bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated report of the phase 2 experience with XL999 administered IV to patients (pts) with NSCLC, renal cell CA (RCC), metastatic colorectal CA (CRC), recurrent ovarian CA, acute myelogenous leaukemia (AML), and multiple myeloma (MM)
Authors: Cripe L. , McGuire W. , Wertheim M. , Eisenberg P. , Stadler W. , Paquette R. , Logan T. , Zimmerman T. , Matei D. , Matulonis U.
Published: March 2020

3591

Background: XL999 is a potent spectrum-selective inhibitor of tyrosine kinases including VEGFR2/KDR, FGFR1/3, PDGFR-β, FLT3, RET, KIT, & SRC. A Ph 1 study in pts w/advanced malignancies has shown anti-tumor activity (3 PRs &10 SD lasting 3–26+ months) DLTs were cardiac failure & transaminase elevation. Methods: XL999 is being investigated in 6 Ph 2 trials. Pts w/histologically confirmed NSCLC, RCC, CRC, recurrent ovarian CA, AML, & MM were enrolled. The primary objectives of these independent studies are to determine response rate and further evaluate safety and tolerability of XL999. The secondary objectives are to assess PFS, duration of response & OS. Pts receive a once wkly 4hr IV administration of XL999 (2.4 mg/kg). Tumor response is assessed every 8 wks. Results: A total of 79 pts were treated. A confirmed PR was reported in 1/ 9 pts w/NSCLC. An additional 2 pts have SD at 2 & 3 months w/1 showing tumor shrinkage (24%). Two of 11 pts w/RCC have SD at 2 & 4 months. Of 14 pts enrolled w/AML, 1 of 3 with an activating FLT3 mutation had a PR, and 8 of 10 w/circulating myeloblasts had >50% reduction in myeloblasts. AEs = Grade 2 in =10% of pts related to XL999 included N/V, constipation, diarrhea, dry mouth, oral hypoesthesia, fatigue, pyrexia, dizziness, dysguesia, & hypertension. Cardiovascular (CV) events considered SAEs were reported in 11 pts (14%), and all but 1 occurred with the 1st dose of XL999.These events were characterized by ST /T wave changes in ECG,LVEF decreases and /or troponin elevation. Most pts with CV SAEs recovered to baseline within 2–3 wks upon withdrawl of further XL999. Conclusions: XL999 administered IV at a dose of 2.4mg/kg wkly was associated w/CV AEs, the majority of which were associated w/the 1st dose and were generally reversible upon XL999 discontinuation. XL999 shows preliminary evidence of anti- tumor activity in pts w/NSCLC & AML.

[Table: see text]
Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial
Authors: Van Cutsem E. , Nowacki M. , Lang I. , Cascinu S. , Shchepotin I. , Maurel J. , Rougier P. , Cunningham D. , Nippgen J. , Köhne C.
Published: March 2020

4000

Background: Cetuximab in combination with irinotecan-based regimens has proven activity in previously-treated patients (pts) with mCRC. The present trial investigated the effectiveness of cetuximab in combination with standard FOLFIRI compared with FOLFIRI alone in the first-line treatment of pts with epidermal growth factor receptor (EGFR)-expressing mCRC. Methods: Pts were randomized 1:1 to receive either cetuximab (400 mg/m2 initial dose then 250 mg/m2/week [w]) plus FOLFIRI q 2 w (irinotecan 180 mg/m2, FA 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 hours) (Group A) or FOLFIRI alone (Group B). The primary endpoint was progression-free survival (PFS), with secondary endpoints of overall survival (OS), response rate (RR), disease control rate and safety. 633 events were required to statistically differentiate PFS between groups with 80% power. Results: Between August 2004 and October 2005, 1,217 pts were randomized, 608 to Group A and 609 to Group B (60% male, median age 61 [19–84], ECOG performance status: 0=54%; 1=43.5%; 2=3.5%). Median PFS was significantly longer for Group A compared to Group B (8,9 months [8 - 9,5] for Group A vs. 8 months [7.6 - 9] for Group B, p=0.036). Response Rate was also significantly increased by cetuximab (46.9% vs. 38.7%, p=0.005). Treatment was generally well tolerated with neutropenia (26.7% Group A, 23.3% Group B), diarrhea (15.2% and 10.5% respectively) and skin reactions (18.7% and 0.2% respectively) being the most common grade 3/4 adverse events. Conclusions: Cetuximab in combination with FOLFIRI significantly increases response rate and significantly prolongs PFS in the first-line treatment of pts with mCRC, reducing the relative risk of progression by approximately 15%. Treatment-related side effects of cetuximab in combination with FOLFIRI were as expected, with diarrhea being moderately and skin reactions significantly more frequent as compared to FOLFIRI alone.

[Table: see text]
Circulating tumor cells (CTC) predict progression free (PFS) and overall survival (OS) in patients with metastatic colorectal cancer
Authors: Meropol N. J. , Cohen S. J. , Iannotti N. , Saidman B. H. , Sabbath K. D. , Miller M. C. , Doyle G. V. , Tissing H. , Terstappen L.W.M.M. , Punt C.J.A.
Published: March 2020

4010

Background: Treatment options for patients with metastatic colorectal cancer (mCRC) have recently expanded. However, the introduction of new regimens has highlighted the need for biomarkers to guide and monitor therapy. This study investigates the hypothesis that CTC levels can predict clinical outcomes in patients with mCRC. Methods: In a prospective multi-center study, 7.5 mL of blood from 456 patients with mCRC were tested for CTC using immunomagnetic separation before starting 1st, 2nd or 3rd line therapy and at subsequent radiographic follow-up timepoints. Response on imaging was determined by participating centers. Results: Patients were stratified into unfavorable and favorable prognostic groups based on levels of =3 or <3 CTC per 7.5mL, respectively. Median PFS, OS and significance between the two groups (log rank test) at different timepoints after the initiation of therapy is indicated in the table . The OS of patients converting to or maintaining unfavorable CTC at follow up timepoints was worse than for patients maintaining favorable CTC (12.6, 7.0 vs. 21.1 months, respectively, p<0.0001). In multivariate analyses, which included age, ECOG performance status, and the line and type of therapy, CTC remained the most significant independent predictor of outcome. Conclusions: CTC levels before treatment and at subsequent timepoints are an independent predictor of PFS and OS in patients with mCRC. CTC levels of =3 per 7.5mL of blood after initiation of therapy are highly predictive of shorter PFS and OS. A large randomized phase III study to confirm these findings in mCRC patients receiving first line therapy recently completed accrual (DCCG CAIRO- 2).

[Table: see text]

No significant financial relationships to disclose.
Analysis of potential predictive factors of clinical benefit in patients (pts) with metastatic colorectal cancer (MCRC) treated with single-agent cetuximab as first-line treatment
Authors: Gravalos C. , Sastre J. , Aranda E. , Massutí B. , Vega-Villegas M. E. , Gómez A. , Varella-Garcia M. , Jimeno A. , Díaz- Rubio E. , Hidalgo M.
Published: March 2020

4120

Background: Our group has recently shown that single-agent cetuximab in first-line treatment of elderly MCRC pts has a favorable safety profile and similar activity to that observed in pretreated pts: 15% RR and 54% disease control (DC) (ESMO 2006: A324O). In this study, we aimed to identify predictive factors of clinical benefit from cetuximab without chemotherapy. Methods: This was a optional prospective ancillary study conducted in 36 of 41 pts included in the TTD 04–01 trial to explore potential predictive factors of response or resistance to single-agent cetuximab (400 mg/m2 as initial dose and 250 mg/m2 weekly thereafter). To this end we conducted a comprehensive analysis of potential predictive assays including polymorphisms of intron 1 of the EGFR gene, EGFR gene copy number by FISH (Varella-García Diagn Pathol 2006), IHC expression of signaling pathway proteins (EGFR, MAPK, AKT, PTEN), K-RAS, B-RAF, PI3KCA and PTEN mutations, as well as basal serum levels and dynamic changes of circulating EGFR after 4 weeks of treatment. Results: 9 of 41 pts (22%; 95%CI: 11–38) achieved DC at 12 weeks (2 CR, 4 PR, and 3 SD) with a median time to progression (TTP) of 8,3 months (range 4–11.3), similar to that observed with FOLFOX or FOLFIRI in first line treatment. Increased EGFR copy number (FISH+: scores 5–6) was observed in a total of 11 pts (11/36: 30,5%). Five of these 11 FISH+ pts had DC at 12w (45%) vs. 3 of 25 FISH- pts (12%) (p=0.04). No correlation was found between DC at 12w and polymorphisms of intron 1 of the EGFR gene, basal serum levels and dynamic changes of EGFR, IHC expression of pEGFR and pMAPK, or PI3KCA mutations. Analyses of PTEN and AKT by IHC, as well as K-RAS and PTEN mutations are ongoing. Conclusions: Although cetuximab provides higher efficacy in combination with chemotherapy, 22% of MCRC pts treated with monotherapy in first-line treatment present a remarkable median TTP of 8,3 months. This subgroup of pts can be selected in advance based on FISH+ combined or not with other possible predictive factors still under analysis. The full detailed analysis of data will be presented at the meeting.

[Table: see text]
Pharmacogenomic analysis of a randomized phase II trial (BOND 2) of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer
Authors: Zhang W. , Yang D. , Capanu M. , Hollywood E. , Lue-Yat M. , Borucka E. , Azuma M. , Gordon M. , Saltz L. , Lenz H.
Published: March 2020

4128

Background: Phase II CBI VS CB trial has shown that bevacizumab added the efficacy of cetuximab and cetuximab/irinotecan in irinotecan-refractory bevacizumab-naïve CRC patients. We tested the germline polymorphisms involved in angiogenesis pathway(VEGF, IL-8, TGF-β), EGFR pathway (EGFR, COX-2, CyclinD1,E-cadherin,FCGR2A,3A), DNA repair pathway(ERCC1, XRCC1, XPD) and drug metabolism pathway (GSTP1, UGT1A1) to evaluate their association with clinical outcome. Here we expand our gene polymorphisms data involving EGFR pathway (EGF, FCGR2B, Survivin, ADAMS10/17), Angiogenesis pathway (Neuropilin-1, HIF-1, Tissue factor) and irinotecan metabolism pathway(ABCB1,OATPC). Methods: Genomic DNA was extracted from blood samples. 65 out of 81 patients enrolled in the BOND 2 trial were available for molecular correlates study. these 65 patients include 44 men, 21 women, median age 58 years (range 24–86). Patients received either with CBI (n=31) (Arm A) or with CB (n=34) (Arm B). In Arm A, 12 pts (43%) had PR, the median TTP was 7.1 months, and the median survival was 18.0 months. In Arm B, 9 pts (27%) had PR, the median TTP was 4.6 months, and the median survival was 10.3 months. PCR-RFLP based technique was used to determine polymorphisms. Univariate analysis (Fisher’s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: For Arm B, we found significant associations between HIF-1 polymorphism and tumor response (P=0.017), between HIF-1, FCGR2B polymorphisms and TTP, and between OATPC polymorphism and OS (P values < 0.05). For Arm A, we found a trend in association between EGF polymorphism and tumor response (P=0.08). Conclusions: These data suggest that germline polymorphisms may be potential molecular markers for clinical outcome for patients with mCRC treated with CBI or CB. Prospective studies are needed to confirm these preliminary findings.

[Table: see text]
Predictive value of skin toxicity severity for response to panitumumab in patients with metastatic colorectal cancer (mCRC): A pooled analysis of five clinical trials
Authors: Berlin J. , Van Cutsem E. , Peeters M. , Hecht J. R. , Ruiz R. , Wolf M. , Amado R. G. , Meropol N. J.
Published: March 2020

4134

Background: Panitumumab, a fully human monoclonal antibody against the epidermal growth factor receptor (EGFr), is approved for EGFr-expressing mCRC patients (pts) with disease progression (PD) on or following fluoropyrimidine (5FU)-, oxaliplatin (Ox)-, and irinotecan (Ir)-containing chemotherapy. Skin toxicities are common with panitumumab; we examined the association between severity of skin toxicity and panitumumab efficacy. Methods: Data from 5 clinical trials were pooled (4 phase II studies and 1 phase III study). Pts with mCRC had documented PD on or after 5FU, Ox, and/or Ir. Pts received panitumumab 6 mg/kg every two weeks (Q2W) or 2.5 mg/kg weekly (QW) until PD or intolerability. Tumors were assessed using modified WHO or RECIST criteria (blinded central review in 4/5 studies). Endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). PFS and OS were measured from enrollment. Only pts with =2 infusions (exposure over 2 wks for QW dosing or over 4 weeks for Q2W dosing) were analyzed to help correct for lead-time bias. Results: 612 of 640 pts were included in the analysis set (62% were male, 92% were white, and median age [range] was 61 [21, 88] years). The median (95% CI) duration of PFS was 8.4 weeks (8.0 to 11.3), the median (95% CI) survival was 6.9 months (6.2 to 7.9), and the ORR (95% CI) was 9.0% (6.8 to 11.5). The most common skin toxicities (any grade, grade 3/4) were erythema (54%, 4%) pruritus (53%, 2%), dermatitis acneiform (52%, 5%), and rash (39%, 2%). ORR, PFS, and OS appeared to favor pts with grade 2–4 skin toxicity vs pts with grade 0- 1 skin toxicity ( table ). Conclusion: In this large combined analysis, severity of skin rash was correlated with increased efficacy of panitumumab in terms of ORR, PFS, and OS.

[Table: see text]

No significant financial relationships to disclose.
A phase II study of sunitinib in patients with advanced hepatocellular carcinoma
Authors: Zhu A. X. , Sahani D. V. , di Tomaso E. , Duda D. , Sindhwani V. , Yoon S. S. , Blaszkowsky L. S. , Clark J. W. , Ryan D. P. , Jain R. K.
Published: March 2020

4637

Background: Patients (pts) with advanced hepatocellular carcinoma (HCC) have a poor prognosis. HCC is a highly vascular tumor with increased levels of angiogenic factors including VEGF and VEGFR. Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor with activity against VEGFR, PDGFR, and c-KIT. We performed a phase II study to evaluate the efficacy and toxicity of sunitinib in advanced HCC. Methods: Eligibility criteria included unresectable or metastatic measurable HCC, 0–1 prior chemotherapy regimens, performance status = 1, CLIP score = 3, and adequate organ functions. Pts were treated with sunitinib at 37.5 mg po qd on a standard 4 weeks on, 2 weeks off regimen (6 weeks/cycle). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed to assess changes in tumor permeability. Plasma angiogenic markers were assayed by multiplex array. The primary endpoint of the study is progression-free survival (PFS). Results: 19 pts have been enrolled since May 2, 2006: median age = 59 (30–77), M/F = 16/3, ECOG 0/1 = 7/12, CLIP 1/2/3=7/7/5. The treatment was generally well tolerated. Grade 3/4 toxicities included neutropenia (n=4, 21%), lymphopenia (n=3, 16%), SGOT/SGPT (n=3, 16%), fatigue (n=2, 11%), rash (n=2, 11%), and thrombocytopenia (n=2, 11%). One pt had a partial response and 8 pts had stable disease of at least 12 weeks; 8 pts currently remain on study. The median number of treatment cycles received per patient was 2 (range 1–6). The mean tumor permeability (Ktrans) following 2 weeks of sunitinib administration in 13 pts decreased from mean baseline value of 3.77 to 1.06 (an average of 52% decrease). Of the 15 pts analyzed, changes in plasma angiogenic markers from baseline to day 15 following sunitinib treatment were observed as follows: sVEGFR1 remained constant in 15 pts; 8/15 had decreased sVEGFR2 levels; 13/15 and 11/15 pts had increased PlGF and VEGF levels respectively; bFGF levels decreased in 9 and increased in 5 patients. Conclusions: Sunitinib administered in the current dose schedule can be safely given with close monitoring in HCC patients. Preliminary evidence of antitumor activity was observed. Changes in angiogenic parameters on DCE-MRI and in blood markers were seen following sunitinib administration.

[Table: see text]
Could treatment with tamoxifen be superior to aromatase inhibitors in early-stage breast cancer after pharmacogenomic testing? A modeling analysis
Authors: Punglia R. S. , Winer E. P. , Weeks J. C. , Burstein H. J.
Published: March 2020

502

Background: Adjuvant endocrine treatment with upfront aromatase inhibitors yields improved disease-free survival compared to tamoxifen in unselected women with estrogen receptor-positive breast cancer. However, levels of endoxifen, the active tamoxifen metabolite, are known to vary with the number of mutant alleles of the cytochrome P450 CYP2D6 enzyme. We created a Markov model to examine whether the optimal treatment strategy for patients with wild type genetics (wt/wt) might differ from that for patients with homozygous (*4/*4) or heterozygous (wt/*4) mutations. Methods: Annual recurrence risks with aromatase inhibitors and tamoxifen in unselected women were taken from the BIG 1–98 trial. Based on data from Goetz et al., we assumed that the percent of patients who are homozygous and heterozygous for mutations are 6.8% and 21.1%, respectively, and that the hazard ratio (HR) for increased cancer recurrence on tamoxifen among *4/*4 carriers is 1.86 relative to patients with wt/wt or wt/*4 genotypes. Because the efficacy of tamoxifen among wt/*4 patients is not known, we tested the full possible range, from efficacy same as wt/wt patients (Ehet=0) to that of *4/*4 mutation carriers (Ehet=1). Results: In the unselected group, 5-year disease-free survival (5-DFS) with aromatase inhibitors and tamoxifen was 0.840 and 0.813, respectively. Under baseline assumptions, tamoxifen is more effective than aromatase inhibitors among wt/wt patients as long as the effect in heterozygotes is at least 54% (Ehet=0.54) of that in *4/*4 patients. With increasing HR for *4/*4 patients, tamoxifen estimates exceed those of aromatase inhibitors in the wt/wt cohort even at lower assumed Ehet ratios (see table ). Conclusion: In patients without CYP2D6 mutations, modeling suggests that initial treatment with tamoxifen could be superior to treatment with aromatase inhibitors, supporting the use of genetic testing to determine the optimal treatment strategy.

[Table: see text]

No significant financial relationships to disclose.
WBC changes as a pharmacodynamic marker of outcome in metastatic renal cell carcinoma (mRCC) patients (Pts) receiving sunitinib
Authors: George S. , Richmond A. , Elson P. , Jin T. , Wood L. , Garcia J. A. , Rini B. I. , Finke J. , Bukowski R. M.
Published: March 2020

5043

Background: Sunitinib is a VEGF, PDGF, c-Kit and FLT-3 inhibitor with significant anti-tumor activity in mRCC. Myelosuppression is a common side effect observed in mRCC pts treated with sunitinib. Thus, the association of myelosuppression with clinical outcome was investigated. Methods: All mRCC pts receiving sunitinib at The Cleveland Clinic Taussig Cancer Center with available data were investigated. White blood cell (WBC) and differential counts at baseline and day 28 of cycle 1 were collected. Peripheral blood mononuclear cell (PBMC) T helper 1 (Th1), T helper 2 (Th2) and T regulatory cell (Treg) numbers at baseline and day 28 of C1 were determined using flow cytometry. Hematologic parameters were analyzed as continuous variables and also dichotomized using a recursive partitioning algorithm. Fisher’s exact test was used to analyze categorical data, the log rank test was used to assess time to progression (TTP) and Spearman’s rank correlation was used to summarize associations between hematologic and immune parameters. Results: Sixty-seven pts were studied (75% male, median age 59 yrs). Objective responses (OR) included 2 complete and 35 partial responses (overall response rate 55%), with a median (m) TTP of 12.4 months. There was a significant reduction (end of C1 vs. baseline) in the absolute neutrophil count (ANC) (m decrease of 46.4%; p <0.001) and absolute monocyte count (m decrease of 41.3%; p<0.001), but not absolute lymphocyte count (m 6.6% decrease; p=0.5). A decrease in the ANC of =2.5K/uL compared to <2.5 K/uL was associated with improved OR (64% vs. 36%; p= .07) and TTP (m 20.6 months vs. 8 months; p=.003). Patients demonstrating a maximum lymphocyte count =1.2 K/uL at anytime during treatment compared to patients with a maximum lymphocyte count <1.2 K/uL also had a greater OR (64% vs. 25%, p=.02) and TTP (m 17.6 months vs. 4.2 months, p=.03). Changes in Treg number and Th1 and Th2 response bias of PBMC did not correlate with ANC/ lymphocyte changes or clinical outcome. Conclusions: Treatment with sunitinib produces significant neutropenia with minimal effects on total lymphocyte numbers. Changes in ANC and maximum lymphocyte count could represent a pharmacodynamic marker of clinical outcome for mRCC patients treated with sunitinib.

No significant financial relationships to disclose.
Randomized trial of active cellular immunotherapy with sipuleucel-T in androgen dependent prostate cancer (ADPC)
Authors: Beer T. M. , Bernstein G. T. , Corman J. M. , Glode M. L. , Hall S. , Poll W. L. , Schellhammer P. F. , Xu Y. , Yu L. , Frohlich M. W.
Published: March 2020

5059

Background: Sipuleucel-T is an investigational, active cellular immunotherapy product for prostate cancer. To explore the potential benefit in ADPC, sipuleucel-T was studied in a randomized, double blind, multicenter, placebo controlled study, P-11. Methods: ADPC patients with a rise in serum prostate specific antigen (PSA) as the only sign of disease recurrence after prostatectomy were randomized (2:1) to sipuleucel-T or placebo, administered in weeks 0, 2, and 4, following 3-months of hormonal therapy. PSA kinetics were evaluated by time to biochemical failure (BF), defined as any PSA = 3 ng/mL (primary endpoint), as well as PSA doubling time (PSADT). Clinical endpoints included time to distant metastases (DF) and survival. The effect of a single booster infusion of sipuleucel-T on the immune system was also evaluated. Results: 176 patients were randomized (117 sipuleucel-T:59 placebo) and analyzed by intent to treat. Median time to BF was 18.0 months for sipuleucel-T and 15.4 months for placebo (hazard ratio (HR)=0.94 [95% confidence interval (CI): 0.64, 1.38]; p>0.05, log rank). The hazard ratio for BF was 0.80 in favor of sipuleucal-T ([95%CI: 0.53, 1.20], p>0.05) when the analysis was restricted to patients with a confirmed BF. An analysis of PSADT calculated from 90 days following randomization to BF or the initiation of systemic therapy demonstrated that patients randomized to sipuleucel-T had a 35% increase in PSADT (125 vs 91 days; p=0.046, F-test). PSADT calculated after testosterone recovery to baseline levels demonstrated a 48% increase in PSADT for the sipuleucel-T arm (155 vs 105 days; p=0.038). Only 16% of patients developed distant metastases. The hazard ratio for time to DF was 0.78 (95%CI: 0.34, 1.58, p>0.05, log rank). Patients are still being followed for DF and survival. The most common treatment-associated adverse events were chills, fatigue, headache, and pyrexia, which were primarily Grade 1–2. Conclusions: Time to BF was not different between the two study arms. The effect on PSADT, an important prognostic indicator in ADPC, may suggest the biologic activity of sipuleucel-T in this population. Additional follow-up for clinical endpoints of DF and survival is of interest.

No significant financial relationships to disclose.
Phase III results of adjuvant radiotherapy (RT) versus wait-and-see (WS) in patients with pT3 prostate cancer following radical prostatectomy (RP)(ARO 96–02/AUO AP 09/95)
Authors: Wiegel T. , Bottke D. , Willich N. , Piechota H. , Siegmann A. , Stoeckle M. , Ruebe C. , Hinke A. , Hinkelbein W. , Miller K.
Published: March 2020

5060

Background: Adjuvant RT for pT3 R1 or R0 patients (pts.) after RP remains controversial. Results of an EORTC-phase-III- study (with unknown PSA-status after RP) suggested a 20% better biochemical control (bNED) after 5 years for RT. Methods: 385 men with prostate cancer were randomized to either 60 Gy RT (arm A; n=193) or WS (arm B; n=192) before achieving an undetectable PSA. Pts. were stratified for Gleason-score, margin status, neoadjuvant hormonal treatment and stage (pT3A+B vs. C). When the undetectable PSA-level after RP was not achieved, the pts. were stated as progressive disease and left arm A/B and were irradiated. PSA-progression for pts. with undetectable PSA was stated after two consecutive increasing PSA out of the undetectable range. Primary endpoint was bNED. Study was powered to demonstrate a 15% increase in bNED for RT. Results: 78 pts. (20%) did not achieve an undetectable PSA and were stated as progressive disease (arm A: 45 pts., arm B: 33 pts.). Additionally, 34 pts. (23%) from the RT-arm did not receive RT. Therefore, 114 pts. had RT (arm A) and 159 pts. WS (arm B). Median follow up was 53.6 months for arm A and 53.7 months for arm B. BNED at 5 years increased to 72% for arm A (RT) compared with 54% for arm B (WS) (p=0.0015, hazard ratio 0.53). Pts. with a preop. PSA > 10 ng/ml, tumor stage =pT3b, Gleason score =8 as well as positive margins profited significantly from adjuvant RT. The rate of late grade II side effects for the rectum was 1%. Conclusions: Adjuvant radiotherapy for pT3 prostate cancer significantly reduces the risk of biochemical progression after radical prostatectomy. The rate of side effects is very low.

No significant financial relationships to disclose.
A novel intermediate endpoint for predicting overall survival in men with metastatic castration-recurrent prostate cancer (CRPC)
Authors: Halabi S. , Ou S. , Vogelzang N. J. , Scher H. , Small E. J.
Published: March 2020

5113

Background: In this proposed study, we developed and validated a novel composite clinical benefit endpoint constructed from symptoms that have intrinsic clinical importance in 800 men with CRPC who were treated with front-line chemotherapy. Methods: Data from nine multimember trials (five phase II and four randomized phase III studies) conducted by the Cancer and Leukemia Group B (CALGB) from 1992–2004 were combined. Eligible patients had progressive adenocarcinoma of the prostate during androgen ablation (despite castrate testosterone levels), an ECOG performance status of 0–2, adequate hematologic, renal and hepatic functions. The tripartite composite clinical benefit endpoint (TCCBE) had three components: one based on disease progression (whether it be PSA, bone, or soft tissue progression), and the second based on weight loss (defined as at least 10% decline from baseline) or on performance status (PS) decline (by at least one level) to capture clinical deterioration. The third component was based on pain control and opioid analgesic use (no or yes). For a person to fall in the TCCBE “yes” category, at least two of the three components had to be recorded as no. For instance, if a patient at 3 months had no progression, no change in weight and did not use opioid analgesic, then he will be classified in the “yes” group and for the purpose of this analysis was considered as someone who achieved “clinical benefit”. The sample was randomly split into 526 (67%) and 274 (33%) men in the training and testing datasets, respectively. Results: From the training dataset, the median survival times in men who had and did not have clinical benefit were 20.9 months (95% confidence interval (CI) = 18.5–22.8) and 11.1 months (95% = 8.79–12.6, p- value<0.001). In the testing dataset, the median survival times in men with and without clinical benefit were 21.7 months (95% CI= 19.1–26.1) and 8.8 months (95% CI= 7.8–11.6) and in men. The hazard ratio (HR) for men with a clinical benefit compared to men without was 0.52 (95% CI= 0.43–0.62, P<0.001). Conclusions: The TCCBE is a statistically significant intermediate endpoint for predicting overall survival. Prospective validation of this endpoint is needed.

No significant financial relationships to disclose.
Prevalence of osteoporosis and osteopenia during androgen deprivation (ADT) for prostate cancer: Baseline data from a large randomized controlled trial
Authors: Malkowicz S. B. , Chu F. , Forrest J. , Smith M. R. , Price D. , Sieber P. , Barnette K. G. , Rodriguez D. , Steiner M. S.
Published: March 2020

5116

Background: Androgen deprivation therapy (ADT) is the standard treatment for men with advanced prostate cancer. ADT decreases bone mineral density (BMD) and increases fracture risk although there is limited information about the prevalence of osteopenia and osteoporosis during ADT. We evaluated the baseline data from a large fracture prevention study to better characterize the prevalence of ostepenia and osteoporosis in men receiving ADT for prostate cancer. Methods: In an ongoing phase 3 fracture prevention study, 1,392 men = 50 years old with histologically documented prostate cancer and receiving ADT were randomized to placebo or toremifene 80 mg, a selective estrogen receptor modulator. The phase 3 study included men at increased risk of fracture based on age = 70 years or low baseline BMD of the hip or spine as assessed by dual energy x-ray absorptiometry. Subjects with metabolic bone disease or receiving treatment for osteoporosis were excluded. In the current analyses, we report the baseline BMD and prevalence of osteopenia (T score -1.0 to -2.5 total hip, femoral neck or spine) and osteoporosis (T score = -2.5 total hip, femoral neck or spine) for the 1,139 subjects older than 70 years. The analyses were restricted to subjects =70 years because these subjects were included in the study regardless of baseline BMD. Results: Mean (± standard deviation) age was 76 ± 7 years. Mean duration on ADT was 39 ± 36 months. For men 70 years of age or older, mean T scores for the total hip, femoral neck, and spine are -1.01 ± 1.14, -1.50 ± 1.06 and 0.37 ± 1.88 respectively. A total of 73% of subjects 70 years of age or older were classified with osteopenia (55%) or osteoporosis (18%). Conclusions: In this large cross- sectional analysis, the vast majority of older men receiving ADT for prostate cancer have either osteopenia or osteoporosis. These observations provide further evidence that close attention to skeletal health is warranted during ADT for prostate cancer.

No significant financial relationships to disclose.
Clinical course of 771 patients with bilateral breast cancer (BBC): Characteristics associated with overall and recurrence-free survival
Authors: Beinart G. A. , Gonzalez-Angulo A. M. , Broglio K. , Mejia J. , Ruggeri A. , Mininberg E. , Hortobagyi G. N. , Valero V.
Published: March 2020

546

Background:
Women with a personal history of breast cancer have an annual incidence of 0.5–1% and a cumulative incidence from 3–20% of subsequently developing contralateral breast cancer. Despite numerous retrospective and case-control studies, risk factors related to overall (OS) and recurrence-free survival (RFS) in BBC are still being defined. The purpose of our study was to describe tumor properties, patient characteristics, and method of cancer detection for a large cohort of BBC patients, and to assess the associations of these factors with OS and RFS.
Methods:
A retrospective chart review was conducted of the BCMS (Breast Cancer Management System) database at MD Anderson Cancer Center. Among BBC patients, we compared primary versus contralateral tumors and synchronous versus metachronous cancers. Patient and second tumor characteristics were evaluated for an association with OS and RFS, as measured from diagnosis of the second tumor.
Results:
Of 11,234 primary breast cancer patients seen for an initial visit between 7/1/1997 to 12/31/2004, 771 patients (6.9%) were diagnosed with BBC. One hundred forty nine (19.3%) patients have died, and one hundred forty eight (19%) have relapsed. Stage 0 was present in 39.4% of synchronous second tumors disease versus 20.6% of metachronous second tumors (p<0.001). The 5-year OS rates based on stage of the second tumor were 87.7%, 87.7%, 69.6%, 45.1%, and 23.8% for Stages 0, I, II, III, and IV, respectively (p<0.0001). The 5-year OS rates for second tumor detection via mammogram/prophylactic mastectomy, physical exam, and self-exam were 81.6%, 70.9%, and 65.3%, respectively (p=0.01). In addition, lymphovascular invasion (LVI), nuclear grade, hormonal receptor status, and histology were significantly associated with OS and RFS (p<0.05). In a multivariable analysis, clinical stage and LVI remained significantly associated with OS (p<0.05).
Conclusions:
This study represents the largest single institution review of BBC. Numerous second tumor characteristics were associated with survival. The results emphasize the importance of earlier detection and improved staging for contralateral breast cancer.

No significant financial relationships to disclose.
Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery versus upfront surgery followed by chemotherapy (CT) in advanced epithelial ovarian carcinoma (EOC): A prospective randomized study—Interim results
Authors: Kumar Prof L. , Hariprasad R. , Kumar S. , Bhatla N. , Thulkar S. , Vijayaraghavan M. , Deo S. , Shukla N. , Singh R.
Published: March 2020

5531

Background: To determine the impact of NACT on surgical debulking rate, overall and disease-free survival and quality of life (QOL) in patients with advanced EOC. Methods: Between Oct 2001 and Dec 2006, 128 previously untreated EOC patients (median age- 50 years, range 30 to 65) with FIGO stage III C & IV (pleural effusion only) have been randomized into - Arm A (n=65) upfront debulking Surgery followed by 6 cycles of Paclitaxel & carboplatin (PC) and Arm B (n=63): NACT with 3 cycles of PC followed by debulking Surgery then 3 more cycles. Eligibility criteria include - age 18 to 65 years, biopsy / cytological proven EOC, adequate hematological, renal, liver & cardiac functions, normal upper & lower GI endoscopy & CEA levels. Both groups were compared for debulking rate, duration of surgery, blood loss, intra & postoperative morbidity & mortality, overall response to treatment and QOL (FACT- O questionnaire). Results: 100 of 128 patients have completed treatment (arm A- 56, B-44). 7 patients were not evaluable; (Germ cell tumor-1, mixed Mullerian tumor-2, dual primary-1 and krukenburg-3). 93 patients are evaluable. Patients’ characteristics are similar in both arms. Grade III-IV - GIT (3% vs. 4%) & bone marrow (9% Vs 7%, p=ns) toxicity was similar in arm A & B, among 463 CT cycles administered. Patients in NACT arm had higher optimum debulking rate, p<. 0001, decreased blood loss during surgery (mean vol 520 vs 373 ml p<0.003) and reduced postoperative infections 14.8 % vs. 2.5%, p<0.04. Mean operative time (110 vs 95 minutes, p=0.12) and hospital stay (12 Vs 9.4 days, p=0.1) were similar in arm A & B. The median overall survival (arm A & B: 42 vs 29 months, p=0.07) and disease free survival (20 vs 25 months, p=0.11) is not different at a median follow up of 41 months. QOL score was significantly better in NACT arm at the end of treatment. (93 vs 114, p<. 001). Conclusions: Neoadjuvant chemotherapy in advanced epithelial ovarian cancer is associated with higher optimum debulking rate with reduced postoperative morbidity and improved quality of life.

No significant financial relationships to disclose.
The comparison of accuracy between PET and PET/CT for detecting lymph node metastasis in cervical cancer: Prospective surgicopathologic study
Authors: Park J. , Seo S. , Kang S. , Lim S. , Lim M. , Choi H. , Kim S. , Yoo C. , Kim J. , Park S.
Published: March 2020

5587

Background: Previosly, we reported the accuracy of positron emission tomography with 2-[fluorine18] fluoro-2-deoxy-D- glucose (FDG-PET) for detecting metastatic lymph node (LN) in cervical cancer (Eur J Cancer 2005: 41; 2086–92). The aim of this prospective study was to evaluate the accuracy of PET/CT for detecting lymph node metastasis in cervical cancer and to compare the accuracy between PET and PET/CT. Methods: From May 2002 to Jul 2006, 86 patients with untreated stage IB-IVA cervical cancer were enrolled. All patients underwent pretreatment clinical staging including PET (May 2002-Aug 2003, 54 patients) or PET/CT (Jan 2004-Jul 2006, 32 patients) followed by surgical staging including systematic pelvic and paraaortic lymph node (PLN and PALN) dissection. To enable region specific comparisons, PALN and PLN were divided into eight regions: both PALN, both common iliac areas, both external iliac areas, and both internal iliac/obturator areas. Each lymph node was sliced at 2-mm intervals perpendicular to the greatest dimension to maximize the likelihood of detecting micrometastases. All metastatic tumor size in each involved lymph node was measured. Histopathologic evaluation of lymph nodes was the diagnostic standard. The study protocol was approved by Institutioal Review Board, and a written informed consent was obtained. Results: A total of 688 LN regions were evaluated. The sensitivity, specificity, positive predictive value, and negative predictive value of PET and PET/CT are shown in Table 1 . As the metastatic tumor size increased, the sensitivity of PET and PET/CT was improved. Although there were no differences in sensitivity for detecting large sized (> 5mm or 10mm) metastatic tumor, PET/CT was more sensitive than PET for all pathologically proven LN metastasis which included small sized (< 5mm) metastatic tumor. Conclusions: PET/CT was more sensitive than PET for detecting small sized (<5mm) lymph node metastasis in cervical cancer.

[Table: see text]

No significant financial relationships to disclose.
Endometrial effects of exemestane compared to tamoxifen within the TEAM trial: Results of a prospective randomized study
Authors: Kieback D. G. , Harbeck N. , Bauer W. , Hadji P. , Weyer G. , Hasenburg A.
Published: March 2020

572

Background: A prospective open label randomized multicenter substudy was performed in the German TEAM Trial Group to compare the effects of the irreversible aromatase antagonist Exemestane (EXE) and the ER agonist/antagonist Tamoxifen (TAM) on the endometrium during adjuvant treatment for postmenopausal estrogen receptor positive breast cancer. Methods: Transvaginal Ultrasound Scans (TVS) were performed at baseline, 6 and 12 months of treatment if no proliferation >5mm was present, and in 3 months intervals if endometrial thickness exceeded 5mm. Intent-to-treat analysis was performed based on 158 patients. Primary endpoint was the time interval from randomization to the earliest occurrence of endometrial hyperplasia > 10mm. Secondary endpoints were the time from randomization to endometrial hyperplasia > 5mm and the time interval from randomization to vaginal bleeding. Analysis of Time to Event Curves was performed by Kaplan-Meier method, analysis of differences between treatments by two-sided Logrank test and Cox Proportional Hazards. Differences in frequency were compared by Fisher‘s Exact Test. Results: 65 patients were available for analysis in the TAM arm, 78 in the EXE arm. Both groups were comparable regarding age, height, tumor grade,and stage. Median follow-up was 727 (EXE) and 526 days (TAM). In this time period, there were no (EXE) vs. 11 (TAM) cases of endometrial hyperplasia >10mm (p<0.0001), 11 (EXE) vs. 34 (TAM) patients with hyperplasia >5mm (p< 0.006). In total, endometrial hyperplasia was observed 11 times in the EXE arm vs. 45 times in the TAM arm (p<0.0001). Time to endometrial hyperplasia was significantly longer in the EXE group (p<0.0001); HR was 0.160 indicating an 84% risk reduction of hyperplasia in the EXE group. Increase in endometrial thickness from baseline to 6mo. was 2.94mm (EXE) vs. 5.41mm(TAM), from baseline to 12 mo 2.64mm vs. 6.0 mm respectively (p<0.0006). Only 1 patient underwent histological sampling in the EXE group (no hyperplasia) vs. 18 in the TAM subset. Conclusions: In a TEAM subprotocol, irreversible inactivation of aromatase by EXE resulted in significantly less endometrial proliferation than TAM during adjuvant therapy of receptor positive postmenopausal breast cancer.

No significant financial relationships to disclose.
Prospective multicenter study of the impact of the 21-gene recurrence score (RS) assay on medical oncologist (MO) and patient (pt) adjuvant breast cancer (BC) treatment selection
Authors: Lo S. S. , Norton J. , Mumby P. B. , Smerage J. , Kash J. , Chew H. K. , Hayes D. , Epstein A. , Albain K. S.
Published: March 2020

577

Background: The 21-gene RS assay has been validated to quantify the risk of distant recurrence in tamoxifen treated pts in N-ER+BC and predict magnitude of chemotherapy benefit. Since there is little data regarding the impact of RS on MO and pt decision making, this multi-center study was designed to prospectively examine whether RS affects MO and pt adjuvant treatment selection. Methods: MOs stated their treatment recommendation and confidence in it while pts indicated treatment choice pre and post RS assay. RS were returned to MO and pt for routine clinical care. Frequency distributions and co-frequency tables are used to display categorical distributions of nominal variables; means and standard deviations are used to summarize continuous variables. Results: 15 MOs at 1 community and 3 academic practices consecutively enrolled 93 pts (89 evaluable) with N-ER+BC. The treatment plan changed in 31.5% of MOs and 27% of pts. The frequency of treatment changes are in the table below. The largest change induced by RS results was conversion from pre-test CHT to post-test HT (22.5% of MO, 10.1% of pts). MOs stated RS results increased confidence in 68 (76%). 90% of pts felt the RS assay influenced their treatment choice; 95% were glad they took the test. Conclusion: The results of this study indicate that the RS assay does impact MO adjuvant treatment recommendations, pt treatment choice, and confidence in the treatment plan. Investigator initiated trial supported by an unrestricted clinical trial grant from Genomic Health Inc.

[Table: see text]

No significant financial relationships to disclose.
pKDR/KDR ratio predicts response in a phase I/II pharmacodynamic study of erlotinib and bevacizumab for recurrent or metastatic head and neck cancer (HNC)
Authors: Seiwert T. Y. , Davis D. W. , Yan D. , Mauer A. M. , Karrison T. , Kozloff M. , Dekker A. , Wong S. J. , Vokes E. E. , Cohen E. E.
Published: March 2020

6021

Background: EGFR activation up-regulates VEGF, which has been correlated with resistance to anti-EGFR agents. We previously reported early results (Vokes, JCO, 2005) of a phase I-II study of the EGFR inhibitor erlotinib (E) with the VEGF antibody bevacizumab (B) in recurrent or metastatic HNC. We now present results from the pharmacodynamic analysis as well as updated outcome data. Methods: Phase I/II trial of fixed dose erlotinib (E) 150 mg orally daily with escalation of bevacizumab (B) to a maximum of 15 mg/kg q 3 weeks and continued at 15 mg/kg in the phase II portion. Pts were randomized to receive the initial bevacizumab dose on either day 1 or 15. Paired biopsies were taken at baseline and after 2 weeks of treatment (after E alone or E+B) and analyzed by immunofluorescence and laser scanning analysis for target inhibition and apoptosis markers (VEGFR2/KDR, EGFR, CD31, and respective activated forms [pKDR, pEGFR]). Results: Paired biopsies were available from 20 patients. At baseline pKDR/KDR (ratio) correlated with clinical outcome and differed significantly between responses (CR>SD: p<0.01; CR>PD: p<0.0005). Interestingly, endothelial cell EGFR levels also appeared to correlate with response (CR+SD>PD: p<0.03). Paired tissue samples showed that E or E +B treatment increased apoptosis in tumor cells (pre: 0.96%, post: 7.02%: p<0.05) and endothelial cells (pre: 0%, post: 12%: p=0.15). Further, E+B treatment reduced expression of endothelial KDR, EGFR and VEGF levels compared to E alone. We previously reported an overall response rate of 14.6% (48 evaluable patients in the phase II cohort). Updated median follow-up was 7.3 months (2.1 years for patients still alive). The updated median overall/ progression free survival was 7.3 months/ 3.9 months with 30.6%/ 8.2% of patients alive at 1/2 years. Conclusions: Compared to E alone the combination of E + B showed increased inhibition of endothelial survival factors. pKDR/KDR appears to predict response to E+B. The promising clinical efficacy of E+B and potential predictive biomarkers warrant further validation in larger cohorts. (Supported by NIH N01 CM-57018–16)

No significant financial relationships to disclose.
Visits to urologists and radiation oncologists prior to treatment decision making for clinically localized prostate cancer (LCaP)
Authors: Jang T. L. , Bekelman J. E. , Liu Y. , Bach P. B. , Basch E. M. , Elkin E. B. , Zelefsky M. J. , Scardino P. T. , Begg C. B. , Schrag D.
Published: March 2020

6506

Background: The two primary therapies for LCaP are delivered by different types of physicians, urologists and radiation oncologists. We evaluated how visits to various specialists relate to treatment choice. Methods: Using data from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked program, we evaluated 85,088 men with LCaP aged 65 and older diagnosed between 1994 and 2002 who received either radical prostatectomy (n=18,201), radiotherapy (n=35,925), primary androgen deprivation therapy (n=14,021), or expectant management (n=16,941) within 9 months of diagnosis. Prostate cancer specialists were identified by Medicare claims or data from the AMA Physician Masterfile. Results: Table 1 shows a strong association between the different specialists consulted and primary therapy received. When men aged 65 to 69 saw only a urologist, 70% had a radical prostatectomy; when also seen by a radiation oncologist, 15% had a radical prostatectomy. We found greater than expected variation in the propensity of a particular urologist’s patients to undergo radiotherapy evaluation, suggesting that some men are seen by a radiation oncologist less frequently (and others more frequently) than would be explained by chance. Conclusions: Recognizing that prostate cancer specialists have different viewpoints on the most appropriate management strategy, it is imperative to ensure that all men have access to balanced information prior to definitive therapy.

No significant financial relationships to disclose.

[Table: see text]
Comparing two methods of meta-analysis in clinical research - individual patient data-based (IPD) and literature-based abstracted data (AD) methods: Analyzing five oncology issues involving more than 10,000 patients in randomized clinical trials (RCTs)
Authors: Bria E. , Gralla R. J. , Raftopoulos H. , Giannarelli D.
Published: March 2020

6512

Background: Meta-analyses are one of the highest recommendations levels in Evidence-Based Medicine (EBM). Recently, meta-analyses have increased using either IPD or AD methods. Controversy exists regarding reliability, applicability and feasibility of the different methods to draw conclusions from conflicting RCTs and to estimate magnitude of benefit of different treatments. Methods: As seen in the table , we selected 5 major issues in 3 malignancies subjected to IPD meta-analysis, and then conducted AD meta-analyses from publications of the individual studies, using published methods (Bria, Cancer Treat Rev 2006). We required that >90% of patient numbers for both IPD and AD analyses be available. Event-based relative risk ratios (RRs) with 95% confidence intervals (CI) were derived. Fixed- and random-effect models, and absolute benefits (AB) were calculated. Correlations between IPD Hazard Ratios (HRs) and AD-RRs were estimated using a linear regression model according to Pearson (r) and R2 coefficients (parametric) and Spearman (Rho) coefficient (non- parametric). Results: Results are below. A strong linear correlation exists between IPD-HRs and AD-RRs (r=0.994, R2=0.989; p<0.001; Rho=1.00). Conclusions: The strong correlation supports using high quality meta-analyses with either method to resolve major issues. Differences exist between the methods: IDP is well-suited for sensitivity analyses and for hypothesis generation involving issues not originally anticipated; AD is a practical method allowing EBM to be applied rapidly to major issues in oncology in a timely fashion.

No significant financial relationships to disclose.

[Table: see text]