bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of neoadjuvant docetaxel and androgen suppression (AS) plus radiation therapy (RT) for high-risk localized prostate cancer (HRLCaP)
Authors: McKenzie M. R. , Chi K. N. , Neville A. , Ellard S. , Baerg B. , Ruether D. , Winquist E. , Segal R. , Lukka H.
Published: March 2020

4631

Background: Docetaxel increases survival in hormone-refractory prostate cancer and is active in hormone-sensitive disease. In HRLCaP, improvement upon AS plus RT is required, as many patients eventually develop metastases. This trial’s objective was to assess the tolerability of neoadjuvant docetaxel plus AS and RT in men with HRLCaP. Methods: Fifty-four men with newly diagnosed previously untreated HRLCaP were accrued to a Phase II single-arm, 2-stage, open-label study involving 7 Canadian centres. All were to receive 3 years of AS (LHRH-agonist + antiandrogen for 4 weeks). Chemotherapy started week 5. Twenty-four men received docetaxel 35 mg m2 iv weekly × 6 q8 weeks for 2 cycles, RT starting week 25. After protocol revision, 30 men received docetaxel 75 mg m2 iv q3 weekly for 4 cycles, RT starting week 21. The primary endpoint was unacceptable toxicity (UT), defined as ≥Grade 3 non-hematologic toxicity (except nausea/vomiting, tearing, short-term fatigue, and easily-controlled diarrhea), grade 4 thrombocytopenia, grade 4 neutropenia lasting >7 days, febrile neutropenia, or toxicity-related RT change (delay>2 weeks, >25% dose reduction). Results: Median age was 68 (49–79) years. Median iPSA was 19.15 (2.8–138) μg/L. Gleason Score and T-stage were ≥8 and ≥T3a in 70.4% and 42.6%, respectively. All patients have completed RT. Adverse events were as expected for docetaxel. UT occurred in 8 patients (14.8%), including 5 with qweekly docetaxel (Grade 3 acute RT-related genitourinary toxicity - 3, Grade 3 docetaxel hypersensitivity - 1, Grade 3 fatigue >2 weeks - 1) and 3 with q3 weekly docetaxel (Grade 3 acute RT-related genitourinary toxicity - 1, febrile neutropenia - 1, Grade 4 neutropenia >7 days - 1). The following table summarizes PSA response to neoadjuvant treatment. Conclusions: Neoadjuvant AS and docetaxel plus RT in men with HRLCaP appeared well tolerated. Patients will be followed for other outcomes. This approach will be tested in a phase 3 trial.

[Table: see text]

No significant financial relationships to disclose.
Response to low-dose ketoconazole and subsequent dose escalation to high-dose ketoconazole in patients with androgen-independent prostate cancer
Authors: Nakabayashi M. , Xie W. , Regan M. M. , Jackman D. M. , Kantoff P. W. , Oh W. K.
Published: March 2020

4646

Background: High dose ketoconazole (HDK) in combination with steroids has been recognized as an effective secondary hormonal therapy in androgen independent prostate cancer (AIPC). However, HDK causes more severe adverse events than low dose ketoconazole (LDK). Relatively little is known about the efficacy of LDK in AIPC. We evaluated the efficacy of LDK and of subsequent dose escalation from LDK to HDK as secondary hormonal therapy in patients with AIPC. Methods: We retrospectively identified patients with AIPC in a single institution treated with LDK (200 mg PO TID) as secondary hormonal therapy with or without concomitant steroids. Additionally, patients were identified who received dose escalation to HDK (400 mg PO TID) after experiencing a rising prostate-specific antigen (PSA). Results: 138 patients were eligible for the study. Median age was 64 years (range: 41–84); median PSA at initiation of ketoconazole was 37.4 ng/ml (range: 0.8–2279). Patients received LDK as either second (25.4%), third (50.0%) or fourth (21.7%) line hormonal therapy. Thirty-nine of 138 patients (28.3%, 95% CI 20.9%–36.6%) treated with LDK treatment experienced PSA declines ≥50%. Median duration of LDK was 6.4 months in responders and 2.9 months in non-responders. Dose escalation to HDK subsequently was performed in 55 (40%) patients, seven of whom (12.7%) demonstrated a subsequent PSA decline ≥50% (5 LDK responders and 2 LDK non-responders, respectively). Overall time to progression with LDK with or without dose escalation was 3.5 months (range 0.1+–61 months). The most common reversible adverse effect on LDK was grade 1 or 2 fatigue (12.3%). 41.8% of dose escalation group experienced either aggravation or development of toxicities. The most common toxicities on HDK were nausea (16.4%) and fatigue (14.5%). Conclusions: LDK is associated with a PSA response rate comparable to HDK as secondary hormonal therapy in patients with AIPC, and appears to be less toxic. Few patients responded to the dose escalation from LDK to HDK but durable additional responses occurred in some.

No significant financial relationships to disclose.
Survival (S) of ovarian cancer (OC) patients (pts) treated on SWOG9701/GOG178: 12 versus (v) 3 cycles (C) of monthly single-agent paclitaxel (PAC) following attainment of a clinically-defined complete response (CR) to platinum (PLAT)/PAC
Authors: Markman M. , Liu P. , Wilczynski S. , Monk B. , Copeland L. , Alberts D.
Published: March 2020

5005

Background: This phase 3 trial was closed by the SWOG Data Safety and Monitoring Committee (DSMC) when a prospectively-defined interim analysis revealed a highly statistically significant difference in progression-free S (PFS) (28 v 21 months [M]; p = 0.0023; hazard ratio [HR] 2.31) (JCO 2003; 21:2460). At study closure, there were insufficient deaths to describe the impact of 12-C of PAC on overall S (OS). Methods: Eligibility included OC or primary peritoneal cancer, attainment of a CR to PLAT/PAC, and ≤ grade 1 neuropathy. Pts entered into the trial (n = 296) received either 12-C or 3-C of PAC (175 mg/m2 q-28 days), and were then observed until progression. Results: Of the 146 pts on the 3-C arm, 9 (6%) actually received prolonged PAC (> 3-C) following closure of the study by the DSMC. Median (12-C v 3-C; intention-to-treat analysis): updated PFS (all pts) 22 v 14 M, p = 0.01; OS (all pts) 53 v 46 M, p = 0.27. Exploratory analysis (Cox models adjusting for stratification factors): 12-C v 3-C HR 0.59 (p = 0.03) if baseline CA-125 ≤ 10 (n = 175), and 1.25 (p = 0.34) for baseline CA-125 >10 (n = 121). The treatment v baseline CA-125 interaction was statistically significant (Cox model p = 0.03). Conclusion: OS was not significantly different between 12-C v. 3-C of PAC, either because (a) treatment at relapse equalized OS; (b) the sample size was insufficient to reveal a difference; (c) the crossover of pts from 3-C to longer treatment masked a potential difference; or (d) treatment was possibly prematurely discontinued at 12-C in pts who had not progressed (suggested by a previously reported exploratory analysis -JCO 2003; 21:2460). Of interest, an exploratory analysis strongly suggested an improvement in S for pts receiving 12-C of PAC if the baseline CA-125 level was ≤10, those individuals likely to have the smallest volume of clinically-undetectable residual OC when single-agent “maintenance” PAC was initiated.

No significant financial relationships to disclose.
Laparoscopic extraperitoneal para-aortic lymphadenectomy in patients with locally advanced cervical cancer: Histopathologic findings and correlation with PET-CT imaging studies
Authors: Coleman R. L. , Ramirez P. T. , Slomovitz B. M. , Levenback C.
Published: March 2020

5014

Objective: To evaluate the safety and feasibility of laparoscopic extraperitoneal para-aortic lymphadenectomy and to correlate histopathologic findings and preoperative PET-CT imaging in patients with locally advanced cervical cancer. Methods: We performed a prospective study of patients with locally advanced cervical cancer. Patients enrolled underwent laparoscopic extraperitoneal para-aortic lymphadenectomy prior to chemoradiation at our tertiary cancer center from April 2004 to June 2005. All patients had a preoperative CT scan and PET-CT scan. Results: 12 patients were enrolled. One patient did not undergo surgery. No patient had evidence of metastatic disease to the para-aortic area by preoperative CT scan. The median age was 48 years (range, 35–67). 10 patients were diagnosed with squamous cell carcinoma, one patient with adenocarcinoma, and one patient with transitional cell carcinoma. The stage distribution was: IB2 (3), IIA (1), IIB (4), IIIA (1), IIIB (3). The median BMI was 26 (range, 18.6–29.7). Two (18%) of 11 patients had a positive preoperative PET-CT imaging study for disease in the para-aortic lymph nodes. The median time of surgery was 162 minutes (range, 52–247). The median blood loss was 25 mL (range, 10–100). There were no intraoperative complications. No patient required intraoperative blood transfusions. The median length of postoperative stay was 1 day (range, 1–2). There were two patients who developed postoperative lymphocysts requiring drainage. The median number of lymph nodes removed was 11 (range, 4–17). A total of 2 (18%) of 11 patients had evidence of histologically confirmed lymph node metastases. Of these, only one patient had evidence of disease by PET-CT scan. Only one of the two patients with a positive PET-CT scan for disease in the para-aortic nodes, actually had disease confirmed histopathologically. The sensitivity and specificity of PET-CT scan is 50% and 89%, respectively. Conclusions: Laparoscopic extraperitoneal para-aortic lymphadenectomy is safe, feasible and appears to increase the precision of identifying occult metastasis. Further patient accrual will be needed to evaluate the ultimate utility of PET-CT imaging in this setting.

No significant financial relationships to disclose.
Long-term impact of chemotherapy on early stage ovarian cancer patients
Authors: Matulonis U. A. , Kornblith A. , Lee H. , Bryan J. , Gibson C. , Wells C. , Lee J. , Sullivan L. , Penson R. T.
Published: March 2020

5024

Background: Quality of life (QOL) assessments in early stage (stage I and II) ovarian cancer survivors (CS) are limited and have to date not focused on CS who have received adjuvant platinum- and taxane-based chemotherapy (CT). Methods: 55 early stage ovarian patients (pts) were identified from patient logs from the Dana-Farber Cancer Institute and Massachusetts General Hospital. 54 pts. received CT. QOL and long-term medical sequelae were measured in pts who were > 3 years from diagnosis and had no evidence of recurrent cancer. Pts were interviewed by phone, and the following surveys were administered: EORTC QLQ-C30 (EORTC) and QLQ-OV28 (OV-28), MHI-17, CALGB sexual functioning, GOG Neuropathy, FACT Fatigue, Beck’s Hopelessness, Fear of Recurrence (FOR), Dyadic Adjustment Scale (DAS), PCL-C post-traumatic stress disorder (PTSD), Unmet Needs, FACT-Spirituality (FACT-Sp), complementary therapy use, and MOS Social Support (MOS). Results: 55 pts were interviewed (mean age 58 yrs, range 34 to 77 yrs). Mean time between diagnosis and interview was 5.6 yrs. CS reported significantly higher MHI-17 scores than the population norm, and higher MHI-17 scores were associated with better overall QOL (EORTC, r = 0.57, p < 0.0001), increased social support (MOS, r = 0.54, p < 0.0001), and better marital relationships (DAS, r = 0.42, p < 0.001). Sexual problems (1.57 out of 6) and unmet needs (1.5 out of 14) were minimal. FOR was correlated with lowered overall QOL (EORTC, r = −0.63, p < 0.0001), increased abdominal symptoms (OV-28 abdominal scale, r = 0.48, p < 0.0002), increased hopelessness (Beck’s, r = 0.46, p < 0.0005), and increased spirituality (FACT-Sp, r = −0.57, p < 0.0001). CS were using 5.4 complementary therapies for QOL purposes and 5.8 for cancer treatment. Minimal negative socioeconomic impact was observed in CS (0.16 out of 4). However, 12.5% of pts had scores indicative of a diagnosis of PTSD. Conclusions: Long-term QOL follow-up of early stage ovarian cancer survivors demonstrated minimal long-term symptoms, excellent mental health, minimal unmet needs, and minimal socioeconomic impact.

No significant financial relationships to disclose.
Phase II study of DMXAA combined with carboplatin and paclitaxel in recurrent ovarian cancer
Authors: Gabra H.
Published: March 2020

5032

Background: DMXAA (AS1404) is a small-molecule vascular disrupting agent, which in animal models shows additive or supra-additive effects with cytotoxics, including taxanes and platinum agents. This phase II study evaluated DMXAA in combination with carboplatin and paclitaxel in recurrent platinum-sensitive ovarian cancer patients with a progression-free interval of more than 6 months after response to platinum-based chemotherapy. Methods: Patients had first diagnosed disease FIGO stage Ic-IV, with presence of recurrent disease confirmed by imaging. Patients were randomised 1:1 to receive up to 6 cycles of carboplatin (AUC 6 mg/ml × min) and paclitaxel (175 mg/m2) with or without DMXAA (1200 mg/m2). Safety assessments included EKG, adverse events, laboratory screens and ophthalmic exam. Efficacy endpoints are objective response rates, time to progression, duration of response and stable disease, and median and 1-year survival. Results: 55 patients have been enrolled to date from a planned total of ∼70. Initial safety findings in the two arms are comparable. Preliminary investigator-assessed RECIST response data show the following unconfirmed outcomes: of 17 patients in the DMXAA arm, there are 10 with partial responses (PRs), 7 with stable disease (SD) and 0 with progressive disease (PD); of 14 patients in the control arm, there are 8 PRs, 6 SDs and 0 PDs. Conclusions: Initial safety findings suggest that addition of DMXAA to standard doses of carboplatin and paclitaxel did not add significantly to toxicity. Efficacy assessments are ongoing to determine the value of the triple combination in recurrent ovarian cancer.

No significant financial relationships to disclose.
Overexpression of the osteopontin correlates with the aggressiveness of endometrial cancer
Authors: Cho C. , Kwon S. , Ramachandran S. , Kwon S. , Kwon K. , Cha S. , Do Y.
Published: March 2020

5038

Background: To test the hypothesis that expression of osteopontin (OPN), an integrin-binding glycoprotein, can independently predict the potential aggressiveness of endometrial cancer. We studied OPN expression in endometrial cell carcinomas and correlated OPN expression levels with clinicopathologic tumor features. Methods: The status of OPN expression in benign and malignant endometrial cancer cell lines and tissues was analyzed by Western blot and immunohistochemistry. Nonparametric Spearman’s correlation coefficient method was used to assess the statistical significance of the correlation between clinicopathologic characteristics of tumor and OPN expression. Results: An increased expression of OPN was observed in the endometrial cancer compared to normal endometrial tissue samples. When the level of OPN in normal tissue was set at 1, its level in benign endometrial hyperplasia was slightly increased at 1.2, whereas the OPN level in the highly malignant endometrial carcinoma tissue was greatly increased by nearly 3- 5 folds. Amongst the 70 cases examined immunocytochemically, of the 23 grade 1 endometrial carcinomas, 6 were unstained and 12 stained weakly positive (+). For the 20 grade 3 or serous type endometrial carcinomas analyzed, 8 (40%) stained strongly positive (+++), 8 (40%) stained moderately positive (++) and 1 stained weakly positive (+). These results showed that the level of OPN expressed between grade 1 and grde 3 or more was significantly different (Spearman’s correlation coefficient method, p = 0.001). Kaplan-Meier survival analysis showed that the increased level of OPN expression was significantly associated with reduced survival time of the patients. Conclusions: The results suggest that the increased OPN level may be involved in the malignant transformation of endometrial adenocarcinoma cells and OPN expression level is an important determinant for patient survival.

No significant financial relationships to disclose.
Exemestane in advanced and recurrent endometrial carcinoma. A phase II study
Authors: Nordstrom B. , Salmi T. , Mirza M. , Abeler V. , Kristensen G.
Published: March 2020

5042

Background: Most entrometrial adenocarcinomas of the endometrioid type express estrogen receptors and are potentially hormone sensitive. The aim of this phase II study was to evaluate the responsiveness of these tumors to treatment with Exemestane, an aromatase inhibitor. Methods: So far, 31 patients have been recruited to this ongoing study. Patients had to have a measurable tumor. Evaluation of response by CT was performed every 3 months. Evaluation of estrogen receptors (ER) was performed by immunohistochemistry and was positive in 17 patients, negative in 5 and not performed in 6 of the 28 patients evaluable for response. Treatment was given with Exemestane 25 mg orally daily. Results: Radiotherapy had been given as part of the initial therapy to 16 patients. Before inclusion into the study, 22 patients had received chemotherapy and 7 of these had also received hormonal treatment with gestagens for relapse. Response to Exemestane treatment was evaluable in 28 patients. In 17 patients with ER positive tumors, 1 showed a complete response, 1 partial response and 6 have had stable disease for 3+ months (3 patients), 6+ months (2) and 9+ months (1). The treatment was well tolerated with no major toxicity. Updated response rates will be presented. Conclusions: Treatment with Exemestane orally showed effect in patients with ER positive tumors in this heavily pre-treated group of patients with endometrioid adenocarcinoma of the endometrium.

No significant financial relationships to disclose.
Serum YKL-40 levels in patients with cervical cancer are elevated compared to patients with cervical intraepithelial neoplasia and healthy controls
Authors: Johansen J. S. , Roslind A. , Palle C. , Christensen I. J. , Nielsen H. J. , Price P. A. , Nielsen D. , Mosgaard B.
Published: March 2020

5047

Background: YKL-40 is secreted by cancer cells, macrophages and neutrophils. The exact function of YKL-40 is unknown. It may be a growth or differentiation factor, play a role in angiogenesis or protect against apoptosis. High serum YKL-40 is associated with poor prognosis in breast-, colorectal-, ovarian-, prostate-, small cell lung cancer and malignant melanoma. The aim was to examine serum YKL-40 in patients with cervical cancer and cervical intraepithelial neoplasia (CIN). Methods: YKL-40 was determined by ELISA (Quidel, Santa Clara, CA) in pretreatment serum samples from 116 patients with cervical cancer (FIGO stage Ia (N = 5), Ib (N = 55), II (N = 27), III (N = 25) and IV (N = 4); median age 50, range 27–87 years) and 152 patients with cervical CIN (34 years, 20–80 years). The controls included 63 healthy women undergoing sterilization (36 years, 25–59 years) and a group of 134 healthy women (51 years, 18–79 years). Results: Serum YKL-40 was increased (p < 0.001) in the patients with cervical cancer (median 76 μg/l, range 20–2310) compared to patients with CIN (45 μg/l, 20–288), women undergoing sterilization (37 μg/l, 20–125) and healthy women (43 μg/l, 20–172). Patients with CIN had slightly elevated serum YKL-40 levels. Serum YKL-40 increased with increasing stage (Ia: median 36 μg/l, range 26–137; Ib: 56 μg/l, 20–984; II: 92 μg/l, 28–2310; III: 163 μg/l, 40–1474; and IV: 224 μg/l, 137–391; p < 0.001 Kruskal-Wallis test). All stage IV patients, 72% stage III, 52% stage II, 24% stage Ib, 40% stage Ia and 13% of patients with CIN had elevated serum YKL-40 compared to healthy controls (95th percentile). Patients with squamous cell carcinoma had higher serum YKL-40 (median 92 μg/l, range 27–2310, N = 86) compared to patients with adenosquamous (67 μg/l, 20–93, N = 9, p = 0.027) and adenocarcinoma (43 μg/l, 20–1472, N = 20, p < 0.001). Conclusion: Median serum YKL-40 is elevated in patients with stage Ib - IV cervical cancer. The serum level of YKL-40 seems to be correlated to the stage.

No significant financial relationships to disclose.
Lymphatic mapping and parametrial lymph nodes identification in patients with early stage cervical cancer
Authors: Li B. , Wu L. , Li X. , Zhang X. , Zhang W. , Gao J.
Published: March 2020

5050

Background: The purpose of this study was to determine the presence, distribution, and metastasis incidence of parametrial lymph nodes (PLN) of patients with cervical cancer, and to investigate the role of lymphatic mapping and topographic section in PLN identification. Methods: Sixty patients with early stage (Ib∼IIa) cervical cancer undergoing radical hysterectomy and pelvic lymphadenectomy were included in the study. Before surgery 4 ml methylene was injected into the cervix around the tumor. The blue-dyed lymph nodes were identified as sentinel lymph nodes (SLN) during operation. An immediate topographic section on uterine specimen was performed to separate the PLNs from parametria for pathologic examination. Results: Ninety five PLNs were presented in 38 (63.3%) of 60 specimens, with a mean size in diameter as (0.67±0.24)cm, and 57 (60.0%) of PLNs were located parallel to the uterine artery through the entire broad ligament. After lymphatic mapping, 69 (72.6%) of PLNs was dyed and found out as SLNs. Parametrial metastasis was found in 12 (20.0%) patients, and parametrium was the only site containing positive nodes in 2 patients with parametrial metastasis. On routine pathologic evaluation, 17 PLNs were found to be positive. Among the remaining 78 PLNs, multilevel sectioning in conjunction with immunohistochemical analysis was carried out and identified 3 other PLNs containing micrometastases. Conclusions: The study showed that PLNs were often found in the parametria, and these nodes often contained metastatic diseases, which were often overlooked. Lymphatic mapping followed by meticulous topographic section is feasible in PLN identification in patients with cervical cancer.

No significant financial relationships to disclose.
HistoScanning, a new device to enhance ultrasound’s contribution to clinical assessment of pelvic masses
Authors: Bleiberg H. , Akakpo J. , Granberg S. , Sideri M. , Mashiach R. , Autier P. , Nir D.
Published: March 2020

5056

Background: HistoScanning (HS) is a medical device developed to improve interpretation of echography. Ovarian (OV) HistoScanning (OVHS) performs computerized analysis of voxel files generated during transvaginal ultrasonography (TVS). OVHS was integrated into a protocol for investigation of ovarian pathologies, primarily cancer (OVCa). Methods: A study was initiated; a/ to standardize the echography procedure, b/ to evaluate OVHS ability to differentiate cancerous to non-cancerous pelvic masses under appropriate conditions. Women (W) ≥18 years old planned to have complete removal of ≥1 OV were eligible. Exclusion criteria include previous diagnosis of OV cancer, pelvic surgery, radiotherapy or chemotherapy for breast or OVCa. Real 3D-TVS were performed before surgery and the voxel data sent to AMD. After OVHS results were locked in the study’s data base, pathological reports were sent to the clinical research organization and the OVHS results were compared to histology. Results: From 09.2004 to 07.2005, 486 data files were obtained from 9 institutions. 120 were used for calibration, 97 had no surgery, and 269 met the protocol requirements. Pelvic histology includes normal OV (87), benign tumors (T) (78), past endometriosis (9), borderline cancers (21), adenocarcinomas (53), carcinomatosis (12), metastases (4) and other cancers (3), others (2). 91 cancers were correctly diagnosed (sensitivity 98%). Reason for false negatives was: lack of voxel data for the lesion (1) and pathology volume bellow US resolution (‘Cystadenofibroma with foci of low malignant potential; Borderline‘) (1). When gain used during TVS was appropriate, the false positive (FP) rate was 3% for normal tissues and 17% for benign tumors. When gain used was inappropriate, FP rate was 10% and 41%, respectively. Conclusion: OVHS seems highly sensitive for the diagnosis of pelvic masses while having an acceptable specificity. A study using 3D-TVS performed with controlled gain level is ongoing.

[Table: see text]
Stratification of the normal range of CA125 after chemotherapy as a predictive factor in carcinoma of the ovary
Authors: Nadal R. M. , Ojeda B. M. , Artigas V. , Bogunà I. , Gich I. , Ribé A. , Prat J. , López López J. , Barnadas A.
Published: March 2020

5059

Background: CA125 is an accurate and reliable marker for monitoring the response to treatment and detecting early relapse in ovarian cancer. The implications of the variation of its normal range are not known.The purpose of this study was to evaluate such variations as a prognostic indicator after first-line chemotherapy Methods: Over a 7 years period (1998–2005), 114 patients (pts) were treated with standard chemotherapy regimen for FIGO stage Ic-IV epithelial ovarian cancer. The median age was 63 years old (24–87) years. The tumors were classified: 56% serous, 12% endometroid, 16% poorly differentiated and 16% clear cell carcinomas. FIGO stage: 12 (11%) Ic, 14 (12%) II, 72 (63%) III, 16, (14%) IV. After surgery, 90% of the patients received a median of 6 cycles/patient with platinum based (cisplatin or carboplatin) chemotherapy in combination with taxane. Serial measurement of CA12.5 had been made before each cycle of chemotherapy and response was assessed according to RECIST or Rustin criteria. Median follow-up has been 31 months. 87 pts achieved levels below 35 u/ml after completion of treatment. The nadir value of CA125 was stratified into three arbitrary groups: group 1, ≤ 10 U/ml, group 2, 11–20 U/ml, and group 3, 21–35 U/ml. The χ2/Fisher’s exact test was used to examine patients characteristics for categorical variables. Survival analysis was performed by Kaplan-Meier method with long-rank test for determining statistical significance. Results: No statistical relationship between FIGO stage and gross residual tumor vs nadir groups (p = 0.48 and p = 0.2) was found. Median duration of progression free survival according to 3 groups was 34, 20, 14 months, respectively (p= 0.003). The median overall survival for the group 1 is not yet available, however, the corresponding median overall survival for groups 2 and 3 were 3.8 and 2.7 years, respectively (p = 0.006) Conclusions: Within normal range, the differences between CA125 levels could add prognostic information and stratify patients according to the risk of progression.

No significant financial relationships to disclose.
CA125 nadir as a prognostic factor in advanced ovarian carcinoma: A retrospective study of 84 patients achieving clinical CR
Authors: Tanabe H. , Katsumata N. , Matsumoto K. , Nishio S. , Kato Y. , Yonemori K. , Kouno T. , Shimizu C. , Ando M. , Fujiwara Y.
Published: March 2020

5060

Background: There have been few reports of the relationship between CA125 nadir and the prognosis in patients with advanced ovarian carcinoma (AOC) who achieve a complete clinical response by multivariate analysis. Methods: CA125 nadir and the prognosis after the initial therapy (debulking surgery + first line chemotherapy) were retrospectively investigated in patients (pts) who had AOC meeting the criteria below and received therapy at National Cancer Center Hospital, between 1998 and 2004. The eligibility criteria were: 1) histological diagnosis of mullerian carcinoma, 2) FIGO stages III and IV, 3) a combination of platinum and taxane was administered as the first line chemotherapy, and 4) achieved clinically defined complete response (CR) after the initial therapy (ie, no cancer-related symptoms; normal physical examination, computed tomography scan of the abdomen/pelvis and chest x-ray). The possibility of CA125 nadir being a prognostic factor was investigated in pts who met these criteria by multivariate analysis (age (<50 years or 50 years≤), stage (III or IV), histological type (serous adenocarcinoma (serous) or non-serous), residual tumor diameter (<2 cm or 2 cm≤) and CA125 nadir (<10 U/ml or 10 U/ml≤)) using the Cox regression model. Results: There were 84 pts with a median age of 55.5 years (26–74). The stage was III in 59 pts and IV in 25 pts, the histological type was serous in 71 pts and non-serous in 13pts, and the residual tumor diameter was <2 cm in 72 pts and >2 cm in 12 pts and the median of CA125 before the initial therapy was 535 U/ml (13–28190), the CA125 nadir was <10 U/ml in 54 pts and 10 U/ml≤ in 30 pts, respectively. Regarding the prognosis, the median progression free survival (PFS) was 19 months (6–82), and the median overall survival (OS) was 36.5 months (10–82). By multivariate analysis, the CA125 nadir was significantly associated with the prognosis (hazard ratio of PFS was 0.39 (95% CI, 0.21–0.71), hazard ratio of OS was 0.28 (95% CI, 0.11–0.72)). Conclusion: CA125 nadir is a prognostic factor in patients with AOC who achieved clinically defined CR after the initial therapy, when the cut-off value was set to 10 U/ml. CA125 nadir may be an important factor for identifying pts for whom maintenance chemotherapy is effective.

[Table: see text]
Somatic mutation in the EGFR gene in ovarian carcinoma detected by SSCP and direct sequencing
Authors: Terai Y. , Sugita M. , Ueda M. , Ueki M. , Bemis L. , Haney J. , Franklin W. A.
Published: March 2020

5063

Background: Recently, mutations of the EGFR kinase domain have been described in adenocarcinoma of lung and are particularly common in non-smoking females of Japan. These tumors are more responsive to blockade of the EGFR TK domain than non-mutant tumors. Ovarian tumors are known to express EGFR but the frequency of EGFR mutation at this site has not been explored. Methods: We have searched for mutations in the EGFR gene in ovarian carcinoma in two ways, first by single stranded conformation polymorphism (SSCP) analysis of appropriately amplified DNA from microdissected paraffin sections and then by direct forward and reverse sequencing of the DNA for mutations in exons 18, 19 and 21. Results: There was poor correlation between the two methods. By direct sequencing and evaluation of sequence chromatograms by Mutation Surveyor, mutations were detected in 8 of 79 patients (10.1%). Three of the mutations have been previously described in NSCLC including two in-frame deletions in exon 19 (codons 746–750) and one point mutation in exon 21 (L858R). Previously undescribed point mutations resulting in amino substitutions were found in an additional 5 patients including two patients with multiple mutations. These point mutations included 3 in exon 18 (Q701R, L704S and T725A) and 5 in exon 21 (N830G, R832C, T852M, I853V and Q868D). Deletions were detected by SSCP but point mutations were not detected. Conclusions: We conclude that a low but definite frequency of mutation in the EGFR tyrosine kinase domain occurs in ovarian carcinoma in the Japanese population and that these tumors may be targeted by EGFR blockers. SSCP can detect multibase deletions but is an unreliable method for detection of point mutations.

No significant financial relationships to disclose.
Evaluation of serial serum IL-6 levels in women with newly diagnosed ovarian cancer on a prospective clinical trial
Authors: Mahoney J. , Lee H. , Foster R. , Matulonis U. , Duan Z. , Seiden M. V.
Published: March 2020

5065

Background: Elevated levels of IL-6 in serum have been reported in patients (pts) with mullerian malignancies (MM) and have been associated with a poor prognosis. Little is know about the behavior of IL-6 during effective cytotoxic therapy and its correlation to various clinical parameters. Methods: Pts with surgically debulked FIGO Stage II, III, and IV MM were enrolled in the Modified Triple Doublets trial. 83 pts were assigned to a cohort in accordance with the extent of surgical debulking. Cohort I included women who had been optimally cytoreduced to <1cm of residual tumor. Cohort II consisted of pts who had either post-debulking residual disease >1cm or stage IV disease. Both cohorts were treated with 3 sequential chemotherapy doublets, gemcitabine/carboplatin, paclitaxel/carboplatin, and adriamycin/topotecan. Each doublet was delivered for 3 cycles. Serum was collected from pts prior to initiating each doublet at cycles 1, 4, 7 and at the end of study (post cycle 9). Serum IL-6 levels were measured in triplicate by sandwich ELISA. Results: Pts with MM had elevated levels of IL-6 following debulking surgery (mean = 12.7 pg/ml) as compared to normal controls (n = 11, mean IL-6 = 1.5 pg/ml, p =.01). While there was no significant correlation between IL-6 levels and stage of disease, the IL-6 serum concentrations did correlate with extent of surgical debulking (p = 0.0182). IL-6 concentrations dropped throughout all cycles of platinum based treatment with post platinum treatment mean concentration of 3.9pg/ml. IL-6 levels did not correlate with outcome of second look operation and there was no statistically significant correlation between IL-6 and CA-125 levels (p = 0.1612). Survival data is still immature with a median follow-up of 34 months, yet elevation of IL-6 levels following surgery demonstrates a trend towards inferior survival. Conclusions: IL-6 levels are elevated in ovarian cancer pts following surgical debulking and correlate with the volume of residual disease following surgical cytoreduction. Values decrease during cytoreductive platinum based chemotherapy although IL-6 was not as predictive of response as was CA-125. Data demonstrates a weak correlation betweenworse survival and elevated IL-6 levels. Supported by the Lana Vento Foundation.

No significant financial relationships to disclose.
Randomized trial of systematic lymphadenectomy (LY) vs nodal sampling (SA) at second look surgery (SLS) in ovarian cancer patients: Final results
Authors: Landoni F. , Maggioni A. , Dell’anna T. , Benedetti Panici P. , Manci N. , Torri V. , Tironi R. , Garcia Parra R. , Falci C. , Fossati R.
Published: March 2020

5068

Background: The role of systematic pelvic and para-aortic lymphadenectomy at SLS in ovarian cancer patients has not been addressed by randomized clinical trials (RCTs). We conducted a RCT to determine whether LY improves progression-free (PFS) and overall survival (OS) compared with SA. Methods: From January 1991 through December 1999, 303 eligible patients (i.e. patients with FIGO stage I-IV epithelial ovarian carcinoma at up front surgery and in complete remission after primary debulking surgery and first line chemotherapy) were randomly assigned to undergo LY (N = 156) or SA (N = 147) at the end of SLS. Survival was analyzed using a Cox multivariable regression analysis. All statistical tests were two-sided. Results: Median operating time was longer and the percentage of patients requiring blood transfusions was higher in the LY arm than the SA (240 vs 135 min., P < .001, and 30% vs 10%, P < .001, respectively). In the LY arm and SA arm the median number of removed nodes and the percentages of patients with nodal involvement was statistically different (44 vs 8, P < .0001, and 24% vs 13%, P = 0.018, respectively). At a median follow-up of 59 months, 156 events (i.e., recurrences or deaths) were observed, and 98 patients had died. The 5-year progression-free and overall survival was 41% and 65% for LY, 49% and 61% for SA, respectively. The risk for first event (hazard ratio [HR] = 1.11, 95% CI = 0.81 to 1.53; P = .50) and death (HR = 0.79, 95% CI = 0.53 to 1.18; P = .24) after adjustment for residual tumor at first surgery was not significantly different between the two arms. Conclusions: Although LY at SLS seemed to improve overall survival, this survival gain (21% decrease in the hazard of death) was not statistically significant and therefore the routine use of LY at SLS for ovarian cancer is not supported by this RCT.

No significant financial relationships to disclose.
The role of extensive lymphadenectomy in stage I ovarian cancer
Authors: Munro E. G. , Karnik Lee N. , Cheung M. K. , Osann K. , Husain A. , Teng N. N. , Kapp D. S. , Berek J. S. , Chan J. K.
Published: March 2020

5069

Background: To determine if extent of lymphadenectomy affects the survival of women with stage I ovarian cancer. Methods: Demographic and clinico-pathologic information were obtained from the Surveillance, Epidemiology and End Results Program from 1988–2001 and analyzed using Kaplan-Meier methods and Cox proportional hazards regression. Results: Of the 6,686 women diagnosed with stage I ovarian cancer, 4,092 (61.2%) had stage IA, 392 (5.9%) had stage IB, 1,840 (27.5%) had stage IC, and 362 (5.4%) had unspecified stage I disease. The median age was 53 (range: 1–99). 5,625 (84.1%) were White, 388 (5.8%) Black, 488 (7.3%) Asian, and 185 (2.8%) were Other. All patients underwent primary surgery; of which, 3,824 women had no nodes, 1,533 had <10 nodes, and 1,329 had ≥10 nodes resected. Of the patients who underwent a lymphadenectomy, the median number of nodes resected was 9 (range: 1–84). The extent of lymphadenectomy (0, <10, and ≥10 nodes) increased the survival of patients with stage IC disease from 72.8%, 86.7%, to 90.1% (p < 0.0001), but not in those with stage IA (p = 0.07) or stage IB (p = 0.04) disease. In patients with non-clear cell epithelial carcinoma, the extent of lymphadenectomy was associated with improved 5-year disease-specific survivals of 85.6%, 93.3%, and 93.5%, respectively (p < 0.0001). However, the benefit associated with an extensive lymphadenectomy was not evident in clear cell (p = 0.09), sarcoma (p = 0.33), germ cell (p = 0.55), or sex cord stromal tumors of the ovary (p = 0.99). Similarly, patients with grade 3 disease had an improved survival associated with the extent of lymph node resection, 74.4%, 87.5%, to 90.5% (p < 0.0001), but not in those with grade 1 (p = 0.18) or grade 2 (p = 0.27) disease. In multivariate analysis, a more extensive lymphadenectomy remained significant as an independent prognostic factor for improved survival after adjusting for all other independent prognostic factors including age, surgery, histology, stage, and grade. Conclusions: Our findings suggest that the extent of lymphadenectomy was associated with an improvement in the survival of women with stage IC ovarian cancer.

No significant financial relationships to disclose.
A phase IB, open label, safety and pharmacokinetic (PK) study of escalating doses of PTK787/ZK 222584 (PTK/ZK) in combination with paclitaxel and carboplatin in patients (Pts) with stage IC to IV epithelial ovarian cancer (EOC)
Authors: Schroder W. , Campone M. , Abadie S. , Witteveen P. , Viens P. , Jalava T. , Palacay-Radona M. , Bilic S. , Laurent D. , Du Bois A.
Published: March 2020

5075

Background: Vascular endothelial growth factors (VEGFs) and VEGF receptors (VEGFRs) are important mediators of tumor growth and metastasis and their expression is associated with poor prognosis in EOC. PTK/ZK is a novel, oral, angiogenesis and lymphangiogenesis inhibitor that blocks tyrosine kinase signaling from all known VEGFRs. Methods: An open label, multicenter, phase IB dose escalation study evaluating PTK/ZK with chemotherapy as first line therapy in Pts with stage IC to IV EOC. Maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of PTK/ZK were assessed; PK of PTK/ZK, carboplatin and paclitaxel was characterized. Paclitaxel was administered as a 3-hour infusion on day 1 of each 21-day cycle at a dose of 175 mg/m2. Carboplatin was given immediately after paclitaxel as a 30-min IV infusion to AUC of 5 mg min/mL. PTK/ZK was given once daily from day 3 to day 21 of each chemotherapy cycle. Cohorts of 3 to 6 Pts received doses of PTK/ZK at 250, 500, 750, 1000 or 1250 mg/day. Dose expansion in 21 additional Pts was conducted with 1250 mg/day without reaching MTD. After completion of chemotherapy, PTK/ZK was given continuously until disease progression. PK samples were collected in cycle 1 (without PTK/ZK) and cycle 2 (after PTK/ZK pre-treatment). Results: 42 Pts were enrolled. To date 39 Pts are evaluated for safety, 19 Pts for DLT, 35 Pts for PK and 21 Pts with residual disease for tumor response. No DLTs were reported. The most frequently observed grade 3/4 toxicity was neutropenia (31%), leucopenia (18%) and hypertension (10%). PTK/ZK did not aggravate chemotherapy related side effects. To date 67% of Pts had achieved CR/PR, 9% SD, 5% PD and 19% UNK. PTK/ZK exposure at steady state was similar in cycle 1 and 2. PTK/ZK had no impact on the systemic exposure of carboplatin. Paclitaxel exposure was decreased by an average of 18% in cycle 2 compared to cycle 1 for Pts treated with PTK/ZK 1250 mg/day. Conclusion: Combination of PTK/ZK with paclitaxel and carboplatin is feasible and shows favorable safety profile. The combination is active in EOC and deserves further evaluation.

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Prevalence of BRCA1 mutations in triple negative breast cancer (BC)
Authors: Kandel M. J. , Stadler Z. , Masciari S. , Collins L. , Schnitt S. , Harris L. , Miron A. , Richardson A. , Garber J. E.
Published: March 2020

508

Background: 90% of BCs in women with germline BRCA1 mutations are ER, PR and HER2 negative (so-called “Triple Negatives”), and 80–90% of triple negative BCs are “basal-like” by DNA microarray and IHC analysis. Prevalence of germline BRCA1 mutations among women with triple negative BC may therefore, be elevated, and underestimated by available calculation models, which do not take tumor features into account. Methods: We randomly identified 200 women from the Dana-Farber/Harvard Cancer Center SPORE annotated specimen bank with histologically confirmed primary invasive, ER, PR and HER2 negative BC. Myriad prevalence tables for BRCA1 were used to estimate the probability that each subject carried a BRCA1 mutation according to age at BC diagnosis, family and personal history of breast and/or ovarian cancer, and Ashkenazi Jewish ancestry. Full sequencing analysis for BRCA1 germline mutations is in progress. Results: The median age at diagnosis of triple negative BC was 49 years (range 26–79). The majority of tumors were high grade (89%) ductal (95%) carcinomas; median tumor size was 2 cm, 50% had positive nodes. 3 patients had a personal history of ovarian cancer and 13 reported Ashkenazi Jewish ancestry. 44% had at least one first or second degree relative with BC; 12% had at least one relative with ovarian cancer. The estimated probability of detecting a BRCA1 mutation according to the Myriad tables ranged from 0.019 to 0.386 (median 0.039): the total expected number of BRCA1 mutations was 11. In a subgroup of 23 patients (12%), who had undergone clinical testing, 2.7 BRCA1 and 1.4 BRCA2 mutations were expected according to the Myriad tables. However, 9 deleterious BRCA1 mutations (39.1%) were found; 2 patients had a BRCA2 mutation (8.7%). Conclusions: The relative excess of BRCA1 mutations in a small group of patients with triple negative BC suggests that established risk factors alone may underestimate the prevalence of BRCA1 mutations among women with this BC subtype. We anticipate that complete BRCA1 analysis of our entire group will more definitively estimate the prevalence BRCA1 mutations among women with triple negative BC.

No significant financial relationships to disclose.
TOP2A aberrations as predictive and prognostic marker in high-risk breast cancer patients. A randomized DBCG Trial (DBCG89D)
Authors: Knoop A. , Knudsen H. , Balslev E. , Rasmussen B. B. , Overgaard J. , During M. , Nielsen K. V. , Jørgensen J. T. , Mouridsen H. , Ejlertsen B.
Published: March 2020

532

Background: The primary objective of the study was to evaluate TOP2A as predictive marker for adjuvant treatment with epirubicin in high-risk breast cancer patients. As a secondary objective the prognostic characteristics of TOP2A gene aberrations was investigated. The data presented on the predictive properties is a follow-up to the data previously published (Knoop et al, J Clin Oncol 2005; 23: 7483–90). Methods: 962 pre- and postmenopausal high-risk Danish patients were enrolled in the DBCG89D protocol. The patients were randomly allocated to either 9 × CMF (cyclophosphamide, methotrexate, 5-flurouracil) (n=495) or 9 × CEF (cyclophosphamide, epirubicin, 5-flurouracil) (n=467) every 3 weeks. Tumor-tissue was available from 806 patients (84%). The tumors were analyzed for TOP2A copy number changes with the TOP2A FISH pharmDx Kit (Dako, Glostrup). Recurrence-free survival (RFS) was used as primary end-point. Univariate and multivariate statistics were used to assess the predictive and prognostic properties of the TOP2A gene aberrations. Results: The TOP2A test was successful in 96% of the patients. Ninety-two (12.0%) patients were found to have TOP2A amplified tumors, and 86 (11.1%) to have TOP2A deleted tumors. For the primary study endpoint (RFS) a significant predictive value of TOP2A gene amplifications was found (HR=0.39; CI: 0.22–0.70; p=0.0017). A similar trend was seen with respect to TOP2A deletions (HR=0.61; CI: 0.35–1.07; p=0.082). TOP2A gene aberrations were significantly associated with several established prognostic factors and had independent prognostic value, associated with a significant worse prognosis both for RFS (p=0.036) and overall survival (p=0.012). Conclusions: The DBCG89D study has shown that TOP2A amplifications are associated with a favorable outcome of adjuvant treatment with epirubicin in primary breast cancer. Further, TOP2A aberrations demonstrated an independent prognostic value.

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DNA-repair gene (DRG) single nucleotide polymorphisms (SNPs) influence on response and survival in stage IV SCCHN patients treated with CDDP-based therapy
Authors: Quintela-Fandino M. , Hitt R. , Medina P. P. , Gamarra S. , Amador M. , Manso L. , Cortes Funes H. , Sanchez-Cespedes M.
Published: March 2020

5505

Background: CDDP kills tumor cells by DNA cross-linking. SNPS at DRG may influence the ability of patients to respond to CDDP. We studied the role of the SNPs XPD-Asp312Asn, XPD-Lys751Gln, ERCC1-C8092A and XRCC1-Arg399Gln to influence the response to CDDP-based therapy and to predict survival in SCCHN patients Methods: SNPs were genotyped in DNA from peripheral lymphocytes using PCR-restriction fragment length polymorphism in 103 stage IV (0% M1) SCCHN patients followed prospectively. Treatment schedules were concurrent CDDP/RT (n = 28), CDDP + fluoropyrimidine (FP)→ CDDP/RT (33) or CDDP + FP + taxane→CDDP/RT (42). Endpoints: to assess the impact of the SNPs in OS (Kaplan Meier and Cox’s model) and in response to chemotherapy (multivariate multinomial regression). The covariables gender, age, treatment type, number of polymorphic (poly.) variants (0–8), smoking and alcohol consumption and amount (mg) of CDDP were included in the multivariate analysis Results: Median age 60 yrs (39–94); 97 (94%) male. After 78 months of follow-up, 24% had died, 22% had relapsed and 51% were free of disease. The allele frequencies for the homozygous common allele, heterozygous and homozygous poly. variant were: ERCC1: 53, 40 and 7%; XPD312: 50, 42 and 8%; XPD751: 35, 57 and 8%; XRCC1: 35, 51 and 13%. Overall, 9%, 16%, 22%, 20%, 24%, 6%, 1% and 1% of the patients harbored 0, 1, 2, 3, 4, 5, 6 and 7 poly. variants simultaneously. Table shows OS according to genotype. Patients with only common alleles had a median OS of 5.1 months (4.3–6.0) vs not reached for patients with ≥1 variant (p = 0.0000)(mean 6.2 (4–8.4) vs 61.3 (53–59.8). Each variant allele decreases the probability of dying 2.1 fold (p = 0.0000) on the Cox’s analysis (7 variants = 175 fold protection) and increases 2.94 fold (multinom. reg.)the probability of achieving a CR vs PD (p = 0.041) Conclusions: In our series the poly. variants at DRG are the strongest prognosis factors and accurately predict clinical response among SCCHN patients.

[Table: see text]

No significant financial relationships to disclose.