bluuebunny/crossref_metadata_2025 huggingface dataset:
Race/ethnicity, literacy, and prostate cancer: Initial findings from the COMPARE registry
Authors: Sartor O. , Bennett C. L. , Halabi S. , Kattan M. , Scardino P.
Published: March 2020

4620

Background: Comprehensive Multicenter Prostate Adenocarcinoma Registry (COMPARE) evaluates variations in initial prostate cancer (PCa) therapy according to race/ethnicity. Similar studies for prostate cancer patients with PSA failure following radiation therapy or radical prostatectomy are unreported. Poor health literacy and African American race are predictive of advanced stage prostate cancers at diagnosis. Methods: COMPARE includes 778 men (62% >70 yr; 80% white and 13% AA) with rising PSA post-localized PCa therapy. Median follow-up post-registry entry is 5 months. Enrollment at 146 sites to date: urology (N = 129), radiation oncology (n = 12), other (n = 5). Most sites are private practice (n = 132) vs academic (n = 14). Health literacy was tested with a 7-item validated word recognition test; scores of ≥4 correlate with ≥6th grade literacy. Variations in therapy, both initial and after PSA failure, were assessed as a function of patient/regional factors. Results: Initial therapy included radical prostatectomy (RP) 44.5%, external beam radiation therapy (EBRT) 30.7%, brachytherapy (BT) 13.1%, other (11.5%). Literacy data are available for 725 men, one fifth had poor literacy skills (<4); higher rates of low literacy were present in AA vs white men (p < 0.05). Significant variations in initial care were associated with poor vs normal literacy skills (brachytherapy: 8% vs 16%; radical prostatectomy: 52% vs 44%, p < 0.05). Watchful waiting was the most common management for PSA failure patients, 82% for men aged ≤70 yr and 77% for men >70 yr. Among prostate cancer patients >70 yr, after adjustment for literacy and Gleason score, African American men were only 41% as likely as whites to undergo watchful waiting (95% CI, 19% to 92%). Conclusions: Poor health literacy is common among men with prostate cancer; these men are more likely to receive radical prostatectomy. With men >70 yr with PSA failure post-radical prostatectomy or post-radiation therapy, African American men were 2.5× more likely than white men to choose therapy (primarily castration) over watchful waiting. Findings from smaller cohorts found that urologic symptoms were the most important factor associated with use of castration versus watchful waiting for PSA failure.

No significant financial relationships to disclose.
Utility of prostate specific antigen doubling time (PSA-DT) at the start of androgen independent prostate cancer (AIPC) and immediately before chemotherapy in predicting efficacy of taxane chemotherapy
Authors: Regan M. M. , Daskivich T. J. , Kantoff P. W. , Oh W. K.
Published: March 2020

4640

Background: PSA-DT has been used to predict efficacy of various treatments for prostate cancer. No study has evaluated the ability of PSA-DT to predict efficacy of taxane chemotherapy, the standard of care for patients with metastatic AIPC. Methods: PSA-DT was retrospectively calculated in 148 AIPC patients treated with taxane chemotherapy. PSA-DT at the start of AIPC (PSA-DT “at AIPC”) was calculated as log 2 divided by the slope of the linear regression of log PSA vs. time, from the first rise above the PSA nadir on androgen deprivation therapy (ADT) until the start of the next treatment. PSA-DT immediately prior to chemotherapy (“pre-chemotherapy” PSA-DT) was calculated similarly, using the three PSA values closest to and no longer than three months before the start of taxane chemotherapy. PSA-DT was divided into tertiles for analysis. Primary outcome was response to chemotherapy, defined as >50% maximum percent reduction in PSA from the start of chemotherapy and was analyzed using logistic regression. Results: PSA-DT at AIPC and pre-chemotherapy PSA-DT could be calculated for 91 and 109 patients, respectively. Rapid pre-chemotherapy PSA-DT (<5 wks) showed a trend towards higher >50% PSA response rates, when compared with intermediate (5–10 wks) and slow PSA-DT (≥10 wks) (74%, 62%, 54%, respectively, P = 0.08 for trend). At androgen independence, rapid PSA-DT (≤ 6 wks) also showed higher >50% PSA response rates than intermediate (6–12 wks) or slow PSA-DT (>12 wks) (81%, 61%, and 62%, respectively) but were not significantly different (P = 0.07, ≤6 vs. >6 wks). Conclusions: Short PSA-DT directly before taxane chemotherapy and also at androgen independence shows a trend towards higher > 50% PSA response rates. PSA-DT at these timepoints will be important to analyze in larger prospective studies.

No significant financial relationships to disclose.
The impact of lymphadenectomy in women with endometrioid uterine cancer: A study of 39,396 women
Authors: Karnik Lee N. , Wu H. , Cheung M. K. , Osann K. , Husain A. , Teng N. N. , Berek J. S. , Kapp D. S. , Chan J. K.
Published: March 2020

5000

Background: To determine the potential benefit of lymphadenectomy (LNX) during surgical staging procedure in women with early and advanced endometrioid uterine cancers. Methods: Demographic and clinico-pathologic information were obtained from the Surveillance, Epidemiology and End Results program from 1988 to 2001. Data were analyzed by using Kaplan-Meier methods and Cox proportional hazards regression. Results: Of 39,396 women (median age: 65; range 19–102) with endometrioid uterine cancers, 12,333 (31.3%) underwent a surgical staging procedure with LNX. The remainder received a hysterectomy and bilateral salpingo-oophorectomy only. 34,871 (88.5%) were Caucasian, 1,742 (4.4%) were African-American, 1,841 (4.7%) were Asian and 942 (2.4%) were other. The 5-year disease-specific survivals (DSS) were 93.3%, 85.4%, 69.3%, and 38.3% in patients with FIGO stage I-IV diseases, respectively. The 5-year DSS of stage I-IV women who underwent LNX were 95.5%, 90.4%, 73.0%, and 53.3% compared to 96.6%, 82.3%, 61.2%, and 28.2% in those without LNX. Those with stage II (p < 0.001), III (p < 0.001), and IV (p < 0.001) diseases after LNX had significantly better survival; however, the benefit of LNX was not demonstrated in stage I disease. The proportion of stage I patients with grade I histology or tumors limited to the endometrium was significantly higher in those who did not receive LNX compared to those who did (54.8% vs. 34.7%; p < 0.001 for grade I disease; 26.6% vs. 15.9%; p < 0.001 for non-myometrial invasion). In stage I grade 3 endometrioid uterine cancer, patients with LNX had a better 5-year DSS than those without LNX (90.0% vs. 84.97%; p = 0.0001); however, these findings were not seen in grade I (p = 0.26) and grade II (p = 0.14) diseases. In the subset of patients with stage IC grade 3 disease, there was a trend toward an improvement in survival associated with LNX (81.7% vs. 76.5%; p = 0.07). In the overall study group, younger age, African-American race, advanced stage disease, grade 3 histology, and lymphadenectomy. Conclusions: Our data suggest that lymphadenectomy improves the survival of women with stage I grade 3, stage II-IV endometrioid uterine cancers.

No significant financial relationships to disclose.
GOG0182-ICON5: 5-arm phase III randomized trial of paclitaxel (P) and carboplatin (C) vs combinations with gemcitabine (G), PEG-lipososomal doxorubicin (D), or topotecan (T) in patients (pts) with advanced-stage epithelial ovarian (EOC) or primary peritoneal (PPC) carcinoma
Authors: Bookman M. A.
Published: March 2020

5002

Background: P-C is a global standard for treatment of EOC and PPC (GCIG Consensus Conference 2005). Although effective, most patients recur with resistant disease. Agents were selected for new combinations based on clinical activity, interaction with cisplatin in tumor models, and feasibility. Methods: Eligible pts had appropriate initial surgery without other therapy, GOG/WHO PS 0–2, and adequate vital organ function. Pts were stratified by group, diagnosis (EOC vs PPC), stage (III vs IV), macroscopic residual tumor (yes vs no), and intent for interval cytoreduction (yes vs no). An event-triggered interim analysis (IA) of progression-free survival (PFS) was to identify arms for full accrual. The primary endpoint was overall survival (OS), determined by an event-triggered pair-wise comparison to the standard regimen (intent-to-treat), with a 90% chance of detecting a true hazard ratio (HR) of 1.33, limiting type I error to 1.25% (two-tailed) for each comparison. Sample size to be adjusted based on accrual rate and IA. Results: Accrual exceeded 1200/yr. IA for PFS (May 2004) with 1,345 events. Median PFS ranged from 15.4–17.5 m. PFS HRs ranged from 0.94–1.07 with the standard error of each log HR approximately 0.086. Extension was not recommended, and accrual closed at 4312 pts (177 ineligible). Median age 58 yrs; 13% PPC, 14% stage IV, 22% microscopic. 81% completed therapy, 4% progressed, 9% discontinued for toxicity. At least 42 deaths possibly treatment-related (<1%). Expected hematologic toxicity related to regimen intensity. Conclusions: For the regimens evaluated, there is no evidence that adding a third active cytotoxic agent prolongs PFS in EOC. Analysis of OS and impact of stratification factors are in progress.

[Table: see text]

[Table: see text]
Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer
Authors: Lin N. U. , Carey L. A. , Liu M. C. , Younger J. , Come S. E. , Bullitt E. , Van Den Abbeele A. D. , Li X. , Hochberg F. H. , Winer E. P.
Published: March 2020

503

Background: One-third of women with HER2+ metastatic breast cancer develop central nervous system (CNS) metastases. This study evaluated the safety and efficacy of lapatinib, an oral inhibitor of EGFR and HER2, in patients with HER2+ brain metastases. Methods: Eligible patients (pts) had HER2+ breast cancer, new or progressive brain metastases, and at least one measurable (LD ≥1.0cm) lesion. Pts received lapatinib 750 mg PO BID. Tumor response was assessed by MRI every 8 wks. FDG-PET scans were performed at baseline, and repeated at wks 1 and 8. The primary endpoint was objective response (CR+PR) in the brain by RECIST. Secondary endpoints included safety, quality-of-life (QOL), and PET changes. Sample size was calculated using a 2-stage design to distinguish objective response of 5% (H0) vs 20% (HA); ≥ 4 objective responses were required to reject the null hypothesis. Results: 39 pts were enrolled, mean age 52 yrs (range 31–76). All pts developed CNS disease on trastuzumab; 38 progressed after prior radiation. Toxicity data are available for 38 pts; the most common AEs were diarrhea (grade 3, 21%), fatigue (grade 3, 16%), and rash (grade 3, 5%). Three pts remain on active treatment. Two pts achieved a PR by RECIST, and remained on study for 158 and 347 days. An additional pt achieved >30% decrease in LD of her CNS lesion but, upon central radiology review, did not meet RECIST criteria for measurable disease and was excluded from analysis of the primary endpoint. Five additional pts achieved SD≥16 wks. Median time to treatment failure was 3.2 mo (95% CI 2.3 to 3.8). Preliminary volumetric analysis of 20/39 pts demonstrates 5 pts with ≥30% volumetric decline in CNS lesions, and an additional 3 pts with 15–30% volumetric decline. Analyses of QOL and correlation of PET with clinical outcomes will be presented. Conclusion: Lapatinib is well-tolerated in this population. Although the study failed to demonstrate the hypothesized level of activity as assessed by RECIST, there is sufficient evidence of clinical effect, albeit preliminary, to suggest that lapatinib can penetrate the CNS. Further investigation of lapatinib in HER2+ CNS disease is warranted and ongoing. Acknowledgements: AVON PFP award; NCI-SPORE in Breast Cancer at DF/HCC(CA89393), UNC(CA58223), Georgetown; ASCO YIA.

[Table: see text]
A randomized multicenter phase III trial of topotecan monotherapy versus topotecan + etoposide versus topotecan + gemcitabine for second-line treatment of recurrent ovarian cancer
Authors: Sehouli J. , Sommer H. , Klare P. , Stauch M. , Zeimet A. , Paulenz A. , Steck T. , Riedel H. , Keil E. , Stengel D. , Kuznik A. , Lichtenegger W.
Published: March 2020

5030

Background: Topotecan combined with etoposide (GINECO 1998) and gemcitabine (NOGGO 2001) proved effective for second-line treatment of recurrent ovarian cancer. It is, however, unclear whether combined treatment improves survival and tumor control compared to topotecan alone. Methods: Women with recurrent ovarian cancer after primary surgery and platinum therapy were enrolled in an open-label randomized phase-III trial at 93 German institutions. Stratifying for treatment-free intervals (TFI) of less or more than 12 months, subjects were centrally allocated to topotecan 1.25 mg/m2/d (TM), topotecan 1.0 mg/m2/d plus oral etoposide 50 mg/d (TE) on day 6–12, or topotecan 0.5 mg/m2/d plus gemcitabine (TG) 800 mg/m2/d1 and 600 mg/m2/d8 every three weeks. Local institutional review boards approved this study, and all patients provided written informed consent. With 145 subjects each arm, this study yielded 90% power to detect a Hazard Ratio (HR) of 0.60 in overall survival (OS) at a two-sided alpha of 0.01. We employed Cox regression for primary endpoint analysis, and addressed progression-free survival (PFS) and toxicity descriptively. Results: Between September 1999 and November 2004, 3036 courses were administered to 505 patients (mean age 60.4 [SD 11.3] years), 208 of whom had a TFI <12 months. Women assigned to TM, TE, and TG received a median of 6.7 (range, 0–10), 6.2 (0–9), and 5.4 (1–42) cycles. Median OS after TM, TE, and TG was 17.8, 17.8, and 15.3 months. Setting TM as the reference, HRs for OS with TE and TG were 1.13 (95% confidence interval [CI] 0.87–1.47) and 1.07 (95% CI 0.80–1.43, p = 0.590). HRs for PFS with TE and TG versus TM were calculated at 0.84 (95% CI 0.66–1.07) each. Subgroup analysis suggested enhanced PFS among subjects with TFI ≥12 months who received TE (HR 0.62, 95% CI 0.42–0.91) or TG (HR 0.68, 95% CI 0.46–1.01) rather than TM. TE produced higher CTC grade 3/4 hematotoxicity than TM or TG, with cumulative incidences of 24.4% (95% CI 20.2–29.0%), 16.0% (95% CI 11.9–20.9%), and 14.7% (10.6–19.5%). Conclusions: This large RCT does not provide evidence that combined treatment performs generally better than topotecan monotherapy in recurrent ovarian cancer.

No significant financial relationships to disclose.
A multicentre phase 2 study of carboplatin (C) plus pegylated liposomal doxorubicin (PLD) as first-line chemotherapy for patients (pts) with advanced or recurrent endometrial carcinoma (AEC): The END-1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer) Group
Authors: Lorusso D. , Pignata S. , Scambia G. , Zagonel V. , Riva N. , Febbraro A. , Pisano C. , Greggi S. , Breda E. , Morabito A.
Published: March 2020

5041

Background: Anthracyclines and platinum derivates are active drugs for pts with AEC, but new schedules with higher efficacy and better tolerability are needed. A prospective phase 2 study was conducted to describe tolerability and activity of C + PLD in pts with AEC. Methods: Pts with chemo-naïve AEC, PS ≤2, aged less than 75 years and with at least one measurable lesion were eligible. Treatment was C (AUC 5) + PLD (40 mg/m2) on day 1 every 4 weeks, up to 6 cycles. A single-stage design was applied. With objective response as primary endpoint, type I error = 0.05 and II error = 0.10, p0 = 0.20, p1= 0.40, 42 patients were needed, with at least 13 objective responses to define the treatment active. Response was assessed by RECIST and toxicity was coded with NCI-CTC. Results: From November 2002 to July 2005, 42 pts were enrolled at 5 Institutions. Median age was 64 years (31–74). PS was 0/1/2 in 28/13/1 pts, respectively. 62% of pts were stage IV. Out of 40 pts out of treatment, 3 complete (7.5%) and 20 partial responses (50%) have been already observed, for an overall response rate of 57.5% (95% exact CI: 40.9–73.0). One death potentially related to treatment was recorded (death at home for unknown reasons after 6th cycle). Other relevant toxicities (% of pts) were g3/4 neutropenia 30%/15%, febrile neutropenia 5%, g3/4 thrombocytopenia pts 17.5%/5%, g3/4 anemia 32.5%/5%, g3 heart rhythm 1 pt, g2 liver toxicity 1pt. Skin toxicity was mild: g1 12.5%, g2 7.5%, g3 5%. Hair loss: complete 1 pt, partial 12.5%. Conclusions: The combination of C and PLD shows a good activity and a favourable toxicity profile in first-line chemotherapy of pts with AEC, deserving further studies in this setting.

No significant financial relationships to disclose.
Loss of Apaf-1 expression and resistance to hypoxia-induced apoptosis in cervical cancer
Authors: Leo C. , Horn L. , Rauscher C. , Richter C. E. , Hentschel B. , Hoeckel M.
Published: March 2020

5046

Background: Clinical observations suggest that intratumoral hypoxia may increase the aggressiveness of tumors through clonal selection of cancer cells that have lost their apoptotic potential. We have shown previously that patients with hypoxic cervical cancers displaying a low apoptosis rate had a significantly worse prognosis compared to all other patients. The aim of this study, therefore, was to investigate the expression of the proapoptotic protein Apaf-1 in cervical cancers and to analyze its relation to intratumoral hypoxia and apoptosis. Methods: 56 patients with cervical cancer (FIGO stage IB to IV) were subjected to pretherapeutical intratumoral pO2 measurement with the Eppendorf electrode after informed written consent was given by each patient. The study was approved by the Ethics Committee of the University of Leipzig. Cervical cancer tissue from these patients was taken by needle core biopsy and analyzed by TUNEL assays as well as by immunohistochemistry with an anti-Apaf-1-antibody. For statistical analysis, Fisher’s exact test was used. Results: Apaf-1 was expressed in 86% of cervical cancers. The median apoptosis rate was 1.0% (range: 0.3– 3.4%). There was no direct correlation between Apaf-1 expression and intratumoral hypoxia. However, in the group of hypoxic cervical cancers (pO2 <10 mmHg) with a low apoptosis rate (<1.0%), 43.8 % (95% CI: 19.8–70.1%) of tumors showed a negative Apaf-1 expression compared to only 2.5% (95% CI: 0.06–13.1%) in non-hypoxic cancers and hypoxic cancers with a high apoptosis rate (p = 0.0003, Fisher’s exact test). Conclusions: While Apaf-1 is expressed in the vast majority of cervical cancers, a significant proportion of tumors with low apoptosis rates despite intratumoral hypoxia showed a loss of Apaf-1 expression. This finding suggests a mechanism by which hypoxic cervical cancers acquire resistance to apoptosis.

No significant financial relationships to disclose.
Gene expression signature predicts chemoresponse of microdissected papillary serous ovarian tumors
Authors: Ozbun L. , Bonome T. , Johnson M. E. , Radonovich M. , Pise-Masison C. , Brady J. , Mok S. , Birrer M. E.
Published: March 2020

5064

Background: The purpose of this study was to identify a predictive gene signature for chemoresponse in patients with advanced stage papillary serous ovarian cancer. Methods: Expression profiling was performed on 50 chemonaive, microdissected advanced stage papillary serous ovarian cancers using Affymetrix Human Genome U133 Plus 2.0 microarrays. Chemoresistance was defined as disease progression while the patients remained on primary chemotherapy. Nine normal human ovarian surface epithelial (HOSE) brushings were also assessed to quantify normal gene expression levels. Validation was performed by quantitative real time PCR using the HOSE isolates and microdissected ovarian tumor samples. Results: A supervised learning algorithm applied to genes differentially expressed between chemosensitive/resistance tumors (p < 0.001) using leave-one-out cross-validation (LOOCV), identified over 2000 genes associated with tumor chemosensitivity. The chemoresponsive gene list was further refined to 576 genes by including only genes used for all LOOCV iterations. An independent gene list was generated comparing expression profiles of chemoresistant tumors to HOSE. The two lists were compared to identify common genes, generating final classifier list of 75 genes that included genes involved in apoptosis, RNA processing, protein ubiquitination, transcription regulation, and other novel genes. We hypothesized genes identified in both data sets would be predictive and biologically relevant. Of these 75 genes, 20 were validated by real-time PCR. Validated genes were ranked by a univariate t-stat value to further resolve the predictor. 4 multivariate predictor algorithms demonstrated the 10 top ranked validated genes maximixed prediction accuracy (compound covariate, 91%; diagonal linear discriminant analysis, 91%; 3-nearest neighbor, 86%; nearest centroid, 95%). The predictive value of these genes will be evaluated on an independent sample set. Conclusions: Gene expression profiling can distinguish between chemosensitive and chemoresistant ovarian cancers. This signature can predict response to therapy and has identified novel biologically and clinically relevant targets.

No significant financial relationships to disclose.
Comprehensive analysis integrating both clinicopathological and gene expression data in more than 1,500 samples: Proliferation captured by gene expression grade index appears to be the strongest prognostic factor in breast cancer (BC)
Authors: Sotiriou C. , Wirapati P. , Loi S. , Haibe-Kains B. , Desmedt C. , Tutt A. , Ellis P. , Buyse M. , Delorenzi M. , Piccart M.
Published: March 2020

507

Background: Although, the development of high-throughput gene expression technologies has allowed the identification of several “molecular signatures” predicting clinical outcome, no attempt has been made yet to perform a comprehensive analysis integrating both clinicopathological, and gene expression data. Here, we aim to elucidate the relationship between clinical parameters and tumor markers, with gene expression patterns and their interaction with prognosis. Methods: We analyzed gene expression and clinical data from several published studies, including more than 1500 BC patients. We developed several gene expression indices associated with different biological stages of disease characterized by the expression of hormone receptors, HER2 amplification, p53 mutation, angiogenesis, tumor invasion and proliferation. Multivariable analyses were used to characterize the dependency patterns between these indices and their impact on survival. Results: Estrogen receptor (ER) and HER2 indices were the most prominent discriminators dichotomizing tumor samples into two main subsets in agreement with the previously proposed BC subtypes. Tumor proliferation, assessed by our previously reported gene expression index (GGI), was the most strongly associated with prognosis (HR 2.29, CI 1.88–2.78, p<0.0001). Almost all ER- and HER2+ tumors were associated with high GGI scores. In contrast, ER+ and HER2- tumors showed a whole range of GGI values. Within the high proliferation subset, ER- and HER2+ indices did not have any prognostic value. Similar results were found with relation to p53 mutation index. Nodal status and tumor size, which essentially measure the duration of disease, retained prognostic value in addition to proliferation. Conclusions: Proliferation captured by the GGI appears to be a key biological factor, downstream of ER, HER2 and p53. Although understanding the upstream factors is important for advancing biological knowledge and therapeutic interventions, GGI seems to be the most important factor predicting clinical outcome in BC and deserves consideration as stratification factor in clinical trials.

No significant financial relationships to disclose.
Change in patient weight during platinum/paclitaxel-based chemotherapy for ovarian cancer: A Gynecologic Oncology Group study
Authors: Hess L. M. , Tian C. , Barakat R. , Ozols R. , Alberts D.
Published: March 2020

5073

Background: Platinum/paclitaxel (P)-based chemotherapy is current treatment (tx) for advanced epithelial ovarian cancer (EOC). Previous studies suggest this regimen may induce weight change, which is a surrogate for body reaction to tx and may predict quality of life and clinical outcomes. We sought to explore the association between weight change during treatment and survival. Methods: A retrospective data review was conducted of 792 patients who participated in a Gynecologic Oncology Group (GOG) phase III randomized treatment trial (GOG 158) using cisplatin (Cis)/P vs carboplatin (Carbo)/P in optimal stage III EOC. Pretreatment body mass index (BMI) was calculated based on patient height and weight following surgery. Weight change during tx was defined as the ratio of body weight at completion of protocol therapy to pretreatment body weight. Progression-free survival (PFS) and overall survival (OS), classified by BMI or relative weight change, were estimated by Kaplan-Meier, and the associations between BMI, relative weight change and PFS and OS were assessed using Cox model controlled for known prognostic variables. Results: The median BMI was 24.9. There was no significant difference in PFS or OS related to BMI; however, there was a significant relationship between median OS and weight change as follows: >5% decrease = 48.0 months; 0–5% decrease = 49.3 months; 0–5% increase = 61.1 months; and >5% increase = 68.2 months (p = 0.006). The relative risk of death increased by 7% for each 5% decrease in body weight (HR = 0.93, 95% CI = 0.88–0.99; p = 0.013) adjusted for covariates. Results suggest more evident weight loss in the Cis/P arm than the Carbo/P arm during the first cycle of tx (−2.2 kg vs. −1.2 kg), and decreased weight was more likely to return to pretreatment level in the Carbo/P arm. Conclusions: Loss of body weight, but not BMI, during platinum/P-based chemotherapy is an indicator for poor OS in EOC patients. Cis/P may be associated with more weight loss compared to Carbo/P. This exploratory study supports the development of treatment strategies that minimize weight loss-producing toxicities to improve outcomes in this patient population.

No significant financial relationships to disclose.
Phase II trial of GM-CSF in women with asymptomatic müllerian cancer
Authors: Roche M. , Matulonis U. , Krasner C. , Penson R. , Horowitz N. , Berkenblit A. , Findley M. , Lee J. , Horick N. , Seiden M. V.
Published: March 2020

5081

Background: GM-CSF is a recombinant human cytokine, which increases the proliferation of granulocytes and monocytes. Experience with this agent, including adjuvant studies in melanoma, vaccine-based studies using autologous tumor vaccines that secrete human GM-CSF, and studies in prostate cancer using GM-CSF have all suggested that GM-CSF might provide anti-tumor activity in a subset of cancer patients. Methods: Open label phase II study performed in asymptomatic patients with recurrent mullerian malignancy without an indication for immediate systemic chemotherapy. Patients could have measurable or evaluable disease (defined as CA-125 >35 U/ml or 2 successively rising values with the most recent 3x the nadir value.) GM-CSF 250 mcg/m2 was administered subcutaneously on days 1–14 of a 28-day cycle. Monthly follow-up included interim history, physical exam and CA-125, with radiologic evaluation q 3 months. Results: Enrollment to this cohort is complete. Thirty-five women with a median age of 60 were enrolled; data are available on 33:30 women with ovarian and 3 with primary peritoneal cancers. To date 31 women are evaluable for response. Best overall response of patients who have completed the study includes 6 patients with stable disease (18%). Median time to treatment termination (TTT) was 76 days. Four patients remain on study, 2 with SD >6 months. Toxicity was generally mild, including injection site reaction, fatigue, and bone pain, however 2 patients experienced excessive toxicity and withdrew consent. There were 3 bowel obstructions thought related to disease but contribution of drug could not be ruled out. After 14 days of GM-CSF, CA-125 dropped in 23 of 33 women (70%) from their baseline on study value (median change -23%, range −48 to +158%). The magnitude of CA-125 drop during the first two weeks of therapy was significantly and positively correlated with day 15 WBC (p = 0.04.) Conclusions: GM-CSF is well tolerated and frequently associated with a decline in CA-125 that is correlated with leukocytosis. Although median TTT for the entire group is modest, a subset of women have had prolonged stable disease. Strategies to maintain and titrate leukocytosis are now being explored in a separate cohort.

No significant financial relationships to disclose.
Phase II study of sorafenib (BAY 43–9006) in combination with gemcitabine in recurrent epithelial ovarian cancer: A PMH phase II consortium trial
Authors: Welch S. , Hirte H. , Schilder R. J. , Elit L. , Townsley C. , Tinker L. , Pond G. , Afinec A. , Wright J. J. , Oza A. M.
Published: March 2020

5084

Background: Sorafenib (BAY 43–9006; SOR) is a novel multi-targeted kinase inhibitor that targets the RAF/MEK/ERK signaling pathway, vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor and flt-3. VEGFR is over-expressed in human ovarian tumors and this is associated with poor prognosis. Gemcitabine (GEM) is known to have single-agent activity in recurrent ovarian cancer (OC). A recent phase I study of GEM/SOR has demonstrated manageable toxicity and some objective responses in recurrent OC patients. We have designed a phase II trial to evaluate the efficacy of this novel combination in patients with recurrent OC. Methods: A two-stage, phase II clinical trial is underway for women with recurrent or refractory OC. Eligible patients may have received up to 2 prior lines of chemotherapy following recurrence, but must be GEM-naive. The treatment consists of SOR, 400mg PO bid continuously, in combination with GEM, IV weekly, 1000 mg/m2. Cycle 1 is an extended cycle of 7 weeks of GEM followed by a 1-week break. GEM is administered weekly for the first 3 weeks of each subsequent 4-week cycle. The primary endpoint is objective response rate, with response evaluated every 8 weeks. Results: 26 patients have been enrolled at 3 centers. 84 cycles have been administered (median 3; range 1–10). Median age was 57 (range: 37–77). 42% were ECOG PS 0 and 58% were PS 1. Of 18 patients evaluable for objective response, 1 patient had a confirmed PR by RECIST criteria and 5 patients had a confirmed PR by CA-125 criteria, yielding a combined RR of 33% in evaluable patients (RR by ITT = 23%). An additional 10 patients had SD. The median time to progression is 7.6 months (95% CI: 5.6-NA). 7 patients are inevaluable for objective response due to the following in cycle 1: withdrawal of consent (3), toxicity (2), and clinical PD (2). 1 patient on-study is yet to have a response evaluation. Grade 3 or 4 toxicities seen in more than 2 patients include: lymphopenia (8), thrombocytopenia (6), hypertension (3), hand-foot syndrome (3), pain (3), neutropenia (3) and hypokalemia (3). Conclusions: The preliminary results show encouraging activity with tolerable toxicity. This trial continues to accrue into a second stage.

No significant financial relationships to disclose.
A phase II study of oral gimatecan (ST1481) in women with progressing or recurring advanced epithelial ovarian, fallopian tube and peritoneal cancers
Authors: Pecorelli S. , Ray-Coquard I. , Colombo N. , Katsaros D. , Lhomme C. , Lissoni A. , Vermorken J. B. , Du Bois A. , Poveda A. , Frigerio L.
Published: March 2020

5088

Background: Gimatecan, a new camptothecin derivative, is a potent topoisomerase I inhibitor, active by oral route. Methods: A multicenter two stage Simon design phase II study was performed to evaluate the single agent antitumor activity of gimatecan. Secondary objectives were safety, time to event/time related parameters, and translational medicine evaluations. Women with advanced epithelial ovarian, fallopian tube or peritoneal cancer who had progressed or recurred after prior treatment with platinum and taxanes, had a progression-free interval from last platinum-based therapy < 12 months, had measurable disease by RECIST or assessable by CA 125 (GCIG criteria) and a ECOG performance status ≤ 1 were eligible. Gimatecan 0.8 mg/m2 was administrated orally for five consecutive days every four weeks. Radiological response was assessed every two cycles. Results: From June to December 2005, 70 women [median age 61 years (range 37–79)] were treated in 10 European sites. Number of prior chemotherapy regimens was: 1 in 20, 2 in 35, 3 in 15 patients, respectively. Progression-free interval from last platinum-based therapy was 0–6 months in 51 patients and 6–12 months in 19 patients. The study is still ongoing, and to date 40 consecutive patients are assessable. Preliminary response analysis indicated a 23.5% response rate based on CA 125 (8/34) and a 10% response rate based on RECIST (3/29). Main toxicity was hematological, namely thrombocytopenia and neutropenia. Conclusions: Preliminary results suggest that oral gimatecan administered as single agent is active, with bone marrow suppression resulting at present as the main toxicity in these patients previously treated with platinum and taxanes. However, many patients are still on treatment and data need to mature to have a broader picture of activity and safety.

[Table: see text]
Extending the platinum-free interval (PFI) with a non-platinum therapy in platinum (P)- sensitive recurrent ovarian cancer (OC): Results from the SOCRATES retrospective study
Authors: Pignata S. , Odicino F. , Scambia G. , Cormio G. , Katsaros D. , Stellato G. , Scollo P. , Costa B. , Magni G. , Iaffaioli R. V.
Published: March 2020

5093

Background: Chance of response to P is correlated to PFI (Markman, J Clin Oncol 1991). It has been proposed that extending PFI by interposing non-P therapy increase activity of delayed P retreatment in patients (pts) with P-sensitive recurrent OC, but this strategy is based on data from small series. The SOCRATES study retrospectively assessed the pattern of treatment of a cohort of pts with P-sensitive recurrent OC. Methods: Data of pts treated between 2000 and 2002 at 37 centers were collected in 2005. Pts with recurrent OC were eligible if P-sensitive [interval from end of first line to relapse (RFI) > 6 months]. Results: Data on chemotherapy at relapse were available in 428 pts. RFI was 6–12 months in 40% and >12 months in 60%. Pts received a 2nd (100%), 3rd (80%), 4th (50%), 5th (28%), 6th (12%) line of chemotherapy. 282 pts (65.9%) received P at first relapse (Group A) after a median RFI of 19 months, with a 74.4% response rate (RR) out of 246 evaluable pts. 67 pts (15.7%) received non-P at first relapse after a median RFI of 9.6 months, with a RR of 44.6% out of 56 evaluable pts, and then received P at later relapse after a median PFI of 23 months, with a 57.4% RR out of 47 evaluable pts (Group B). 79 pts (18.5%), with a median RFI of 8.4 months, had a on-P 2nd line with a RR of 28.8% out of 66 evaluable pts, and never received P later (Group C). The difference in RR to P given as 2nd line and delayed P is statistically significant (p = 0.02, Fisher exact test). Median overall survival was 27.2, 26.1 and 16.8 months for Group A, B and C, respectively. Conclusions: With the limits of a retrospective study, our data show that, although P was given in the group B after a similar PFI than in the group A, due to the interposition of a non-P therapy, activity of P was higher when given immediately after relapse than when postponed at subsequent lines. Overall, these data suggest that P-sensitive pts should receive P as soon as possible, and delaying it may preclude the chance of receiving the best treatment. (Study sponsored by GlaxoSmithKline).

No significant financial relationships to disclose.
A new measurement of residual cancer burden to predict survival after neoadjuvant chemotherapy
Authors: Symmans W. , Peintinger F. , Hatzis C. , Kuerer H. , Valero V. , Hennessy B. , Green M. , Singletary E. , Hortobagyi G. , Pusztai L.
Published: March 2020

536

Background: The strength of association between tumor response and survival is critical for neoadjuvant chemotherapy trials. Pathologic complete response (pCR) reliably predicts survival benefit, but residual disease contains a range of pathologic responses that likely contain different prognostic groups, including near complete response and resistance. Methods: Pathologic slides and reports were reviewed from 432 patients in two completed neoadjuvant trials: 1) fluorouracil, doxorubicin and cyclophosphamide (FAC) in 189 patients, and 2) paclitaxel followed by FAC (T/FAC) in 243 patients. Paclitaxel was administered as twelve weekly (n=126) or four 3-weekly cycles (n=117). Residual cancer burden (RCB) was calculated as an index that combines pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size). We compared four RCB categories, from RCB-0 (pCR) to RCB-3 (chemoresistant), and post-treatment revised AJCC Stage (0-III) for prediction of distant relapse-free survival (DRFS) in multivariate Cox regression analyses (stratified by ER status). Results: The pCR rate was greater after T/FAC than FAC (24% vs. 16%, LR p<0.05), and after weekly (vs. 3-weekly) paclitaxel in T/FAC (30% vs. 16%, LR p<0.01). In patients with residual disease, RCB measurements were significantly lower after T/FAC than FAC (t-test, p<0.0001), but were not different between paclitaxel schedules in T/FAC. RCB was a continuous predictor of DRFS after T/FAC (HR=1.86, 95%CI 1.51–2.30) or FAC (HR=1.67, CI 1.38–2.01) with median follow-up 5 and 8 years, respectively. The resistant category RCB-3 predicted relapse more strongly than AJCC Stage III and identified a larger group of high-risk patients ( Table ). Conclusions: RCB is a new continuous measure of pathologic response that is defined from routine pathologic materials, represents the distribution of residual disease, is a significant predictor of DRFS, and defines chemotherapy resistance more effectively than revised AJCC Stage.

[Table: see text]

[Table: see text]
Mortality benefit of switching to an aromatase inhibitor in early breast carcinoma: Pooled analysis of two consecutive trials
Authors: Boccardo F. M. , Guglielmini P. , Rubagotti A.
Published: March 2020

548

Background: The superiority of new generation aromatase inhibitors (AI) over tamoxifen (T) in the adjuvant treatment of early breast ca. has emerged from several randomized trials. However no mortality benefit has emerged so far from previous trials. Methods: A pooled analysis of GROCTA 4 and ITA trials, two consecutive, multicentric trials performed by our group and sharing the same study design, was performed. The results of both trials have been published previously [JCO 19:4209–15, 2001; JCO 23:5138–47, 2005] and have been updated for the present analysis. In both trials women already on treatment with T for 2 or 3 years have been randomly assigned to continue T for additional 3–2 years or to be switched to aminoglutethimide (AG) or anastrozole (AN) for a comparable time period. In each treatment group mortality was analysed according to cause of death and patient and tumor variables. Results: 828 postmenopausal ER+ve women, most of whom were also node +ve, who had been followed up for a median time of 68 months (range 1–141 months) were analysed. Of these women, 415 had been randomized to continue T and 413 to be switched to AG or AN. In both groups total duration of endocrine therapy was 5 years. All-cause mortality and breast cancer specific mortality were significantly improved by switching: HR=0.60 (0.41–0.87) p=0.007; HR=0.62 (0.39–0.97) p=0.03 respectively. Though more women continued to T died in absence of obvious disease relapse, there was no significant difference between groups in breast cancer unrelated mortality (p=0.1). Multivariate analysis showed that patient age, tumor size, allocated treatment and N status in the order were independent mortality predictors. Tumor size, N status and allocated treatment were independent predictors of breast cancer related mortality as well. Noteworthy, age at randomization was the only statistically significant predictor of breast cancer unrelated mortality. Conclusions: Switching to an AI after 2 or 3 years of T therapy significantly improved survival as compared to 3 or 2 years of additional treatment with T. These findings reinforce the indication to switching for the women actually receiving adjuvant treatment with T.

No significant financial relationships to disclose.
Prognostic implication of p53 mutations in HNSCC: Results of Intragroup margin study (E4393)
Authors: Poeta L. M. , Goldwasser M. A. , Forastiere A. , Benoit N. , Califano J. , Ridge J. A. , Goodwin J. , Kenady D. , Sidransky D. , Koch W. M.
Published: March 2020

5504

Background: The role of p53 as a prognostic marker in head and neck squamous cell carcinoma (HNSCC) is controversial. The intent of this study was to evaluate rigorously the prognostic value of p53 genetic status. Methods: Tumor samples from 480 HNSCC patients treated surgically with curative intent were collected in a prospective multicenter study over 5 years. 57 cases were not analyzed due to technical or administrative factors. Mutation status was determined in the 423 remaining cases, using p53 chip (GP53 GeneChip from Affymetrix, Inc., Santa Clara, CA) which identifies mutations in exons 2 through 11. Indeterminate calls were investigated using Surveyor and/or DHPLC analysis and all mutations were confirmed with an automated fluorescent system or manual sequencing. Clinical follow-up was accomplished following Eastern Cooperative Oncology Group protocol. Results: Median follow-up of the 423 evaluable subjects was 5.4 years with all patients followed at least 3 years. Mutation of p53 gene was present in 224 (53%) cases. There we significantly fewer mutations in tumors arising in the oropharynx (chi-square p = 0.02). The presence of p53 mutation was significantly associated with decreased overall survival. Median survival for patients with tumors with p53 mutation was 3.1 years compared to 5.4 years fro WT tumors (HR = 1.4, 95% CI =1.1 to 1.8, p = 0.01 log-rank test). This proved to be independent of tumor site in multivariate analysis. When mutations were segregated according to their effect on biological function through alteration of key DNA binding domains a Cox regression analysis revealed a statistically significant linear effect of the more disruptive mutations on overall survival with a HR of 1.3 for comparison of each group to the one of lower risk (more vs. less disruptive mutation v. WT (p = 0.001 Wald test). Conclusions: This large prospective series shows a strong relationship between TP53 mutation and prognosis in HNSCC patients. Furthermore, the biological impact of specific mutations has a predictable graded relation to clinical outcome. The results set the stage for use of p53 genetic status in the design of future clinical trials and support the development of targeted therapy to restore wild-type p53 function.

No significant financial relationships to disclose.
Analysis of EGFr, VEGF and p53 in serum of head and neck squamous cell cancer (HNSCC) : Preliminary results of the GORTEC 99–02 randomized trial
Authors: Metges J. , Guenet D. , Auperin A. , Gregoire V. , Maingon P. , Lesaunier J. , Calais G. , Zelek L. , Bourhis J.
Published: March 2020

5509

Background: Predictive and prognostic markers are warranted in HNSCC. We designed a prospective study to analyze EGFr, VEGF and P53 both in the serum and in the tumor of HNSCC patients included in the GORTEC 99–02 prospective phase III trial which compared conventional radiotherapy (RT) plus 5FU and carboplatin (FUP) vs RT with a concomitant boost and FUP vs a very accelerated RT. Methods: This prospective study has been designed to include 820 patients, we present here the results in a sub group of 216 patients for whom the biological markers were analyzed. Association between these markers and TNM staging, age, sex, disease progression and survival was evaluated. Serum analysis was performed for serum EGFr (Oncogene Science), VEGF (R&D systems) and p53 serum-autoantibodies (Immunotech). Statistical analysis were performed using Spearman correlation coefficient, Kruskal-Wallis test for quantitative variables, chi2 and Fischer exact test for qualitative varaibles and Logrank test and cox model for survival analysis. Multivariate analysis of survival took into account T and N status, tumor localisation and the type of treatment. Results: No correlation was found between the serum levels of VEGF and EGFr, neither between EGFr and p53. There was a borderline significant association (p = 0.07) towards higher VEGF serum levels in p53 negative, compared to p53 positive patients. No correlation was found between age, sex, T and N staging and all the serum markers. The VEGF level was significantly higher in laryngeal and hypopharyngeal primaries and lower in oropharyngeal and buccal primaries (p = 0.04). The EGFr level seemed also associated with the tumor localisation (p = 0.055). The median follow up was 2 years. High levels of serum EGFR were associated with better overall survival in univariate and multivariate analysis (p < 0.01). Overall survival was not significantly higher in positive serum p53 patients than in negative p53 patients (p = 0.11 in multivariate analysis). VEGF was not associated with survival. Conclusions: These preliminary resulst suggest that high levels of serum EGFr was associated with a better outcome in this homogenous, prospective series of HNSCC. Work supported by a french PHRC from the National Institutes of Health.

No significant financial relationships to disclose.
Randomized phase II trial of concomitant CT/RT versus TPF followed by concomitant CT/RT in locally advanced squamous cell carcinoma of the head and neck (LASCCHN)
Authors: Paccagnella A. , Buffoli A. , Koussis H. , D’Amanzo P. , Loreggian L. , Bonetti A. , Valduga F. , Gava A. , Ardizzoia A. , Sguotti C.
Published: March 2020

5518

Background: Concomitant CT/RT is the standard treatment for LASCCHN. Induction chemotherapy followed by CT/RT vs CT/RT alone have not yet been compared. The feasibility of TPF followed by CT/RT has been evaluated in a previous study (Int J Rad Oncol Biol Phys 2004, 59:481). Methods: Pts with inoperable stage III-IVa, PS 0–1, were randomized to CT/RT [2 cycles of Cisplatin 20 mg/sqm days 1–4, 5FU 800 mg/sqm 96 hours c.i. weeks 1 and 6 during RT (66–70 Gy)] (Arm A) or 3 cycles of neoadjuvant TPF (Docetaxel 75mg/sqm day1, Cisplatin 80mg/sqm day1, 5FU 800mg/sqm 96 hours c.i) followed by the same CT/RT (Arm B). Pts were stratified according to tumor site, T stage and nodal status. Neck dissection was performed in N2-N3 patients with pathological CR on primary tumor. The planned sample size was 96 pts to detect a difference in CR (primary endpoint) up to 15% in favour of arm B. The radiological responses were evaluated by an internal committee according to RECIST criteria. Results: Preliminary data are available for 84/96 randomized pts (42 arm A, 42 arm B). Pts/tumor characteristics are well balanced in the two arms. Toxicities during induction TPF consisted primarily of G3–4 granulocytopenia 56% (febrile neutropenia: 7.5%). Grade 3–4 toxicities during CT/RT in arm A and B were mucositis (42% and 26%), dysphagia (20% and 9%), skin reaction (12% and 8.6%), asthenia (5% and 3%); G3 weight loss (2% and 3%), G3 dry-mouth (0% and 3%). Duration of CT/RT was equivalent: 6.1 wks (4.2–8.7) in arm A and 6.3 wks (3.8–9.5) in arm B. At the end of CT/RT, in the 82 pts evaluable for efficacy, radiological CR were 20% (95% CI 8–37%) in arm A and 64% (95% CI 45–80%) in arm B. Conclusions: Three cycles of neoadjuvant TPF are feasible and don’t compromise subsequent concomitant CT/RT with comparable toxicity pattern. At the end of the treatment sequence serious adverse events were 31% in arm A and 34% in arm B. The difference in CR of 40% in favour of arm B justifies the following phase III study. Final results including pCR and DFS will be presented at the meeting.

[Table: see text]