bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II randomized study of oral seliciclib in patients with previously treated nasopharyngeal carcinoma
Authors: Yeo W. , Goh B. , Le Tourneau C. , Green S. R. , Chiao J. H. , Siu L. L.
Published: August 2020

6026

Background: Seliciclib is a selective inhibitor of cyclin dependent kinases (CDKs) 2, 7 and 9. In a phase I study of 2 weeks of oral administration, clinical antitumor activity was observed in patients with treatment-naive nasopharyngeal carcinoma (NPC) and biological effects consistent with CDK inhibition were detected in tumor biopsy samples. We are conducting a multicenter, randomized phase 2 study to evaluate the safety and efficacy of prolonged administration of seliciclib in patients with previously treated NPC. The study has a lead-in phase where the safety and tolerability of 2 dosing schedules of seliciclib are to be confirmed in patients with advanced solid tumors (including NPC) before being used in the randomized phase of the study where only NPC patients are eligible to participate. The primary efficacy endpoint is 6-month progression free survival. Here we report interim findings from the lead-in phase. Methods: Eligible patients must be ≥18 years with previously treated NPC or other incurable solid tumors; must have measurable disease according to RECIST, ECOG 0–1, and adequate bone marrow, hepatic and renal function. The planned sample size is 6 to 12 patients per dosing schedule. A dosing schedule is considered tolerable for proceeding to the randomized phase if <33% patients experienced dose-limiting toxicities (DLT) during the first treatment cycle. Results: Twenty-three patients (age 38 - 74) were enrolled and treated. DLTs were observed in 4 patients: grade 3 increase in ALT or AST (n=3), and treatment delay > 2 weeks for grade 1 creatinine (n=1). Common adverse events (all grades, regardless of causality) included fatigue, nausea/vomiting, constipation, cough, fever, hypokalemia, hyponatremia, and elevation in ALT/AST, most of which were mild to moderate in intensity. Conclusions: These interim data confirm that both dosing schedules are tolerable for proceeding to the randomized phase. Majority of stable disease occurred in NPC patients. Updated data will be presented at the meeting.

[Table: see text]

No significant financial relationships to disclose.
Screening of nasopharyngeal carcinoma by serology and nasopharyngoscopy and treatment outcome in endemic region
Authors: Chua D. T. , Ji M. , Zong Y. , Chan K. , Ng M.
Published: August 2020

6029

Background: To study the incidence and treatment outcome of nasopharyngeal carcinoma (NPC) detected by serology and nasopharyngoscopy in endemic region. Methods: A prospective screening program for NPC using Epstein-Barr virus-specific viral capsid antigen IgA antibody level and nasopharyngoscopy was carried out in Southern China from 1996 to 2002. Subjects without NPC at the time of enrollment were followed-up annually by serology and clinical examination irrespective of their serology status. Subjects diagnosed to have NPC at the time of enrollment or during follow-up received conventional radiotherapy using megavoltage photon. Results: A total of 42,048 adults in Zhongshan city of China were enrolled into the screening program. About 7.4% had elevated IgA titre at the time of enrollment. NPC was diagnosed at first screening in 40 subjects and during follow-up in 131 subjects. Among the 171 NPC patients, 74 were asymptomatic and the disease was detected by the screening procedures, whereas the disease was detected in 97 following onset of symptoms. Stage distribution in those diagnosed by screening program was 59.5% stage I, 8.1% stage II, 21.6% stage III, and 10.8% stage IV. The corresponding stage distribution in subjects diagnosed after onset of symptoms was 7.2%, 12.4%, 39.2%, and 41.2%. In all NPC patients the IgA titre was found elevated and there was a serologic window in which the raised titre preceded the diagnosis of NPC for a period of up to 10 years. The median interval of this serologic window was 29 months in patients with stage I NPC and 39 months in those with stage II-IV disease. The 5-year disease-specific survival rate was 90% for stage I disease, 56% for stage II, 48% for stage III, and 52% for stage IV. Conclusions: Screening by serology and nasopharyngoscopy leads to the early diagnosis of NPC in endemic region with a high survival rate after treatment for stage I disease. In view of the rapid transition of disease from stage I to more advanced stage, a screening interval shorter than 10 months is recommended for subjects entering the serologic window.

No significant financial relationships to disclose.
Outcome and molecular features of head and neck squamous cell carcinomas (HNSCC) bearing a p16 high phenotype
Authors: Psyrri D. , Pectasides E. , Weinberger P. , Sasaki C. , Burtness B. , Fountzilas G.
Published: August 2020

6031

Background: We have previously demonstrated that p16 expression defines a biologically distinct subgroup of oropharyngeal squamous cell cancers (OSCC). Thus, OSCC can be Class I: human papillomavirus (HPV)-, Class II: HPV16+/p16-, or Class III: HPV16+/p16+. Tumors bearing a high p16 phenotype were associated with superior outcome. Using in situ automated quantitative protein expression analysis (AQUA) to explore the biomarker signatures of these 3 classes we found that beta-catenin, epidermal growth factor receptor (EGFR) and Met were upregulated in class III tumors. Our aim was to validate these findings using an independent cohort. Methods: A tissue microarray composed of 122 specimens from primary HNSCC cases treated with either external beam radiotherapy (EBRT) or gross total surgical resection and EBRT was constructed. Protein expression levels for a panel of 13 markers (EGFR, MET, STAT 3, ERK 1/2, pAkt, PI3Kp85, PI3Kp110, PTEN, p53, Bcl-2, E-cadherin, β-catenin, NFκB) were analyzed using AQUA. P16 protein levels were correlated with progression-free (PFS) and overall survival (OS). Survival analysis was performed by Kaplan-Meier method with log-rank test for assessing statistical significance.Comparison of expression between the p16 positive and p16 negative groups was done using unpaired t-tests. Results: Mean follow-up time for the cohort was 40 months. AQUA scores were divided into quartiles. Survival analysis showed that patients in the top quartile had a significantly better DFS (p = 0.01) and OS (p = 0.002). In multivariable analysis, adjusting for well-characterized prognostic variables, p16 expression retained its prognostic significance. Expression of E-cadherin and β-catenin was significantly higher in the p16 positive versus the p16 negative group (p = 0.014 and p = 0.006, respectively). p16 positive tumors also expressed higher levels of PTEN (p = 0.0009), PI3Kp110 (p = 0.03), NFκB (p = 0.007), and Bcl-2 (p = 0.005). Conclusions: These results validate p16 as a favorable prognostic marker in HNSCC. They also validate beta-catenin as a distinct biomarker in HNSCC bearing high p16 phenotype. Given that HPV+ tumors are p16+, beta-catenin is a candidate biomarker that distinguishes HPV+ versus HPV- HNSCC.

No significant financial relationships to disclose.
Clinical significance of type 1 insulin-like growth factor receptor and insulin-like growth factor binding protein-3 expression in squamous cell carcinoma of head and neck
Authors: Jun H. , Chang M. , Ko Y. , Ahn Y. , Jeong H. , Son Y. , Baek J. , Park Y. , Park K. , Ahn M.
Published: August 2020

6036

Background: Type 1 insulin-like growth factor receptor (IGF-1R) plays an important role in the growth and apoptosis of cancer cell. The activities of IGF-1R are modulated by a family of high-affinity insulin-like growth factor binding proteins (IGFBPs), of which IGFBP-3 is the major serum carrier protein. The expression and significance of IGF-1R and IGFBP-3 in squamous cell carcinoma of the head and neck (SCCHN) is unknown. Methods: This study explored immunohistochemical expression of IGF-1R and IGFBP-3 in tumor samples from 131 patients with surgically resected SCCHN. Results: The positive expression of IGF-1R and IGFBP-3 was observed in 96 (73.3%) and 117 (89.3%) patients. There were no significant differences in baseline characteristics between the positive and negative expressed groups of IGF-1R and IGFBP-3. With the median follow up of 53.5 months, 3 year progression free (PFS) and overall (OS) survival rate was 64.0% and 72.9%, neither IGF-1R nor IGFBP-3 expression had prognostic values in the whole cohort. Thirty-seven (67.3%) of 55 stage IV patients demonstrated IGF-1R positivity. The subgroup analysis of in stage IV patients showed the poor PFS ( = 0.029) and OS (pp = 0.025) in IGF-1R positive groups. In a multivariate analysis using IGF-1R expression and other clinicopathological parameters, the IGF-1R expression was remained as an independent factor for PFS (p = 0.037, HR = 2.816, 95% C.I. 1.065 - 7.446) and OS (p = 0.034, HR = 3.169, 95% C.I. 1.089 - 9.225). Conclusions: Our work exhibited that IGF-1R expression is frequent in SCCHN patients and related with poor survival in advanced stage, this could support the attempts using the IGF-1R inhibitor for treatment of SCCHN.

No significant financial relationships to disclose.
A pilot study of modified neoadjuvant docetaxel/cisplatin/5-FU (TPF) to concomitant chemoradiotherapy (CT/RT) in locally advanced head and neck cancer (LAHNC): Preliminary results
Authors: Isla D. , Martínez-Trufero J. , Morales S. , Yubero A. , Lambea J. , Álvarez I. , Polo E. , Seguí M. A. , Pujol E. , Pastor P.
Published: August 2020

6039

Background: Sequential treatment with induction CT followed by CT/RT is highly active and under study in ongoing randomized trials. We started a pilot phase II trial to explore the efficacy, toxicity profile and organ preservation of a modified neoadjuvant TPF to concurrent CT/RT in both resectable (R) and unresectable (UR) LAHNC. Methods: One hundred seventy patients(p) with stage III-IV, PS ECOG 0–2, were included to receive 3 cycles of docetaxel 75 mg/m2 iv day(d) 1, cisplatin(P) 75 mg/m2 iv d2 and 5-FU 750 mg/m2 iv continuous infusion d2–5, every 3 weeks with prophylactic ciprofloxacin 500 mg twice daily from d6–15 of each cycle and granulocyte colony-stimulating factor as secondary or primary setting, followed by P 100 mg/m2 iv d1, 22, 43 concomitant with RT (66–70 Gy, conventional fractionation). Neck dissection was planned for p with stage N2–3 after induction CT or salvage surgery for resectable p with persistent disease at the end of treatment. Results: Main p characteristics were: median age 58 years (39–77), male 89%, ECOG 0/1/2 47%/50.6%/2.4%, stage IV 62.7%, larynx/hipopharynx/oral cavity/oropharynx 45%/12%/17.3%/25.7% and R/UR 41.8%/58.2%. Median TPF/P cycles administered were 3/3. Neoadjuvant CT/total treatment overall response rate evaluation (R/UR): 70% (73%/68%)/86% (84%/88%). Neck dissection was performed in 16 p and salvage surgery in 6 p. Organ preservation was achieved in 90.8% of R p. Main G3–4 toxicity during TPF treatment was neutropenia 11.2%, febrile neutropenia 11.2%, mucositis 11.2%, and during CT/RT mucositis 16.5%, neutropenia 16.5%. Median time to progression was 19.5 m(R:15.6, UR:20.3), and median overall survival was not reached (R:not reached, UR:32.8). Conclusions: Preliminary results indicate that modified neoadjuvant TPF followed by CT/RT is an active and well tolerated regimen in LAHNC, with satisfactory organ preservation and survival.

No significant financial relationships to disclose.
Phase II study of depsipeptide (DEP) in radioiodine (RAI)-refractory metastatic nonmedullary thyroid carcinoma
Authors: Sherman E. J. , Fury M. G. , Tuttle R. M. , Ghossein R. , Stambuk H. , Baum M. , Lisa D. , Su Y. B. , Shaha A. , Pfister D. G.
Published: August 2020

6059

Background: Historically, systemic therapy for radioactive iodine (RAI)-refractory thyroid cancer has been understudied. Available drugs have modest efficacy. Depsipeptide (DEP) is a histone deacetylase inhibitor with potent anti-tumor effects both in vitro and in vivo. In thyroid cancer cell lines, DEP increases expression of both thyroglobulin and the sodium/iodine symporter messenger RNAs, offering the possibility of improved iodine concentrating ability of radioactive iodine (RAI)-resistant tumors. Methods: Eligible patients (pts) must have progressive, RAI-refractory, recurrent/metastatic, non-medullary, non-anaplastic thyroid cancer; RECIST measurable disease; and adequate organ/marrow function. Exclusionary criteria include prior chemotherapy in the recurrent/metastatic setting; cardiac disease or dysfunction; QTc prolongation or co-administration of drugs that prolong the QTc. DEP 13 mg/m2 IV is administered on days 1, 8, 15, every 28 days. The primary endpoint is response rate by RECIST criteria; change in RAI avidity is a secondary endpoint. The study closed early due to poor accrual after an unexpected grade 5 adverse event (AE) that prompted protocol suspension. Results: 20 pts were enrolled: female-50%; median age-64 years; histology-papillary (8)/follicular (1)/Hürthle (11). Grade 4–5 AE possibly related to drug: grade 5 sudden death (1); grade 4 -pulmonary embolus (1). Twelve of 20 subjects had a reported AE. No RECIST major responses have been seen. Evaluation of response: stable disease (10); progression (3); early death (1); unknown/inevaluable (6: 5 - temporary protocol suspension; 1 - withdrew consent). Restoration of RAI avidity was documented in 2 pts. For evaluable patients (14) only, median overall survival and time on study was 36 (.5–45+) months and 1.7 (0.46–12) months, respectively. Conclusions: We observed preliminary signs of in vivo reversal of RAI resistance after treatment with DEP. However, no major responses were observed and accrual was poor after the grade 5 AE. (Study funded by grant N01 CM 62206)

No significant financial relationships to disclose.
Measuring the symptom burden of head and neck cancer patients undergoing concurrent chemotherapy and radiation therapy using area under the curve
Authors: Mendoza T. , Rosenthal D. , Wang X. , Mobley G. , Cleeland C.
Published: August 2020

6067

Background: Patients with head and neck cancer (HNC) experience a significant treatment-related symptom burden during therapy that presents management challenges for both patients and treatment staff. Typical symptom measurement approaches have failed to capture the extent of this symptom burden over the course of therapy. We evaluated frequent symptom measurement summarized as area under the curve (AUC) as a way of portraying treatment related symptom burden in HNC patients, and explored this method for comparing symptoms produced by treatments that were expected to produce different levels of symptom impact. Methods: The M. D. Anderson Symptom Inventory - Head and Neck module - was administered at baseline and weekly for 10 weeks following the start of treatment to patients undergoing radiation therapy (XRT) as a single modality therapy (N = 49) and a second group receiving chemoradiotherapy CXRT (N = 53). We expected that treatment-related symptom burden would be greater for those patients receiving CXRT. A single value (AUC) was calculated based on the core symptoms reported by both groups of patients. Results: AUC comparisons for mean symptom severity for core symptom items demonstrated the expected greater symptom burden associated with CXRT (170.6 vs 120.9, p < 0.008). The AUC for symptom interference, as measured by the MDASI-HN, was also greater for the CXRT group (p < 0.002). AUCs for individual symptoms, such as fatigue (p < 0.002), sleep disturbance (p < 0.05) and lack of appetite (p < 0.02), were also significantly larger for the CXRT group. Conclusions: The AUC of individual and combined symptoms during cancer therapy present a useful summary of treatment related symptoms that can be used to compare treatment-related symptom burden between different treatment strategies used for the same disease.

No significant financial relationships to disclose.
Expression of excision repair cross-complementation group 1 protein and outcome in patients with nasopharyngeal cancer
Authors: Lee H. , Hwang Y. , Han J. , Choi J. , Kang S. , Jeong S. , Ann M. , Oh Y. , Kim J. , Kim C.
Published: August 2020

6085

Background: We evaluated the prognostic significance of thymidylate synthase (TS), and Excision Repair Cross-Complementation Group 1 protein (ERCC1) in patients (pts) with nasopharyngeal cancer (NPC) treated with concurrent chemoradiotherapy (CCRT). Methods: Pretreatment tumor biopsy specimens from 41 pts with locally advanced NPC were analyzed for TS and ERCC1 expression by immunohistochemistry. All patients were treated with 1 cycle of induction chemotherapy (5-fluorouracil 1,000 mg/m2/day and cisplatin 20 mg/m2/day, days 1–4) followed by CCRT starting on day 22. CCRT consisted of radiotherapy (70Gy/35 fractions for 7 weeks) with cisplatin 20mg/m2/day for 4 days on weeks 1, 4, 7 of radiotherapy. Results: Complete response and partial response were achieved in 34 pts (83%) and 6 pts (15%), respectively. Within median follow up duration of 101 months (26–147months) in survivors, 5-years overall survival (OS) of all pts was 50%. High expression of TS and ERCC1 was observed in 21 (51%) and 25 (60%) pts, respectively. High expression of ERCC1 was associated with WHO type 1 or 2 histology (p = 0.045). In univariate analysis, high expression of ERCC1 was associated with poor OS (5-year: 73% versus 35%; p = 0.005), while high expression of TS was not correlated with pts outcome (p = 0.867). In multivariate analysis, high expression of ERCC1 was a significant independent predictor of poor OS (p = 0.041) along with WHO type 1 or 2 histology (p = 0.004). Conclusions: High expression of ERCC1 protein may be useful for prediction of poor outcome in pts with NPC treated with CCRT.

No significant financial relationships to disclose.
A prospective clinical study for molecular intra-operative detection of lymph node metastasis in breast cancer patients by one step nucleic acid amplification (OSNA) in comparison to intensive histological investigation
Authors: Di Filippo F. , Mottolese M. , Botti C. , Marandino F. , Psaila A. , Perri P. , Di Filippo S. , Pasqualoni R. , Ferranti F. , Buglioni S.
Published: August 2020

609

Background: The aims of the study were 1) to assess the accuracy of a new intra-operative molecular diagnostic tool named OSNA, based on the measurement of cytokeratin 19 (CK19) mRNA, in the detection of axillary sentinel lymph node (SLN) metastases in patients with breast carcinoma 2) to determine the concordance of OSNA analysis with multilevel haematoxylin and eosin (H&E) and immunohistochemical (IHC) examination. Methods: A prospective series of 247 consecutive SLNs from 187 breast cancer patients was evaluated. The OSNA assay (Sysmex, Kobe - Japan) follows a short sample preparation step and subsequent rapid amplification of CK19 mRNA based on reverse transcription loop-mediated isothermal amplification. Each SLN was immediately divided into four slices. Two alternate slices were used for the intra-operative OSNA assay. The remaining two slices were investigated by six-level histopathology with 100 μm skip ribbons using routine H&E and CK19 IHC staining. The results of histology and OSNA were then compared. Results: Pts characteristics: infiltrating ductal/infiltrating lobular/mucinous/medullar/DCIS: 130/10/1/1/25. OSNA and histo-pathological methods identified 54 SLNs positive and 185 negative cases (2/3 contained isolated tumour cells). We found 8 discordant cases, 2 OSNA negative with micrometastasis found by IHC/H&E analysis, 5 OSNA positive for micrometastases but IHC/H&E negative and 1 case macrometastatic at OSNA, while negative at IHC/H&E analysis. The overall concordance of OSNA with histopathology was 96.7% with a specificity of 96.8% and sensitivity of 96.4%. These discordances could be due to sampling bias such that a micrometastasis was confined to the slices used for OSNA or the slices used for histology. Conclusions: The current study suggests that the performance provided by OSNA assay is comparable to intensive histopathological work-up even when using only half a lymph node. The method could be applied as a rapid and reliable intra-operative diagnostic tool thus preventing breast cancer patients from a diagnostic delay or second surgery due to a postoperatively diagnosed positive SLN.

No significant financial relationships to disclose.
Use of quantitative RT-PCR assay to predict metastases size of sentinel node from breast cancer patients
Authors: Durbecq V. , Majjaj S. , Nogaret J. , Sirtaine N. , Schobbens J. , Noterman D. , Hertens D. , Filipov V. , Larsimont D. , Veys I.
Published: August 2020

621

Background: A RT-PCR Assay (GeneSearch, Veridex, LLC), FDA approved and CE marked to detect metastases > 0.2 mm in sentinel lymph nodes (SLNs) of breast cancer patients, has been in clinical use in our institute for 25 months. The assay gives qualitative (negative/positive) results by applying cutoff values to cycle times (Cts) of mammaglobin (MG) and cytokeratin 19 (CK19) (cutoff values = 30 / 31 Cts). This study evaluates if quantitative Ct values can be used to estimate the probable size of nodal metastases. Methods: To date 384 patients have been clinically tested with the BLN Assay at Institut Jules Bordet. An additional 74 patients were tested in a pilot study. Both sets had SLNs of breast cancer patients divided in ∼2 mm pieces. Alternating pieces were homogenized and intra-operatively processed by the assay. The remaining pieces were used for histological analysis (positive when > 0.2 mm). During clinical use, same-surgery complete axillary dissection was performed when the assay was positive (n=59). Results: Performance of the assay's qualitative results against permanent section H&E was similar for both groups (total N = 458), for a total sensitivity 89% (68/76), specificity 95% (364/382) and overall agreement 94%. The marker Ct values are correlated with metastases size as determined by H&E on adjacent node pieces (r = -0.74 for MG and -0.77 for CK19, p < 0.001). Lower Ct values indicate increased likelihood of macrometastases reported by H&E, as described in the table. Additionally, Assay Ct values in the SLN were predictive of metastases in non-SLN nodes. For example when CK19 and MG < 24 Cts, the non-SLN positivity rate jumps from 29% to 58%. Conclusions: The BLN Assay's high intra- operative qualitative performance minimizes the need for second surgeries for complete axillary dissections. Results from this investigational study examining the marker Ct values suggest that the assay may provide valuable individual tumor volume data intra- operatively or post-operatively.

[Table: see text]

[Table: see text]
Primary endocrine therapy for early operable primary breast cancer in elderly women: A large series from a single institution
Authors: Al-Khyatt W. , Syed B. M. , Morgan D. A. , Cheung K. L.
Published: August 2020

630

Background: A recent Cochrane review of seven randomised trials involving 1,446 elderly women (unselected for oestrogen receptor (ER) status) has shown no significant difference in overall survival between surgery (with or without adjuvant tamoxifen) and primary endocrine therapy using tamoxifen. We report our experience of using primary endocrine therapy in a single centre with a dedicated elderly breast cancer service. Methods: Over a 20-year period, 825 elderly (>70 years) women with early operable primary breast cancer were treated with primary endocrine therapy (>80% using tamoxifen as first-line agent), due to patient choice or being unfit for surgery. All patients had disease assessable for response according to UICC criteria, and had treatment for ≥6 months unless the disease progressed prior. Results: Median age was 80 (range: 70–99) years. When the disease progressed, some patients received further lines of therapy and the overall results are summarised (Table). Conclusions: Compared to the general use of endocrine therapy reported in advanced breast cancer (where CB rate is around 70%), primary endocrine therapy in this context appears to produce superior results. They support its use as an excellent alternative in elderly women who refuse or are unfit for surgery. Its precise role compared to surgery is the focus of a national randomised trial in the UK. CR: complete response; PR: partial response; SD: stable disease; CB: clinical benefit = CR + PR + SD; PD: progressive disease; DoCB: duration of CB; TTP: time to progression (all in months).

[Table: see text]

No significant financial relationships to disclose.
Factors associated with bilateral versus single mastectomy in a diverse, population-based sample of breast cancer patients
Authors: Hawley S. , Jagsi R. , Hamilton A. S. , Graff J. , Griggs J. J. , Katz S. J.
Published: August 2020

6502

Background: Rates of bilateral mastectomy are increasing in the U.S., even among women with cancer in only one breast. The goal of this analysis was to assess correlates of bilateral mastectomy in a large, racially/ethnically diverse sample of breast cancer patients. Methods: All women with ductal carcinoma-in-situ and a 20% random sample of women with invasive breast cancer aged < 79 years who were diagnosed in 2002 and reported to the Detroit and Los Angeles SEER registries were surveyed shortly after receipt of surgical treatment (response rate, 77.4%; n = 1,844). Patient survey data were merged with SEER data. The primary dependent variable, receipt of bilateral mastectomy, was obtained from patient report and validated by SEER. Independent variables included patient demographics, family history of breast cancer, tumor stage, and patient concerns about recurrence and body image. Logistic regression was used to evaluate factors associated with receipt of all mastectomy (including bilateral) vs. lumpectomy, and then to evaluate bilateral vs. single mastectomy. Results: The mean age was 60 years. 70% were white, 18% Black, and 12% Latina. Overall, 5% of women received bilateral mastectomy (13% of those getting mastectomy). The Table shows factors associated with receipt of any mastectomy vs. lumpectomy (model 1) and bilateral vs. single mastectomy (model 2). Advanced stage and concerns about recurrence were associated with increased odds of any mastectomy while body image concerns were associated with lumpectomy (P<0.05) (model 1). Model 2 shows family history (OR: 3.00; 95% CI 1.36–6.61) and concerns about recurrence (OR: 2.76, 95% CI 1.14–6.68) were associated with greater odds of receiving bilateral vs. single mastectomy. Conclusions: Decision making for any mastectomy vs. lumpectomy is quite different from that for bilateral vs. single mastectomy. The latter appears to be driven by genetic predisposition, but there continues to be a strong influence of women's concerns about recurrence.

[Table: see text]

No significant financial relationships to disclose.
Development of combination chemotherapy regimens: What is the yield of published phase II trials?
Authors: Hudoba C. , Maitland M. L. , Snider K. L. , Ratain M. J.
Published: August 2020

6510

Background: Although combination therapy presents an opportunity to advance cancer care, how well typical phase II development methods screen for regimens that improve care is not known. Since single arm phase II trials have fundamental flaws that could be magnified in combination treatment studies, we hypothesized that these phase II trials would have a low positive predictive value. Methods: We searched medline for phase II combination chemotherapy clinical trials published in 2001 and 2002, and selected for those which tested only systemic therapies in oncology patients, yielding 364 published trials. These studies were rated as positive, negative, or inconclusive based on review of abstract and text statements by the authors. The Web of Science Index (Thomson Reuters, NY, NY) was searched for all articles published between 2003 and October 2007 that cited at least one of these 364 source papers. Results: Of 364 published phase II combination chemotherapy trials (including 16,033 subjects), 262 were declared to be positive. The Web of Science search identified 3,764 unique subsequent citing papers. Of these, 20 reported randomized phase III trials testing the same combination in the same disease as the source paper, and 9 studies resulted in findings that improved standards of care. Based on these data, for any published, reported positive, phase II combination chemotherapy trial the likelihood that it will result in a published, confirmatory randomized trial demonstrating an improvement in standard of care within 5 years is 0.034 (95% confidence interval - 0.016, 0.064). Conclusions: For combination chemotherapy phase II trials performed by standards of published studies in 2001–02, the positive predictive value is low despite the participation of a large number of subjects. Historical approaches to the development of combination chemotherapy regimens have been an inefficient use of patient resources. Future phase II studies of combination regimens require better methods to screen for treatments most likely to improve standards of care.

[Table: see text]
Electronic patient-reported data capture as the foundation of a learning health care system
Authors: Abernethy A. P. , Zafar S. Y. , Coeytaux R. , Rowe K. , Wheeler J. L. , Lyerly H. K.
Published: August 2020

6522

Background: In a “learning healthcare system” clinical decisions are supported by accurate information delivered at point of care; information gathered today iteratively informs future care and research. Methods: Customized software on wireless tablet personal computers presented a review of systems (ROS) instrument, validated research surveys (e.g., quality of life [QOL]), and a satisfaction survey, tailored by user. The system was piloted in the Duke Cancer Clinics and affiliated hospitals. We previously demonstrated equivalence of electronic and paper survey data. We conducted a series of studies using similar procedures to evaluate feasibility, acceptability, and utility. Results: First, we assessed the ability to collect ROS data at point of care to inform the clinic visit for participating breast (n = 65), gastrointestinal (n = 113), and lung (n = 97) cancer patients. Duke physicians reported that the system's clinical reports informed care and increased dictation efficiency. Second, we assessed patient satisfaction in the breast cancer cohort. Participants found the computers easy to read (94%), navigate (99%), and use (98%); the system helped 74% remember forgotten concerns to report to their clinician. Third, we assessed whether these data could contribute to current research. If the patient was on another clinical trial, PRO data (e.g., pain, QOL) were delivered to the investigator for research purposes in real time; data governance rules provided assurance to investigators. Fourth, we identified whether the PRO data could inform future research directions. Symptoms monitored longitudinally in aggregate uncovered unmet needs. Sexual distress was an underserved concern; intervention studies were initiated. Warehoused PRO data were integrated with clinical trials, genomic, biomarker, radiology, and administrative datasets for analyses. The approach has been scaled to 4 clinics and 3 hospitals. Conclusions: An integrated, real-time, electronic data capture system that interdigitates PROs with clinical and other data allows creation of a learning oncology environment that continuously improves care and research. Advantages include: patient-centeredness, description of the PRO phenotype, interoperability, and interface with caBIG infrastructure.

No significant financial relationships to disclose.
Assessing the impact of a targeted educational initiative on colorectal cancer lymph node retrieval: A Fox Chase Cancer Center Partners' quality initiative
Authors: Curley B. , O'Grady M. A. , Litwin S. , Stitzenberg K. , Armitage H. , Bapat A. , Sigurdson E. R. , Meropol N. J. , Engstrom P. F. , Cohen S. J.
Published: August 2020

6524

Background: The retrieval of ≥12 lymph nodes in a colorectal cancer surgical specimen is an established quality metric. The impact of targeted education to improve nodal yield at community hospitals has not been studied. We initiated an intensive educational program through the Fox Chase Cancer Center Partner (FCCCP) hospitals to improve nodal retrieval in colon cancer specimens. Methods: At 12 FCCCP community hospitals from 2004–05, educational initiatives were conducted by FCCC staff and included group presentations at hospital tumor boards, cancer and quality committees, and regional CME. Individual presentations to pathologists and surgeons were held. Tumor registry data were retrospectively collected from FCCCP from 2003 (pre-intervention) to 2006 (post-intervention) for patients undergoing curative colon cancer surgery. Data abstracted were age, sex, race, stage, surgical procedure, and total number of nodes examined. The primary end point was % surgical specimens with ≥12 lymph nodes. Obtaining at least 250 records per year would allow ≥90% power to detect a change from a baseline level of ∼40% to ≥50% after intervention. Results: Data from 4,208 patients from 12 FCCCP hospitals were collected. Overall characteristics: male/female (48%/52%), race (W 83%, AA 7%, other 10%), age (<50:6%, 50–70: 34%, >70:60%), node ± (39%/61%). The % of colon cancer operations with ≥12 nodes significantly increased over the four years of the study (Table, p<.00001). This difference persisted when pooling years before and after the intervention (2003–04 vs. 2005–06, p <0.0001). There was no difference in nodal yield between two pre-intervention years (2003 vs. 2004, p=0.1). No differences in other characteristics such as age, sex, race, or % lymph node positive were noted between years. Conclusions: A multi-intervention targeted educational initiative in a large community cancer network is feasible and associated with increased colon cancer nodal retrieval.

[Table: see text]

No significant financial relationships to disclose.
Availability of experimental therapy outside of randomized clinical trials in oncology
Authors: Hamilton E. P. , Lyman G. H. , Kim S. , Peppercorn J.
Published: August 2020

6539

Background: Investigational cancer therapies may be available outside of trials, or “off protocol” (OPRx), with implications for patient safety, trial accrual, and access to care. Previous studies suggest OPRx is prevalent in oncology, but there is little consensus on when it should or should not be considered. We evaluated the scope and impact of OPRx through assessment of availability of the experimental arms of recent randomized trials (RCT), and evaluation of study outcomes and accrual. Methods: We conducted a Medline search to identify all English language phase III RCT of medical interventions in oncology over a 2-year period ending April 17, 2008. We determined availability of experimental interventions based on FDA approval for any indication. We limited assessment of accrual (time to trial completion, patients/month) to studies with US sites. Significance of results was assessed by Fisher's exact test and unpaired t-test. Results: We identified 172 eligible RCT. The majority of RCT (108, 63%) evaluated drugs that were available OPRx at trial initiation, while an additional 19 (11%) trial drugs became available during the trial. 64 (55%) were available due to FDA approval for the same cancer in a different setting, 40 (35%) for a different cancer, and 12 (10%) for a non-cancer indication. 25% of trials were conducted at only US sites, 15% included US and international sites, and 60% were international only. Trials in which OPRx was available had slower time to completion compared to trials in which OPRx was unavailable (48 vs. 26 months, p = 0.04) and a trend towards slower accrual (14.0 vs. 40.7 patients/month, p = 0.06). For the majority of RCT (66%), there was at least one grade 3/4 toxicity that was greater in the experimental arm, for 47% the experimental interventions proved superior for 1 major outcome, and 27% demonstrated improvement in overall survival. These outcomes did not vary based on availability OPRx. Conclusions: The majority of recent oncology trials involve experimental regimens that are available outside of a trial. The safety and efficacy of novel interventions must be determined by trials but availability of OPRX may impact accrual. Guidelines are needed for OPRx in oncology.

No significant financial relationships to disclose.
Cost implications of delayed radiotherapy for early stage breast cancer
Authors: Gold H. T. , Do H. T. , Dick A. W.
Published: August 2020

6549

Background: Delayed radiotherapy (RT) for early invasive breast cancer has been shown to increase recurrence rates, but whether it influences costs of treatment or downstream medical care is unknown. Methods: Using linked SEER-Medicare data from 1992–2005 for 5,905 women ages 66+ diagnosed with stage I breast cancer undergoing post-lumpectomy RT, we estimated mean total monthly costs paid by Medicare by phase of care (treatment, continuing, or terminal care). Continuing care covers costs after treatment including for recurrences, and terminal phase includes costs in the last 6 months of life. We evaluated whether costs were different by timely vs. delayed RT (delay = 12 weeks post-surgery, or 8 weeks post-chemotherapy) and patient characteristics including comorbidity, age, and race. Results: Mean monthly treatment costs were $427 lower for women with delayed RT (p < 0.00001), but monthly continuing-care costs were $129 higher (p < 0.00001). Delayed RT yielded a 26% decrease in monthly treatment costs (p < 0.0001) and 20% increase in continuing-care costs (p < 0.0001) in multivariable analyses, and inpatient comorbidity index>1 yielded cost increases of 12% (p = 0.03) and 70% (p < 0.0001) in those phases, respectively, compared to no comorbidity. Terminal phase costs were affected primarily by inpatient comorbidity index>1 (86% cost increase compared to no comorbidity, p < 0.0001) and black race (52% cost increase compared to white, p = 0.02), but not delayed RT. Treatment phase averaged 2.5 months longer for women with delayed RT (p < 0.00001). Average post-treatment follow-up was 7 years. Conclusions: Delayed RT is associated with lower mean monthly costs for treatment but higher continuing-care phase costs, possibly due to higher recurrence rates. Treatment was longer for women with delayed RT, even if total treatment cost is the same, making the average monthly cost for delayed RT lower. Preliminary analysis suggests that total average costs through follow-up are nearly $11K higher for women experiencing delayed RT. Combined with higher recurrence rates, delayed RT likely is worse in terms of both costs and effectiveness.

No significant financial relationships to disclose.
Impact of brain metastases on health care costs in metastatic breast cancer: A multinational study
Authors: Walker M. D. , Lykopoulos K. , McLeod E. , Cottrell S. , Christova L.
Published: August 2020

6555

Background: Incidence of brain metastases (BM) are thought to be particularly high among patients with ErbB2+ (HER2+) breast cancer and have been associated with a poor survival prognosis. A previous study identified such patients as a considerable financial burden for health systems in Germany and France when compared to metastatic breast cancer (MBC) without BM. The objective of this study was to extend that analysis to estimate health care costs in Italy, Spain and the UK. Methods: Patient treatment histories, including drugs, specialist visits, procedures, inpatient stays etc, were collected retrospectively from a panel of oncologists for women with MBC across Italy, Spain and the UK, last seen by the responding oncologist during Q3-Q4 2006 or Q3-Q4 2007. To identify ErbB2+ patients they all had to have received/were receiving trastuzumab (TZ) for MBC. Patients were sampled so as to ensure the collection contained a minimum of 50 cases with BM and 200 histories overall (remainder controls). All costs within the observation period (initiation of TZ to date last seen) were calculated from a payer's perspective for patients who had developed BM and those who had not. Linear stepwise regression took into account potential confounding of time related covariates. Results: The study included 268 Italian (146 cases), 215 Spanish (126 cases) and 243 UK patients (103 cases). BM diagnosis was associated with significantly more expensive treatment histories than those patients without. Service costs such as radiotherapy and hospital visits were found to be key drivers for these differences (p<.001). Conclusions: The significantly greater cost associated with treatment of BMs in ErbB2+ MBC patients from Italy, Spain and the UK is consistent with results from identical French and German analyses. Therapies that reduce the incidence of BMs may therefore decrease the overall financial burden of ErbB2+ MBC.

[Table: see text]

[Table: see text]
Challenges to accrual predictions to phase III cancer clinical trials: A survey of study chairs and lead statisticians of 248 NCI-sponsored trials
Authors: Schroen A. T. , Petroni G. R. , Wang H. , Djulbegovic B. , Slingluff C. L. , Wang X. F. , Gray R. , Sargent D. J. , Cronin W. , Benedetti J.
Published: August 2020

6562

Background: Trial closure due to inadequate accrual presents a common problem in cancer research. We sought to identify factors related to trial design common to trials with successful versus unsuccessful accrual. Methods: In 2008, a 30-question web-based survey was sent to the study chair (SC) and lead statistician (LS) for all 248 phase III trials open in 1993–2002 by five national cooperative groups (NCG). SC and LS level of experience, trial design elements, accrual predictions, and perceived accrual influences were queried. Accrual success was categorized based on NCG records: successful trials (ST) closed with complete accrual or at interim analysis while unsuccessful trials (UT) closed due to inadequate accrual. Responses were analyzed by respondent role (SC/LS) and accrual success. Results: 309 eligible responses were included (response rate, 62%: LS 81%, SC 45%). Respondents represented ST (65%) and UT (35%) with no response bias by accrual success. SC academic rank was not linked to accrual success. Literature review, SC experience, and expert opinion within NCG most commonly influenced control arm selection, but did not impact accrual success. NCG experience had the greatest influence on accrual predictions in both ST and UT. Trials comparing novel with established therapies were more likely to be ST (72%) than UT (28%); head-to-head comparisons of established therapies were more equally divided between ST (59%) and UT (41%). Among the 41% of respondents citing significant accrual difficulties, no factors negatively influencing accrual were consistently identified. Among respondents not citing accrual difficulties, factors credited with positively influencing accrual were clinical relevance of study question, lack of competing trials, and protocol paralleling normal practice. Conclusions: No consistent factors were identified to explain poor trial accrual, suggesting that reasons for poor accrual are not well understood and warrant further study. An objective measure of clinical relevance would be useful to inform trial prioritization practices. Research into alternative strategies for accrual prediction is needed since NCG experience is linked to both successful and unsuccessful accrual.

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Importance of stratification when measuring quality of care: Results from the Project for an Ontario Women's Health Evidence-Based Report Card (POWER) study
Authors: Krzyzanowska M. K. , Barbera L. , Elit L. , Saskin R. , Yeritsyan N. , Bierman A.
Published: August 2020

6573

Background: The goal of the POWER study is to improve health and reduce inequities among women of Ontario using population-based performance measurement. All selected indicators are stratified by sex, age, income and place of residence to determine whether there are disparities in performance associated with these factors. Results pertaining to cancer (CA) indicators are presented. Methods: A modified Delphi approach was used to identify performance measures spanning the disease spectrum from screening through follow-up care and feasible to be evaluated from administrative data. Most recently available data (2003–2005) from the Ontario Cancer Registry, Registered Persons, billing and hospital databases were then used to evaluate the selected measures stratified by above four factors. Results: Twenty-nine cancer-specific indicators were selected by the panel, majority of which related to processes of care: general indicators relevant to multiple cancers (3), screening (5), breast CA (5), lung CA (3), colorectal CA (4), gynecologic CA (4), and end-of-life care (5). Among measures relating to non-sex specific cancers, few sex-related differences in care were identified. Income-based differences in care were most pronounced among the screening indicators with individuals from low-income neighborhoods less likely to receive appropriate screening or follow-up after an abnormal screening test. Among measures relating to treatment, age was the factor most frequently associated with differences in care especially in regards to radiation- or chemotherapy-related processes of care. There were geographic differences in quality of care within the province along the entire trajectory of cancer care from screening through end-of-life care. Conclusions: Among the cancer quality indicators considered, few sex-based differences exist. However, factors such as age, income and where one lives are important predictors of care underscoring the importance of stratification by such factors when evaluating quality of care. Further work is necessary to determine whether these differences in processes of care affect outcomes and how to facilitate access to care by disadvantaged groups.

No significant financial relationships to disclose.
Patient out-of-pocket payments for oral oncologic therapies: Updated results from a U.S. claims data analysis
Authors: Pelletier E. , Tierce J. , Yim Y. , Reyes C.
Published: August 2020

6582

Background: Oral oncologic therapies are increasingly becoming part of treatment options for cancer. These agents often fall within the pharmacy benefit, with the potential for increased out-of-pocket (OOP) cost burden to patients. The objective of this study is to evaluate patient OOP payments for oral oncologic therapies in U.S. managed care plans. Methods: Patients aged 18+ years with 1 of 13 oral oncologics (bexarotene, capecitabine, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lenalidomide, sorafenib, sunitinib, temozolomide, thalidomide, vorinostat) were identified in 2007 from a nationally representative database of medical and pharmacy claims from over 90 U.S. health plans. OOP payments were calculated as the allowed amount (dollar amount a health plan allows for a therapy, including any member liability) minus the paid amount (dollar amount paid by a health plan for a therapy). Results: 10,400 patients with evidence of at least 1 of 13 oral oncologic therapies were identified in 2007. The mean age was 59.2 years, 48% were male, and 83% had a commercial payer; 26% of patients were diagnosed with lung cancer, 14% with breast cancer, and 13% with colorectal cancer at the time of the first evidence of therapy use in 2007. Mean and median OOP payments for the 13 oral oncologic therapies are provided in the table below. Medicare Advantage and Medicaid had higher mean OOP payments for most therapies compared to commercial payers and self-insured patients. Conclusions: This study evaluated OOP payments for oral oncologic therapies using current claims data. Among the 13 oral oncologics studied, the average OOP costs ranged from $117 to $1,014. As costs for therapy become a greater part of treatment decisions, an understanding of patient OOP costs will be critical in informing choices.

[Table: see text]

[Table: see text]