bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase III trial of conventional-dose chemotherapy alone or with high-dose chemotherapy for metastatic germ cell tumors (GCT) patients (PTS): A cooperative group trial by Memorial Sloan-Kettering Cancer Center, ECOG, SWOG, and CALGB
Authors: Bajorin D. F. , Nichols C. R. , Margolin K. A. , Bacik J. , Richardson P. G. , Vogelzang N. J. , Einhorn L. , Mazumdar M. , Bosl G. J. , Motzer R. J.
Published: March 2020

4510

Background: First-line high-dose chemotherapy (HDCT) for poor-prognosis GCT PTS demonstrated improved relapse-free and overall survival compared to historical controls receiving conventional-dose regimens (JCO 1996;14:2546). Retrospective studies also showed correlations between long-term outcome and initial declines of alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (HCG). This trial sought to determine: 1) if early intervention with HDCT resulted in an outcome superior to standard-dose chemotherapy and 2) whether AFP and HCG declines during cycles 1 & 2 correlated with long-term treatment outcome. Methods: PTS with untreated intermediate- or poor-risk GCT by International criteria (IGCCCG) were randomized to either 2 cycles of standard BEP (bleomycin, etoposide & cisplatin) followed by 2 cycles of HDCT (cyclophosphamide, etoposide, carboplatin) plus stem-cell rescue (BEP + HDCT) or to 4 cycles of BEP. The primary endpoint was the percent of PTS in complete response at 1 year (CR-1 yr). Based on an historical CR-1 yr of 45% for BEP, targeted accrual was 109 PTS/arm to detect a 20% improvement in PTS receiving BEP + HDCT with an alpha of 5% and 80% power. Randomization used random permuted blocks; strata were risk status (poor/intermediate) and treatment center. An independent DSMB performed one interim analysis of CR-1yr and survival in May 2000. Results: 219 PTS were randomized; 108 to BEP + HDCT and 111 to BEP alone. Final analysis demonstrated a CR-1yr of 52% for BEP + HDCT and 48% for BEP alone (P = .53 via actuarial methods). Slow marker decline PTS (AFP and/or HCG) during cycles 1 & 2 of BEP had a shorter progression-free and overall survival compared to satisfactory decline PTS (P ≤ .02) Among 70 PTS with unsatisfactory marker decline in cycles 1 & 2, the CR-1 yr was 61% for PTS receiving HDCT for cycles 3 & 4 versus 31% for those receiving 2 more cycles of BEP (P = .008). Conclusions: The routine inclusion of HDCT for intermediate- and poor-risk GCT does not improve treatment outcome. Serum marker decline during the first 2 cycles of BEP chemotherapy provides a clinically useful estimate of outcome. Research support provided by the NIH.

[Table: see text]
Phase II study of volociximab (M200), an α5β1 anti-integrin antibody in refractory metastatic clear cell renal cell cancer (RCC)
Authors: Figlin R. A. , Kondagunta G. V. , Yazji S. , Motzer R. J. , Bukowski R. M.
Published: March 2020

4535

Background: Blocking angiogenesis has been shown to be an effective strategy for controlling tumor growth in RCC. Tumor angiogenesis occurs when pro-angiogenic growth factors are released, stimulating endothelial cell proliferation and migration to form neovessels. M200 is an IgG4 chimeric monoclonal antibody that targets α5β1, thereby inducing apoptosis of proliferating endothelial cells. M200 activity is independent of growth factor stimulus, suggesting that binding of fibronectin to α5β1 occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. Methods: This is a multicenter, open label, single cohort pilot phase II study of 40 patients (pts) with RCC. Pts received no more than 2 prior regimens. Pts received M200 10 mg/kg IV every 2 weeks until disease progression. Pts were evaluated for efficacy every 8 weeks by objective response using RECIST criteria. An independent data safety monitoring board was utilized to review safety data. Results: A total of 40 pts were enrolled. All pts were evaluable for safety and 37 pts for objective response (to date). Median age was 62.8 years. ECOG score was 0 in 27 (67.5%) and 1 in 13 (32.5%) pts. Prior nephrectomy occured in 39 (97%) pts. Other prior treatment included IL-2 in 15 (37.5%), interferon alpha in 6 (15%), IL-2 + interferon in 2 (5%) pts. Most frequent side effects were fatigue 37.5%, nausea 15% and hypertension 7.5%. Five pts died in the study, four with progressive disease (PD) and 1 with arrhythmia (unrelated to M200). SD was observed in 32/37 (87%) of pts. No changes in hematological, renal and hepatic parameters were noted. Median time to progression was 113+ days. The average peak and trough concentrations of circulating M200 following 6 weeks of treatment were 390 μg/mL and 140 μg/mL, respectively. There were no detectable immune responses to M200. Conclusions: M200 is well tolerated at 10 mg/kg Q2W. Stable disease is noted in 87% of pts. Follow-up continues. A higher dose level is being evaluated.

[Table: see text]
Prospective trial of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with advanced non-transitional cell (non-TCC) carcinomas of the urothelial tract
Authors: Galsky M. D. , Iasonos A. , Mironov S. , Scattergood J. , Donat S. M. , Bochner B. H. , Herr H. W. , Russo P. , Boyle M. G. , Bajorin D. F.
Published: March 2020

4542

Background: Non-TCC’s account for 5–10% of urothelial tract tumors and are each characterized by unique demographics, risk factors, and patterns of spread. A unifying feature of these malignancies is their aggressive course and poor outcomes with standard chemotherapeutic regimens. Given the rarity of these tumors, no prospective data are available to guide management. Methods: Patients with unresectable/metastatic adenocarcinoma, squamous cell, small cell, sarcomatoid, and poorly differentiated carcinomas of the urothelial tract were eligible. Treatment consisted of: Paclitaxel 200 mg/m2 IV on day 1, cisplatin 70 mg/m2 IV on day 1, ifosfamide 1500 mg/m2 IV on days 1–3 + mesna. GCSF was administered with each cycle. Treatment was recycled every 3 weeks for a maximum of 6 cycles. The primary endpoint was the response rate. Results: Twenty patients (pts) were enrolled with the following histologic types: adenocarcinoma 11/20, squamous cell carcinoma 8/20, small cell carcinoma 1/20. Pts received a median of 4 cycles (range, 1–6). The grade 3–4 toxicities included neutropenia (6/20), anemia (9/20), thrombocytopenia (4/20), confusion (1/20), seizure (1/20), neuropathy (1/20), renal insufficiency (2/20), fatigue (2/20), and hyponatremia (1/20). Thirteen of the 20 pts have died. The median survival for pts with adenocarcinoma is 24 months (95% CI 9.6–32.4) and with squamous cell carcinoma is 8.4 months (95% CI 5.3-NR). Five pts achieved durable disease-free survival (1+, 2+, 4+, 6+, and 8+ years) after ITP ± surgical consolidation. Conclusions: ITP is an active regimen in pts with advanced non-TCC’s of the urothelial tract. To our knowledge, this is the first prospective study of a chemotherapeutic regimen in this patient population.

[Table: see text]

[Table: see text]
Clinical outcome of patients managed for late relapse of germ cell tumor
Authors: Sharp D. S. , Carver B. S. , Eggener S. E. , Kondagunta G. V. , Motzer R. J. , Bosl G. J. , Sheinfeld J.
Published: March 2020

4550

Background: The significance of late relapse (LR) of germ cell tumor (GCT) and its association with poor survival is becoming increasingly recognized. Methods: Between 1990 and 2004, 75 patients (pts) were managed for LR of GCT at MSKCC. Using our prospective databases and following IRB approval, clinical and pathologic parameters were reviewed. Estimates of cancer-specific survival were generated using the Kaplan-Meier method and Cox-proportional hazards model was used to assess for predictors of outcome. Results: Clinical stage (CS) at initial presentation was I in 15 (21%), II in 32 (44%), and III in 26 (36%) of pts. Management prior to LR included surveillance in 10 (13%) pts, RPLND only in 8 (11%) pts, chemotherapy only in 19 (25%) pts, and both chemotherapy (induction or adjuvant) and RPLND in 38 (51%) pts. The median time to LR was 6.8 (2.1–37.7) years. Overall, 56/75 (75%) of pts had LR in the retroperitoneum (RP), including 25 of 27 (93%) initially managed without RPLND prior to LR. At LR, 45/75 (60%) of pts were symptomatic and 46/75 (61%) pts had elevated serum tumor markers (STM) (78% AFP and 39% βHCG). Overall 5 year cancer-specific survival (CSS) was 59% (95% CI 47%–72%). Pts who underwent complete resection (with or without salvage chemotherapy) at time of LR (n = 44) had a 5 year CSS of 77% (95% CI 62%–92%). In contrast, 5 year CSS for patients treated without complete surgical resection (n = 31) was 39% (95% CI 21%–57%) (p = 0.0001). The pathology of 69 pts at LR revealed viable GCT in 39 (57%), only teratoma in 13 (19%), malignant transformation in 14 (20%), and fibrosis in 3 (4%). A multivariable analysis of pretreatment parameters showed that at time of LR, a solitary site of metastasis (HR 2.6, 95% CI 1.1–6.2, p = 0.03) and no prior chemotherapy (HR 4.2, 95% CI 1.2–14.2, p = 0.02) were predictive of improved cancer-specific survival. Elevated STM and presence of symptoms did not impact survival independently in this model. Conclusions: Although LR of GCT is associated with poor survival, pts who are chemotherapy naïve and have a solitary metastatic site at LR experience improved survival. The data suggest that meticulous control of the RP is critical to prevent LR in the RP. Survival is greatly improved if complete surgical excision of disease at LR is attained, highlighting the critical role for surgery in these patients.

No significant financial relationships to disclose.
Metabolic syndrome predicts for shorter response to hormonal therapy in prostate cancer
Authors: Flanagan J. R. , Carney-Doebbeling C. , Jones L. , Sweeney C.
Published: March 2020

4554

Background: Metabolic syndrome (MS) includes obesity, insulin resistance, dyslipidemia and hypertension. Recent studies have linked the individual components of MS to an increased risk for prostate cancer (PC) and worse PC outcomes. Methods: A retrospective chart review was performed on 100 consecutive patients treated for prostate cancer at a Veteran’s Administration oncology clinic between 1998–2005. MS was diagnosed according to Adult Treatment Panel III criteria, and was present with ≥3 of 5 components: hypertension (SBP ≥140 mmHg and/or DBP ≥90 mmHg on 2 outpatient visits; obesity (BMI ≥30); hypertriglyceridemia (>150 mg/dL on 2 fasting laboratories); LDL 110 mg/dL (2 outpatient am values while not on steroids). PC variables included baseline PSA at time of PC diagnosis, PSA at initiation of hormonal therapy (HT), presence of documented metastasis at time of HT, and primary PC treatment. We examined time to PSA progression (TTP) and median overall survival (OS) for PC among patients with and without MS using Kaplan-Meier curves and Cox proportional hazard models. Results: 83 patients treated with HT for PC were identified, and 41 (49%) met criteria for MS. Median age in both groups was 68. Median TTP was 16 months with MS vs. 46 months without MS (p = 0.001). In those patients with documented metastasis (DM) at time of HT, median TTP was 11 months with MS vs. 32 months without MS (p = 0.006). OS from time of HT was 40 months with MS, and median survival time for no MS was not reached. In multivariate regression analyses, the hazard ratio (HR) for increased TTP with MS was 3.49 (95% CI 1.86–6.54). HR for TTP with documented metastasis was 5.3 (95% CI 2.65–12.8). Conclusions: This retrospective analysis suggests patients with MS treated with HT for PC have significantly shorter time to PSA progression and worse overall survival. This analysis supports the need for a prospective evaluation of MS as a risk factor for early development of HRPC.

[Table: see text]

No significant financial relationships to disclose.
Limitation of prostate-specific antigen doubling time as a predictor of outcome in hormone-naive prostate cancer
Authors: Nelson J. B. , Sleep D. J. , Isaacson J. D. , Carducci M. A.
Published: March 2020

4566

Background: Prostate-specific antigen doubling time (PSADT) is used to monitor progression after primary therapy for prostate cancer. Increasingly in this population, PSADT is an efficacy measure in therapeutic trials, many of which are uncontrolled. Examination of PSADT response on placebo in a randomized controlled study may evaluate the utility of PSADT as an outcome measure in patients with hormone-naive prostate cancer. Methods: Patients with biochemical failure post radical prostatectomy were enrolled in a randomized, double-blind, placebo-controlled trial of atrasentan 10 mg. Eligibility criteria included baseline PSA between 0.4 ng/mL and 5 ng/mL with a PSADT ≤12 months based on two PSA values at least 2 weeks apart. On-treatment PSADT was compared between treatment groups in patients with at least 3 on-treatment PSA values collected every 12 weeks while on study drug. Categorical analysis comparing PSADT between groups was performed using Cochran-Mantel-Haenszel methodology. Mean change from baseline in PSA velocity (log PSA vs time) was analyzed using a one-way analysis of variance with treatment as the factor. Results: Of 222 patients enrolled, 209 had 3 PSA values on study: N=107 for placebo; N = 102 for atrasentan. Baseline PSA was lower for patients in the placebo arm than for those in the atrasentan arm (mean of 1.4 ng/mL [SE 0.1] vs 1.8 ng/mL [SE 0.1] P =.012). On-treatment PSADT was similar between treatment arms (P =.363); the proportion of patients whose PSADT was >1 year on study was 55% with placebo and 51% with atrasentan. More notably, PSADT lengthened on study for most patients in both arms (76/107, 71% for placebo and 68/102, 64% for atrasentan). PSA velocity was also protracted for patients in both treatment arms (placebo: slope = 1.47 at baseline to 0.96, P < .001; atrasentan: slope = 1.56 at baseline to 1.26, P =.017). Conclusions: The fact that over 70% of patients receiving placebo experienced lengthened PSADT suggests that, in the absence of a control arm, changes in PSADT from baseline are not a reliable measure of treatment effect in trials in early prostate cancer. PSADT data from trials in this population should be interpreted with caution.

[Table: see text]
Long-term complications of platinum in testicular cancer survivors
Authors: Oh J. H. , Baum D. D. , Ensor J. , Pham S. , Muddiman M. D. , Nguyen S. , Chen I.
Published: March 2020

4589

Background: Long-term medical complications of platinum have become a major priority in the care of testicular cancer survivors. This study aimed to describe the prevalence of these complications from platinum-based therapy in American testicular cancer survivors. Methods: Testicular cancer survivors with no evidence of disease for at least 2 years were interviewed, had lab tests, and charts reviewed. Demographics, comorbidities, blood pressure, treatment, and outcomes were compared between all treatment modalities. NHANES 2002 and NHIS 2004 were used to obtain national estimates. Results: The mean age was 41 years; 72.7 % had nonseminoma, 96.5% had orchiectomy, 21.0% received radiation (XRT), and 82.5% platinum. The mean follow-up was 8.4 years. There was no statistical difference in the rates of Coronary Artery Disease (CAD), hyperlipidemia, hypertension (HTN), renal insufficiency (RI), or hypomagnesemia (see table ). There was a trend toward an increase in hyperlipidemia at follow-up compared to initial visit in all treatment groups but HTN increased only in those who did not receive platinum. Conclusion: Excluding HTN, we observed a trend toward an increase in the prevalence of RI, hypomagnesemia, hyperlipidemia, and CAD among patients who received platinum when compared to their baseline rates. Similar to a recent study by Huddart et al, we saw a trend toward higher risk of developing CAD in those who received both platinum and XRT. These findings suggest that hyperlipidemia and HTN may be more related to orchiectomy or the germ cell tumor itself than being a complication of platinum. Further prospective cohort studies with a larger group of survivors who have not received platinum are warranted to determine if HTN and hyperlipidemia are true complications of platinum-based chemotherapy.

[Table: see text]

No significant financial relationships to disclose.
Predictors of survival in patients undergoing post-chemotherapy retroperitoneal lymph node dissection
Authors: Spiess P. E. , Brown G. A. , Liu P. , Tannir N. M. , Tu S. , Kamat A. M. , Pisters L. L.
Published: March 2020

4593

Background: The majority of patients with testicular cancer have a favorable prognosis yet a subset of patients will succumb to this disease. The aim of this study was to identify the clinical and pathological parameters which predict the outcome of patients post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND). Methods: From 1980 to 2003, 236 patients with clinical stage IIA-III non-seminoma germ cell tumors (NSGCT) underwent a PC-RPLND. We retrospectively reviewed their medical records for pertinent clinical and treatment-related outcomes. The 5-year disease-specific and recurrence-free survival was 85% and 75%, respectively with the median length of follow-up following RPLND of 45 months (6 to 250 months). Results: The median age of patients at diagnosis was 28 years with all patients receiving systemic chemotherapy (median of 5 cycles) prior to RPLND. On multivariate analysis, predictors of disease-specific survival (DSS) included systemic symptoms at presentation (P = 0.05), elevated pre-RPLND serum alpha fetoprotein (AFP, P = 0.006) and ß-human chorionic gonadotropin (HCG, P = 0.004), post-operative complications (P = 0.03), and recurrence (P < 0.0001). Predictors of recurrence-free survival (RFS) included advanced clinical stage (IIC-III, P = 0.001) and presence of viable tumor in the RPLND specimen (P = 0.03). A pre-RPLND serum AFP > 9 ng/ml and HCG > 4.1 mIU/ml was found to predict DSS (P = 0.03 and 0.03, respectively). Conclusions: Survival of patients undergoing PC-RPLND can be predicted by pre-operative tumor markers, and by development of post-operative complications or recurrence. Advanced clinical stage and viable tumor in the surgical specimen predict RFS.

No significant financial relationships to disclose.
A brief symptom index for renal cell carcinoma
Authors: Eton D. T. , Cella D. , Bacik J. , Motzer R. J.
Published: March 2020

4595

Background: Renal cell carcinoma (RCC) occurs in over 30,000 Americans each year. Since it is often diagnosed in later stages and metastatic sites are variable, an array of symptoms and concerns affect patients with this disease. Our objective was to test a brief, symptom index for advanced RCC. Methods: We conducted secondary data analyses on patient-reported outcomes from a completed Phase III trial of 284 patients with metastatic RCC treated with interferon + 13-cis-retinoic acid or interferon alone (Motzer et al., 2000). Patient-reported outcomes were collected using the FACT-Biological Response Modifier (FACT-BRM) module at baseline, 2 weeks, and 8 weeks. We analyzed data from eight FACT-BRM items that were previously identified by clinical experts to represent the most important symptoms of advanced RCC. Items comprising the proposed Kidney Cancer Symptom Index (KCSI) assess nausea, pain, appetite, perceived sickness, fatigue and weakness, with higher KCSI scores indicating fewer symptoms. We determined the reliability and concurrent validity of the KCSI and estimated a minimally important difference (MID). Results: The KCSI had excellent internal reliability at all three time points (alphas = 0.85). Baseline KCSI scores were able to discriminate patients across Karnofsky performance status (KPS 80–90 > KPS 70; F (2, 210) = 15.5, p < .001), number of identified metastatic sites (0–1 site > 2+ sites; t (211) = 3.2, p < .01), and risk group categories (favorable or intermediate risk > poor risk; F (2, 205) = 9.9, p < .001). No differences were observed in KCSI change scores over time across two objective clinical indicators: response to treatment and time to progression. All patients evidenced declines in scores from baseline likely indicative of the toxic nature of the treatments. Distribution- and anchor-based methods converged on an MID estimate of 2 to 3 points for the KCSI. Conclusions: The 8-item KCSI appears to be a psychometrically sound measure of patient-reported symptoms of RCC. It is a brief, reliable, and valid measure that can easily be adapted for use in clinical trials and observational studies.

[Table: see text]
Novel mutations in tyrosine kinase domain of epidermal growth factor receptor in prostate cancer
Authors: Douglas D. , Zhong H. , Ro J. , Oddoux C. , Pincus M. , Satagopan J. , Gerald W. , Scher H. , Lee P. , Osman I.
Published: March 2020

4611

Background: We recently reported that EGFR protein overexpression is significantly more common in African American (AA) prostate cancer patients compared to White patients (Shuch et al. 2004 JCO, 22:4673–4677). In the current study, we further explore EGFR dysregulation in prostate cancer patients of different ethnicities by examining mutations in the EGFR tyrosine kinase (TK) domain. In addition to AA and White prostate cancer patients, we included South Korean patients in light of recent reports that EGFR mutations are more common in Asian patients with non-small cell lung cancer. Methods: Normal and tumor DNA from radical prostatectomy cases (n = 89: Koreans n = 36, AA n = 27, Whites n = 26) were studied for mutations in the EGFR TK domain using genomic DNA sequencing. Results: We identified 4/89 (5%) novel missense mutations in exons 19, 20 and 21 of TK domain: 3 in Koreans (8%, 95%, CI = 2%– 22%) and 1 in White (4%, 95% CI = 0.1%–20%) but none in AA. These mutations, which were not described before, are expected to affect TK activity based on the change of the amino acid phosphorylation pattern and the 3-dimensional structure of TK domain. We also identified 5 distinct synonymous DNA sequence changes in exons 20 and 21 in 31/89 (35%) patients. These synonymous sequence changes were not observed in the corresponding normal DNA in 8/31 (25.8%) patients, indicating the presence of de novo somatic mutation in those patients, and are likely to affect mRNA splicing leading to altered EGFR protein transcripts. Conclusions: Several independent mechanisms of EGFR dysregulation operate in prostate cancer including EGFR protein overexpression, missense mutations, and somatic synonymous sequence changes in the TK domain. Validation on a larger sample size in addition to functional studies are needed to determine the specific association between a patient’s ethnicity, EGFR dysregulation, and response to EGFR inhibitors in prostate cancer.

No significant financial relationships to disclose.
Impact of zoledronic acid (Z) on pain in prostate cancer patients with bone metastases in a randomised placebo-control trial
Authors: Abetz L. , Barghout V. , Arbuckle R. , Bosch V. , Shirina N. , Saad F.
Published: March 2020

4638

Background: Bone metastases occur in up to 80% of advanced prostate cancer patients and can results in painful Skeletal-Related Events (SREs). Z is the only biphosphonate approved for metastatic prostate cancer that decreases the occurrence of SREs which include pathologic fractures, severe bone pain requiring radiation therapy, spinal cord compression, surgery to bone and hypercalcemia of malignancy which may lead to daily activity limitations. We performed retrospective analyses on data from a placebo-controlled study of Z to investigate which items of the Brief Pain Inventory (BPI) were most sensitive to changes in patient’s pain due to treatment. Methods: Prostate cancer patients with bone metastases received Zoledronate 4 mg (n = 201) or placebo (n = 201). The BPI was administered at baseline (visit 2), and visits 3 (weeks 3–4), 4 (weeks 6–8), and then every second visit (every 6 weeks) until study end. Changes in BPI individual item scores and the Pain Severity and Pain Interference scale scores were compared between Z and placebo groups. Post-baseline missing data was replaced by Last Observation Carried Forward (LOCF). Results: Z was statistically significantly better than placebo for changes in BPI items ‘pain at its worst’, ‘pain at its least’, ‘pain on average’, and the BPI pain severity scale (p < 0.05) at visit 4 (weeks 6–8), and visit 6 (week 12). For ‘pain right now’ there were statistically significant differences at visit 4, but not visit 6. Z was also superior to placebo for ‘pain right now’ and the Pain Severity and Interference scales at visit 12 (week 30–32) (p < 0.05). Finally Z was superior to placebo for ‘interference with general activities’ at visits 12 (week 30–32), 16 (weeks 42–44), and LOCF (p < 0.05). Conclusion: Our findings suggest that Z significantly reduces bone pain and general activity limitations in prostate cancer patients with bone metastases. Several items in the BPI are more sensitive to Z treatment including ‘pain at its worst’, ‘pain at its least’, ‘pain on average’, and the BPI Pain Severity scale.

[Table: see text]
Update on a phase II study of cyclophosphamide, etoposide and estramustine in patients with androgen independent prostate cancer
Authors: Moffett P. U. , Choudry M. A. , Ferguson L. A. , Williams D. A. , La Rocca R. V. , Hendler F. J. , Laber D. A.
Published: March 2020

4647

Background: Oral therapy offers the tremendous advantage of independence and avoids all the catheter-related complications. Cyclophosphamide (C), etoposide (E) and estramustine (E) are active against androgen-independent prostate cancer (AIPC). The optimal dose and schedule of these agents have not been defined. Methods: Objectives are to evaluate the efficacy and safety of this triple drug regimen (CEE). Each treatment cycle consists of cyclophosphamide 50 mg/m2 p.o., etoposide 50 mg/m2 p.o. and estramustine 280 mg p.o. administered on days 1–14, every 28 days. Response was assessed by changes in size of measurable and non-measurable lesions (RECIST JNCI 92(3):205–216, 2000), and PSA levels (JCO 17(11):3461–7, 1999). Results: Twenty-nine subjects with AIPC were enrolled. 25 patients, who completed at least 2 cycles, are evaluable for toxicity and response. Median baseline characteristics: age 68 years (52–86); ECOG performance status 2 (0–3); PSA 148 ng/ml (26–2268); and 8 had prior chemotherapy. Total number of cycles administered: 98 with median of 3 cycles/patient. Response: PSA response: Out of 25 subjects, 7 (28%) had >50% decrease and 5 (20%) had >75% decrease, for an overall PSA response of 58%. Measurable disease: 13 patients had measurable lesions by RECIST criteria. One pt had a complete response (8%), seven had SD (54%) and there were 5 PD (38%). 44% of the subjects experienced an improvement in their ECOG performance status and 64% reported improvement in their level of pain. Toxicity: Grade 3–4: 36% neutropenia, 12% thrombocytopenia, 5% anemia. Four patients (27%) developed a thrombotic event. 3 with DVTs, two spontaneous and one after a 14-hours car trip. One subject with a strong history of cardiac complications had a myocardial infarction. Neutropenic fever requiring antibiotic use occurred in 2 patients. Conclusions: CEE is a well-tolerated, all oral, easy to administer and effective triple drug therapy for patients with metastatic androgen-independent prostate cancer.

No significant financial relationships to disclose.
Extended vs. limited laparoscopic pelvic lymph node dissection for prostate cancer: The value of Partin tables in selection of the need for and the extent of dissection
Authors: Touijer K. , Rabbani F. , Romero Otero J. , Secin F. , Guillonneau B.
Published: March 2020

4654

Background: To determine if pelvic lymph node dissection (LND) can be omitted in prostate cancer patients at low risk of nodal metastases according to the Partin tables and to determine the yield on extended vs limited LND in patients at high risk to better define the appropriate template of dissection. Methods: A total of 577 patients with clinically localized prostate cancer underwent a laparoscopic radical prostatectomy (LRP). In the first 363 patients, a cutoff of 1% on the Partin tables’ predicted probability of lymph node invasion (PPLNI) was used to select patients for a limited LND (external iliac nodes only). In the subsequent 214 patients, all patients underwent an extended LND (external iliac, obturator and hypogastric nodes). Patients were classified into 4 groups: Group I, 186 patients with a PPLNI ≤1%, did not undergo a LND; Group II, 110 patients with PPLNI ≤ 1%, underwent an extended LND; Group III, 177 patients with PPLNI >1% underwent a limited LND and Group IV, 104 patients with PPLNI >1%, underwent an extended LND. We compared Group I and II to assess the value of the Partin tables in selecting low risk patients for nodal metastasis. Multivariate logistic regression analysis was performed to compare the node positivity rate between groups III and IV, controlling for preoperative and pathological parameters. Results: None of the patients in group II had a positive lymph node after an extended LND. On multivariate analysis, controlling for PSA, biopsy Gleason, clinical stage, pathological Gleason and stage, and seminal vesicle invasion, the extended LND independently impacted the rate of node positivity with a relative risk (RR) of 15.6 (95% CI 3.7 -66.4, p < 0.001). The median (mean) number of nodes retrieved was 9 (10) and 14 (15) after limited and extended LND respectively (p < 0.001). Conclusions: A lymph node dissection including the external iliac, obturator and hypogastric lymph node groups yields positive nodes more frequently and retrieves a higher total nodal count than the often-performed LND limited to the external iliac nodes. Decision to forgo LND in low risk patients needs to be validated by long-term biochemical recurrence data

No significant financial relationships to disclose.
Does timing of androgen deprivation influence radiation-induced toxicity? A secondary analysis of Radiation Therapy Oncology Group protocol 9413
Authors: Bahary J. , Bae K. , Taussky D. , Roach M. , Sandler H. M. , Shipley W. U.
Published: March 2020

4655

Background: We conducted a secondary analysis of RTOG 9413 to compare if the timing of antiandrogen-therapy, concomitant versus adjuvant, influences the incidence of rectal toxicity in whole pelvic radiotherapy. Methods: For the purpose of this secondary analysis, we analyzed the 2 of the 4 arms of the study, in which all patients received radiotherapy to the whole pelvis followed by a boost to the prostate and excluded the two arms that received prostate only radiotherapy. The 2 arms differed only in the timing of the total of 4 months of total androgen deprivation (TAD): arm I (320 patients), TAD was begun 2 months before the start of radiotherapy and continued during radiotherapy. Arm III (319 patients), TAD started immediately after the completion of radiotherapy. Both acute rectal and acute urinary toxicities (CTC v.2.0), testosterone (measured at baseline and yearly after) and other patients data were modeled using the multivariate logistic regression and the multivariate Cox-proportional hazards regression. Results: Median follow up for all patients is 6.0 and 5.8 years (arm I and II, resp.). 43 (13%) patients in each arm had abnormally low testosterone before start of TAD. Late grade 2 - 5 rectal toxicity occurred in 16% and 13% and urinary toxicity in 18% and 20% (arm I and II, resp.). Frequency (or occurrence) of late rectal toxicity (grade 0–1 vs. 2–5, p = 0.2170) and late urinary toxicity (grade 0–1 vs. 2–5, p = 0.4204) are not significantly different between the two arms. The only risk factors for late rectal toxicity in a multivariate regression model was acute rectal toxicity (OR 1.48, p = 0.025), but not abnormal testosterone level at baseline (p = 0.718) or treatment arm (p = 0.874). For late urinary toxicity: age (OR = 1.588, p = 0.010), RT field size (OR 1.004, p < 0.025), baseline testosterone (OR 1.718, p = 0.028), and acute (grade 2–4) toxicity (OR = 1.664, p = 0.006) but not treatment arm (p = 0.928) were risk factors. Conclusions: While late toxicity was not different for concomitant vs. adjuvant hormonal therapy, an abnormally low testosterone level at baseline is a risk factor for late urinary toxicity and not late rectal toxicity.

No significant financial relationships to disclose.
Cytochrome P450 2D6 status predicts breast cancer relapse in women receiving adjuvant tamoxifen (Tam)
Authors: Knox S. K. , Ingle J. N. , Suman V. J. , Rae J. M. , Flockhart D. A. , Zeruesenay D. , Ames M. M. , Visscher D. W. , Perez E. A. , Goetz M. P.
Published: March 2020

504

Background: CYP2D6 genetic variants and concurrent administration of potent inhibitors (Inh) of the enzyme markedly reduce the plasma concentrations of endoxifen (Jin. JNCI 2005;97:30–9). We have shown that genetic variation in CYP2D6 is associated with a higher risk of relapse in Tam treated patients (pts) (Goetz. JCO 2005;23:9312–18), but the impact of CYP2D6 inhibition on Tam clinical outcome is unknown. Methods: Using the North Central Cancer Treatment Group 89–30–52 adjuvant Tam trial (1989–1994), we evaluated the effect of co-administration of CYP2D6 Inh and CYP2D6*4 genotype on relapse in pts receiving tam alone. Patient charts were reviewed at each randomizing site to record the following known CYP2D6 Inh: fluoxetine (F), paroxetine (P), sertraline (S), cimetidine (C), amiodarone (A), doxepin (D), ticlopidine (T) and haloperidol (H). Poor metabolizers (PM) were defined as pts who were CYP2D6 *4/*4 and/or known to receive a CYP2D6 Inh. Intermediate metabolizers (IM) were defined as WT/*4 without CYP2D6 Inh, and extensive metabolizers (EM) as WT/WT without CYP2D6 Inh. The association between CYP2D6 status and Tam clinical outcome was determined using the log-rank test. Multivariate Cox modeling was performed using traditional prognostic factors. Results: CYP2D6*4 genotype was obtained in 190 of 256 eligible pts, with a CYP2D6*4/*4 genotype frequency of 6.8% as described previously (Goetz JCO 2005). Medication history was available in 171/256 eligible pts and in 143/190 pts with CYP2D6 genotype. Eleven of 173 patients were concomitantly administered these CYP2D6 Inh: F(2), P(2), S(2), H(1), C(4), and D(1). The median duration of use was 2.5 yrs. Twenty-four pts met criteria for PM [13 by *4/*4 genotype and 11 by CYP2D6 Inh (7 WT/WT, 1 WT/*4, and 3 unknown genotype)], 21 for IM, and 102 for EM. Compared with either IM or EM, PMs had significantly worse time to recurrence and disease free survival in both the univariate (HR 2.5, p=0.02; and 2.2, p=0.01) and multivariate (HR 2.7, p=0.01; and HR 2.2 p=.02) analyses utilizing tumor size, nodal status, and tumor grade. Conclusion: Our data indicate that CYP2D6 status can be used to identify pts who should receive tam therapy and tam treated pts should not be co-administered potent CYP2D6 inhibitors.

No significant financial relationships to disclose.
A validation study of a scoring system to estimate the risk of lymph node metastasis for patients with endometrial carcinoma for tailoring the indication of lymphadenectomy
Authors: Todo Y. , Ebina Y. , Watari H. , Sakuragi N.
Published: March 2020

5040

Background: The present standard treatment for cases with endometrial cancer is surgical staging including lymphadenectomy. Elimination of lymphadenectomy will not be approved of unless strict condition are met. Our aim is to verify whether a preoperative scoring system to estimate the risk of lymph node metastasis (LNM) in endometrial carcinoma is clinically useful for tailoring the indication of lymphadenectomy. Methods: This study was carried out on 211 patients with endometrial carcinoma for whom volume index, serum CA125 level, tumor grade/histology were preoperatively confirmed. LNM score was set up using these three risk factors as reported in our previous study (Am J Obstet Gynecol 2003). We analyzed whether these factors remain still valid in a different cohort of patients. Based on the LNM score before a validation study was started, the estimated rate of lymph node metastasis (para-aortic lymph node metastasis) in a low risk group was 3.4% (0.0%), an intermediate group 7.7% (5.8%), a high risk group 44.4% (30.6%) and an extremely high risk group 70.0% (50.0%). Results: Volume index, serum CA125 level, and tumor grade/histology, were found to be independent risk factors for LNM in the cohort of this validation study. The actual rate of lymph node metastasis (para-aortic lymph node metastasis) in a low risk group was 3.2% (1.0%), an intermediate group 15.3% (11.9%), a high risk group 30.2% (23.8%) and an extremely high risk group 78.6% (57.1%). Conclusions: LNM frequencies increased in proportion to the impact of the LNM score and the actual rate of lymph node metastasis for each score was quite consistent with the estimated rate of lymph node metastasis.Our LNM score for patients with endometrial carcinoma is useful.

No significant financial relationships to disclose.
SUV in pelvic lymph node is a significant prognostic factor in previously untreated squamous carcinoma of the uterine cervix
Authors: Lai C. , Yen T. , Ma S. , Tsai C. , Ng K. , Chang T.
Published: March 2020

5051

Background: The aim of this prospective study was to identify prognostic factors (including 18F-fluorodeoxyglucose positron emission tomography [FDG-PET] parameters) in previously untreated squamous carcinoma of the uterine cervix with MRI- or CT-defined pelvic or para-aortic lymph node (PLN or PALN) metastasis. Methods: This study included pooled patients selected from two prospective studies who had untreated squamous cell cervical cancer and PLN or PALN metastasis (diagnostic score 3 or 4) by CT-MRI and additional FDG-PET scans were performed for primary staging. Recurrence-free and overall survivals (RFS and OS) were evaluated using the Kaplan-Meier method. Prognostic variables were assessed by the log-rank test and Cox proportional hazards regression method. Optimal cut-offs of standardized uptake value (SUV) in primary tumor, PLN and PALN were determined by receiver operating characteristic and area under the curve analysis. Results: A total of 70 patients were eligible for analysis. The follow-up time ranged 16–59 months (mean ± SD: 38 ± 18). In univariate analyses, FIGO stage ≥ III, PET defined bilateral PLN-positive, PET defined PLN-positive, PET defined PALN-positive and SUV cut-off of 3.04 at PLN and 4.18 at PALN were significant for RFS. FIGO stage ≥ III, SUV cut-offs of 2.94–3.15 at PLN and SUV cut-offs of 2.61–4.91 at PALN were significant for OS. Multivariate analysis showed only SUVmax cut-off of 3.04 at PLN was a significant adverse factors for RFS (RR: 10.1 95% CI 2.2–46.0; P = 0.003) and OS (RR: 11.7 95% CI 1.5–92.6; P = 0.019), while SUVmax cut-off of 4.18 at PALN (P = 0.062) was marginally significant for OS. Conclusions: SUVmax cut-off of 3.04 at PLN was a significant adverse factor for RFS and OS in previously untreated squamous carcinoma of the uterine cervix with MRI- or CT-defined PLN or PALN metastasis.

No significant financial relationships to disclose.
Phase I study of irinotecan (Iri) and cisplatin (Cp) in combination with pelvic radiotherapy for the treatment (Tt) of advanced cervical cancer (ACC): A GINECO trial
Authors: Fabbro M. , Gladieff L. , Geay J. F. , Guichard F. , Lemanski C. , Dalenc F. , Paraiso D. , Delannes M. , Pujade-Lauraine E.
Published: March 2020

5054

Background: Chemoradiotherapy with weekly Cp has become standard for ACC treatment. Combining Cp with another active drug in ACC such as Ir may increase the activity of Tt. Methods: Treatment consisted of 6 weekly cycles with escalating dose of Ir and fixed dose of Cp (20 mg/m2) administered during pelvic radiotherapy (45–50 Gy). Brachytherapy and/or surgery were allowed after pelvic chemoradiotherapy according to center policy. Cohorts of 3 to 6 pts with FIGO stage IB-IVA newly diagnosed ACC, performance status ECOG 1–2 and adequate major organ function were eligible at each dose level. Results: 15 pts were accrued at dose level I (n = 6), II (n = 3) and Intermediate (Int) (n = 6). Dose levels (DL) for Ir were 30 mg/m2 (I), 40 (II) and 35 (Int). Dose limiting toxicity (DLT) was observed in 2/3 pts at DL II (Gr 3 asthenia in 2/3 pts including Gr 3 diarrhea and abdominal pain in one). DLT was observed in 2/6 pts at DL I (NCI-CTC Gr 3 diarrhea in 2/6 pts including Gr 3 asthenia and abdominal pain in one) and DL Int (Gr 3 asthenia in 2/6 pts including febrile neutropenia in one). However, 3/4 pts without DLT at DL Int did not complete the whole chemotherapy schedule due to pelvic mucositis and skin toxicity (dose reduction: 2pts, early stopping at 3 cycles : 1 pt). In contrast, 5/6 non-progressive pts at DL I completed their scheduled chemo-radiotherapy, with dose reduction in only 1 pt who experienced a DLT. Efficacy evaluation showed complete and partial response in 6 and 5 of the 12 evaluable patients. Conclusions: the recommended dose for future phase II study of chemoradiotherapy in ACC is irinotecan (30mg/m2, weekly) with cisplatin (20 mg/m2, weekly).

No significant financial relationships to disclose.
VEGF-A and COX-2 expression correlate with platinum resistance in ovarian cancers
Authors: Engels K. , Moll P. , Harter P. , Du Bois A. , Fisseler-Eckhoff A. , Kommoss F. , Kaufmann M. , Loibl S.
Published: March 2020

5062

Background: Regulators of angiogenesis such as VEGF-A and cell cycle such as p53 and COX-2 influence tumor behavior and response to chemotherapy. Methods: 114 patients with primary ovarian cancer treated in Frankfurt or Wiesbaden between 1999 and 2004 were examined. Primary surgery was followed by a platinum and taxane based chemotherapy in all patients. Expression of i-NOS, COX-2, VEGF-A, HIF-1 alpha was analyzed immunohistochemically using tissue micro arrays of primary tumor samples. Results were scored according to staining intensity and percentage of positive tumor cells resulting in an immune-reactive score (IRS) from 0 to 12. Vascularity was assessed using the Chalkley-Grid method after highlighting vessels with CD34 antibodies in whole tissue sections. These results were correlated with classical prognostic factors and survival. Non-parametric correlations were done using Spearman’s rho, correlations were significant at the 0,05 level (2-tailed). Results: The median age at the time of surgery was 63y (33–89y). The majority of the patients (85%) had advanced disease (FIGO III-IV). Tumor grading was G1 in 2%, G2 in 37%, and G3 in 61%. Expressions were as follows: i-NOS 60% positive (IRS ≥4); COX-2 50% positive (IRS ≥5); VEGF-A 50% strong (IRS ≥8), 32% moderate (IRS 4–7), 18% weak (IRS ≤4); HIF-1 alpha 37% positive (IRS ≥3), p53 33% weak (IRS ≤4), 67% strong (IRS >4); vascularity 41% low (≤5), 52% moderate (6–9), 7% high (>9). I-NOS correlated positively with COX-2 (p = 0,03), VEGF-A (p = 0,05), and p53 (p = 0,01). Grading correlated positively with HIF-1 alpha (p = 0,02) and vascularity (p = 0,01). Up to now none of the new parameters did show correlations with recurrence free survival (median follow-up 36 months). Platinum resistant tumors (time from primary diagnosis to relapse <12 months) were significantly more often negative for VEGF-A (p = 0,005) and COX-2 (p = 0,02). Conclusions: I-NOS correlates with markers of angiogenesis and cell cycle regulation. VEGF-A and COX-2 expression might predict platinum resistance in ovarian cancers.

No significant financial relationships to disclose.
Carboplatin and paclitaxel versus cisplatin, paclitaxel and doxorubicin for frontline chemotherapy of advanced ovarian carcinoma (AOC): A Hellenic Cooperative Oncology Group Study
Authors: Aravantinos G. , Fountzilas G. , Kalofonos H. P. , Skarlos D. V. , Kosmidis P. , Grimani I. , Pavlidis N. , Bafaloukos D. , Pectasides D. , Dimopoulos M. A.
Published: March 2020

5074

Background: Carboplatin combined with paclitaxel are considered treatment of choice as initial chemotherapy for AOC. We compared this combination with a regimen combining cisplatin plus paclitaxel and doxorubicin. In the pre-taxane era the addition of doxorubicin to the cisplatin-based regimens appeared to improve survival. Therefore, there was a significant interest in assessing the role of a taxane/platinum/ anthracycline combination therapy in a randomized study. Methods: Patients with AOC after the initial cytoreductive surgery were stratified according to the FIGO stage and the presence of residual disease and randomized to either 6 courses of paclitaxel 175 mg/m2 as 3h infusion plus carboplatin 7AUC (group A) or paclitaxel at the same dose plus cisplatin 75 mg/m2 plus doxorubicin 40 mg/m2 and G-CSF (Lenograsim) 0.263 mg sc from day 7 to day 11 (group B). Primary endpoint was overall survival (OS). At alpha = 5%, 400 patients were required, to detect with power of 80%, a ±15% difference to a baseline survival rate of 50% at the 3-year time point. Results: Intent to treat analysis was performed on 432 patients (group A: 210, B: 222). The treatment groups were well balanced in terms of major patient and tumor characteristics. 70% of the patients had stage III and 23% stage IV disease. Significantly more patients developed febrile neutropenia in group B (p = 0.01). No other significant differences were observed in terms of severe toxicity and no difference was found between the two groups in complete and overall response rate. With a median follow up of 44 months, median survival was 37.2 months in group A and 45.2 months in group B (p = 0.33). Conclusions: Both regimens are well tolerated and effective as first line chemotherapy of AOC. Combination of cisplatin, paclitaxel and doxorubicin does not seem to improve survival as compared with the standard carboplatin/paclitaxel regimen.

No significant financial relationships to disclose.
Final follow up survey of the randomized Pbo-controlled study of oregovomab (Ov) as a consolidation treatment for advanced ovarian cancer (OC): Insights into surveillance approaches
Authors: Nicodemus C. F. , Berek J. S. , Schultes B. C. , Balser J. P. , Taylor P. T.
Published: March 2020

5079

Background: Ov is a monoclonal antibody specific for CA125 currently in two phase III studies as a consolidation immunotherapy for OC. A five year outcome follow up for patients participating in the prior randomized phase II study used to design the current pivotal trials has been completed. An assessment of survival post relapse (SPR) as a function of identifiable risk factors, and implications for long term survival survey methodology were reviewed. Methods: OC patients with no evaluable disease post front-line chemotherapy were randomized to IV infusions of OV or Pbo Q4 wks × 3, then Q12 wks. At relapse, therapy was stopped and second-line Rx was initiated without restriction. All patients were surveyed quarterly for long term outcomes for a pre-specified 5 years from initial randomization. A Kaplan-Meier (KM) analysis of overall survival and Cox multivariate analysis of SPR was completed. Results: 145 randomized participants were followed, including 67 designated as the successful front-line (SFLT) subpopulation identified to have characteristics favorable for intervention with immunotherapy (basis of ongoing phase III program). At five years, 47% of Ov (n = 73) and 37% of Pbo (n = 72) patients were alive overall, and 56% of Ov (n = 34) and 32% of Pbo (n = 33) were alive in the SFLT population. KM estimates of median survival are 57.5 mo [44.5-non-estimable (ne)] for Ov and 48.6 mo [30.9-ne] for Pbo in the overall population and ne mo [50.5-ne] for Ov and 48.6 mo [24-ne] for Pbo (p = 0.11) in the subpopulation. For relapsed patients, improved survival post relapse was most associated (Cox regression p < 0.10) with lower CA125 velocity at relapse, treatment (Ov), and longer time to relapse. Conclusions: Survival data was consistent with previously reported time to relapse data in this study. For the SFLT, the 5 yr duration of survival survey and sample size were insufficient for a definitive outcome. However, results support the hypothesis that treatment with OvaRex may provide clinical benefit. The ongoing phase III studies will include a 10 year survival survey of 354 patients to definitively assess the impact of this treatment on long term survival.

[Table: see text]