bluuebunny/crossref_metadata_2025 huggingface dataset:
APOLLO: A phase I study of adaptive memory natural killer (NK) cells in recurrent ovarian cancer.
Authors: Geller Melissa Ann , Cooley Sarah A. , Wallet Mark , Valamehr Bahram , Teoh Deanna Gek Koon , DeFor Todd E. , Felices Martin , Miller Jeffrey
Published: May 2020

6044

Background: Human cytomegalovirus (CMV) infection induces a subset of long-lived CD57+NKG2C+ adaptive NK cells that exhibit enhanced antibody-dependent cellular cytotoxicity and resistance to tumor-suppressive mechanisms. We developed a 7-day culture process using a GSK3 inhibitor and IL-15 to manufacture modulated adaptive NK cells (FATE-NK100) from CMV+ haploidentical donors for adoptive transfer. The phase I Apollo trial tests the maximum tolerated dose/maximum feasible dose (MTD/MFD) of FATE-NK100 administered intraperitoneally (IP) to treat platinum-sensitive or -resistant recurrent ovarian, fallopian tube, and primary peritoneal cancer. Methods: FATE-NK100 via IP port was tested using 3 dose cohorts ([DC]; 1 × 107 cells/kg; >1 × 107 cells/kg to ≤3 × 107 cells/kg; or >3 × 107 to ≤10 × 107 cells/kg) after lympho-conditioning with fludarabine 25 mg/m2 IV and cyclophosphamide 300 mg/m2 IV on days −6 and −5. After FATE-NK100 infusion on day 0, rhIL-2 at 6 million IU was given IP 3 times a week for 6 doses for in vivo NK activation. IP fluid and peripheral blood were collected regularly until response assessment (day 28). Patients with stable disease or better were eligible for retreatment. Pre- and post-treatment tumor biopsies were collected. Results: Nine patients were treated with no dose-limiting toxicities (DLTs) to date. Retreatment based on clinical benefit was performed on 3 patients (33%), 2 following stable disease (DC 2) and 1 with partial remission (48% tumor reduction, DC 3). IP samples were collected for PK and functional analysis. FATE-NK100 product was detected by flow cytometry in 5 of 6 patients with evaluable samples (range 4.8%–91.2% donor NK cells at day +5-7). Retreatment samples were available in 1 patient, where FATE-NK100 persisted to day +21, demonstrating that repeated IP dosing did not accelerate clearance of the donor NK cells. In that same patient, measurement of NK cell CD107a degranulation or IFNg production in response to K562 targets demonstrated sustained enhanced in vivo function of FATE-NK100 compared to endogenous patient NK cells (e.g. at Day +12 CD107a+ NK were 39.0% vs. 22.5% cycle 1, and 40.3% vs. 18.2% retreatment cycle 2, and IFNg+ NK were 12.3% vs. 5.9% cycle 1, and 2.4% vs. 0.2% retreatment cycle 2). Conclusions: IP delivery of FATE-NK100 is safe, with clinical benefit in 3/9 patients treated. The allogeneic product cells persist and have enhanced function compared to patient NK cells for up to 21 days, even after retreatment. This phase I study in recurrent/refractory ovarian cancer shows promise for IP NK cell delivery. Clinical trial information: NCT00652899.
Long-term survival outcomes of intravenous versus intraperitoneal chemotherapy in the treatment of advanced ovarian cancer.
Authors: Kim Rachel Soyoun , Maganti Manjula , Bernardini Marcus , Laframboise Stephane , Ferguson Sarah E. , May Taymaa
Published: May 2020

6046

Background: The role of intraperitoneal (IP) chemotherapy in the management of advanced ovarian cancer has been questioned given emerging evidence showing lack of survival benefits. The objective of this study was to compare the long-term survival associated with IP chemotherapy at a tertiary cancer center. Methods: We reviewed the long-term survival records of 271 women with stage IIIC or IV high-grade serous ovarian cancer treated with primary cytoreductive surgery (PCS) followed by IP or intravenous (IV) chemotherapy between 2001-2015 with a minimum follow-up of 4 years. 5-year progression free (PFS) and overall survival (OS) rates were compared using Kaplan-Meier survival analysis and covariates were evaluated using Cox regression analysis. Results: Women who received IP chemotherapy after PCS (n = 91) were more likely to have undergone aggressive surgery (p < 0.001), longer surgery (p < 0.001), and had no residual disease (p < 0.001) compared to the IV arm (n = 180). Median follow-up was 51.6 months. Five-year PFS was 19% vs. 18% (p = 0.63) and OS was 73% vs. 44% (p = 0.00016) in the IP vs. IV arms, respectively. After controlling for covariates in a multivariable model, the use of IP was no longer a significant predictor of OS in the entire cohort (p = 0.12). In patients with 0mm residual disease, PFS was 28% vs. 26% (p = 0.67) and OS was 81% vs. 60% (p = 0.059) in IP (n = 61) vs. IV (n = 69), respectively. In patients with residual of 1-9mm, PFS was 30% vs. 48% (p = 0.076) and OS was 60% vs. 43% (p = 0.74) in IP (n = 29) vs. IV (n = 31), respectively. Conclusions: IP chemotherapy showed a trend towards improved survival over conventional IV chemotherapy, especially in patients with no residual disease. Given the retrospective nature and small numbers in this study, prospective non-randomized cohort studies are warranted to evaluate the role of IP chemotherapy in advanced ovarian cancer.
Olaparib maintenance monotherapy for non-germline BRCA1/2-mutated (non-gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase IIIb OPINION interim analysis.
Authors: Poveda Andres , Lheureux Stephanie , Colombo Nicoletta , Cibula David , Lindemann Kristina , Weberpals Johanne I , Bjurberg Maria , Oaknin Ana , Sikorska Magdalena , Gonzalez Martin Antonio , Madry Radoslaw , Rubio Pérez Maria Jesus , Davidson Richard , Blakeley Christopher , Bennett James , Barnicle Alan , Skof Erik
Published: May 2020

6057

Background: In the Phase II Study 19 trial (NCT00753545; Ledermann et al. Lancet Oncol 2014), maintenance olaparib improved progression-free survival (PFS) vs placebo in PSR OC pts, including those in the non-BRCAm subgroup. A significant PFS benefit was also seen with maintenance olaparib vs placebo in gBRCAm PSR OC pts in the Phase III SOLO2 trial (NCT01874353; Pujade-Lauraine et al. Lancet Oncol 2017). To investigate olaparib maintenance monotherapy in non-gBRCAm PSR OC pts who had received ≥2 previous lines of platinum-based chemotherapy, we performed the Phase IIIb, single-arm, OPINION study (NCT03402841). Methods: Pts had high-grade serous or endometrioid OC and had responded to platinum-based chemotherapy. Pts initiated maintenance olaparib tablets (300 mg bid) until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed PFS (modified RECIST 1.1). Secondary endpoints included PFS by homologous recombination repair deficiency (HRD; assessed with the Myriad myChoice HRD plus test; HRD+ve: score ≥42) and somatic BRCA mutation (sBRCAm) status. An interim analysis was planned after ~135 PFS events. Results: 279 pts were enrolled from 17 countries (mean age: 64 yrs); 94.3% were confirmed non-gBRCAm by local testing. At data cut-off (Nov 15, 2019), the median PFS was 9.2 months (95% confidence interval [CI]: 7.6–10.9 months), with 152 PFS events (54.5% maturity). The Table presents PFS outcomes by key subgroups. The median exposure to olaparib was 8.1 months. Grade ≥3 adverse events (AEs) occurred in 72 (26%) pts. 19% of pts reported serious AEs. No deaths related to AEs were reported. AEs led to dose interruption, dose reduction and treatment discontinuation in 39%, 15% and 7% of pts, respectively. Conclusions: Maintenance olaparib demonstrated activity in non-gBRCAm PSR OC pts. There were no new safety signals. Clinical trial information: NCT03402841. [Table: see text]
Are symptoms distinguishable in ovarian cancer? A nested case control study of insurance claims.
Authors: Langabeer Denise Manon , Krause Trudy , Ganduglia Cazaban Cecilia M , Swartz Michael D , Lopez David S , Bodurka Diane C.
Published: May 2020

6063

Background: Over 60% of ovarian cancer cases are diagnosed with Stage III and IV disease. The US healthcare system does not support a standard screening method for ovarian cancer. Our goal was to determine whether certain symptoms based on ICD-9 categories are distinguishable among women diagnosed with ovarian cancer and women without ovarian cancer. Methods: Women diagnosed with ovarian cancer were randomly matched 1:1 to women without cancer to support a nested case-control analysis of health insurance claims between 2008 through 2013 from a commercial payer. The following eligibility criteria were applied: 1) 24 years of age or older; 2) continuously enrolled in healthcare plan for a minimum period of 6 months; 3) experienced more than 1 symptom over the observation period; and 4) an observation period of a minimum of 6 months. Symptoms were based on 47 ICD-9 diagnosis codes and categorized specific to pain, abdominal and pelvic, digestive, and bladder. The analysis was based on 1,578 women (789 cases; 789 controls). Results: Overall, 90% (n = 1,421) of the women experienced abdominal and pelvic symptoms, and 92% (n = 725) of the women with ovarian cancer visited their physician for this complaint 6-70 months prior to diagnosis, OR 1.66 (CI 1.14 to 2.41; p = .008). Pain was reported as a complaint by cases at nearly 60% (n = 464) and controls at 48% (n = 376); OR 1.75 (CI 1.39 to 2.19; p < .001). Symptoms for bladder and digestive combined represented 68% of complaints for both cases (n = 507) and controls (n = 555), p = .024 and p = .298, respectively. Of the 1,578 women, 77% (cases = 621; controls = 595) experienced more than one category of symptoms. Both cases (n = 206) and controls (n = 153) complained of abdomen and pelvic symptoms along with pain; OR 1.54 (CI 1.19 to 1.99; p = .001). A second combination included abdomen and pelvic symptoms with pain and digestive symptoms in 14% of women (cases n = 99; controls n = 67); OR 1.58 (CI 1.13 to 2.22; p = .008). Sixty percent (n = 473) of women with ovarian cancer experienced the majority of associated pre-diagnosed symptoms analyzed for the study. Conclusions: Certain recurring symptoms associated with abdomen and pelvic as well as pain appear to indicate an association with ovarian cancer, signifying that symptom awareness remains relevant to this disease that is diagnosed at a late stage and currently does not have routine screening methods to support early detection.
Risk of venous thromboembolism in patients receiving neoadjuvant chemotherapy for ovarian cancer.
Authors: Basaran Derman , Suhner Jessa , Sassine Dib , Boerner Thomas , Liu Ying L , Grisham Rachel N. , Tew William P. , Gardner Ginger J. , Zivanovic Oliver , Sonoda Yukio , Long-Roche Kara C. , Chi Dennis , Soff Gerald A. , Jewell Elizabeth Lin
Published: May 2020

6073

Background: To identify the incidence of newly occurring venous thromboembolism (VTE) in patients with ovarian cancer receiving neoadjuvant chemotherapy (NACT). Methods: Using our prospectively maintained ovarian cancer database, we identified all ovarian cancer patients who received NACT at our institution from 4/15-9/18. VTE events included clinically diagnosed deep venous thrombosis (DVT) or pulmonary embolism (PE). Patients who presented with VTE prior to induction of NACT or patients on anticoagulation therapy prior to diagnosis were excluded. The incidence of newly occurring thrombotic events were categorized according to treatment phases, defined as 1) NACT prior to interval debulking surgery (IDS); 2) intraoperative and 30-day post-IDS; and 3) adjuvant chemotherapy. Results: 290 patients underwent NACT during the study period. Thirty-eight patients (13%) who presented with VTE, 12 (4%) on anticoagulation at presentation, and 4 (1.4%) seeking only a second opinion were excluded from analysis. Of the 236 evaluable patients, the overall rate of VTE during all treatment phases was 15% (35/236). In treatment phase I, 11% (27/236) of patients experienced VTE during NACT. In phase II, an additional 2.5% (6/236) developed VTE in the intraoperative and 30-day postoperative period. In phase III, an additional 0.8% (2/236) experienced a thrombotic event >30 days postoperatively. Sevety-seven percent (27/35) of VTE events occured during phase I. Conclusions: Patients receiving NACT for advanced ovarian cancer are at high risk for the development of clinically detectable thromboembolic events. The highest rate of new VTE events was seen during induction of NACT, a phase of treatment traditionally without any prophylactic anticoagulation. Further research regarding the timing of thromboprophylaxis for this patient population is warranted. [Table: see text]
Influence of BRCA pathogenic variants in the benefit of secondary cytoreductive surgery.
Authors: Estati Felipe Leonardo , Alencar Viviane , Pirolli Rafaela , Ribeiro Adriana Regina Goncalves , Torrezan Giovana Tardin , Carraro Dirce Maria , Formiga Maria Nirvana , Guimaraes Andrea Paiva , Baiocchi Glauco , Da Costa Alexandre Andre B. A.
Published: May 2020

6076

Background: Germline BRCA pathogenic variants are present in 15% to 25% of ovarian carcinoma patients. These tumors are more sensitive to platinum and PARP inhibitor therapy and have a better prognosis. Two retrospective studies with limited number of patients have shown conflicting results regarding the benefit of secondary cytoreductive surgery (SCS) in patients with BRCA mutations. Our aim was to evaluate the impact of SCS in recurrent ovarian cancer according to BRCA status. Methods: All patients with ovarian carcinoma with recurrent disease and who were tested for BRCA pathogenic variants treated at a tertiary Cancer Center in Brazil were included. Patients characteristics were compared between patients treated with SCS and not treated with SCS. Cox regression analysis was used to evaluate the impact of SCS on progression free survival (PFS) and the influence of BRCA pathogenic variants on the effect of SCS. Results: One hundred and forty patients were included, 49.6% were treated with SCS and chemotherapy and 50.4% treated with chemotherapy only. Patients treated with SCS were younger, presented better performance status, lower CA 125 and longer platinum free interval. After adjusting for relevant covariables SCS was associated with longer PFS (HR 0.53, 95%CI 0.29-0.97, p = 0.039). Germline BRCA pathogenic variants were found in 37 patients (26.4%). No patient was treated with PARP inhibitors. Among non-carriers of pathogenic variants in BRCA, SCS lead to a longer PFS (HR 0.48, 95%CI 0.28-0.81, p = 0.006) but among carriers there was no benefit of SCS (HR 0.84, 95%CI 0.30-2.34, p = 0.735). Test for interaction was not statistically significant (p = 0.359). Conclusions: Our study is the second to demonstrate no benefit of SCS among patients with BRCA pathogenic variants and not treated with PARP inhibitor. The only other study to show a benefit of SCS in this group of patients included a limited number of patients and all of them were treated with PARP inhibitors. BRCA germline status might influence the efficacy of SCS, and should be evaluated as a potential biomarker to be assessed together with clinical factors to better select patients for SCS.
An open-label, multicenter, phase Ib/II study of rebastinib in combination with paclitaxel in a dose-expansion cohort to assess safety and preliminary efficacy in patients with advanced or metastatic endometrial cancer.
Authors: Janku Filip , Hamilton Erika Paige , Chu Christina , Richardson Debra L. , Arend Rebecca Christian , Kuida Keisuke , Achour Haroun , Ruiz-Soto Rodrigo , Hays John L.
Published: May 2020

6085

Background: Rebastinib is a switch control inhibitor targeting tunica interna endothelial cell kinase (TIE2). TIE2 is primarily expressed in endothelial cells playing a role in angiogenesis. TIE2 is also expressed in a subset of macrophages with pro-metastatic and immunosuppressive properties and linked to chemo-resistance. This study is a 2-part open-label, phase Ib/II, multicenter study of rebastinib orally administered, in combination with paclitaxel. In Part 1, we observed encouraging antitumor activity of rebastinib with 5 PRs in 24 patients (pts) at 50 mg BID and 3 PRs in 19 pts at 100 mg BID from a heavily pretreated heterogeneous patient population. Here we summarize preliminary results from the endometrial cancer (EC) cohort of Part 2. Methods: Part 2 of this study has four disease-specific cohorts (TNBC, inflammatory breast cancer, ovarian cancer and EC). Pts were evaluated for safety (CTCAE v5.0) and efficacy (RECIST v1.1). According to the Simon 2-stage design of this study, for each cohort, 15 additional pts will be enrolled if more than 4 PRs are observed. Results: As of Jan 21, 2020, 19 EC pts were enrolled with a median age of 66 years. All pts received at least one prior line of paclitaxel and 12 (63%) pts received >3 prior anti-cancer therapies. Sixteen pts were treated with rebastinib starting dose 100 mg BID (reduced to 50 mg BID due to a higher frequency of muscular weakness) and 3 pts with 50 mg BID, in combination with 80 mg/m2 weekly paclitaxel with a median duration of treatment 85 days (6, 225). In 15 evaluable pts, there were 5 PRs (4 confirmed) and 6 SD8 weeks for an ORR of 33% and clinical benefit rate of 73%. Treatment-emergent AEs (>20%) were mostly ≤ grade 2: constipation, fatigue (each n=9); alopecia, peripheral edema (each n=8); dysgeusia, peripheral sensory neuropathy, arthralgia (each n=6); diarrhea, hypomagnesaemia, vomiting, dry mouth (each n=5); anemia, decreased appetite, dyspnea, nausea, and muscular weakness (each n=4). Serious AEs possibly related or related to rebastinib included muscular weakness (n=2, at 100 mg BID), head discomfort (n=1) and increase troponin (n=1) which resolved after dose interruption. Conclusions: Preliminary activity of rebastinib in combination with paclitaxel was encouraging in heavily pretreated EC pts, all of whom received prior paclitaxel. The safety profile of rebastinib at 50 mg BID was generally well tolerated. The EC cohort is enrolling at 50 mg BID in stage 2 of the study. Clinical trial information: NCT03601897.
Efficacy and safety of laterally extended endopelvic resection for the pelvic side wall gynecologic tumors: A four-year prospective cohort study with historical comparison.
Authors: Paik Haerin , Park Soo Jin , Kim Hee Seung , Kim Jae-Weon
Published: May 2020

6092

Background: Although laterally extended endopelvic resection (LEER) has been introduced to control the pelvic sidewall tumors, there is a lack of evidence about its efficacy and safety despite high skillful procedure, compared with the other treatments. Thus, we performed a prospective cohort study with historical comparison for four years. Methods: One gynecologic oncologist performed LEER consecutively for patients with the pelvic sidewall tumors between March 2014 and July 2018. We compared clinicopathologic characteristics and survival between patients who received primary LEER and with those treated with other treatments. Results: We enrolled 37 patients treated with LEER. Among them, 22 (59.5%) and 15 (40.5%) had recurrent and primary disease. Among perioperative outcomes, there was more estimated blood loss, and hospitalization was longer in recurrent disease and previous surgery (p < 0.05). In recurrent disease, previous progression-free survival < 8 months was related to poor recurrence-free survival after LEER (median, 5.4 vs. 10.2 months; p < 0.05). When LEER was applied for the first recurrence of cervical cancer, recurrence-free survival and overall survival after treatment seemed to be longer in LEER (n = 9) than in palliative chemotherapy (n = 27) without statistical significance (median, 12.2 vs. 4.7 months and 23.2 vs. 12.4 months; p = 0.13 and p = 0.63). In 15 patients with primary locally advanced cervical cancer, LEER after partial response to neoadjuvant chemotherapy showed longer progression-free survival than LEER after stable or progressive disease to neoadjuvant chemotherapy and primary radiotherapy (p = 0.012). After LEER, grade 3 and 4 complications developed in 15 (23.1%) and 2 (3.1%) patients. Conclusions: Compared with palliative chemotherapy, LEER followed by palliative chemotherapy may improve progression-free survival in patients with recurrent cervical cancer located in the pelvic sidewall. If possible, it is more effective to apply LEER without preceding palliative chemotherapy for recurrent cervical cancer located in the pelvic sidewall.
GEM20110714: Final overall survival results of the phase III study of first-line gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma.
Authors: Hong Shaodong , Huang Yan , Yang Yunpeng , Yu Gengsheng , Jia Jun , Peng Jiewen , Lin Qing , Xi Xuping , Peng Peijian , Chen Dongping , Xu Mingjun , Lu Xiaojun , Zhang Li
Published: May 2020

6521

Background: GEM20110714, the first randomized, phase III study (NCT01528618) of systemic chemotherapy in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC), reported significant reduction of disease progression with gemcitabine plus cisplatin (GP) versus fluorouracil plus cisplatin (FP; hazard ratio [HR], 0.55; 95% CI, 0·44–0·68; P < .001). This study establishes GP as the standard-of-care for first-line treatment of R/M NPC. We present the final overall survival (OS) analysis here. Methods: In this multicenter, open-label study conducted in China, patients who had an Eastern Cooperative Oncology Group performance status of 0 or 1 and R/M NPC were randomly assigned (1:1) to receive up to six cycles of either GP or FP once every 3 weeks. The primary endpoint was PFS, which has been previously reported; OS was a secondary endpoint. The final OS analysis was conducted with the data cutoff date of December 17, 2019. Results: After a median follow-up time of 64.4 months (95% CI, 61.1-67.6), 148 (81.8%) and 165 (91.2%) deaths occurred in the GP and FP arms, respectively. The estimated hazard ratio for OS was 0.723 (95% CI, 0.578 to 0.904; two-sided P = .004). The median OS was 22.1 months with GP versus 18.6 months with FP. The OS probabilities at 1, 3, and 5 years were 79.9% vs. 71.8%, 31.0% vs. 20.4%, and 18.5% vs. 7.6%, respectively. Un-predefined subgroup analyses based on baseline characteristics were consistent with the primary OS analysis. Postdiscontinuation systemic therapy use was similar: GP, 52%; FP, 57%. No new safety signals emerged. Conclusions: In patients with R/M NPC, GP is the first regimen to show significant improvement in OS in a phase III randomized study compared with a traditional chemotherapy regimen (i.e. FP). GP should be considered the standard treatment option for these patients. Clinical trial information: NCT01528618 .
Final results of the multicenter, open-label, randomized phase II trial PAZOTHYR evaluating continuous versus intermittent administration of pazopanib in radio-iodine-refractory thyroid cancers (NCT01813136).
Authors: De La Fouchardiere Christelle , Godbert Yann , Dalban Cécile , Do Cao Christine , Illouz Frederic , Zerdoud Slimane , Wassermann Johanna , Bardet Stephane , Rodien Patrice , Chougnet Cecile N , Benisvy Danielle , Niccoli Patricia , Ravaud Alain , Lebosse William , Bourne-Branchu Valérie , Gautier Julien , Leboulleux Sophie ,   Tuthyref
Published: May 2020

6540

Background: Multikinase inhibitors (MKI) targeting angiogenesis, including pazopanib (P), have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC) but are accompanied by adverse effects, leading to dose adjustments/interruptions. We aimed to investigate the efficacy and tolerance of a discontinuous scheme of pazopanib administration in this situation. Methods: This randomized phase II study enrolled RAIR-TC patients (pts) in first or second-line of MKI with documented disease progression within 12 months (m). After a 6-m pazopanib continuous induction phase, pts with stable disease (SD) or tumor response were randomly assigned in a 1:1 ratio to receive continuous pazopanib (CP) or intermittent pazopanib (IP) until progression and restart. They were stratified by best tumor response [stable disease vs. objective response] and prior MKI treatment [yes vs. no]). Primary endpoint was time to treatment failure (TTF) defined as time between randomization and permanent discontinuation of pazopanib (either for disease progression or intolerance); secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and safety. Results: 168 pts (66.5 years median age; 51.8% female) were included and 100 pts randomized (CP: 50, IP: 50). The median number of metastatic sites was 2.0 (1-7) and 50 pts (29.8%) were pretreated with MKI. With a median follow-up of 31.3 m, we did not show any statistically significant difference in the TTF, 80% (66.0-88.7%)] of the pts being under P at 6 m after randomization in the IP arm versus 78% (63.8-87.2%) in the CP arm. Median TTF was 14.7 m 95% CI [9.3; 17.4] and 11.9 m 95% CI [7.5; 15.6] respectively (HR 0.79 [0.49-1.27]). The best response with P was 35.6% (95% CI [28.2; 43.6]) and the disease control rate was 89.4% 95% CI [83.5; 93.7]. Median time to progression under P was not statistically different between 2 arms (5.7m 95% CI [4.8;7.8] in the IP arm vs. 9.2m 95% CI [7.3;11.1] in the CP arm (HR 1.36 [0.88; 2.12]). 36/100 pts (36%) experienced pazopanib-related grade 3/4 AEs (CP:17; IP: 19) mainly represented by gastrointestinal disorders, hypertension, cardiac disorders and asthenia. Five pazopanib-related deaths were reported (CP:1;IP: 4). Conclusions: The intermittent administration of pazopanib study did not significantly demonstrate superiority in efficacy or tolerance over continuous treatment. Continuous administration of MKI remains the standard in RAIR-TC. Clinical trial information: NCT01813136 .
Overall survival modeling and association with serum biomarkers in durvalumab-treated patients with head and neck cancer.
Authors: Pierre Vadryn , Guo Xiang , Gonzalez-Garcia Ignacio , Morsli Nassim , Yovine Alejandro Javier , Li Weimin , Narwal Rajesh , Roskos Lorin , Baverel Paul
Published: May 2020

6549

Background: Optimal patient selection for immunotherapy remains a challenge as most patients fail to respond. We aim to assess baseline factors for association with long-term survival from durvalumab treatment in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)1,2. Methods: Pooled longitudinal tumor size, survival, and dropout data from four trials (1108: NCT01693562, CONDOR: NCT02319044 , HAWK: NCT02207530, and EAGLE: NCT02369874) involving 467 HNSCC patients were used to develop tumor size-driven hazard models. A panel of 66 serum protein biomarkers at baseline and 4 relevant clinical markers from 346 out of 413 patients treated with durvalumab (all studies except 1108) were initially screened to select a pool of 21 candidate covariates. The criteria for dimensionality reduction comprised correlation strength between biomarkers and pharmacological hypotheses pertaining to a prior analysis3 (inflammation, immunomodulation, tumor burden and angiogenesis). Results: The final tumor model highlighted that high tumor burden, elevated LDH and neutrophil-lymphocyte ratio were associated with faster tumor growth while patients with lower baseline tumor burden had an increase in net tumor shrinkage. For overall survival, the model suggested that high levels of immunomodulators (IL23, Osteocalcin), low inflammation (IL6, NLR), low tumor burden, and low angiogenesis factors (von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1)) were associated with survival benefits for patients treated with durvalumab. Specifically, these patients had baseline serum IL23 > 2.1 pg/mL and Osteocalcin > 32 pg/mL or serum PAI-1 < 229 pg/mL and serum IL6 < 5.4 pg/mL which corresponded to a hazard ratio estimate (HR and 95%CI) of 0.36 (0.27- 0.47), logrank p-value: 2.3x10−14. The median (n, 95%CI) overall survival time for the patients with favorable biomarker profile was 14.6 months (n = 129, 11.2-21.4) vs. 4.4 months (n = 217, 3.6-5.3). Conclusions: Our results corroborate the prior hypothesis highlighting the prognostic value of inflammation, disease burden, tumor angiogenesis, and immunomodulatory factors on the clinical outcomes of HNSCC patients treated with durvalumab3. Collectively, we identified a serum biomarker profile of HNSCC patients with median survival times exceeding 1 year which may potentially be used for patient enrichment following further validation in prospective studies. References: 1Yanan CPT 2017, 2Baverel, 2018 ENA, 3Guo, X, 2019 Asco P6048 Clinical trial information: NCT01693562, NCT02319044, NCT02207530, NCT02369874 .
Immune functional portraits of head and neck cancer using next generation sequencing.
Authors: Raju Paul Susan , Kotlov Nikita , Svekolkin Viktor , Frenkel Felix , Almog Nava , Tsiper Maria , Nomie Krystle , Fowler Nathan Hale , Lin Derrick , Valine Laura , Sluder Ann , Bagaev Alexander , Ataullakhanov Ravshan , Poznansky Mark C , Wirth Lori J.
Published: May 2020

6561

Background: The addition of biomarkers as companion diagnostics and Next Generation Sequencing (NGS) have dramatically increased therapeutic efficacy and have aided precision medicine development. The unique genomic profile and tumor microenvironment (TME) composition of each patient can be ascertained through NGS. Using TCGA and Geo datasets, we characterized head and neck cancers (HNC) according to the cellular and functional state of their TME and conducted a pilot validation study using prospectively collected HNC tumors. Methods: To stratify the TME of HNC tumors into molecular functional portraits, we analyzed the sequencing data of 1,486 HNC tumor samples and 143 controls (normal, oral leukoplakia) from TCGA and GEO data sets. For the prospective pilot study, resected tissue from oropharyngeal carcinomas independent of HPV status were processed for whole exome (WES) and RNA-seq (n = 6; HPV-positive = 1). Results: To characterize the cellular composition and functional state of HNC tumors and their TMEs, we created 26 separate molecular signatures related to functional processes such as immune checkpoint inhibition, immune infiltration, immunosuppression, and stromal activities represented by angiogenesis and mesenchymal stromal cells. Unsupervised clustering of these signatures delineated tumors into 4 types: immune infiltration with increased stromal signatures (type A), immune infiltration with decreased stromal signatures (type B), no immune infiltration with increased stromal signature (type C), and no immune infiltration and decreased stromal signatures (type D). Most HPV-positive tumors were type B (p = 1e-27) and associated with increased survival compared to the HPV-negative tumors (types C and D; p = 3e-05). Type B HPV-positive tumors had reduced FAT1 and TP53 mutations, whereas type B HPV-negative tumors had increased caspase 8 mutations/loss. In the validation cohort, actionable mutations were found in PI3KCA and TSC2 in types A and B HPV-negative tumors. Moreover, while the HPV-positive tumor was classified as type C, we identified a caspase 8 homozygous deletion and absence of FAT1 and TP53 mutations, supporting the TCGA and GEO analysis. Conclusions: Exome and transcriptome analyses with cellular deconvolution from bulk RNA-seq enrich tumor characterization by including major TME components, providing a comprehensive biomarker profile for precision therapy and clinical decision making. Our prospective analysis identified TME parameters comparable with the large datasets and revealed targetable genomic alterations.
18 FDG PET/CT prediction of treatment outcomes in patients with p16-positive, non-smoking associated, locoregionally advanced oropharyngeal cancer (LA-OPC) receiving deintensified therapy: Results from NRG-HN002.
Authors: Subramaniam Rathan M , Demora Lyudmila , Yao Min , Yom Sue S. , Gillison Maura L. , Caudell Jimmy J. , Waldron John , Xia Ping , Chung Christine H. , Truong Minh-Tam , Harrison Louis B , Chan Jason , Geiger Jessica Lyn , Mell Loren , Seaward Samantha A. , Thorstad Wade , Beitler Jonathan Jay , Sultanem Khalil , Blakaj Dukagjin , Le Quynh-Thu
Published: May 2020

6563

Background: To determine the negative predictive value (NPV) of 12-14 week post-treatment PET/CT for 2-year progression-free survival (PFS) and 2-year locoregional control (LRC) in NRG-HN002, which is a two-arm phase II trial for patients with low-risk, non-smoking associated p16-positive LA-OPC randomized in a 1:1 ratio to reduced-dose IMRT with or without cisplatin. Methods: PET/CT scans were reviewed both centrally and locally by participating institutions. Tumor response evaluations for primary site, right neck, and left neck were carried out using a 5-point ordinal scale (‘Hopkins Criteria’). Overall scores were then assigned as ‘Negative,’ Positive,’ or ‘Indeterminate.’ Patients who had a ‘Negative’ score for all three evaluation sites were given an overall score of ‘Negative.’ The endpoints were NPV for LRC and PFS at 2 years testing NPV ≤ 90% vs > 90% (1-sided alpha 0.10 and 76% power). Results: There were 316 patients enrolled, of whom 306 were randomized and eligible. Of these, 131 (42.8%) patients consented to a post-therapy PET/CT, and 117 (89.3%) patients were eligible for PET/CT analysis. The median time from end of treatment to PET/CT scan was 94 days (range 52-139). The rates of 2-yr PFS and LRC in the analysis subgroup were 91.3% and 93.8%, respectively. Based on central review, post-treatment scans were negative for residual tumor for 115 patients (98.3%) and positive for 2 patients (1.7%). The NPV for 2-year LRC was 94.5% (90% lower confidence bound [LCB] 90.6%; p = 0.07). NPV for 2-year PFS was 92.0% (90% LCB 87.7%; p = 0.30). Similar NPV results were obtained based on analysis of local reviews. Conclusion: Within the context of deintensification with reduced-dose radiation, the NPV of a 12-14 week post-therapy PET/CT for 2-year LRC is statistically > 90%, similar to that reported for patients receiving standard chemoradiation. However, in this study, there was not enough evidence to conclude that the NPV of a 12-14 week post-therapy PET/CT for 2-year PFS is > 90%. Grant acknowledgement: This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA180803 (IROC), UG1CA189867 (NRG Oncology NCORP) from the National Cancer Institute (NCI). This project is funded, in part, under a Grant with the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. Clinical trial information: NCT02254278 .
Effect of mammography screening frequency on false-positive biopsy rates and detection of local recurrence among breast cancer survivors.
Authors: McGuinness Julia E , Manley Haley , Yuan Sarah , Pan Samuel M , Zhao Ziyi , Ha Richard D. , Genkinger Jeanine M , Crew Katherine D.
Published: May 2020

7016

Background: Current guidelines recommend that women with a history of early-stage breast cancer treated with breast-conserving therapy (BCT) continue screening mammography after treatment. One strategy is semi-annual ipsilateral mammography for the first 3 years after diagnosis, when risk of local recurrence is highest. However, a potential harm of more frequent screening is false-positive breast biopsy. We examined the association between screening frequency and rates of false-positive biopsy and local recurrence among breast cancer survivors. Methods: We conducted a retrospective cohort study at Columbia University Irving Medical Center (CUIMC) in New York, NY, of women diagnosed with stage 0-III breast cancer from 2007 to 2017, who were treated with BCT and had at least 2 screening mammograms at CUIMC within the first 3 years after diagnosis. Demographic and clinical information were collected from the electronic health record. Frequency of mammography screening was defined as the median interval between two consecutive mammograms (every 6 months vs. yearly). False-positive biopsy and local recurrence were identified by review of breast pathology reports. A false-positive biopsy was defined as a breast biopsy without evidence of invasive or non-invasive cancer. Descriptive statistics and logistic regression models were conducted to examine relationships between covariates and either false-positive biopsy or local recurrence. Results: In our study cohort (n = 1404), the median age at breast cancer diagnosis was 61 years (range, 24-94), including 45% white, 14% black, 32% Hispanic, and 8% Asian. Eighty percent of women had screening mammography of the ipsilateral breast every 6 months during the first 3 years after diagnosis. Comparing women who screened every 6 months vs. yearly, there was no difference in local recurrence rates (4.0% vs. 4.1%), including screen-detected and invasive recurrences, but a higher rate of false-positive biopsy (13.5% vs. 7.5%). In multivariable analysis, women who screened every 6 months had about a 2-fold increased risk of having a false-positive biopsy (OR 1.93; 95% CI 1.17-3.19); no other factors were significantly associated with false-positive biopsy. Conclusions: We observed that women with early-stage breast cancer treated with BCT who underwent more frequent screening mammography had more false-positive breast biopsies, but no difference in local recurrence rates. Future studies are needed to determine optimal screening strategies for breast cancer survivors.
Effect of shorter time to treatment on survival in rural patients with breast cancer.
Authors: Kamath Suneel Deepak , Wei Wei , Tullio Katherine , Cooper Gregory S. , Khorana Alok A.
Published: May 2020

7027

Background: Rural cancer care in the United States has unique challenges from variable access to care. This study examined differences in time to first treatment (TTT), a potential surrogate for access, and predictors of overall survival (OS) between rural and non-rural patients with breast cancer. Methods: Women with stage I-III breast cancer from 2004-2012 in the National Cancer Database of Commission on Cancer (CoC)-accredited facilities were included and categorized as rural and non-rural. Differences in demographic, disease and treatment characteristics, socioeconomic factors and TTT (< 4 weeks, 4-8 weeks and > 8 weeks) between rural and non-rural patients were assessed by Chi-square test. The effect of age, insurance status, cancer center type, community median income, community % no high school, and TTT on OS were assessed using univariate and multivariate Cox models. Results: The study included 1,205,031 patients, 18,417 (2%) of whom were rural. Compared to non-rural patients, rural patients were more likely to be age > 65, Caucasian, receive care at non-academic centers, have government insurance, have lower income and less education (p < 0.0001 for all). Significant demographic and socioeconomic differences are shown in Table. Rural patients had shorter mean TTT (3.72 vs. 4.35 weeks, p < 0.0001). More rural patients had TTT < 4 weeks (67% vs. 57%) and < 8 weeks (94% vs. 90%), p < 0.0001 for both. Shorter TTT (both < 4 weeks vs. 8 weeks and 4-8 weeks vs. > 8 weeks) was associated with improved OS (HR: 0.84, 95% CI: 0.82-0.86, p < 0.0001 and HR: 0.82, 95% CI: 0.81-0.83, p < 0.0001, respectively). After adjusting for demographic, socioeconomic, disease stage and treatment factors, rural status was associated with significantly better OS compared to non-rural status (HR: 0.92, 95% CI: 0.89-0.96, p < 0.0001). Conclusions: Despite several adverse socioeconomic factors, rural patients with breast cancer with access to CoC-accredited facilities had significantly shorter TTT and better OS compared to non-rural patients. These data suggest improving TTT can mitigate disparities in rural cancer care. It is unclear whether our data apply to non-CoC-accredited facilities in rural United States. [Table: see text]
Morbidity, mortality and healthcare use among siblings of children with cancer: A population-based study.
Authors: Desai Aditi , Lau Cindy , Sutradhar Rinku , Lee Douglas , Nathan Paul C. , Gupta Sumit
Published: May 2020

7040

Background: Siblings of children with cancer are at increased risk of adverse mental health outcomes; impact of the childhood cancer experience on these siblings’ physical health is unclear. We characterized the long-term risk of adverse physical health outcomes and healthcare use among siblings of children with cancer. Methods: Pediatric cancer patients in Ontario diagnosed between 1988 and 2016 were linked to their biological siblings to form the siblings/case cohort. Cases were matched to population controls based on sex, age, and residence area. Index date for cases was the date of their brother’s or sister’s cancer diagnosis (controls had the same index date as cases). After individual linkage to health services data, we compared several outcomes between these two groups: 1) physical health conditions (e.g. cancer, hypertension, injuries, death); 2) acute healthcare use (hospitalization, emergency department [ED] visits), and; 3) preventative healthcare use (periodic health checkups, influenza vaccinations). Predictors of outcomes, including demographics and characteristics of the cancer-affected child, were examined in cases. Cox proportional hazards, recurrent event, or logistic regression models were used as appropriate. Results: We identified 8,529 cases and 30,364 matched controls [median age at index: 6 years, interquartile range (IQR) 0-10; median follow-up time: 9 years, IQR 5-15]. Compared to controls, cases had increased risk of hypertension [hazard ratio (HR) 1.8; 95% confidence interval (95CI) 1.1-2.9; p = 0.01]. They also had higher rates of ED visits [rate ratio 1.1; 95CI 1.1-1.2; p < 0.001] and increased risk of hospitalization [HR 1.1; 95CI 1.1-1.2; p < 0.001]. Cases were more likely to undergo periodic health checkups [odds ratio (OR) 1.1; 95CI 1.0-1.1; p = 0.01] and influenza vaccinations [OR 1.5; 95CI 1.4-1.6; p < 0.001]. In multivariable analysis restricted to cases, rurality and bereavement, among other predictors, were associated with increased use of acute healthcare. Conclusions: Increased risk of hypertension and hospitalization in cases suggests that these siblings are experiencing poorer physical health compared to their peers. Increased rates of ED visits and preventive healthcare suggests parental anxiety surrounding these siblings’ health. Siblings at highest risk of adverse outcomes could be identified through demographic characteristics, among others. Siblings would benefit from targeted surveillance and further investigation to elucidate underlying mechanisms influencing their health.
Breast cancer patients’ insurance status correlates with their adherence to endocrine therapy: Analysis of ECOG-ACRIN TAILORx trial.
Authors: Sadigh Gelareh , Gray Robert James , Yanez Betina , Wagner Lynne I. , Garcia Sofia F. , Sparano Joseph A. , Cella David , Carlos Ruth
Published: May 2020

7041

Background: Cancer patients spend substantial amounts on their healthcare services, and are at high risk for financial toxicity, a patient-reported outcome shown to be associated with care non-adherence. Even with insurance, cancer patients often face unpredictable or unmanageable costs. In women with breast cancer enrolled in TAILORx trial, we investigated the association between study entry insurance status and adherence to endocrine therapy (ET). Methods: Women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer enrolled in TAILORx clinical trial who started ET within a year of study entry were included. Early discontinuation was defined as stopping ET within 4 years of start for reasons other than distant recurrence or death, and the rate was calculated using Kaplan-Meier estimates. Cox proportional hazards model was used to analyze association between the patients’ insurance status at study entry and early discontinuation of ET incorporating patients’ treatment, age, race and Recurrence Score in the model. Results: A total of 9,475 patients were included (mean age: 55.6; 84% white; 9% Hispanic). A total of 58.0% had private insurance, while 11.7% had Medicare; 5.8% had Medicaid; 0.98% had military/VA insurance; 3.8% were self-pay, and 19.1% were patient recruited from international sites. The rates of 4-year early discontinuation were highest among self-pay (18.7%) and Medicaid patients (18%) and lowest among patients with military/VA insurance (8.6%) and international sites (9.8%). In multivariable analysis, compared to private insurance patients with Medicaid (HR 1.6; 95% CI 1.3-2.0) and self-pay (HR 1.6; 95% CI 1.3-2.1) had higher probability of discontinuing ET within 4 years of start and those at international sites had lower probability of early discontinuation (HR 0.8; 95% CI 0.7-0.9) (All p values < 0.05). Conclusions: Patients’ insurance status plays an important role in adherence to ET with uninsured and underinsured having a high rate of treatment non-adherence. Early identification of patients at risk and enrollment in insurance optimization programs may improve adherence to therapy. Clinical trial information: NCT00310180 .
Concurrent and sequential chemoradiation therapy are associated with improved survival among unresected stage III non-small cell lung cancer patients in the United States.
Authors: Zheng Zhiyuan , Rengan Ramesh , Zhao Jingxuan , Sineshaw Helmneh M. , Chun Stephen G. , Han Xuesong , Yong Candice , Seal Brian S. , Makari Doris , Simone Charles B.
Published: May 2020

7043

Background: Concurrent chemoradiation therapy (cCRT) has been shown to improve survival outcomes among inoperable stage III non-small cell lung cancer (NSCLC) patients compared to sequential CRT (sCRT) and single-modality therapy in clinical trials. However, many “real world” patients do not receive CRT, and less is known about the survival benefits of concurrent CRT vs other treatment modalities in pragmatic, non-clinical trial settings. Methods: We used the National Cancer Database (2004-2011) to identify unresected stage III NSCLC patients (ages 18-79 years) with Charlson comorbidity score ≤1 and 5-year follow up through the end of 2016. cCRT was defined as the initiations of chemotherapy (CT) and radiation therapy (RT) that were ≤14 days (n = 30,290) apart, whereas sCRT was defined as > 14 days apart (total n = 10,596). The remaining three treatment groups included CT only (n = 11,216), RT only (n = 7,772), and neither CT/RT during first course treatment (n = 10,694). Cox proportional hazard model was used to examine the 5-year survival by treatment modalities, controlling for patient demographics, comorbidity score, health insurance, facility type, area-level social deprivation index (SDI, a composite measure for area-level socio-economic status), driving time to the treatment facility, diagnosis year, and region. Adjusted hazard ratios (HR), and medium survivals were generated by treatment modalities. Results: Among 70,568 unresected stage III NSCLC patients, 61,487 (87.1%) patients died within the 5-year follow-up period. In adjusted analyses, cCRT and sCRT had similar survival (median survivals: 15.3 months), whereas other treatment modalities were associated with worse survival compared to cCRT: CT only (median survival: 10.8 months; HR [95%CI]: 1.46 [1.43-1.50]), RT only (median survival: 6.7 months; HR [95%CI]: 1.93[1.88-1.99]), and no treatment (median survival: 3.2 months; HR [95%CI]: 2.64 [2.58-2.71]), all p < 0.001. Higher comorbidity score (Charlson score 1 vs 0, HR [95%CI]: 1.18 [1.16-1.21]), non-private insurance (Medicaid: 1.16 [1.12-1.20]; Medicare: 1.10 [1.08-1.13]; uninsured: 1.21 [1.16-1.26]) were all associated with worse survival (all p < 0.001). Conclusions: Concurrent CRT and sequential CRT have similar survival outcomes among unresected stage III NSCLC patients with minimum comorbidities, however, single modality and no therapy are associated with much poorer survival among “real world” patients, and should be avoided unless clinically appropriate.