bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical relevance of specialist pathologic testicular tumor review.
Authors: Church David N. , Protheroe Andrew , Roberts Ian SD , Crane Gemma Louise , Turner Gareth D , Verrill Clare
Published: March 2020

4599

Background: Therapeutic options in stage IA/B testicular cancer include surveillance, retroperitoneal lymph node dissection, and adjuvant chemotherapy/radiotherapy; clinician and patient choice is guided by recurrence risk. Specialist pathologic review is important in informing this decision as it may alter diagnosis and staging. Methods: Analysis of a prospective supraregional database of 627 testicular tumors diagnosed in Oxford or referred for central review between 2004 and 2012. Tumor histology, stage (AJCC 7th ed.), and other factors predictive of relapse were compared between referring and final pathology reports. Results: Of 402 cases referred from 11 hospitals during the study period, 370 primary testicular tumors with an informative initial pathology report were analysed. There was a discrepancy between referring and final reports in 116 cases (31.4%), with significant variation between referring units in the frequency of discordance (20.0-89.9%, p<0.0001, x2). Changes to histological diagnosis in 34 cases (9.2%) were minor alterations in type and proportion of non-seminomatous germ cell tumor (NSGCT) elements of no clinical significance, with exception of one classical seminoma reclassified as spermatocytic seminoma. For seminomas (n=201) the commonest discrepancies were in identification of rete testis invasion (RTI) (15.9%); lymphovascular invasion (LVI) (9.5%); and spermatic cord invasion (SCI) (5.0%). RTI was more frequently under-reported (14.4%), and LVI over-reported (8.0%) on initial assessment. Disparity of tumor size in 2 cases (1.0%) was of no clinical significance. For NSGCT (n=150) the commonest discrepancies were in RTI (9.3%), LVI (7.3%) and SCI (6.7%), with LVI typically over-reported (4.0%) and RTI and SCI under-reported (6.7%, 5.3% respectively) on primary analysis. Central review resulted in change of primary tumor stage in 45 cases (12.1%). 12 (6.0%) and 16 (8.0%) seminomas, and 12 (8.0%) and 5 (3.3%) NSGCTs were upstaged and downstaged respectively. Conclusions: Central pathology review results in frequent alteration of factors predictive of relapse in stage IA/B testicular cancer. Particular attention should be directed to review of RTI, LVI and SCI to ensure accurate prognostication.
Post-axitinib systemic therapy in metastatic renal cell carcinoma (mRCC).
Authors: Haddad Housam , Rini Brian I. , Jonasch Eric , Tannir Nizar M. , Dreicer Robert , Garcia Jorge A. , Wood Laura S. , Elson Paul
Published: March 2020

4609

Background: Axitinib is a potent and selective inhibitor of the VEGF receptor family with efficacy as a second-line therapy in mRCC. Evaluation of further systemic therapy following axitinib has not been previously reported. Methods: The medical records ofmRCCpatients (pts) treated at The Cleveland Clinic or MD Anderson Cancer Center who received axitinib were retrospectively reviewed. Patient characteristics including best response and duration of treatment on axitinib and each subsequent line of therapy were recorded. Results: Eighty-one patients were initially identified; 29 patients received at least one approved targeted agent following axitinib and are included in this analysis. The remainder of pts were excluded due to ongoing axitinib (n=16), lack of subsequent therapy (n=13), lost to follow up (n=11), received experimental agents post-axitinib (n=7) or were inevaluable (n=2). Three pts were excluded due to ≤ 21 days on axitinib. Pt characteristics at start of axitinib included 76% male, median age 59 (range, 44-78); 97% clear cell; 93% prior nephrectomy; 64% previously-treated. Pts were favorable (39%) or intermediate (60%) risk based on Heng criteria. Overall response rate to axitinib was 52% and median duration of treatment of 11.2 months (range, 1.1-90). Thirty eight percent of patients had new brain, bone, and/or liver metastases at disease progression on axitinib. For the first subsequent therapy post axitinib (n=25), pts were treated with tyrosine kinase inhibitors (72%) or mTOR inhibitors (28%). Overall 8% of pts achieved partial responses (one pt each to sunitinib and pazopanib) and 52% had a best response of stable disease. Estimated median duration of therapy was 4.4 months (range, 0.2-27.5+). Fifteen pts received a second post-axitinib targeted therapy with mTOR inhibitors (60%) or TKIs (40%). One patient (7%) achieved a partial response to pazopanib and 8 patients (53%) had a best response of SD. Estimated median treatment duration was 4.8 months (range, 0.7-19.1+). Conclusions: There are objective responses and stable disease to post-axitinib targeted therapies, consistent with previous series and trials in refractory RCC patients.
Outcome of rapid disease progression in the treatment break following cytoreductive nephrectomy (CN) after presurgical sunitinib in patients with primary metastatic renal cell carcinoma (RCC).
Authors: Bex Axel , Powles Thomas , Blank Christian U. , Chowdhury Simon , Horenblas Simon , Peters John , Boleti Ekaterini , Haanen John B. A. G.
Published: March 2020

4611

Background: There is concern that interruption of tyrosine kinase inhibitors (TKI) triggers disease progression (PD) and metastasis. This is based on preclinical models and observation of rapid PD in the postsurgical treatment break in patients pretreated with TKI. Little is known about the frequency of PD during postsurgical TKI interruption and its outcome. These data may have implications for neoadjuvant or presurgical treatment concepts. Methods: Of 66 patients from two closed phase II trials investigating 2-3 months presurgical sunitinib for primary metastatic clear-cell RCC, 45 were evaluated in this retrospective analysis because they had absence of PD prior to planned surgery and underwent CN (35 [78%] MSKCC intermediate and 10 [22%] poor risk). Patients had CT scans at the end of pretreatment and at 4 weeks post-nephrectomy before restarting sunitinib. In patients with postsurgical RECIST PD at 4 weeks when compared to the preoperative CT scan overall survival (OS) was measured from the time of nephrectomy and compared to patients without treatment break PD. Results: Median OS of 45 patients from the time of surgery was 22 months (13.0-31.5 months). Overall 14 patients progressed during treatment break (31%), with new sites of disease in 5/14 (35%). Reintroduction of sunitinib resulted in disease stabilisation or better in 13. Patients with poor risk were represented in the progressors (n=4[28%]) and non-progressors (n=6 [19%]) (p=0.7 fishers exact test). The hazard ratio (HR) for death associated with PD during treatment break was 1.90 (95% CI 0.89-4.08). OS for non-progressors was 25 months (15-NA) and 13 months (6-27) for progressors. Conclusions: A significant proportion of patients develop PD upon sunitinib withdrawal in a 4 week recovery period following CN. In view of the small sample size these data suggest a strong trend toward treatment break PD being associated with a poor outcome. It is not clear whether this PD is related to interruption of TKI, surgery or a combination of factors. The EORTC SURTIME trial investigates treatment break PD after immediate CN and CN after sunitinib and may answer this question.
Adherence to oral anticancer drugs (OAD) in patients (pts) with metastatic renal cancer (mRCC): First results of the prospective observational multicenter IPSOC study (Investigating Patient Satisfaction with Oral Anti-cancer Treatment).
Authors: Wolter Pascal , Hendrickx Tine , Renard Vincent , Mebis Jeroen , Debruyne Philip R. , Wynendaele Wim , Schallier Denis C. C. , Vermeij Joanna , Nielander Aldrik , Machiels Jean-Pascal H. , Rottey Sylvie , Delande Stephanie , Goeminne Jean-Charles , Schoffski Patrick , De Coster Sandra , Lacour Valerie , Foulon Veerle
Published: March 2020

4622

Background: Patient adherence to oral therapy is a critical issue in cancer treatment. The aim of this study is to investigate the prevalence and severity of non-adherence to OAD in mRCC and to identify factors predictive of non-adherence. Methods: Prospective observational multicenter trial performed at 11 Belgian academic and non-academic centers. All pts with mRCC starting OADs (sunitinib, pazopanib, everolimus or sorafenib) are eligible for the study. Pts are contacted by phone at baseline and at 1, 3, 6 and 12 months. At each contact, pts are asked to complete questionnaires investigating 1) medication adherence (MMAS), 2) patient satisfaction with treatment (CTSQ) and with treatment education (PS-CaTE), 3) the extent of information desire (EID), 4) quality of life (FACT-G and FKSI) and 5) the role of the pharmacist (SWiP). Adherence is measured using an electronic medication event monitoring system (MEMS, Aardex). Results: Between 02/2011 and 11/2011, 49 pts (m: 33, f: 16) with a median age of 63 years (range 25 - 87) have participated in the IPSOC study. Twenty-nine pts (64%) were treated with an OAD in first-line, 15 pts (33%) in second-line. With a median follow-up of 131 days (range 2 - 313) 45 pts (92%) claimed to be fully adherent to their treatment (based on MMAS and CTSQ data). Four patients indicated to have missed at least one dose, of whom two indicated they occasionally forgot their medication and two others interrupted treatment because of side effects. Based on MEMS data, mean adherence, defined as the percentage of days with at least the prescribed number of dosage taken, was 98.91%. Conclusions: The IPSOC study, the first to examine adherence to OAD among mRCC pts, shows that mRCC pts are almost fully adherent to treatment recommendations. This seems to be in contrast to adherence data for other, long-lasting, anti-cancer treatments. Further investigations will focus on the question whether extensive counseling and participation in side-effect programs contribute to the high percentage of adherence in this study.
Updated safety results from EXIST-2: Everolimus therapy for angiomyolipoma (AML) associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM).
Authors: Bissler John , Kingswood Christopher , Zonnenberg B. A. , Frost Michael , Belousova Elena , Radzikowska Elzbieta , Sauter Matthias , Nonomura Norio , Brakemeier Susan , de Vries Petrus , Klimovsky Judith , Shah Gaurav D. , Miao Sara , Lincy Jeremie , Budde Klemens
Published: March 2020

4632

Background: EXIST-2 (NCT00790400) is a randomized, double-blind, placebo-controlled, phase 3 trial assessing the efficacy and safety of everolimus, an oral mTOR inhibitor, for treating AML in patients with TSC or sLAM. We have previously reported that everolimus resulted in a significantly higher AML response rate vs placebo (41.8% vs 0%; 95% CI: 23.5–58.4; p<0.0001) with a consistent safety profile (Bissler et al. J Am Soc Nephrol. 22, 2011, Abstract LB-PO3159). Here we present a 90-day safety update. Methods: 118 eligible patients were randomized 2:1 to receive everolimus 10 mg daily (n=79) or placebo (n=39). The primary efficacy endpoint was AML response rate (proportion of patients with best overall AML response status of “response”). Original cut-off date for data analysis was 30 Jun 2011. An updated analysis of the safety data for the safety set (all patients receiving ≥1 dose of double-blind study drug with a valid post-baseline assessment) to 14 Oct 2011 are presented here. Results: As of 14 Oct 2011, median treatment duration was 48.1 and 45.0 weeks for everolimus and placebo arms, respectively. Discontinuations in the double-blind period were the same in the everolimus arm as the initial analysis, but had increased by 4 patients in the placebo arm since initial analysis (3 due to disease progression, 1 withdrew consent). The majority of adverse events (AEs) continued to be grade 1 or 2; the incidence of serious AEs was slightly higher than initially reported, particularly in the placebo arm (everolimus 20.3%, placebo 23.1%). AE incidence leading to discontinuation was the same as initially reported (everolimus 3.8%, placebo 10.3%). In the updated data, 3 additional everolimus patients required dose interruption or reduction due to AEs; dose reduction/interruption remained more common in the everolimus arm (51.9% vs. 20.5%). Conclusions: Overall, the 90-day updated safety data analysis from the EXIST-2 trial has not revealed any additional safety concerns. No other patients receiving everolimus withdrew for any reason, whereas 3 more patients receiving placebo withdrew due to disease progression.
Proton radiotherapy for prostate cancer in the Medicare population: Patterns of care and comparison of early toxicity with IMRT.
Authors: Yu James B. , Soulos Pamela R. , Cramer Laura D. , Roberts Kenneth B , Herrin Jeph , Potosky Arnold L. , Gross Cary P.
Published: March 2020

4651

Background: Proton radiotherapy (PRT) is a costly treatment used for prostate cancer despite little evidence supporting its use. We examined patterns of PRT use in the Medicare program and assessed the short-term toxicity of PRT vs. intensity modulated radiation therapy (IMRT). Methods: Using national Medicare claims from 2008-2009, we identified a sample of prostate cancer patients ages 66-94 who had received PRT or IMRT. We used multivariable logistic regression to identify patient and regional factors associated with receipt of PRT. We searched claims for procedure and diagnosis codes indicative of treatment-related complications and grouped the complications into genitourinary (GU), gastrointestinal (GI), and other complications. To compare the effect of PRT and IMRT on short-term toxicity, we used a Mahalanobis distance approach to match each PRT patient to two IMRT patients, achieving balanced distribution of clinical and sociodemographic characteristics. We compared six-month and one-year outcomes between the two treatment groups using conditional logistic regression. Results: We identified 27,647 men; 421 (2%) received PRT and 27,226 (98%) received IMRT. Patients who received PRT were widely geographically distributed, with some patients traveling >500 miles for treatment. PRT patients were younger, healthier, and of higher socioeconomic status. Although PRT was associated with a significant reduction in GU complications at six-months compared with IMRT (6.1% vs. 12.0%, OR 0.60 [95% CI 0.38-0.96], p=0.03), at one-year post-treatment there was no longer any difference in cumulative complication rates (18.9% vs. 21.9%, OR 0.96 [95% CI 0.61-1.53], p=0.88). There was no significant difference in GI or other complications at six-months or one-year post-treatment. Conclusions: Although PRT remains a scarcely used treatment, some prostate cancer patients traveled great distances for treatment. While PRT was associated with a reduction in six-month GU toxicity, there were no differences in toxicity at one-year. Further study on longer-term effects and other clinical and patient-reported outcomes is needed to inform the widespread application of PRT.
Liver metastases (LM) to predict for short overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).
Authors: Kelly William Kevin , Halabi Susan , Carducci Michael Anthony , George Daniel J. , Mahoney John Francis , Stadler Walter Michael , Morris Michael J. , Kantoff Philip W. , Monk J. P. , Small Eric Jay ,   Alliance for Clinical Trials in Oncology
Published: March 2020

4655

Background: Patients withCRPC with LM represent a subset of patients with a poor prognosis. An exploratory analysis was performed to evaluate the difference in baseline characteristics and clinical outcomes in patients with and without LM from a randomized phase III trial (CALGB 90401) in men with mCRPC. Methods: Data from 1,050 men treated with docetaxel, prednisone with either bevacizumab or placebo were used. Pts were chemotherapy naïve, and had evidence of progressive mCRPC despite castrate testosterone levels and anti-androgen withdrawal, ECOG performance status ≤ 2, and adequate bone marrow, hepatic and renal functions. The proportional hazards model was used to assess the prognostic significance of LM in predicting OS and progression free survival (PFS) adjusting for stratification factors. Results: Fifty-nine (5.6%) of the 1045 pts with a complete data set had documented LM. Patients with LM had higher baseline alkaline phosphatase (ALK, 167 vs 117 U/L, p =0.0205) and lactate dehydrogenase (LDH, 262 vs 205 U/L, p =0.0001) compared to patients without LM. There were strong associations between LM status and lung metastasis (p=0.0004) and other visceral disease (p=<0.001) but not with bone disease. Clinical outcomes as a function of LM status are listed in the table. The median OS time in LM pts was 14.4 compared to 22.6 months, with a hazard ratio (HR) 1.4. The HR for treatment effect (DP+B vs. DP) for LM was not statistically significant for either group. Conclusions: Compared to pts without LM, mCRPC with LM are characterized by higher LDH and ALK and have a poor OS despite having similar PFS and objectivebiochemical response to docetaxel based therapy. [Table: see text]
Prostate-specific antigen (PSA) screening in the United States: Patterns of use and PSA outcomes in screened versus unscreened men.
Authors: Allen Ian M. , Hendrix Laura H , Royce Trevor Joseph , Stokes William A. , Wang Andrew , Godley Paul Alphonso , Chen Ronald C.
Published: March 2020

4658

Background: PSA screening is a subject of substantial controversy. We examined patterns of PSA screening using a recent cohort from the population-based National Health and Nutrition Examination Survey (NHANES) study and compared PSA levels of previously screened vs. never screened men. Methods: NHANES is a cross-sectional study which collects health-related information (including cancer screening history, family history and socioeconomic variables) and blood samples from nationally representative samples of the US population. We included 2,078 previously screened men and 1,902 never screened men surveyed from 2003-8. Statistical analysis accounted for sampling weights. Results: 25% of men age 40-49 years had prior PSA screening; 56% age 50-59, and 72% age 60-69. Screening rates were higher for men with family history (68% vs. 50% no history, p<.001), health insurance (58% vs. 21% no insurance, p<.001), and Caucasians (59% vs. 44% non-Caucasian, p<.001). No significant differences were seen in the PSA values of screened vs. never screened men stratified by age (Table), or by race/ethnicity, insurance status, or family history. Conclusions: Rates of PSA screening in the US differ by age, family history, race/ethnicity and insurance status. However, no significant differences were seen in PSA values of screened vs. unscreened men, and very few patients under 60 years of age had PSA values ≥10. Despite questions about the appropriate role of PSA testing, population-based prostate cancer screening is routinely conducted among Caucasian and non-Caucasian men 50 years of age and older. [Table: see text]
Association of decreased expression of protein phosphatase 2A subunit PR55γ (PPP2R2C) with an increased risk of metastases and prostate cancer-specific mortality.
Authors: Spencer Elysia Sophia , Bluemn Eric Gregory , Johnston Richard , Zhang Xiaotun , Gordon Ryan Robert , Lewinshtein Daniel , Lucas Jared , Nelson Peter , Porter Christopher R.
Published: March 2020

4669

Background: The protein phosphatase 2A (PP2A) holoenzyme complex negatively controls cell growth, differentiation and apoptosis. Down regulation of PP2A activity is associated with oncogenic transformation of papillomas and is a target for the small-T viral oncogene. The PR55γ (2R2C) subunit regulates PP2A target specificity, inhibiting c-Src activity in some cell lines. c-Src activity enhances growth and invasion in prostate cancer. This study evaluates whether PPP2R2C protein levels in radical prostatectomy (RP) specimens were predictive for the development of metastases or prostate-cancer specific mortality (PCSM). Methods: From 1954-1997, 1004 consecutive patients underwent RP at Virginia Mason Medical Center in Seattle. Metastases were confirmed radiographically or by tissue diagnosis. Death certificates confirmed PCSM. Patients without stored tissue were excluded. 34 patients with metastases or PCSM were matched to patients without recurrence (NR) at a 1:2 ratio. Paraffin-embedded tissue was stained with anti-PPP2R2C monoclonal antibody, clone 6D1 (Abnova, Taiwan). A pathologist evaluated the percentage and intensity of nuclei stained using a 4-point scale. Statistical analysis was performed on SAS. Results: Mean follow up was 10.26 years. PPP2R2C was detected in 13/18 (72.2%) PCSM, 18/22 (81.8%) metastases and 45/49 (91.8%) NR patients. Mean expression was lower in cancerous vs benign glands, 1.74 vs 2.04 (p = 0.001). Expression intensity from PCSM vs NR was 1.45 vs 1.80 (p = 0.041). On multivariate analysis, expression was lower in metastases or PCSM versus NR 1.79 vs 2.35 (p = 0.002), independent of pre-op PSA and Gleason grade. Conclusions: PPP2R2C loss was highly correlated with metastasis and PCSM. Patients with the lowest levels of expression were at the highest risk for PCSM. As tissue was obtained at time of surgery, this analysis reflects a truly prognostic biomarker, independent of Gleason grade and PSA. We have shown that PPP2R2C scoring is a useful metric to identify patients at high risk of developing advanced disease. With further validation may allow for more accurate individual patient treatment plans and counseling.
Prospective assessment of cost, morbidity, and survival associated with lymphadenectomy in low-risk endometrial cancer.
Authors: Dowdy Sean Christopher , Borah Bijan J , Bakkum-Gamez Jamie Nadine , Weaver Amy , McGree Michaela , Haas Lindsey R , Martin Jan , Keeney Gary L. , Mariani Andrea , Podratz Karl C.
Published: March 2020

5004

Background: Since 1999, patients with low-risk endometrial cancer (EC) as defined by the Mayo criteria have preferably not undergone lymphadenectomy (LND) at our institution. We assess survival, sites of recurrence, morbidity, and cost per up-staged case in this low-risk cohort. Methods: Consecutive patients with Mayo-defined low-risk EC managed without (non-LND) and with LND were compared. Cause-specific survival (CSS) was estimated using the Kaplan-Meier method and compared using the log-rank test. 30-day cost analyses were equated to 2010 Medicare dollars. Results: Among 1,393 consecutive surgically managed EC cases, 385 (27.6%) met the Mayo low-risk criteria, accounting for 34.1% of type I EC. The 5-year CSS of the low-risk cases was 98.6 %. There were 80 LND cases (median # nodes, 29) and 305 non-LND cases. Complications within 30 days occurred in 37.5% and 19.3% of LND and non-LND cases, respectively (P<0.001). Nodal metastasis was identified in a single LND case (1.3%). There were 11 recurrences, 6 of which were vaginal. Not a single recurrence was detected in the pelvic or paraaortic nodal areas in these 385 patients, with a median follow-up of 5.4 years. The estimated prevalence (combining surgery and surveillance) of lymph node metastasis was 0.3%. The 5-year CSS in LND and non-LND cases was 97.3% and 99.0%, respectively (P=0.32). Patients were more than seven times as likely to die of co-morbidities than from EC. The 30-day median cost of care was $15,678 for LND cases compared to $11,028 for non-LND cases (P<0.001). The estimated cost per up-staged low-risk case was $439,990 if performed via endoscopy and $327,866 via laparotomy. If the 305 non-LND cases had been subjected to LND, an estimated additional $1,418,189 would have been expended. Conclusions: For patients with low-risk EC as defined by the Mayo criteria, lymphadenectomy dramatically increases morbidity and 30-day cost of care without discernible short- or long-term benefits: CSS was 99% with a 0.3% rate of nodal metastasis. In these low-risk patients, hysterectomy with salpingo-oophorectomy alone is appropriate surgical management and should be standard of care.
A randomized, phase III trial of paclitaxel plus carboplatin (TC) versus paclitaxel plus cisplatin (TP) in stage IVb, persistent or recurrent cervical cancer: Japan Clinical Oncology Group study (JCOG0505).
Authors: Kitagawa Ryo , Katsumata Noriyuki , Shibata Taro , Nakanishi Toru , Nishimura Sadako , Ushijima Kimio , Takano Masashi , Satoh Toyomi , Yoshikawa Hiroyuki , Kamura Toshiharu ,   Japan Clinical Oncology Group
Published: March 2020

5006

Background: TC is a less toxic regimen in terms of milder nephropathy, neuropathy and no need of hospitalization. This multicenter phase III trial was designed to evaluate the clinical benefits of TC compared with TP which is current standard chemotherapy for stage IVB or recurrent cervical cancer. Methods: Patients (pts) with stage IVB or recurrent cervical cancer; not amenable to curative therapy; 0-1 prior platinum; no prior taxanes; were randomized with minimization method to either TP (T 135 mg/m2 24h d1 + P 50 mg/m2 2h d2) or TC (T 175 mg/m2 3h d1 + C AUC5 1h d1), both for maximum 6 cycles every 21 days. Primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), toxicities, and the proportion of non-hospitalization periods (NHP) as a surrogate for QoL. The trial was powered at least 70% to confirm the non-inferiority of TC to TP (threshold hazard ratio [HR] 1.29) in terms of OS, and the planned sample size was 250 pts with one-sided alpha 5%. HR is estimated by a stratified Cox regression. Results: From 2/06 to 11/09, 253 pts were enrolled. 71% pts of TP arm and TC arm each received 6 cycles. Median follow-up is 17.4 mo. Results are as below. As an alpha level for an interim analysis was less than 0.0001, significance level for the final analysis is approximately 5% even after the multiplicity adjustment. Conclusions: This first randomized controlled trial comparing carboplatin doublet with cisplatin doublet showed significant non-inferiority of TC in terms of OS. More feasible and less toxic TC can be recommended as the new standard treatment for stage IVB or recurrent cervical cancer. [Table: see text]
Survival after radiation therapy for early-stage endometrial carcinoma: The Oslo study revisited after up to 43 years of follow-up.
Authors: Lindemann Kristina , Onsrud Mathias , Kristensen Gunnar , Trope Claes
Published: March 2020

5008

Background: There is an ongoing debate regarding the benefit of radiation in patients with early stage endometrial carcinoma. Data on long time risk conferred by radiation is scarce. This study is a long-term follow-up on survival and secondary cancers of a previously published randomized study (Aalders J. et al., Obstet Gynecol 1980; 56: 419-27). Methods: Between 1968 and 1974, 568 patients with endometrial cancer FIGO stage I primarily treated with abdominal hysterectomy and bilateral salpingo-oophorectomy were included in the study. Patients were postoperatively randomized to receive either vaginal radium brachytherapy followed by external pelvic radiation 40 Gy (N=288) or brachytherapy alone (N=280). Survival data and data on incident secondary cancers were obtained by individual linkage to the Registry of Statistics Norway and Cancer Registry of Norway. By the end of follow-up at 1 November 2011, 45 (7.9%) patients were still alive. We used Cox proportional hazards model to estimate hazard ratios (HR) with 95% confidence intervals (95% CI). We also conducted analyses stratified by age groups. Results: After median 21 (range 0-43.4) years of follow-up there was no significant difference in overall survival or relapse free survival between treatment arms with HR of 1.12 (95% CI: 0.95-1.33) and HR 0.88 (95% CI: 0.55-1.40), respectively. Patients treated with external radiation had significantly lower risk of developing locoregional relapse (p<0.001). However, women younger than 60 years had a significant poorer survival after external radiation (HR 1.36; 95% Cl: 1.06-1.76). In this patient group the risk of secondary cancer was significantly increased (HR 1.9; 95% CI: 1.23-3.03). Conclusions: We observed no survival benefit of external pelvic radiation in early stage endometrial carcinoma. In women younger than 60 years, pelvic radiation decreased survival, probably due to increased risk of subsequent second neoplasms. Adjuvant external radiotherapy cannot be recommended to this patient group. Those who have received such treatment might eventually benefit from prolonged post treatment surveillance with respect to secondary cancer.
Phase II trial of bevacizumab and pemetrexed for recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer.
Authors: Hagemann Andrea R. , Zighelboim Israel , Novetsky Akiva Pesach , Gao Feng , Massad L. Stewart , Thaker Premal H. , Powell Matthew A. , Mutch David Gardner , Wright Jason D.
Published: March 2020

5013

Background: This phase II clinical trial evaluated the efficacy and safety of the combination of bevacizumab, a VEGF inhibitor, and pemetrexed, a multi-targeted antifolate agent inhibiting thymidylate synthase, for recurrent or persistent epithelial ovarian, fallopian tube (FT) or primary peritoneal (PP) cancer. Methods: Patients with measurable recurrent/persistent epithelial ovarian, FT or PP cancer after at least one prior platinum- and taxane-containing regimen were eligible. Patients might have received < 2 prior cytotoxic chemotherapy regimens but no prior bevacizumab. Pemetrexed 500 mg/m2 IV and bevacizumab 15 mg/kg IV were given every 3 weeks until progression, unacceptable adverse effects, or patient/physician choice. 32 patients were needed to have 90% power to detect the primary endpoint of 6-month PFS ≥ 40% with a two-sided 0.05 significance. Secondary endpoints included toxicity and response by RECIST and CA-125 criteria. Results: Thirty-four patients received a median of 7 treatment cycles (range, 2-26). Twenty-eight patients (82%, 95% CI: 66-92) were platinum-sensitive. Median follow-up was 17.1 months (range, 2.7-31.2). The 6-month PFS was 58.2% (95%CI: 40-73) for all patients and 50% (19-81) for platinum-resistant patients. Objective response rates by RECIST criteria included (%; 95%CI): 0 CR, 14 PR (41%; 25-59), 18 SD (53%; 35-70) and 2 PD (6%; 1-20). Of 27 patients evaluable by CA-125, levels declined ≥50% in 17 (62%; 44-79), and ≥75% in 8 (30%; 16-49). 12-month OS was 88% (95%CI: 71-95) and median PFS was 7.8 months (95%CI: 4.7-10.7). Of the 34 patients, grade 3-4 hematologic toxicities occurred in 53% (neutropenia 50%, leukopenia 26%, thrombocytopenia 12%, anemia 9%). Other grade 3-4 toxicities included metabolic (29%), constitutional (18%), pain (18%) and gastrointestinal (15%). No bowel perforations occurred. Conclusions: Combined bevacizumab/pemetrexed is well tolerated and highly active for the treatment of recurrent ovarian cancer. The dose and schedule tested here warrant further investigation in phase III trials.
Phase I/II study of weekly paclitaxel with or without MLN8237 (alisertib), an investigational aurora A kinase inhibitor, in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (OC), or breast cancer (BrC): Phase I results.
Authors: Falchook Gerald Steven , Goff Barbara Ann , Kurzrock Razelle , Gray Heidi J. , Martin Lainie P. , Coleman Robert L. , Liu Hua , Zhou Xiaofei , Benaim Ely , Schilder Russell
Published: March 2020

5021

Background: Preclinical data indicate that inhibiting aurora A kinase (AAK), a key mitotic regulator, in OC can enhance the activity of taxane-based chemotherapy. This is the first clinical study to evaluate the AAK inhibitor MLN8237 (A) in combination with paclitaxel (P). Methods: Eligible women (aged ≥18 y) had previously treated, metastatic or locally recurrent OC or BrC. OC pts had previously received a platinum and taxane, and had disease recurrence within 12 mo of discontinuing platinum. Pts received IV P (D1, 8, 15) with oral A (enteric coated tablet, 3 d on, 4 d off, wkly for 3 wks) in 28-d cycles. Doses were escalated in a 3+3 schema. Phase I endpoints were safety, response by RECIST and CA125, and pharmacokinetics (PK). Results: 28 pts were treated at doses of P80 mg/m2 + A10 mg BID (n=5), P80+A20 (n=6), P60+A20 (n=4), P60+A30 (n=6), P60+A40 (n=4) and P60+A50 (n=3). 25 pts had OC (20 ovarian, 4 primary peritoneal, 1 mullerian) and 3 BrC. Median age was 59 y (range 37–72). Pts received a median of 2.5 (1–16) and 2.5 cycles (1–15) of A and P, respectively. 11 pts are ongoing. 3 pts had DLTs: Gr 4 diarrhea (P80+A20), Gr 3 stomatitis (P80+A20) and Gr 4 neutropenia for >7 d with fever (P60+A30). MTD has not yet been reached. 27 pts had ≥1 drug-related adverse event (AE); most common were neutropenia (n=18), anemia (n=13) and nausea (n=12). 21 pts had Gr ≥3 drug-related AEs; the most common was neutropenia (n=15). 5 pts had drug-related SAEs. No pts have died on study. Preliminary PK data (n=24) indicated fast absorption of A with a median Tmax of 3 hr. Geometric means of A AUC0–12hr on D3 were 3740 nM*hr (CV: 22%), 7180 nM*hr (31%), 11,900 nM*hr (49%) and 15,100 nM*hr (72%) at 10, 20, 30 and 40 mg BID, respectively. A exposures increased approximately dose proportionally. Partial responses by RECIST (n=5) and/or CA125 (n=7) in 8 pts (29%; 7 OC, 1 BrC); 3 pts had stable disease ≥6 mo. Conclusions: Emerging data from this first combination study suggest that P+A is generally well tolerated and has antitumor activity in pts with OC/BrC. Dose-escalation is ongoing to determine the recommended phase II dose.
A snapshot of potentially personalized care: Molecular diagnostics in gynecologic cancer.
Authors: Sales Elizabeth , Penson Richard T. , Sullivan Laura A , Borger Darrell R. , Krasner Carolyn N. , Goodman Annekathryn , del Carmen Marcela G , Growdon Whitfield Board , Schorge John O. , Boruta David M. , Birrer Michael J.
Published: March 2020

5029

Background: Genetic abnormalities underlie the development of cancer. It has been proposed that tumors be recategorized by gene mutation such as BRAF in LG serous, TP53 in HG serous, and PIK3CA in clear cell and endometrioid tumors. These targets potentially represent an opportunity for personalizing cancer therapy. Methods: Gynecologic Oncology patients at the MGH Cancer Center can have their tumor genotyped for a panel of mutations by SNaPshot, a validated, CLIA approved assay developed by MGH that uses DNA from FFPE tissue to interrogate 160 site-specific mutations across 15 genes (AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, IDH1, KIT, KRAS, MAP2K1, NOTCH1, NRAS, PIK3CA, PTEN, TP53). At present SNaPshot has no validated endpoints in GYN Cancers but may help identify a useful clinical trial. Results: Between 5/17/10 and 10/17/11, 125 patients consented to SNaPshot genotyping. Patients had a median age of 59 (24-78) yrs. Tumors were ovarian 70(56%), uterine clear, UPSC, or MMMT 16(13%), uterine endometrioid 10(8%), fallopian tube 8(6%), PPC 7(6%), cervical 6(5%), uterine sarcomas (3), ACUP (2), vulvovaginal (2), metastatic (1). A mutation was identified in 41(33%), with 9 of these (23%) having 2 or 3 (n=2) mutations. In the 85 ovarian, FT, and PPC cancers 33% were +ve, but 50% were in TP53. The low mutation rate for TP53 is likely explained by copy number abnormalities (Amplification). 50% of the 10 uterine tumors were +ve, with 3 of those 5 having multiple mutations in the PIK3CA pathway, while 69% of the non-endometrioid uterine tumors had mutations. Only 20% of the vulvo-vaginal and Cx tumors had mutations, both PIK3CA. 19% of the purely serous tumors (n=58) had TP53 mutations, and 37% of the purely clear/endometrioid tumors (n=19) had mutations in PIK3CA, PTEN or AKT. Certain rare tumors did not have identifiable mutations: granulosa cell tumors (2), ovarian small cell (2). 5 pts with a PIK3CA mutation were enrolled on a clinical trial (2 phase II, 3 phase I, 3 uterine, 1 ovary, 1 cervix). Conclusions: SNaPshot can identify potentially important therapeutic targets. However, the incidence of "drugable" targets in ovarian cancer is low, and <5% subjects eventually were treated on a relevant clinical trial.
Carboplatin dosing in the treatment of epithelial ovarian cancer (EOC): A Gynecologic Oncology Group (GOG) study.
Authors: O'Cearbhaill Roisin Eilish , Miller Austin , Muggia Franco , Smith Judith A. , Bookman Michael A. , Sabbatini Paul ,   Gynecologic Oncology Group
Published: March 2020

5041

Background: Optimal carboplatin dosing (CPRx) for patients (pts) with renal dysfunction or low creatinine (Cr) values in the setting of malnutrition and ascites is unknown. Multiple methods have been utilized to estimate Cr clearance (CrCl) but these perform differently in pts with abnormal Cr values. We sought to determine 1) the relationship between adverse events (AE) and baseline CrCl used for CPRx; 2) the effect on CPRx of using Cockcroft-Gault (CG) +/- the NCI/CTEP recommended limits (CGL), Modification of diet in renal disease (MDRD) or Jelliffe Formula (J) renal function estimates. Methods: Retrospective data were drawn from pts treated on GOG 182, a phase III trial of carboplatin doublet vs triplet or sequential doublet combinations in stage III/IV EOC. For patient safety, the protocol was amended to assign the lower limit of Cr at 0.6mg/dl for CPRx. Area under the receiver operating characteristic curve (AUC) was used to describe associations between CrClJ and various AE. Sensitivity and positive predictive values (PPV) described the AE rate in pts with CrClJ <60ml/min. CPRx for each pt was calculated using J, CG, CGL and MDRD. Results: 3830 evaluable pts had a mean age 58.7yrs, mean BMI 26.8kg/m2 and mean baseline CrClJ 81.9ml/min (range 23.4-239). The AUC statistics (range 0.52-0.64) show that the log(CrClJ) was not a good predictor of grade ≥3 AE (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). A cutoff value of CrClJ <60 ml/min would have deemed 15% of pts treated on GOG182 ineligible. The range of PPV for the above AEs in pts with CrClJ <60 ml/min was 1.8-15%. Using CG, CGL, MDRD instead of J for CPRx would have resulted in >10% decrease in CPRx in 21%, 32% and 12% of pts, respectively. Using CG, CGL, MDRD instead of J for CPRx would have resulted in >10% increase in CPRx in 45%, 9.6% and 5.2% of pts, respectively. Conclusions: Our data do not support excluding patients with CrClJ <60ml/min from clinical trials. The new GOG guidelines replacing J with CGL affect CPRx. The clinical significance of this change with regards to toxicity, particularly in pts with abnormally low Cr values, is yet to be determined.
What do 676 primary and recurrent ovarian cancer (OC) patients expect from their doctors and therapy management? Results of a German survey of the northeastern German Society of Gynecological Oncology (NOGGO).
Authors: Oskay-Özcelik Gülten , Chekerov Radoslav , Neubert Sylvia , Münstedt Karsten , Hindenburg Hans-Joachim , Liebrich Clemens , Hanker Lars Christian , Lorenz Ralf , Wimberger Pauline , Sehouli Jalid
Published: March 2020

5044

Background: The primary aim of this study was to investigate information needs and preferences among patients with ovarian cancer, focusing especially on doctor-patient relationships and therapy management. Methods: A 42-item questionnaire was developed and validated in a mono-centre phase I study and was then provided to primary and recurrent ovarian cancer patients via internet (online) or as a print-version. In the first part basic data (age, tumour status, therapy) were requested. In the second part, most of the questions try to evaluate the expectations and needs concerning their therapy management and doctor-patients communication. Results: From January to November 2009, a total of 676 (201 online; 475 print version) patients with ovarian cancer from 44 German centres took part in the survey.The median age of the online group was 49 years (range 19-84), for the print group 62 years (26-92). Nearly all patients (98.7%) had a primary surgery and a primary chemotherapy (89%). Asked for side effects during therapy, the most frequent answers were alopecia, paraesthesia/dysaesthesia and fatigue. Most of the patients were content with the completeness and understandability of the explanations about the therapies from their doctors . The three most important aspects, which were proposed by patients to improve therapy against ovarian cancer were: “Doctors should have more time for explanations”, “The therapy should not lead to any loss of hair”, and “The therapy should be more effective”. Conclusions: This study underlines the high need of ovarian cancer patients to discuss all details concerning treatment options and clinical management. As matter of fact, the physician involved in the treatment is the most important source of information.
Longitudinal health-related quality of life assessment: Implications for prognosis in ovarian cancer.
Authors: Braun Donald Peter , Gupta Digant , Staren Edgar Donald , Markman Maurie
Published: March 2020

5049

Background: Several studies in the oncology literature have demonstrated the prognostic value of baseline quality of life (QoL). However, there is little to no information on the prognostic effects of changes in QoL during treatment. We investigated whether changes in QoL could predict survival in ovarian cancer patients treated with an integrative model of care. Methods: We evaluated 137 ovarian cancer patients treated at our institution between Jan 2001 and Dec 2009 who were available for a minimum follow-up of 3 months. QoL was evaluated at baseline and after 3 months of treatment using EORTC-QLQ-C30. The QLQ-C30 incorporates a global scale, 5 function scales and 8 symptom scales. Patient survival was defined as the time between date of first patient visit and date of death from any cause/date of last contact. Cox regression was performed to evaluate the prognostic significance of baseline and changes in QoL scores after adjusting for age, treatment history and stage at diagnosis. Results: Mean age at diagnosis was 51.1 years. 28 patients were newly diagnosed while 109 were previously treated. Stage at diagnosis was I, 16; II, 15; III, 72; IV, 28; and 6 indeterminate. Median overall survival was 33.5 months (95% CI: 11.5-55.6 months). Baseline QoL scale predictive of survival upon multivariate analysis was nausea/vomiting (p=0.04). Associations between changes in QoL and survival were observed for global function, appetite loss and constipation. Every 10-point increase (improvement) in global function from baseline to 3 months was associated with a 10% decreased risk of death (HR=0.90; 95% CI=0.81 to 0.99, p=0.03). The corresponding HRs for 10-point increase (deterioration) in appetite loss and constipation scales were 1.20 (1.06 to 1.35; p=0.005) and 1.13 (1.02, 1.24; p=0.02) respectively. Conclusions: This exploratory study provides some preliminary evidence to indicate that ovarian cancer patients whose QoL improves within 3 months of treatment have a significantly increased survival time compared to those who fail to demonstrate improvement. These findings might be used in clinical practice to systematically address QoL-related problems of ovarian cancer patients throughout their treatment course.
Sexual function, sexual activity, and quality of life in women with ovarian and endometrial cancer.
Authors: Harter Philipp , Schrof Inga , Lehmann Karl M , Hils Rita , Kullmann Verena , Traut Alexander , Scheller Herbert , Du Bois Andreas
Published: March 2020

5051

Background: Gynecological cancer (GC) is generally assumed to have an impact on sexual function and activity. Although there are several studies addressing the issue, case control studies are currently limited. Methods: We performed a cross-sectional investigation of sexual function and activity utilizing the sexual activity questionnaire, the female sexual function index, and parts of the EORTC QLQ C30. Patients with gynecological cancer (GC) like ovarian and endometrial cancer were compared with a control group (C) of non-cancer patients. Inclusion of GC was only allowed if treatment was completed ≥12 months previously and patients were disease-free. Results: The questionnaires were sent out to 727 women (335 x GC and 392 x C), 22.8% of which responded. Response rates in both groups were equivalent (79 pts with GC [23.6%] and 87 control subjects [22.2%]). Median age was 57 years (C) and 62 years (GC), respectively (p=0.237). 51.5% (C) and 59.5% (GC) were not sexually active, mainly owing to lack of a partner (37%) or lack of interest (21%) in controls and lack of interest (40%, p<0.05), self-reported physical problems (31.9%, p<0.05), and physical problems of the partner (21%, p<0.05). There were significant differences between both groups in the SAQ discomfort score (p<0.05). We did not observe significant differences in quality of life or other scores regarding sexuality. Conclusions: About half of the women in both groups were not sexually active. However, reasons for non-activity differ. Quality of sexuality tends to be impaired in GC patients, but this seems not to influence quality of life. A shift of priority caused by substantial anxiety regarding cancer specific survival might explain our findings.
The effect of the APPRISE mandate on use of erythropoiesis-stimulating agents and transfusion rates in ovarian cancer patients.
Authors: Boone Jonathan David , Walters Christy Lynn , Fauci Janelle M. , Whitworth Jenny M. , Bevis Kerri S. , Alvarez Ronald David
Published: March 2020

5060

Background: Erythropoiesis-stimulating agents (ESAs) have long been used to support chemotherapy-induced anemia in patients with epithelial ovarian cancer (EOC). Recent studies have demonstrated that ESAs may lead to increased tumor growth and shorter survival. The FDA mandated new guidelines (APPRISE, for Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) for consenting patients before ESA administration. We sought to quantify the change in ESA use and RBC transfusion rates after the APPRISE mandate was instituted. Methods: A retrospective chart review identified patients with EOC undergoing chemotherapy after initiating the APPRISE mandate. A similar subset of patients treated prior to the APPRISE guidelines served as a control cohort. Abstracted data included patient demographics, primary or second line treatment status, chemotherapy regimen, number of patients requiring ESA or RBCs, or both, and a cost savings analysis. Results: 84 patients with EOC were identified as having undergone 367 cycles of first or second line chemotherapy after the APPRISE guidelines were instituted. A matched set of 88 patients receiving 613 cycles of chemotherapy within a year prior to institution of the APPRISE guidelines was analyzed for comparison. The two groups were statistically similar. Most patients in each group were initially diagnosed with advanced stage disease, were receiving primary chemotherapy, and were receiving taxane/platinum-based chemotherapy. 45 of 88 patients (51%) in the pre-APPRISE group received a total of 196 ESA injections compared to 0 of 84 patients (0%) in the post-APPRISE group. In spite of discontinuing the use of ESAs and no change in transfusion thresholds, RBC transfusion in the post-APPRISE group was similar to that in the pre-APPRRISE group (8.3% vs. 14.8%, p=.28). Omission of ESAs in the post-APPRISE group resulted in a cost-savings of an estimated $700,000 in billable charges. Conclusions: In our institution, the APPRISE guidelines resulted in complete cessation of ESA use in patients with EOC, resulting in considerable cost savings. Importantly, RBC transfusion rates did not increase after the guidelines were imposed.