bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of the MARS study on the management of antiangiogenics’ renovascular safety in ovarian cancer.
Authors: Launay-Vacher Vincent , Janus Nicolas , Selle Frédéric , Goldwasser Francois , Mir Olivier , Spano Jean-Philippe , Thery Jean Christophe , Beuzeboc Philippe , Rey Jean-Baptiste , Jouannaud Christelle , Morere Jean F. , Oudard Stephane , Gligorov Joseph , Azizi Michel , Dorent Richard , Deray Gilbert , Ray-Coquard Isabelle Laure , Scotte Florian
Published: March 2020

5567

Background: Anti-VEGF drugs (AVD) are widely used in cancer patients (pts). Hypertension (HTN) and proteinuria (Pu) are class-side-effects of AVD, related to the inhibition of the VEGF pathway. The MARS study has been conducted to assess the renovascular tolerance of these drugs in the clinical setting. Methods: This multicentric, prospective, observational study evaluated the renovascular safety of AVD in pts naive from any AVD, conducted in 7 centres in France, from 2009 to 2012, with a follow-up (f/u) of 1 year. Data collected included: gender, age, serum creatinine (SCr), HTN, hematuria (Hu) and dipstick Pu, at baseline and at each visit. Results: 1,124 pts were included. 79 pts had ovarian cancer (OC) and all received bevacizumab. Median age at inclusion was 61 years. Visceral, bone and cerebral metastasis frequencies were 74.1, 52.7 and 6.0%, respectively. HTN prevalence was 16.5%. Baseline renal assessment retrieved: Pu 36.0%, Hu 21.3%, mean aMDRD 83.0 ml/min/1.73m2 and 5 pts with aMDRD<60. The incidence of de novo Pu and HTA during f/u was 56.8 and 21.2% (Table). 88.9 % of pts with Pu at inclusion improved or remained stable. Among pts with de novo Pu, 64.0% afterwards improved/normalized. No Grade 4 Pu has been reported (at inclusion or during f/u). Renal function remained stable with a mean aMDRD of 83.2 at the end of f/u. 6.0% had grade 2 SCr increase (no grade 3-4). No thrombotic micro-angiopathy (TMA) was reported. Conclusions: These results on the renovascular safety of bevacizumab in OC patients showed that 1) TMA is rare, 2) Pu develops in 56.8% of the pts, however with only 1 Grade 3/4, 3) 21.2% developed HTN, and 4) aMDRD was stable. Furthermore, in case of a renovascular effect, investigators followed the recommendations from the French Society of Nephrology (Halimi JM. Nephrol Ther 2008) and no treatment withdrawal for unmanageable renovascular toxicity occurred. [Table: see text]
Venous thromboembolism in advanced ovarian cancer patients undergoing front-line adjuvant chemotherapy.
Authors: Pant Alok , Schink Julian C.
Published: March 2020

5570

Background: To define the incidence and prognostic significance of venous thromboembolism (VTE) in patients with advanced, epithelial ovarian cancer undergoing front-line adjuvant chemotherapy after extended period (28 day) post-operative prophylaxis. Methods: A retrospective analysis of patients with advanced, epithelial ovarian cancer who underwent surgery and chemotherapy at a single institution from January 2008 through December 2011 was performed. Exclusion criteria were prior history of VTE, VTE during the post-operative period, clear cell histology, use of anti-coagulation for a different indication, and lack of compliance with 28 days of post-operative prophylaxis with a low molecular weight heparin. Results: 128 patients met criteria for inclusion. Sixteen patients had a reported VTE during the time they were on front line chemotherapy (12.5%). Nine patients (7%) had a pulmonary embolus (PE) and 8 (6.3%) had a deep vein thrombus (DVT). The average BMI in the group that developed VTE was 28 and in the group without VTE was 26.5 (p = 0.23). Three out of 16 (23%) patients who developed VTE had undergone a suboptimal cytoreduction compared to 12/112 (11%) in the group with no VTE (p = 0.4). Six of the 16 (37%) patients who developed VTE during chemotherapy underwent a bowel resection and/or splenectomy during their cytoreductive surgery compared to 18 of 112 (16%) patients who did not develop VTE (p=0.079). Eight of the patients in the VTE group had indwelling venous catheters during chemotherapy (50%) compared to 39 (35%) in the group with no VTE (p = 0.27). In the group that developed VTE, there was a trend towards increased pre-operative CA-125, higher rates of bowel resection and/or splenectomy during surgery, decreased use of aspirin, and inferior survival. On multivariate analysis, patients who developed VTE had significantly longer post-operative hospital stays (7 vs 5 days [p = 0.009]) and lower rates of complete response (p = 0.01). Conclusions: A 12.5% risk of VTE merits consideration of prophylaxis during chemotherapy in this cohort. A randomized, controlled trial is needed to clarify whether the benefits of long term prophylaxis outweigh the risks and costs of such therapy.
Clinical management and resolution of stomatitis in BOLERO-2.
Authors: Perez Alejandra T. , Rugo Hope S. , Baselga José , Hart Lowell , Pritchard Kathleen I. , Arena Francis P. , Eakle J F , Geberth M , Hortobagyi Gabriel N. , Csõszi Tibor , Gnant Michael , Chouinard Edmond Emilien , Noguchi Shinzaburo , Srimuninnimit Vichien , Puttawibul Puttisak , Heng Daniel Yick Chin , Panneerselvam Ashok , Taran Tanya , Sahmoud Tarek , Burris Howard A.
Published: March 2020

558

Background: In BOLERO-2, adding everolimus (EVE) to exemestane (EXE) more than doubled progression-free survival without affecting quality of life vs EXE alone in postmenopausal women with hormone-receptor–positive advanced breast cancer who had recurrence or progression on/after nonsteroidal aromatase inhibitor therapy. Although mTOR inhibitors are generally well tolerated, stomatitis is one of their most clinically relevant and potentially dose-limiting toxicities (Sonis Cancer2010). The incidence, grade, and clinical course of stomatitis among patients (pts) participating in the BOLERO-2 study are described. Methods: Pts were randomized 2:1 to receive EVE+EXE or placebo (PBO)+EXE. Stomatitis incidence, severity, consequent dose interruptions/adjustments, study drug discontinuations, and time to resolution were recorded. Results: The median duration of EVE+EXE treatment exposure was 30 wk (range, 1-123 wk). Stomatitis (any grade) occurred more frequently with EVE+EXE than with PBO+EXE (59% vs 12%, respectively). Grade 3 stomatitis occurred in 8% vs 1% of pts receiving EVE+EXE vs PBO+EXE, respectively; no grade 4 was reported. Onset of grade ≥2 stomatitis after treatment initiation was earlier in the EVE+EXE arm vs the PBO+EXE arm: median time was 15d vs 24d, respectively. In the EVE+EXE arm, 97% of pts with grade 3 stomatitis (n=38) improved to ≤1 after a median of 13 d. Complete resolution was observed in 82% of these pts after a median of 38 d. In the PBO+EXE arm, all pts with grade 3 stomatitis (n=2) improved to ≤1 after a median of 18 d. Complete resolution was observed after a median of 29 d. Overall, 24% of pts in the EVE+EXE arm required dose interruptions/adjustments vs 1% of pts in the PBO+EXE arm, and 3% of pts (n=13) discontinued EVE+EXE vs <1% of pts (n=1) discontinuing PBO+EXE, all related to stomatitis. Conclusions: The BOLERO-2 data foster a new era of combining targeted and endocrine therapies. In the study, treatment-emergent stomatitis was of mild to moderate intensity, occurred shortly after treatment initiation, and was generally reversible. Most incidents were successfully managed with palliative interventions and temporary dose modifications. Oral hygiene and other preventive measures are recommended. Clinical trial information: NCT00863655.
Results of a phase II clinical trial to evaluate a re-challenge of intraperitoneal catumaxomab for treatment of malignant ascites (MA) due to epithelial cancer (SECIMAS).
Authors: Pietzner Klaus , Vergote Ignace , Santoro Armando , Marme Frederik , Rosenberg Per , Friccius-Quecke Hilke , Sehouli Jalid
Published: March 2020

5582

Background: Catumaxomab is approved in Europe for the i.p. treatment of MA. With a growing number of patients (pts) treated, the question arises, if a re-challenge is feasible and effective despite the immunogenicity of this non-humanised antibody. Methods: Pts were eligible if they received 4 i.p. applications of catumaxomab in the CASIMAS study and benefitted with a puncture free interval of > 60 days. Primary endpoint was to determine the proportion of pts who were able to receive at least 3 catumaxomab applications. Secondary endpoints were the development of human anti-drug antibodies (ADA) as well as the safety profile of a second catumaxomab cycle including a composite safety score (CSS) summarizing the worst CTCAE grades for the main adverse reactions (pyrexia, nausea, vomiting, abdominal pain). Efficacy endpoints were time to puncture (TTPu), overall survival (OS) and puncture-free survival (PuFS). Results: Median age was 59.0 years. 8 out of 9 screened pts were treated with a second cycle of catumaxomab. The primary tumor was ovarian cancer in 5 (62.5%), breast cancer in 2 (25%) and urachal cancer in 1 (12.5%) pts. All 8 (100%) pts received all 4 infusions within 20 days. Median CSS was 3.0 after the second cycle while it was 3.4 after the first cycle in the CASIMAS study for these 8 pts. Only less pts had AEs with CTC >3 (SECIMAS 25%; CASIMAS 70.1%). All 8 (100%) pts were ADA-positive at study entry. ADA levels were consistently higher in the plasma than in the ascites fluid. During treatment, highest ADA values were found on day 10 for ascites and day 11 for plasma up to values of > 1 mg/ml. PuFS was 47.5 days and TTPu 60 days after the second cycle, and 37 days and 102 days, respectively after the first cycle. Median OS was 406.5. Conclusions: This first experience with a re-challenge of catumaxomab in MA, demonstrates a tolerable safety profile without acute allergic reactions, in spite of the high immunogenicity of catumaxomab and the repeated application. Efficacy was not impaired despite ADA response and the advanced disease of the pts. A re-challenge seems feasible for selected pts suffering from recurrent MA after a first cycle of catumaxomab. Clinical trial information: NCT01065246.
Impact of wait times on survival of women with uterine cancer.
Authors: Elit Lorraine , O'Leary Erin , Seow Hsien , Pond Gregory Russell
Published: March 2020

5586

Background: Reducing cancer wait times have been a priority investment for Cancer Care Ontario since 2005. Our objective was to determine whether wait time from histologic diagnosis of uterine cancer to time of definitive surgery by hysterectomy impacted on all cause survival. Methods: Cases were identified in the Ontario Cancer Registry using ICD-09 codes 179 and 182. Excluded were women without histologic/cytologic confirmation of cancer prior to surgery, with no definitive surgery, or with wait times of ≤14 days or >2 years. Survival was calculated using the Kaplan-Meier method from the day of hysterectomy. Factors were evaluated for their prognostic ability on survival using Cox proportional hazards regression. Wait time was evaluated as a continuous variable and dichotomized at selected cutpoints in the univariable analyses and in a multivariable model adjusting for significant patient factors identified using forward stepwise selection. Results: The final study population included 8,744 women. 51.9% had surgery by a gynaecologist and 69.9% had endometrioid adenocarcinoma. The optimal model is shown below. Multivariable analysis of factors prognostic for survival. Longer wait times remained a statistically significant negative prognostic factor for survival regardless of definition, univariably (p<0.002) and multivariably after adjusting for other significant factors (p<0.001). The final multivariable model is shown. 5-year (95%CI) survival for women with more than 12 week wait times was 61.4 (57.8-64.8)% versus 71.9 (69.9-73.8)% for women with less than 6 week wait time. Conclusions: The longer a woman waits from diagnosis of uterine cancer to definitive surgery negatively impacts her overall survival. [Table: see text]
A retrospective assessment of outcomes of chemotherapy-based versus radiation-only adjuvant treatment for completely resected stage I–IV uterine carcinosarcoma (UCS) with rhabdomyosarcoma (RMS) differentiation.
Authors: Makker Vicky , Kravetz Sara Jane , Gallagher Jacqueline , Orodel Oana , Iasonos Alexia , DeLair Deborah , Zhou Qin , Aghajanian Carol , Hensley Martee Leigh
Published: March 2020

5595

Background: UCS with RMS differentiation are aggressive cancers with poor survival, and without an established standard treatment (txt). We aimed to determine the progression-free survival (PFS) and overall survival (OS) in patients (pts) who received either platinum-based chemo with or w/o radiation therapy (pelvic or IVRT), or RT alone (pelvic or IVRT). Methods: MSKCC EMR from 1990 to 2012 was reviewed for pt age, diag. date, primary surgery, residual disease at completion of primary surgery, FIGO stage, txt details, dates of progression, death, site(s) of first recurrence. Univariate analysis for PFS/OS utilized Kaplan Meier method. Differences between PFS/OS and categorical variables of stage + txt type were assessed using log-rank test. All analyses utilized SAS version 9.2. Pts who received chemo with or w/o RT or RT alone were included in the analysis. Results: 53 pts met study criteria. 41/53 (77.4%) pts received chemo: 30/41 (73.2%) paclitaxel-carboplatin (TC); 3/41 (7.3%) ifosfamide (I)-platinum; 3/41 (7.3%) weekly cisplatin followed by TC; 2/41 (4.9%) other platinum-doublets; 3/41 (7.3%) IT. 34% of the chemo pts also received pelvic or IVRT. 12/53 (22.6%) pts received only pelvic RT+/-IVRT. FIGO stage: I =16 (30%); II =5 (9%); III =14 (26%); IV =18 (34%). Median PFS for the entire cohort: 11.7 mos (95% CI 6.4, 14.1). Median OS for the entire cohort: 21.8 mos (95% CI 14.9, 31.8). Median PFS by stage: 14.3 mos for early stage (stages I and II) vs 9.9 mos for late stage (stages III and IV), p=0.0217. Median OS by stage: not reached in the early stage cohort. Median OS for the late stage: 19.9 mos, p=0.0106. Median PFS by txt: 10.7 mos for the Pelvic RT+/- IVRT group vs 13.5 mos for chemo+/-Pelvic RT+/- IVRT group, p=0.5126. Median OS treatment: 23.9 mos for the chemo+/-Pelvic RT+/- IVRT group vs 17.4 mos for the Pelvic RT+/- IVRT group, p = 0.5191. Conclusions: PFS and OS outcomes in our cohort of pts with UCS with RMS differentiation were similar to survival outcomes among pts treated with platinum-based chemo on GOG 150 and GOG232B. The role of adjuvant RT in addition to chemo warrants further investigation.
Impact of socioeconomic status and degree of ethnic isolation on cervical cancer incidence among Hispanics and Asians in California.
Authors: Froment Marie-Anne , Roux Audrey , DeRouen Mindy C. , Gomez Scarlett Lin , Kidd Elizabeth A.
Published: March 2020

5605

Background: The incidence of cervical cancer in the United States has declined since the introduction of the pap smear. However, differences exist based on ethnicity and socioeconomic status (SES).This study aimed to evaluate the impact of nativity, neighborhood SES and enclave (degree of ethnic isolation) on the incidence of cervical cancer in California. Methods: Using data from the California Cancer Registry, comprising three of the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) program registries, information on all primary invasive cervical cancer diagnosed in California from January 1, 1990, through December 31, 2004 was obtained. We analyzed the influence of enclave, SES, and nativity on cervical cancer incidence. Results: Among the 22,189 invasive cervical cancer cases diagnosed between 1990 and 2004, 50% were non-Hispanic white (NHW), 39% Hispanic and 11% Asian women. Seventy percent (70%) of the invasive cervical cancer cases were squamous cell carcinoma (SCC), 19% were adenocarcinoma and 11% other histologies. Approximately half (51%) of patients presented with localized disease, 33% regional disease, 10% distant disease and 6% unknown. By ethnic group, US born women showed lower rates of SCC compared to foreign-born women. Seventy-six percent (76%) of invasive cervical cases were observed in high enclave neighborhoods, and seventy percent (70%) were noted in low SES neighborhoods. Hispanics living in low SES and high enclave had 12.7 times (95% CI; 11.2-14.3) higher rate of cervical cancer than those living in high SES, low enclave neighborhoods. For Asian women incidence rates were 6 times (95% CI; 4.9-7.5) higher in the low SES, high enclave neighborhoods compared to those living in high SES, low enclave neighborhoods. Conclusions: More efforts should be done to reach out to and increase pap smear screening for women living in high enclave neighborhoods to help decrease the incidence of invasive cervical cancer cases in these groups of women.
Male workers’ influence on partners uptake of pap smear screening in a teaching hospital in Nigeria.
Authors: Olowokere Idowu Emmanuel , Roberts Olumuyiwa Adebola
Published: March 2020

5606

Background: Cervical cancer remains a major global health issue still claiming the lives of African women despite the availability of screening facilities. Male involvement has paid off in enhancing uptake of contraception in Africa as reported by several empirical studies. It may be worthwhile in encouraging women uptake of the screening services. This formed the basis for this study. Methods: The study adopted a cross sectional descriptive survey that involved 350 respondents. Their involvement was assessed using a structured questionnaire with cronbach reliability coefficient of 0.78. The study was analyzed using SPSS version 16 by computing the frequency, means and standard deviations. Chi-square was employed to test the significance of associations at p < 0.05. Results: The results showed that all (n = 350) male medical staff of the hospital were aware about cervical cancer and pap smear screening test for premalignant lesions of the cervix compared to 90% and 77% observed in paramedics and non-medical groups respectively. At least, an episode of Pap smear screening test had been done by the partners of 52.4% of the medical staff; while only 30.2% and 13% of the partners of paramedics and non-medical workers respectively had undergone the test. Among those whose partners had participated in screening; 78.9% (n = 95) of the men initiated the screening. Eighty two percent (82%, n = 95) paid for their wives’ transportation while 78.9% (n = 95) have at least once followed their partners to the screening centre. Chi square result showed that men with higher level of education are likely to support their partners to participate in screening for cervical cancer (p < 0.005). There was no significant association between religion and male support for Pap smear uptake (p < 0.407). Conclusions: The study showed that the medical male workers were more involved in facilitating partners screening for cervical cancer. This may not be unconnected with their knowledge of the consequences of late identification of the disease. The study therefore concluded that knowledge of cervical cancer and its consequences by men will enhance their involvement in encouraging partners to utilize screening facilities.
Long-term survival following robot-assisted surgical treatment of early cervical cancer.
Authors: Jackson Amanda Lynn , Kilgore Joshua , Ko Emily Meichun , Craven Renatta , Gehrig Paola A. , Soper John T. , Boggess John
Published: March 2020

5607

Background: To determine progression-free survival (PFS) and overall survival (OS) for patients with early stage cervical cancer surgically treated using robotic-assisted laparoscopy compared to open radical hysterectomy. Methods: A retrospective analysis of women that underwent a robotic-assisted surgery (RAS) for early stage cervical cancer was performed. Surgical procedures included radical hysterectomy, parametrectomy, and trachelectomy from 2005 to May 2012. Patient demographics, clinicopathologic data, and disease status were analyzed. Comparison was made to open radical hysterectomies (ORH) from 2000 to May 2012. Survival statistics were analyzed using the Kaplan-Meier method. Results: 147 patients underwent RAS; 97 patients underwent ORH in our comparison group. Surgery was aborted in 8 RAS and 5 ORH due to extent of disease. The robotic surgical treatments included 121 (82.3%) radical hysterectomies, 14 (9.5%) trachelectomies, and 12 (8.2%) parametrectomies. In the RAS, the mean age was 44.3 (range 17-75); the mean body mass index (BMI) was 27.7 (range 16-50). Most patients presented with clinical stage IBI disease (79.9%). Squamous cell histology was most common (55.4%) followed by adenosquamous (36.7%). No significant differences were found between the RAS and ORH with regards age, BMI, surgical stage, grade, short and long-term complications, and comorbidities. The mean follow up time was 24.7 (range 0-82.1) months. Recurrence was documented in 3 patients after RAS and 11 patients after ORH; 3 deaths were recorded in the RAS group and 10 in the ORH. One patient had persistent adenocarcinoma in situ after robotic trachelectomy. Compared to ORH, there was a significantly better PFS in RAS (HR .312, CI 0 .099-0.98, p = 0.046) while no difference was seen in OS (p = 0.172). Conclusions: The results demonstrate that RAS is associated with lower rates of recurrence and no difference in overall survival. These findings provide further evidence that robotic-assisted surgical treatment is not associated with inferior results when compared to laparotomy or traditional laparoscopy. As robotic-assisted surgery is associated with a less steep learning curve, it may become the surgical approach of choice.
Comparative analysis of bone marrow micrometastases with sentinel lymph node status in early-stage breast cancer.
Authors: Arora Madan L. , Mistry Shams , Shaik Mohammed , Tyagi Neha , Korant Alpesh K. , Saha Supriya Kumar , Johnston Gregory , Abadeer Benjamin , Dhar Vikrom K. , Wiese David , Saha Sukamal
Published: March 2020

570

Background: A definitive relationship between bone marrow (BM) micrometastases (M) and sentinel lymph node (SLN) status has not been established in Breast Cancer (BRCa). Hence, a retrospective study was done to examine the relationship between BMM and SLN status in BRCa patients (pts). Methods: T1/T2 BRCa pts underwent SLN biopsy and definitive surgery for primary tumors. At the operation, BM aspiration from bilateral post-superior iliac spines was performed. BM samples were examined using a Cytokeratin Detection Kit using CAM 5.2 monoclonal antibody and visualization achieved with a Ventana iView V-Red detection system. An Automated Cellular Imaging System was applied to identify metastatic BRCa cells. Pts with +ve BM underwent repeat BM analysis 6 months after completing initial treatments. Data was collected for T-stages, SLN, BM, ER/PR receptor and Her-2/neu statuses and analyzed using Chi-Square Analysis or Fischer’s Exact Test. Results: We analyzed 458 consecutive pts, of which SLN metastasesv(mets) were detected in 22.9% and BMM were detected in 8.1%. BMM were found 23% bilaterally and 77% unilaterally. BMM were detected in 11.4% of SLN +ve pts versus 7.1% of SLN -ve ptsv(p=0.15) and 6.8% of T1 pts versus 12.3% of T2 ptsvv(p=0.07). BMM were found in 8.7% of ER/PR +ve pts versus 4.5% of ER/PR –ve ptsvv(p=0.1) and 9.5% of HER2/neu +ve pts versus 7.7% of HER2/neu –ve ptsv (p=0.5) (Table). Repeat BM analysis detected BMM only in 6.6% pts. Conclusions: Bilateral BM aspirate resulted in a significant increase in detection of micrometastases. BM metastases may occur independently of lymphatic metastasis. Therefore, evaluation for the presence of BMM may help identify high risk pts with node negative disease in early stage BRCa. [Table: see text]
Effect of fertility concerns on tamoxifen use in young survivors of breast cancer.
Authors: Llarena Natalia , Nunez Omar , Kane Anna , Jeruss Jacqueline Sara
Published: March 2020

572

Background: For premenopausal patients with ER+ breast cancer, a 5-year course of tamoxifen results in a 47% reduction in annual recurrence risk and a 26% reduction in annual mortality. Despite these benefits, adherence rates for tamoxifen are low, particularly among younger women. We hypothesize that fertility concerns are causally related to the poor tamoxifen adherence rates observed among young breast cancer survivors. Methods: With IRB approval, a retrospective analysis of 535 women with breast cancer between 2000-2012 was undertaken. Patients were younger than age 46, premenopausal and had ER+ breast cancer. 138 patients did not complete a 5-year course. Patient and provider factors that influenced tamoxifen initiation and adherence were reviewed: (1) evidence of referral to a fertility specialist; (2) documentation of discussion about tamoxifen-related fertility concerns; (3) agreement to take tamoxifen; (4) duration of tamoxifen use. Phone interviews conducted with 27 patients focused on lack of initiation or early discontinuation. The Log-rank (Mantel-Cox) test was used to compare Kaplan-Meier curves and generate hazard ratios. Results: Of the 138 patients who did not complete 5 years of therapy, 38 (27.5%) failed to initiate or discontinued tamoxifen secondary to fertility concerns. Only 114 (21.3%) charts documented referral to a fertility specialist. Patients who expressed a desire to maintain fertility or to have children in the future (115 patients, 21.5%) were more likely to discontinue tamoxifen treatment (HR=2.7, p=0.001). Other critical factors included being unmarried (HR=1.9, p=0.011) and lack of college education (HR=2.5, p=0.0008). Major themes from phone interviews: (1) patients felt they were not adequately informed about fertility preservation and had to pursue information independently; (2) patients did not initiate/resume tamoxifen postpartum because of inadequate physician guidance. Conclusions: Concerns about fertility have a significant negative impact on the initiation and adherence to tamoxifen for young breast cancer patients. Efforts to improve tamoxifen adherence among young cancer patients should include prioritization of fertility preservation as part of the treatment plan.
Classifying circulating, mutation bearing tumor cells from breast cancer patients.
Authors: Strauss William , Dempsey Paul W. , Winer-Jones Jessamine , Bingham Catherine , Alpaugh R. Katherine , Cristofanilli Massimo
Published: March 2020

580

Background: The treatment of advanced breast cancer demands systemic therapies that can address disease heterogeneity and the development of treatment resistance without a “real-time” molecular window into disease biology. New technologies have focused on increased capture and molecular analysis of circulating tumor cells (CTCs) including cells undergoing epithelial mesenchymal transition (EMT). We conducted a pilot experiment to test the efficiency of capture and cytokeratin (CK) detection and the presence of single point variants (SNV) to determine the best utility of scoring alternatives for CTC. Methods: EpCAM expressing CTC were recovered from breast cancer patients using CellSearch (Veridex) and LiquidBiopsy (Cynvenio Biosystems). EpCAM recovery and CK scoring were indexed in spiked samples and in 12 inflammatory breast cancer (IBC) patient samples using antibodies against CKs 7, 8 or CKs 1-8, 10, 13-16, 18, 19. Additionally, LiquidBiopsy template was analyzed using an Ampliseq 1.0 panel on the IonTorrent PGM. SNV present in the CTC but not white blood cell (WBC) negative controls were identified and where possible, compared to tissue biopsy SNV analyzed using Foundation One (Foundation Medicine). Results: CTCs were detected using CellSearch 10/12 (83%) (range 0-2502 CTC/7.5ml) and LiquidBiopsy 12/12 (100%) (range 6-2800 CTC/7.5mL). More CK positive events were scored using CKs 1-8, 10, 13-16, 18, 19 than CKs 7, 8 in patient samples. Upon sequencing, shared germline polymorphisms were observed in CTC and WBC. Conversely, 1 or 2 SNV were detected in the Epcam selected population but not WBC controls from 6/12 patients (frequency 1.1%-2.1% with 520-5160x coverage) with SNV observed in TP53, MPL, PIK3ca, MET and IDH1. All but one of the PIK3ca mutations were absent in evaluable tissue biopsy. Conclusions: CTC recovery and scoring are two separate events. Altered CK detection emphasized the need to tailor CTC classification to specific disease settings. Sequence analysis showed one correlated SNV among 6 evaluable comparisons to tissue reflecting variable analysis as well as the biologic disparity of metastatic disease. This pilot demonstrates the feasibility of using CTC for molecular analysis.
Sym004, a novel strategy to target EGFR with an antibody mixture, in patients with advanced SCCHN progressing after anti-EGFR monoclonal antibody: A proof of concept study.
Authors: Machiels Jean-Pascal H. , Specenier Pol M. , Krauss Jürgen , Dietz Andreas , Kaminsky Marie-Christine , Lalami Yassine , Henke Michael , Keilholz Ulrich , Knecht Rainald , Skartved Niels Jorgen Ostergaard , Horak Ivan David , Flensburg Mimi F , Gauler Thomas Christoph
Published: March 2020

6002

Background: Sym004 is a first-in-class drug mixture of two mAbs targeting non-overlapping epitopes on the EGFR. In preclinical models, Sym004 exhibited more pronounced EGFR internalization, degradation and tumor growth inhibition than cetuximab. Sym004 was investigated as monotherapy in palliative squamous cell carcinoma of the head and neck (SCCHN) patients (pts). Methods: SCCHN pts progressing after anti-EGFR mAbs for palliation were eligible. Documented clinical benefit (PR, CR or SD for at least 8 weeks according to RECIST) on an anti-EGFR mAb-containing regimen followed by disease progression during or within 12 weeks after treatment cessation was required. The primary endpoint of this multicentre single arm trial was centrally evaluated progression-free survival (PFS), estimated by median PFS and 24 week progression free rate. Secondary endpoints included objective tumor response, safety, biomarkers and pharmacokinetics. Pts received weekly iv infusions of 12 mg/kg Sym004 until disease progression. Tumor evaluation was performed week 6, 12 and every 8 weeks thereafter. Results: Based on the statistical hypothesis, 26 pts were included, of whom 23 had progressed while on anti-EGFR mAb treatment. One of 19 evaluable pts was HPV positive and no EGFRvIII mutation was detected in 21 evaluable pts. No anti-drug antibodies were detected. Independent central review of CT/MRI scans from 20 evaluable pts showed tumor shrinkage in 8 pts (% decrease in sum of the largest diameters: 6.5, 7.1, 9.6, 10.2, 11.3, 13.6, 16.7, 27.1) and 14 pts had SD as best overall response. Median PFS was 82 days (95% CI: 41, 140) and 24 week progression free rate was 12% (95% CI: 1, 39). During treatment 25/26 (96%) pts developed skin rash with ≥ grade 3 reported in 11/26 (42%) pts. Hypomagnesemia ≥ grade 3 was reported in 10/26 (38%) pts. Sym004 treatment resulted in a marked down regulation of EGFR in centrally reviewed biopsies from skin and tumors. Conclusions: Sym004 demonstrated clinical activity in heavily pretreated, predominately HPV negative pts with advanced SCCHN previously progressing on or after anti-EGFR mAbs. No unexpected toxicities were reported. Clinical trial information: NCT01417936.
A phase II-III study comparing concomitant chemoradiotherapy (CRT) versus cetuximab/RT (CET/RT) with or without induction docetaxel/cisplatin/5-fluorouracil (TPF) in locally advanced head and neck squamous cell carcinoma (LASCCHN): Efficacy results (NCT01086826).
Authors: Ghi Maria Grazia , Paccagnella Adriano , Ferrari Daris , Foa Paolo , Cossu Rocca Maria , Verri Elena , Maiello Evaristo , Azzarello Giuseppe , D'Ambrosio Consuelo , Casanova Claudia , Guaraldi Monica , Mantovani Giovanni , Rossetto Ciro , Bonetti Andrea , Cipani Tiziana , Crino Lucio , Koussis Haralabos , Pieri Gabriella , Gava Alessandro , Floriani Irene ,   for the GSTTC Italian Study Group
Published: March 2020

6003

Background: This is the first phase III study directly comparing CRT vs CET/RT in LASCCHN. Primary endpoints of this study were to compare: 1) overall survival (OS) of induction vs. no induction arms; 2) Grade 3-4 in-field toxicity of CRT vs. CET/RT. Preliminary toxicity results of concomitant treatments (primary endpoint for this comparison) were reported at the 2012 ASCO meeting. Here we present response rate and survival data for the two concomitant treatments (CRT vs. CET/RT), irrespective of induction chemotherapy. Methods: Untreated patients with unresectable LASCCHN, stage III-IV, ECOG PS 0–1 were randomized to a 2x2 factorial design: Arm A1: CRT (2 cycles of cisplatin/5fluorouracil concomitant to RT); Arm A2: CET/RT; Arm B1: 3 cycles of TPF followed by the same CRT; Arm B2:3 cycles of TPF followed by CET/RT. Results: A total of421 patients were randomized: 261 received CRT (131 Arm A1+ 130 Arm B1) and 160 received CET/RT (80 Arm A2+ 80 Arm B2). 82% were male; median age was 60y; PS of 0 (79%) or 1 (21%). Stage was III (32%) or IV (68%). Sites of disease were: oral cavity 20%, oropharynx 57%, hypopharynx: 23%. No significant differences were observed in patients’ characteristics distribution. At a median follow-up of 32.9 months, a total of 174 deaths occurred (204 required for final OS analysis). Data on activity and efficacy of CRT and CET/RT are shown in the Table. Conclusions: No significant differences were observed in response rate, progression free survival and OS between CRT and CET/RT. Pts are still being followed-up to assess OS of induction vs. no induction arms. Clinical trial information: NCT01086826. [Table: see text]
Sorafenib in recurrent and/or metastatic salivary gland carcinomas (RMSGCs): An investigator-initiated phase II trial (NCT01703455).
Authors: Locati Laura D. , Bossi Paolo , Civelli Enrico M. , Perrone Federica , Bergamini Cristiana , Cortelazzi Barbara , Quattrone Pasquale , Imbimbo Martina , Mirabile Aurora , Granata Roberta , Resteghini Carlo , Mariani Luigi , Tosarello Davide , Cassani Camilla , Marchiano' Alfonso , Saibene Gabriella , Pilotti Silvana , Licitra Lisa F.
Published: March 2020

6020

Background: Palliative chemotherapy is the standard of care for RMSGCs. However its activity is usually poor especially in adenoid cystic carcinoma (ACC), while in histotypes other than ACC (non ACC) the response, if any, is of short duration. Some preclinical and clinical evidence suggest a rationale for the employment of anti-angiogenetic agents in RMSGCs, such as sorafenib. Methods: Subjects withproven RMSGC not amenable to surgery and/or radiotherapy were enrolled to receive sorafenib at 400 mg BID q28 days until disease progression, unacceptable toxicity or consent withdrawal. Primary endpoint was response rate (RR) (CR+PR) according to RECIST; secondary objectives included RR according to CHOI criteria, disease control rate (DCR) and toxicity. 37 subjects were required to test the null hypothesis that RR will be ≤ 5% versus the alternative that RR ≥ 20% within a two stage Simon design. At least 4 responders were necessary to reject the null hypothesis. Results: 19 ACC and 18 non ACC subjects were accrued from September 2010 to September 2012. 21 patients had received at least one chemotherapy regimen for RMSGC. Overall 6 PRs according to RECIST were recorded corresponding to a RR of 16% (95% CI 6,2-32,0) (11% in ACC and 22% in non ACC). PR according to CHOI was observed in 10 cases (of which only 2 were concordant with RECIST); no response was reported in 15 cases while CHOI response was not evaluable in 12 patients. A dramatic necrotic evolution of the disease, which resulted in cavitation of metastatic lesions in one case, was observed in two patients with mucoepidermoid cancer (MEC). SD was 57% lasting a median of 7 months (range 2-15+ months). At a median follow up of 10 months (range 3-28+ months): 5 patients are still receiving sorafenib; 15 are no longer being treated and 17 have died. AEs were generally consistent with previous sorafenib studies, except for one G5 toxicity due to meningitis (probably related to necrosis of a local relapse) and one G3 aspergillus abscess. Conclusions: Sorafenib is the first anti-angiogenetic agent to demonstrate some activity in RMSGCs, particularly in MEC. Molecular analyses, typifying MEC and ACC are ongoing. Clinical trial information: NCT01703455.
Activity of cetuximab (C) in head and neck squamous cell carcinoma (HNSCC) patients (pts) with PTEN loss or PIK3CA mutation treated on E5397, a phase III trial of cisplatin (CDDP) with placebo (P) or C.
Authors: Burtness Barbara , Lee Ju-Whei , Yang Donghua , Zhu Fang , Garcia Joaquin J. , Forastiere Arlene A. , Chung Christine H.
Published: March 2020

6028

Background: Abnormalities in EGFR signaling targets are associated with C resistance but no biomarker of C resistance has been identified in HNSCC. We hypothesized that cases with loss of PTEN protein expression (PTEN null) or PIK3CA mutation would display C resistance in HNSCC. Methods: E5397 was a phase III trial of CDDP plus P or CDDP plus C and enrolled 117 eligible and evaluable pts. PIK3CA and PTEN were analyzed for 52 and 67 consented pts, respectively. PTEN expression (PTEN Cell Signaling Technology, Cat. 9559) was determined by automated quantitative analysis (AQUA) on the PM-2000 (HistoRx, New Haven) using a cutpoint generated in 5 HNSCC tissue microarrays, each consisting of HNSCC as well as positive (small intestine, median AQUA score 2833.2) and negative controls (breast and colon carcinoma, median AQUA score 205.5). A cutpoint of 570 provides 100% specificity, 100% sensitivity, and identified 30% of the HNSCCs as PTEN null, consonant with the literature. The 3 most common PIK3CA mutations (E542K and E545K in exon 9 and H1047R in exon 20) were determined by BEAMing (Inostics, Heidelberg, Germany). Response, overall survival (OS) and progression-free survival (PFS) were compared between PTEN null or PIK3CA mutated pts and all others. Log rank and multivariable Cox proportional hazards modeling were used to calculate p values. Results: 23/67 (34%) tumors were PTEN null and 2/52 (4%) had PIK3CA mutations (E542K and E545K). Both tumors with PIK3CA mutation had PTEN expression. No statistically significant differences in response, OS or PFS were noted in this small sample. However, among PTEN expressing/PIK3CA WT pts, median PFS increased to 4.2 months (m) for C (N=22) from 2.9 m for P (N=26) (Wald p=0.07), compared with 4.6 m for C (N=12) and 3.5 m for P (n=13) among the PTEN null/PIK3CA mutated (Wald p=0.60). Conclusions: The PTEN loss or PIK3CA mutation signature warrants further investigation as a predictor of C resistance.
Randomized phase II trial of cixutumumab (CIX) alone or with cetuximab (CET) for refractory recurrent/metastatic squamous cancer of head and neck (R/M-SCCHN).
Authors: Glisson Bonnie S. , Tseng Jennifer , Marur Shanthi , Shin Dong M , Murphy Barbara A. , Cohen Ezra E.W. , Thomas Christopher Y. , Willey Richard , Cosaert Jan , William William Nassib , Harun Nusrat , Lee J. Jack , Haddad Robert I.
Published: March 2020

6030

Background: Preclinical evidence supports clinical investigation of IGF-1R inhibitors alone, or combined with EGFR inhibitors, in SCCHN patients (pts). CIX and CET monoclonal antibodies block ligand binding to IGF-1R and EGFR, respectively. CIX mono and CIX+CET combo were studied in pts with chemotherapy-refractory R/M-SCCHN. Methods: This open-label phase II trial randomized 97 pts with R/M-SCCHN, ECOG PS 0-2 and disease progression following (<90 days) platinum-based chemotherapy, to CIX 10 mg/kg alone (Arm A) or with CET 500 mg/m2 (Arm B) every 2 wks. Time to recurrence from last anti-EGFR exposure had to be >90 days; pts were stratified by prior CET exposure. Primary endpoint was median PFS (RECIST assessments every 8 wks). Efficacy endpoints in the CET-naïve patients, immunohistochemical analysis of 10 relevant markers on tumor specimens, and cytokine/angiogenic factor profiling of blood samples obtained serially through treatment were also examined. Results: 47 Arm A and 44 arm B pts were treated: median age: 60.0 y (35 - 81), PS 0/1/2: 17.6%/62.6%/19.8%, male (80.2%), tumors originating mainly from oropharynx (67.1%), supraglottic (9.9%) and oral cavity (13.2%), with 33% moderately and 36.3% poorly differentiated tumors, previous therapy: 98.9% chemotherapy and 82.4% radiotherapy indicating no baseline differences. Most common tx-emergent AEs were fatigue (55.3 vs. 61.4%), dermatitis acneiform (6.4 vs 63.6%), nausea (29.8 vs. 34.1%), weight decreased (25.5 vs. 29.5%), hyperglycemia (25.5% vs. 29.5%), vomiting (21.3 vs. 20.5%), and headache (17 vs. 25%). Efficacy: See Table. Conclusions: Targeting IGF-1R alone with CIX or co-targeting IGF-1R and EGFR with CIX and CET did not result in improved PFS compared to historical data with CET alone in patients with chemotherapy-refractory R/M-SCCHN. The results of this study do not support CIX single-agent activity in this patient population. Therapy on both arms was feasible. There was no apparent exacerbation of CET toxicity by concurrent CIX exposure. Clinical trial information: NCT00617734. [Table: see text]
A phase III randomized trial of two cisplatin-based concurrent chemoradiation (CCRT) regimens for locally advanced head and neck squamous cell carcinoma (LAHNSCC).
Authors: Rodriguez Cristina P. , Adelstein David J. , Rybicki Lisa A. , Savvides Panayiotis , Saxton Jerrold P. , Koyfman Shlomo A. , Greskovich John , Yao Min , Scharpf Joseph , Lavertu Pierre , Wood Benjamin J. , Burkey Brian , Lorenz Robert , Rezaee Rod , Zender Chad , Ives Denise I.
Published: March 2020

6035

Background: Excellent outcomes have been reported using both single and multiagent CCRT in LAHNSCC. This trial compares a 5FU/cisplatin regimen to single agent cisplatin CCRT. Methods: Patients (pts) with previously untreated stage III-IV, M0, LAHNSCC of the larynx, oropharynx (OP), oral cavity or hypopharynx received definitive once or twice daily radiation (70-74.4 Gy) and were randomized between concurrent chemotherapy with either Arm A: cisplatin 100mg/m2 on days 1, 22 and 43 or Arm B: cisplatin (20mg/m2/day) and 5-FU (1000mg/m2/day) as continuous 96 hour infusions weeks 1 and 4. ECOG performance status ≤ 1, and adequate renal, liver and marrow function were required for entry. The primary endpoint was recurrence free survival (RFS). Results: Between 2/2008 and 10/2011, 69 pts were enrolled. An accrual of 126 pts was planned in order to demonstrate an improvement in 2-year RFS from 55% to 75%. The study was closed prematurely when a scheduled interim analysis confirmed markedly better outcomes in both arms and the futility of further comparison. Pt and tumor characteristics were well balanced in both arms. OP cancer was diagnosed in 83% of pts; 86% of the OP cancers were HPV/p16+. With a median follow up of 29.4 months, 2 yr Kaplan-Meier outcome estimates were similar between arms (Table). Pts on Arm A experienced more nephrotoxicity (26% vs. 3%; p=0.007) and ototoxicity (11% vs. 0%; p=0.042), but less Grade ≥2 radiation dermatitis (43% vs. 68%; p=0.038), neutropenia <1000/mm3 (34% vs. 65%; p=0.012), and unplanned hospitalization (43% vs. 68% p=0.038). Treatment outcomes were inferior and feeding tube requirements greater in the HPV/p16 negative and actively smoking pts. Conclusions: Although these CCRT regimens produced similar outcomes, their toxicity profiles proved different and may serve to inform individual pt treatment. Tobacco use and HPV status had far greater impact on treatment outcomes than did the CCRT regimen. Clinical trial information: NCT00608205. [Table: see text]
Impact of obesity on survival in patients (pts) with early-stage squamous cell carcinoma (SCC) of the oral tongue.
Authors: Iyengar Neil M. , Kochhar Amit , Morris Patrick Glyn , Morris Luc G. , Zhou Xi Kathy , Pino Alejandro , Fury Matthew G. , Pfister David G. , Patel Snehal G. , Boyle Jay , Hudis Clifford , Dannenberg Andrew J.
Published: March 2020

6048

Background: Obesity is a risk factor for several malignancies and an independent predictor of worse outcomes. In contrast, low body mass index (BMI) has been associated with increased risk of oropharyngeal cancers and poorer prognosis. In tongue SCC, impaired nutrition, smoking, and alcohol use impact BMI, and pre-diagnosis weight (wgt) loss negatively affects survival. The prognostic effect of obesity in tongue cancer is unknown. Methods: We conducted a single-institution, retrospective study of pts who underwent resection of T1/T2 SCC of the oral tongue. All pts underwent nutritional assessment prior to surgery. BMI was calculated from measured height and wgt at surgery and categorized as obese (≥30), overwgt (25-29.9), or normal (18.5-24.9). The association between BMI and the primary endpoint, disease specific survival (DSS), was evaluated by Cox regression. The effect of BMI on the secondary endpoints, recurrence free survival (RFS) and overall survival (OS), was also assessed. Results: From 2000 to 2005, 155 pts (90 men, 65 women) of median age 57 (range 18-86) were included. Clinicopathologic characteristics were similar by BMI group. Obesity was significantly associated with adverse DSS compared with normal wgt in univariable (Table) and multivariable analyses (HR 2.87; 95% CI, 1.08-7.67; p=0.04). Obesity was also significantly associated with adverse RFS (HR 2.53; 95% CI, 1.12-5.74; p=0.03). Overwgt subjects may also have worse RFS (HR 1.74; 95% CI, 0.85-3.55; p=0.13). In pts without pre-diagnosis wgt loss (n=94), obesity was significantly associated with adverse OS (HR 2.70; 95% CI, 1.12-6.54; p=0.03). Conclusions: These data suggest that obesity is associated with a worse prognosis in tongue cancer, which may not have previously been appreciated due to confounding by pre-diagnosis wgt loss. [Table: see text]
Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).
Authors: Datko Farrah Mikhail , D'Andrea Gabriella , Dickler Maura N. , Goldfarb Shari Beth , Theodoulou Maria , Lake Diana , Fornier Monica Nancy , Modi Shanu , Fasano Julie , Comen Elizabeth Anne , Gajria Devika , Moynahan Mary Ellen , Traina Tiffany A. , Chen Melanie , Hamilton Nicola , Patil Sujata , Chandarlapaty Sarat , Hudis Clifford , Dang Chau T.
Published: March 2020

606

Background: Pertuzumab is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab, disrupting HER2 dimerization and signaling. Pertuzumab improves progression-free survival (PFS) and overall survival when combined with docetaxel/trastuzumab. We report results of a phase II study to evaluate the efficacy and safety of pertuzumab, trastuzumab and weekly paclitaxel. Methods: Patients (pts) with HER2+ MBC with 0-1 prior treatment (Rx) were eligible. Rx is weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → 420mg). The primary endpoint is PFS at 6 months (mo). Evaluable pts are those who started study Rx and are assessed at 6 mo for PFS, including pts who progressed prior to 6mo. Secondary endpoints include response, safety (including cardiac events), and tolerability. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 1-18-13, 53 pts are enrolled; 36 are evaluable at 6 mo. At 6 mo, 29/36 pts (81%) are progression-free (4 CR, 14 PR and 11 SD); 7 pts progressed. The 6 mo PFS results for all patients will be updated. Median LVEF is 64% at baseline (range 50-72%), 63% at 3 mo (range 50-73%), and 62% at 6 mo (range 49-69%). There are no cardiac events to date. Of the 36 pts, grade 3/4 toxicities include fatigue (3 pts, 8%), peripheral neuropathy (2 pts, 6%), sepsis (1pt, 3%), cellulitis (1pt, 3%), neutropenia (1pt, 3%), and skin ulceration (1pt, 3%). There are no grade 3 diarrhea or febrile neutropenic events in the evaluable pts to date. Conclusions: The preliminary 6-month PFS is 81% (95% CI 67-91%) in evaluable patients. The study is closing to accrual. Treatment is ongoing, with few grade 3/4 toxicities and no signal of increased cardiac toxicity to date. This phase II study demonstrates efficacy and safety for pertuzumab with trastuzumab and weekly paclitaxel in HER2+ MBC. Clinical trial information: NCT01276041.