety. Results: Baseline characteristics were well balanced for randomised pts. Median tumour size was 5.5 cm (range 1.5–20.0). Inflammatory breast cancer (IBC) was present in 40% of HER2-positive vs 14% of HER2-negative tumours, while 35% vs 65%, respectively, were hormone receptor positive. Left ventricular ejection fraction (LVEF) at baseline was similar in all 3 groups. Adding H to AT/T/CMF improved ORR (81% vs 73%; p=0.18) and significantly increased pCR rate (43% vs 23%; p=0.002). This response pattern was also seen in IBC pts. ORR (66%) and pCR rate (17%) for pts with HER2-negative disease were similar to pt responses in the HER2-positive group who did not receive H. The most common serious adverse event was febrile neutropenia (8% with H vs 4% without). Only 11% of pts receiving H had absolute LVEF decreases of =10% and 1 pt treated with H experienced a cardiac event with an LVEF value of <45%. One pt with HER2-negative disease died after surgery due to pulmonary embolism. Conclusions: Neoadjuvant H plus AT/CMF-containing chemotherapy significantly improved the pCR rate of LABC vs chemotherapy alone. Treatment was well tolerated with acceptable cardiac safety. Follow-up is ongoing and EFS is maturing. [Table: see text]
Time-dependent patterns of recurrence after early stage breast cancer: Preliminary observations and methodological issues
Authors: Dignam J. J. , Dukic V. M. , Anderson S. J. , Mamounas E. P. , Jeong J. H. , Costantino J. P. 
Published: March 2020

536 Background: For patients with lymph node-negative (n0) breast cancer, benefit from adjuvant therapy is established. However, absolute gains are smaller than in node-positive disease and thus more selective use is warranted, prompting development of risk profiling to identify those most (or least) likely to benefit. In addition to defining risk based on recurrence-free status to specific time landmarks, examination of the magnitude and changes in the risk (hazard) of failure over time may be informative. We investigate recurrence hazards in n0 breast cancer. Methods: In a cohort of 9,279 participants from 5 NSABP randomized trials (accrual 1982–1998) investigating cytotoxic chemotherapy (CTX) and tamoxifen (TAM) for n0 breast cancer, we examine recurrence-free survival curves and recurrence hazards over time. The latter presents analytic challenges, because empirical (i.e., nonparametric) estimates are too unstable to provide reliable inference on patterns and do not incorporate covariates, while traditional semi-parametric (i.e., Cox) and parametric survival models are too restrictive to permit hazard changes. We apply flexible extensions of these models to examine and compare time-varying hazard profiles. Results: In patients undergoing surgery only, distinctive recurrence risk patterns between estrogen receptor (ER)-negative (-) and ER- positive (+) patients emerge. We observe an earlier, larger hazard peak in ER- patients, but a more persistent hazard in ER+ patients and a crossover (hazard for ER+ > ER-) occurring around 48 months. Under adjuvant treatment (CTX in ER- and TAM or TAM+CTX in ER+), magnitudes of failure hazards are reduced but other inter-relationships are largely maintained. For example, while TAM decreases the early hazard in ER+ patients to a level comparable to CTX treated ER- disease, in later follow-up (>5 years) the ER+ hazard again exceeds that of ER- patients. Adding CTX to TAM results in hazard reductions in both early and later periods. Conclusions: Examination of recurrence hazards over time with our models reveals changes in risk that may have biologic and therapeutic strategy relevance. The proposed analytic approaches address shortcomings of standard methods and will be developed further. No significant financial relationships to disclose.
Central assessment of ER, PgR and HER2 in BIG 1–98 evaluating letrozole (L) compared to tamoxifen (T) as initial adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer
Authors: Rasmussen B. B. , Regan M. M. , Lykkesfeldt A. E. , Dell’Orto P. , Curto B. Del , Henriksen K. L. , Mastropasqua M. G. , Thürlimann B. , Viale G. 
Published: March 2020

538 Background: The BIG 1–98 trial, a randomized double-blind Phase III trial, showed that L significantly improved disease-free survival (DFS) as compared with T. It is uncertain whether benefit of aromatase inhibitors vs. T differs according to PgR and/or HER2 status of the tumor. A central assessment of ER, PgR and HER2 was undertaken for BIG 1–98 to investigate this question. Methods: Paraffin-embedded primary tumor material was evaluable for 3650 (74%) of the 4922 patients (pts) randomized to the 2 monotherapy arms (L or T for 5 years; 51 months median follow-up). ER and PgR were measured by immunohistochemistry (IHC) and positivity was defined as =1% immunoreactive cells. HER2 expression was determined by IHC and positivity was confirmed by FISH. Cox modeling estimated hazard ratios (HR) comparing L vs. T on DFS and assessed treatment-by-covariate interactions. Results: By central assessment, 86% and 10% of tumors were classified as ER+/PgR+ and ER+/PgR-, respectively. Among these (n=3533), 7% were ER+/HER2+. DFS was superior in pts with ER+/PgR+ vs. ER+/PgR- tumors and in pts with ER+/HER2- vs. ER+/HER2+ tumors. The benefit of L vs. T did not differ by PgR (P=.48) or HER2 status (P=.55). Conclusion: In postmenopausal patients with ER+ tumors (=1% immunoreactive cells), of which 10% were PgR- and 7% HER2+, both PgR- and HER2+ status were associated with poorer DFS. The benefit of L over T was observed in all ER+ patients irrespective of PgR or HER2 status. In patients with ER+ tumors, PgR and HER2 status do not appear to be selection criteria for treatment with L vs. T. [Table: see text] No significant financial relationships to disclose.
Optimal use of aromatase inhibitors for adjuvant treatment of hormone-sensitive early breast cancer: Up front or sequenced after tamoxifen?
Authors: Cuzick J. , Sasieni P. , Howell A. 
Published: March 2020

541 Background: The aromatase inhibitors (AIs) are more effective than tamoxifen when used for the adjuvant treatment of early breast cancer. However, it is still unclear whether it is better to start initially with an AI or use it after a 2–3-year period of tamoxifen treatment. No clinical trial data are likely to be available until 2008, although earlier modeling data have shown that an upfront strategy may be more favorable (Cuzick et al. Br J Cancer 2006: 27; 460–464). Here we update the model with all newly reported data. Methods: A model has been constructed to compare the use of an AI upfront with AI sequencing after varying periods of initial treatment with tamoxifen. Recurrence rates and time lost to recurrence for the first 10 years of follow-up are modeled for a range of efficacy parameters. Results: Results predicted from the model are presented in the table . For a 5-year carryover period, the predicted recurrence rate at 10 years is 17.7% for upfront use of an AI compared with 22.9% for 5 years of tamoxifen, leading to one less recurrence for every 19 women treated. The average time lost to recurrence is reduced by 2.8% or 3.4 months. With updated data, the model predicts an AI upfront strategy will dominate a sequencing strategy. However, the model also demonstrates that using 10 years of tamoxifen, or a sequence of 5 years of tamoxifen followed by 5 years of an AI, is superior to using 5 years of tamoxifen. This indicates that longer duration of treatment with an AI is likely to be beneficial, especially for younger women, and deserves further investigation. Conclusion: The current modeling data suggest that using an AI as upfront adjuvant treatment is better than using an AI in sequence after 2 or more years of tamoxifen. [Table: see text] No significant financial relationships to disclose.