bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Inflammatory and locally advanced breast cancer respond similar to operable breast cancer to neoadjuvant chemotherapy: Results from 278 patients with cT4a-d tumors of the GeparTRIO trial
Authors: Minckwitz G. Von , Kümmel S. , Vogel P. , Hanusch C. , Eidtmann H. , Hilfrich J. , Gerber B. , Huober J. , Costa S. D. , Loibl S.
Published: March 2020

542

Background: Neoadjuvant chemotherapy is the treatment of choice in patients with T4a-c and inflammatory (T4d) breast cancer. However, data on large-scale, multicentre, prospective trials are missing. In the GeparTRIO study (SABCS 2006, abstr. 42) 278 of 2,090 patients with cT4a-c or T4d tumors were included as a separate stratum for inoperable disease for a prospectively planned analysis. Methods: Patients were treated with 2 cycles TAC (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2, q d 21). If tumor reduction was >50%, patients were randomized to receive 4 or 6 additional TAC cycles. If tumor reduction was less, patients were randomized to 4 additional TAC cycles or to 4 NX cycles (vinorelbine 25 mg/m2 day 1 + 8, capecitabine 2,000 mg/m2 day 1 14, q21). Efficacy endpoints were pCR-rate (no invasive and no non-invasive residuals in breast and lymph nodes) (primary), clinical response before surgery and breast conserving therapy (BCT) rate (secondary). Results: 95 (4.6%) T4d, 183 (8.9%) cT4a-c, and 1,767 (86.4%) T1–3 tumors were registered in GeparTRIO within 36 months. Patients with inoperable/operable tumors had a median age of 53.9/49.0 years, median cT size: 7.0/4.0cm, cN+: 75.6/52.0%, ductal: 76.3/78.4%, lobular: 14.0/13.5%, multiple lesions: 28.5/19.5%, grade 3: 34.8/39.9%, hormone receptor (HR) neg: 24.7/36.6%, HER-2 pos: 41.0/35.5%. Response rates for T4d, T4a-c, T1–3 were 8.4, 10.9, 17.5% (pCR, p=0.007), 36.7, 59.4, 72.6% (palpation after 2 cycles TAC, p<0.0001), 64.2, 62.3, 77.8% (palpation before surgery, p<0.0001), 52.6, 51.9, 67.4% (ultrasound before surgery, p<0.0001). BCT was performed in 12.6, 31.7, 69.5% (p<0.0001). Response after two cycles, negative HR content, young age, high grade, ductal type, but not tumor stage or size, were independent predictors for pCR in the total population. Conclusions: Inflammatory and cT4a-c breast carcinomas, compared to cT1–3 tumors, show less favorable tumor characteristics but a comparable pattern of response to TAC/NX. These patients do not need separate neoadjuvant trials.

[Table: see text]
Meta-analysis of adjuvant trastuzumab for early breast cancer: Cardiotoxicity and brain metastases incidence
Authors: Cuppone F. , Bria E. , Giannarelli D. , Nisticò C. , Sperduti I. , Carlini P. , Milella M. , Ciccarese M. , Cognetti F. , Terzoli E.
Published: March 2020

543

Background: The introduction of adjuvant trastuzumab (T) for early breast cancer overexpressing HER-2 has extraordinarily decreased the risk of both recurrence and death in 5 randomized clinical trials (RCTs). Nevertheless, the issue regarding the long-term safety profile of such drug is still open; in particular, questions remain about long-term cardiotoxicity, and specific pattern of relapse such as brain metastases (BM). In order to quantify the magnitude of these 2 risks, together with the survival outcome, a literature-based meta-analysis was performed. Methods: All phase III trials were considered eligible. A literature-based meta-analysis was accomplished, and event-based relative risk ratios (RR) with 95% confidence interval (CI) were derived. A fixed- and a random-effect model according to the inverse variance and the Mantel-Haenzel method were applied. Heterogeneity test was applied as well. Absolute differences (AD) and the number of patients needed to treat or to harm (NNT/NNH) were calculated. Primary end-points were: 1) chronic heart failure grade III-IV rate (CHF), 2) 10% reduction of L-FEV rate (L-FEV) and 3) BM rate. In order to quantify the magnitude of the significant benefit already found in the original RCTs, secondary end-points were: 1) disease-free survival (DFS) and 2) overall survival (OS). Results: Five RCTs were gathered (11,187 patients); at an average 2-yrs follow-up, all data were available for the cardiotoxicity and outcome end-points, while 3 RCTs reported results for BM analysis (6,738 patients). Conclusions: The overall outcome stresses that trastuzumab is likely to be one of the most important discovery in clinical oncology. Nevertheless, the biological activity of trastuzumab needs to be investigated more extensively to explore both long-term safety and specific relapse pattern.

[Table: see text]

No significant financial relationships to disclose.
Adjuvant external beam radiotherapy (EBRT) in the treatment of endometrial cancer: Results of the randomised MRC ASTEC and NCIC CTG EN.5 trial
Authors: Orton J. , Blake P.
Published: March 2020

5504

Background: Patients with stage I endometrial cancer at high risk of relapse generally receive adjuvant EBRT following surgery, despite lack of evidence that radiotherapy improves overall survival (OS). ASTEC/EN.5 was designed to investigate whether OS is improved by adjuvant EBRT. An important secondary outcome was pelvic recurrence-free survival. Methods: Patients were randomised to receive immediate EBRT (with linear accelerator delivering 40–46Gy in 20–25 fractions to pelvis) or no EBRT until clinically indicated. Vault brachytherapy (4Gy in 2 fractions (HDR) or 15Gy (LDR)) could be used regardless of EBRT allocation. Centers were required to specify in advance whether brachytherapy would be offered to all patients or to none. The study was powered both to 1) detect a 9–10% absolute improvement in 5-year OS with adjuvant EBRT; and 2) reliably exclude an absolute 5% difference in 5-year OS when combined with other major studies (PORTEC and GOG 99). Results: Between Oct 1996 to Apr 2005, 906 patients (452 EBRT, 454 no EBRT) were randomised internationally. Pre-treatment characteristics were well balanced: median age 66 years; 98% of women WHO PS 0–1; 30% with lymph nodes removed at surgery; 84% endometrioid histology; depth of invasion to endometrium only, inner half and outer half of myometrium 3%, 20% and 77%, respectively; degree of differentiation to grade 1, 2, and 3 26%, 42%, and 31%, respectively. 92% patients in EBRT arm received immediate treatment, 90% receiving all protocol specified treatment. 2% patients in no EBRT arm received immediate EBRT. Brachytherapy was given to 52% patients in both arms. Morbidity was higher in EBRT arm, 56% compared with 24% in no EBRT arm reporting complications of treatment. Grade 3 or higher toxicity was rare. With a median follow-up of 46 months at the time of analysis, 117(13%) have died and 136(17%) have recurred or died. 130 deaths are required to detect a 10% difference in 5-year OS with 5% significance level and 90% power and this will be achieved by April 2007. Conclusions: Compliance was high. Serious complications were rare. The ASTEC/EN.5 trial alone and in combination with PORTEC and GOG99 will answer the question of the benefit of post-operative adjuvant EBRT in patients with endometrial cancer.

No significant financial relationships to disclose.
Results from a phase II randomized, placebo-controlled, double-blind trial suggest improved PFS with the addition of pertuzumab to gemcitabine in patients with platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer
Authors: Makhija S. , Glenn D. , Ueland F. , Gold M. , Dizon D. , Paton V. , Birkner M. , Lin C. , Derynck M. , Matulonis U.
Published: March 2020

5507

Background: Pertuzumab (P) is a humanized monoclonal antibody that blocks the ability of HER2 to heterodimerize with other HER/ErbB receptors. As a single agent, P has demonstrated clinical activity in relapsed/refractory epithelial ovarian cancer (EOC). Since platinum-resistant (CDDP-R) EOC remains a difficult disease to treat, this phase II study was conducted to determine if addition of P to gemcitabine (G) would improve results. Methods: Patients with CDDP-R EOC (including ovarian, fallopian tube, or primary peritoneal cancer) who had received up to one prior treatment for CDDP-R disease were randomized to Gem 800 mg/m2 on D1, 8 of a 21-day cycle ± P or placebo (pl). P was given as an 840 mg initial dose followed by 420mg IV every 3 weeks. Tumor response was assessed by RECIST every 6 weeks using GOG criteria. The primary endpoint was progression free survival (PFS). Results: One hundred thirty patients (n = 65 each treatment cohort) were treated. Clinical characteristics were balanced between the treatment groups. Pts received a median of 2 prior regimens (range 1–6) for EOC. Based on 83 events, the adjusted hazard ratio for PFS was 0.67 (95% CI: 0.43–1.02), p =0.06 in favor of P+Gem. The median PFS was 3.0 months (0–8.7 months) vs. 2.6 months (0–9+ months), and the PFS rate at 4 months was 49% vs. 34% in the P+Gem and Gem/pl arms, respectively. The most common AEs increased in the P-treated pts were fatigue, nausea, diarrhea, back pain, Gr 3–4 neutropenia, rash, headache, stomatitis, epistaxis, and rhinorrhea. Clinically significant CHF was reported in one patient in the pertuzumab cohort. There was no imbalance in the LVEF results between treatment arms. One patient who received pertuzumab + gemcitabine experienced an adverse event that resulted in death (hemolytic-uremic syndrome). Conclusions: These data suggest that pertuzumab may add activity to gemcitabine as reflected by improvements in PFS in patients with CDDP-R ovarian, primary peritoneal, or fallopian tube cancer. Survival data will be presented at ASCO.

No significant financial relationships to disclose.
A prospective multi-center ovarian cancer screening study in women at increased risk
Authors: Skates S. J. , Drescher C. W. , Isaacs C. , Schildkraut J. M. , Armstrong D. K. , Buys S. S. , Brewster W. R. , Daly M. B. , Finkelstein D. M. , Lu K. H. ,   ROCA Screening Study Group
Published: March 2020

5510

Background: No proven ovarian cancer (OC) screening strategy exists for women who are at increased risk for the disease. A risk of ovarian cancer algorithm (ROCA) using serial CA125 values has previously shown greater positive predictive value (PPV) and sensitivity than a single CA125 in screening women at general population risk. We hypothesized that using ROCA would yield a reasonable PPV for ovarian cancer screening in a cohort at increased risk. Methods: Between 7/2001 and 9/2006, 25 sites (14 Cancer Genetics Network, 3 ovarian SPOREs, 1 EDRN, 7 others) prospectively enrolled patients. Inclusion criteria included: among self, 1° or 2° relatives in same lineage either (i) BRCA1/2 mutation, or (ii) two of OC or early onset (age = 50) breast cancer (BC), or (iii) Ashkenazi ethnicity and 1 of OC or BC. A previous diagnosis of OC excluded subjects. Subjects underwent CA125 every 3 months and the risk of having ovarian cancer based on the CA125 profile was recalculated after each test. ROCA referred subjects with risk > 1% to ultrasound (US), and risk > 10% additionally to a gynecologic oncologist. Objectives included PPV for study indicated surgery, sensitivity, and compliance. Sample size was chosen to observe 8 OC endpoints with a power of 80% to rule out PPV = 10% if the true PPV = 20%. Results: 2,343 high risk women enrolled, with 6,284 women years of screening and 19,549 CA125s obtained. There were 628 (10%/yr) referrals to US with 414 US performed. 38 women underwent study indicated surgeries. 9 OCs were identified during screening, 3 were prevalent (1 early, 2 late stage), and 6 were incident (5/6 = 83% early, 1 late). 3 of the 6 incident cases were found on prophylatic oophorectomy in early stage. ROCA detected 2 in early stage of remaining 3 incident cases, and 3 of 3 prevalent cases. The PPV was 5/38 = 13% (95% CI 4.4%, 28%) and sensitivity was 5/6 = 83%, CI (36%, 99%). There was high compliance with CA125 testing throughout study, with 84%, 85%, 85%, 82% subjects returning within 1 month of schedule for first 4 tests. Conclusions: Frequent CA125 testing using ROCA results in an acceptable PPV and high compliance in a cohort of women at increased risk for OC. A definitive screening study (= 30 incident cases) using ROCA with serial CA125 and possibly additional markers is required to define sensitivity for early stage OC.

[Table: see text]
STK15 F31I polymorphisms and uterine cancer risk: A case-control analysis
Authors: Milam M. R. , Gu J. , Yang H. , Celestino J. , Wu W. , Horwitz I. , Lacour R. A. , Westin S. N. , Gershenson D. M. , Wu X. , Lu K. H.
Published: March 2020

5511

Background: STK15 is a serine threonine kinase which assists chromosomal separation and mitotic spindle stability through interaction with the centrosome during mitosis. STK15 polymorphisms have been associated with an increased risk for breast cancer in several case-control studies. We hypothesized that STK15 polymorphisms might modulate risk of uterine cancer. Methods: Uterine cancer patients treated at M. D. Anderson Cancer Center were identified from the tumor bank database from January 1, 2000 to June 30, 2006. Two common STK15 single nucleotide polymorphisms (SNPs), F31I (T/A) and V57I (G/A), were genotyped in patients with uterine cancer and in a control population matched for age, race, and smoking status. Odds ratios (OR) and 95% confidence intervals (CI) were obtained using unconditional logistic regression analysis. Results: A total of 193 women with uterine cancer and 218 controls were genotyped for both SNPs. After adjustment for age, race, and smoking status for the F31I SNP, the homozygous variant genotype (AA) was associated with a significantly increased uterine cancer risk (OR 10.2; 95% CI 2.23–46.5). Individuals with the heterozygous genotype (TA) and a history of tobacco use also exhibited an increased risk for uterine cancer (OR 2.63; 95% CI 1.20–5.76). For the V57I SNP, neither the homozygous (AA) nor the heterozygous (GA) variant genotypes were associated with significantly altered risk for uterine cancer (OR 0.76; 95% CI 0.18–3.25 and OR 0.88; 95% CI 0.52–1.49). Conclusions: Our study demonstrates that STK15 F31I SNP is associated with an increased risk for uterine cancer. Confirmation of this pilot study is needed in a larger case-control population to evaluate this genetic variant with other known risk factors for uterine cancer.

No significant financial relationships to disclose.
Survival in advanced-stage ovarian cancer patients with non-Ashkenazi Jewish BRCA mutations
Authors: Lacour R. A. , Westin S. N. , Daniels M. S. , Milam M. R. , Sun C. C. , Urbauer D. L. , Ramirez P. T. , Bodurka D. C. , Gershenson D. M. , Lu K. H.
Published: March 2020

5514

Background: Previous studies have shown a survival advantage in ovarian cancer patients with Ashkenazi-Jewish BRCA founder mutations compared to sporadic ovarian cancer patients. The purpose of this study is to determine if this association exists in ovarian cancer patients with non- Ashkenazi Jewish (non-AJ) BRCA1 or BRCA2 mutations. Methods: Patients with stage III or IV ovarian, fallopian tube, or primary peritoneal cancer and a BRCA1 or BRCA2 mutation, seen for genetic testing between January 1996 and October 2006, were identified from the institutional and genetics databases. Medical records were reviewed for clinical factors including response to initial chemotherapy. Response is defined as no clinical evidence of disease with normalization of serum CA-125 and no radiographic evidence of disease or a negative second-look surgery. Patients with sporadic ovarian cancer, without a family history of breast or ovarian cancer, were compared to similar cases, matched by age, stage, and year of diagnosis. Progression-free and overall survival were calculated by the method of Kaplan-Meier. Chi-square tests and univariate logistic regression were also used in the data analysis. Results: Thirty-nine advanced-stage ovarian cancer patients with non-AJ BRCA mutations and 47 matched, advanced-stage sporadic ovarian cancer patients have been analyzed. Compared to patients with sporadic ovarian cancer, non-AJ BRCA mutation carriers had a longer progression-free survival (PFS, 32.4 mos. vs. 22.1 mos., p = 0.0303) and overall survival (OS, 101.4 mos. vs. 51.3 mos., p < 0.001). Similarly, 72% of the non-AJ BRCA mutation carriers had a complete response to initial treatment, compared to 45% of the sporadic ovarian cancer patients (p = 0.01). The odds of complete response to initial treatment were 3.2 times greater in the non-AJ BRCA group than in the sporadic group (OR 3.2; 95% CI 1.27 - 8.15). Conclusions: This study demonstrates a significant survival advantage in advanced-stage ovarian cancer patients with non-AJ BRCA mutations when compared to similar patients with sporadic ovarian cancer. Response to initial treatment appears to impact this improved survival.

No significant financial relationships to disclose.
Durable clinical responses in patients (pts) with ovarian carcinoma treated on a phase II trial of autologous dendritic cells (DC) pulsed with MUC1
Authors: Mitchell P. , Loveland B. E. , Quinn M. A. , Grant P. T. , Allen D. G. , Jobling T. W. , White S. C. , Wall D. M. , Zhao A. , Karanikas V.
Published: March 2020

5515

Background: Mucin 1 (MUC1) is a glycoprotein highly expressed by ovarian carcinoma and is thus a potential antigen for immunotherapy. Following successful phase I results (Loveland et al. Clin Can Res 2006; 12:869), using DC pulsed with mannan-MUC1 fusion protein (DC-MFP), we report a phase II trial in similarly treated pts with ovarian carcinoma. Methods: Eligibility: incurable disease; age = 18 yrs; PS 0–2; no autoimmune disorders; rising CA125 levels (= 25% in 1 mth, confirmed). The primary endpoint was CA125 response (major = 50%, minor = 25%, each confirmed at = 4 wk) or stabilisation (= 3 mths). PBMC were collected by leukapheresis, cultured with IL-4 and GM-CSF to generate DC, and pulsed with MFP on d5. DC were reinjected on d6 as 8 i.d. injections (each 5x106), given 4-weekly × 3, then 10- weekly to 12 mths. Excess cells were cryopreserved for subsequent injections. Results: 28 pts were recruited, with all evaluable for toxicity and 21 for efficacy (received = 3 vaccinations). Characteristics were: serous histology 24 (86%) pts; median age 58 yrs (34–78); PS 0–1 27 (96%) pts; prior systemic therapy (all pts platinum-treated) 1 line 5 pts, 2 line 4 pts, 3 line 10 pts, = 4 lines 9 pts. Leukapheresis was generally required only 6-monthly. Following ex vivo culture, the proportion of CD86+ cells ranged from 40 - 85%. There was no grade = 3 therapy-related toxicity. Of 21 pts, 4 (19%) showed CA125 response or stabilisation. 2 pts had major response: 1 pt with 4 previous lines of systemic therapy (DC-MFP response duration 12+ mths) and 1 pt treated second line (duration 14 mths). One pt had stable disease of 7 mths duration which included 10 wks classified as minor response and one pt, treated fifth-line, had stable disease for 5 mths. An additional pt, treated fourth-line, had >25% CA125 reduction which was not confirmed by repeat CA125. CT scan results were generally concordant with CA125 status. No relationship was seen between clinical benefit and HLA type. 88% of tumours were MUC1+ on IHC. Conclusions: Study treatment was well tolerated and acceptable to pts. There was clear evidence of clinical benefit, including pts who were heavily pre-treated. This approach warrants further study in ovarian carcinoma. Supported by grants from PrimaBiomed Ltd.

No significant financial relationships to disclose.
Safety of maintenance bevacizumab after first-line chemotherapy for advanced ovarian and müllerian cancers
Authors: Campos S. M. , Dizon D. S. , Cannistra S. A. , Roche M. , Krasner C. N. , Berlin S. T. , Horowitz N. S. , DiSilvestro P. , Matulonis U. A. , Penson R. T.
Published: March 2020

5517

Background: Bevacizumab is a recombinant humanized monoclonal antibody that neutralizes VEGF, but is associated with arterial complications and GI perforations in patients with advanced ovarian cancer. Maintenance antiangiogenic therapy is an attractive strategy for patients after first line therapy. However, no data exist on the safety of maintenance bevacizumab in this setting. Methods: An open label phase II clinical trial of carboplatin, paclitaxel and bevacizumab (CPB) in newly diagnosed patients =ECOG 2, with chemotherapy naïve, stage =IC, epithelial müllerian tumors. Patients receive carboplatin AUC 5 IV, paclitaxel 175 mg/m2 IV, and bevacizumab 15 mg/kg IV for 6–8 cycles D1 Q21. Bevacizumab is omitted in the first cycle, and continued as single agent for one year. Results: 58 patients are evaluable. Median age is 58 (18–77), and 39(67%) were ECOG 1. 43(74%) have ovarian, 8(14%) uterine papillary serous (UPSC) tumors, 4(7%) peritoneal, and 3(5%) fallopian tube cancers. 38(65%) were serous, 8(14%) MMMT, 4(7%) clear cell, and 3(5%) endometrioid cancers (5(9%) mixed/other). 36(62%) were stage III and 11(19%) stage IV. Surgery was optimal in 45(80%) patients. 50 patients have completed chemotherapy, associated with 2 PEs, and 2 GI perforations, all occurring during the induction chemotherapy phase of treatment. 43 patients have received 360 cycles of maintenance therapy with mild toxicity. 6(14%) have come off for PD, 4(9%) for toxicity (inc. 1 nasal perforation), 4 withdrew consent, and 3 patients asymptomatic, continue despite a rising CA125. During maintenance there has been no grade IV toxicity, and 13 grade III toxicities (musculoskeletal pain (5), dyspnea, hyperglycemia, hypertension (1 grade III, 4 grade II), infection, lymphopenia, thrombocytopenia, proteinuria, syncope). Radiographic responses were documented in 21 of 28 (75%: CR 11, PR 10). Median PFS is 11(1–21) months at 13 months median FU. Conclusion: Maintenance bevacizumab is feasible and well tolerated with mild myalgias, and hypertension common but treatable side effects.

No significant financial relationships to disclose.
Results of all-intraperitoneal carboplatin and paclitaxel regimen shows good tolerability and efficacy for advanced ovarian cancer
Authors: Krasner C. N. , Seiden M. V. , Fuller A. F. , Supko J. G. , Roche M. , Kendall D. L. , Lee J. , Berkowitz R. , Berlin S. , Matulonis U. A. ,   Dana-Farber/Harvard Cancer Center Gynecologic Oncology Research Group
Published: March 2020

5521

Background: A phase III trial (GOG 172) demonstrated improved survival for patients (pts) with optimally-debulked ovarian cancer treated with intraperitoneal (IP) cisplatin and paclitaxel, as compared with standard IV dosing. Studies to further enhance efficacy and minimize toxicity of IP platinum/taxane regimens are needed. We present the clinical results of a novel IP regimen in follow-up to the pharmacokinetics (pk) results presented last year. Methods: Carboplatin at an AUC 6 on day 1 and paclitaxel 60 mg/m2 on days 1, 8, 15 was given, IV in cycle 1 and IP in the 5 subsequent 21-day cycles. The initial IV cycle was designed to allow for intra-patient IV vs. IP pk comparison. Pts completing 6 cycles with clinical complete response (CCR) underwent second-look operation (SLO). Results: Accrual is complete with 40 evaluable pts, 8 pts remain on trial. Pts came off study for: port-related complications (7), allergy (2), heme tox (2), vaginal leak (2), and infection (4). Toxicity was mild, with grade 3 or 4 toxicity consisting of neutropenia: 10 (25%), plts: 2 (5%), vomiting: 2 (5%), fatigue: 2 (5%) and anemia: 1 (2.5%). There was no grade 3 or 4 peripheral neuropathy or alopecia. Completion rate was good with 82% of pts completing = 4 cycles, as compared with 52% in GOG 172. All pts completing chemotherapy were judged to be in CCR; there was no progressive disease on trial. Of the pts undergoing SLO, 14 pts were negative, 4 pts were positive, for complete pathological response rate of 78%. Conclusions: Pts were able to complete more cycles of therapy on this regimen as compared with GOG 172. The incidence of gastrointestinal, metabolic, and neurotoxicity is very low. Preliminary SLO rate compares favorably to the 57% seen in GOG 172. Previously reported pk results as well as tolerability and efficacy are encouraging and suggest this regimen should be studied in a larger population. Final toxicity and response data will be available.

No significant financial relationships to disclose.
A phase II study of intravenous (IV) and intraperitoneal (IP) paclitaxel (Tax), IP cisplatin (Cis), and IV bevacizumab (Bev) as first-line chemotherapy for optimal stage II or III ovarian, primary peritoneal, and fallopian tube cancer
Authors: Konner J. A. , Fallon K. , Pezzuli S. , Iasonos A. , Sabbatini P. , Hensley M. , Chiang A. , Tew W. , Spriggs D. , Aghajanian C.
Published: March 2020

5523

Background: IP Cis plus IV/IP Tax is a standard therapy for optimally debulked ovarian cancer. Bev is a recombinant humanized IgG1 monoclonal antibody directed against vascular endothelial growth factor (VEGF). Activity of Bev against recurrent ovarian cancer has been reported in phase II trials. In this study IP Cis and IV/IP Tax are combined with IV Bev as front-line therapy to assess safety and tolerability. Methods: Patients with optimal (<1 cm residual), FIGO stage II or III, epithelial ovarian, fallopian tube, or peritoneal cancer, acceptable organ function, and KPS = 70% are eligible. Patients receive 6 cycles of chemotherapy plus Bev (starting cycle 2): Tax 135 mg/m2 IV over 3 hours on Day 1, Cis 75 mg/m2 IP on Day 2, Tax 60 mg/m2 IP on Day 8, Bev 15 mg/kg IV on Day 1. Extended treatment with Bev is continued every 3 weeks for 17 treatments after chemotherapy is complete. The study will enroll 41 patients. The primary endpoint is safety and tolerability, determined by the proportion of patients who complete the prescribed 6 cycles of cytotoxic chemotherapy without discontinuation and without dose-limiting non-hematologic and non-electrolyte toxicity. A stopping rule will be applied if excessive toxicity is encountered. Results: To date, 8 women have been treated on the study. Median age: 53 (48–59). All 31 planned doses of chemotherapy have been administered in full. One dose of IP Tax was delayed for 2 days due to abdominal pain. One patient had her first dose of Bev delayed for 1 cycle due to surgical wound infection. There have been no toxicities > grade 3. Grade 1/2 toxicities include: fatigue (87.5%); nausea (50%); and hypomagnesemia (37.5%). Grade 3 toxicities per patient: fatigue (12.5%); hyponatremia (25%); hypokalemia (25%); hypertension (12.5%); abdominal pain (12.5%); and neutropenia (12.5%). Of the 5 patients with pretreatment CA125 >35 Units/mL, 4 normalized their value after 1 cycle of chemotherapy and 1 patient normalized after 2 cycles. Conclusions: Preliminary experience suggests that the combination of IV Bev with IP Cis plus IV/IP Tax may be well tolerated. Enrollment continues and updated results will be presented.

No significant financial relationships to disclose.