bluuebunny/crossref_metadata_2025 huggingface dataset:
What do patients think about CA-125 monitoring in the follow-up? Results from a multicenter trial in 1,060 patients with ovarian cancer
Authors: Oskay-Oezcelik G. , du Bois A. , Fasching P. A. , Mahner S. , Liebrich C. , Glaβ A. , Schmidt-Wetze S. , Sepp L. , Münstedt K. , Lichtenegger W. , Sehouli J.
Published: August 2020

5522

Background: In the clinical day CA-125 monitoring is frequently used as a part of follow-up care for patients with ovarian cancer (OC). However, the potential benefit of CA-125 controls in the absence clinical symptoms are still unclear.There is little known about the expectations and preferences of patients with OC. Therefore we have initiated a multi-institutional survey. Methods: A semi-structered consisting 15 questions was developed in a pilot-study of 20 patients. After this validation all gynecological departments and gynecological-oncological practices were invited to participate in this trial using an anonynomous print version of the questionaire Results: Between December 2006 and December 2007 a total of 1,060 patients were enrolled. The median age of the patients was 58 years (range 16–87). 60% of the patients had primary ovarian cancer, 40% had relapsed ovarian cancer. Routine follow-up visits were mostly performed by gynaecologists in a gynaecological practice (56.9%) and in hospitals (49.5%). Patients were informed about the procedures and goals of cancer care predominantly after primary surgery (62.5%) and in 15.7% after last cycle of first-line chemotherapy. 7.7% declared that they were informed only at the first follow-up visit, 9.2% stated that they have never received any information about their cancer care management. According the patient´s opinion the main objective for the follow-up is the early detection of relapse and a prolongation of overall survival (95.8%). About more than 90% get CA-125 measurements. These were the procedures with highest anxiety but also the most important procedure for the patient. Finally, most patients (89%) were satisfied from their management of cancer care. Conclusions: The present study is the largest survey about cancer care so far and provides several important data for physician-patient communication concerning the follow-up management of patients OC.

No significant financial relationships to disclose.
Tissue levels of cisplatin in previously traumatized tissue without adhesion formation in a rabbit sidewall adhesion and intraperitoneal delivery model
Authors: Awtrey C. S. , Greenawalt K. E. , Colt J. M. , Corazzini R. L. , Philbrook M. , Santos M. R. , Bristow R. E.
Published: August 2020

5525

Background: It has been hypothesized that the presence of extensive adhesions after ovarian cancer resection may limit the distribution of intraperitoneal (IP) chemotherapeutics. The objective of this study was to determine if using a hyaluronate/carboxymethylcellulose (HA/CMC) barrier to prevent adhesions during a simulated tumor resection surgery would increase tissue drug levels following subsequent IP chemotherapy. Methods: A sidewall defect/cecal abrasion model was used to induce adhesion formation and simulate tumor resection trauma in 22 rabbits. Seven rabbits received HA/CMC at the end of the surgery. Four weeks after surgery, cisplatin (2.5mg/kg) was administered IP to HA/CMC treated and untreated animals or IV to untreated controls. Animals were sacrificed 24hrs after infusion and tissue samples were collected from inside the defect (with or without adhesions) and outside the defect on the contralateral sidewall. Samples were cryosectioned and analyzed for platinum content by ICP/MS. Results: Platinum tissue levels in the uppermost peritoneal layer (0–1mm) were significantly higher for IP delivery than IV and were the highest for IP delivery when no adhesions were present inside the defect. Platinum levels were significantly higher in the previously traumatized tissue inside the defect than in untraumatized tissue outside the defect. This was consistent for both IP or IV and HA/CMC treated or untreated animals. The benefit of HA/CMC was underscored by the fact that samples under adhesions could not be obtained for that group due to the significant reduction in adhesion formation compared to untreated controls. Conclusions: Recently traumatized tissue without adhesions had the highest platinum levels following IP cisplatin in this model. The previously traumatized tissue had significantly higher platinum levels than untraumatized tissue likely due to both increased peritoneal diffusion and systemic delivery components.

[Table: see text]

[Table: see text]
Randomized trial of intrapatient dose escalation of single agent carboplatin as first-line treatment for advanced ovarian cancer: An SGCTG study (SCOTROC 4)
Authors: Kaye S. B. , Vasey P. , Rustin G. , Pledge S. , Williams C. , Gabra H. , Skailes G. , Lamont A. , Lewsley L. , Paul J. ,   Scottish Gynaecological Cancer Trials Group
Published: August 2020

5537

Background: In the absence of toxicity, carboplatin (the most widely used drug in ovarian cancer) is generally given at the same (flat) dose with each treatment cycle. However, retrospective data suggest a correlation between extent of myelosuppression and outcome, as has been observed in other diseases. Our hypothesis was therefore that intrapatient dose escalation, according to nadir blood counts, could lead to an improved outcome compared to conventional flat dosing. Methods: Patients with previously untreated stage IC to IV ovarian cancer were randomized to receive 6 cycles of carboplatin AUC 6 q3 w either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2–6 based on nadir FBC (Arm B). The primary outcome measure was progression-free survival (PFS), and a target accrual of 1300 pts was envisaged, aimed at detecting a 20% increase in PFS with 80% power (5% 2-sided level of statistical significance). Results: From March 2004 to November 2008, 937 pts were recruited from 70 centres. Dose escalation occurred in 82% pts on Arm B. The median AUCs actually received were 6.0 (Arm A) and 6.84 (Arm B). As expected, more myelosuppression was seen in Arm B (p < 0.001 for all parameters). More grade 3/4 non-haematological toxicity was also seen in Arm B (31%, vs 22% in Arm A, p < 0.001) but there was no significant difference in global quality of life. To date, 477 PFS events have been observed out of a planned total of 950. The median PFS was 13.9m in Arm A, and 13.5m in Arm B, and the observed hazard ratio (Arm B/Arm A) is 1.04, with 95% C.I. of 0.87 to 1.24. This excludes the clinically relevant benefit of 0.83 used to design the study. A futility analysis also indicated that the probability of a statistically significant result in favour of Arm B at the planned study end was 0.12 at best. Conclusions: Following the Data Monitoring Committee recommendation, the trial has therefore been closed to recruitment, with no evidence of benefit for intra-patient dose escalation of carboplatin. A separate analysis of tissue samples, aimed at elucidating mechanisms of (single agent) carboplatin resistance is ongoing.

No significant financial relationships to disclose.
Persistance of circulating tumor cells (CTCs) in peripheral blood of breast cancer (BC) patients two years after primary diagnosis
Authors: Rack B. K. , Schindlbeck C. , Schneeweiss A. , Schrader I. , Lorenz R. , Beckmann M. , Pantel K. , Lichtenegger W. , Sommer H. , Janni W.
Published: August 2020

554

Background: In metastatic BC, CTCs have shown to predict treatment efficacy and reduced survival. Recent data also indicate a potential prognostic relevance of CTCs after adjuvant chemotherapy. The SUCCESS trial evaluates the role of persisting CTCs two years after diagnosis in primary BC patients treated with zoledronate. Methods: We analyzed 23 mL of peripheral blood in N+ and high-risk N- primary BC pts receiving 3xFEC(500/100/500)-3xDoc100 q3w vs. 3xFEC(500/100/500)-3xDocgemcitabine (75/1000 d1+8) chemotherapy followed by 2 yrs (4mg q3mx24m) vs. 5 yrs (4mg q3mx24m followed by q6mx36m) of zoledronate. CTC results after two years are shown. CTCs were assessed with the CellSearchSystem (Veridex, Warren, USA). After immunomagnetic enrichment with an anti-Epcam-antibody, cells were labelled with anti-cytokeratin (8,18,19) and anti-CD45 antibodies. Pts were examined after a mean of 29 months (range 20–43). Results: The data of 579 pts two years after diagnosis are available. 4.3% of pts (n = 25) presented with >1CTC in peripheral blood. In pts with the detection of CTCs, the mean number of cells was 1 (range 1–29). While we found 1 CTC in 5.9% and 2 CTCs in 1.6% of pts, 1.5% had 3–5 CTCs, 1.2% >5 CTCs. The presence of >1CTC did not correlate with tumor size (p = 0.41), nodal status (p = 0.41), grading (p = 0.45), hormonal status (p = 0.92) or HER-2-Status of the tumor (p = 0.59). In this patient group, 9.7% and 6.9% of pts had presented with >1CTC at primary diagnosis and after chemotherapy, respectively. While the presence of CTCs at diagnosis was associated with CTCs after two years (p = 0.03), there was no correlation of CTCs after chemotherapy with the results at primary diagnosis (p = 0.08) or at two years (p = 0.23). In 184 postmenopausal HR+ pts endocrine treatment data was analyzed. CTCs at two years were detected in 6.8% of pts on tamoxifen (n = 9), while 1.9% of pts were positive on anastrozole treatment (n = 1; p = 0.19). Conclusions: CTCs persisting cytostatic, endocrine and zoledronate treatment, can be observed in a relevant number of clinically recurrence-free BC patients. Longer follow-up within the German SUCCESS study will give further insight in their prognostic relevance and show whether they can be used for real time tumor phenotyping or serve as treatment target.

[Table: see text]
Adding the specific COX-2 inhibitor celecoxib to docetaxel plus carboplatin in first line for stage IC-IV epithelial ovarian cancer: A randomized phase II study
Authors: Reyners A. , Smit W. M. , Schaapveld M. S. , Hoekman K. , Erdkamp F. , Lalisang R. , Graaf H. , Wymenga M. A. , Polee M. , Willemse P. H.
Published: August 2020

5545

Background: Inhibition of COX-2 reduces the growth rate of tumors in vitro and COX-2 is over-expressed in ovarian cancer, so a COX-2 inhibitor might be beneficial. Methods: After debulking surgery patients (pts) with advanced epithelial ovarian cancer (FIGO IC-IV) received docetaxel 75 mg/m2 and carboplatin AUC=5 (CT) for 6–9 cycles q 3-wks and were randomized to celecoxib 400 mg BID (COX) for max three years or to control (CTR), stratified for residual tumor present in 58% vs 54%. Response rates and progression-free survival were based on CA-125 levels according to Rustin. Primary endpoints were biochemical CR (bCR)and safety, secondary progression free- (PFS) and overall survival (OS). Results: 183 of 201 pts enrolled were analyzed and baseline characteristics were well balanced between COX (n = 91) and control (CTR) arms (n = 93). Safety: Docetaxel and carboplatin was given full dose in 89% vs 84% pts and creatinine clearance remained stable vs baseline in both arms (96% vs 97% at Cycle 6). Toxicity grade 3–4 (COX vs CTR) was neutropenia in 26 vs 32, febrile neutropenia 12 vs 12, N/V 6 vs 5, allergy 7 vs 0 pts. Neurosensory grade 2–3 was less in COX (4 vs 13 pts, p< 0.05). Efficacy: Median duration of COX treatment was 6 months and 60% completed the combination with six or more cycles of CT. At a median follow-up of 20 months, CA-125 normalized (bCR) in COX 55/74 (74%) and CTR 49/74 (66%) pts with elevated baseline levels (n.s.). Median PFS was 17.4 vs 14.5 months (n.s.) and median survival 34.2 vs 34.7 months (n.s.). Conclusions: Celecoxib added to docetaxel/carboplatin in epithelial ovarian cancer had no effect on creatinine clearance, CA-125 response, PFS or OS. Celecoxib during CT was associated with allergic skin reactions but less neurotoxicity.

No significant financial relationships to disclose.
Plasma levels of estrone sulfate (ES) in postmenopausal women with breast cancer (BC) during letrozole (L) treatment: Association with single nucleotide polymorphisms (SNPs) of CYP19A1
Authors: Lunardi G. , Del Mastro L. , Serra M. , Driol P. , Boni C. , Cognetti F. , Ponzone R. , Porpiglia M. , Venturini M. , Pronzato P.
Published: August 2020

555

Background: The CYP19A1 gene encodes aromatase, a key enzyme for estrogen biosynthesis. We investigated the association between four CYP19A1 SNPs, affecting different circulating estrogen levels (rs10046 C>T, rs4646 G>T, rs749292 C>T, rs727479 T>G), and suppression of plasma ES levels induced by 6 weeks (time needed to reach L steady-state concentrations) of L (25 mg/d). Methods: Patients were enrolled into a prospective, italian multi-centre trial (GIM5) testing the correlation of CYP19A1 SNPs with the efficacy of L adjuvant therapy, after 5 years of tamoxifen, in postmenopausal early BC patients. Blood samples for hormone measurements were obtained immediately before starting L (baseline) and following 6 wks of treatment. SNPs were identified from DNA obtained from peripheral blood cells by Hexaprimer Amplification Refractory Mutation System PCR (H-ARMS-PCR). Plasma ES levels were evaluated by Radio Immuno Assay (RIA). Results: SNPs and hormone levels were evaluated in at least 129 patients. SNPs of CYP19A1 were associated with different baseline plasma ES levels. Mean inhibition of aromatase activity induced by L ranges from 71% to 79%, as a function of the SNPs. After 6 weeks of L no difference in ES levels was observed between patients with different SNPs (Table). Conclusions: L therapy induces a higher aromatase suppression in patients with SNPs associated with higher baseline plasma ES levels. The difference in ES levels associated with genetic variation at the CYP19A1 locus disappeared after L therapy.

[Table: see text]

[Table: see text]
Eribulin mesylate (halichondrin B Analog E7389) in platinum-resistant epithelial ovarian cancer (PR-EOC): A CTEP-sponsored phase II study
Authors: Hensley M. L. , Kravetz S. , Sima C. , Tew W. , Pereira L. , Sabbatini P. , Whalen C. , Aghajanian C. A. , Zarwan C. , Berlin S.
Published: August 2020

5561

Background: Eribulin mesylate is a tubulin inhibitor whose mechanism of action differs from that of other anti-tubulin agents, suppressing microtubule growth without affecting depolymerization, and sequestering tubulin into non-functional aggregates. In NIH:OVCAR-3 human EOC xenograft models, eribulin increased survival and reduced size and number of metastases, with activity superior to paclitaxel. We sought to determine the frequency of objective response to treatment with eribulin in patients (pts) with PR-EOC. Methods: Pts with PR-EOC, fallopian tube or peritoneal cancer (progression-free interval from last platinum-based therapy < 6 months), measurable disease, < 2 prior cytotoxic regimens, ECOG performance status 0–1, and adequate organ function were eligible. Treatment: eribulin 1.4 mg/m2 over 15 minutes IV days 1 and 8, every 21 days. Response assessed by CT for RECIST every other cycle. Results: 36 pts (median age 61, range 38–80; median platinum-free interval 3 months, range 0.1–5.9; all having received platinum-taxane first-line treatment) enrolled. 35 are evaluable for response (1 pt off-study for unrelated myocardial infarction in cycle 1). Two pts achieved partial responses (PR-5.7%), with response durations of 84 days and 128 days. Time to PR was 2.8 months in both. >50% decrease in CA125 for more than two measurements was observed in 3/31 CA125-evaluable pts. 16/35 (46%) had stable disease as best response. Median progression-free survival was 2 months (range 1–7 months). Per patient, at least possibly-related grade 3–4 toxicities were: neutropenia 44%, leucopenia 31%, anemia 3%, lymphopenia 3%, febrile neutropenia 3%, muscle weakness 3%, hypophosphatemia 3%, hypokalemia 6%, infection 6%, thrombosis 6%. Conclusions: Eribulin has minimal activity in PR-EOC with objective response observed in only 5.7% of pts. Time to objective response was nearly 3 months. Median PFS was 2 months. Activity of eribulin in platinum-sensitive patients is being studied in a separate phase II cohort.

[Table: see text]
Performance of a biomarker panel to identify malignancy within a pelvic mass population
Authors: Chen L. , Homesley H. D. , Scribner D. R. , Cantuaria G. H. , He Q. , Cheek R. L. , Whitehead C. M. , Doobay H. , Fischer T. J.
Published: August 2020

5566

Background: We previously reported the performance of biomarker combinations that displayed utility in identifying ovarian cancer from normal sera and in monitoring for disease recurrence. In this study, we evaluated the performance of a subset of these markers in differentiating ovarian cancer from benign pelvic mass. Methods: Pre-operative serum samples were prospectively collected from 254 patients undergoing surgical evaluation for differential diagnosis of a pelvic mass. Pathology showed 76 cases of epithelial ovarian carcinoma (EOC), 17 borderline tumors, 11 other gynecologic cancers, and 150 benign masses. 18 (23.7%) of the EOC patients had stage I tumors; 6 (7.9%) stage II; 44 (57.9%) stage III; and 8 (10.5%) stage IV. Serum levels of CA125, HE4, glycodelin, SLPI, MMP7, and Plau-R were ascertained. Biomarker performance was evaluated by a logistic regression model and leave one out cross-validation analysis. All calculations compared the benign vs. EOC and borderline tumor populations. Results: Individual biomarker sensitivity ranged from 28% to 77% at 85% specificity. The combination of CA125, HE4 and glycodelin exhibited the highest overall performance in identifying malignancy from benign masses, demonstrating 80% sensitivity, 80% specificity in patients <55 years, and 89% sensitivity, 80% specificity in patients ≥55. Total cohort performance was 85% sensitivity and 80% specificity. Glycodelin identified 7/22 CA125 and HE4 double negative patients, 5/7 of these patients were early stage (borderline, I or II), while only adding 4/150 false positive cases. Conclusions: Biomarker analysis within this test cohort demonstrates potential clinical utility in the differential diagnosis of pelvic mass patients, especially for the detection of early stage disease. The addition of glycodelin improved the detection of early stage cancer in sera that were negative for both HE4 and CA125.

[Table: see text]
Association between Mad1 G558A and ERCC1 C8092A polymorphisms and response to induction chemotherapy in advanced ovarian carcinoma
Authors: Figueroa P. , Castro Hernández C. , Santibáñez Andrade M. , Díaz Romero M. , Morales Vázquez F. , Gallardo Rincón D. , Herrera Montalvo L. A.
Published: August 2020

5568

Background: Platinum and taxane remain active drugs in the treatment of ovarian cancer.The polymorphism C8092A of ERCC1 is involved in NER pathway of platinum induced damage DNA and Mad1 G558A with modulation of the chromosomal segregation. As primary aim we evaluated the influence of these polymorphisms in the chemotherapy response. Methods: ERCC1 C8092A and Mad1 G558A polymorphism allelic and genotypic frequency was determined on DNA isolated from blood tumor samples by PCR and specific digestion in 56 patients with cancer of advanced ovary who received induction chemotherapy with 3 courses of paclitaxel 175 mg/m2 and AUC6 carboplatin every 3 weeks. Informed consent was obtained for all subjects and the study was approved by the hospital ethic committee. Results: Between January 2008 to June 2008, 56 women were evaluated, with age media was 53 years, majority characteristics were stages III (66.9%) 37 and IV (33.1%) 19 patients, histology serous papillary (94.6%) high-grade differenced (73.2%). Mad1 genotype were 7 G/G (12.5%), 30 were G/A (53.6%), 19 were A/A( 33.9%), and ERCC1 genotype were 20 C/C (35.7%), 30 were C/A (53.6%) and 6 were A/A (10.7%). All biochemical response by Rustin criteria was noted in 89.28%. Allele A for Mad1 is more frequently observed in patients with ovarian carcinoma versus in mexican healthy women (61% vs. 49%) and suggests the possibility that the polymorphism of Mad1 is a marker of risk for ovary cancer (RR = 1, 15, p < 0, 05). According our aim we observed a higher response in allele G (91.89%) than allele A (87.75%) of Mad1 (p < 0.10).Interestingly allele A of ERRC1 was not associated greater response (88.88% vs. 92%, p > 0.10). Additionally we evaluated the predictive value of Ca 125 return to normal range after 3 chemotherapy courses, showed in 22 patients (39.28%) in univariate analysis we noted that allele G of Mad1 has been linked to improved response (p = 0.041). Conclusions: This is the first study in ovary cancer that evaluates predictive value of two SNP, one of them involved in the spindle checkpoint and the other in DNA repair mechanism (NER), suggesting to Mad1 G558A likely risk polymorphism for ovary cancer and response to chemotherapy based on taxanes, which may be a predictive biomarker.

No significant financial relationships to disclose.
Paclitaxel, ifosfamide, and cisplatin regimen as neoadjuvant chemotherapy in young women with locally advanced squamous cervical cancer
Authors: Marinaccio M. , De Marino E. , Mele E. , Catacchio R. , Pellegrino C. , Pinto V. , Schonauer S.
Published: August 2020

5587

Background: Chemoradiotherapy is the standard treatment of advanced cervical cancer. Neoadjuvant chemotherapy (NAC) may represent an alternative for locally advanced cervical cancer (LACC).This study was undertaken to evaluate the efficacy of NAC in young patients with squamous LACC. Methods: Since 2000 to 2008, 61 pts (mean age 43 yrs) with squamous LACC were treated with NAC and afterwards evaluated for radical surgery. Eligibility included proven histologically diagnosis of squamous cervical carcinoma, FIGO stage IB2/IIA>4cm/IIB, measurable disease, ECOG PS 0–2, no prior therapy and age under 49 years. All patients received TIP regimen (cisplatin 50 mg/m2 i.v. day 1, paclitaxel 175 mg/m2 over 3 hrs i.v.day1, ifosfamide 5,000 mg/m2 plus mesna 6,000 mg/m2 over 24 hrs i.v. day 1–2). Each cycle was repeated every 21 days. Patients were evaluated 4–6 weeks after the completion of the third cycle with the purpose to perform radical surgery according to clinical response. Results: 35pts (57.4%) were stage IB2; 9 (14.7%) were IIA >4cm; and 17 (27.9%) were IIB. After restaging the clinical results were: CR = 4/61 (6.6%), PR = 51/61 (83.6%); no response = 5/61 (8.2%); progression = 1/61 (1.6%). A total of 55 pts (90.1%) were eligible for surgery; 6/61 pts (9.8%) were submitted to curative radiotherapy (until 2004) or chemoradiotherapy. Pathological responses after surgery were: 4 pCR (7.3%); 46 pPR (83.6%); and 5 (9.1%) pPR with presence of positive surgical margins or metastatic lymph nodes. Out of 55 pts, 50 received 2 cycles of TIP regimen as a consolidation therapy before follow-up; 5 pts with incomplete pPR underwent radio/chemoradiotherapy. After NAC an overall downstaging of LACC was obtained in 50/61 pts (82.0%). In this group of pts at the median follow-up of 42 months (range 4–98) updated as of December 2008, the 3-years progression-free survival and overall survival are 85.9% and 82.0%, respectively. Conclusions: Our results indicate that TIP regimen-based NAC is an attractive option in young women with squamous LACC (IB2,IIA >4cm, IIB) that strongly desire surgery.The rate of patients with a prolonged remission of disease (82.0%) suggests that the clinical benefit of TIP regimen-based NAC followed by surgery may be comparable to chemoradiotherapy.

No significant financial relationships to disclose.
A phase II study of aflibercept (VEGF trap) in recurrent or metastatic gynecologic soft-tissue sarcomas: A study of the Princess Margaret Hospital Phase II Consortium
Authors: Townsley C. , Hirte H. , Hoskins P. , Buckanovich R. , Mackay H. , Welch S. , Wang L. , Polintan R. , Chen A. , Oza A. M.
Published: August 2020

5591

Background: Targeting angiogenesis and vascular endothelial growth factor (VEGF) represents a promising approach to treat highly vascular tumors, like gynecologic sarcomas. Aflibercept, a long-acting inhibitor of VEGF signaling, potently binds and inactivates VEGF, thus blocking tumor angiogenesis and growth. Methods: This is a single-arm, open-label, two-stage phase II clinical trial designed to evaluate the efficacy and toxicity of aflibercept as treatment for patients (pts) with recurrent, or metastatic gynecologic soft tissue sarcoma. Aflibercept was administered at 4 mg/kg IV every 2 weeks and pts had radiologic imaging performed every 8 weeks. The primary endpoints were response rate and prolonged stable disease. Results: Twenty-five pts with leiomyosarcoma of the uterus and 13 pts with carcinosarcoma of the uterus were enrolled in 2 cohorts. In the leiomyosarcoma group, 24/25 pts had an ECOG of <1, most pts (22/25) had <1 previous lines of treatment and 7/25 pts had prior radiotherapy. A total of 149 cycles were administered for this group, with a median of 4 (range 2–28). In the carcinosarcoma group, 10/13 pts had an ECOG of <1, most pts (12/13) had <1 previous lines of treatment and 5/13 pts had prior radiotherapy. A total of 31 cycles were administered with a median of 3 (range 1–4). The most frequent adverse events experienced by all pts, of any grade, were fatigue 71% pts, constipation 53% and hypertension 39% . The most frequent grade 3 or higher, adverse events were hypertension 18%, fatigue 13% and lymphopenia 8%. Eight pts with leiomyosarcoma had stable disease (4pts > 6 mo). No reponses were seen in either cohort and no stable disease was seen in the carcinosarcoma group. Median overall survival was 15.1 mo (95% CI: 8.5 - not reached) for the leiomyosarcoma cohort and 3.1 mo for the carcinosarcoma cohort (95% CI: 1.9 - not reached). The requirements to proceed to stage 2, in leiomyosarcoma, were met after more than 2/21 patients had > 6 mo PFS. Carcinosarcoma cohort has not finished stage 1 and both cohorts continue accrual. Conclusions: VEGF-trap was well tolerated in this pt population with acceptable side effects. Initial efficacy data suggests modest activity, particularly in patients with leiomyosarcoma.

[Table: see text]
Evaluation of the protective effects of zoledronic acid on bone mass in premenopausal women undergoing adjuvant chemotherapy following treatment discontinuation
Authors: Hershman D. L. , McMahon D. , Crew K. D. , Shao T. , Cremers S. , Brafman L. , Awad D. , Shane E.
Published: August 2020

562

Background: Adjuvant chemotherapy is associated with a significant reduction in bone mineral density (BMD) in premenopausal women with breast cancer (BC). We previously showed that this loss of BMD can be prevented with zoledronic acid (ZA) every 3 months for a year. Since bone loss in women with osteoporosis is prevented with annual ZA, we examined whether protection from bone loss by ZA in women with BC persists following discontinuation of ZA. Methods: A randomized, double-blind, multicenter, phase III trial comparing ZA (4 mg every 3 months) versus placebo for 1 year in premenopausal women with BC undergoing adjuvant chemotherapy was conducted. Patients had serial BMD measurement at 0 (after surgery and before chemotherapy), 6, 12 and 24 months. Demographic, clinical, and tumor characteristics were collected. Serum was stored at -70°C and analyzed in batches. The secondary outcome of percent change in BMD at 24 months, one year following the last ZA/placebo, is presented. Intention-to-treat analyses with linear mixed models were performed using SAS version 9. Results: Of 101 patients randomized, 85 completed 12 month, and 62 completed 24 month evaluations; mean age 41 (SD 5.2). Demographic and baseline characteristics were similar between treatment groups. By 24 months, 38 (61%) had not regained their menses; 22 patients were on tamoxifen, 25 were on an aromatase inhibitor. Chemotherapy without ZA was associated with a significant decline from baseline in lumbar spine (LS) BMD after both 12 (-5.4%) and 24 (-6.3%) months. Similarly total hip (TH) and femoral neck (FN) BMD declined by 2.6% and 2.4% by 24 months, respectively. In contrast, BMD remained stable in ZA-treated patients (p < 0.0001 vs placebo). Patients who received ZA had stable BMD at 24 months (LS -0.58%, TH 0.83%, FN 0.04%). Analysis of bone turnover markers is ongoing. Conclusions: Premenopausal women receiving adjuvant chemotherapy for BC had significant bone loss in the first year that persisted in the second year. ZA every 3 months for a year effectively prevented bone loss during the first year and 1 year after completion of ZA treatment. One year of ZA maintains BMD in premenopausal BC patients for an additional year after discontinuation of ZA.

[Table: see text]
Randomized phase II study of neoadjuvant chemotherapy and trastuzumab for operable breast cancer with overexpression of HER2
Authors: Masuda N. , Ando M. , Aogi K. , Ino H. , Iwata H. , Tokuda Y. , Nakamura S. , Yamamoto N. , Fujiwara Y.
Published: August 2020

565

Background: Achievement of pathological complete response (pCR) by primary systemic therapy (PST) correlates with improved survival in operable breast cancer patients. Based on data of the higher pCR rate with concomitant chemotherapy and trastuzumab (H) reported by some clinical trials, we performed a multi-center, prospective randomized phase II study to evaluate the efficacy of adding H to standard chemotherapy and to determine more effective agent which will show higher pCR by the comparison between weekly paclitaxel (P) and tri-weekly docetaxel (D) in neo-adjuvant setting for HER-2+ pts. Methods: Generally, the concomitant combination with anthracycline and H is not recommended because of the increasing cardiac toxicity. PST regimen was scheduled as the sequential chemotherapy with 4 cycles of CEF (cyclophosphamide, epirubicin 100 mg/m2, 5FU) followed by 4 cycles of q3w H with qw P 80 mg/m2 (HP) or q3w D 75 mg/m2 (HD). The primary objective was designed to evaluate the pCR, defined as no evidence of residual invasive cancer in axilla and breast. The inclusion criteria was pts with Stage II or IIIA, HER-2 overexpression, under 65-yo, adequate cardiac function (EF>=60%) and a written informed consent. The sample size was estimated to detect the difference of pCR rate >=10% from 30% baseline, as at least 100 pts. The pathological response was evaluated by central review. Results: From March 2007 to June 2008, 102 pts were enrolled and randomized as well balance in the same number, median age (51yo), and the same distribution of clinical stage. 88 pts (86%) was successful on complete treatment course. Pre-matured data was available for 60 pts whom central review had been completed: there was no significantly difference in pCR rate between two groups, 53% (95%CI: 35.4–71.1%) on HP and 47% (28.8–64.5%) on HD. Out of 30 pts with pCR, 13 pts had component of DCIS. Serious adverse events were reported on 13 cases; mainly febrile neutropenia was experienced on 6 pts. One after the HP course had experienced the cardiac failure to fall in LVEF to 39%. Conclusions: In HER-2+ pts, PST with CEF followed by HP or HD might be equally active and achieving high pCR without significant toxicity. The final reviewed results will be established until May 2009, and presented at the ASCO meeting.

No significant financial relationships to disclose.
Gain study: A phase III trial to compare ETC versus EC-TX and ibandronate versus observation in patients with node-positive primary breast cancer
Authors: Möbus V. , Conrad B. , Schneeweis A. , Kreienberg R. , Solomayer E. F. , Clemens M. R. , Tesch H. , Loibl S. , Nekljudova V. , von Minckwitz G.
Published: August 2020

568

Background: Möbus et al. showed that dd epirubicin (E), paclitaxel (T), cyclophosphamide (C) results in a superior DFS compared to conventionally dosed EC-T in pts with primary breast cancer (PBC) and ≥3 involved lymph nodes (LN). In this study, the dd, dose intensified strategy has been further investigated as well as the use of ibandronate (I) adjuvant and ESF. Methods: A prospective, multi-center, controlled, non-blinded, randomized phase III trial investigating ETC (E: 150 mg/m2, T: 225 mg/m2, C: 2,000 mg/m2, i.v. day 1, q15 for 3 cycles each: A1; or EC→TX (E: 112.5 mg/m2 + C: 600 mg/m2, i.v. day 1 q 15 for 4 cycles → T: 67.5 mg/m2 i.v. day 1, q 8 for 10 weeks + X: 2000 mg/m2 p. o. day 1–14, q 22 for 4 cycles: A2). Pts were further randomized in a 2:1 ratio to receive I: 50 mg/day p.o. for 2 years (B1) or observation (B2). Pts received a primary prophylaxis with either epoetin β or darbepoetin α and during ETC/EC with pegfilgrastim. After recruitment of 1500 pts prophylactic ciprofloxacin was implemented. Eligible: Females ≥18 and <65 years, histologically confirmed LN positive uni- or bilateral PBC; adequate surgery, ≥1 pos. LN out of ≥ 10; no previous/concurrent therapy; ECOG ≤2; written informed consent. Primary objective: compare DFS A1 vs. A2 and B1 vs. B2. Secondary objectives: OS, safety, incidence of secondary primaries, and EFS in subgroups of hormone sensitivity and pos. LN between arms; assessment of compliance and responders to ESF; determine prognostic factors. 3,000 pts with 801 events are needed to show an increase of 5-year DFS from 75% to 79% for pts receiving EC→TX and 728 events to show an increase of 5-year DFS from 75% to 79.5% for pts receiving I, assuming a drop-out rate of 5%. A clinically relevant difference between the arms is to be detected at α = 0.05 (two-sided) with 80% power. Results: 3024 patients were recruited between June 2004 and August 2008. The trial was amended several times implementing an oral antibiotic prophylaxis, reducing the dose of C; reducing the dose of dexamethasone in the group receiving weekly T, and using an Hb adapted dosing of ESF. Conclusions: The therapy in the two regimen seems feasible if precautions are taken. Final safety data will be presented at the Meeting.

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Personalizing treatment in early-stage breast cancer: The role of standard clinical factors and genomic information in adjuvant chemotherapy decision making
Authors: Gold J. M. , Najita J. S. , Lester S. , Richardson A. L. , Morganstern D. E. , Chen W. Y. , Partridge A. H. , Krop I. E. , Winer E. P. , Burstein H. J.
Published: August 2020

572

Background: The Oncotype DX recurrence score (RS) independently predicts the likelihood of benefit from adjuvant chemotherapy. However, the clinical factors that influence chemotherapy recommendations in addition to RS are not well characterized. We sought to determine how clinicians integrate the RS and standard clinicopathologic data when choosing adjuvant chemotherapy. Methods: We identified women with ER+, HER2-, LN- breast cancer seen at DFCI in whom RS testing was performed between November 2004 and October 2008. Clinical and pathological characteristics, RS and chemotherapy treatment were identified from electronic medical records. A multivariable model was used to examine which factors drove the decision to administer chemotherapy. Results: RS was performed on 269 women with the following case distribution: RS low (<18) 50%, RS intermediate (18–30) 41%, RS high (>30) 9%. Chemotherapy was given to 7% of women with low RS, compared to 42% and 86% of women with intermediate and high RS, respectively. Tumor grade, T stage, progesterone receptor expression and RS were associated with receipt of chemotherapy in univariate analyses but age, LVI and menopausal status were not. In a multivariable logistic regression model, tumor grade, size, and RS were independent predictors of chemotherapy administration. Conclusions: Oncotype DX RS plays a critical role in medical decision making for women with early stage breast cancer at this single academic institution. However, other tumor and clinical features independently contribute to chemotherapy decisions, suggesting that tailored treatment does, and should, integrate both traditional and molecular pathological factors.

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No significant financial relationships to disclose.
Phase II trial of neoadjuvant sequential FEC100 followed by docetaxel and capecitabine for HER2-negative locally advanced breast cancer (LABC): A multicenter study from British Columbia
Authors: Chia S. K. , Lohrisch C. , Gelmon K. , Kennecke H. , Pansegrau G. , Taylor M. , Attwell A. , Jepson D. , Hayes M. , Shenkier T.
Published: August 2020

598

Background: Anthracyclines and taxanes are now standard of care for LABC. Phase III trials have demonstrated pathological complete responses of the breast (pCR) of 20–34% in studies of primary operable and LABC. Recent trials in the HER-2 negative population reported pCR rates of 20–29%.We have completed a multi-centre phase II trial of a neoadjuvant sequential anthracycline and taxane combination regimen in a HER-2 negative LABC population. Methods: Women with HER-2 negative stage IIB-IIIC breast cancer were enrolled. Treatment consisted of 4 cycles of FEC100 (5-FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2) followed by 4 cycles of XT (docetaxel 75 mg/m2 and capecitabine 1,000 mg/m2 PO BID x 14 days q3 weekly). Hormone receptor positive cases were prescribed standard endocrine therapy. A correlative translational component with baseline and interval biopsies and serum collection was also performed. Results: A total of 51 patients (27% stage IIB; 43% IIIA; 20% IIIB; and 10% IIIC) were accrued across 4 BCCA centres from November 2004-December 2007. Median age was 54 years (33–67 years). 59% of tumours were ER positive. There were no primary progressors on FEC100, though 2 patients had significant toxicities requiring early discontinuation. 3 patients (6%) developed clinical progression on XT. The majority of patients (79%) on XT required a dose reduction or delay. There were 5 episodes (10%) of febrile neutropenia. 15 patients (29%) underwent adjuvant radiotherapy prior to surgery. The pCR rate (breast and axilla) for the entire study population was 22% (11/51). In the ER+ and triple negative subtypes the pCR (breast and axilla) was 13% and 42%, respectively. Conclusions: This multi-centre phase II trial demonstrates activity for neoadjuvant anthracyclines followed by combination docetaxel/capecitabine in a HER-2 negative LABC population. Though the pCR rate was greater in the triple negative cohort, significant improvements are still required across the biological subtypes in HER-2 negative LABC.

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Biomarker potential of EGFR gene copy number by FISH in the phase III EXTREME study: Platinum-based CT plus cetuximab in first-line R/M SCCHN
Authors: Licitra L. , Rolland F. , Bokemeyer C. , Remenar E. , Kienzer H. , Stoerkel S. , Scheid S. , Stroh C. , Mesia R.
Published: August 2020

6005

Background: Platinum-based CT + cetuximab is the first systemic therapy in ∼30 years to show a survival benefit vs platinum-based CT in first-line R/M SCCHN (Vermorken JB, et al. N Engl J Med 2008;359:1116–1127). A retrospective analysis has evaluated the influence of EGFR gene copy number, determined by FISH, on clinical outcome in the EXTREME study. Methods: Pts were randomized to 3-weekly cycles of platinum-based CT (cisplatin 100 mg/m2 or carboplatin AUC 5, day 1; 5-fluorouracil 1000 mg/m2/day continuous infusion, days 1–4) with or without cetuximab (initial dose 400 mg/m2, then 250 mg/m2 weekly). The proportion of FISH+ cells per pt (FISH score) was determined using 5 different enrichment models. Tumors were also classified as FISH+ or FISH- using the Colorado scoring system. Results: In the overall population (n=442), addition of cetuximab significantly improved median OS (10.1 vs 7.4 months; p=0.04). No association between FISH score and OS, PFS, or best overall response was determined for any enrichment model. Pts with Colorado FISH+ tumors were evenly distributed between the CT + cetuximab (50/158) and CT-alone (51/154) arms of the FISH- evaluable population (71% of ITT population). Colorado FISH status had no influence on OS in either treatment arm, on PFS in the CT-alone arm, or on RR in the CT + cetuximab arm (see table ). In the CT + cetuximab arm, pts with FISH+ tumors had a lower risk of progression than pts with FISH- tumors. Higher RRs among pts with FISH- tumors in the CT-alone arm may have been due to twice as many nonevaluable response observations in the FISH+ vs the FISH- population (percentage of pts with SD or PD was comparable). Conclusions: EGFR gene copy number, as determined by FISH, is not a predictive biomarker for cetuximab efficacy in R/M SCCHN.

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Oral mucositis prevention by low-level laser therapy in head and neck cancer patients submitted to concurrent chemoradiation: A prospective randomized study
Authors: Castro G. , de Lima A. G. , Lopes D. R. , Ortegosa M. V. , Rosalmeida M. C. , Gil E. , Cavalcanti Leal A. I. , Federico M. H. , Villar R. C. , Snitcovsky I.
Published: August 2020

6019

Background: Oral mucositis is a major treatment-related complication of concurrent chemoradiation (CRT) in head and neck cancer (HNC) patients (pts), affecting nutrition, pain control, quality of life and adequate treatment delivery. Low level laser (LLL) is a promising preventive therapy. We aimed to evaluate the efficacy of LLL to decrease and delay severe oral mucositis and its impact on RT interruptions. Methods: In this prospective, randomized, double-blind, phase III trial, pts were treated with either daily He-Ne LLL 2.5 J/cm2, or placebo laser, before RT. Eligible pts had to be diagnosed with SCC or undifferentiated carcinoma of oral cavity, pharynx, larynx, or metastatic to the neck with unknown primary site (UPS); age > 18 y; candidates to adjuvant or definitive CRT; signed informed consent. CRT consisted of conventional RT 60–70 Gy (1.8–2.0 Gy/d, 5 times/wk) + concurrent cisplatin 100 mg/m2 every 3 wks. Main endpoints were oral mucositis severity in wks 2, 4 and 6 (CTC-NCI v.2.0); RT interruptions due to mucositis; pain intensity (VAS). To detect a decrease in the incidence of grade 3 or 4 oral mucositis from 80 to 50%, we planned to enroll 74 pts, error I/II 5 and 20%, respectively. Results: 73 pts were included (77% male; mean age 53 y); primary site: oropharynx (31 pts), larynx (15), nasopharynx (10), hypopharynx (8), oral cavity (7 pts), UPS (2); 36 pts received prophylactic LLL. Mean delivered RT dose (Gy) was higher in pts treated with LLL (69.3 vs. 67.8, p = 0.04). The number of treatment fields was the same (6 vs. 6, p = 0.50) and the mean cisplatin dose-intensity was 40.9 and 40.1 mg/m2/wk (p = 0.3) between pts treated with LLL or placebo, respectively. During CRT, the number of pts diagnosed with grade 3 or 4 oral mucositis treated with LLL/placebo was 4/5 (wk 2, p = 1.0); 4/11 (wk 4, p = 0.08); and 8/9 (wk 6, p = 1.0), respectively. More pts treated with placebo had RT interruptions due to mucositis (6 vs. 0, p =0.02). The occurrence of severe pain did not differ between the study arms in wks 2, 4 and 6 (5/5, 8/8 and 8/8, p = 1.0). Conclusions: LLL therapy was effective in reducing grade 3 or 4 oral mucositis and in reducing RT interruptions in these HNC pts treated with concurrent CRT, which may translate into improved CRT efficacy and tolerance.

No significant financial relationships to disclose.
Epstein-Barr virus (EBV)-specific immunotherapy in nasopharygneal carcinoma (NPC)
Authors: Wirth L. J. , Fogg M. , Wang F. , Lorch J. , Haddad R. I. , Posner M. R.
Published: August 2020

6025

Background: Immunotherapy for EBV-associated NPC is intriguing, as viral proteins serve as foreign tumor antigens for cytotoxic T cells (CTLs). EBV-specific CTLs are effective in PTLD, but translating this success to NPC is challenging. We conducted a feasibility study to establish the manufacture and administration of autologous EBV-specific CTLs and explore correlates of response. Methods: Eligibility criteria include incurable EBV+ NPC, ECOG PS ≤ 1, adequate end-organ function, and no chemotherapy within 2 weeks (wks). CTLs were generated using autologous EBV-transformed B cells to generate autologous EBV-specific CTLs. CTLs were administered in 2 infusions, 2 wks apart (2 X 107 and 1 X 108 cells/m2, respectively, for the 1st 3 patients, then 1 X 108 cells/m2 X 2 for remaining patients). Response was determined at 8 wks. Results: Ten patients were enrolled. CTLs were successfully generated in 9. Two patients came off study during CTL manufacture, due to decline in PS (n = 1) and tumor invasion into the brain (n = 1). One patient has a product available when clinically appropriate. There were no infusion-related events. Seven patients received CTLs. One had stable disease (SD) and remains progression-free at 64 wks, 4 had progressive disease and 2 await restaging. Five patients had EBV viral loads (VL) pre- and post-CTLs. VL remained undetectable in 1, decreased from 5300 to 1300 copies/ml in 1, increased from undetectable to 153 copies/ml in 1, and in 2 increased from 46,524 to 269,072 and 7,621 to 59,336 copies/ml, respectively. A CD3+/CD8+ phenotype predominated in the CTLs. LMP2- and EBNA-1 CTL specificity was evaluated by IFN-γ ELISPOTs. There were 2 responders to EBNA-1 (range: 100 to 150 sfc/106 cells), and 7 responders to LMP2 (range: 120 to 433 sfc/106 cells). Conclusions: EBV-specific CTLs can be generated from patients with NPC. CTLs are well-tolerated and may have some efficacy, as seen in 1 patient with SD. LMP2-specific CTLs were frequent, whereas EBNA-1-specificity was less common. While the sample size is small, the presence of LMP2 activity alone may not account for response. Factors critical to EBV-specific immunotherapy in NPC remain unclear. A phase II study to establish efficacy of this approach in less heavily pretreated NPC is underway.

No significant financial relationships to disclose.
Detection of Merkel cell polyomavirus in formalin-fixed, paraffin-embedded tissue of Merkel cell carcinoma and its correlation with prognosis
Authors: Andea A. A. , Patel R. , Ponnazhagan S. , Kumar S. , DeVilliers P. , Jhala D. , Eltoum I. , Manne U. , Siegal G.
Published: August 2020

6027

Background: Polyomaviruses are frequently associated with malignancies in their hosts. Recently, a novel polyoma virus, named Merkel cell polyomavirus (MCV) was identified integrated to the genome of 6 of 10 fresh frozen samples of MCC. These findings suggest an involvement of MCV in the pathogenesis of MCC. Because MCC is a rare tumor, the most readily available tissue is archival formalin-fixed, paraffin-embedded (FFPE) material. In this study we evaluated the presence of MCV in FFPE tissue and correlated its presence with tumor progression. Methods: Representative FFPE specimens from 18 tumors belonging to 14 patients with a diagnosis of MCC were retrieved. Following DNA extraction, we performed PCR using 4 different primer pairs amplifying sequences within the T antigen and VP1 gene of MCV. The identity of the PCR products was confirmed by direct sequencing. For clinical outcome analysis we used our MCC database containing 40 patients from 1997 to 2008 with a median follow-up interval of 20 months (range 1–108 months). Results: We detected MCV amplicons in 8 of 18 analyzed tumors (44.4%) from 7 of 14 cases (50%). PCR products from the T antigen portion of MCV were found in 6 of 18 tumors (33.3%) and from the VP1 gene in 2 of 18 tumors (11.1%). For 3 patients, MCV detection was performed in both the primary and metastatic tumors. In one of these the virus was found in both lesions while in the other 2 only the primary tumor demonstrated the virus. Two- and 5-year survival rates for the MCCs containing the virus were 47.6% and 0% respectively while for the rest of the cases in our database 2- and 5-year survival rates were 61.6% and 40.8% respectively; the difference did not reach however, statistical significance (p = 0.3). Conclusions: We identified MCV sequences in half of the cases analyzed demonstrating the feasibility of this technique in FFPE tissue. We also found that the tumors harboring MCV exhibit a trend for more aggressive behavior compared to the rest of MCCs. These findings suggest that MCV might have an etiologic role in carcinogenesis or tumor progression in MCC. Further studies investigating the biological significance of MCV integration in the human genome and the presence of MCV in other neuroendocrine tumors are warranted.

No significant financial relationships to disclose.