bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of residual retroperitoneal mass histology following postchemotherapy retroperitoneal surgery for metastatic nonseminomatous germ cell tumors: Role of MDR-1 and mismatch repair genes
Authors: Heidenreich A. N. , Pfister D. , Thüer D. , Engelmann U. H. , Ohlmann C. H.
Published: March 2020

5088

Background: Following inductive chemotherapy for metastatic nonseminomatous germ cell tumours (NSGCT) about 35% and 15% of patients undergoing residual tumor resection (RTR) demonstrate mature teratoma and vital cancer, respectively. It was the aim of our study to evaluate the expression of mdr-1, hMLH1 and hMLH2 in primary NSGCT and their resected residual tumors. Methods: 185 patients with NSGCT underwent RTR of retroperitoneal masses. Immunohistochemical investigations of mdr-1, hMLH1/2 were performed on paraffin-embedded tissue section of the primary tumour and the resected lymph nodes using monoclonal, commercially available antibodies. Staining was analysed according to a semiquantitative scoring system; furthermore, detailed morphometry was performed. Preoperative serum and clinical parameters were assessed to predict necrosis/fibrosis or teratoma in residual tumors. Statistical analysis was performed by uni- and multivariate analysis to correlate data with histology of the RTR specimens. Parameters were statistically significant if p<0.05. Results: A total of 122 patients (65.9%) had necrosis, 23 patients (12.4%) and 40 patients (21.6%) had viable cancer and mature teratoma, resp. After multivariate analysis pre-chemotherapeutic AFP-levels, tumor size before RTR, mature teratoma in the primary and mdr-1 expression in the primary were independent predictors of final necrosis. Positive predictive values were 74%, 76%, 78% and 88% resp., sensitivity was 81%, 52.8%, 65% and 86%, resp.; specificity was 59%, 79.3%, 81% and 90% resp.. Nonseminomatous elements demonstrated a significantly higher staining intensity for hMLH1 than seminomas, whereas staining intensity for hMLH2 was lower (p=0.03). IHC for hMLH1/2 of GCT with necrosis was higher as compared to GCT exhibiting mature teratoma or vital cancer approaching statistical significance (p=0.07). Conclusions: Pre-chemotherapy AFP levels < 15 ng/ml and a residual mass < 2 cm are associated with a favourable histology in the RTR specimen. The addition of mdr-1 expression in the primary NSGCT improves sensitivity to 88% and represents a clinically useful prediction marker.

No significant financial relationships to disclose.
Results with salvage chemotherapy with high dose carboplatin + etoposide and peripheral blood stem cell transplant in male choriocarcinoma
Authors: Brames M. , Papiani G. , Einhorn L.
Published: March 2020

5091

Background: Choriocarcinoma in males is seen usually as a small component of a mixed germ cell tumor. Pure choriocarcinoma accounts for a poor prognosis, usually presenting with high level of human chorionic gonadotropin (hCG > 50,000 mIU/ml) and with pulmonary and non-pulmonary visceral metastases. Results with salvage chemotherapy in the past have been very poor with very few long-term survivors. Methods: Retrospective review of 184 germ cell patients treated with salvage high dose chemotherapy (HDCT) at Indiana University between 2–96 and 12–04 was presented (Proc Amer Soc Clin Oncol 24:228, abstract 4549, 2006). Thirteen of these patients had pure choriocarcinoma of the testis or choriocarcinoma syndrome (normal testes by palpation and ultrasound, normal serum alpha-fetoprotein, advanced hematogenous metastases, high level of hCG). Before HDCT, all the patients were treated with one or two regimens of standard cisplatin combination chemotherapy. HDCT regimen consisted of carboplatin 700 mg/m2 and etoposide 750 mg/m2 i.v. given for 3 consecutive days. A second course was given after hematologic recovery. Results: Toxicity was previously described (JCO 18:3346, 2000).The median survival was 19 months (range 5–90 months). Six patients (46%) are alive and continuously disease-free (cNED) with a median follow-up of 37 months (range 19–75). One additional patient is currently NED following subsequent chemotherapy and surgery. 3 of 7 patients with pure choriocarcinoma are cNED and 3 of 6 with choriocarcinoma syndrome are cNED. Six of 10 patients receiving HDCT as initial salvage therapy are cNED compared to 1 of 3 as third-line treatment. Conclusions: Salvage HDCT offers long-term disease-free survival and potential cure in patients with pure choriocarcinoma or choriocarcinoma syndrome that progressed after standard cisplatin combination chemotherapy.

No significant financial relationships to disclose.
Phase I/II study of sunitinib malate in combination with gefitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)
Authors: Patel P. H. , Kondagunta G. V. , Redman B. G. , Hudes G. R. , Kim S. T. , Chen I. , Motzer R. J.
Published: March 2020

5097

Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGF- and PDGF- receptors with substantial antitumor activity against mRCC (JAMA 2006;295:2516). This study was conducted to evaluate the safety and efficacy of sunitinib in combination with gefitinib, an EGF-receptor inhibitor. Methods: Eligibility included mRCC with clear cell component. The phase 1 part of the study was conducted to determine the maximum tolerated dose (MTD) of sunitinib in combination with gefitinib, and subsequently pts were enrolled in the phase 2 part to further evaluate safety and antitumor activity. Pts were treated with sunitinib at assigned dose level (37.5 mg or 50 mg) orally daily for 4 weeks on, followed by 2 weeks off (Schedule 4/2) and gefitinib at 250 mg daily. The primary endpoint for the phase 2 part of the study was objective response according to RECIST. Results: Forty-two pts were enrolled; 11 pts in phase 1 and 31 pts in phase 2. Median age was 65 years (range: 29–78) and 35 pts (83%) had =2 metastatic sites. Twenty-eight pts (67%) had prior cytokine therapy, 11 pts (26%) had no prior cytokine therapy, and 3 pts (7%) received prior vaccine therapy. Two dose limiting toxicities (DLTs) were observed at the 50-mg dose level (grade 3 fatigue and grade 2 ejection fraction decline), and 37.5 mg on Schedule 4/2 in combination with gefitinib 250 mg daily was determined to be the MTD. The median duration on treatment was 8.3 months for phase 1. Thirty-six pts are evaluable for response and 6 are too early. Eleven pts (30%) achieved a partial response and 15 pts (42%) stable disease. The most common grade 3 treatment-related adverse events observed in phase 1 were diarrhea and nausea (n=2) and for phase 2 were diarrhea (10%) and gastrointestinal hemorrhage (6%). Two pts from phase 2 were withdrawn from the study due to treatment-related adverse event; ejection fraction decline and cardiac arrhythmia, both of which were reversible after treatment discontinuation. Conclusions: The study established dose and feasibility for sunitinib in combination with gefitinib. Early evaluation of the data suggests tolerability for the combination and relative efficacy data compared to sunitinib monotherapy will be assessed with longer patient follow-up.

No significant financial relationships to disclose.
A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC)
Authors: Jac J. , Giessinger S. , Khan M. , Willis J. , Chiang S. , Amato R.
Published: March 2020

5107

Background: RAD001 is an oral mammalian target of Rapamycin (mTOR) inhibitor. Three mechanisms of anti-tumor activity; shuts down tumor response to nutrients and growth factors; cell cycle arrest at late G1 and anti-angiogenesis via VEGF. Molecular alterations in the mTOR modular pathway increase sensitivity in PTEN deficient tumors such as RCC. Endpoints: time-to-progression (TTP), response rate (RR), overall survival (OS), toxicity, and to assess changes in metabolic imaging utilizing CT-PET. Methods: Eligibility included; predominant clear cell, progressive measurable MRCC, adequate organ/marrow function, zubrod performance status (ZPS) = 2, no more than 1 prior therapy, and no active CNS involvement. RAD001 is given orally at a dose of 10mg daily without an interruption (28-day cycle), with dose modifications for toxicity. Re-evaluation was assessed every 2 cycles (8 weeks). RECIST criteria is utilized. TTP and OS are determined from entry into the study. Results: 41 pts have been enrolled. 37 pts are evaluable for response/toxicity. 2 pts toxicity only. 2 pts screened failures. 31 were male/8 female, median age 60 (38–80) years. 31 pts received prior therapy. 23 pts had a ZPS of 0, 13 /1 and 3/2. Sites of disease included; lung, nodal, liver, bone, adrenal, and kidney. 9 pts had 1 metastatic site, 17 pts/2 and 13 pts/3 or more. 15 pts continue to receive RAD001. 12 pts had partial responses, 19 pts were stable for 3+ months. Median duration of therapy is 8+ (range 01–20+) months. Treatment related adverse events; mucositis, skin rash, pneumonitis, hypophosphatemia, hyperglycemia, hypertriglyceridemia, hypercholesterolemia, thrombocytopenia, anemia and elevated LFTs. PET scans have demonstrated decreased metabolic activity in responding or stable pts. Median overall survival is 11.5+ months (range 01–20+). Conclusion: RAD001 has promising anti-tumor activity in pts with MRCC demonstrated by partial response rate. Anti-tumor activity is further suggested by prolonged TTP =3 months. Anti-tumor activity, toxicity and metabolic imaging correlation will be presented. An additional 40 pts who failed prior sunitinib or sorafenib therapy are being enrolled.

No significant financial relationships to disclose.
A consensus prognostic factor model for survival in patients with metastatic renal cell carcinoma: A Kidney Cancer Association’s International Kidney Cancer Working Group (IKCWG) study
Authors: Royston P. , Bacik J. , Elson P. , Manola J. B. , Mazumdar M.
Published: March 2020

5109

Background: Numerous well-designed retrospective studies of prognostic factors (pf) for survival (S) in metastatic renal cell carcinoma (mRCC) patients (pts) have been conducted since 1986. However, no single model for describing S in this population has been universally accepted. Methods: Authors of several existing prognostic indices, and others, formed the IKCWG to develop a single validated S model. The IKCWG has established a comprehensive database of previously reported clinical pf from 3748 previously untreated mRCC pts entered on institution review board approved clinical trials conducted by 11 centers in Europe and the United States from 1975–2002. Results: Median age at study entry was 58, 70% of pts were male, 89% had ECOG performance status (PS) 0 or 1; 75% had prior nephrectomy. 72%, 30%, and 19% of pts had lung, bone, and liver metastases (mets), respectively. 72% received interferon-a and/or interleukin-2 based treatments (tx); 25% were txd with chemotherapy/hormones only; 3% received other tx. 88% of pts have died; median S was 11.1 months (m). All examined factors except sex, age, and histology impacted S at p<.001 in univariable analysis. Multivariable analysis using a log-logistic model stratified by center and multivariable fractional polynomials was performed to identify independent predictors of S. Missing data were handled using multiple imputation methods. Using p=.0044 as the criterion for variable selection to avoid overly complex models, a model comprising tx, PS, number of met sites, interval from diagnosis to tx, and pre-tx hemoglobin, WBC, LDH, alkaline phosphatase and calcium was identified. The 25th and 75th percentiles of the prognostic index formed by multiplying each factor by its regression coefficient were used as cutpoints to form three risk (r) groups with median S times (SE) of: favorable r (n=937; 27.8 (0.4) m), intermediate r (n=1874; 11.4 (0.2) m), and poor r (n=937; 4.1 (0.1) m). Conclusions: 9 clinical factors can be used to model S in mRCC and form 3 distinct prognostic groups. Additional model building to determine if model complexity can be reduced further, validation in independent data and comparison to existing prognostic models are underway.

No significant financial relationships to disclose.
Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer
Authors: Perez E. A. , Romond E. H. , Suman V. J. , Jeong J. , Davidson N. E. , Geyer C. E. , Martino S. , Mamounas E. P. , Kauffman P. A. , Wolmark N.
Published: March 2020

512

Background: The joint efficacy analysis of NCCTG N9831 and NSABP B-31 demonstrated improved outcomes with the addition of trastuzumab (H) to doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) in women with surgically removed HER2- positive breast cancer (NEJM 2005). Following this report, patients randomized to AC→T and less than 6 months from completion of chemotherapy were eligible to receive H. We have updated the initial combined results of these two trials. Methods: Primary and secondary efficacy endpoint were disease free survival (DFS) and overall survival (OS). Cox modeling was performed. Hazard ratios are adjusted for nodal status, tumor size, T schedule, hormone receptor status, and trial (also age for OS). Results: Among the 3,969 women enrolled (ages: 22 to 80yrs), there have been 619 events (H group: 222, non-H: 397). First events were: recurrence (511), contralateral breast disease (18), other second primary cancers (48), and death without recurrence or second primary cancers (42). The median follow-up among the 3,711 women still alive is 2.9 years (range up to 6,4 years). The 4 yr DFS rate and 4 yr OS rate respectively were: 85.9% (95%CI: 84.0–87.8%) and 92.6% (95%CI: 91.2–94.2%) in H group and 73.1% (95%CI: 70.6–75.8%) and 89.4% (95%CI: 87.6–91.2%) in non- H group. Hazard ratio for adjuvant (H/non-H) was 0.49 (P<0.0001; 95%CI: 0.41–0.58) for DFS and 0.63 (P=0.0004; 95%CI: 0.49–0.81) for OS.The rates of a first event per 1,000 women/year during yrs 1–4 were: 26.7, 52.9, 49.6 and 23.2 for H and 42.3, 102.3, 107.6 and 61.5 for non-H. The impact of crossover on clinical outcome will be explored. Conclusions: With an increase in the median follow-up of 11 months and with 225 additional events, the demonstration of substantial improvement in outcomes with the addition of trastuzumab to chemotherapy persist. This improvement continues in spite of some degree of cross-over occurring after the initial results were reported.Updated data regarding crossover outcomes and H duration (as they relate to disease free survival) will be presented.

[Table: see text]
Phase II monotherapy study of YM155, a novel survivin suppressant, administered by 168-hour continuous infusion in previously treated hormone refractory prostate cancer (HRPC)
Authors: Karavasilis V. , Mita A. , Hudes G. , Quinn D. , Ferrari A. , Kocak I. , Keating A. , Bartes P. , Charleston D. , de Bono J.
Published: March 2020

5135

Background: In a PC-3 tumor cell model YM155 inhibited survivin mRNA transcription and survivin protein expression and showed potent (nM) anti-proliferation activity with strong signs of tumor regression. In a phase I study, two highly refractory HRPC patients exhibited a > 50% reduction of PSA from baseline. Methods: Patients with metastatic HRPC who received prior taxane chemotherapy were eligible. The primary endpoint is PSA response rate (decline by ≥ 50%). Other endpoints include objective tumor response by RECIST and evaluation of toxicity. A two stage Simon study design required one response in stage I (N=13) and 3 responses in stage II (N=14). If 4 responses are achieved then an additional 33 pts (N=60) will be enrolled to further characterize the efficacy and safety. Patients are considered evaluable if they complete 2 cycles. YM155 is given as a 168 hour continuous infusion every three weeks (1 cycle) at a dose of 4.8 mg/m2/day. Results: First two stages are enrolled with treatment ongoing. Data on 32 pts is provided. Median age is 67 y/o (range 53 - 81) with ECOG PS of 0 - 2. All but one patient received at least one prior taxane containing regimen. Two patients are PSA responders to date. One achieved response at cycle 2 (currently at cycle 3) and one at cycle 6 (currently at cycle 10). The median number of cycles is 3 (range 1 - 10). Two patients discontinued due to adverse events; in only one patient was the event (fever) considered related to study drug. Five/32 patients reported grade 3, 4, or 5 AE considered related to drug (coagulopathy secondary to coumadin therapy followed by intracranial hemorrhage, fatigue, URI, decreased Hgb, thrombocytopenia). Seven/32 patients remain on drug including the two responders. Conclusions: The preliminary data of YM155 in HRPC demonstrates activity and has an acceptable toxicity profile.

No significant financial relationships to disclose.
EMD121974 (NSC 707544, cilengitide) in asymptomatic metastatic androgen independent prostate cancer (AIPCa) patients (pts): A randomized trial by the Prostate Cancer Clinical Trials Consortium (NCI 6372)
Authors: Bradley D. A. , Dunn R. , Ryan C. , DiPaola R. , Smith D. C. , Cooney K. A. , Mathew P. , Gross M. , Colevas A. D. , Hussain M.
Published: March 2020

5137

Background: Integrins avβ3 and avβ5 are essential to PCa metastasis by regulating cell adhesion, migration, invasion and motility. Cilengitide is a potent and selective avβ3 and avβ5 integrin receptor antagonist that in phase I studies has shown clinical activity. Methods: Pts with asymptomatic, metastatic chemo-naive AIPCa with PSA or objective progression, no visceral disease, minimum PSA of 5ng/ml, and adequate organ function were randomized to cilengitide 500 mg or 2,000 mg IV 2X weekly in 6-week cycles, using modified randomized selection design. Disease status was assessed every 12 weeks. The primary end point is objective progression rate (not including PSA) at 6 months. The Simon 2-stage optimal design is used to accrue 53 pts/arm. After first stage (20 pts/arm), accrual continues if ≥ 6 pts have not progressed. If second stage accrual is initiated, at end of study, the better performing arm will be chosen for further study provided at least 18/53 pts in that arm have not progressed. Secondary end points include safety, response rates and correlative measures of cilengitide effect on circulating and bone marrow tumor and endothelial cells and on bone remodeling markers. Results: First stage accrual is complete with 42 pts registered. Median performance status is 0, median age is 71 years (range 52–85), and median PSA is 44ng/ml (range 5–870). Disease progression at registration was defined by PSA in 90%, soft tissue in 36% and bone in 31% of pts. Median number of cilengitide cycles is 3 (range 1–8). To date, 32/42 pts have received ≥ 2 cycles. The most common (>5%) treatment related adverse events (AE): fatigue (38%), constipation (13%), anorexia (10%), leucopenia (8%) and nausea (8%). There were only 3 grade (G) 3 AEs (neutropenia, lymph node pain, lymph NOS) and no G4 AEs. Only 3 pts required dose modification. 25/42 pts were removed from protocol on or before 6 months, 6 pts received therapy for more than 6 months, and 11 are too early to assess. Conclusions: Cilengitide is well tolerated. Final results (efficacy, safety, correlative studies) of the first stage of accrual will be reported. Supported by CTEP, Prostate SPORE Grant P50 CA069568- 09, PC051375, Merck KGaA, PC051382.

[Table: see text]
Testosterone recovery after two years of androgen suppression in prostate cancer patients
Authors: Yoon F. , Choo R. , Gardner S. L. , Morton G. , Szumacher E. F. , Cheung P. , Loblaw D. A. , Danjoux C.
Published: March 2020

5144

Background: The time course of testosterone (TST) recovery after prolonged androgen suppression (AS) is not well established. We examined TST recovery prospectively in prostate cancer (PCa) patients treated with 2 years of AS. Methods: 153 PCa men with pT3N0 or positive margins after radical prostatectomy (RP), or with PSA relapse (persistently detectable postoperative PSA [= 0.2 ng/mL], delayed detectable PSA = 6 months after surgery, or palpable/biopsy proven local recurrence after RP), were treated with radiation (RT) to the prostate bed (60 - 70 Gy in 30 - 35 fractions) plus 2 years of AS as part of a phase II study. AS consisted of nilutamide 100 mg PO tid for 4 weeks, starting within 1 week after completing RT, and busereline acetate 6.6 mg SC every 2 months for 2 years, starting within 2 weeks of nilutamide. The primary endpoint was PSA relapse-free survival. Serum TST levels were measured at baseline, every 4 months during AS, and every 6 months after completing AS. The planned sample size was 150 patients. Time to TST recovery was analyzed using the Kaplan-Meier method. Cox Proportional Hazards regression was used for a multivariate analysis of predictive factors for TST recovery. Results: 122 men completed the planned AS. Median follow up after finishing AS was 36.4 months (range 9.4 - 76.2). A castrate TST level was defined as =1.7 nmol/L (50 ng/dL), with normal levels being 10 - 40 nmol/L. All men achieved castrate TST levels on AS. Table 1 shows TST recovery at 36 months after completing AS and median times to recovery. Median recovery time to normal TST was 27 months, although 8% of men did not recover to above castrate levels by 3 years. On multivariate analysis, younger age (<60 vs. =60) predicted for a significantly shorter recovery time to normal TST (P = <0.0001), while baseline TST (<10 nmol/L vs. =10.0 nmol/L) was of borderline significance (P = 0.06). Conclusions: TST recovery after 2 years of AS is protracted. Older men have significantly longer recovery times.

[Table: see text]

[Table: see text]
Neoadjuvant docetaxel and capecitabine in patients (Pts) with high-risk prostate cancer (PCa): Final results of a phase II trial
Authors: Friedman J. D. , Vaishampayan U. , Wood D. , Wu A. , Bradley D. , Dunn R. L. , Montie J. , Sarkar F. H. , Shah R. , Hussain M.
Published: March 2020

5147

Background: Docetaxel is the most active cytotoxic agent in PCa. Pre-clinically docetaxel increases the expression of thymidine phosphorylase (TP), an enzyme responsible for activation of capecitabine to 5-fluorouracil. We assessed the activity and safety of neoadjuvant docetaxel and capecitabine (DC) in pts with high risk PCa. Methods: Non-metastatic PCa pts with clinical stage >T2, or PSA = 15 ng/ml or biopsy Gleason sum (GS) = 8 received 3–6 cycles of docetaxel (36 mg/m2 IV on days 1, 8, and 15) and capecitabine (1,250 mg/m2/day PO on days 5–18) q 28 days, followed by local therapy. The primary endpoint of this 2-stage phase II trial was rate of = 50% decline in PSA. Secondary endpoints included safety and correlative measures of treatment effect (qualitative changes in histology, tissue TP and survivin expression, and CK18Asp396 [apoptosis marker] in serum). Results: Fifteen pts were enrolled with median age of 58 years, median GS =8 and PSA of 23.2 ng/mL. Five pts met 1, 7 met 2, and 3 met 3 entry criteria. 14 pts completed 3 or more cycles of DC, with a median follow up of 17.5 months (9–34). Six of the 15 patients (40%) experienced a = 50% decline in PSA, which was below the 7 required for expansion of the study. Median testosterone did not change post therapy. Eleven pts underwent radical prostatectomy (RP), with no increase in surgical complications. Six pts had positive margins, and 2 had lymph node involvement. Of the 8 patients who underwent RP alone, 5 developed a biochemical recurrence in a median time of 11 months. Grade 3 or 4 toxicities were diarrhea(3), mucositis(2), hand foot syndrome(1) and neutropenia(2). Post versus pre therapy tissue had only mild chemotherapy-effects (4/7 samples), including focal clear cell changes, apoptosis/pyknosis, and necrosis. While there was no discernable pattern of increased TP expression, 4/7 specimens showed decreased survivin expression, suggesting a possible mechanism for chemotherapy-induced apoptosis. There was no correlation of PSA response and survivin expression and no increase in serum CK18Asp396. Conclusions: Docetaxel and capecitabine in the neoadjuvant setting is well tolerated, but results in modest pathologic and PSA responses. Supported by Sanofi- Aventis.

No significant financial relationships to disclose.
Phase I study of docetaxel and 153Sm repetitively administered for castrate metastatic prostate cancer (CMPC)
Authors: Morris M. J. , Pandit-Taskar N. , Amodio A. J. , Gignac G. A. , Flatts E. , Slovin S. , Solit D. , Rathkopf D. , Larson S. , Scher H. I.
Published: March 2020

5152

Background: Docetaxel (Tax) prolongs survival in patients (pts) with CMPC. Early clinical data suggest that Tax combined with bone seeking radiopharmaceuticals may improve survival relative to chemotherapy alone. 153Sm-lexidronam (Sam) (Quadramet, Cytogen Inc.) is a radiopharmaceutical with a short T1/2 and a favorable toxicity profile. Methods: Pts with progressive CMPC are treated in cohorts of 3–6. Prior treatment with taxanes is permissible. Cohorts are defined by dose escalations of: Tax 65, 70, 75, 75, 75 mg/m2 and Sam 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle is 6 weeks. Tax is given day 1 and 22 and Sam day -1 to 1 of each cycle. DLT is defined as cycle 1 = grade 3 non-hematologic toxicity, grade 3 neutropenia that lasts for >29 days, or grade 3- 4 anemia or thrombocytopenia of = 5 days. Pts with an ANC of grade 0–1 or platelet count (PLT) of >100,000/mm3 at the end of cycle 1 may receive additional cycles. Pts are treated until progression or toxicity. Results: 18 pts have been treated in 5 cohorts of 3 pts to date. 6 pts were treated in cohort 2. Two pts have not yet received enough treatment to be evaluable. DLT has not yet been reached. The mean number of cycles/pt is 3 (range 1–6). As anticipated, toxicities have primarily been hematologic (see table ). Two pts came off study for hematologic toxicity; one in cohort 2 had grade 3 PLT after 5 cycles and has not recovered at >175 days and 1 pt (cohort 2) failed to recover PLT in the allotted time frame during cycle 4 prohibiting further treatment. No other pts required treatment delays for hematologic toxicity. Mean baseline PSA was 294.6ng/ml with 7/16 (44%) pts achieving = 50% decline in PSA. Conclusions: Coadministration of Tax and Sam has been well tolerated. Repetitive dosing is feasible. Standard approved doses of each drug are being tested in the present (and final) cohort. DLT has not yet been reached. Accrual continues, to refine the optimal dose and schedule in preparation for phase II. Support: Cytogen, Inc., NIH CA102544

[Table: see text]

No significant financial relationships to disclose.
Effect on patient outcome of residual DCIS in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy
Authors: Mazouni C. , Peintinger F. , Wan-Kau S. , Andre F. , Gonzalez-Angulo A. M. , Symmans F. , Meric-Bernstam F. , Valero V. , Hortobagyi G. , Pusztai L.
Published: March 2020

530

Background: To determine whether residual ductal carcinoma in situ (DCIS) after completion of preoperative chemotherapy affects the outcome of patients with hiostologically defined complete eradication of invasive cancer. Methods: Retrospective analysis of a database including 2,302 breast cancer patients treated prospectively with neoadjuvant chemotherapy at the UT MD Anderson Cancer Center between 1980 and 2004 was performed. The overall, disease-free and local recurrence-free survivals were compared for patients with no residual invasive or in situ cancer (pCR) and those with no residual invasive cancer but persistent in situ disease (pCR+DCIS). Results: The mean follow-up was 250 months. Of the 2,302 treated patients 78 (3.4%) had pCR, 199 (8.6%) had pCR+DCIS, and 2025 (88%) had residual invasive cancer. The 5-year (87.1% in both) and 10-year (81.3% vs 81.7%) disease-free survival rates were similar for cases with pCR and pCR+DCIS. The 5-year (91.9% vs. 92.5%) and 10-year (91.8% vs. 92.5%) overall survival rates were also similar and significantly better than the rate of patients with residual invasive cancer (74.4%, p<0.001). The 5-year local-regional recurrence-free survival rates were also not different for patients with pCR (92.8%, 95% CI: 86.1%-96.4%) and those with pCR+DCIS (90.9%, 95% CI: 77.3%- 96.5%), p=0.63. Conclusions: Residual DCIS in patients who experience complete eradication of the invasive cancer in the breast and lymph nodes does not adversely affect survival or local recurrence rate. Inclusion of cases with residual DCIS in the definition of pathologic complete response is justified when this outcome is used as early surrogate for long term-survival.

No significant financial relationships to disclose.
Competing causes of death in NCIC CTG MA.17, a placebo-controlled trial of letrozole as extended adjuvant therapy for breast cancer patients
Authors: Chapman J. , Meng D. , Shepherd L. , Parulekar W. , Ingle J. N. , Muss H. B. , Palmer M. , Yu C. , Goss P. E.
Published: March 2020

540

Background: Risk of death from other malignancies (OM) and other causes (OC) than breast cancer (BC) increases with age. Effects of baseline factors on type of death were assessed with competing risks analyses. Methods: In NCIC CTG MA.17, 5,187 women free of recurrent breast cancer after 5 years of tamoxifen were randomized to letrozole (L, 2,593 women) or placebo (P, 2,594 women). The primary endpoint was disease free survival (DFS), and secondary, overall survival (OS). Follow-up was to October 9, 2005: median 3.9 years, range <0.1 to 7.0 years. Effects of competing risks were examined for endpoints of BC, OM, and OC for 11 baseline trial factors: treatment, age, menopausal status, duration of prior tamoxifen, adjuvant radiotherapy, bone fracture, osteoporosis, cardiovascular disease, hormone receptor status, nodal status, adjuvant chemotherapy. Lagakos’ hierarchical method (Lagakos, Appl. Statist. 1978; 27:235–241) was used to test for differential effects of baseline factors on type of death (BC, OM, OC). Results: Rate of censoring was 97.8%, with 256 deaths (BC, 102; OM, 50; OC, 100; unknown, 4). Non-breast cancer deaths accounted for 60% of known deaths; 72%, for those ≥70 years; and 48%, for those <70 years. Two baseline factors differentially affected type of death. Women with cardiovascular disease were more likely to die from OC (p=0.02), while those with osteoporosis were more likely to die of OM (p=0.03). Age and nodal status had directionally similar effects. Older women had shorter survival from all 3 causes of death (p=0.01). Lymph node positivity was associated with worse survival (p=0.003). Conclusions: Extended L provides similar proportional benefit in improving DFS for all ages of women (Muss ref abstract SABCS 2006). However, the magnitude of competing non-breast cancer, and non-treatment related, causes of death needs to be considered more frequently, since with early detection and improved therapies, breast cancer patients may increasingly be expected to survive their disease to die from another cause. The novel association between baseline osteoporosis and other malignancies is being explored quantitatively.

No significant financial relationships to disclose.
Updated 12-year results of a randomized clinical trial comparing standard-dose to high-dose myeloablative chemotherapy in the adjuvant treatment of breast cancer with more than three positive nodes (LN+)
Authors: Gianni A. M. , Bonadonna G. , Michelangelo G.
Published: March 2020

549

Aims: We conducted a multicenter randomized trial comparing sequential adjuvant standard-dose with high-dose chemotherapy in breast cancer patients younger than 60 years, with 4 or more positive nodes. Patients: Following surgery, patients were stratified by number of positive nodes (4–9 or 9), and randomly assigned to either conventional Epi–CMF (3 courses of epirubicin 120 mg/m2, followed by 6 courses of CMF), or high-dose chemotherapy (HDS) with stem cells support (one course of cyclophosphamide 7 g/m2, followed by one course of methotrexate 8 g/m2 with leukovorin rescue, by two courses of epirubicin 120 mg/m2, and by one course of thiotepa 600 mg/m2 plus melphalan 160–180 mg/m2 with stem cell autografting). Tamoxifen (20 mg/d × 5 yr) was also planned regardless of menopausal and receptor status. The study was designed with a power of 80% to detect a 15% increase in progression-free survival at 5 years in the HDS arm. Results: Of the initially enrolled 398 patients, 16 were ineligible, and the remaining 382 patients (Epi–CMF: 197 patients, HDS: 185 patients) were analyzed according to intent-to- treat. One patient treated with HDS (0.5%) died of interstitial pneumonia. With a median follow-up of 136 months, the 12-year progression-free survival rates were 44% and 52% for the Epi–CMF and the HDS groups, respectively, and the overall survival rates were 51% and 60%, respectively. However, among the 68 patients younger than 36 years, and the 189 patients with 4–9 LN+, those in the HDS group showed a trend for a progression-free survival advantage (HR 0.76 and 0.74, respectively). Conclusions: In the intent-to-treat analysis the 9% overall survival advantage associated with the HDS regimen failed to reach statistical significance in a study powered to detect a 15% difference. To reliably define the role of high-dose therapy, meta-analysis of patient data from all relevant randomized trials (such as that planned by the Early Breast Cancer Trialists’ Collaborative Group) is needed. Supported in part by AIRC and Pharmacia & Upjohn, Milano, Italy.

No significant financial relationships to disclose.
A phase III adjuvant trial of sequenced EC + filgrastim + epoetin-alpha followed by paclitaxel compared to sequenced AC followed by paclitaxel compared to CEF in women with node-positive or high-risk node-negative breast cancer (NCIC CTG MA.21)
Authors: Burnell M. J. , Levine M. N. , Chapman J. A. , Bramwell V. , Vandenberg T. , Chalchal H. I. , Albain K. , Perez E. , Rugo H. , Pritchard K.
Published: March 2020

550

Background: CEF and AC followed by paclitaxel (AC/T) are commonly used adjuvant regimens in women with early breast cancer. In a trial conducted by the EORTC, NCIC CTG, and SAKK three months of dose-dense EC was equivalent to six months of CEF in women with locally advanced breast cancer. We hypothesized that three months of a taxane following dose-dense EC would be superior to CEF alone or AC/T. The results of a planned interim analysis were presented in San Antonio 2006 (Abstract #53). We now present more detailed results on efficacy and toxicity. Methods: Women 60 years of age or younger, with axillary node positive or high risk node negative breast cancer were randomized to CEF, EC/T or AC/T for six months. Results: Between December 2000 and April 2005, 2104 patients were enrolled. The median follow-up is 30.4 months. Hazard ratios for recurrence are: AC/T vs. CEF, 1.49 (95% CI, 1.12–1.99), p=0.005; AC/T vs. EC/T, 1.68 (95% CI, 1.25–2.27), p=0.0006; and EC/T vs. CEF, 0.89 (95% CI, 0.64–1.22), p=0.46. Three year recurrence-free survival rates for CEF, EC/T, and AC/T are 90.1, 89.5 and 85.0%, respectively. There was no significant interaction between ER status and treatment. Multivariate analysis of predictive factors will be presented. The numbers of deaths are 50 (CEF), 47 (EC/T) and 65 (AC/T). There was more toxicity in CEF and EC/T compared to AC/T. Conclusion: AC/T given every three weeks, although less toxic is significantly inferior to CEF or EC/T in terms of relapse-free survival. It is too early to detect any difference between CEF and dose-dense EC/T. Our results indicate that there is still room to explore anthracycline and taxane adjuvant chemotherapy regimens. Supported by: NCI Canada and Canadian Cancer Society, Pfizer, Bristol-Myers Squibb, Amgen, Janssen Ortho, Ortho Biotech, and NCI US.

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No significant financial relationships to disclose.
Use of predictive gene expression signature from advanced-stage serous papillary ovarian cancer to identify biologically relevant molecular targets for chemoresponse
Authors: Ozbun L. , Bonome T. , Radonovich M. , Pise-Masison C. , Brady J. , Caplen N. , Johnson M. , Mok S. C. , Birrer M. J.
Published: March 2020

5500

Background: The aim of our study was to develop and validate a gene expression signature predictive for chemoresponse in advanced stage serous papillary ovarian cancer. Methods: Gene expression profiling was performed on 52 chemonaive, microdissected advanced stage, high-grade papillary serous ovarian cancers using Affymetrix whole-genome microarrays. Patient samples were grouped based on chemoresponse. 19 nonresponders were refractory to chemotherapy, 14 responders relapsing 6 months were considered chemosensitive. Each group was divided into training/validation sets. To generate a predictive gene signature, class prediction algorithms were applied to genes differentially expressed between chemosensitive/resistant or chemosensitive/refractory tumors (p<0.001) using leave-one-out cross-validation. Array validation was performed by qRT-PCR. Select genes underwent biological validation in a series of ovarian cancer cell lines. Results: 31 genes predictive for resistance and 105 genes predictive for refractory to chemotherapy were identified. Percentages of arrays accurately predicted in independent validation sets were 90% (9/10) for resistant and 92% (12/13) for refractory gene signatures. Correlations between microarray/qRT-PCR data were robust for both resistant (17/23 genes) and refractory gene signatures (25/34 genes). Data mining of the predictive signatures using PathwayStudio software identified several biological processes (collagen regulation, apoptosis, cell survival, and DNA repair) implicated in conferring resistance to chemotherapy. We transiently transfected RNAi molecules to silence several signature genes and determine their contribution to taxol/cisplatin sensitivity in a series ofl ovarian cancer cell lines. Preliminary data showed DUSP1 gene expression knockdown potentiated cisplatin sensitivity in SKOV3/OVCA429 cell lines, while POLH knockdown potentiated cisplatin sensitivity in OVCA429/OVCA420 cell lines. Conclusions: A gene expression signature predicts for chemoresponse in ovarian cancers, and has identified novel targets of biological/therapeutic interest.

No significant financial relationships to disclose.
VEGF-Trap for patients (pts) with recurrent platinum-resistant epithelial ovarian cancer (EOC): Preliminary results of a randomized, multicenter phase II study
Authors: Tew W. P. , Colombo N. , Ray-Coquard I. , Oza A. , del Campo J. , Scambia G. , Spriggs D.
Published: March 2020

5508

Background: Vascular endothelial growth factor (VEGF) is over-expressed in EOC and associated with poor prognosis. VEGF Trap, a potent angiogenesis inhibitor fusion protein, is comprised of portions of human VEGF-receptor R1+R2 (Flt-1, KDR) extracellular domains and fused to the Fc portion of human IgG. VEGF Trap binds VEGF-A and neutralizes all VEGF-A isoforms plus placental growth factor. Methods: This is a randomized, double blind, multicenter, 2-stage, phase II trial of VEGF Trap (2 or 4 mg/kg) administered intravenously every 2 weeks, in pts with recurrent EOC. Eligible criteria included 2 or 3 prior chemo regimens for advanced disease; platinum- resistance, topotecan- and/or liposomal doxorubicin-resistance; no prior VEGF inhibitor treatment; ECOG performance status 0–2; normal organ function; no proteinuria (<500 mg/24hrs or UPCR =1); controlled blood pressure. This Simon 2 stage design, requires 3 responders out of 42 evaluable, in each arm to continue accrual into stage 2. Results: Across 62 centers in Europe, Canada and US, rapid accrual led to 162 pts randomized from 5/06 to 12/06. Median age: 58, PS (0,1,2): 56,40,4%. Of 45 pts currently in the database, across the two arms, adverse events included (any grade): headache (38%), fatigue (36%), dysphonia (33%), nausea (29%), asthenia (24%), diarrhea (18%), hypertension (16%), proteinuria (7%), renal dysfunction (4%). Grade 3–4, included: hypertension (9%), proteinuria (4%), encephalopathy (2%) and renal failure (2%). Of the 162 pts who had at minimum one cycle, study drug-related SAE include (N): thrombocytopenia (1), anemia (1), headache (1) asthenia (2),dyspnea (1), hypertension (4), bowel perforation (2), encephalopathy (1), renal failure (2), proteinuria (1), phlebitis (1) and pulmonary embolism (1). 5 partial responses (11%) have been reported. Conclusions: VEGF Trap has activity in this heavily-pretreated EOC population. The first stage of accrual is complete and updated results will be presented.

No significant financial relationships to disclose.
Results of a phase II evaluation of nanoparticle albumin bound paclitaxel (nab-paclitaxel) in platinum-sensitive patients with recurrent ovarian, peritoneal, or fallopian tube cancer
Authors: Teneriello M. G. , Tseng P. C. , Crozier M. , Encarnacion C. , Hancock K. , Messing M. J. , Boehm K. A. , Williams A. , Ilegbodu D. , Asmar L.
Published: March 2020

5525

Background: Patients (pts) with recurrent ovarian, peritoneal, or fallopian tube cancer generally have a poor outcome with current therapies. There are no reports of albumin-bound paclitaxel (nab-paclitaxel) in pts with platinum sensitive recurrent disease. We are reporting our preliminary efficacy and toxicity results with nab-paclitaxel in this group. Methods: 47 pts were enrolled (44 available for analysis). Main inclusion criteria: histologically or cytologically confirmed epithelial cancer of the ovary, fallopian tube, or peritoneum (any stage, grade 2–3 if stage I) and measurable disease by RECIST or elevated CA-125 (>70 units/mL) in the absence of measurable disease; nonepithelial disease was excluded. Pts received 260 mg/m2 of nab-paclitaxel IV over 30 minutes Day 1 of each 21-day cycle. Pts continued until progressive disease (PD) up to a maximum of 6 cycles. Results: Median age was 65.5 years (range, 42- 84), Stage IIIC (53%) or IV (23%); ECOG PS=0 (87%), and prior surgery (94%). For evaluable pts the overall response rate (ORR) was 50% (13 CR and 9 PR in 44 pts). In pts followed by RECIST only, the ORR was 27% (1 CR and 2 PR in 11 pts). In pts with only CA-125, it was 64% (5 CR and 2 PR in 11 pts). In pts meeting both RECIST and CA-125 criteria, the ORR was 54.5 % (7 CR and 5 PR in 22 pts. Median time to response was 1.8 months (range, 1 to 2.1). The most frequent Grade 3–4 treatment-related toxicities were: neutropenia (8.7%) and fatigue, diarrhea, and dyspepsia (2.2%, each); alopecia (Grades 1–2) occurred in 84.8%. All other adverse events were Grade 1–2. To date, 46 pts are surviving; one death was related to progressive disease. Conclusions: Nab-paclitaxel was very active in this group of pts with recurrent ovarian, peritoneal, or fallopian tube cancer. The ORR was 50%. Toxicities were minimal and manageable. Response and survival analysis and review of the methods of disease assessment are ongoing. Further studies of nab-paclitaxel are warranted. This research was supported, in part, from a research grant from Abraxis BioScience, Inc., Santa Monica, CA.

[Table: see text]
Effect of monthly oral ibandronate on anastrozole-induced bone loss during adjuvant treatment for breast cancer: One-year results from the ARIBON study
Authors: Lester J. E. , Gutcher S. A. , Ellis S. P. , Thorpe R. , Horsman J. M. , Brown J. E. , Purohit O. P. , Dodwell D. , Coleman R. E.
Published: March 2020

553

Background: The aromatase inhibitor anastrozole is a highly effective treatment for breast cancer with superior efficacy and tolerability advantages over tamoxifen. However its use is associated with significant declines in bone mineral density (BMD) with an increase in fracture risk. The ARIBON trial is a double blind, randomised, placebo-controlled study designed to evaluate the impact of bisphosphonate treatment on BMD in women taking anastrozole. The study also aims to explore the relationship between levels of biochemical markers of bone metabolism with longer term changes in BMD as measured by Dual energy Xray Absorptiometry (DXA). Methods: 131 postmenopausal, surgically treated breast cancer patients were recruited from oncology clinics in Leeds and Sheffield, UK. Following consent, baseline bone densitometry showed that 68, 50 and 13 patients were found to be normal (T >-1.0), osteopenic (T -1.0 to -2.5) and osteoporotic (T < -2.5) respectively. All patients were treated with anastrozole 1mg once a day and offered calcium and vitamin D supplementation. In addition, osteopenic patients were randomised on a 1:1 basis to receive either treatment with ibandronate 150 mg orally every month or placebo. Osteoporotic patients were treated with open label ibandronate orally 150mg every month. Results: After I year, osteopenic patients treated with ibandronate gained +2.78% (range -3.8, +15.1) and +1.35% (range -4.1, +5.6) at the lumbar spine and hip respectively. Patients treated with placebo however lost -2.61% (range -11.0, +2.2) at the lumbar spine and -2.34% (range -10.4, +5.2) at the hip. The differences between the two treatment arms were statistically significant at both sites (p<0.001, independent samples t-test). Patients with osteoporosis gained +5.05% (range -8.7, +15.2) at the lumbar spine and +2.62% (range -1.0, +8.6) at the hip after 1 year. Conclusions: Ibandronate 150 mg by mouth once a month prevents anastrozole induced bone loss and results in significant increases in BMD at the hip and lumbar spine in osteopenic and osteoporotic patients. Analysis of the biochemical markers of bone metabolism is underway and relationships between biochemical and BMD changes will be presented.

No significant financial relationships to disclose.
Improved overall survival for patients with advanced ovarian, tubal, and primary peritoneal carcinoma as a result of a change in surgical approach: A follow-up study
Authors: Chi D. S. , Eisenhauer E. L. , Sonoda Y. , Abu-Rustum N. R. , Gemignani M. L. , Levine D. A. , Hensley M. L. , Sabbatini P. , Brown C. L. , Barakat R. R.
Published: March 2020

5530

Background: In January 2001, we initiated a programatic change in our primary surgical approach to advanced ovarian carcinoma utilizing extensive upper abdominal procedures as needed to achieve maximal cytoreduction. The objective of this study was to determine the impact of incorporating these procedures on overall survival in advanced ovarian, fallopian tube, and primary peritoneal carcinomas. Methods: Two groups of patients (pts) with stage IIIC and IV ovarian, tubal, and primary peritoneal carcinoma were identified for comparison. Group 1, the control group, consisted of all 168 pts who underwent primary cytoreduction between 1/96 and 12/99. Group 2, the study group, was composed of all 209 pts who underwent primary surgery between 1/01 and 12/04, during which time a more comprehensive debulking of upper abdominal disease was used, including diaphragm peritonectomy/resection, splenectomy, distal pancreatectomy, liver resection, resection of porta hepatis tumor, and cholecystectomy. Results: Comparison between the 2 groups revealed no significant difference in age, BMI, performance status, stage, tumor grade, proportion with primary ovarian cancer, preoperative CA-125 levels, preoperative platelet counts, percentage with ascites, or type of postoperative primary chemotherapy. The only 2 variables that differed significantly between the 2 groups were percentage of pts who had extensive upper abdominal surgery and percentage of pts cytoreduced to ≤1 cm residual disease (RD). Patients in Group 2 were more likely to have undergone extensive upper abdominal procedure(s) (37% vs. 1%; P <0.001). Cytoreduction to RD ≤1 cm was achieved in 50% of Group 1 pts compared to 80% of Group 2 pts (P <0.01). Overall median survival was significantly improved in Group 2 versus Group 1 pts (58 vs. 43 mos, [P=0.042], respectively). Conclusions: The recent incorporation of extensive upper abdominal surgical procedures to increase the rate of primary cytoreduction to residual disease ≤1 cm resulted in significantly improved overall survival. A paradigm shift toward more complete primary cytoreduction can improve survival for pts with advanced ovarian, fallopian tube, and primary peritoneal carcinomas.

No significant financial relationships to disclose.