bluuebunny/crossref_metadata_2025 huggingface dataset:
Are men with larger prostates and bothersome voiding symptoms less likely to have significant prostate cancer?
Authors: Porter C. R. , Wright J. , Borden L. , Jason K. , Latchemsetty K.
Published: March 2020

4656

Background: Gleason Sum (GS) predicts clinically significant prostate cancer (CAP) and prostate specific antigen (PSA) survival in men undergoing prostatectomy for CAP. BPH can also elevate PSA. Objective: evaluate prostate gland volume (PV) and American Urologic Symptom Score (AUASS) in men undergoing prostate needle biopsy (PNB) to detect CAP. Analysis endpoints: 1) CAP and 2) GS ≥7. Methods: From 1/2000–7/2005, 1,078 men undergoing PNB were prospectively examined. Urinary voiding symptoms were measured by AUASS. All men were examined by 1 surgeon: DRE and Transrectal Ultrasound (TRUS) were given levels of suspicion (LOS) from 1 = low suspicion (smooth DRE, homogeneous TRUS) to 5 = high suspicion (hard DRE, hypoechoic lesion). LOS ≥3 was abnormal. Prebiopsy parameters: PSA, DRE, age, race, biopsy history, prostate volume (PV), TRUS lesion, and AUASS. All men had 10-core biopsy. 1) Predictors for CAP were evaluated by Univariate (UVA) and multivariate (MVA) analysis (logistic regression) for 1,078 men. 2) Predictors for GS≥7 were evaluated in men with no prior biopsy (NOPB). Results: Median PSA = 5.4 ng/ml (mean 10.4), 38% and 52% had abnormal TRUS & DRE respectively. Mean patient age = 64 years. Mean AUASS = 10.4. Positive biopsy rate = 38%. AUASS: 47% had low symptoms scores (<7), 39% had moderate scores (8–19), and 14% had severe scores (20–35). UVA & MVA (N = 1,078) showed that PSA was not an independent predictor of CAP (p = 0.18), but abnormal DRE, age, low AUASS, no prior biopsy (NOPB), race (AA), abnormal TRUS, and low PV were all independent predictors (p < 0.03). Subset MVA analysis of men in PSA range of 2.5–10 (N = 738), demonstrated that low AUASS (p = 0.05) & low PV (p = 0.00001) were predictors of CAP, while DRE, NOPB, and age were also independent predictors. MVA of men with NOPB (N = 790), indicated that low PV, PSA, DRE, and Age were independent predictors for CAP (p < 0.0001). The multivariate risk of having GS ≥7 on biopsy was independently associate with both low PV (p = 0.001) and abnormal DRE (p = 0.001). The relationship between PV and GS ≥7 showed that for every 1 cc increase in gland volume the risk of GS ≥7 CAP decreases by 2.2%. Conclusions: Men with smaller prostates are more likely to have cancer and are more likely to have significant disease.

No significant financial relationships to disclose.
A Gynecologic Oncology Group randomized trial of whole abdominal irradiation (WAI) vs cisplatin-ifosfamide+mesna (CIM) in optimally debulked stage I-IV carcinosarcoma (CS) of the uterus
Authors: Wolfson A. H. , Brady M. F. , Mannel R. S. , Lee Y. , Futoran R. J. , Cohn D. , Ioffe O. B. , Rocereto T. F.
Published: March 2020

5001

Background: Besides initial surgery, there has been no established consensus regarding adjunctive therapy for optimally debulked patients with uterine CS. This study was designed to compare progression-free interval (PFI), overall survival (OS), toxicity, and failure patterns using WAI vs CIM chemotherapy for this uncommon group of female malignancies. Methods: Patients with stage I-IV disease, ≤ 1 cm residual tumor, and no extra-abdominal involvement were randomly assigned to either WAI (approximately 30 Gy followed by pelvic boost) or cisplatin 20 mg/m2/d × 4, ifosfamide 1.5 g/m2/d × 4 and mesna 120 mg/m2 loading dose, then 1.5 g/m2/d × 24 h, repeated q 3 weeks × 3 cycles. Results: 224 patients were enrolled, of whom 207 (WAI = 105; CIM = 102) were eligible. Patient demographics and characteristics were similar between arms. FIGO stage (both arms) was: I = 64 (31%); II = 26 (12%); III = 93 (45%); IV = 24 (11%). GI toxicity ≥ grade 2 occurred frequently and similarly (31%, both arms). CIM was associated with more ≥ grade 3 anemia (11% vs 1%) and neurotoxicity (9% vs 0%) compared to WAI. Two deaths were attributed to RT-induced hepatitis. Sites of first recurrence in WAI vs CIM among the 97 (47%) patients who relapsed were: vagina, 4 vs 10; pelvis, 12 vs 12; abdomen, 23 vs 14; lung, 13 vs 13; other, 13 vs 9. The estimated probability of recurring within 5 years is 55% (WAI) and 49% (CIM). Adjusting for stage, the recurrence rate was 28.5% lower for CIM patients relative to WAI patients (hazard ratio [HR]: 0.715, 95% confidence interval [CI]: 0.474–1.077, p = 0.108, 2-tail test). The estimated death rate for CIM is 32.8% lower relative to WAI (HR: 0.672, 95% CI: 0.458–.986, p = 0.042). Conclusion: Compared to WAI, adjuvant CIM reduces the recurrence rate and significantly prolongs OS in optimally debulked uterine CS patients; however, due to a high relapse rate and poor OS, the imperative for new adjuvant therapies remains.

No significant financial relationships to disclose.
Radiation ±cisplatin for bulky stage IB cervical carcinoma; Long-term follow-up of a GOG trial
Authors: Stehman F. B. , Ali S. , Gallup D. G. , Key H.
Published: March 2020

5015

Purpose: To confirm that concurrent cisplatin (CT) with radiation (RT) is associated with improved long-term progression-free survival (PFS), overall survival (OS), and decreased morbidity compared to RT stage IB bulky carcinoma of the cervix, when both groups’ therapy is followed by hysterectomy. Methods: Three hundred seventy-four patients entered this trial. There were 369 evaluable patients; 186 were randomly allocated to receive RT alone and 183 to receive CT+RT. Radiation dosage was 40 Gray (Gy) in 20 fractions followed by a single low dose-rate intracavitary application of 30 Gy to Point A. Chemotherapy consisted of cisplatin 40 mg/M2 every week for up to six weekly cycles. Total extrafascial hysterectomy followed the completion of RT by 3–6 weeks. Results: Preliminary results have been published, at which time there many censored observations and limited follow-up. Patient and tumor characteristics were well-balanced between the regimens. The median patient age was 41.5 years; 81% had squamous tumors; 59% were white. Median follow-up is 101 months. The relative risk for progression was 0.61 favoring CT+RT (95% confidence interval [CI]: 0.43–0.85, p < 0.004). At 72 months 71% of patients receiving CT+RT were predicted to be alive and disease-free when adjusting age and for tumor size compared to 60% of those receiving RT alone. The adjusted death hazard ratio was 0.63 (95% CI: 0.43–0.91, p < 0.015) favoring CT+RT. At 72 months, 78% of CT+RT patients were predicted to be alive compared to 64% of RT patients. An increased rate of early hematologic and gastrointestinal toxicity was seen with CT+RT. There was no detectable difference in the frequency of late adverse events. Conclusion: Concurrent weekly cisplatin with RT significantly improves long term PFS and OS when compared to RT alone. Serious late effects were not increased. The inclusion of hysterectomy has been discontinued on the basis of another trial. Pending further trials, weekly cisplatin with radiation is the standard against which other regimens must be compared. Key Words: Cervical carcinoma, chemoradiotherapy.

No significant financial relationships to disclose.
Analysis of the VEGF family and their receptors in serum/plasma of patients with pre-invasive and invasive cervical cancer
Authors: Landt S. , Thomas A. , Fueger A. , Jeschke S. , Korlach S. , Adam H. , Ulm K. , Schmid P. , Blohmer J. , Lichtenegger W. , Kuemmel S.
Published: March 2020

5016

Background: The vascular endothelial growth factor (VEGF) family and their receptors are essential regulators of angiogenesis and lymphangiogenesis. This study examined the significance of circulating VEGF, VEGF-C, VEGF-D and their receptors VEGFR-1 and VEGFR-2 in patients with preinvasive and invasive cancer in relation to conventional prognostic parameters. Methods: Blood samples were obtained from 125 women before initial treatment (CIN I-III n = 50; FIGO stage I-IV n = 51; relapse n = 24). Plasma (p) and serum(s) levels of pVEGF, sVEGF-D, sVEGFR-1, sVEGFR-2 (R&D Systems, USA) and sVEGF-C (IBL, Japan) were determined by using a quantitative sandwich enzyme-linked immunosorbent assay (ELISA). Results: The highest level of pVEGF (p = 0.007) and sVEGFR-2 (p = 0.014) were detected in patients with recurrent disease, whereas the highest level of sVEGF-D (p = 0.046) were measured in patients with preinvasive lesions (CIN I-III). Furthermore, significantly elevated levels of sVEGF-C (p = 0.021) were detected in early stages (FIGO I-II) in comparison with advanced stages (FIGO III-IV) of cervical cancer. No significant difference in concentration was observed between the various grades of cervical intraepithelial neoplasia (CIN I-III). Correlations between conventional prognostic markers such as lymph node status (N0/N1), lymphangioinvasion (L0/L1), angioinvasion (V0/V1) and grading (G1/G2/G3) were investigated. Increased plasma levels of VEGF (p = 0.036) correlate with the dissemination of tumor cells to regional lymph nodes (N1),whereas serum VEGF-D levels were significantly decreased in women with lymph-node involvement (N1) (p = 0.045) and vascular invasion (L1) (p = 0.019). None of these members of the VEGF family were found to correlate significantly with histological subtype (squamous cell carcinoma, adenocarcinoma, adeno-squamous cell carcinoma) or grading of the tumor cells (G1/G2/G3). Conclusions: These results show that circulating concentrations of VEGF are associated with the stage of disease. In an early stage of cervical cancer a switch to a lymphangiogenic phenotype (VEGF-D, VEGF-C) might be possible.

No significant financial relationships to disclose.
Molecular markers for lymph node involvement in locally advanced cervical carcinomas
Authors: Kristensen G. B. , Lyng H. , Svendsrud D. H. , Holm R. , Knutstad K. , Brøvig R. , Sundfoer K. , Oksefjell H. , Stokke T.
Published: March 2020

5049

Background: Lymph node involvement is the first indication of cervical cancer spread and a strong prognostic factor. The aims of the present study were to identify genes associated with lymph node involvement. Methods: The nodal status and tumor volume were determined from MR images in 48 patients with FIGO stage 2a to 4a at the time of diagnosis. cDNA microarray technique was used to identify genes that differed in expression between node positive and negative tumors. Biopsies enriched for carcinoma tissue were co-hybridized with a common reference sample in a dye-swap design. Quantitative real time PCR (qRT PCR) and immunohistochemistry were used to validate microarray results and determine protein expression of selected genes. Results: Pathologic lymph nodes were seen in 29 patients and normal nodes in 19. We identified 16 genes with higher and 15 with lower expression in node positive tumors as compared to the negative ones. QRT PCR data of 4 genes were consistent with these findings. CKS2, MRPS23, MRPL11, LSM3 and PDK2 were upregulated in node positive tumors suggesting high proliferation activity and oxygen consumption. MSN, KLF3 and TBX3 were downregulated. CKS2, MRPS23, MRPL11, PDK2, LSM3, TBX3, KLF3 and MSN were significantly related to progression free survival in univariate analysis. Protein expression, determined for CKS2 and MSN, was significantly correlated to survival, consistent with these results. In multivariate analysis including only gene variables, MRPL11, PDK2 and TBX3 were significant. Including also clinical and MRI variables, tumor volume, KLF3 and TBX3 were significant. NEK1, CSTA, ANX4 and DDOST were upregulated indicating activated DNA damage repair (NEK1) and resistance to apoptosis (CSTA, ANX4, DDOST). NTN4 and HYAL1, which are involved in cell-matrix interactions, were downregulated, suggesting mechanisms for increased cell migration and invasive growth. Conclusions: Our findings are consistent with known phenotypic characteristics of node positive cervical tumors, such as hypoxia and high lactate content. They point to molecular mechanisms for development of hypoxia, deregulation of glucose metabolism, activation of survival strategies and interactions between carcinoma cells and tumor stroma that may promote metastasis formation.

No significant financial relationships to disclose.
A multi-institutional study of radiation therapy for isolated para-aortic lymph node recurrence in uterine cervical carcinoma: 84 subjects out of over 5,000 population
Authors: Niibe Y. , Hayakawa K. , Michimoto K. , Kenjo M. , Kazumoto T. , Takayama M. , Yamauchi C. , Kataoka M. , Suzuki K. , Oguchi M.
Published: March 2020

5052

Background: Most patient who had any recurrent sites of cancer, have been considered to be last-stage of life. However, recent advances of clinical research reveal some patients achieve long-term survival even in recurrence cases. Furthermore, patients who had only one recurrent region, even radiation therapy could play an important role. As for uterine cervical carcinoma, the most common recurrent site other than pelvis is para-aortic lymph node. Furthermore, improvement of diagnostic imaging enables us to detect more frequently isolated para-aortic lymph node recurrence. Thus, we conducted the current study. Methods: Between 1994 and 2003, over 5000 uterine cervical carcinoma patients treated with curative intended treatments at sixteen Japanese major hospitals. Out of them, 84 patients developed para-arotic lymph node recurrence as the only site of initial tumor progression. Seventy-four patitents had squamous cell carcinoma and 5 had adenosquamous cell carcinoma and 5 had adenocarcinoma. These patients were treated with external beam radiation therapy prescribing 1.7–2.0 Gy per fraction, 5 fractions per week and median total dose was 50 Gy (25–60 Gy). Thirty-two patients received adjuvant systemic chemotherapy. Results: Median follow-up time of all patients was 20 months (2–92 months). Three- and 5-year overall survival rates of all patients were 49.5% and 31.3%, respectively. Stratified by patients with or without chemotherapy, 3-year overall survival rate of patients with chemotherapy group was 37.7% and those without group was 56.7% (p = 0.69). Moreover, stratified by symptom sign, 3-year overall survival rate of symptom positive group was 27.6% and those of negative group was 56.1% (p = 0.018). Three-year overall survival rates of the total dose ≥ 51Gy and that of ≤ 50 Gy were 58.0% and 42.8%, respectively (p = 0.07). AS for morbidity, no patients received G3 or greater late toxicity (CTCAE ver. 3.0). Conclusions: The current study suggested that radiation therapy for isolated para-aortic lymph node recurrence in uterine cervical carcinoma could have significant impact on overall survival. Furthermore, no symptom group and over 51Gy irradiation group could achieve better prognosis.

No significant financial relationships to disclose.
A phase I study of docetaxel as a radiosensitizer for locally advanced squamous cell cervical cancer
Authors: Alvarez E. A. , Wolfson A. H. , Pearson J. M. , Crisp M. , Lambrou N. C. , Auguste F. , Lucci J. A.
Published: March 2020

5053

Background: Concomitant radiotherapy with cisplatin chemotherapy is the standard of care for locally advanced squamous cell cervical cancer (LASCCC). Alternatives to cisplatin are needed due to patient intolerance or toxicity. Taxanes have demonstrated clinical cytotoxic activity to SCCC and in-vitro radio-sensitization. This study was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly docetaxel with concurrent radiotherapy for the primary treatment of LASCCC. Methods: Twenty-three patients with FIGO stage IIB-IVA LASCCC without para-aortic lymph node involvement were screened and 13 enrolled in a dose-escalating phase I study. Docetaxel dose levels were 20 mg/m2, 30 mg/m2 and 40 mg/m2 given intravenously every 7 days for 6 cycles. Three patients were treated at each dose level and six patients received the MTD. Radiation therapy (RT) delivered a total dose of approximately 85 Gy to Point “A”. RT was administered with megavoltage external beam irradiation (EBI) at 1.8 Gy/fraction (fx) for 30 fxs to the pelvis over 6 weeks using a 4-field “box” technique for the first 25 fxs. A midline shield was applied for the last 5 fxs. Following EBI, patients underwent low-dose-rate brachytherapy. Results: Thirteen patients completed 4 - 6 cycles of chemotherapy. The other patients withdrew consent or needed alternative treatment before initiating the study. Reasons for completing less than 6 cycles were: noncompliance (5), adverse event (2), progression (1). One patient was lost to follow-up after 4 cycles. DLT’s were not observed at the 20 mg/m2 dose level. At the 30 mg/m2 dose level, 1/4 patient had a treatment-unrelated pelvic abscess and celiotomy. Another had progression 4 months after treatment. At the 40 mg/m2 dose level, 1/6 patients had progression and experienced grade 2 pneumonia, not treatment related. DLT was not observed in 6 patients at the 40 mg/m2 level. Overall, 5/13 (38%) experienced grade 2 diarrhea, 5 had grade 2 hematologic toxicity, and 2 had grade 2 hypersensitivity. Seven of 9 patients (78%) had no evidence of disease with follow-up ranging from 10–21 months. Conclusions: The recommended phase II dose of docetaxel administered weekly with concurrent radiotherapy for LASCCC is 40 mg/m2. The phase II trial is underway.

No significant financial relationships to disclose.
Impact of infertility treatment in patients with previous history of borderline ovarian tumors: Results of a multicenter study
Authors: Fortin A. , Morice P. , Thoury A. , Yazbeck C. , Camatte S. , Atallah D. , Zafrani Y. , Dhainaut C. , Madelenat P.
Published: March 2020

5055

Background: The use of infertility drugs (ID) in infertile patients treated conservatively for ovarian malignancies remains theoretically contraindicated. Few recent case reports seem to suggest that ID could be used in patients treated for a borderline ovarian tumors (BOT). The aim of this multicenter retrospective study was to report the outcomes of the largest series of patients with a previous history of a BOT who underwent the use of ID. Methods: A multicenter retrospective study was conducted among centers which participate in the French National Register on In Vitro Fertilization registry to evaluate the outcomes of patients with a previous history of a BOT treated with ID. Four criteria were defined to select cases: 1. Histologic confirmation of BOT, 2. The use of a conservative surgery, 3. The use of ID and 4. A follow-up ≥ 12 months after the end of infertility treatment. Results: Thirty cases fulfilled inclusion criteria. Infertility therapy began in November 1989. Disease stages were: I (n = 20), II /III with noninvasive implants (n = 8) and unknown in 2 cases. The mean number of cycles of ovarian induction per patient was 2.6 (range,1–10). After a median follow-up of 42 months after infertility treatment, 4 recurrences were observed (all of them were borderline tumors on a remaining ovary treated by surgery alone). All patients are currently disease-free. Thirteen patients have since become pregnant. The median interval between treatment of the BOT and the use of ID is shorter in patients who relapsed compared to patients who did not (5 versus 29 months; p=.07). Conclusions: These results suggest that infertility drugs could be safely used in patients who experience infertility after conservative management of an early-stage BOT. A minimal interval should be respected between treatment of the ovarian tumor and the use of infertility drugs in order to decrease the risk of recurrence.

No significant financial relationships to disclose.
Nomogram for survival after primary surgery for bulky stage IIIC ovarian carcinoma
Authors: Chi D. S. , Sonoda Y. , Abu-Rustum N. R. , Awtrey C. S. , Huh J. , Barakat R. R. , Kattan M. W.
Published: March 2020

5058

Background: Nomograms have been developed for numerous malignancies to predict a specific individual’s probability of long-term survival based on known prognostic factors. To date, no prediction model has been developed for patients with ovarian cancer. The objective of this study was to develop a nomogram to predict the probability of 4-year survival after primary cytoreductive surgery for bulky stage IIIC ovarian carcinoma. Methods: Nomogram predictor variables included age, tumor grade, histologic type, preoperative platelet count, the presence or absence of ascites, and residual disease status after primary cytoreduction. Disease-specific survival was estimated using the Kaplan-Meier method. Cox proportional hazards regression was used for multivariable analysis. The Cox model was the basis for the nomogram. The concordance index was used as an accuracy measure, with bootstrapping to correct for optimistic bias. Calibration plots were constructed. Results: A total of 462patients with bulky stage IIIC ovarian carcinoma underwent primary cytoreductive surgery at our institution during the study period of 1/89 to 12/03, of whom 397 were evaluable for inclusion in the study. The median age of the study population was 60 years (range 22–87). The primary surgeon in all cases was an attending gynecologic oncologist. Postoperatively, all patients received platinum-based systemic chemotherapy. Ovarian cancer-specific survival at 4 years was 51%. A nomogram was constructed on the basis of a Cox regression model and the 6 predictor variables. This nomogram was internally validated using bootstrapping and shown to have excellent calibration with a bootstrap-corrected concordance index of 0.67. Conclusions: A nomogram was developed to predict 4-year disease-specific survival after primary cytoreductive surgery for bulky stage IIIC ovarian carcinoma. The nomogram utilizes 6 predictor variables that are readily accessible, assigns a point value to each variable, and then predicts the probability of 4-year survival based on the total point value for an individual patient. This tool should be useful for patient counseling, clinical trial eligibility determination, postoperative management, and follow-up.

No significant financial relationships to disclose.
The prognostic effects of performance status (PS) and quality of life (QoL) scores on progression-free survival (PFS) and overall survival (OS) in advanced ovarian cancer
Authors: Carey M. S. , Bacon M. , Tu D. , Bezjak A. , Stuart G. C.
Published: March 2020

5066

Background: Performance status is an important prognostic factor in advanced ovarian cancer. We sought to evaluate the relationship between PS and EORTC QLQ-C30 QoL scores and the PFS and OS in advanced ovarian cancer. Methods: Canadian data was analyzed as part of an intergroup randomized trial in ovarian cancer (NCIC-OV10). Patients were randomized to receive either standard chemotherapy using cisplatin/cyclophosphamide or cisplatin/paclitaxel chemotherapy. The EORTC QoL questionnaire QLQ-C30 was administered just prior to starting chemotherapy, at each cycle, and every 3 months thereafter for two years or until disease progression. We determined PS and QoL scores in the following domains: physical, role, emotion, cognitive, social function and global QoL at baseline and 6 months after completing chemotherapy. Effects of multiple variables including treatment, PS, QoL scores, age, stage, grade, residual disease and histology were analyzed by Cox stepwise regression using PFS and OS as the outcome variables. Results: At baseline and at 6 months after chemotherapy, there were 151 and 80 patients respectively who completed QoL assessments. The Cox model revealed that baseline PS, global QoL and treatment were independent predictors for both PFS and OS, and grade and cognitive functioning were additional independent predictors for OS. Physical function at six months after completion of chemotherapy was the only significant independent predictor of both PFS and OS, with age and grade as two additional independent predictors for subsequent OS. Conclusions: Performance status and global quality of life scores at baseline are prognostic factors in advanced ovarian cancer for both PFS and OS. Higher baseline cognitive functioning scores were also associated with improved survival. Higher physical function scores at six months after completing chemotherapy predicted longer PFS and OS. (This research was supported by the NCIC through funds received by the Canadian Cancer Society).

No significant financial relationships to disclose.
A phase-II study evaluatin safety and efficacy with weekly paclitaxel and carboplatin as a primary treatment for patients with advanced epithelial ovarian cancer (EOC)
Authors: Safra T. , Bernstein Molho R. , Grisaru D. , Spigel S. , Geva R. , Matcejevsky D. , Inbar M. , Menzcer J. , Levy T.
Published: March 2020

5077

Background: The standard chemotherapy for epithelial ovarian cancer (EOC) is carboplatin and paclitaxel every 3 weeks together with debulking surgery. This phase II trial was designed to determine the safety and efficacy of weekly carboplatin and paclitaxel treatment in patients with EOC. Methods: Between October 2003 to August 2005, 37 patients with stage Ic-IV epithelial ovarian, tubal or primary peritoneal carcinoma were enrolled into the study. Carboplatin at AUC=2 and paclitaxel at 80 mg/m2 were administered on days 1,8,15 of a 28-day cycle. Cytoreductive surgery was performed as primary treatment or after 3 cycles of neoadjuvant chemotherapy with additional chemotherapy after the surgery. Results: Median age of the patients was 67 (range 49–82). A mean of 6 chemotherapy cycles were administered (range 3–8). Median time of follow-up (from the beginning of chemotherapy until the last follow-up visit) was 15.57 months (range 0.2–26months). Thirty-three patients were evaluable for response. Complete response (CR) was observed in 26 patients (78.8%) and partial response (PR) in 7 (21.8%). By the time of data collection 13 out of 33 women (39.4%) experienced recurrent or persistent disease and one patient (3%) died from progressive disease during 2nd line chemotherapy. Since 20 out of 33 patients are still free of disease and all but one are still alive, it is too early to evaluate time to progression (TTP) and overall survival (OS). The median time to disease recurrence or progression after completion of primary chemotherapy was 7.5+ months (0.2–18.2+). As for toxicity; grade 3 and 4 neutropenia were seen in 5 (13.5%) and one patient (2.7%) respectively. There was no neutropenic fever. Other grade 3 and 4 hematologic toxicities were not observed. Six (16.2%) and 5 (13.5%) patients needed G-CSF and Epoetin support respectively. The main non-hematologic toxicities were alopecia (grade 1) and fatigue (grade 3 in two patients). Only two patients (5.4%) experienced grade 3 neuropathy. Conclusion: Weekly treatment with carboplatin and paclitaxel is feasible and well tolerated. The low toxicity rate especially regarding neuropathy warrants further investigation of this regimen.

No significant financial relationships to disclose.
Phase II study of oxaliplatin (OXA) and docetaxel (DTX) in recurrent ovarian cancer
Authors: Ferrandina G. , Ludovisi M. , D’Agostino G. , Naldini A. , Lorusso D. , Testa A. C. , Legge F. , Salutari V. , Scambia G.
Published: March 2020

5086

Background: We conducted a phase II study to evaluate the efficacy and safety of OXA and DTX in recurrent platinum-sensitive ovarian cancer patients. Methods: Patients received DTX 75 mg/m2 (60-min i.v.) on day 1, followed by OXA 100 mg/ m2 (120-min i.v.) on day 1 every 21 days. Results: Between October 2002 and November 2005, 30 Caucasian patients (median age: 53.5 yrs; range, 31–73) were enrolled; 7 (23.3%) patients had FIGO stage I-II disease, 22 (73.3%) had FIGO stage III, and 1 (3.3%) had FIGO stage IV disease. Sites of relapse were as follows: abdominal 3 (10.0%), pelvis 5 (16.7%), lymph nodes 10 (33.3%), peritoneal 7 (23.3%), lung 1 (3.3%), and mixed 4 (13.3%). The median PFI was 28.5 months (range 13–91). The median CA125 was 182 U/ml (range 21–5,596 U/ml). Of the 30 patients evaluable, 13 (43.3%) had complete responses and 7 (23.3%) had partial responses, for an overall response rate of 66.6%. The median time to response was 9.5 wks (range 5–32) and the median duration of response was 43 wks (range 5–124). 8 (26.7%) patients had stable disease (median duration of stabilization: 26.5 wks, range 12–43). 2 (6.7%) patients progressed while on treatment. An overall clinical benefit was observed in 93.3% of patients. All patients were evaluable for toxicity. A total of 186 courses were given, with a median of 6 cycles per patient (range 2–11). Severe toxicities (Grade 3–4 NCI-CTC) included: neutropenia in 29.4% of cycles; severe anemia and thrombocytopenia were not observed. Grade 3–4 neurotoxicity and alopecia were detected in 2.8% and 22.8% of cycles respectively. Allergic reaction was observed only in one case. Doses were reduced by 20% in 14.0% of cycles. Conclusions: In recurrent platinum-sensitive ovarian cancer patients the OXA/DTX combination is highly active with acceptable toxicity, thus making it an attractive regimen.

No significant financial relationships to disclose.
Left ventricular function following adjuvant chemotherapy for breast cancer: The NCIC CTG MA5 experience
Authors: Shepherd L. E. , Parulekar W. , Pritchard K. I. , Trudeau M. , Paul N. , Tu D. , Levine M.
Published: March 2020

522

Background: Cardiac toxicity associated with anthracylines and more recently herceptin used in adjuvant breast cancer treatment is well recognized. Little is known about long term cardiac function as measured by left ventricular ejection fraction (LVEF) in patients post therapy. We analyzed the database of a randomized Phase 3 NCIC CTG study to assess changes over time in LVEF. Methods: Between 1989–1993, 710 pre/perimenopausal patients with node positive breast cancer were allocated to receive CEF (cyclophosphamide (C) 75 mg/m2 po d 1–14, epirubicin (E) 60 mg/m2 IV and fluorouracil (F) 500mg/m2 IV d1,d8) or CMF (C 100mg/m2 po d1–14, methotrexate (M) 40mg/m2 and F 600mg/m2 IV d1,8) given every 28 days for 6 cycles. The 10 year relapse-free survival was 52% (CEF) vs 45% (CMF), HR 1.31; stratified log rank, P=.007 (JCO, 2005,23;5166). LVEF was measured on both arms at baseline, months 6, 12, 36, and 60. Results: Compliance was good with measurements available on 100% of women at baseline, and 39% and 40% of patients at 60 months on the CEF and CMF arms respectively. Changes in LVEF from baseline are shown in the table . Conclusion: Changes in cardiac function as measured by a decrease in LVEF are not infrequent in patients after adjuvant therapy, even in the absence of anthracyclines. At 60 months, decreases of >10% were seen in up to 25% of patients receiving epirubicin administered at a cumulative dose of 720mg/m2 and in up to 10% of patients receiving CMF on whom measurements were available. The clinical significance of these findings needs to be assessed. Acknowledgements: This study was supported by funding from the Canadian Cancer Society through the National Cancer Institute of Canada and Pfizer Inc.

[Table: see text]

[Table: see text]
Two year analysis of treatment efficacy and cosmesis by the American Society of Breast Surgeons (ASBS) MammoSite Breast Brachytherapy Registry Trial in patients treated with accelerated partial breast irradiation (APBI)
Authors: Vicini F. , Beitsch P. , Quiet C. , Keleher A. , Garcia D. , Snider H. , Gittleman M. , Zannis V. , Kuerer H. , Whitacre E.
Published: March 2020

529

Background: This report presents 2-year data on treatment efficacy and cosmesis for patients enrolled on the ASBS sponsored MammoSite Registry trial. Methods: 1449 patients were treated with the MammoSite device to deliver APBI. 924 patients have been followed ≥ 12 months, 586 ≥ 18 months, 316 ≥ 24 months and 52 ≥ 36 months. Median follow-up for surviving patients was 14 months. Results: Eleven patients (0.8%) developed an ipsilateral breast tumor recurrence (IBTR) as some component of their initial failure (prior to distant metastases [DM]) for a 2-yr actuarial rate of 1.2%. The 2-yr actuarial rate of isolated IBTR was 0.8% (n=8). Six patients (0.4%) developed an axillary failure (AF) as some component of their initial failure (prior to DM) for a 2-yr actuarial rate of 1.0%. The 2-yr actuarial rate of isolated AF was 0.6% (n=3). The only variable associated with the development of an isolated IBTR (n=8) included an extensive intraductal component (p=0.073) (patient age, margin status, grade, histology, tumor size, nodal status, use of systemic therapy and method of device placement were not associated with IBTR). The only variable associated with the development of all IBTRs (n=11) was tumor location (inner quadrant, p=0.079). The percentage of patients with good/excellent cosmetic results at 6, 12, 18, 24 and 36 months were as follows: 95.1% (n=769 patients), 93.7% (n=621 patients), 91.3% (n=344 patients), 93.5% (n=248 patients), and 90.4% (n=52 patients) (p=NS). For the 174 patients with both a 12-month and 24 month cosmetic assessment, the rate of good/excellent cosmetic results was 94% at 12 and 24 months. At 24 months (n=248 patients), factors associated with good/excellent cosmetic results included increased skin spacing as a categorical variable (94.8% versus 86.1%, p=0.064), no infection (94.8% versus 85.7%, p=0.057), and no systemic chemotherapy treatment (95.3% versus 82.4%, p=0.012). Conclusions: Treatment efficacy and cosmesis 2 years after treatment with APBI using the MammoSite device are excellent and appear similar to those reported with standard whole breast RT.

No significant financial relationships to disclose.
Comparison of outcome prediction in node-negative breast cancer based on biomarkers uPA/PAI-1 or Adjuvant Online using the 10-year follow-up of the randomized multicenter Chemo N0 trial
Authors: Euler U. , Meisner C. , Friedel C. , Schmidt M. , Untch M. , Lisboa B. , Jaenicke F. , Schmitt M. , Thomssen C. , Harbeck N.
Published: March 2020

534

Background: Chemo N0 was the first multicenter randomized clinical trial in breast cancer using biomarkers uPA/PAI-1 for risk stratification and chemotherapy selection. Chemo N0 validated uPA/PAI-1 as clinically relevant parameters for risk assessment in N0 breast cancer. About 50% of N0 patients have low uPA/PAI-1 in their primary tumor with excellent 5-year OS (>95%), even without adjuvant therapy. Patients with high uPA/PAI-1 benefit from adjuvant chemotherapy. We evaluated whether biomarkers can predict outcome more accurately than a computer-program. Methods: In Chemo N0, patients (n=689, 1993–98) were stratified according to uPA/PAI-1: High-risk patients were randomized (6x CMF vs. observation), low-risk patients observed. Retrospectively, we divided recruited patients into two groups (chemotherapy vs. no adjuvant therapy) and stratified using uPA/PAI-1 (low vs. high). Individual 10-year OS was calculated by www.adjuvantonline.org (Version 7.0); these estimated values were compared to the observed 10-year OS in Chemo N0. Results: 81/151 patients with already available complete follow-up data 10 years after trial start have 10-year OS results. Median 10-year OS estimated by Adjuvant Online was 77.1% (median 78.6%) taking into account administered adjuvant therapy. 10-year Chemo N0 follow-up revealed an observed 10-year OS of 66.7% (27/81 deceased). 64/81 did not receive chemotherapy: In high-risk untreated patients (n=22), 10-year OS was 54.6% vs. estimated 75.0%. In CMF-treated patients (all high-risk, n=17), observed OS was 58.8% vs. estimated 74.6%. Conclusions: For the first time, risk assessment by novel biomarkers is compared to that by Adjuvant Online in data from a randomized clinical trial. In patients with high uPA/PAI-1, the individual 10-year OS calculated by Adjuvant Online seems to be underestimated compared to observed patient outcome. Further follow-up data will show whether uPA/PAI-1 can predict the individual course of disease more precisely than a computer-program based on large clinical data sets. Final Chemo N0 10-year follow-up is currently being completed.

No significant financial relationships to disclose.
Proteomic prediction in hormone receptor-positive breast cancer
Authors: Hennessy B. T. , Gonzalez-Angulo A. M. , Lu Y. , Tibes R. , Siwak D. , Sahin A. , Kau S. , Hortobagyi G. N. , Valero V. , Mills G. B.
Published: March 2020

541

Background:
Hormone receptor-positive breast cancer (HR+BC) is heterogeneous. Attempts to use transcriptional analysis such as Oncotype Dx facilitate therapy planning but fail to identify patients who will relapse or potential therapy targets.
Methods:
We used reverse phase protein lysate arrays and Microvigene software to quantify expression of estrogen receptor (ERα) and 36 total/activated components of the HER2, phosphatidylinositol-3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and STAT pathways in 64 HR+BCs and 40 breast cancer cell lines. Clustering was performed with Xcluster and Treeview.
Results:
47/64 HR+BC patients were treated with adjuvant hormone therapy and 43/64 with chemotherapy. There were 12 recurrences including 5 patients diagnosed with metastases within 0–3 months of diagnosis. Unsupervised analysis using the expression of all 37 proteins revealed two large subclusters of HR+BCs. One large cluster was composed of tumors with lower ERα expression levels and was driven by an antibody group composed mostly of phosphoproteins indicative of activated growth factor signaling pathways. Thus, there were significant inverse correlations between ERα expression and the expression and activation of components of the PI3K/MAPK pathways including EGFR, src, AKT, 4EBP1, and PKCα (p≤0.05 for each). Similar inverse correlations were seen in 40 assayed breast cancer cell lines. The clinicoproteomic predictors of relapse among HR+BCs were nuclear grade (p=0.001), low expression of ERα (p=0.04), low p38 phosphorylation (p=0.02), and high p53 (p=0.02). There also was a trend (p≤0.1) to the association of low MAPK and S6 phosphorylation, low p27, and high cyclin B1 with relapse. Using these antibodies to perform a supervised analysis, we found a small group of p53-high, cyclin B1-high, ERα-low HR+BCs with a 75% likelihood of relapse, significantly greater than in other tumors (p<0.003). Since 10/12 relapses occurred in 26 grade 3 tumors, we searched for and found a ‘grade 3’ HR+BC 6 antibody signature associated with a recurrence-free survival at 20 months of 17% compared to 100% in other patients (p=0.002).
Conclusion:
Although patient numbers are small and the findings require validation, kinase signaling profiles have potential in breast cancer prediction.

No significant financial relationships to disclose.
Neo-adjuvant treatment with erlotinb in squamous cell carcinoma head and neck (SCCHN) patients before surgery provides an opportunity to find predictive factors of response
Authors: Delord J. , Thomas F. , Benlyazid A. , Sarini J. , Rives M. , Begue M. , Courbon F. , Lefebvre J. , Rochaix P.
Published: March 2020

5513

Background: To date, neither immunohistochemistry (IHC) nor molecular analyses have identified prognostic markers of response to epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors in SCCHN. Thus, the selection of patients who could benefit from such agents remains a challenge. We designed a ‘pilot’ clinical trial of patients (pts) with SCCHN pending first-line surgery of their disease. Methods: Pts with resectable SCCHN received erlotinib at 150mg/day during the period between pan-endoscopy and surgery. Pharmacokinetic (PK) samples were collected during treatment, which ceased the day before surgery. Results: Thirty five pts were recruited. All of them had resectable SCCHN: oral cavity (17 pts), oropharyngeal (7 pts), hypopharyngeal (5 pts), larygeal (6 pts). Thirty pts received full treatment with erlotinib and the main reason for discontinuation was rash. The median duration of treatment was 21 days (14–27). All pts were evaluated clinically and their tumors assessed radiologically before and after treatment. Out of 30 evaluable pts, 8 were considered as good responders (30–80% decrease in tumor size), 18 had stable disease and 2 had minor progression. Expected toxicities were observed: rash (grade 2/3 in 11 pts), diarrhea (grade 2 in 1 pt). All pts underwent surgery. The incidence of post-operative complications was similar to our historical series. No mutations in the catalytic domain of EGFR TK were found. All tumors were positive for EGFR by IHC. Correlative statistical analyses between PK, toxicity and response data are ongoing and will be presented. Neither over expression of EGFR nor other IHC markers alone were found to be good predictive markers of efficacy. Retrospective analysis of morphological and IHC evaluation in some cell cycle regulators (mainly p21) appeared to be predictive of erlotinib efficacy (sensitivity 87.5%, specificity 88%). Conclusions: Neo-adjuvant treatment with erlotinib in SCCHN pts is well-tolerated. This trial demonstrated a useful prospective method to potentially aid patient selection to improve the design of post-operative adjuvant treatment combinations.

No significant financial relationships to disclose.
A randomized phase III multicenter trial of neoadjuvant docetaxel plus cisplatin and 5-fluorouracil (TPF) versus neoadjuvant PF in patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN). Final analysis of EORTC 24971
Authors: Remenar E. , Van Herpen C. , Germa Lluch J. , Stewart S. , Gorlia T. , Degardin M. , Bernier J. , Spirlet C. , Vermorken J. B.
Published: March 2020

5516

Background: So far, the Wayne State regimen combining 100 mg/m2 cisplatin on day 1 and 1000 mg/m2/d continuous infusion 5-fluorouracil over 5 days (PF), is the gold standard in advanced SCCHN. Improvement of PF induction chemotherapy by adding a taxane has been suggested from phase II studies and 2 randomized phase III trials. We now report the final analysis of EORTC 24971. Methods: Eligible were patients (pts) with unresectable stage III/IV SCCHN (no distant metastases), 18 to 70 yrs of age, PS≤1, and adequate hematologic, renal and hepatic function. Pts were stratified by primary disease site (oral cavity, oropharynx, hypopharynx, larynx) and treatment center and randomized to PF (as above) or TPF (T 75 mg/m2/1h, P 75 mg/m2/1h, both d1, F 750 mg/m2/d, d1–5) q 3 wks, for 4 cycles unless progression (PD) or unacceptable toxicity, or refusal. Thereafter (interval 4–7 wks), all pts not in PD received radiotherapy (RT: conventional [66–70 Gy], accelerated [max. 70 Gy] / hyperfractionated [max. 74 Gy]). Surgery was allowed before RT (neck) or 3 months after RT (primary, neck). Primary endpoint was progression-free survival (PFS), and 348 pts and 260 events were needed to detect a 50% increase in median PFS (10 vs 15 mo) with 85% power. Results: Between April 1999 and March 2002, 358 pts were accrued (181 PF, 177 TPF). At a median follow-up (FUP) of 32 mo, PFS was significantly improved with TPF (HR 0.72, p = 0.0071; median 8.2 vs 11.0 mo). A 51 mo median FUP showed an overall survival (OS) benefit with TPF (HR 0.71, p = 0.0052; median 14.2 vs 18.6 mo). Estimated 3-yr survival rates are 23.9% (95% CI: 17.9%;30.5%) for PF and 36.5% (29.3%;43.6%) for TPF. Response rate also favored TPF (53.6% vs 67.8%, p = 0.006). There was more severe (G3+4) leucopenia (41.6% vs 22.9%) and neutropenia (76.9% vs 52.5%) with TPF, and more severe thrombocytopenia with PF (17.9% vs 5.2%). Severe alopecia occured more with TPF (55.5% vs 11.7%); hearing loss (2.8% vs 0%) and toxic death (7.8% vs 3.7%) more with PF. Conclusions: TPF (→ RT) is superior to PF (→ RT) for PFS, OS (including long-term), response rate, and is better tolerated.

[Table: see text]
Sequential evaluation of reduced radiotherapy doses in a phase II trial of induction chemotherapy (IndCT) followed by concomitant chemoradiotherapy (CTX) for advanced head and neck cancer (HNC)
Authors: Vokes E. E. , Stenson K. M. , Kistner E. , Mittal B. , Cohen E. E. , List M. A. , Brockstein B. E. , Rosen F. R. , Witt M. , Haraf D. J.
Published: March 2020

5528

Background: CTX constitutes a standard for locoregionally advanced HNC. IndCT may decrease distant failure rates (Brockstein Ann Oncol, 2003). The combination of these approaches has resulted in favorable early survival outcomes. CTX is limited by acute mucositis and long-term functional impairment. We examined the feasibility of lowering radiotherapy doses in sequential groups of patients (pts) to maintain high antitumor activity while decreasing toxicities. Methods: This was a 3-part, nonrandomized, phase II trial. Pts with stage IV (M0) HNC received 8 weeks of IndCT with carboplatin and paclitaxel (groups A & B ); carboplatin, AUC 2, and paclitaxel 135 mg/m2 weekly x 6; group C carboplatin AUC 6 day 1, and paclitaxel 100 mg/m2 days 1, 8, and 15 with cycle 2 beginning day 28. All pts received alternating week CTX with paclitaxel, infusional fluorouracil, oral hydroxyurea, and twice daily radiotherapy (T-FHX) (Kies JCO 2001). Radiotherapy to gross disease, high risk, and low risk microscopic disease consisted of group A (n = 68): 75, 60, 45 Gy; group B (n = 64): 75, 54, 39 Gy; group C (n = 90): 72, 51, 36 Gy. We have previously reported outcome data on groups A & B (Vokes JCO 2002 & Haraf CCR 2003). Results: A total of 222 pts were treated between 11/1998 and 2/2001. 74% were male, median age was 57. Best overall response (groups A/B/C): CR: 83/93/68%. With median follow-up time of 64/53/39 months; 3-year overall survival is 72%/67%/67% (logrank p = 0.76), progression-free survival 72%/65%/59% (logrank p = 0.44), time to progression (TTP, in which deaths prior to progression are censored unless due to treatment-related toxicity) 82%/86%/67% (logrank p = 0.019), and local control92%/97%/86% (logrank p = 0.10). Acute toxicities during concurrent chemoradiotherapy included grade 3/4 mucositis 72/2%; 65/11%; 57/8%; and dermatitis 47/15%; 19/26%; 28/2%. Conclusions: This 3-stage study suggests that acute toxicity can be reduced and high overall survival rates maintained while reducing doses of radiotherapy. The lower 3 year TTP rate in cohort C suggests a dose-response curve in the CTX setting. Schedule B may represent the best therapeutic index. Functional outcomes data are presented separately.

[Table: see text]