bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II evaluation of paclitaxel and carboplatin in the treatment of carcinosarcoma of the uterus: A Gynecologic Oncology Group (GOG) study
Authors: Powell M. A. , Filiaci V. L. , Rose P. G. , Mannel R. S. , Hanjani P. , DeGeest K. , Miller B. E. , Susumu N. , Ueland F. R.
Published: August 2020

5515

Background: Both platinum and taxane compounds have demonstrated activity in uterine carcinosarcoma (malignant mixed Mullerian tumor). Ifosfamide plus paclitaxel is the regimen supported by randomized phase III trials through the GOG. However, the toxicity, multi-day schedule, and limited activity of this regimen indicate that development of other regimens is still needed. The primary aims of this prospective study were to estimate the antitumor activity and toxicity of paclitaxel plus carboplatin in patients with uterine carcinosarcomas. Methods: Eligible patients had advanced stage (III or IV), persistent, or recurrent measurable disease with histologic confirmation of the primary tumor, no prior chemotherapy, and a GOG Performance Status of 2 or better. At entry hematologic and all other labs were within pre-defined limits. Patients received the combination of paclitaxel 175 mg/m2 IV over 3 hours plus carboplatin (AUC 6) IV over 30 minutes every 3 weeks until disease progression or adverse effects prohibit further therapy. The primary endpoint of confirmed response was assessed by RECIST criteria. CTCAE v3 was used to grade adverse events. This study used an optimal but flexible two-stage design with early stopping guidelines intended to limit patient accrual to inactive treatments. Forty to 47 eligible patients were targeted for accrual. Central pathology review (CPR) is still pending for 5 patients. Results: Fifty-five patients were entered on study with 9 being excluded from analysis; 7 with unconfirmed diagnosis at CPR and 2 were never treated. Treatment was generally tolerated with expected hematologic toxicity and minimal non-hematologic grade 4 toxicity (1 cardiovascular and 2 pain) with 59% of patients completing 6 or more cycles of chemotherapy. The proportion of patients with confirmed complete and partial responses were 11% and 41%, respectively (52%; 95% CI 37%-67%). Additionally 4% experienced an unconfirmed response and 26% had stable disease. Conclusions: Paclitaxel plus carboplatin demonstrates anti-tumor activity against uterine carcinosarcoma with acceptable toxicity and warrants further evaluation in phase III randomized trials.

No significant financial relationships to disclose.
Effect of treatment of patients with early-stage uterine carcinosarcoma
Authors: Cantrell L. A. , Havrilesky L. , O'Malley D. , Liotta M. , Secord A. A. , Nagel C. , Fader A. N. , Wallace A. , Rose P. , Gehrig P. A.
Published: August 2020

5516

Background: The treatment of early stage uterine carcinosarcoma is controversial. We sought to retrospectively review factors that influence progression and survival. Methods: A retrospective, multi-institution study of women diagnosed from 1997–2007 was performed. Postoperative treatment included either observation (OBS), RT (brachytherapy, whole pelvic, or combination), chemotherapy (CT) alone or with RT (CT+RT). Data collected included time to recurrence, overall survival, and sites of recurrence. Statistics included ANOVA and Kaplan Meier. Results: One hundred and forty-six patients were diagnosed with early stage (stages 1 and 2) uterine carcinocarcoma. The median age at diagnosis was 68 years (range:40–91). The majority (62%) were Caucasian, 49 (34%) were African-American and the remainder were other ethnicities. One hundred and seventeen had stage 1 disease and 29 had stage 2. The majority of patients (N = 54, 37 %) were observed, 36 (25%) were treated with CT, 31 (21%) were treated with RT and 17 (12%) were treated with CT + RT. The median progression free survival (PFS) for patients diagnosed with early stage disease was 16.7 months for the OBS cohort and 38.2 months for the CT cohort (p < 0.01). Median overall survival was 23 months for the OBS cohort and 39.3 months for the CT cohort (p = 0.02). The cohorts that underwent RT or CT+RT had improved median progression free (29.9, 20 months) and overall survival (31.7, 20.8 months) as compared to the OBS cohort, however this was not a statistically significant difference. Conclusions: We report on the largest experience in the literature on early stage uterine carcinosarcoma and the first to show that women with early stage disease may benefit from adjuvant chemotherapy. The role of radiation therapy or combination chemotherapy and radiation could not be adequately assessed from this retrospective analysis, but a trend toward improved survival was present. Prospective trials evaluating the best treatment for patients with early stage carcinosarcoma of the uterus should be undertaken to better answer this question.

No significant financial relationships to disclose.
Nomogram for predicting 5-year survival after primary surgery for epithelial ovarian cancer
Authors: Chi D. , Zivanovic O. , Kolev V. , Yu C. , Levine D. A. , Sonoda Y. , Abu-Rustum N. R. , Huh J. , Barakat R. R. , Kattan M. W.
Published: August 2020

5523

Background: Nomograms have been shown to be superior to traditional staging systems for predicting an individual's probability of long-term survival. Our objective was to develop a nomogram based on established prognostic factors to predict the probability of 5-year disease-specific survival (DSS) after primary surgery for patients with epithelial ovarian cancer (EOC) and to compare its predictive accuracy with the currently used FIGO staging system. Methods: We identified all pts with EOC who had their primary staging/cytoreductive surgery at our institution from January 1996-December 2004. DSS was estimated using the Kaplan-Meier method. We analyzed 28 clinical and pathologic factors for prognostic significance. Significant factors on univariate analysis were then included in the Cox proportional hazards regression model, which identified the factors to be used to construct the nomogram. The concordance index (CI) was used as an accuracy measure, with bootstrapping to correct for optimistic bias. Calibration plots were constructed. Results: There were 478 evaluable pts on the study. The median age was 58 years (range 25–96). The primary surgeon in all cases was an attending gynecologic oncologist. All patients received platinum-based systemic chemotherapy postop. DSS at 5 years was 52%. The most predictive nomogram was constructed using the following 7 predictor variables: age, ASA status, family history suggestive of hereditary breast/ovarian cancer syndrome, preoperative serum albumin level, FIGO stage, tumor histology, and residual disease status after primary surgery. This nomogram was internally validated using bootstrapping and shown to have excellent calibration with a bootstrap-corrected CI of 0.721. The CI for FIGO staging alone was significantly less at 0.62 (p = 0.002). Conclusions: We developed a nomogram to predict 5-year DSS after primary surgery for EOC. The nomogram uses 7 variables that are readily accessible, assigns a point value to each variable, and then predicts the probability of 5-year survival based on the total point value for an individual patient. This tool is more accurate than FIGO staging and should be useful for patient counseling, clinical trial eligibility determination, postop management, and follow-up.

No significant financial relationships to disclose.
Health-related quality of life/patient-reported outcomes in relapsed ovarian cancer: Results from a randomized phase III study of trabectedin with pegylated liposomal doxorubicin (PLD) versus PLD alone
Authors: Krasner C. N. , Poveda A. , Herzog T. , Vermorken J. , Monk B. , Zintl P. , Li J. , Su Y. , Dhawan R. , Kaye S.
Published: August 2020

5526

Background: In an open-label, multicenter, randomized phase III study comparing the combination of trabectedin and PLD to PLD alone in patients with relapsed ovarian cancer, the combination demonstrated significantly improved progression free survival and response rates, manageable non-cumulative toxicity, and fewer PLD-associated adverse events. We studied the impact of the combination of trabectedin with PLD on the quality of life (QoL)/patient-reported outcomes (PRO) evaluated as part of the trial. Methods: QoL/PRO questionnaires, EORTC-QLQ C30, OV28, and EQ-5D were completed by patients at screening and on Day 1 of every other treatment cycle starting with Cycle 1, and at the end-of-treatment visit. Global health status/QoL, fatigue, rain subscales from QLQ C30, and abdominal pain/GI symptoms scale from OV28 were chosen a priori for primary analyses. Other scales of the three questionnaires were analyzed on a supportive basis. Results: A total of 672 patients were randomized. 663 (98%) completed at least the baseline questionnaires. Median cycles of treatment was 6 (131 days) for the combination arm and 5 (143 days) for the monotherapy arm. Mixed effects models (using a covariance structure of AR[1]) predicting the score at baseline and follow-up scores as a function of treatment, days after baseline, and interaction between treatment and days after baseline showed no significant differences between the treatment arms for any of the prespecified scales. Similar analyses of other scales, including EQ-5D Health Index scores and Health State on the Visual Analog Scale, support the findings. Conclusions: The addition of trabectedin to PLD results in superior efficacy in patients with relapsed ovarian cancer, with no added decrement to overall health status as assessed by PRO.

[Table: see text]
Results from a phase II study to assess the efficacy and tolerability of fulvestrant 250 mg/month as treatment of recurrent or metastatic endometrial carcinoma
Authors: Emons G. , Guenthert A. , Thiel F. , Camara O. , Strauss H. , Breitbach G. , Koelbl H. , Reimer T. , Finas D. , Rensing K.
Published: August 2020

5532

Background: Fulvestrant (F) is a pure anti-estrogen with no agonistic action and no known adverse effects on the endometrium. This may be an advantage over tamoxifen, which has been successfully used in the treatment of hormone-receptor (HR) positive recurrent or metastatic endometrial carcinoma. Methods: This was an open label single-arm multicentre phase II study (AGO-Uterus 5) in patients with recurrent or metastatic endometrial carcinoma and measurable disease (RECIST). Pts. received monthly 250 mg F i.m. injections. The primary objective was clinical response after 3 injections, measured 4 weeks after injection 3 (ITT-pop.). Safety and tolerability were secondary endpoints. Results: Between March 2003 and May 2006, 35 pts. were included. Mean age was 70 years (range 45–83), first diagnosis was a mean 2.6 years ago, diagnosis of recurrence 10.2 months ago. 25 pts. (73.5%) had a FIGO 4B; 24 pts. (71%) had endometrioid cancer, 5 (15%) serous and 5 other carcinoma. All pts. had a positive ER and/or PgR status. 1 pt. had received no surgery for her disease; 21 pts. (61.8%) had prior radiotherapy; 13 pts. (38.2%) chemotherapy. 26 pts. were assessed as planned (ITT); 5 pts. received fewer than 3 injections, 4 pts. were not seen 4 weeks after inj. 3. Response to F was PR in 5 pts. (19.2%) and SD in 8 pts. (30.8%), adding up to a 50% disease control rate. 13 pts. had PD. Tolerability was good, no previously unknown side effects occurred. Conclusions: F showed encouraging response rates in our patient collective and was well tolerated. Further studies are warranted with F in HR pos. endometrial carcinoma. This study was supported by AstraZeneca. F is licensed for treatment of ER+, advanced breast cancer after an antioestrogen in postmenopausal women.

[Table: see text]
Microsatellite instability and loss of PTEN expression in early versus late-stage endometrial cancer: Results from studies of the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG)
Authors: Mackay H. , Gallinger S. , Tsao M. , McLachlin C. M. , Kieser K. , Eisenhauer E. , Tu D. , Oza A.
Published: August 2020

5534

Background: Microsatellite instability (MSI+) and inactivation of the tumor suppressor gene PTEN are implicated in the development of endometrial cancer (EC). The aim of this study was to compare the prognostic value of MSI and PTEN in 2 patient (pt) populations, early stage vs. advanced/recurrent disease. Methods: Archival paraffin embedded tumor from pts with EC enrolled in closed NCIC-CTG studies: stage I/II (EN5) and advanced/recurrent disease(IND 126, 148 and 160) were examined for MSI (BAT 25/26) and for PTEN expression (immunohistochemistry). PTEN and MSI status were correlated with clinicopathologic features and outcome from NCIC-CTG trial databases. Results: 188 pt samples (97 stage I/II;91 advanced/recurrent disease) were examined. Results are available for PTEN in 129 pts and MSI in 166 pts. Overall, 55% were PTEN negative (-) and 19.3% MSI+. 33 (56.9%) pts were PTEN - in EN5 vs. 38 pts (53.5%) IND studies (p = 0.73). Overall, no association was seen between PTEN or MSI status and age, performance status (PS), tumor grade or histology. In univariate analysis, there was a trend towards improved survival (S) in pts with PTEN - EC (HR = 0.61; 95% CI, 0.36 -1.04, p = 0.07), weaker in multivariate analysis (HR = 0.56; 95% CI, 0.26–1.18 p = 0.12). In EN5, PTEN status was not associated with S in uni-or multivariate analyses. In the IND studies there was a trend towards improved S in univariate analysis (HR = 0.57; 95% CI, 0.32–1.06 p = 0.07). More pts were MSI+ in EN5, 23 (27.4%) vs. IND studies, 9 (11%) p = 0.01. In EN5, microsatellite stable (MSS) tumors were associated with a better prognosis in both univariate (HR = 0.18; 95% CI, 0.06–0.51, p < 0.0001) and multivariate analysis (HR = 0.16; 95% CI, 0.05 to 0.5, p < 0.0001). There was no difference in S between pts with MSS vs. MSI+ tumors overall, or in the IND studies. in uni- or multivariate analyses. There was no correlation between MSI and PTEN status overall or in either group of pts. Conclusions: MSI+ tumors are more common, and are associated with a worse prognosis, in early stage EC. There is a trend towards improved S for pts with PTEN- advanced EC. There is no association between PTEN and MSI status.

No significant financial relationships to disclose.
A phase II study of intravenous (IV) and intraperitoneal (IP) paclitaxel, IP cisplatin, and IV bevacizumab as first-line chemotherapy for optimal stage II or III ovarian, primary peritoneal, and fallopian tube cancer
Authors: Konner J. A. , Grabon D. , Pezzulli S. , Iasonos A. , Sabbatini P. , Hensley M. , Bell-McGuinn K. , Tew W. , Spriggs D. , Aghajanian C.
Published: August 2020

5539

Background: IP cisplatin (Cis) plus IV/IP paclitaxel (Tax) is a standard therapy for optimally debulked ovarian cancer. Bevacizumab (Bev) is a recombinant humanized IgG1 monoclonal antibody directed against vascular endothelial growth factor. Activity of Bev in recurrent ovarian cancer has been reported in phase II trials. In this study IP Cis and IV/IP Tax are combined with IV Bev as front-line therapy. Methods: Patients with optimal (<1 cm residual), FIGO stage II or III, epithelial ovarian, fallopian tube, or peritoneal cancer, acceptable organ function, and KPS ≥ 70% are eligible. Patients receive 6 cycles of chemotherapy plus Bev: Tax 135 mg/m2 IV over 3 hours on Day 1, Cis 75 mg/m2 IP on Day 2, Tax 60 mg/m2 IP on Day 8, Bev 15 mg/kg IV on Day 1 (starting cycle 2). Bev is continued every 3 weeks for 17 treatments after chemotherapy is complete. This study will enroll 41 patients. The primary endpoint is safety and tolerability, determined by whether at least 60% of patients complete the prescribed 6 cycles of cytotoxic chemotherapy without unacceptable toxicity. Results: Thirty-nine women [median age 56 (40–69)] have been treated on study: 26 (67%) completed 6 IV/IP cycles; 5 (13%) are receiving ongoing IV/IP treatment; 4 (10%) experienced IP port malfunction (3 finished 5 IV/IP cycles, 1 came off study for port revision); 3 (8%) switched from IP Cis to IV carboplatin due to grade 3 nephrotoxicity in cycle 1 (n = 2) or grade 3 hypertension in cycle 6 (n = 1); and 1 (2.5%) patient died following rectosigmoid anastomotic dehiscence during cycle 4. Grade 3/4 treatment-related toxicities include hypertension (10%), vasovagal events (10%), neutropenia (26%), nausea/vomiting (10%), and hypomagnesemia (8%). There were 3 occurrences of grade 3 abdominal pain (8%); and 3 adhesion-related grade 3 small bowel obstructions (8%), during cycles 3, 9, and 15, respectively. Conclusions: The addition of Bev to this IV/IP regimen appears to be feasible. Bev may increase the risk of small bowel obstruction/perforation in these patients. Enrollment continues and updated results will be presented.

[Table: see text]
Effects of weekly bevacizumab and pegylated liposomal doxorubicin in heavily pretreated patients with recurrent or progressed ovarian cancer
Authors: Kikuchi Y. , Kouta H. , Kikuchi R. , Takano M. , Kita T. , Kudoh K. , Aoki D. , Sugiyama T. , Isonishi S.
Published: August 2020

5547

Background: Vascular endothelial growth factor (VEGF) plays a central role in tumor angiogenesis and is regarded a promising therapeutic target. Bevacizumab (A) has significant antitumor activity in combination with cytotoxic agents. Currently, pegylated liposomal doxorubicin (D) is provided as one of the standard treatment options in recurrent ovarian cancer. Thus, we attempted to determine effects in combination of A and D for heavily pretreated patients with recurrent or progressed ovarian cancer. Methods: Twenty-two patients with heavily pretreated (more than one regimen or more than 6 cycles by paclitaxerl and carboplatin) received at least more than 3 cycles of weekly A-D consisting of A: 2 mg/kg and D: 10 mg/m2 (3 weeks, one week rest). The primary endpoint was response according to CA 125 and response evaluation criteria in solid tumor (RECIST) criteria. Results: Of 22 patients evaluable for CA 125 response, 7 (32%) had a response (decrease of >50%), and 8 (36%) patients had not progressed (doubling of CA 125) following 6 months on treatment. In RECIST evaluation, 2 (9%) patients had complete remission (CR) and 6 (27%) had partial remission (PR), resulting in 55% clinical benefit rate (CBR). Progression free interval (PFI) showed more than 6 months. Any hematological adverse effect was not observed in the present study. Gastrointestinal perforation was observed in only one case and was conservatively treated. Although nasal bleeding was frequently observed, no treatment was required. A induced hypertension was also observed and manageable. Hand-foot syndrome seemed due to D was seen in 3 of 22 patients and treatment was required in only one case. Conclusions: B seemed to enhance effect of D. This is the first study of weekly A-D in heavily pretreated ovarian cancer patients. Weekly A-D warrants further clinical study in such clinical settings.

No significant financial relationships to disclose.
Correlation of CA-125 and RECIST evaluation in recurrent ovarian cancer (ROC): Results from a randomized phase III study of trabectedin (T) with pegylated liposomal doxorubicin (PLD) versus PLD alone
Authors: Herzog T. J. , Vermorken J. B. , Pujade-Lauraine E. , Li J. , Bayever E. , Gomez J. , Yovine A. , Monk B. J.
Published: August 2020

5550

Background: OVA-301, an open-label, multicenter, randomized phase III study comparing the combination of T and PLD to PLD alone in 672 ovarian cancer patients, showed significant prolongation in Progression-Free Survival (PFS) and higher Objective Response (OR) in the combination arm (T-PLD) by three separate assessments, investigator assessment (IA), independent radiology (IR) and oncology review (IO). The purpose of this analysis is to examine: 1) the impact of early changes in CA-125 over the subsequent best OR by RECIST; 2) the concordance between best OR determined by CA-125 and RECIST; 3) the value of CA-125 to predict radiological response. Methods: Tumor assessments by imaging and CA-125 were performed at baseline, and every 8 weeks during study in both arms. Radiological tumor assessment, regardless of CA-125 changes, determined the study conduct. Early CA-125 changes were those assessed at the first and second evaluation. Analyses were based on “all randomized patients.” Results: Response rate by RECIST (IR)/CA-125 was 28%/48% for T-PLD vs. 19%/33% for PLD. The association between CA-125 and RECIST response was stronger for IA relative to IR/IO, with 79% concordance for both arms, 65% overall positive predictive value (PPV) and 89% negative predictive value (NPV) for IA and 74%/75% concordance, 46%/49% PPV and 93%/92% NPV for IR/IO. Early CA-125 changes were assessed in 514 patients. Early ≥25% CA-125 decreases in the first/second evaluation occurred in 85%/95% of RECIST responders in the T-PLD arm and in 81/82% responders treated with PLD. Conclusions: The predictive value of CA-125 response was high and similar in both arms. The addition of T to PLD resulted in superior efficacy in this patient population as assessed by IA, IR and IO, with a favorable trend for CA-125 response assessment. RECIST response was preceded by a significant CA-125 decrease in a high proportion of patients.

[Table: see text]
Circulating tumor cells (CTC) in a study of relapsed/recurrent advanced ovarian cancer: An exploratory analysis in the ova-301 phase III study of pegylated liposomal doxorubicin (PLD) compared with trabectedin and PLD
Authors: Poveda A. , Kaye S. B. , McCormack R. T. , Wang S. , Ricci D. , Broderick E. , Parekh T. , Lebedinsky C. , Tecero J. C. , Monk B. J.
Published: August 2020

5551

Background: Circulating tumor cells (CTC) have demonstrated predictive and prognostic value among patients with metastatic breast, colorectal, and prostate cancer. In a phase III study of pegylated liposomal doxorubicin (PLD) with trabectedin (T) vs PLD for relapsed ovarian cancer, we assessed the affect of CTCs on progression free survival, (PFS) and overall survival (OS). Methods: CTCs were isolated from peripheral blood (10 mLs) using the CellSearch system and reagents (Veridex). A CTC is defined as EpCAM+, cytokeratin+, CD45-, and is positive for the nuclear stain DAPI. The normal reference range for CellSearch is < 2 CTC/7.5 mLs of blood. Hazard ratios adjusted for known prognostic factors were estimated by Cox regression. Results: 216 subjects had baseline CTC measurements of which 111 (51.4%) were randomized to the PLD+T arm; 143/216 patients (66.2%) were platinum sensitive. Thirty-one/216 patients (14.4%) had 2 or more CTCs detected prior to the start of therapy (range 2–566). Univariate Cox regression analyses indicated that patient's > 2 CTCs prior to therapy have 1.89 (p = 0.003) and 2.06 (p = 0.003) fold higher risk for progression and death respectively. Multivariate analyses that include baseline CTC, baseline CA125, platinum sensitivity status, largest diameter lesion, number of tumor lesions, ECOG PS, age, tumor histology, tumor grade and prior taxane show that patients with elevated baseline CTC have 1.58 (p = 0.058) and 1.54 (p = 0.096) fold higher risk for progression and death respectively. Conclusions: Results from this study indicate that although CTC detection in blood from relapsed recurrent ovarian cancer patients is relatively low, elevated numbers of CTCs imparts an unfavorable prognosis for patients. Multivariate analysis indicates that CTCs have prognostic value that is independent of established factors and thus provides a clinically useful tool for assessing prognosis in this difficult to treat patient population.

[Table: see text]
Prediction of nutritional status and intestinal tumor involvement in patients with primary or recurrent ovarian cancer: Results of a prospective study
Authors: Kuhberg M. , Skowronek P. , Chen F. , Oskay-Oezcelik G. , Oskay-Oezcelik G. , Lichtenegger W. , Lichtenegger W. , Sehouli J.
Published: August 2020

5570

Background: Global malnutrition is widespread among patients with ovarian cancer. The objective of this study was to investigate the influence of the nutritional status on the clinical outcome of patients with primary or recurrent ovarian and peritoneal cancer. Methods: In a two-year-period (January 2007 - December 2008) 152 consecutive patients were analysed. 79 (52%) of them had primary and 73 (48%) recurrent disease. At the time of admission for surgical therapy, the body composition was analysed with Bioelectrical Impedance Analysis (BIA) using phase angle alpha and ratio of extra-cellular mass and body cell mass (ECM/BCM). Serum protein parameters were registered. The risk of malnutrition was estimated by Nutritional Risk Score (NRS). During operation a standardised and validated tumor documentation tool (IMO) was performed. Nutritional parameters were correlated with IMO-parameters. Results: The median age of patients was 56 years (range 48–66) with median BMI 24.4 kg/m2 (range 21.8–27.3). In 23% primary and 14% recurrent cases a high nutritional risk was classified (NRS≥3). These patients had significantly lower serum albumin, pre-albumin and transferrin levels compared to patients with NRS<3 (p < 0.05). FIGO stage and NRS correlated negatively with phase angle alpha and positively with ECM/BCM in patients with primary diagnosis (p < 0.05). Patients with primary or recurrent disease who required surgical resection of small or large intestine, phase angle alpha and serum albumin level were significantly lower than in patients with no intestinal involvement (p < 0.05). Conclusions: Independent of tumor stage, the preoperative evaluation of BIA, especially phase angle α, is a valid method to predict surgical outcome in patients with ovarian and peritoneal cancer.

No significant financial relationships to disclose.
Validation of a novel staging system for breast cancer patients treated with neoadjuvant chemotherapy
Authors: Mittendorf E. A. , Tucker S. L. , Jeruss J. S. , Gonzalez-Angulo A. M. , Buchholz T. A. , Sahin A. A. , Cormier J. N. , Buzdar A. U. , Hortobagyi G. N. , Hunt K. K.
Published: August 2020

558

Background: We previously described a novel staging system to assess patient prognosis after neoadjuvant chemotherapy based on pretreatment clinical stage (CS), post-treatment pathologic stage (PS), estrogen receptor (E) status and grade (G). This CPS+EG staging system was determined by points assigned for each variable and allowed for better determination of breast cancer specific survival than either CS or PS alone. The current study was undertaken to validate this staging system in a more contemporary cohort of patients. Methods: A prospectively collected database of patients treated with neoadjuvant chemotherapy from 2003 to 2005 identified 804 eligible patients for analysis. Because determination of the CPS+EG staging system predated the use of neoadjuvant trastuzumab therapy, patients receiving neoadjuvant trastuzumab were excluded from the validation cohort. Clinicopathologic characteristics, treatment regimens and patient outcomes were assessed. Patient outcomes were stratified according to their CPS+EG score. Results: Median follow-up time was 3.4 years (range 0.3–5.9 years). The 5-year disease specific survival (DSS) rate for the entire cohort was 77% (95% CI: 72–82). The table summarizes 5-year DSS rates for each CPS+EG score. The pattern of prediction determined in the initial cohort was again seen in the validation cohort. Application of the staging system facilitated separation of patients into more refined subgroups by outcome than the current AJCC staging system applied to either presenting clinical stage or final pathologic stage. Conclusions: This study validates our previously published CPS+EG staging system. We suggest that the AJCC staging system should be revised to incorporate biologic markers and response to treatment for patients receiving neoadjuvant chemotherapy. As targeted agents are being increasingly employed in treatment regimens, future work will focus on further refinement of the staging system with additional biologic markers.

[Table: see text]

No significant financial relationships to disclose.
Factors associated with regression of cervical dysplasia in adolescents: A retrospective study
Authors: Chen C. , Campbell F. , Patruno J. , Kimmel S. , Boulay R. , Meyers C. , Martino M.
Published: August 2020

5582

Background: Sexually active adolescents have high rates of infection with human papilloma virus (HPV) and abnormal pap smears. They are considered a special population as they are likely to regress to normal cytology. The aim of our study was to identify factors associated with regression of cervical dysplasia in adolescents. Methods: We identified adolescent patients (aged 12–21 years) who had abnormal pap smears at the Center for Women's Medicine at Lehigh Valley Hospital in Allentown, PA, by CPT code from a database between Jan 2004 and Dec 2006. A chart review was performed to capture demographic data, cytology, smoking history, number of sexual partners, parity, race, contraceptive choice, use of barrier contraception. Chi-square analysis with logistic regression and multivariate analysis were used to identify factors associated with regression of cervical dysplasia. Results: Two-hundred two patients were identified. Mean age was 18.84 years (14–22 years). One hundred twenty-two (57.8%) were Hispanic, 71 (33.6%) Caucasian, and 16 (7.6%) Black. Fifty-two (24.6%) were pregnant at the time of diagnosis. Seventy-six (36%) were smokers. There were 125 (61.9%) cases of ASCUS, 33.7% (68 cases) LGSIL and 4.5% (9 cases) HGSIL on initial pap smear. One hundred eighteen (55.9%) patients had colposcopy, and of these, 32 (15.2%) had surgical intervention. Follow-up demonstrated that 72 (57.6%) patients had disease regression, 24 (19.2%) persistence and 29 (23.2%) progression. On multivariate analysis, patients who did not smoke were significantly more likely to show regression of cervical dysplasia on pap smear than women who smoked (OR 2.17, 95% CI 1.03–4.55, p = 0.039). Other factors were not statistically significant in predicting regression of cervical dysplasia. Conclusions: Adolescents who smoke were more likely to have persistent cervical dysplasia than non-smoking adolescents, putting smokers at an increased risk of advanced disease. We suggest that this subset have follow-up at shorter intervals and be enrolled in a smoking cessation program.

No significant financial relationships to disclose.
Evaluation of tumor-infiltrating lymphocytes (TIL) and tumor cell apoptosis as predictive markers for response to neoadjuvant chemotherapy in triple-negative breast cancer
Authors: Ono M. , Tsuda H. , Shimizu C. , Yamamoto S. , Shibata T. , Kouno T. , Tamura K. , Ando M. , Katsumata N. , KInoshita T. , Fujiwara Y.
Published: August 2020

559

Background: Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PgR) and HER-2. Pathological complete response (pCR) of TNBC to neoadjuvant chemotherapy (NAC) is correlated with excellent clinical outcome. We examined the value of histological parameters including tumor-infiltrating lymphocytes (TIL) and tumor cell apoptosis as surrogate markers for pCR in TNBC. Methods: Of 474 patients who received NAC and subsequent surgical therapy to stage II-III invasive breast carcinoma between 1999 and 2007, 102 (22%) had TNBC, and 92 core needle biopsy (CNB) specimens before NAC were available. We first immunohistochemically confirmed TNBC and basal-like subtype by current criteria for ER, PgR, and HER-2, cytokeratin (CK) 5/6, CK14, EGFR, and p53. All cases were TNBC, and 54 tumors (59%) were basal-like subtype defined as expression of at least one of CK5/6, CK14 and EGFR in >1% of cancer cells. Totally, 26 tumors (28%) showed pCR. Thirteen histopathological parameters were examined, and their correlation with pCR rate was tested. These parameters were also examined in resected tumor specimens from 21 non-pCR cases. Results: The pCR rate was significantly higher in the patients with tumors with TIL (24 of 68, 35%) than in those without (2 of 24, 8%, p = 0.01), and higher in tumors with high-score apoptosis (9 of 19, 47%) than in those with low-score apoptosis (17 of 73, 23%, p = 0.04). Tumors showing medullary features and p53-negative tended to show pCR more frequently (38% and 35%) than those with non-medullary features and with p53-positive (25% and 24%), but the differences were not significant. Of 21 non-pCR cases, TIL was consistently negative before and after NAC in 8, but TIL emerged after NAC in 13. The pCR rate did not differ significantly between the basal-like type (31%) and non-basal-like type (24%). Conclusions: TIL and the level of tumor cell apoptosis appeared predictive markers for response to NAC in TNBC. Patients’ host factors correlated with immune response appears play a substantial role in the response to NAC in TNBC.

No significant financial relationships to disclose.
Postoperative morbidity after completion surgery in patients undergoing chemoradiotherapy for locally advanced cervical carcinoma
Authors: Touboul C. , Uzan C. , Gouy S. , Rey A. , Maugen A. , Delpech Y. , Chanelles O. , Pautier P. , Lhomme C. , Duvillard P. , Haie-Meder C. , Morice P.
Published: August 2020

5595

Background: The aim of this study was to evaluate the morbidity rate in patients undergoing completion surgery after homogeneous chemoradiation therapy (CRT) for locally advanced stage cervical cancer. Methods: Patients fulfilling following inclusion criteria were studied: 1. Stage IB2-IVA cervical carcinoma; 2. Tumor confined radiologically initially to the pelvic cavity; 3. Pelvic external radiation therapy with delivery of 45 Gy in pelvic cavity with concomitant chemotherapy (cisplatin 40 mg/m2/week) followed by utero-vaginal brachytherapy; 4. Completion surgery after the end of radiation therapy including at least a hysterectomy. Modalities of this completion surgery depended on the presence, location and size of residual disease. Results: One-hundred and fifty patients treated between 1998 and 2007 fulfilled inclusion criteria. Modalities of hysterectomy performed were: extrafascial hysterectomy in 106 (71%) patients and radical hysterectomy in 44 (29%). Para-aortic lymphadenectomy was performed in 131 (87%) patients and pelvic lymphadenectomy in 34 (23%) patients. Thirty-four (23%) patients had macroscopic (> 1 cm) residual disease on pathologic examination. Twenty-five (23%) patients had post-operative complications (in whom 17 severe morbidity requiring surgical or radiological treatment). Presence of residual disease was the only factor associated with overall morbidity rate in univariate and multivariate analysis. The use of radical hysterectomy and pelvic lymphadenectomy increased significantly the rate of severe morbidity (particularly bowel and urinary tract morbidity). Conclusions: In the present study involving a large number of patients undergoing completion surgery after homogeneous CRT in locally advanced cervical carcinoma the morbidity rate is important. Radical hysterectomy and pelvic lymphadenectomy increase the rate of severe morbidity. The interest on the survival of this completion surgery should be evaluated in prospective trial.

No significant financial relationships to disclose.
Effect of BRAFV600E on response to sorafenib in advanced thyroid cancer patients
Authors: Brose M. S. , Troxel A. B. , Redlinger M. , Harlacker K. , Redlinger C. , Chalian A. A. , Flaherty K. T. , Loevner L. A. , Mandel S. J. , O'Dwyer P. J.
Published: August 2020

6002

Background: We are conducting an open-label phase II study of sorafenib in patients with metastatic, iodine-refractory thyroid carcinoma. Methods: 55 Patients were administered sorafenib 400 mg orally BID. Responses were monitored by PET and CT. Primary endpoints were response rate (RR) and progression free survival (PFS) by RECIST criteria. BRAF and RAS mutation status is determined by DNA sequencing. Outcome data is evaluated using the Kaplan-Meier method and log-rank test. Biologic activity in tissue obtained during treatment at response and progression is being explored using immunohistochemistry (IHC) to pERK, pAKT and Ki-67 among others, in pretreatment blocks from virtually all patients, and a subset of 14 patients in whom on-treatment tissue is available. Results: We have completed accrual of the 55 patients planned for enrollment; median time on study is 34 weeks and 25 pts (45%) are male. Histological subtypes include papillary (PTC): 25 pts (47%); follicular/Hürthle Cell (FTC): 19 pts (36%); medullary: 4 pts (8%), and poorly differentiated/anaplastic: 5 pts (9%). 52/55 patients are evaluable for response at this time. Median PFS was 84 wks. Genotyping of BRAF is complete in 16 patients. For patients with PTC/FTC, the PFS for those with BRAFwt was 54 wks compared to 84+ wks for patients with BRAFV600E (p = 0.028). On-treatment tissue at progression demonstrates heterogeneity, with p-ERK and p-AKT suppressed in some areas, but highly expressed in others. Data at 6 months post accrual of the last patient will be presented along with patient thyroglobulin levels, PET and CT scans. IHC and additional genotyping will also be presented. Conclusions: Sorafenib has activity in patients with advanced thyroid cancer with an overall PFS of 84 wks. While most patients with PTC or FTC achieve durable responses, patients whose tumors harbor BRAFV600E have significantly longer PFS than those that are BRAFwt.

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Randomized study of darbepoetin alfa as modifier of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC): Final outcome of the DAHANCA 10 trial
Authors: Overgaard J. , Hoff C. M. , Hansen H. S. , Specht L. , Overgaard M. , Grau C. , Andersen E. , Johansen J. , Andersen L. J. , Evensen J. F. ,   Danish Head and Neck Cancer Group (DAHANCA)
Published: August 2020

6007

Background: The study aimed to evaluate if correction of low hemoglobin (Hb) levels by means of the erythropoietin stimulating agent: darbepoetin alpha (Aranesp) during radiotherapy (RT) improves outcome in patients with HNSCC. Following a planned interim analysis which showed inferiority of the experimental treatment, the trial was stopped in November 2006. Methods: Pts with HNSCC eligible for primary RT alone and with Hb values below 14.0 g/dl were randomized to receive Aranesp together with accelerated fractionated RT. Pts. were stratified according to gender, T and N staging, tumor site, and institution. Aranesp was given subcutaneously in a dose of 150 micrograms weekly during RT, or stopped earlier if the Hb exceeded 15.5 g/dl. Results: In total, 522 patients (of a planned intake of 600) were included at the time of the interim analysis. Of these 514 pts were eligible for analysis (255 pts treated with Aranesp and 259 pts in the control group) with a median follow up of 49 months. Among these, 201 developed a loco-regional failure (primary endpoint). There have been 238 deaths of which 176 are due to HNSCC. The patients were evenly distributed according to the stratification parameters (gender, T and N staging, tumor site, institution).Aranesp resulted in the expected increase in Hb in more than 81% of the patients. The compliance to Aranesp was good with no significant difference in serious (cardiovascular) adverse events (3% vs. 1%). Overall, the results showed a poorer outcome in 5-year loco-regional control (59% vs. 68% (p = 0.04, RR: 1.47 [1.14–1.94]) for the Aranesp vs. control arm. This was also seen for the endpoint of disease-free survival (37% vs. 47%, p = 0.02, RR: 1.32 [1.04–1.68]), whereas there was no significant difference in overall survival (40% vs. 51%, p = 0.16, RR: 1.20 [0.93–1.55]). There were no differences in radiation related morbidity. All univariate analyses were confirmed in a multivariate setting. Conclusions: Correction of the Hb level with Aranesp in patients with HNSCC resulted in a significantly poorer tumor control after radiotherapy. The treatment principle was abandoned and the difference in outcome is being subjected to further examination.

No significant financial relationships to disclose.
A randomized double-blind phase III study of efficacy of lactobacillus CD2 lozenges in preventing radiation- and chemotherapy-induced oral mucositis in head and neck cancer patients: Interim analysis
Authors: Sharma A. , Rath G. K. , Choudhary S. P. , Thakar A. , Mohanti B. K. , Bahadur S. , Sahu A. R. , Johar A. , Dwary A.
Published: August 2020

6008

Background: Oral mucositis is major toxicity in patients receiving RT with or without chemotherapy (CTRT) for squamous cell carcinoma of head and neck (SCCHN). This compromises ones ability to tolerate and complete treatment. Interventions available till date to limit and restrict mucositis are unsatisfactory. This study was undertaken to test the efficacy of lactobacillus CD2 in rendering patients more tolerant to the anticancer therapy. Methods: Prospective randomized double blind phase III study. Inclusion criteria were: resectable SCCHN patients suitable for CTRT or radical RT, age group 18–70 years, KPS>70%, normal hematological and biochemical functions. Eligible patients were randomized to receive total of 6 lozenges (to be dissolved by itself in the mouth) of either study product or placebo daily from the day anticancer treatment was started until one week after completion of anticancer therapy. Randomization was done in block of 10 patients. Initially it was planned to enroll 150 evaluable patients but protocol was amended to have total of 200 patients, to have interim analysis after 150 evaluable patients. This would have α and β error of 0.05 and 0.20, respectively. RT was given as 70 Gy/ 35# over 7 weeks with cisplatin 40 mg/m2 weekly x 7. Study was started in January 2007. Primary end points are: percentage of patients able to complete anticancer treatment and incidence of grade 3 and 4 mucositis. Results: This analysis was carried out on first 150 evaluable patients (75 in each arm). 135 were stage III or IV. Forty one (54.7%) in study arm and 36 (48%) in placebo arm took lozenges as planned (p = 0.414). Sixty seven (89.3%) in study arm and 56 (74.7%) in placebo arm could complete anticancer treatment (two sided p = 0.023). Grade 3 and 4 mucositis was seen in 40 (55.6%) and 44 (58.9%) patients respectively in study product and placebo arms (two sided p = 0.062). Conclusions: Study met one of its primary endpoint. Significantly more patients could complete anticancer treatment in study product arm and there was reduction in incidence of grade III and IV mucositis. We expect final results to be available before meeting.

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Low pathologic complete response (pCR) rate to neoadjuvant chemotherapy in invasive lobular carcinoma of breast: Analysis of subgroup of four phase II trials
Authors: Khosravi-Shahi P. , Izarzugaza Peron Y. , Perez-Manga G.
Published: August 2020

601

Background: Pathologic complete response (pCR) after preoperative chemotherapy (PCT) is associated with better outcome in locally advanced breast cancer (LABC). However, the pCR rate according to histology usually is not considered in trials. Methods: Patients (p) with histologically confirmed lobular carcinoma (LC), including in four phase II trials (AT, ATX, TXH, and BTX) conducted in our center, were eligible. Radiotherapy (RT) and hormone therapy (Ht) were allowed after surgery. Expression of markers was determined by IHC before CT. Primary objective of the study was to evaluate pCR rate in this subgroup of ps. Secondary endpoints were: clinical response rate (CRR), breast conservative surgery rate (BCSR), pathologic tumoral size (pTS), disease-free survival (DFS), and overall survival (OS). Results: A total of 185 ps including in the four trials were evaluated. Sixteen ps had LC (16/185 = 8.65%): median age = 50 y (38–66); premenopausal = 56.2%; left breast = 56.2%; median clinical (c) tumor size = 5 cm (3–6); stage:IIA = 6.7%; IIB = 26.7%; IIIA = 33.3%; IIIB = 33.3%; T:cT3 = 50%; cT4 = 28.6%; cN+ = 71.4% (median pN = 2 [0–32]); grade: G2 = 60%, G3 = 40%; ER+ = 78.6%; PgR+ = 64.3%; HER-2+ = 6.25%; phenotype by IHC: Luminal (HR+/HER-2-) = 75% (12/16); Luminal/HER-2+ (HR+/HER-2+) = 6.25%; triple negative (3/16) = 18.75%; p53+ = 25%; EGFR negative = 90%; median Ki-67 = 20% (5–70); adjuvant trastuzumab (H) = 6.25%; RT = 60%, median dose = 50Gy; Ht = 78.6% (tamoxifen = 55%; AI = 45%); type of PCT: docetaxel (T), capecitabine (X), and H (TXH) = 1p (6.2%); doxorubicin (A), T, and X (ATX) = 5 ps (31.2%); bevacizumab, T, and X (BTX) = 5 ps (31.2%); AT = 5 ps (31.2%); median of 5 cycles (2–6). Primary End-Point: Only 1 p (6.25%) had pCR in breast and nodes, and another p had a pCR only in breast, but not in nodes (pCR in breast = 2/16). Second End-Points: 1) CRR = 56.25% (complete = 12.5%; partial = 43.75%; no response = 37.5%; progression = 6.25%); 2) BCSR = 12.5%; 3) Median pTS = 2 cm(0 cm-6 cm); 4) Survival data are not mature. Only four events had occurred. With a median follow-up of 31 months, median DSF and OS has not been reached. Four-years DFS = 57%; and 3-y OS = 81%. Survival data will be updated in the meeting. Conclusions: PCT in LC is associated with very low pCR.

No significant financial relationships to disclose.
Sequential chemoradiotherapy (SCRT) for larynx preservation (LP): Preliminary results of the randomized phase II TREMPLIN study
Authors: Lefebvre J. , Pointreau Y. , Rolland F. , Alfonsi M. , Baudoux A. , Sire C. , de Raucourt D. , Bardet E. , Tuchais C. , Calais G. ,   Groupe Oncologie Radiotherapie Tete Et Cou (GORTEC)
Published: August 2020

6010

Background: Induction chemotherapy (ICT) followed by irradiation (RT) and concurrent chemoradiotherapy (CRT) are validated options for LP. Docetaxel-based ICT, concurrent cetuximab and RT are new options and SCRT (ICT followed by CRT) has been reported as a potential new approach. However, to date there are no data assessing SCRT specifically for LP. Methods: Previously untreated patients (pts) with larynx or hypopharynx squamous cell carcinoma and candidates for a total laryngectomy were eligible for this randomized phase II study. Eligible pts received 3 cycles of ICT (docetaxel and cisplatin both 75 mg/m2 on day 1 and 5-FU 750 mg/m2/day on days 1–5). In case of response ≥ 50 % pts were randomized to receive either in arm A: RT (70 Gy) with cisplatin (100 mg/m2 on days 1, 22 and 43 of RT) or in arm B: Cetuximab (400 mg/m2 loading dose before RT and 250 mg/m2 on the first day of the 7 weeks of RT. Pts with response < 50% had salvage surgery. Primary endpoint was LP 3 months after treatment, secondary endpoints were larynx function preservation at 18 months, quality of function and tolerance to treatment. Results: From March 2006 to April 2008 (end of accrual), 153 pts with stage III-IV larynx/hypopharynx cancer were enrolled in the study and could start ICT. Of them 74 % could receive the planned ICT while the others had either reduced dosages or less than 3 cycles. Toxic deaths occurred in 3 pts (2%). Of the 147 evaluable pts after ICT, 22 were non-responders (15%), 4 pts were withdrawn from the study, 6 responding pts with ICT-related toxicity precluding any further cisplatin could not be randomized and finally 115 pts could be randomized (59 in arm A and 56 in arm B). 3 months after treatment there was no significant difference in LP (93% in arm A and 96% in arm B). In arm A, 45 % of pts could receive the full CRT protocol vs 71 % in arm B. In arm A 50% of pts had cisplatin-related toxicity (definitive in 52% the cases) while in arm B 26 % of patients had cetuximab-related toxicity (definitive in only 1 case). There was no CRT treatment-related death. Conclusions: SCRT is considered for LP. ICT followed by RT with concurrent cetuximab appeared better tolerated than with concurrent cisplatin with the same LP rate 3 months after treatment.

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